Table of Contents

Formal Essays:
Inebration and Authenticity
 “Oppos[e na/i]tional Agency” rap essay about salmon fisheries + annotations
The Paradox of Normal
Childhood Trauma Explains Pathology in Cannabis Dependent Adolescents (annotated bibliography; essay available on request)

First Hand Accounts and Informal Essays:
Highlights from 2015 in Marijuana Science
King’s College London Causes Psychosis
Can we please stop assuming that marijuana is harmful to young people?
Before the Drunk God / Fought Darius Against Kay / and Zach Against Zach
Yet Another White Man’s Burden (Normal: redux)
Why I Must Refuse My Degree (short version)
Iboga: Serious Business
Rob Ford is not an Addict: Rob Ford is a Monster

Drug education articles:
Why Do We Use Drugs?
Psychedelic Defined
The Psychotherapeutic Setting
Cleansing and Banishing Rituals
Caring for the Body
Three Traditional Ways to Prepare for an Intense Trip
Recreational Use
Sex and Drugs

Do Psychedelics Encourage False Beliefs?
An Herb to Know: Kudzu
Cannabis: What’s it Good For?
What Does Marijuana Do? It Rebalances Everything

Keep On Trollin
Yet Another White Man’s Burden (Normal: redux)
How Gays Marrying “Threatens” the Institution of Marriage

Visual Art:
Line and Colour
Experimental Images

Project Ballyhoo (media campaign in 2011 to mark the anniversary of the Toronto G20):
Reasons People Were Arrested at the Toronto G20
Project Ballyhoo Zine 

Open, Inclusive Drug Education: High Chance or Pipe Dream?
Poems Español
Research Occupy Toronto
Drafts and Concepts

Highlights from 2015 in Marijuana Science

2015 was a big year for marijuana, socially and politically, with massive progress made towards ending the unjust incarceration of its users. However, it was also a big year in terms of scientific research. Here are my pick of the top marijuana-related scientific papers of the year.

Mokrysz C, Gage S, Landy R, Munafo M, Roiser J, Curran H. 2015. “Neuropsychological and educational outcomes related to adolescent cannabis use, a prospective cohort study” Eur Neuropsychopharmacol 24(2): S695

What they found: teens who heavily used marijuana exhibited an IQ decline, but it was attributable to confounding factors. Once enough factors are controlled for, marijuana use is not associated with IQ decline.

Why this matters: teenagers already undergoing an IQ decline are more likely than those not to become dependent on marijuana, leading to a spurious association between marijuana and IQ decline in poorly controlled studies. This study demonstrates that marijuana does not cause a cognitive decline, alleviating concern about its use among adolescents.

White H, Bechtold J, Loeber R, Pardini D. 2015. “Divergent marijuana trajectories among men: socioeconomic, relationship, and life satisfaction outcomes in the mid-30s” Drug and Alcohol Dependence 156: 62-69

Bechtold J, Simpson T, White H, Pardini D. 2015. “Chronic adolescent marijuana use as a risk factor for physical and mental health problems in young adult men” Psychology of Addictive Behaviors 29(3): 552-563

What they found: once confounding factors are controlled for, marijuana use by adolescents is not associated with health problems or poor socio-economic outcomes in adulthood

Why this matters: prohibitionists, as well as advocates of legalise-and-regulate models, continue to assume that we need to keep marijuana away from adolescents to protect them from harm, but these studies show that marijuana use alone is not associated with harm beyond the influence of confounding factors. The associations between early marijuana use, pathology, and poor outcomes are spurious, and marijuana is not the problem — rather, adolescents with certain problems are more likely to use marijuana, and to be at risk for additional factors. The persisting fears are unfounded, and we do not need to concern ourselves with restricting access by age.

Alshaarawy O, Anthony J. 2015. “Cannabis smoking and serum C-reactive protein: a quantile regressions approach based on NHANES 2005-2010” Drug Alcohol Depend 147: 203-207

What they found: marijuana smoking is associated with lower levels of C-reactive protein, a marker of inflammation.

Why this matters: marijuana’s anti-inflammatory effects have been known for millennia, but remain poorly understood by many researchers and the public. This is not the first study showing reduced CRP in marijuana users, but the more the better. Most of the disorders which people believe marijuana to alleviate, or suspect it of causing, are mediated by inflammation. Claims that marijuana protects against disease, or exacerbates it, rest in large part upon its effects on inflammation. If it cannot be shown that marijuana causes inflammation, then the biological plausibility of it causing harm would be impugned.

Chiurchiù V, Leuti A, Maccarrone M. 2015. “Cannabinoid signaling and neuroinflammatory diseases: a melting pot for the regulation of brain immune responses” Journal of Neuroimmune Pharmacology 10(2): 268-280

What they found: marijuana has profound immunoregulatory and anti-inflammatory properties which may ameliorate or protect against numerous inflammation-related disorders.

Why this matters: well, we already knew this, but one more review is always nice. Neuroinflammation is incredibly important in nearly all modern disease, and marijuana’s ability to attenuate it without causing immunosuppression would seem to validate its status as a “wonder drug.” Those who wish to attribute disease to marijuana use will have to show how and in what circumstances marijuana can increase inflammation; skeptics can instead take the position that it is not surprising to find evidence of inflammation in people who depend on anti-inflammatories, and therefore rest assured that marijuana is not causing the disorders with which its heavy use is correlated.

Giacoppo S, Galuppo M, Pollastro F, Grassi G, Bramanti P, Mazzon E. 2015. “A new formulation of cannabidiol in cream shows therapeutic effects in a mouse model of experimental autoimmune encephalomyelitis” Daru 23: 48

What they found: topical CBD reduced inflammation and even resulted in remyelination of spinal neurons in mice with experimental autoimmune encephalomyelitis

Why this matters: another study showing profound immunoregulatory and anti-inflammatory effects from a constituent of marijuana. Here it was found that topical application of a cream containing 1% CBD was sufficient to reverse inflammation-mediated paralysis and to heal damaged spinal neurons. This shows that smoking, vaping and eating are not the only effective routes of administration for combating neuroinflammation. That topical application of cannabinoids can improve skin conditions such as psoriasis and acne was previously shown, but remyelination of a demyelinated spinal cord is a very impressive finding.

Arain M, Khan M, Craig L, Nakanishi S. 2015. “Cannabinoid agonist rescues learning and memory after a traumatic brain injury” Ann Clin Transl Neurol 2(3): 289-294

What they found: administering a CB1 agonist to rats following head injury reduced the extent of brain damage

Why this matters: THC is a CB1 agonist, and is believed to protect against brain injury. This study supports that position.

Bonnet A, Marchalant Y. 2015. “Potential therapeutic contributions of the endocannabinoid system towards aging and Alzheimer’s Disease” Aging Dis 6(5): 400-405

What they found: the endocannabinoid system is a promising target for protecting against the neuroinflammation which contributes to disorders such as Alzheimer’s Disease

Why this matters: marijuana stimulates the endocannabinoid system, and is believed to protect against Alzheimer’s Disease. This paper reviews some of the mechanisms involved.

Tao Y, Tang J, Chen Q, Guo J, Li L, Yang L, Feng H, Zhu G, Chen Z. 2015. “Cannabinoid CB2 receptor stimulation attenuates brain edema and neurological deficits in a germinal matrix hemorrhage rat model” Brain Res 1602:127-35

What they found: CB2 activation protected against brain edema, and improved morphological and neurofunctional outcomes following germinal matrix hemorrhage, one of the most common and devastating cerebrovascular events that affect premature infants. Microglial activation and TNF-α release were found to be reduced.

Why this matters: yet more evidence of neuroprotective effects of cannabinoid receptor stimulation in yet another serious condition, specifically implicating the anti-inflammatory effects of CB2 activation.

England T, Hind W, Rasid N, O’Sullivan S. 2015. “Cannabinoids in experimental stroke: a systematic review and meta-analysis” J Cereb Blood Flow Metab 35(3): 348-58

What they found: reviewing 144 experiments, cannabinoids, including both THC and CBD, significantly and consistently reduced infarct size resulting from stroke in rats.

Why this matters: the relation between marijuana use and stroke remains controversial. The cases have been made both that marijuana may prevent some strokes, and that it may be a risk factor for one or more kinds of stroke. While this review cannot address the questions of incidence or prevalence, it suggests that the use of marijuana may reduce severity among users who experience a stroke (whether or not they would have had one anyway). Future studies into incidence, prevalence and severity of stroke in human marijuana users are necessary.

Blázquez C, Chiarlone A, Bellocchio L, Resel E, Pruunsild P, Garcia-Rincon D, Sentner M, Timmusk T, Lutz B, Galve-Roperh I, Guzman M. 2015. “The CB1 cannabinoid receptor signals striatal neuroprotection via a PI3K-Akt/mTORC1/BDNF pathway” Cell Death Differ 22(1): 1618-1629

What they found: the AKT pathway is involved in cannabinoid neuroprotection in the striatum

Why this matters: numerous mechanisms mediating cannabinoid neuroprotection were already established, such as reduction in microglial activation, inhibition of excitotoxic cytokine release by astrocytes, recruitment of regulatory t-cells, etc. This research adds activation of the AKT pathway to that list, improving our understanding of how the neuroprotective effects of cannabinoids actually take place at a cellular level. Activation of AKT also seems to clarify the relationship between marijuana use and dopamine signalling, because dopamine receptors also activate AKT. This may indicate that some of marijuana’s effects are dopamine-like without mediation by dopamine itself.

Bossong M, Mehta M, van Berckel B, Howes O, Kahn R, Stokes P. 2015. “Further human evidence for striatal dopamine release induced by administration of ∆9-tetrahydrocannabinol (THC): selectivity to limbic striatum” Psychopharmacology (Berl) 232(15):2723-9

What they found: increase in dopamine signalling following THC administration is very limited, and insufficient to explain the association of early onset marijuana use with schizophrenia.

Why this matters: researchers have been claiming for decades with no good human evidence that marijuana works “like other drugs of abuse” by stimulating dopamine release, leading to dependency. This narrative is not only terribly reductive, but false. While there is a small increase in striatal dopamine release following THC administration, it is an order of magnitude less than that associated with other drugs, and is far from the most important of marijuana’s effects. Hopefully now we can lay to rest the canard of THC having its effects by stimulating dopamine. Given that alterations to dopamine signalling are considered the “final common pathway” in psychosis, this is of particular relevance to schizophrenia research: the mechanism once believed to explain the association cannot explain it. Confounding by factors such as childhood trauma increasingly seem to be the more likely explanation for the association.

Cortes-Briones J, Cahill J, Skosnik P, Mathalon D, Williams A, Sewell R, Roach B, Ford J, Ranganathan M, D’Souza D. 2015. “The psychosis-like effects of Δ(9)-tetrahydrocannabinol are associated with increased cortical noise in healthy humans” Biol Psychiatry 78(11): 805-13

What they found: THC increased neural noise, and this effect was strongly related to its psychosis-like effects.

Why this matters: chaotic neural signalling can lead to strange sensations and experiences. It remains controversial whether using marijuana increases the risk of psychosis. This study suggests that psychosis-like effects of THC are due to an increase in neural noise, most likely due to transient reduction in the activity of GABAergic interneurons, which implies that the pathways implicated in the pathophysiology of schizophrenia, which have not been clearly shown to be exacerbated by marijuana use, are not necessary to produce the effect. This would suggest that THC’s effects might be mistaken for, but neither cause nor exacerbate, schizophrenia-related pathology.

Power B, Dragovic M, Badcock J, Morgan V, Castle D, Jablensky A, Stefanis N. 2015. “No additive effect of cannabis on cognition in schizophrenia” Schizophr Res 168(1-2): 245-51

What they found: cannabis use or dependence among schizophrenics does not worsen their cognitive function. The association between marijuana use and cognitive function is confounded by other factors and does not survive careful control.

Why this matters: there is concern that marijuana use can cause cognitive impairment, or exacerbate cognitive impairment in those with pre-existing problems such as schizophrenia. This study shows that this is not likely to be the case, which should alleviate concern about the use of marijuana by those with or at risk for schizophrenia.

Carey C, Agrawal A, Zhang B, Conley E, Degenhardt L, Heath A, Li D, Lynskey M, Martin N, Montgomery G, Wang T, Bierut L, Hariri A, Nelson E, Bogdan R. 2015. “Monoacylglycerol lipase (MGLL) polymorphism rs604300 interacts with childhood adversity to predict cannabis dependence symptoms and amygdala habituation: evidence from an endocannabinoid system-level analysis” J Abnorm Psychol 124(4): 860-77

What they found: people who were sexually abused were much more likely to subsequently become dependent on marijuana if they had two copies of a common version of the gene for an enzyme (MGLL, aka MAGL) involved in the synthesis of 2-AG, the most potent endocannabinoid.

Why this matters: the relationship between childhood trauma and marijuana dependence is well established. Trauma disorders are also known to be associated with impairment of the endocannabinoid system, and that marijuana use can partially compensate for this by stimulating that system is a reasonable explanation for the association. This study supports this position, by showing that it is not all sexual abuse survivors who are liable to become dependent on marijuana, but those whose endocannabinoid system is genetically vulnerable to impairment if they are exposed to severe stress (for example from sexual abuse). Interestingly, those vulnerable appear to be those with the more common version of the gene in question, which runs contrary to the assumption that risk is related to “bad genes” or restricted to a small minority of the population.

Chakraborty A, Anstice N, Jacobs R, LaGasse L, Lester B, Wouldes T, Thompson B. 2015. “Prenatal exposure to recreational drugs affects global motion perception in preschool children” Nature: Scientific Reports 5: 16921

What they found: children who were exposed to marijuana prior to birth had superior global motion perception to children not so exposed.

Why this matters: the effects of marijuana on early neurodevelopment remain controversial. The mainstream assumption is that marijuana use will impair or interfere with neurodevelopment and thus should be avoided during pregnancy, and that marijuana should be kept away from children. This study challenges that assumption, by showing an improvement in an area also shown to be damaged by alcohol. This is also one more piece of evidence showing that marijuana use may protect against alcohol-related brain damage.

Rivera P, Blanco E, Bindila L, Alen F, Vargas A, Rubio L, Pavon F, Serrano A, Lutz B, Rodriguez de Fonseca F, Suarez J. 2015. “Pharmacological activation of CB2 receptors counteracts the deleterious effect of ethanol on cell proliferation in the main neurogenic zones of the adult rat brain.” Front Cell Neurosci 9: 379

What they found: CB2 receptor activation protected against brain damage from giving alcohol to rats.

Why this matters: one more study suggesting that use of marijuana (which activates CB2 receptors) can protect against the adverse effects of alcohol.

Sabia J, Swigert J, Young T. 2015. “The effect of medical marijuana laws on body weight” Health Economics DOI: 10.1002/hec.3267

What they found: enforcement of medical marijuana laws is associated with a 2% to 6% decline in the prevalence of obesity, suggesting that the availability of medical marijuana saves from $58 to $115 per year per person in obesity-related medical costs alone.

Why this matters: obesity is a major contributor to poor health, and a several percent reduction in the overall rate of obesity is a very significant effect. This provides compelling support for the argument that increasing marijuana availability constitutes a legitimate and pressing public health objective. The authors cite increased mobility due to medicinal effects, and reduced consumption of alcohol due to people switching from alcohol to marijuana, to explain the effect. Unfortunately, they did not consider the regulatory, metabolic or anti-inflammatory effects, but future studies can be expected to follow this up.

Cluny N, Keenan C, Reimer R, Le Foll B, Sharkey K. 2015. “Prevention of diet-induced obesity effects on body weight and gut microbiota in mice treated chronically with Δ9-tetrahydrocannabinol” PLoS One  DOI: 10.1371/journal.pone.0144270

What they found: THC protected mice against developing diet-induced-obesity, and protected against obesity-related changes to the gut microbiota, without altering whole gut transit

Why this matters: it has been known for some time that marijuana users have lower than expected rates of obesity. This study provides additional evidence that THC can counteract the effects of high-risk diets and protect against obesity, and suggests that it is not only increased mobility and reduced alcohol consumption which explain the effect. Even with an equally fattening diet, and without any increase in physical activity, obesity was still prevented, because of THC’s effects on metabolism, inflammation and the gut microbiota.

Lutz B, Marsicano G, Maldonado R, Hillard C. 2015. “The endocannabinoid system in guarding against fear, anxiety and stress” Nature Reviews Neuroscience 16: 705-718

Morena M, Patel S, Bains J, Hill M. 2015. “Neurobiological interactions between stress and the endocannabinoid system” Neuropsychopharmacology  doi:10.1038/npp.2015.166

What they found: the endocannabinoid system regulates response to stress and fear-evoking stimuli, which is essential for long term viability, homeostasis and stress resilience.

Why this matters: dysregulation of the endocannabinoid system is observed in conditions such as PTSD and depression which are associated with marijuana use. Marijuana use is believed to assist in the regulation of this system and can therefore protect against or alleviate certain types of pathology. Reviews such as these are very useful for understanding exactly how this takes place, what cellular systems, proteins and enzymes are involved, etc.

Lynch M, Ware M. 2015. “Cannabinoids for the treatment of chronic non-cancer pain: an updated systematic review of randomized controlled trials” J Neuroimmune Pharmacol 10(2): 293-301

Ware M, Tongtong W, Shapiro S, Collet J-P. 2015. “Cannabis for the management of pain: assessment of safety study (COMPASS)” The Journal of Pain 16(12): 1233-1242

What they found: cannabinoids are safe, modestly effective analgesics in the management of chronic pain.

Why this matters: mild-moderate adverse effects, such as dizziness, were noted, but were not severe, and were generally well tolerated. This supports the use of marijuana in pain management.

Roulette C, Kazanji M, Breurec S, Hagen E. 2015. “High prevalence of cannabis use among Aka foragers of the Congo Basin and its possible relationship to helminthiasis” American Journal of Human Biology DOI: 10.1002/ajhb.22740

What they found: use of marijuana by foragers in the Congo was negatively associated with parasitic infection.

Why this matters: because of marijuana’s anti-inflammatory effects, it has been speculated that it could produce vulnerability to infections, such as by parasites. This study suggests that the opposite is the case, with marijuana possibly providing protection against the parasite (helminths) studied.

Pagliaccio D, Barch D, Bogdan R, Wood P, Lynskey M, Heath A, Agrawal A. 2015. “Shared predisposition in the association between cannabis use and subcortical brain structure” JAMA Psychiatry 72(1): 994-1001

What they found: marijuana use was associated with smaller amygdala volume, but this is not caused by marijuana but relates to underlying genetic associations. Siblings of marijuana users who did not use marijuana themselves have similar amygdalae to their marijuana using siblings.

Why this matters: changes in the amygdala have been suspected of being related to marijuana use, but the evidence has been inconsistent. This study demonstrates that the association is only correlative, and is not causally related to marijuana use.

Weiland B, Thayer R, Depue B, Sabbineni A, Bryan A, Hutchison K. 2015. “Daily marijuana use is not associated with brain morphometric results in adolescents or adults” Neurobiology of Disease 35(4): 1505-1512

What they found: marijuana use is not associated with previously suspected brain changes, such as in the nucleus accumbens, amygdala, hippocampus, and cerebellum, once confounding variables are controlled for.

Why this matters: they were specifically replicating Jodi Gilman’s “worst paper of 2014” which violated various principles of statistical analysis to show that recreational marijuana use was associated with (very small) morphometric changes in the amygdala, which it is not. Her paper was fraudulent, and that was already obvious (her data did not support her conclusions, and even her conclusions did not justify her press release), but the attempted replication and unambiguous rejection of her findings is nonetheless appreciated. Unfortunately, Gilman’s fraudulent results continue to be repeated by prohibitionists as proof that marijuana is harmful. Fortunately, more scientists than ever are objecting to this disreputable conduct, and it is very simple now to contrast this paper’s findings with her findings to judge for oneself.

Those highlights out of the way, the anti-highlight of the year remains the recent bit of scientific infamy I’ve already discussed from King’s College London’s faculty of Psychosis Studies, which had the press claiming that smoking skunk “wrecks your brain,” because of a 2% difference in one brain region between people who prefer bud and people who prefer hash in a badly controlled study. Their data, taken without the ridiculous fear-mongering, shows a marked absence of harm. Small differences associated with preferences are to be expected, whether it’s a preference for green as opposed to black olives, or for green as opposed to black marijuana products. If what they were claiming were true, that high potency strains “wreck brains,” there would be much more than this tiny non-effect to show for it. Unfortunately, King’s College does not deserve its prestigious reputation, and has allowed for blatant dishonesty in the service of justifying mass incarceration.

All in all, this year in marijuana science increasingly clarified what was already apparent, which is that the various harms we were concerned that marijuana might be causing are not, in fact, caused by marijuana use, but most of them involve inflammation, with which marijuana can help.

King’s College London Causes Psychosis (with anti-marijuana propaganda)

Psychosis is a state of aberrant salience in which faulty perceptions (hallucinations) and faulty beliefs (delusions) combine to produce problematic behaviour. Many researchers around the world are studying this phenomena to try to alleviate it, but at least one faculty is pretending to study it in order to engineer a panic about a plant which psychotic patients often find to be extremely useful, but which it is politically expedient to blame. Psychosis Studies at King’s College London has released numerous studies which betray fundamental failures of understanding regarding the condition in their faculty’s title, especially the role of negative symptoms in psychotic disorders such as schizophrenia. It is hard to be sympathetic towards these failures, when their interpretations combine wilful use of stigmatising language, misdirection and exaggeration to try to disprove the fact that their patients sometimes use tobacco and marijuana because they find them to be helpful, and to “prove” on the contrary that these plants are the cause of the harms in question, using studies incapable of showing causation. In this article I will review just three such studies, although their other material is riddled with the same problems.

Let’s start with a study in which they contradicted themselves in their own abstract, displaying a shocking lack of willingness to listen to their patients or honestly consider their reasons for use:

Kolliakou A, Castle D, Sallis H, Joseph C, O’Conner J, Wiffen B, Gayer-Anderson C, McQueen G, Taylor H, Bonaccorso S, Gaughran F, Smith S, Greenwood K, Murray R, Di Forti M, Atakan Z, Ismail K. 2015. “Reasons for cannabis use in first-episode psychosis: Does strength of endorsement change over 12 months?” European Psychiatry 30(1): 152-159

To excerpt from the abstract: “At each time-point, patients endorsed ‘enhancement’ followed by ‘coping with unpleasant affect’ and ‘social motive’ more highly for their cannabis use than any other reason… Little support for the self-medication or alleviation of dysphoria models was found. Rather, patients rated ‘enhancement’ most highly for their cannabis use”

Positive psychotic symptoms do not occur in a vacuum, but are associated with negative symptoms, which generally precede by years the onset of first episode psychosis. Negative symptoms consist of absences, such as cognitive impairment, anhedonia or lack of motivation. These are primary sources of suffering for people with psychotic disorders, and arguably constitute “the core of the disorder,” at least if that disorder is schizophrenia. Relief from negative symptoms — enhancement, coping with unpleasant affect, etc — is therefore extremely important, and it’s ridiculous to say that patients’ endorsements for enhancement do not support self-medication. What they found was that their patients find cannabis to alleviate the core symptoms of their condition; what they reported was that self-medication can be rejected, on the basis of which we are to conclude that the relative increase in use among prodromal schizophrenics is proof that marijuana use causes schizophrenia, a hypothesis for which there is a mountain of countervailing evidence they do not consider.

Now let’s look at their work which compares users who prefer relatively stimulating, high THC marijuana over relatively relaxing formulations such as hash:

Di Forti M, Marconi A, Carra E, Fraietta S, Trotta A, Bonomo M, Bianconi F, Gardner-Sood P, O’Conner J, Russo M, Stilo S, Marques T, Mondelli V, Dazzan P, Pariante C, David A, Gaughran F, Atakan Z, Iyegbe C, Powell J, Morgan C, Lynskey M, Murray R. 2015. “Proportion of patients in south London with first-episode psychosis attributable to use of high potency cannabis: a case control study” S2215-0366(14)00117-5

Although their sample showed no association between cannabis use and psychosis, they dichotomised the cannabis users into “skunk using” and “hash using” groups — using the term “skunk” to refer to relatively more stimulating bud (not to a specific strain), apparently only because that’s easier to stigmatise, since “skunk” sounds worse than, say, “girl scout cookies” — and showed that the rate of psychosis was somewhat higher in the “skunk using” group. As above, they reject self medication on the basis that THC does not alleviate positive symptoms of psychosis, while ignoring that it DOES alleviate NEGATIVE symptoms of psychotic disorders. They say: “That people who already have prodromal symptoms would choose a type of cannabis that is high in THC and has little cannabidiol (such as skunk), which might exacerbate their symptoms, rather than a cannabidiol-containing type (such as hash), would seem counterintuitive” — this is only counterintuitive if you completely ignore negative symptoms, and the fact that THC alleviates them. This would be more forgiveable if they hadn’t also published studies in which they had interviewed schizophrenics who TOLD them why they use it. Just to break it down really simply: people suffering from negative symptoms enjoy and value THC because it is stimulating, not because it is relaxing. You can’t in good faith reject “self medication” while ignoring self-medication for the symptoms that are actually the greatest source of suffering in the patients’ lives and only focusing on other symptoms for which, it’s true, THC is not effective, and can even exacerbate (while some people with psychotic symptoms value marijuana, others stay away from it; it makes it worse for some and helps for others). It’s not “counterintuitive” that people in a prodromal period  — those for whom positive symptoms are not yet overwhelming — prefer stimulating cannabis over relaxing cannabis. I would accuse Psychosis Studies at King’s College London of incompetence, but their use of the stigmatising term “skunk,” combined with this flagrant disregard for the well being of their patients has eroded all my sympathy for them, and so instead I’ll just call them corrupt, shameful propagandists actively hurting the public by manipulating data to create undue concern. At that, they are not incompetent, but apparently quite adept.

and now the new study that came out this week:

Rigucci S, Marques T, Di Forti M, Taylor H, Dell’Acqua F, Mondelli V, Bonaccorso S, Simmons A, David A, Girardi P, Pariante C, Murray R, Dazzan P. 2015. “Effect of high-potency cannabis on corpus callosum microstructurePsychological Medicine Published online November 27 2015

As in the above study, they dichotomised users with a preference for stimulating cannabis from users with a preference for relaxing cannabis, and looked for evidence of differences in brain structure between the groups, finding a very small difference in the corpus callosum. That is, users with a preference for stimulating cannabis have 2% thinner corpus callosa than users with a preference for relaxing cannabis. The difference is too small to realistically consider as damage, and the study cannot show causation, but it’s assumed that any difference at all must be proof of harm, and so causation is assumed. The title even says “effect of high-potency cannabis on corpus callosum microstructure,” despite no evidence that this was an “effect of high-potency cannabis,” as opposed to an effect of a slightly thinner corpus callosum making users more likely to prefer relatively stimulating forms of cannabis, or some form of confounding (for example, they did not control for childhood trauma, which is known both to damage the corpus callosum and to greatly increase the rate of marijuana dependence among its survivors).

They conclude:
“Since high-potency preparations are now replacing traditional herbal drugs in many European countries, raising awareness about the risks of high-potency cannabis is crucial.”

Setting aside the fact that cannabis IS a traditional herbal drug, listed in every pharmacopoeia ever written (excluding those pressured to exclude it during the war on drugs), claiming their finding as a “risk of high potency cannabis” is indefensible. There is no scientific justification for their position. Prematurely claiming harm simply because you found — in a small, badly controlled study –that a small difference in one area correlates with one preference as opposed to another will only raise alarm, and make people who are not at risk think they are at risk, or even to create risk where it wasn’t previously by promoting nocebo effects, and inevitably iatrogenic harm.

I conclude:
The faculty of Psychosis Studies at King’s College London is encouraging harmful delusions, to the detriment of everybody. Since we are at a moment of redefining laws governing access to this plant, raising awareness about the actual reasons why people use it, and its actual effects, is crucial. Ignorant and inflammatory anti-marijuana propaganda of this ilk should no longer be tolerated. If psychosis researchers don’t understand what negative symptoms are or why the stimulating effects of THC might be relevant to them, they should have no business writing about the “effects of high potency cannabis” while displaying a name so prestigious as King’s College. If King’s College would like to retain its prestigious status, and not be associated with this sort of indefensible nonsense, this faculty should be defunded immediately.


Studies showing corpus callosum damage in childhood trauma survivors:

Studies showing that marijuana alleviates negative symptoms:

Can we please stop assuming that marijuana is harmful to young people?

This is a controversial topic, and it’s important that we look at the evidence, and not simply rest on our assumptions or politics. We do not want young people to use anything which is likely to harm them or interfere in their development; we also do not want to prevent young people from accessing anything which could protect them from harm or improve their quality of life. But which is marijuana? Is it good for the health, bad for the health, or both? Does the answer to that question depend on the age of the user?

Is there any proof that marijuana is bad for the health of its users?

Short answer: No.

Many types of pathology have been suspected of being caused by marijuana use or overuse, but so far none of them have stood up to empirical investigation. This is not for lack of trying.  Three examples:

It’s intuitively obvious that habitual smoke inhalation would damage the throat and lungs, and habitual tobacco smoking certainly does. But after decades of research, it has become obvious that any damage from marijuana itself is clinically insignificant. Long term heavy users have actually been found on average to have greater lung capacities than non-users. They also exhale marginally more slowly, and since bronchitis is diagnosed by measuring the ratio between lung capacity and rate of exhalation, they are slightly more likely to meet the technical criteria for bronchitis, but this effect is driven primarily by *increased lung capacity* and it is dishonest to claim as proof of harm. Throat irritation and a cough however are real side effects, though rarely severe enough to be clinically significant. Avoiding this irritation is the main advantage of switching to vaporisers instead of smoking, but, for many smokers, the irritation remains an acceptable side effect, and evidence of long term harm is lacking. (1,2)

The munchies are not a myth (although not everyone gets them, and marijuana actually reduces appetite in a minority of users); on average, marijuana users eat ~50% more calories than non-users, sometimes gorging on “junk” foods. This would increase risk for Type II diabetes, were it not for marijuana’s anti-inflammatory and regulatory effects, which appear to protect the pancreas from damage. Several large epidemiological studies have now reported that there is no association, or a negative association, between marijuana use and diabetes. Marijuana users are evidently able to eat more food than non-users with less harm to the pancreas. (3,4,5)

Brain Damage:
Heavy use of marijuana often makes people feel foggy in the head, can slow reaction time, and moderately impairs some memory functions, so it seems reasonable to infer that this is related to damage. What people often do not realise, however, is that brain damage — whether triggered by a head injury, a virus, a seizure or emotional abuse — is mediated by excitotoxicity, which is when neurons are excited to the point that they fry themselves out. Marijuana reduces brain activity through multiple convergent mechanisms, and dramatically increases the activity of the system the brain uses to protect against excito-toxicity (the endocannabinoid system). This protects against brain damage, and there are many studies to prove it, and no studies which demonstrate brain damage from any level of marijuana use at any age: the brains of even very heavy long term users are no worse off than those of non-users. Marijuana users are even more likely to survive head injuries sustained in car accidents. The reason people are concerned about marijuana’s brain effects is precisely because it reduces activity, but it’s too MUCH activity which causes brain damage, not too little. In other words, not only is there no empirical evidence that marijuana causes brain damage in humans, it is also not biologically plausible that it would. (6,7,8,9,10,11,12,13)

It’s important to stress that the burden of proof is on the positive position, which is the claim that marijuana is causing harm. Absence of evidence should mean absence of concern — public policy should not be founded on the assumption that marijuana is causing harms which are both empirically and theoretically unsupported, despite decades of extensive research funded by organisations such as the National Institute on Drug Abuse. If it was harmful, wouldn’t they have proven it by now?

Is there a critical window of vulnerability in which young people are at risk if they use marijuana?

Short answer: No.

Despite the well documented absence of harm from marijuana use, the possibility has been suggested — and frequently repeated, not only by prohibitionists but also as a concession by marijuana advocates wishing to appear moderate — that teenagers might be experiencing harm from using even if adults are not. Increased concern about effects (of anything) on children makes sense, because anything which could interfere in ongoing neurodevelopment will have a ripple effect, and earlier exposure could have more negative effects than later exposure. This is certainly true of trauma: traumatic experiences in early childhood lead to more diverse symptoms and worse outcomes than traumas later in life. Unlike trauma, however, use of marijuana at an early age is not associated with cognitive impairment or poor health outcomes at a later age once other factors are controlled for. Trauma is, however, strongly associated with early onset of marijuana use, and especially with marijuana dependence, and so studies which examine people who became dependent on marijuana at an early age sometimes find evidence of trauma-related pathology when these people are compared with healthy controls. That is presented as evidence that marijuana is causing harm, even though the harms in question are not found in the majority of early-onset users, or even in the majority of heavy users, but only the most dependent early-onset users, and only in studies which did not control for trauma. Once childhood trauma is taken into consideration (unfortunately, it is usually ignored), the association between early marijuana use and harm evaporates. (14,15,16,17,18,19,20,21,22)

Obviously, the health of young people is very important, and we should not be overly hasty to dismiss possible risks. But there is no proof of any kind of harm at any age from any level of marijuana use, and it is dishonest to insist that there is. Thus there is no empirically sound public health argument for restricting marijuana availability or preventing young people from using it. Anybody who wishes to disagree would do well to perform a review of the literature with the confound of trauma in mind. If you would like more detail, citations, and in depth discussion of each of the harms spuriously associated with early-onset marijuana dependence (brain damage, depression, schizophrenia and IQ decline), contact me and I will furnish you with all you need. There is much to say, but for this article I’m trying to keep things brief: the bottom line is that nobody has ever clearly shown that teenagers who use marijuana are any worse off on average than if they had not used it.

Does marijuana help with stress and trauma-related pathology?

Short answer: Yes.

That marijuana has anti-inflammatory properties and can assist in stress relief is widely known. However, the relevance of these facts to the question of pathology has not been properly considered by most writers on the subject. Childhood trauma is strongly associated with all of the harms spuriously associated with marijuana use, and these harms are driven by neuro-inflammation, which marijuana use reduces. It’s helpful to understand the system marijuana works upon, the endocannabinoid system, which is a system the brain uses to protect itself from inflammation and excitotoxicity. Chronic stress however can cause this system to fail, producing an endocannabinoid deficiency which allows damage to proliferate. Marijuana’s main effect is boosting the activity of this system, which can compensate for or reverse the loss of feedback inhibition associated with chronic stress and trauma. This is why so many people with traumatic childhoods are dependent on marijuana: it helps. The critical question, then, is whether excessive marijuana use can cause the endocannabinoid system to downregulate, leading to a loss of this protection, but, even though this is often claimed by organisations such as NIDA, their own data shows it not to be the case. Marijuana use does not suppress the endocannabinoid system, it enhances it, and this make it extremely useful in inflammatory conditions, such as those related to trauma and chronic stress. (23,24,25,26,27,28,29,30)

Childhood trauma explains the modestly elevated pathology observed in cannabis-dependent adolescents. It explains why they begin using it, why they sometimes become dependent on it, why they have brain damage which sometimes turns up in badly designed studies trying to look for marijuana effects without controlling for trauma, and an examination of the mechanisms involved reveals no biologically plausibility that marijuana is worsening any of these conditions.

So can we please stop saying that it harms children when there’s no evidence of that, and when there’s much clearer evidence that it’s helping?

And can we please not design legislation which makes preventing young people from accessing it a goal in and of itself?

It’s high time we actually focused on improving outcomes for people at risk, and stopped blaming their problems on the things they find helpful.

Short Bibliography (click for full bibliography, with or without excerpts/annotations)

(1) Tashkin DP. 2013. “Effects of Marijuana Smoking on the Lung” Annals of the American Thoracic Society 10(3):239-247

(2) Kempker J, Honig E, Martin G. 2014. “Effects of marijuana exposure on expiratory airflow: a study of adults who participated in the US National Health and Nutrition Examination Study” Ann Am Thorac Soc [epub ahead of print]

(3) Rajavashisth TB, Shaheen M, Norris KC, Pan D, Sinha SK, Ortega J, Friedman TC. 2012. “Decreased prevalance of diabetes in marijuana users: cross-sectional data from the National Health and Nutrition Examination Survey (NHANES) III” BMJ Open 2:e000494

(4) Le Strat Y, Le Foll B. 2011. “Obesity and Cannabis Use: Results from 2 Representative National Surveys” American Journal of Epidemiology doi: 10.1093/aje/kwr200

(5) Rodondi N, Pletcher MJ, Liu K, Hulley SB, Sidney S. 2006. “Marijuana use, diet, body mass index and cardiovascular risk factors (from the CARDIA study)” American Journal of Cardiology 15;98(4): 478-84

(6) Weiland B, Thayer R, Depue B, Sabbineni A, Bryan A, Hutchison K. 2015. “Daily marijuana use is not associated with brain morphometric results in adolescents or adults” Neurobiology of Disease 35(4): 1505-1512

(7) Fagan S, Campbell V. 2013. “The influence of cannabinoids on generic traits of neurodegeneration.” British Journal of Pharmacology 2014: 171; 1347-1360

(8) Sánchez-Blázquez P, Rodríguez-Muñoz M, Vicente-Sánchez A, Garzón J. 2013. “Cannabinoid receptors couple to NMDA receptors to reduce the production of NO and the mobilization of zinc induced by glutamate” Antioxid Redux Signal 19(15): 1766-1782

(9) Nguyen B, Kim D, Bricker S, Bongard F, Neville A, Putnam B, Smith J, Plurad D. 2014. “Effect of marijuana use on outcomes in traumatic brain injury” Am Surg 80(10): 979-83

(10) Katona I, Freund T. 2008. “Endocannabinoid signaling as a synaptic circuit breaker in neurological disease” Nat Med 14(9): 923-30

(11) Tzilos G, Cintron C, Wood J, Simpson N, Young A, Pope H Jr, Yurgelun-Todd D. 2005. “Lack of hippocampal volume change in long-term heavy cannabis users” Am J Addict 14(1):64-72

(12) Block R, O’Leary D, Ehrhardt J, Augustinack J, Ghoneim M, Arndt S, Hall J. 2000. “Effects of frequent marijuana use on brain tissue and composition” Neuroreport 11(3): 491-6

(13) DeLisi L, Bertisch H, Szulc K, Majcher M, Brown K, Bappal A, Ardekani B. 2006. “A preliminary DTI study showing no brain structural change associated with adolescent cannabis use.” Harm Reduct J 3: 17

(14) Cornelius J, Kirisci L, Reynolds M, Clark D, Hayes J, Tarter R. 2009. “PTSD contributes to teen and young adult cannabis use disorders” Addictive Behaviors 35(2):91-94

(15) Butters J. 2002. “Family stressors and adolescent cannabis use: a pathway to problem use” J Adolesc 25(6): 645-54

(16) Hyman S, Sinha R. 2009. “Stress-Related Factors in Cannabis Use and Misuse: Implications for Prevention and Treatment” J Subst Abuse Treat 36(4): 400-413

(17) Barnes G, Barnes M, Patton D. 2005. “Prevalence and predictors of “heavy” marijuana use in a Canadian youth sample” Subst Use Misuse 40(12): 1849-63

(18) Murphy J, Houston J, Shevlin M, Adamson G. 2013. “Childhood sexual trauma, cannabis use and psychosis: statistically controlling for pre-trauma psychosis and psychopathology” Soc Psychiatry Psychiatr Epidemiol 48:853-861

(19) Dube SR, Felitti VJ, Dong M, Chapman DP, Giles WH, Anda RF. 2003. “Childhood abuse, neglect, and household dysfunction and the risk of illicit drug use: the adverse childhood experiences study.” Pediatrics 111(3):564-72

(20) Gupta M. 2013. “Review of somatic symptoms in post-traumatic stress disorder” Int Rev Psychiatry 25(1): 86-99

(21) D’Andrea W, Ford J, Stolbach B, Spinazzola J, van der Kolk B. 2012. “Understanding Interpersonal Trauma in Children: Why We Need a Developmentally Appropriate Trauma Diagnosis” American Journal of Orthopsychiatry 82(2): 187-200

(22) Kaffman A. 2009. “The Silent Epidemic of Neurodevelopmental Injuries” Biol Psychiatry 66(7): 624-626

(23) Alshaarawy O, Anthony J. 2015. “Cannabis smoking and serum C-reactive protein: a quantile regressions approach based on NHANES 2005-2010” Drug Alcohol Depend 147: 203-207

(24) Gaffal E, Cron M, Glodde N, Tuting T. 2013. “Anti-inflammatory activity of topical THC in DNFB-mediated mouse allergic contact dermatitis independent of CB1 and CB2 receptors” Allergy68(8): 994-1000

(25) Cabral G, Raborn E, Griffin L, Dennis J, Marciano-Cabral F. 2008. “CB2 receptors in the brain: role in central immune function” Br J Pharmacol 153(2): 240-251

(26) Greer G, Grob C, Halberstadt A. 2014 “PTSD symptom reports of patients evaluated for the New Mexico medical cannabis program” Journal of Psychoactive Drugs 46(1): 73-77

(27) Neumeister A, Normandin M. 2013. “Elevated Brain Cannabinoid CB1 Receptor Availability in Posttraumatic Stress Disorder: A Positron Emission Tomography Study” Molecular Psychiatry 18(9): 1034-1040

(28) Passie T, Emrich H, Karst M, Brandt S, Halpern J. 2012. “Mitigation of post-traumatic stress symptoms by Cannabis resin: a review of the clinical and neurobiological evidence” Drug Test Anal 4(7-8):649-59

(29) Rossi S, de Chiara V, Musella A, Kusayanagi H, Mataluni G, Bernardi G, Usiello A, Centonze D. 2008. “Chronic psychoemotional stress impairs cannabinoid-receptor-mediated control of GABA transmission in the striatum” J Neurosci 28(29): 7284-92

(30) McPartland J, Guy G, Di Marzo V. 2014. “Care and feeding of the endocannabinoid system: a systematic review of potential clinical interventions that upregulate the endocannabinoid system” PLOS ONE 9(3) e89566

I acknowledge that marijuana is not useful in every situation, that some people react badly to it and should not use it, and that young people should be educated about appropriate and inappropriate dosage strategies, and not simply encouraged to use all day every day. However, I insist that our focus should be on preventing trauma and alleviating its effects, not on denying access to a plant which many trauma survivors, of any age, find to be incredibly helpful. If future study reveals conclusive evidence of harm, I will gladly revise my position accordingly, but the more evidence emerges, the less plausible that seems. If it was harmful, there would be proof by now. Don’t pretend that this is totally uncharted territory — thousands of studies have been performed, and yet the claims of harm remain unsupported. It’s time we stopped assuming and insisting that marijuana has health effects which it demonstrably does not have.

Drafts and Concepts

In 2011, when I was turning out one article every week, I also began working on a number of other articles which I intended to finish, before life intervened and I got sidetracked from that work. Since then I’ve come up with many more ideas than I’ve actually written articles. The purpose of this post is to list a few of those ideas and concepts, many of them already half-finished, both for you to know what else I’ve been working on beyond what’s publicly available, and to provide an opportunity for anybody to request that I put in the time to finish and publish an article they would like to see. This is, however, not a complete list, either of ideas I have (some I’m not ready to talk about this publicly), or of ideas you could suggest for me to write on.😉

Guide, Guardian or Gondolier? Three models for the psychedelic trip-sitter
Immersion; from dissociation to flow and beyond
The Mushrooms are a Metaphor
Checking In for Trippers and Sober Sitters
In Trips and Out Trips: Mystery and Communion
Visions and Visuals
Writing on Stimulants
Why I Must Refuse My Degree (long version)
Marijuana and Memory
Generic Traits of Mental Illness
How Trauma Works
Psychosis Does Not Cause Schizophrenia
How Psychosis and Addiction Scientists Ignore their Subjects to the Detriment of Everybody
Boyfriends Make Terrible Therapists: how not to retraumatise one another
Haikubed: a Haiku of Haikus of Haikus
BDSM and Consciousness Alteration
Normality and Its Perversions
Your Swordsmanship Offends Me – on offensiveness and courtesy
The Two Schools of Natural Philosophy – why modern medicine and traditional Chinese medicine are so different

etc… the major work I spent the past year on (2014/2015), Childhood Trauma Explains Pathology in Cannabis Dependent Adolescents, ought also to be made public, but I still feel I should publish it scientifically before making it completely available (for now, request the PDF if you wish to read it). The above list includes some articles which would use material from that project. I also have a lot more thoughts on sex, gender and sexuality which I would eventually like to develop into articles, but most of that isn’t near enough ready yet. I’ve also been studying historical combat, particularly Chinese martial arts, and I now have a certificate in Medical Qigong, so I’ve been considering writing on those topics as well, but remain unsure of exactly the angle to come at them from: much of my other material is both very general as well as largely original, and therefore very different from talking about an established system which I am both learning and practising. But insofar as I have knowledge which is both interesting and useful, hopefully I can strike an appropriate balance.

What would you most like to see?

Childhood trauma explains pathology in cannabis dependent adolescents – bibliography with excerpts/annotations

Annotated bibliography:

Acheson D, Gresack J, Risbrough V. 2012. “Hippocampal dysfunction effects on context memory: possible etiology for posttraumatic stress disorder” Neuropharmacology 62(2): 674-85

the hippocampus is critical for encoding memories in which a complex configuration of multiple cues is associated with the aversive event. Conversely, the hippocampus is not required for associations with discrete cues. In animal studies, if configural memory is disrupted, learning strategies using discrete cue associations predominate. These data suggest poor hippocampal function could bias the organism towards forming multiple simple cue associations during trauma, thus increasing the chances of fear responses in multiple environments (or contexts) in which these cues may be present. Here we will examine clinical and animal literature to support a theory of hippocampal dysfunction as a primary contributory factor to the etiology of PTSD

Epigenetic factors that contribute to increased stress responses in adulthood are particularly interesting as these can both be non heritable (e.g. methylation occurring due to early life stress; McGowan et al., 2009) and heritable depending upon the developmental period of epigenetic programming (e.g. in utero methylation occurring in primordial germ cells that is passed on to subsequent offspring; Dunn et al., in press)

Another robust finding in neuroimaging research is reduced gray matter volume in the ACC in patients with PTSD (Yamasue et al., 2003; Corbo et al, 2005; Kitayama et al., 2006). Kasai and colleagues (2008)found that combat-exposed twins with PTSD had lower gray matter volumes in the subgenual ACC compared to their trauma-exposed non-PTSD co-twins. This pattern of finding suggests that subgenual ACC volume reductions are an acquired feature of PTSD

Pooled effect size estimates suggested significant bilateral hippocampal volume reduction in PTSD patients compared to controls. Specifically, PTSD patients had, on average, 7.2% lower right hippocampal volume and 7.0% lower left hippocampal volume. These reductions were somewhat attenuated (Right: 4.3%; Left: 4.5%) when comparing PTSD patients to trauma-exposed controls rather than control subjects without trauma exposure

In PTSD patients, studies have shown hippocampal dysfunction in the form of decreased NAA even in the absence of structural abnormalities (Freeman et al., 2006; Schuff et al., 2001). Karl and Werner (2010)conducted a recent meta-analysis of 16 total MRS studies, 12 of which provided data specific to the hippocampus. They found consistent bilateral hippocampal NAA reductions in PTSD as compared to trauma-exposed non-PTSD subjects, but not when compared to healthy controls. The authors suggested that these findings might indicate resilience, indexed by higher pre-trauma NAA levels, in the trauma-exposed non-PTSD controls relative to a mixed sample of vulnerable and non-vulnerable individuals in the healthy control groups

However when successfully encoding images that are trauma-related, PTSD subjects have been reported to exhibit reduced hippocampal BOLD responses (Hayes, LaBar, McCarthy, Selgrade, Nasser et al, in press). This study also found that reduced hippocampal activation was associated with increased arousal symptoms

Many neuropsychological studies have found deficits in verbal declarative memory in patients with PTSD (Gilbertson et al., 2006; Buckley et al., 2000; Elzinga & Bremner, 2002; Brewin, 2001; Golier & Yehuda, 1998; Bremner et al., 1993; Bermner et al., 1995; Gilbertson et al., 2001; Jenkins et al, 1998; Moradi et al., 1999; Roca & Freeman, 2001; Uddo et al., 1993; Vasterling et al., 1998; Vasterling et al., 2002; Yehuda et al., 1995; Barrett e al, 1996; Gil et al., 1990; Sachinvala et al., 2000; Golier et al, 1997), though some conflicting findings have been reported (Stein et al., 1999; Zalewski et al., 1994). Brewin and colleagues (2007) reviewed 27 studies on verbal and/or visual memory differences for emotionally neutral material between PTSD and healthy controls. The results consistently supported a small to moderate effect for poorer performance on verbal as opposed to visual memory in PTSD subjects

Recently a mutation in the estrogen response binding element of the pituitary adenylate cyclase-activating polypeptide receptor (PAC1) gene was associated with PTSD in women (Ressler et al. 2011). Interestingly this receptor is involved in hippocampal plasticity (Yang et al. 2010), but it is unknown if this mutation is linked to hippocampal function or volume in humans

expression of FKBP5, a cochaperone peptide that inhibits nuclear translocation of bound glucocorticoid receptors, is linked to risk for PTSD in subjects with early life stress (see Mehta and Binder review in this issue)

it has been hypothesized that that trauma exposure induces HPA axis dysregulation, resulting in hippocampal atrophy in vulnerable individuals (Elzinga and Bremner, 2002)

The present article proposes a mechanism through which hippocampal dysfunction may interact with traumatic experience to influence the etiology and maintenance of PTSD. Namely, an inability to adequately form conjunctive context representations may leave an individual dependent upon an elemental context representation strategy, and thus prone to respond with fear in the future presence of single elements encoded during the trauma

Adermark L, Lovinger D. 2009. “Frequency-dependent inversion of net striatal output by endocannabinoid-dependent plasticity at different synaptic inputs” J Neurosci 29(5): 1375-1380

Understanding how striatal neurons integrate glutamatergic and GABAergic inputs is essential for understanding the control of movement and the formation of striatal-based memories. Here we show that GABAergic synapses on striatal medium spiny neurons (MSNs) are more sensitive than glutamatergic synapses on the same cells to endocannabinoid (eCB) signaling, and that protocols that induce short-lasting cannabinoid 1 receptor (CB1R)-dependent depression at glutamatergic synapses are sufficient to induce LTD at GABAergic synapses. We also show that the frequency and duration of glutamatergic input are strong determinants of the net effect of eCB signaling, and key factors in determining if LTD has a net disinhibitory or inhibitory action in striatum. Plastic changes in net output from striatal MSNs are thus a complex function of disinhibitory and inhibitory LTD combined with other forms of synaptic plasticity such as long-term potentiation (LTP) at excitatory synapses

The striatum is the largest nucleus of the basal ganglia and has important roles in planning and execution of controlled movements (Balleine et al., 2007; Graybiel et al., 1994). The majority of synapses (~80%) are asymmetric glutamatergic synapses originating from the cortex (associative areas of the frontal and parietal lobes and motor and somatosensory cortex) and thalamus (lateral parafascicular nucleus and the central lateral nucleus) (Wilson, 2007), while the majority of neurons in the striatum (>90%) are GABAergic medium spiny neurons (MSNs) (Tepper et al., 2007).

GABAergic, presumed inhibitory, synapses are more sensitive to eCB signaling and LTD induction as compared to glutamatergic excitatory synapses in the striatum

the conditions necessary to convert CB1R-mediated short-term synaptic depression to LTD likely vary in a synapse-specific manner

Our findings indicate that with low frequency, short duration repetitive activation of glutamatergic inputs LTD of GABAergic synapses predominates; giving rise to DLL of striatal output. At higher frequencies, or longer stimulus durations, the glutamatergic synapses themselves are depressed, which would decrease output from projection neurons. The frequency of glutamatergic input is thus a strong determinant of the net effect of eCB signaling, and a key factor in determining whether LTD has a net disinhibitory or inhibitory action in striatum

Adriani W, Laviola G. 2004. “Windows of vulnerability to psychopathology and therapeutic strategy in the adolescent rodent model” Behav Pharmacol 15(5-6):341-52

Impulsive SHR animals were characterized by reduced cannabinoid CB1 receptor density in the prefrontal cortex. acute cannabinoid agonist increased levels of self-control behaviour. modulation of cannabinoid system might improve some behavioural anomalies seen in ADHD

Aharonovich E, Brooks A, Nunes E, Hasin D. 2008. “Cognitive deficits in marijuana users: effects on motivational enhancement therapy plus cognitive behavioral therapy treatment outcome” Drug Alcohol Depend 95(3): 279-283

Twenty marijuana-dependent outpatients were administered a neuropsychological battery at treatment entry. All patients received 12 weekly individual sessions of combined motivational enhancement therapy and cognitive behavioral therapy

Marijuana abstinence was unrelated to cognitive functioning. However, dropouts scored significantly lower than completers on measures of abstract reasoning and processing accuracy, providing initial evidence that cognitive functioning plays a role in treatment retention of adult marijuana dependent patients

participants were excluded if they 1) met DSM-IV criteria for current psychiatric disorders requiring intervention (assessed by the SCID) or substance dependence other than cannabis; 2) current use of prescription psychoactive medication 3) history of seizure disorder or head injury with loss of consciousness >1 hour, or 4) prior diagnosis of learning disability

To preclude acute intoxication at testing, patients reported their last marijuana use and submitted observed urine specimens and a breath alcohol test. Participants reporting any new illicit drug or alcohol use <7 h. before testing were rescheduled to avoid acute intoxication effects

Microcog scores among completers ranged from the population mean to about.5 SD above the mean (99.9–107.1). Microcog scores among dropouts ranged from nearly one standard deviation below the population mean to near the population mean (87.7–99.5). Dropouts had significantly lower scores on abstract reasoning, spatial processing and accuracy (Table 1), with similar trends (p<.10) for general cognitive performance and general cognitive proficiency. For example, completers scored about .5 SD above the population mean on abstract reasoning, while dropouts scored approximately .5 SD below the population mean. In contrast, WCST scores of perseverative errors and responses were near the mean and similar among completers and dropouts.

The mean proportion of negative urines did not differ between the high and low cognition groups (.18 and .17, z-statistic 0.47; p=.64)

Higher cognitive ability in the domains of mental reasoning, spatial ability and overall accuracy significantly distinguished completers from dropouts. The association between lower cognition levels at treatment entry and treatment dropout is consistent with studies in cocaine-dependent patients (Aharonovich et al., 2003; 2006) and poly-substance abusers (Fals-Stewart et al., 1994;Teichner et al., 2002)

The study was not designed to investigate differences in acute vs. residual effects of cannabis, or pre-morbid impairment vs. impairment secondary to marijuana dependence

from a treatment development viewpoint, given the high dropout early in outpatient treatment, the source of cognitive impairment may be less important than the need to tailor the initial sessions to accommodate deficits of cognitively impaired patients

Aizer A. 2013. “Juvenile incarceration, human capital and future crime: evidence from randomly assigned judges” National Bureau of Economic Research working paper no 19102

Over 130,000 juveniles are detained in the US each year with 70,000 in detention on any given day

This paper uses the incarceration tendency of randomly-assigned judges as an instrumental variable to estimate causal effects of juvenile incarceration on high school completion and adult recidivism. Estimates based on over 35,000 juvenile offenders over a ten-year period from a large urban county in the US suggest that juvenile incarceration results in large decreases in the likelihood of high school completion and large increases in the likelihood of adult incarceration

At the end of 2011, over 2.2 million people were incarcerated in the US, and an additional 4.8 million were under supervision of correctional systems (Glaze and Parks, 2012). Federal, state, and local expenditures on corrections exceed $82 billion annually, with the direct expenditures on the wider justice system totalling over $250 billion (Kennelman, 2012). Meanwhile, private expenditures that aim to prevent the externalities associated with crime are thought to be of a similar magnitude (Becker (1968). Papers and reviews include Levitt (1998, 2004); Freeman (1996); Glaeser and Sacerdote (1999); Jacob and Lefgren (2003); Di Tella and Schargrodsky , forthcoming; Lee and McCrary (2005); Lochner and Moretti (2004), among others.)

US has a juvenile corrections rate that is five times higher than the next highest country (Hazel, 2008)

In a life-cycle context, incarceration during adolescence may interrupt human and social capital accumulation at a critical moment leading to reduced future wages in the legal sector and greater criminal activity

those incarcerated as a juvenile are 39 percentage points less likely to graduate from high school and are 41 percentage points more likely to have entered adult prison by age 25 compared with other public school students from the same neighborhood. Once we include demographic controls, limit our comparison group to juveniles charged with a crime in court but not incarcerated, and instrument for incarceration, juvenile incarceration is estimated to decrease high school graduation by 13 percentage points and increase adult incarceration by 22 percentage points

the strongest results are for juveniles aged 15 and 16 – a critical period of adolescence when incarceration is most likely to end one’s high school education

In the economic model of crime originally developed by Becker (1968), criminal activity and participation in the legitimate market are substitutes

Freeman (1992) and Western and Beckett (1999). Both find that men who have been incarcerated have lower levels of employment compared with those who have not been incarcerated, controlling for an extensive set of observable characteristics

Alger B, Kim J. 2011. “Supply and demand for endocannabinoids” Trends Neurosci 34(6): 304-315

The endocannabinoid system in the brain primarily influences neuronal synaptic communication, and affects biological – functions including eating, anxiety, learning and memory, growth and development – via an array of actions throughout the nervous system… This review focuses on recent investigations that illuminate fundamental issues of endocannabinoid storage, release, and functional roles.

In some regions, e.g., hippocampus, the highest densities of CB1R are on axon terminals of interneurons that co-express GABA and cholecystokinin (CCK) [3][4]. In other regions, such as in the cerebellum, CB1Rs are more equally distributed on both excitatory and inhibitory terminals

Glia express CB1Rs [8] and respond to CB1R agonists by releasing glutamate and influencing synaptic transmission [9]

Endocannabinoids are directly synthesized from membrane phospholipids in response to an increase in postsynaptic intracellular calcium ([Ca2+]i) alone, or combined with activation of postsynaptic GPCRs, such as group I metabotropic glutamate receptors (mGluRs) [10][11], or M1/M3 muscarinic acetylcholine receptors (mAChRs) [12][13]

Blocking anandamide degradation reduces pain [36][37], inflammation [38], depression [39], and anxiety [40], but does not cause hypothermia, movement disorders or weight gain [40], whereas blocking 2-AG degradation induces hypothermia and hypomotility and analgesia [37]. Simultaneously blocking degradation of both mimics THC in drug discrimination tests, but blocking degradation of only one does not [34]

Construction of a 2-AG-generating system in a model cell requires heterologous expression of only mGluR5, DGLα, and the structural protein Homer 2b [64]

In the striatum, anandamide inhibits the production of 2-AG in some cells by activating TRPV1 channels, thereby decreasing glutathione levels and suppressing DGL [81]

Anandamide acting at CB1Rs seems to be responsible for chronic or constitutive endocannabinoid-mediated regulation of phenomena such as pain, anxiety and analgesia, adult neurogenesis, as well as a form of homeostatic synaptic plasticity in vitro.

Alger B. 2012. “Endocannabinoids at the synapse a decade after the dies mirabilis (29 March 2001): what we still do not know” J Physiol 590(10): 2203-2212

Alemany S, Arias B, Aguilera M, Villa H, Moya J, Ibanez M, Vossen H, Gasto C, Ortet G, Fananas L. 2011. “Childhood abuse, the BDNF-Val66Met polymorphism and adult psychotic-like experiences” British Journal of Psychiatry 199(1): 38-42

Individuals exposed to childhood abuse are more likely to report positive psychotic-like experiences. Met carriers reported more positive psychotic-like experiences when exposed to childhood abuse than did individuals carrying the Val/Val genotype. Therefore, the observed gene–environment interaction effect may be partially responsible for individual variation in response to childhood abuse.

Alisic E, Zalta A, Wesel F, Larsen S, Hafstad G, Hassanpour K, Smid G. 2014. “Rates of post-traumatic stress disorder in trauma-exposed children and adolescents: meta-analysis” BJ Psych 204:335-340

43 independent samples (n = 3563). Samples consisting only of participants seeking or receiving mental health treatment were excluded

The overall rate of PTSD was 15.9% (95% CI 11.5-21.5), which varied according to the type of trauma and gender. Least at risk were boys exposed to non-interpersonal trauma (8.4%, 95% CI 4.7-14.5), whereas girls exposed to interpersonal trauma showed the highest rate (32.9%, 95% CI 19.8-49.3)

Alshaarawy O, Anthony J. 2015. “Cannabis smoking and serum C-reactive protein: a quantile regressions approach based on NHANES 2005-2010” Drug Alcohol Depend 147: 203-207

Evidence suggesting possible cannabis-attributable immunomodulation emerges at CRP levels below the median (p < 0.05)

Extending pre-clinical research on cannabis-attributable immunomodulation, this study’s CRP evidence points toward possible anti-inflammatory effects of cannabis smoking

Anda R, Felitti V, Bremner J, Walker J, Whitfield C, Perry B, Dube S, Giles W. 2006. “The enduring effects of abuse and related adverse experiences in childhood. A convergence of evidence from neurobiology and epidemiology.” Eur Arch Psychiatry Clin Neurosci 256(3): 174-86

For persons with ≥ 4 ACEs, the risk of panic reactions, depressed affect, anxiety, and hallucinations were increased 2.5-, 3.6-, 2.4 and 2.7-fold, respectively; smoking, alcoholism, illicit drug use, and injected drug use were increased 1.8-, 7.2-, 4.5-, and 11.1-fold; the onset of substance abuse corresponds to the time of traumatization in PTSD patients

Andel H, Jansen L, Grietens H, Knorth E, van der Gaag R. 2014. “Salivary cortisol: a possible biomarker in evaluating stress and effects of interventions in young foster children?” European Child & Adolescent Psychiatry 23(1): 3-12

systematic review; nine studies of salivary cortisol in foster families. All found reduced levels in relation to chronic stress related to maltreatment and neglect.

Anderson S, Bechara A, Damasio H, Tranel D, Damasio A. 1999. “Impairment of social and moral behavior related to early damage in human prefrontal cortex” Nature Neuroscience 2(11): 1032-1037

The long-term consequences of early prefrontal cortex lesions occurring before 16 months were investigated in two adults. As is the case when such damage occurs in adulthood, the two early-onset patients had severely impaired social behavior despite normal basic cognitive abilities, and showed insensitivity to future consequences of decisions, defective autonomic responses to punishment contingencies and failure to respond to behavioral interventions. Unlike adult-onset patients, however, the two patients had defective social and moral reasoning, suggesting that the acquisition of complex social conventions and moral rules had been impaired. Thus early-onset prefrontal damage resulted in a syndrome resembling psychopathy

Anderson G, Maes M. 2013. “Schizophrenia: linking prenatal infection to cytokines, the tryptophan catabolite (TRYCAT) pathway, NMDA receptor hypofunction, neurodevelopment and neuroprogression” Prog Neuropsychopharmacol Biol Psychiatry 42:5-19

In 1995, the macrophage-T lymphocyte theory of schizophrenia (Smith and Maes, 1995) considered that activated immuno-inflammatory pathways may account for the higher neurodevelopmental pathology linked with gestational infections through the detrimental effects of activated microglia, oxidative and nitrosative stress (O&NS), cytokine-induced activation of the tryptophan catabolite (TRYCAT) pathway and consequent modulation of the N-methyl d-aspartate receptor (NMDAr) and glutamate production… Accumulating data suggest a powerful role for prenatal infection, both viral and microbial, in driving an early developmental etiology to schizophrenia. Models of prenatal rodent infection show maintained activation of immuno-inflammatory pathways coupled to increased microglia activation.

Maternal infection and subsequent immuno-inflammatory responses are additionally associated with O&NS, including lowered antioxidants such as glutathione. This will contribute to alterations in neurogenesis and myelination. In such a scenario a) a genetic or epigenetic potentiation of immuno-inflammatory pathways may constitute a double hit on their own, stimulating wider immuno-inflammatory responses and thus potentiating the TRYCAT pathway and subsequent NMDAr dysfunction and neuroprogression; and b) antipsychotic-induced changes in immuno-inflammatory, TRYCAT and O&NS pathways would modulate the CNS glia-neuronal interactions that determine synaptic plasticity as well as myelin generation and maintenance

Anderson M, Rees D, Sabia J. 2013. “Medical marijuana laws and suicides by gender and age” American Journal of Public Health 104(12): 2369-2376

legalization was associated with a 10.8% (95% confidence interval [CI] = −17.1%, −3.7%) and 9.4% (95% CI = −16.1%, −2.4%) reduction in the suicide rate of men aged 20 through 29 years and 30 through 39 years, respectively

The negative relationship between legalization and suicides among young men is consistent with the hypothesis that marijuana can be used to cope with stressful life events. However, this relationship may be explained by alcohol consumption

Andersson N, Gustafsson L, Okkels N, Taha F, Cole S, Munk-Jorgensen P, Goodwin R. 2015. “Depression and the risk of autoimmune disease: a nationally representative, prospective longitudinal study” Psychological Medicine 45(16): 3559-3569

A prospective population-based study including approximately 1.1 million people was conducted using linked Danish registries. Depression and autoimmune diseases were diagnosed by physicians and documented in medical records. In total, 145 217 individuals with depression were identified between 1995 and 2012. Survival analyses were used to estimate the relative risk of autoimmune disease among those with, compared to without,

Depression was associated with a significantly increased risk of autoimmune disease [incidence rate ratio (IRR) 1.25, 95% CI 1.19–1.31], compared to those without a history of depression. Results suggest a general increased risk of autoimmune diseases following the onset of depression during first year (IRR 1.29, 95% CI 1.05–1.58), which remained elevated for the ensuing 11 years and beyond (IRR 1.53, 95% CI 1.34–1.76)

Andréasson S, Allebeck P, Engström A, Rydberg U. 1987. “Cannabis and schizophrenia. A longitudinal study of Swedish conscripts” Lancet 2(8574):1483-6

Relative risk for schizophrenia among high consumers of cannabis (use on more than fifty occasions) was 6·0

Angrilli A, Spironelli C, Elbert T, Crow T, Marano G, Stegagno L. 2009. “Schizophrenia as failure of left hemispheric dominance for the phonological component of language” PLoS One 4(2): e4507

the deficit of lateralization in the schizophrenic brain is specific for the phonological component of language

Anisman H, Merali Z, Hayley S. 2008. “Neurotransmitter, peptide and cytokine processes in relation to depressive disorder: comorbidity between depression and neurodegenerative disorders” Prog Neurobiol 85(1): 1-74

inflammatory processes may influence stress-related illness, such as depression, and may be a common denominator for the comorbidity that exists between depression and neurological conditions, including Parkinson’s and Alzheimer’s diseases, as well as cardiovascular-related pathology

Anketell C, Dorahy M, Shannon M, Elder R, Hamilton G, Corry M, MacSherry A, Curran D, O’Rawe B. 2010. “An exploratory analysis of voice hearing in chronic PTSD: potential associated mechanisms” J Trauma Dissociation 11(1): 93-107

Auditory hallucinations (AH) in chronic PTSD is not a rare phenomenon, (b) dissociation is significantly related to AH, and (c) dissociation may be a potential mediating mechanism for AH in PTSD.

Anselmetti S, Cavallaro R, Bechi M, Angelone S, Ermoli E, Cocchi F, Smeraldi E. 2005. “Psychopathological and neuropsychological correlates of source monitoring impairment in schizophrenia” Psychiatry Research 150: 51-59 in dropbox

Schizophrenic patients are known to show a deficit in the source monitoring function, which refers to the set of processes involved in the attribution of an origin to memories and beliefs. A failure in source monitoring was found to be associated with Schneiderian delusions in the recent literature

Recognition of self-generated items was significantly worse than control values in Schneiderian delusional patients only, while source attribution of recognized self-generated items was significantly biased towards the external sources in all delusional patients in comparison to controls. Among schizophrenic patients, source misattribution of self-generated items was significantly correlated to executive, planning performance

theory of Johnson et al. (1993) , most source monitoring decisions are made rapidly and unconsciously, using memory processes, but when percep ual and contextual information is weak , the judgment about the origins of a memory is supported by a reasoning process expect ed to involve executive functions

attribution errors of self-generated items were specifically related to the presence of active delusions. The exclusive influence of the presence of delusions and not of other positive symptoms like hallucinations or disorganization, might appear inconsistent with some previous reports (Bentall et al., 1991; Vinogradov et al., 1997; Bre´bion et al., 2000; Morrison and Haddock, 1997). However, the choice to study a sample of stabilized, an tipsychotic-responder patients may explain differences in results

Among schizophrenic patients only the executive (planning) performance (and not memory performance) was correlated to internal-external discrimination bias

might suffer from a cognitive bias consisting of a tendency to attribute “puzzling” stimuli (as self-generated items are, with weak or no perceptual and contextual information) to the previously presented more strongly contextualized source (Vinogradov, 1997)

This interpretation is consistent with data showing that patients with delusions have a “jumping to conclusion bias” (Garety, 1991)

By contrast delusional non-Schneiderian patients showed a significant performance [impairment] in comparison both to controls and non-delusional patients in the attribution of self-generated items, with a bias towards the external source.

Arain M, Khan M, Craig L, Nakanishi S. 2015. “Cannabinoid agonist rescues learning and memory after a traumatic brain injury” Ann Clin Transl Neurol 2(3): 289-294

Currently, there are no effective treatments for post-TBI cognitive deficits, but research has uncovered some of the pathophysiological mechanisms which include: excitotoxicity, neuroinflammation, and neurometabolic dysfunctions with an associated increase in reactive oxygen species… the cannabinoid receptor 1 (CB1R) mediates the rewarding aspects of marijuana,5 and has been shown to decrease excitotoxicity,6suppress neuroinflammation,7 and modify neurometabolism.8

administration of a CB1R agonist (ACEA) after a moderately severe experimental TBI rescued learning and memory abilities in young adult male rats

Although the CCI injury is a focal TBI with mechanical damage highly localized to the impact area, aspects of the pathological signaling cascades associated with excitotoxicity, neuroinflammation, and metabolic dysfunctions may be dispersed both ipsilateral and contralateral to the directly affected hemisphere…  cannabinoid agonist treatment may have preserved learning and memory in the TBI-treated animals by protecting the intact brain tissue that was not directly damaged by the primary injury, and that the “rescued” brain areas were then able to compensate for the lesioned areas. Alternatively, and/or in parallel, the cannabinoid receptor agonist treatment could also have limited cerebral edema and neuronal cell loss,10,11 diffuse axonal damage, decreased pathological neuroinflammatory processes, or modulated metabolic processes that preserved neuronal tissues or functions.21

Ardiel E, Rankin C. 2010. “The importance of touch in development” Paediatr Child Health 15(3): 153-156

Developmental delay is common in children deprived of normal sensory stimulation

Hopper and Pinneau (2) found that 10 min of additional handling per day resulted in a significant reduction in regurgitation. In addition, Casler (3) reported that institutionalized infants receiving an additional 20 min of tactile stimulation per day for 10 weeks had higher scores on developmental assessments

extra mechanosensory stimulation led to superior growth and developmental performance. Although caloric consumption did not differ between the two groups, infants receiving mechanosensory stimulation averaged 47% greater weight gain per day than the unstimulated controls and were discharged an average of six days earlier. The stimulated infants also spent more time awake and active, and exhibited more mature habituation, orientation, motor and range-of-state behaviours on the Brazelton Neonatal Behavioral Assessment Scale. The positive effects appear to be persistent; when retested eight and 12 months after treatment, the stimulated infants were in a higher weight percentile group, scored better on the Bayley mental and motor assessment tests, and had a reduced incidence of neurological soft signs (minor neurological abnormalities indicating nonspecific cerebral dysfunction)

Hammett (7) reported that rats that were infrequently handled were more timid, apprehensive and high strung than rats that had been ‘petted and gentled’. They were also six times less likely to survive thyroidectomy

Gonzalez et al (8) compared the adult behaviour of maternally reared rats with those isolated in plastic cups, from postnatal days 4 to 20. Despite receiving comparable nutritional input, the pups raised in cups weighed less at weaning. Although this difference did not persist into adulthood, early deprivation did affect adult maternal and emotional behaviour. Compared with maternally reared controls, isolate-reared rats were less attentive to their own offspring, performing fewer pup retrievals and spending less time licking and crouching over pups and spending more time digging, biting the cage, hanging from the top of the cage, eating and tail chasing

full-body stroking partially rescued the behavioural deficits of isolation, with the maximally stimulated pups exhibiting maternal behaviours of durations intermediate to those of the maternally reared and minimally stimulated pups

Lovic and Fleming (9)… isolate-reared rats were hyperactive, easily distracted and less attentive to their own pups – behaviours which could be rescued by introducing licking-like stimulation with a paintbrush

the mechanism of inheritance was nongenomic: biological female offspring of low LG (licking/grooming) mothers fostered into the litter of high LG mothers displayed increased LG levels comparable with unfostered offspring of high LG mothers and vice versa… those reared by low LG mothers displayed impaired learning and memory in the Morris water maze and in object recognition (11,12), and showed substantially more fearful behaviour, as measured by a longer latency to eat food in a novel environment and decreased open-field exploration (13,10). These behavioural studies demonstrate that mechanosensory stimulation can alter the developing rat brain

Liu et al (14) showed that maternal licking altered the pup’s hypothalamic-pituitary-adrenal (HPA) stress reactivity through changes in gene expression in areas of the brain that regulate the behavioural and endocrine response to stress. Adult offspring of low LG mothers had higher HPA responses to restraint stress than those of high LG mothers

elevated exposure to stress hormones has been implicated in the development of many conditions, including visceral obesity, hypertension, diabetes, depression, anxiety, drug addiction and multiple forms of coronary artery disease

A negative feedback loop for this stress response is initiated by the binding of glucocorticoids to glucocorticoid receptors (GR) in the hippocampus. Liu et al (14) showed that as adults, the offspring of low LG mothers had decreased GR expression in the hippocampus, resulting in diminished glucocorticoid feedback sensitivity and increased CRH synthesis and release of plasma adrenocorticotropic hormone… Weaver et al (15) demonstrated that maternal care programs GR gene expression levels in the hippocampus for the lifespan of the animal via epigenetic modification of the GR gene.

administering 15 min of tactile stimulation with a small brush three times per day resulted in increased dendritic spine density in animals with mPFC lesions and increased dendritic length in animals with posterior parietal lesions. The mechanism of action appears to be the release of fibroblast growth factor-2 (FGF-2), because both FGF-2 and its receptor were upregulated in the skin and brain of stimulated rats (17)… stroking a pregnant mother rat also ameliorated the effects of future cortical lesions in her pups, as did prenatal pretreatment with FGF-2 (17)

a microscopic nematode, known as Caenorhabditis elegans, is also sensitive to touch deprivation… worms reared in isolation had a smaller body size (Figures 1A and and1B)1B) and a delayed onset of egg laying compared with colony worms reared in groups of 30 to 40… Rose et al (18) found that worms reared in isolation had weaker synapses than colony-reared worms, but 30 taps administered early in development were sufficient to strengthen them

Reversing the effects of early deprivation is not simple, but the importance of touch is undeniable. Finally, you need not be a worm larvae, rat pup or even human child to reap the rewards of touch. For example, employees receiving chair massages showed a significant reduction in blood pressure (21), anxiety (22) and job stress, and had increased speed and accuracy on math problems (23). Furthermore, patients with ailments ranging from burns (24) to eating disorders (25) have been shown to benefit from massage therapy, with reductions in stress hormone levels, anxiety and clinical symptoms; HIV-positive men receiving daily massages had an increased number of immune cells to combat the virus (26). To paraphrase, a kiss may just be a kiss, a sigh may just be a sigh, but a touch can change your life (or at least your nervous system)!

Arendt M, Rosenberg R, Foldager L, Perto G. 2005. “Cannabis-induced psychosis and subsequent schizophrenia-spectrum disorders: follow-up study of 535 incident cases” British Journal of Psychiatry 187: 510-515

Data on patients treated for cannabis-induced psychotic symptoms between 1994 and 1999 were extracted from the Danish Psychiatric Central Register. Those previously treated for any psychotic symptoms were excluded. The remaining 535 patients were followed for at least 3 years. In a separate analysis, the sample was compared with people referred for schizophrenia-spectrum disorders for the firsttime, but who had no history of cannabis-induced psychosis.

Schizophrenia-spectrum disorders were diagnosed in 44.5% of the sample. New psychotic episodes of any type were diagnosed in 77.2%. Male gender and young age were associated with increased risk. Development of schizophrenia-spectrum disorders was often delayed, and 47.1% of patients received a diagnosis more than a year after seeking treatment for a cannabis-induced psychosis

Cannabis-induced psychotic disorders are of great clinical and prognostic importance

535 cases (66.6%) recorded no history of psychotic symptoms and were included for further analysis.

The mean age at time of first treatment for cannabis-induced symptoms was 27.0 years (s.d.=7.7, 25th percentile=20.9, median=25.5, 75th percentile=31.2); 441 (82.4%) were male. A total of 379 patients were admitted to hospital for a median stay of 13 days (25th percentile=4, 75th percentile=29, mean=30.6) and 156 patients received out-patient treatment only.

238 people (44.5%) diagnosed with cannabis-induced psychotic symptoms later developed a schizophrenia-spectrum disorder… 77.2% experienced new psychotic episodes after index, if transient psychotic conditions and substance-induced psychoses are included. Only 15.9% remained out of psychiatric care throughout the follow-up period

The first episode of schizophrenia-spectrum disorder occurred after a substantial delay for most of the 238 patients (Fig. 1)… more than 1 year for 47.1% of the patients, and 17.2% developed such conditions more than 3 years later.

in accordance with a recent study showing that the age at onset of schizophrenia is lower among patients using cannabis (Veen et al, 2004)

The incidence of cannabis-induced psychotic disorders in Denmark was estimated to be 2.7 per 100 000 person-years. This confirms that such conditions are rare… Danish National Board of Health (2003) shows that 40.9% of all Danish citizens aged 16-24 years have used cannabis at some point in their lifetime, and that 19.7% had used the substance in the previous month

Arendt M, Rosenberg R, Fjordback L, Brandholdt J, Foldager L, Sher L, Munk-Jorgensen P. 2007. “Testing the self-medication hypothesis of depression and aggression in cannabis-dependent subjects” Psychological Medicine 37:935-945 in dropbox

119 cannabis dependent subjects, age range 16-30 (median 22) 83.2% male Subject s were excluded if there was any doubt whether cannabis dependence was the main reason for entering treatment

Nearly all subjects (92.2 %) had used cannabis more than 50 00 times and 66.4 % had used cannabis on more than 10 000 occasions. 82.4% hash most common. 48% heavily used stimulants

Depressed subjects more likely to experience sadness, depression, paranoia and anxiety and less likely to report happiness and euphoria in response to use.

Depressed subjects gave less reasons for use. The only two found more frequently in depressed than not depressed were “to give one more thoughts” and “to feel more emotions”

The majority of each group used to relax, increased pleasure and relieve depression, but depressed not moreso than non-depressed. Majority felt better while high, but a minority still felt bad. Larger minority in depression.

Conclusion is that depression does not increase the likelihood of using to relieve depression, or of experiencing relief from depression.

lowering of aggression proved to be one of the main reasons for cannabis use among subjects with difficulties controlling violent behaviour

Arendt M, Mortensen P, Rosenberg R, Pedersen C, Waltoft B. 2008. “Familial predisposition for psychiatric disorder comparison of subjects treated for cannabis-induced psychosis and schizophrenia” Arch Gen Psychiatry 65(11): 1269-1274

Nationwide population-based sample of all individuals born in Denmark between January 1,1955, and July 1, 1990 (N = 2 276 309)

During the 21.9 million person-years of follow-up between 1994 and 2005, 609 individuals received treatment of a cannabis-induced psychosis and 6476 received treatment of a schizophrenia spectrum disorder

rate ratios of developing cannabis-induced psychosis and schizophrenia spectrum disorder associated with predisposition to schizophrenia spectrum disorder, other psychoses, and other psychiatric disorders in first-degree relatives were of similar magnitude. However, children with a mother with schizophrenia were at a 5-fold increased risk of developing schizophrenia and a 2.5-fold increased risk of developing cannabis-induced psychosis. The risk of a schizophrenia spectrum disorder following a cannabis-induced psychosis and the timing of onset were unrelated to familial predisposition

Cannabis-induced psychosis could be an early sign of schizophrenia rather than a distinct clinical entity

almost 50% of the patients treated because of cannabis-induced psychosis in Denmark, with no history of psychosis, had a diagnosis of a schizophrenia spectrum disorder within a mean follow-up period of 5.9 years.9

the risk of developing a schizophrenia spectrum disorder was increased 3.58-fold, and the risk of developing a cannabis-induced psychosis was 4.51-fold higher in children whose father had a schizophrenia spectrum disorder compared with those whose father did not

Predisposition to psychiatric disorders other than psychosis in fathers (P = .02) was also associated with increased risk of treatment of a cannabis-induced psychosis

Despite much effort, it has been impossible to establish a symptom profile that consistently differentiates persons with cannabis-induced psychosis from those with other psychotic conditions.3,5,6,20,21 The same is true for studies comparing persons with schizophrenia who have or have not been using cannabis.4,8,10,22– 24

individuals who use cannabis or have access to the substance are at risk of having a diagnosis of cannabis-induced psychosis, although in reality they have schizophrenia

Some studies have sporadically mentioned the presence of psychopathologic findings in relatives of subjects with cannabis-induced psychosis or patients with psychoses with cannabis-positive urine screening results, but no consistent pattern has appeared.6– 8,10,26– 31 A recent study by Boydell et al4 is particularly important. These authors studied the family history of schizophrenia in 757 patients who did or did not use cannabis with onset of schizophrenia and found no difference between the groups in the percentage of patients with a positive family history of schizophrenia

However, the results clearly show that cannabis-induced psychoses do not occur randomly. Rather, the degree of hereditary predisposition in individuals who receive treatment of cannabis-induced psychosis closely mirrors that in those who develop schizophrenia with no history of cannabis-induced psychosis. The results agree with those of other studies that show that cannabis predominantly causes psychotic symptoms in those persons who are predisposed to develop psychosis or show signs of psychosis in the absence of cannabis use.7,37,39,44,45

Individuals were included in the study after having received psychiatric treatment. Consequently, they represent the more severe cases of cannabis-induced psychotic symptoms. The results may, therefore, not be generalizable to individuals who develop psychotic symptoms after cannabis use without requiring treatment or who develop psychotic symptoms that last less than 48 hours, which is required according to the ICD-10. This is important because a number of studies have shown that cannabis frequently induces short-lived psychotic symptoms both in nonpsychiatric samples and in individuals with schizophrenia.46– 50

The incidence ratio of cannabis-induced psychosis in Denmark has been estimated to be 2.7 per 100 000 person-years.9

Arnedo J, Svrakic D, Del Val C, Romero-Zaliz R, Hernandez-Cuervo H, Molecular Genetics of Schizophrenia Consortium, Fanous A, Pato M, Pato C, de Erausquin G, Cloninger C, Zwir I. 2014. “Uncovering the Hidden Risk Architecture of the Schizophrenias: Confirmation in Three Independent Genome-Wide Association Studies” Am J Psychiatry doi: 10.1176/appi.ajp.2014.14040435.

Arévalo-Martı́n Á, Vela J, Molina-Holgado E, Borrell J, Guaza C. 2003. “Therapeutic action of cannabinoids in a murine model of multiple sclerosis” Neuroscience 23(7): 2511-2516

Using the Theiler’s murine encephalomyelitis virus model, we report here that treatment with the synthetic cannabinoids WIN 55,212–2, ACEA, and JWH-015 during established disease significantly improved the neurological deficits in a long-lasting way. At a histological level, cannabinoids reduced microglial activation, abrogated major histocompatibility complex class II antigen expression, and decreased the number of CD4+ infiltrating T cells in the spinal cord. Both recovery of motor function and diminution of inflammation paralleled extensive remyelination

Arévalo-Martı́n Á, Garcia-Ovejero D, Gomez O, Rubio-Araiz A, Navarro-Galve B, Guaza C, Molina-Holgado E, Molina-Holgado F. 2008. “CB2 cannabinoid receptors as an emerging target for demyelinating diseases: from neuroimmune interactions to cell replacement strategies” Br J Pharmacol 153(2): 216-225

Amongst the various demyelinating diseases that affect the central nervous system, those induced by an inflammatory response stand out because of their epidemiological relevance. The best known inflammatory-induced demyelinating disease is multiple sclerosis, but the immune response is a common pathogenic mechanism in many other less common pathologies

Demyelination is the loss of the myelin sheath that surrounds axons and it may affect both the central nervous system (CNS) and peripheral nervous system (PNS). Demyelinating pathologies may have a primary genetic aetiology (leukodystrophies) or may be the secondary effect of infections, vascular alterations, toxic insults or inflammatory reactions

MS is the most frequent neurological disease in young adults. In addition to myelin loss, there is also neuronal damage in MS that further contributes to the symptomatology (Ferguson et al., 1997; Mews et al., 1998; Trapp et al., 1998, 1999)

The main reason for inflammatory-mediated damage is thought to be the release of reactive oxygen and nitrogen species by immune cells, as well as that of proteases, which directly mediate cell damage (Correa et al., 2005a, 2005b). In addition, immune cells release cytotoxic/cytostatic cytokines, that not only cause damage but that may also enhance the release of more reactive species and glutamate by the cells in the surrounding tissue

Treatment of TMEV-IDD mice with a CB2 agonist reduces the infiltration of CD4+ T cells to the spinal cord (Arévalo-Martín et al., 2003)… the effect of the reduced infiltration of these cells into the CNS is beneficial as there is a decrease in the release of Th1 cytokines (interferon-γ (IFN-γ), tumour necrosis factor-α (TNF-α) or interleukin-12 (IL-12)) into the surrounding tissue, which is involved in tissue damage. It is known that cannabinoids alter the profile of cytokine expression from a Th1 to a Th2 phenotype in a CB2-dependent manner (Yuan et al., 2002)

In addition IFN-γ induces the expression of the vascular cellular adhesion molecule-1 (VCAM-1) by endothelial cells, which favours the access of activated lymphocytes to the CNS (Groveset al., 1993; Weiser et al., 2007). Therefore, reducing the release of IFN-γ by the Th1 cells could itself block the ‘calling’ signal and therefore, decrease the migration of more primed T cells to the CNS that would amplify the damage.

microglia and macrophages produce several cytokines considered to be pro-inflammatory, such as TNF-α, IL-1β or IL-12. Through CB2 receptors, cannabinoids inhibit the expression of TNF-α, IL-1β and the p40 subunit of IL-12 and IL-23 by microglia/macrophages (Klegeris et al., 2003; Correa et al., 2005a, 2005b). TNF-α causes neuronal death through an excitotoxic mechanism and recruits more lymphocytes to the CNS by upregulating the expression of VCAM-1 and intercellular adhesion molecule-1 (ICAM-1) on endothelial cells (Dobbie et al., 1999; Weiser et al., 2007)

CB2 expression is highly inducible in macrophages or microglia, and its levels in vitro depend on the local environment and the combination of inflammatory molecules (Carlisle et al., 2002; Maresz et al., 2005). In addition, in vivo CB2 is not expressed equally in all microglial populations, but rather it is predominantly present in perivascular or activated microglia (Benito et al., 2003; Nunez et al., 2004)

In [astrocytes], cannabinoids also inhibit the inflammation-induced expression of TNF-α, IL-1β and IL-6 through CB1 and CB2 receptors (Molina-Holgado et al., 1997, 1998; Ortega-Gutierrez et al., 2005)

it was recently shown that cannabinoids can prevent axonal damage in a viral model of MS, interfering with the excitotoxic component in the progression of this disease in a way that requires activation of CB2 receptors (Docagne et al., 2007)

In experimental models of demyelination there is, both neurological and histopathological, evidence of the therapeutic benefit of cannabinoids. Most data indicate that the activation of CB1 or CB2 receptors reduces deficits such as spasticity, tremor or neuropathic pain (Baker et al., 2000), whereas CB2 receptors also regulate inflammatory aspects related to disease progression (Maresz et al., 2007)

cannabinoid-induced attenuation of the inflammatory response was linked to axon remyelination. Oligodendrocyte death and the resulting destruction of myelin plays an important role in axonal degeneration, as demyelinated axons are highly vulnerable to oxidative stress and to cytokine and glutamate toxicity (Werner et al., 2001). Similarly, oligodendrocytes are sensitive to microglial-derived free-radicals and mediators of inflammation (Molina-Holgado et al., 2001; Back et al., 2002; Li et al., 2005).

once oligodendrocytes have lost their myelin membranes, they are unable to remyelinate axons even if they survive the insult (Keirstead and Blakemore, 1997)

Cannabinoids may directly enhance myelin repair by acting on oligodendrocyte progenitors, or they may act indirectly by inhibiting the immune response that might be contributing to demyelination or hampering remyelination

The synthetic cannabinoid agonists HU210 or WIN 55212-2 act on both CB1 and CB2 receptors to protect oligodendrocytes from apoptosis produced by deprivation of trophic support, a mechanism dependent on phosphoinositide 3-kinase/protein kinase B (PI3K/Akt) signalling (Molina-Holgado E et al., 2002) Moreover, cannabinoids suppress the production of inflammatory molecules by astrocytes and microglial cells including IL-1β, TNF-α and NO (Molina-Holgado et al., 1997; Molina-Holgado E et al., 2002;Puffenbarger et al., 2000; Cabral et al., 2001), as well as enhancing the release of the anti-inflammatory cytokines IL-4, IL-10, IL-6 and interleukin-1 receptor antagonist (IL-1ra) (Molina-Holgado et al., 1998,2003; Klein et al., 2000)

CB2 receptor activation could be involved in maintaining the self-renewal capacity of stem cells

Arnone D, Barrick T, Chengappa S, Mackay C, Clark C, Abou-Saleh M. 2008. “Corpus callosum damage in heavy marijuana use: Preliminary evidence from diffusion tensor tractography and tract-based spatial statistics” NeuroImage 41(3): 1067-1074 in dropbox

eleven heavy marijuana users who started using marijuana in early adolescence and eleven age matched controls

MD was significantly increased in marijuana users relative to controls in the region of the CC where white matter passes between the prefrontal lobes

Ashtari M, Avants B, Cyckowski L, Cervellione K, Roofeh D, Cook P, Gee J, Sevy S, Kumra S. 2012. “Medial temporal structures and memory functions in adolescents with heavy cannabis use.” J Psychiatr Res. 45(8): 1055-1066

Heavy-cannabis users showed significantly smaller volumes of the right (p< .04) and left (p< .02) hippocampus, but no significant differences in the amygdala region; smaller right correlated with a higher amount of cannabis use

Fourteen treatment-seeking/ clinically-referred male adolescents … mean age of first time cannabis use of 13.1 years (range: 9.0-15.0 years) with an average cannabis use of 5.8 joints per day from mid-to-low socio-economic, low IQ

comorbid conditions, including post-traumatic stress disorder (n = 2), attention deficit/hyperactivity disorder (n = 2), oppositional defiant/conduct disorder (n = 4), and alcohol abuse (n = 5)

Ashton J, Glass M. 2007. “The cannabinoid CB2 receptor as a target for inflammation-dependent neurodegeneration” Curr Neuropharmacol 5(2): 73-80

Endocannabinoids are released following brain injury and may protect against excitotoxic damage during the acute stage of injury. Brain injury also activates microglia in a secondary inflammatory phase of more widespread damage

cannabinoid CB2 receptors are up-regulated during the activation of microglia following brain injury

Taken together, studies show that CB2 is up-regulated during a process in which microglia become primed to proliferate, and then become fully reactive. In addition, CB2 activation appears to prevent or decrease microglial activation. In a rodent model of Alzheimer’s disease microglial activation was completely prevented by administration of a selective CB2 agonist. The presence of CB2 receptors in microglia in the human Alzheimer’s diseased brain suggests that CB2 may provide a novel target for a range of neuropathologies. We conclude that the administration of CB2 agonists and antagonists may differentially alter microglia-dependent neuroinflammation

It has been known since at least 1994 that the cannabinoids can be neuroprotective [4]

activation of pre-synaptic CB1 receptors is known to reduce neurotransmitter release and, hence, excitotoxicity in postsynaptic neurons [36]. Second, CB1 is involved in the regulation of vasodilation, both directly through vascular CB1 receptors and indirectly through the inhibition of the vasoconstrictor endothelin-1 [60, 71]. Third, CB1 receptors are known to regulate the release of pro-inflammatory factors such as NO and TNF-α in the acute phase of injury [18, 55]

Non-steroidal antinflammatory drugs (NSAIDS) inhibit clot formation, and increase haemorrhaging during brain injury [58]

CB2 also regulates B and T Cell differentiation, and the balance of T helper (Th1) pro-inflam-matory to Th2 anti-inflammatory cytokines [82]. In macrophages, CB2 stimulation suppresses proliferation and the release of pro-inflammatory factors such as NO, IL-12p40, and TNF-α, inhibits phagocytosis, and reduces IL-2 signalling to T-cells [9]. CB2 activation also suppresses neutrophil migration and differentiation [47], but induces natural killer cell migration [31]

CB2 regulates inflammation in a diverse range of animal models, a small sample of which includes gastro-intestinal inflammation [38], acute hindpaw inflammation [11], and pulmonary inflammation [5]. CB2-selective agonists have been particularly promising in the treatment of inflammation-induced hyperalgesia [74]

Inflammation was first suspected to be important in chronic neurodegenerative diseases such as Alzheimer’s disease (AD) early last century [14]. However, this view lost favour, largely because of the widespread belief that the blood-brain barrier provides the CNS with a privileged exemption from blood-borne leukocytes and the immune system.

The discovery that microglia are resident immune cells in the brain lead to the breakdown of this view. This was facilitated by the development of modern gene and protein expression technologies in the 1980’s and 1990’s, which lead to the discovery that many mediators of peripheral inflammation are also involved in neurodegenerative processes, including various growth factors, inflammatory chemokines and cytokines, and nitric oxide

When fully activated, microglia are amoeboid and phenotypically indistinguishable from macrophages, and carry out the various roles that macrophages perform in the periphery, including pro- and antiinflammatory functions, and antigen presentation to immune cells

2-AG induced microglial migration in a dibutyryl cAMP sensitive manner. Anandamide and palmitoylethanolamide (PEA) in combination had the same effect, though neither compound did when alone … both 2-AG and anandamide induced BV-2 microglia migration in a concentration dependent manner. Cannabinol and cannabidiol prevented the effect of 2-AG, by blocking CB2 and cannabidiol-sensitive receptors respectively

Microglia may be either neuroprotective or neurotoxic, depending upon the type and extent of exogenous or endogenous stimuli they receive and the phenotype they assume [64]. For instance, in nerve transection models of glutamate injury, microglial activity is central to the healing response [65]. By contrast, IFN-γ primed microglia then treated with LPS will adopt a phenotype adapted for defensive immunity, and hence cytotoxicity. When microglia are not reactive for defensive immune functions, however, they do not release inflammatory cytokines. Stimulation of microglia by growth factors and mitogens (e.g., M-CSF) may induce a proliferative and chemotaxic phenotype, prior to adopting either neuroprotective or neurotoxic phenotypes, depending upon other stimuli

CB2 appears to be expressed to the greatest degree when microglia are primed to proliferate. Given that 2-AG is mitogenic for this microglial phenotype, and that cannabinoids induce microglial migration and could be critical to chemotaxis, it is possible that CB2 regulates not only the cytotoxic properties of activated microglia, but also the neuroprotective properties of microglia. To our knowledge, this has yet to be determined

A further possibility is that release of the immune suppressive cytokine TGF-β is regulated in microglia by CB2. TGF-β is known to play a critical role in the regulation of TNF-α and IL-1 release from microglia [67] as well as in the induction of neuronal proliferation. In addition, Δ9-THC stimulates TGF-β production in peripheral blood lymphocytes via CB2, and TGF-β regulates lymphocyte CB2 receptor expression [22]

It has been known for several years that cannabinoids stimulate neurogenesis in the adult brain [30]. Recently, Palazuelos et al. [54] reported that CB2 receptors are highly expressed in neural progenitors and immature neurons in vitro and in vivo. Stimulation of CB2 in vitro induced neural progenitor cell proliferation and the formation of neurospheres

cannabinoids acting through the CB2 receptor inhibit the release of pro-inflammatory and cytotoxic factors such as IL-1, NO and TNF-α in microglia previously activated for defensive immunity

CB2 receptor activation appears to have benign effects on microglia potentially primed for adaptive immunity and neuroprotection, to block differentiation of microglia into a neurotoxic phenotype, and to inhibit the release of neurotoxic factors when microglia are activated. In addition, CB2 stimulation is pro-neurogenic in areas of adult neurogenesis

In bone tissue, CB2 receptors stimulate osteoblast function and inhibit osteoclasts, leading to increased bone thickness [49]. Potentially useful for osteoporosis, this also has the promise to help control key mechanisms involved in the generation of pain in bone cancer [27]

Auer R, Vittinghoff E, Yaffe K, Kunzi A, Kertesz S, Levine D, Albanese E, Whitmer R, Jacobs D, Sidney S, Glymour M, Pletcher M. 2016. “Association between lifetime marijuana use and cognitive function in middle age The Coronary Artery Risk Development in Young Adults (CARDIA) Study” JAMA Intern Med doi:10.1001/jamainternmed.2015.7841 add to dropbox

a cohort of 5115 black and white men and women aged 18 to 30 years at baseline from March 25, 1985, to June 7, 1986 (year 0), and followed up over 25 years from June 7, 1986, to August 31, 2011… Linear regression was used to adjust for demographic factors, cardiovascular risk factors, tobacco smoking, use of alcohol and illicit drugs, physical activity, depression, and results of the mirror star tracing test (a measure of cognitivefunction) at year 2

Among 3385 participants with cognitive function measurements at the year 25 visit, 2852 (84.3%) reported past marijuana use, but only 392 (11.6%) continued to use marijuana into middle age. Current use of marijuana was associated with worse verbal memory and processing speed; cumulative lifetime exposure was associated with worse performance in all 3 domains of cognitive function. After excluding current users and adjusting for potential confounders, cumulative lifetime exposure to marijuana remained significantly associated with worse verbal memory. For each 5 years of past exposure, verbal memory was 0.13 standardized units lower (95% CI, −0.24 to −0.02; P = .02), corresponding to a mean of 1 of 2 participants remembering 1 word fewer from a list of 15 words for every 5 years of use. After adjustment, we found no associations with lower executive function (–0.03 [95% CI, −0.12 to 0.07]; P = .56) or processing speed (–0.04 [95% CI, −0.16 to 0.08]; P = .51)

he attenuation of the association be-tween marijuanaexposureandall3measuresof cognitive function was seen mostly after adjustment for race and sex strata and
educationallevel.Sensitivityanalysesdemonstratednoevidence of significant interactions by race or sex

In the context of cognitive decline after stroke, Levine et al 34 used a 0.5-SD cutoff for defining a clinically meaning-ful decline in global cognition. The point estimate for verbal memory in our study for those with 5 marijuana-years of ex-posure (0.13 standardized units; 95% CI, −0.24 to −0.02) is of lesser magnitude than the decline found in the study by Levine et al and the confidence interval excludes the 0.5-SD cutoff

we cannot rule out reverse causation as an explanation for our results… factors significantly associated with marijuana use could confound the association

Aupperle R, Melrose A, Stein M, Paulus M. 2012. “Executive function and PTSD: disengaging from trauma” Neuropharmacology 62: 686-694 in dropbox

estimated 50-60% of people will experience a serious trauma as a result of combat, sexual assault, major accidents, or other real-life horrors at some point in their lives (Kessler et al., 1995). However, only 5-10% of people are estimated to develop symptoms qualifying them for diagnosis of posttraumatic stress disorder (PTSD)

William James, in The Principles of Psychology, defined attention as “the taking possession by the mind, in clear and vivid form, of one out of what seem several simultaneously possible objects or trains of thought” (James, 1890 ). He went on to say that “It implies withdrawal from some things in order to deal effectively with others. ”

1) attention, or the voluntary allocation of processing resources or focusing of one ’s mind on a particular stimulus within the environment, 2) working memory, or the active maintenance and manipulation of information in one’s mind over a short period of time, 3) sustained attention , or the maintenance of attention on one set of stimuli or a task for a prolonged period, 4) inhibitory function, involving the inhibition of automatic responses to maintain goal-directed behavior, 5) flexibility /switching, or the ability to switch between two different task s or strategies, and 6) planning ,or the ability to develop and implement strategic behaviors to obtain a future goal

attentional modification programs may be beneficial in the treatment of anxiety disorders (Amir et al., 2009a; Li et al., 2008; Schmidt et al., 2009; Amir et al., 2009b; Najmi and Amir, 2010; Amir et al., 2008). This suggests that research related to attention and working memory function may not only increase our understanding of PTSD, but may also lead to more effective treatments for these patients

usually impossible to determine whether any observed cognitive dysfunctions represent pre-trauma risk and resiliency factors or if they represent responses to the experience of trauma or PTSD

pre-trauma performances on immediate and delayed verbal recall (California Verbal Learning Test [CVLT]) (Delis et al., 1988), working memory (digit span backward), visuomotor speed (Symbol Digit Modalities Test [SDMT]) ( Smith, 1982), and verbal intelligence (National Adult Reading Test [NART]) ( Nelson, 1982; Nelson and Willison, 1991) was negatively related to post-trauma PTSD re-experiencing and arousal symptoms

Measures of overall IQ, verbal memory (immediate and delayed recall), attention (digit span) (Wechsler, 1987), and executive function (Wisconsin Card-Sorting Test [WCST]) ( Heaton, 1981) performance was decreased not only for the PTSD group, but also their twins, compared to the non-PTSD group and their twins. These results provide further support that lower pre-trauma cognitive functioning particularly in domains of attention, executive function, and memory may serve as a risk factor for the development of PTSD

cognitive function (e.g., learning and memory) found to correlate with PTSD severity above and beyond that accounted for by premorbid IQ (Vasterling et al., 2002; Gilbertson et al., 2001)

A decrease in specific cognitive functions pre-trauma may not only influence the development of PTSD, but may itself be exacerbated by the experience of trauma

Decreased performance on measures of auditory attention and working memory have been found in combat- and sexual assault- related PTSD when compared to victims without PTSD and non-trauma controls (Samuelson et al., 2006; Brandes et al., 2002; Gilbertson et al., 2001; Vasterling et al., 1998, 2002; Marmar et al., 2006; Lagarde et al., 2010; Gilbertson et al., 20 01; Jenkins et al., 2000), and these deficits have been reported to correlate with PTSD symptom severity (Burriss et al., 20 08)

it is unclear whether PTSD is associated with primary problems in attention and working memory, or whether the inconsistent findings are due to difficulties coping with and inhibiting unintentional “distracters”, such as internal (e.g., emotions, cognitions) or external stimuli (e.g., environmental sounds and sights; stimuli presented in previous tasks)

Studies have repeatedly found PTSD patients to exhibit impaired performance (e.g., increased omissions, commissions, or reaction time) in auditory and visual sustained attention (Vasterling et al., 1998; McFarlane et al., 1993; Wu et al., 2010; Shucard et al., 20 08; Jenkins et al., 20 0 0; Vasterling et al., 20 02 ); except see (Golier et al., 1997 ), and the number of correct hits has
been reported to negatively correlate with PTSD symptom severity (Vasterling et al., 20 02 ).

Impaired performance on the color-word Stroop has been reported for various PTSD populations, though it is unclear whether such a deficit is specific to PTSD or a more general impairment across psychiatric disorders (Lagarde et al., 2010; Litz et al., 1996). Interestingly, several studies have also reported PTSD to be associated with increased intrusions during memory recall (Vasterling et al., 1998; Lindauer et al., 2006)

Heightened arousal and re-experiencing symptoms could create more distracters when an individual is attempting to concentrate on the task at hand, thereby interrupting working memory, sustained attention, and inhibitory functions. However, it is also possible that primary inhibitory dysfunction could result not only in decreased performance on cognitive task s, but also impaired ability to inhibit emotional memories and physiological arousal in response to triggers

Neuropsychological research therefore seems to provide inconsistent support for impairment in speed-reliant, attentional switching, but indicates that planning, rule-learning, and untimed strategy switching, may be mostly spared in PTSD

recall of emotional autobiographical events does not influence working memory function any more for PTSD patients than controls

Two studies have been conducted thus far to examine decision making in PTSD patients, both of which found PTSD to be associated with an increase in the number of trials needed to learn optimal patterns of responding (Sailer et al., 20 08; Koenen et al., 20 01)

hyperactivation within limbic regions (particularly amygdala and insula) and hypoactivation of prefrontal regions, including anterior cingulate (ACC; including both rostral and dorsal) and ventromedial prefrontal cortex (vMPFC)

The lateral PFC specifically has been implicated in response inhibition whether it be emotional or non-emotional contexts (Compton et al., 2003; Bledowski et al., 2010). However, the ACC may have some specialization in this regard, as more ventral regions are thought to be primarily involved in inhibition of responses to emotional stimuli, while more dorsal regions are thought to be involved in the inhibition of neutral information (Whalen et al., 1998; Bush et al., 1998; Mohanty et al., 2007; Yamasaki et al., 2002; Fichtenholtz et al., 2004)

PTSD has been associated with increased activation in dorsal ACC and other PFC regions during an auditory oddball task ( Bryant et al., 2005). However, during the go-nogo task , PTSD patients exhibited reduced activation in the inferior frontal and ventral and dorsal lateral PFC, as well the medial OFC ( Falconer et al., 2008 )

PTSD may be associated with hyperactivation of prefrontal areas in response to simple sustained attention tasks, but relative hypoactivation during tasks involving inhibition or “updating” . The former could re flect the hypervigilance and enhanced attention towards“triggers ” associated with PTSD, while the latter could relate to decreased ability to control or inhibit these attentional resources

Attention modification has been effective in reducing symptoms in social anxiety (Li et al., 2008; Schmidt et al., 2009; Amir et al., 2008), generalized anxiety (Amir et al., 2009b ), and sub-clinical obsessive-compulsive disorder (Najmi and Amir, 2010)

if you can ’t inhibit it avoid it

Avitsur R, Stark J, Sheridan J. 2001. “Social stress induces glucocorticoid resistance in subordinate animals” Horm Behav 39(4): 247-57

elevated levels of serum corticosterone and nerve growth factor (NGF). Repeated exposure to an intruder induced a state of glucocorticoid resistance in peripheral immune cells

it may be that the development of glucocorticoid resistance is an adaptive mechanism that allows the inflammatory component of wound healing to occur in the presence of high levels of corticosterone

Azad S, Monory K, Marsicano G, Cravatt B, Lutz B, Zieglgansberg W, Rammes G. 2004. “Circuitry for associative plasticity in the amygdala involves endocannabinoid signaling” J Neurosci 24(44):9953-61

Endocannabinoids are crucial for the extinction of aversive memories. 100 pulses at 1 Hz to afferents in lateral amygdala releases anandamide postsynaptically from neurons in basolateral amygdala of mice in vitro, inducing long-term depression (LTDi) of GABA, which increases amplitude of excitatory currents in principal neurons of central nucleus. LTDi abolished by CB1 antagonist and in receptor-deficient animals. Enhanced in animals lacking FAAH.
could provide a prerequisite for extinction by formation of new memory

Bäckhed F, Roswall J, Peng Y, Feng Q, Jia H, Kovatcheva-Datchary P, Li Y, Xia Y, Xie H, Zhong H, Khan M, Zhang J, Li J, Xiao L, Al-Aama J, Zhang D, Lee Y, Kotowska D, Colding C, Tremaroli V, Yin Y, Bergman S, Xu X, Madsen L, Kristiansen K, Dahlgren J, Wang J. 2015. “Dynamics and stabilization of the human gut microbiome during the first year of life” Cell Host & Microbe 17: 690-703 add to dropbox

In contrast to vaginally delivered infants, the gut microbiota of infant s delivered by C-section showed significantly less resemblance to their mothers. Nutrition had a major impact on early microbiota composition and function, with cessation of breast-feeding, rather than introduction of solid food, being required for maturation into an adult-like microbiota

Compared with vaginally born infants, the C-section fecal microbiome was enriched in MetaOTUs such as Enterobacter hormaechei/E. cancerogenus, Haemophilus parainfluenzae/H.aegyptius/H. influenzae/H. haemolyticus, Staphylococcus saprophyticus/S. lugdunensis/S. auereus, Streptococcus australis and Veillonella dispar/V. parvula, indicating that skin and oral microbes, but also baceria from the surrounding environment during delivery, were the first colonizersin these infants. In contrast, the gut microbiota of vaginally delivered newborns were enriched in microbes from the genera Bacteroides, Bifidobacterium, Parabacteroides, Escherichia/Shigella, which were also the most abundant members of the newborns’ gut microbiota. … The difference between delivery modes gradually decreased at 4 months and then 12 months of age, but the C-section infants remained more heterogeneous compared to the vaginally born infants.

most of the early colonizers of the newborn gut originate from the mother and the mode of birth is an important factor shaping the gut microbiota of term infants in early life

The gut microbiome is an important producer of vitamins. All newborns in Sweden receive prophylactic vitamin K injections to avoid classic hemorrhagic disease. We observed enriched levels of genes for vitamin K2 (menaquinone) synthesis in newborns, which correlated with the high abundance of Bacteroides and Escherichia/Shigella, known vitamin K2 producers. Vitamin K2 is important for bone and heart health, and the microbime was recently described to modulate bone homeostasis. Metabolism of retinol was also most enriched in the newborns, with implications in several essential developmental processes such as vision, bone and teeth. Vitamins from the so-called B complex are needed for the body to convert nutrients into glucose and produce energy. Folate (vitamin B9) is one of the essential B vitamins involved in DNA snthesis and repair. Folate biosynthetic genes were significantly enriched in newborns. Genes for pyridoxal (vintamin B6) and biotin (vitamin B7) synthesis were also significantly enriched in newborns. In contrast, thiamine, pantothenate and cobalamin (vitamins B1, B5, and B12, respectively) biosynthetic genes increased with age, consistent with a previous study. However, modules for vitamin B12 transport system were strongly increased in the newborn metagenome, but decreased with age. Similarly, transporters for iron, hemin and heme, which are linked to vitamin B12 synthesis and important for iron metabolism, were also increased in the microbiome of newborns.

Exclusively breast fed infants (at 4 months) had increased levels of taxa that are used as probiotics such as L. johnsonii/L.gasseri, L. paracasei/L. casei, and B. longum. Four-month-old formulat-fed infants had elevated levels of Clostridium difficile, Granulicatella adiacens, Citrobacer spp., Enterobacter cloacae, Bilophila wadsworthia, in agreement with previous studies… formula fed infants were enriched in functions found in the adult microbiome, such as bile acid biosynthesis and methanogenesis. According to the CAZy database, formula-fed infants exhibited an overrepresentation of GH86, GH116, PL1, and PL2, which are beta-agarase or beta-porphyranase and pectate lyase. In contrast, the microbiome of infants that were exclusively breast-fed had higher levels of KO modules involved in oxidative phosphorylation and synthesis of B vitamins such as riboflavin, tetrahydrofolate, and biotin and GH119.

… Yatsunenko 2012 authors concluded that the infant microbiome gradually matures into an adult-like structure until the age of 3 years. However, this might be more based on the gut microbiota in the Malawian and Amerindian children, as the 1-year old infants from the UNited States were already as close to the adults as teenagers. In our Swedish cohort, infants at 12 months were more similar to their mothers than were newborn infants or newborns at 4 months. However, differences remained in the gut microbiome between the 1-year-old children and the mothers both compositionally and functionally, awaiting further maturation.

Our results underscore the role of the gut microbiota for the production of essential amino acids and vitamins for the growing infant. While the infant gut microbiota acquired significant capacity to produce amino acids and vitamins after 4 months of life, the increase in transporters capacity indicates that the newborn’s microbiome is poised to the upcoming change in the intestinal environment and progression to a mature profile. Intriguingly, considering evidence that the gut microbiota may affect behavior, many functions of the developing gut microbiome linked to the metabolism of vitamins, iron, and amino acids are also required for normal brain development, thus adding to the possibility that the gut microbiota might affect behavior.

Baker S, Yücel M, Fornito A, Allen N, Lubman D. 2013. “A systematic review of diffusion weighted MRI studies of white matter microstructure in adolescent substance users” Neuroscience and Biobehavioral Reviews 37: 1713-1723 in dropbox

White matter alterations may reflect risk for, rather than result from, substance use.
criticism of DW-MRI a finding of lower FA within a voxel may reflect a more complex fibre tract arrangement and is not necessarily indicative of poorer white matter microstructure (Jeurissen   et   al.,  2012) (Jones   et   al.,  2012)

Bachhuber M, Saloner B, Cunningham C, Barry C. 2014. “Medical cannabis laws and opioid analgesic overdose mortality in the United States, 1999-2010” JAMA Intern Med 174(10): 1668-1673

States with medical cannabis laws had a 24.8% lower mean annual opioid overdose mortality rate which strengthened over time

year 1 (−19.9%), year 2 (−25.2%), year 3 (−23.6%), year 4 (−20.2%), year 5 (−33.7%), and year 6 (−33.3%)

Bakker A, Krauss G, Albert M, Speck C, Jones L, Stark C, Yassa M, Bassett A, Gallagher M. 2012. “Reduction of hippocampal hyperactivity improves cognition in amnestic mild cognitive impairment” Neuron 74(3): 467-474

Ballard M, Bedi G, de Wit H. 2012. “Effects of delta-9-tetrahydrocannabinol on evaluation of emotional images” J Psychopharmacol 26(10): 1289-1298

THC significantly impaired recognition of facial fear and anger, but it only marginally impaired recognition of sadness and happiness. The drug did not consistently affect ratings of emotional scenes. THC’ effects on emotional evaluation were not clearly related to its mood-altering effects. These results support our previous work, and show that THC reduces perception of facial threat. Nevertheless, THC does not appear to positively bias evaluation of emotional stimuli in general

Bambico F, Duranti A, Tontini A, Tarzia G, Gobbi G. 2009. “Endocannabinoids in the treatment of mood disorders: evidence from animal models” Curr Pharm Des 15(14): 1623-46

Among all mental disorders, major depression has the highest rate of prevalence and incidence of morbidity. Currently available antidepressant therapies have limited efficacies; consequently, research on new drugs for the treatment of mood disorders has become increasingly critical. Recent preclinical evidences that cannabinoid agonists and endocannabinoid enhancers, such as the fatty acid amide hydrolase (FAAH) inhibitors, can impact mood regulation have opened a new line of research in antidepressant drug discovery

cannabinoid agonists and endocannabinoid enhancers increase serotonin and noradrenergic neuronal firing activity, increase serotonin release in the hippocampus, as well as promote neurogenesis. Since cannabinoid-derived drugs potentiate monoaminergic neurotransmission and hippocampal neurogenesis through distinct pathways compared to classical antidepressants, they may represent an alternative drug class in the pharmacotherapy of mood and other neuropsychiatric disorders

Barnes G, Barnes M, Patton D. 2005. “Prevalence and predictors of “heavy” marijuana use in a Canadian youth sample” Subst Use Misuse 40(12): 1849-63

high scores on father’s alcoholism and family life stress, and low scores on family cohesion were associated with once a week (12.6% of the sample) versus less cannabis use in sample of youth aged 14–25.

Barkus E, Lewis S. 2008. “Schizotypy and psychosis-like experiences from recreational cannabis in a non-clinical sample” Psychol Med 38(9): 1267-76

schizotypy was associated with increased psychosis-like experiences and after-effects, but also found that high-scoring schizotypes reported more pleasurable experiences when smoking cannabis. Using new subscales derived from principal components analysis (PCA), we found that the psychosis-like items were most related to varying rates of schizotypy both during the immediate use of cannabis and in the after-effects of cannabis use. High-scoring schizotypes who used cannabis experienced more psychosis-like symptoms during and after use

cannabis use may reveal an underlying vulnerability to psychosis in those with high schizotypal traits

Barkus E, Morrison P, Vuletic D, Dickson J, Ell P, Pilowsky L, Brenneisen R, Holt D, Powell J, Kapur S, Murray R. 2011. “Does intravenous Δ9-tetrahydrocannabinol increase dopamine release? A SPET study” J Psychopharmacol 25(11): 1462-8

there were no significant differences in binding index in the caudate or putamen under THC compared to placebo conditions. Positive psychotic symptoms and DA release were unrelated. THC did not lead to a significant increase in DA release even though the dose was sufficient for participants to have psychotic symptoms

Batalla A, Bhattacharyya S, Yücel M, Fusar-Poli P, Crippa J, Nogue S, Torrens M, Pujol J, Farre M, Martin-Santos R. 2013. “Structural and Functional Imaging Studies in Chronic Cannabis Users: A Systematic Review of Adolescent and Adult Findings.”  PLOS ONE doi: 10.1371/journal.pone.0055821

Of the seven studies comparing global brain volume measures between chronic cannabis users and healthy controls, there was only one study reporting significant differences

Block et al. (2000) [157] described reduced bilateral rCBF in the posterior cerebellum and ventral prefrontal cortex but increased rCBF in the anterior cingulate cortex in users. Lundqvist et al. (2001) [158] found a trend of lower global CBF in cannabis users, reduced rCBF in the right prefrontal and superior frontal cortex. Sevy et al. (2008)[159] reported lower glucose metabolism in the right orbitofrontal cortex, putamen bilaterally and precuneus in chronic cannabis users.

Chang et al. (2006) [169] used fMRI to compare a visual-attention task in current and abstinent cannabis users with healthy controls. normal task performance, both active and abstinent chronic cannabis users … decreased activation in the right prefrontal, medial and dorsal parietal cortices and medial cerebellar regions but greater activation in regions throughout the frontal, posterior parietal, occipital and cerebellum. … early age of onset and estimated cumulative cannabis lifetime exposure were both associated with reduced activation in the right prefrontal cortex and medial cerebellum.

Harding et al. (2012) [171] demonstrated long-term heavy cannabis associated with increased functional connectivity between several frontal cortex regions and the occipitoparietal cortex using the Multi-Source Interference Task (MSIT). No differences in behavioural performance were evident between groups.

Gruber et al. (2005) [151] lower anterior cingulate activity and higher mid-cingulate and bilateral dorsolateral prefrontal cortex activity in current cannabis users relative to healthy controls, focal increased activity in right dorsolateral prefrontal cortex. …  Eldreth et al. (2004) [166] found in abstinent cannabis users a reduced anterior cingulate activation using H215O-PET during modified Stroop test; reduced dorsolateral prefrontal cortex activation, greater activation in the hippocampus bilaterally

cannabis users showed enhanced reward anticipation activity in the middle temporal gyrus bilaterally, right cuneus and right parahippocampal gyrus. When compared to tobacco-smokers, cannabis users showed reduced anticipation activity in the same areas, with the exception of the nucleus accumbens bilaterally, the right medial frontal gyrus and the left cingulated gyrus, indicating that anticipation activity in these regions may be attenuated by both cannabis and nicotine  [176]

cannabis users demonstrated relatively lower anterior cingulate and amygdalar activity during the presentation of masked angry stimuli sets relative to the control group, who showed relatively higher activation within these regions. In contrast, cannabis users demonstrated a larger pattern of activation during the presentation of masked happy faces within the cingulate as compared to controls, with no increase in amygdalar activation [170]. Furthermore, the total number of smoking episodes per week was positively associated with cingulate activity during the viewing of masked angry faces and positively associated with amygdalar activity during the viewing of masked happy faces [170]. Finally, overall cannabinoid level was positively related to cingulate activity during the viewing of masked happy faces [170]. … suggest a different way of processing emotional information between groups [170].

In a group of abstinent adolescent cannabis users, Padula et al. (2007) [179] described increased activity in the left temporal gyrus and anterior cingulate cortex but lower activity in right temporal gyrus, thalamus, pulvinar and left parahippocampal gyrus related to higher scores on the task, while the reverse pattern was found in the controls. This may suggest that cannabis users employed more of a verbal strategy to achieve the same level of task performance as the controls [179]. Additionally, cannabis users demonstrated greater performance-related activation in the right basal ganglia, precuneus, postcentral gyrus and bilateral superior parietal lobe [179], again suggesting a compensatory neural effort

groups performed at a similar level; recent users showed greater activity in the medial and left superior prefrontal cortices and bilateral insula while abstinent users demonstrated an increased response in the right precentral gyrus [181]

…in the only study where the chronic cannabis users were not abstinent…

studies that merely compare those subjects exposed to an environmental factor from those that are not, are likely to promote interpretation biases whereby study findings, irrespective of their direction, tend to be interpreted as detrimental

Battisti R, Roodenrys S, Johnstone S, Respondek C, Hermens D, Solowij N. 2010. “Chronic use of cannabis and poor neural efficiency in verbal memory ability” Psychopharmacology 209: 319-330 — add to dropbox

The SME (subsequent memory effect) is predictive of recall outcome and originates in structures that are dense with cannabinoid receptors (hippocampus and parahippocampus). The SME and performance on a verbal memory task were compared between 24 cannabis users (mean 17 years of near daily use) in the unintoxicated state and 24 non-using controls

Cannabis users showed poorer recall and altered patterns of SME activation: specifically, attenuation of the negative N4 and an increase in the late positive component. Duration of use and age of initial use correlated significantly with SME amplitudes. A longer history of use also correlated with greater recall that was related to N4 expression

In studies of acute administration, Roser et al (2008) have recently shown that THC modulates the amplitude of teh mismatch negativity component, an early index of sensory memory; Leweke et al (1998) found enhanced positivity from 250 ms onwards following the presentation of previously learned words in an emotional word recognition task; while Ilan et al (2004, 2005) found attenuated ERP amplitudes, including a reduced N400, in spatial working memory and word recognition tasks. In studies of chronic users during the unintoxicated state, Patrick et al (1999) showed a reduced P50 auditory gating response, and Rentzsch et al (2007) determined that this P50 deficit was also evident in 28 day abstinent chronic cannabis users and correlated with the duration of cannabis use. Kempel et al (2003) found evidence of altered selective attentional proceses indexed by the N2 and P3 components, which were associated with early onset cannabis use. Skosnik et al found larger P300 amplitudes to unpleasant trait words in an affect processing task in one study (Skosnik et al 2008) and altered steady-state visual-evoked potentials in another (Skosnik et al 2006). Wolfling  et al (2008) found a larger late positivity in visual ERPs to drug=related cues. Solowij et al (1991, 1995b) and Solowij (1998) observed differential effects of duration versus frequency of cannabis use in a selective attention task. Frontal processing negativity to irrelevant stimuli increased with the duration of exposure to cannabis in current users and in ex-cannabis users (mean abstinence, 2 years), suggesting persistent chagnes in the brain. P300 latency increased with increasing frequency of use in current users only, suggesting a short-term effect potentially associated with a buildup of cannabinoid residues in the brain.

Inclusion required being between the ages of 18-55 and no history of diagnosis with any psychotic disorder or neurological injury. Required to abstain from use for at least 12 h prior to the test session

Information collected included age, handedness, educational, medical, and mental health (both personal and family) histories, as well as detailed questioning regarding any type of susbstance use (including alcohol and tobacco)

6.5 drinks per week in cannabis group, 2.3 in control. 101.3 WAIS-III-R FSIQ, 106.2 for control. 75% of cannabis users were using 25 days or more per month. Median 30. 435 “cones” per month (one third of a joint)

There were more tobacco smokers within the cannabis-using group, and all but four users mixed their cannabis with tobacco.

Cannabis users recealled significantly fewer words than controls across all word lists presented vs controls. As a proportion, this represents an average reduction of 13.5% in correct recall for users in comparison to controls. The mean words recalled per list by users was 6.87, and for controls, 7.94. Percentage of CR words also correlated marginally significantly with duration of regular cannabis use. A longer history of regular use was associated with a greater number of CR words

overall shift to greater positivity (ie, reduced N4 and increased LPC) among users… users showing a shorter N4 latency than controls (mean difference = 13.88 ms)

Groups did not differe in the nature of the primary encoding strategy used, although controls appeared more likely to use visual imagery and less likely to use rote learning stategies than users, and both groups relied heavily upon categorization… user N4, relative to controls, is attenuated particularly on CR trials frontally and on NR trials parietally… User N4 was greater within the left compared to the right sites, whereas the difference was minimal for controls. This pattern varied significantly with condition. Users had greater overall variability between sites with this particularly evident on NR trials. This pattern was not evident for controls.

Controls showed increased N4 at Fz relative to the lateral sites, with this enhancement of N4 at Fz absent in users. A pattern of reduced N4 for the parietal right (P4) relative to the left hemisphere (P3) was present for users but not controls

Controls had a single correlation only with age and N4 amplitude on correct trials, whereas users had significant correlations for age, IQ, and percentage of CR words with N4 amplitude on both trial types. Higher scores on these variables were related to attenuated N4 (ie, more positive as this is a negative-going component). Positive correlations were observed between N4 amplitudes and age of first cannabis use and age of regular use, and with duration of use, although there wer no observed relationships with quantity of exposure per month, or with levels of cannabinoid metabolites or measures of recency of use or withdrawal scores. Controlling for age resulted in a loss of significance for cannabis usage history variables with N4. However, controlling for duration since first use and duration of regular use on CR and NR trials, respectively, resulted in a loss of significance for the N4 correlation with age, thus indicating relationships to be jointly explainable by age and usage variables. There were no significant correlations with N4 latency or the LPC.

An overall shift to positivity and changes to variability within regions was observed for users on both SME components of interests , with N4 earlier and attenuated and LPC increased. Altered activation of the N4 occurred on CR versus NR trials between the two groups, with a longer history of cannabis use related to attenuated N4. … users showed significantly poorer performance in verbal memory, although poorer word recall performance appeared to correlate with a shorter history of regular use. … Notably, the first 350 ms of the ERPs were similar; however, the critical N4-LPC window showed marked differences across groups and conditions. In particular, the overall shift to greater positivity may be due to N4 peaking earlier for users and interpreted as a general failure to efficiently activate memory-related brain structures

Bava S, Frank L, McQueeny T, Schweinsburg B, Schweinsburg A, Tapert S. 2009. “Altered white matter microstructure in adolescent substance users” Psychiatry Res 173(3): 228-237

36 marijuana and alcohol-using (MJ+ALC) adolescents (ages 16-19) and 36 demographically similar non-using controls evaluated with DTI

MJ+ALC teens had significantly lower FA than controls in 10 regions, including left superior longitudinal fasciculus (SLF), left postcentral gyrus, bilateral crus cerebri, and inferior frontal and temporal white matter tracts. These diminutions occurred in the context of increased FA in right occipital, internal capsule, and SLF regions. Changes in MD were less distributed, but increased MD was evident in the right occipital lobe, whereas the left inferior longitudinal fasciculus showed lower MD in MJ+ALC users

Studies examining brain morphology in marijuana users, particularly within white matter, offer equivocal findings. Although some report no changes in white matter volume and composition in adult users (Block et al., 2000; Gruber and Yurgelun-Todd, 2005), reduced white matter volumes in the left parietal lobe and increased tissue density surrounding the left parahippocampal and fusiform gyri have been documented (Matochik et al., 2005). Whether the reported changes in brain structure among marijuana using adolescents persist into adulthood remains tentative. Increased mean diffusivity in the prefrontal fiber bundles of the corpus callosum in adults who initiated use during early adolescence suggests long-term changes to white matter quality as a result of adolescent marijuana use (Arnone et al., 2008). In conflict with these findings, a DTI study using whole-brain voxelwise analysis of 10 young adults who used moderately as adolescents suggested no loss of white matter integrity relative to non-users (Delisi et al., 2006). Still, another report shows higher fractional anisotropy in the rostral body and isthmus of the corpus callosum in adolescent substance users compared to controls (De Bellis et al., 2008)

Although cannabis can prevent oligodendrocyte death (Molina-Holgado et al., 2002b), early or chronic cannabis exposure may cause a down-regulation of CB-1 receptors and suppress oligodendrocyte function during neurodevelopment

pre-onset use white matter integrity in MJ+ALC users is unknown, and pre-existing vulnerabilities including increased incidence of behavioral dysregulation (Kirisci et al., 2004; Tarter et al., 2003) and negative affectivity (Chassin et al., 2004) may be associated with neurological differences that predispose individuals in this group to substance use. Further, MJ+ALC users were more likely to have a parental history of substance use disorders. Considering that white matter changes in adolescent MJ+ALC users may have predated the onset of use, future follow-ups of this cohort will help determine whether increases in substance use result in greater deviations in white matter microstructure

Beaulieu J-M, Sotnikova T, Marion S, Lefkowitz R, Gainetdinov R, Caron M. 2005. “An Akt/β-Arrestin 2/PP2A signaling complex mediates dopaminergic neurotransmission and behavior Cell 122(2): 261-273

β-arrestin 2 deficiency in mice results in reduction of dopamine-dependent behaviors, loss of Akt regulation by dopamine in the striatum, and disruption of the dopamine-dependent interaction of Akt with its negative regulator, protein phosphatase 2A. Importantly, canonical cAMP-mediated dopamine-receptor signaling is not inhibited in the absence of β-arrestin 2. These results demonstrate that, apart from its classical function in receptor desensitization, β-arrestin 2 also acts as a signaling intermediate through a kinase/phosphatase scaffold

Dysregulation of dopaminergic neurotransmission is associated with multiple neurological and psychiatric conditions such as Parkinson’s disease, Huntington’s disease, attention deficit hyperactivity disorder (ADHD), mood disorders, and schizophrenia (Carlsson, 2001 and Gainetdinov and Caron, 2003). In the mammalian brain, most dopaminergic neurons project from the substantia nigra to the striatum, a major area of basal ganglia mostly populated by medium spiny neurons that are responsive to DA (Greengard, 2001). Two classes of GPCR have been shown to mediate all DA functions. D1 class receptors (D1R and D5R) are mostly coupled to Gαs and positively regulate the production of the second messenger cAMP and the activity of its main neuronal target, protein kinase A (PKA) (Missale et al., 1998). D2 class receptors (D2R, D3R, and D4R) couple to Gαi/o, thus downregulating cAMP production and PKA activity (Missale et al., 1998). Moreover, this class of DA receptors can also modulate intracellular Ca2+ levels (Missale et al., 1998 and Nishi et al., 1997), leading to changes in the activity of Ca2+-regulated signaling proteins such as the protein phosphatase calcineurin (PP2B) (Nishi et al., 1997)

prolonged stimulation of D2 class receptors leads to specific dephosphorylation/inactivation of the serine/threonine kinase Akt on its regulatory Thr308 residue (Beaulieu et al., 2004). Interestingly, phosphorylation of Akt on its second regulatory residue (Ser473) was not affected by DA (Beaulieu et al., 2004). Regulation of Akt by DA was observed in the striatum of mice that display persistently elevated levels of extracellular DA due to a lack of the DA transporter (DAT-KO mice). Similar changes in Akt phosphorylation also occurred in normal mice (wt) treated with direct or indirect DA agonists such as apomorphine or amphetamine (Beaulieu et al., 2004). Moreover, depletion of striatal DA in DAT-KO mice or D2 class-receptor blockade resulted in enhanced phosphorylation/activation of Akt, thus indicating that D2 class receptors are responsible for the regulation of Akt by DA (Beaulieu et al., 2004 and Emamian et al., 2004)

Dephosphorylation of Akt in response to DA leads to a reduction of kinase activity and a concomitant activation of its substrates glycogen synthase kinase 3 α and β (GSK3α and GSK3β) since both are negatively regulated by Akt (Beaulieu et al., 2004 and Cross et al., 1995)… mice lacking one allele of the GSK3β gene show markedly reduced locomotor responses to amphetamine (Beaulieu et al., 2004), while mice lacking the Akt isoform Akt1 display behavioral manifestations generally associated with enhanced dopaminergic responses (Emamian et al., 2004),

GPCR activation and their phosphorylation by GPCR kinases (GRKs), β-arrestins bind to the receptors to uncouple them from G proteins and participate in the recruitment of the endocytic protein complex, thus leading to an attenuation of GPCR signaling (Gainetdinov et al., 2004)

most behavioral actions of DA are thought to be associated with the modulation of adenylate cyclase and PKA activity (Greengard, 2001 and Missale et al., 1998)

we have shown that a β-arrestin 2-mediated kinase/phosphatase scaffolding of Akt and PP2A is responsible for the regulation of Akt by DA receptors

Beaulieu J-M, Gainetdinov R, Caron M. 2007. ‘The Akt-GSK-3 signaling cascade in the actions of dopamine” Trends Pharmacol Sci 28(4): 166-72

Classically, dopamine receptors have been shown to regulate cAMP-PKA (protein kinase A) and Ca(2+) pathways through G-protein-mediated signaling. However, it has become apparent that, in addition to this canonical action, D(2)-class dopamine receptors can function through a protein kinase B (Akt)-GSK-3 (glycogen synthase kinase 3) signaling cascade

Bechtold J, Simpson T, White H, Pardini D. 2015. “Chronic adolescent marijuana use as a risk factor for physical and mental health problems in young adult men” Psychology of Addictive Behaviors 29(3): 552-563

Findings from latent class growth curve analysis identified 4 distinct subgroups of marijuana users: early onset chronic users, late increasing users, adolescence-limited users, and low/nonusers. Results indicated that the 4 marijuana use trajectory groups were not significantly different in terms of their physical and mental health problems assessed in the mid-30s

Becker M, Collins P, Luciana M. 2014. “Neurocognition in college-aged daily marijuana users” Journal of Clinical and Experimental Neuropsychology 36(4): 379-398

Marijuana users were high functioning, demonstrating comparable IQs to controls and relatively better processing speed. Marijuana users demonstrated relative cognitive impairments in verbal memory, spatial working memory, spatial planning, and motivated decision making. Comorbid use of alcohol, which was heavier in marijuana users, was unexpectedly found to be associated with better performance in some of these areas

Behan B, Connolly C, Datwani S, Doucet M, Ivanovic J, Morioka R, Stone A, Watts R, Smyth B, Garavan H. 2013. “Response inhibition and elevated parietal-cerebellar correlations in chronic adolescent cannabis users” Neuropharmacology 84:131-7

a cohort of adolescent heavy cannabis users and age-matched non-cannabis -using controls completed a Go/No-Go paradigm. Users were impaired in performance on the task but voxel-wise and region-of-interest comparisons revealed no activation differences between groups. Instead, an analysis of correlation patterns between task-activated areas revea led heightened correlation scores in the users between bilateral inferior parietal lobules and the left cerebellum. The increased correlation activity between these regions was replicated with resting state fMRI data

Seventeen current cannabis users (1 female, mean age: 16.5, range 15 e18) and 18 comparison subjects (1 female, mean age: 16.1, range 14 e19) took part in the experiment. Participants were screened for no history of neurological/psychiatric illness or any past loss of consciousness which required hospitalization. All partic-ipants were right-handed. Users were recruited from several drug treatment centres in Dublin, Ireland and were being treated for cannabis dependency at the time of scanning

Groups significantly differed (t(33) ¼ 2.938, p < 0.01) on intellectual ability (as measured by the word reading section from the wide range achievement test 4 (WRAT 4)) with cannabis users displaying lower scores. Cannabis users also exhibited higher scores for current levels of stress (t(32) ¼ 2.20 4, p < 0.05) and anxiety (t(32) ¼ 2.228, p < 0.05) as indexed by the Depression Anxiety Stress Scales (DASS)…  the cannabis-using group contained more smokers and these had smoked more cigarettes in the week and month prior to participation

increased correlations between parietal and cerebellar regions. This effect was replicated in resting state fMRI data acquired during the same session indicating that the significant correlation pattern between the parietal and cerebellar regions was not solely a response to a particular task demand but may, instead, re fl ect an intrinsic feature of the connectivity of the adolescent cannabis user ’s brain

A potentially unfavourable over-reliance on the cerebellum during cognitive task s has been previously demonstrated in cocaine users ( Hester and Garavan, 20 0 4)…  Desmond et al., 20 03 reported that alcohol-dependent subjects demonstrated increased activation of the right cerebellum, as well as the lef t prefrontal cortex, during a working memory task and maintained similar performance levels to controls… the cerebellum might compensate when other task-related regions are not engaged… we identified lower correlation scores within the cannabis-using group between networks comprising right inferior frontal and right middle frontal gyri… the adolescent cannabis users in the present study did not show increased activity in the cerebellum, only increased correlations with fronto-parietal cortex… with CB1 receptors highly expressed in the cerebellum and previous reports indicating that cerebellar-mediated processes such as eyeblink conditioning are disrupted in young adult cannabis users, any pu-tative compensatory mechanism involving the cerebellum may be disrupted by heavy cannabis use (Quickfall and Crockford, 20 0 6; Skosnik et al., 20 08 ).

cerebral blood volume measures, taken at rest, have been recorded in adult cannabis users following cessation of use (Sneider et al., 20 0 6, 20 08). At day 0 and following seven days of abstinence, users exhibited increased blood volume differences in frontal, temporal and cerebellar areas. However, following 28 days of abstinence, only a lef t temporal area and the cerebellum still displayed increased blood volume rates in users. Such long-lasting cerebellar alterations have been supported by previous structural imaging work demonstrating increased grey matter vermis volumes in adolescent cannabis users following one month of abstinence (Medina et al., 2010 ). Similar differences in cerebellar structure in adult users have also been noted ( Cousijn et al., 2012). It also appears that development of the cerebellum is not as heavily determined by genes as are other brain regions and thus this structure may be particularly vulnerable to environmental conditions (Wallace et al., 20 0 6).

it is acknowledged that the use of other drugs may have impacted upon response inhibition functioning. For example, two recent studies have demonstrated that adult smokers displayed signifi cantly poorer performance levels on Go/No-Go task s (Luijten et al., 2011; Nestor et al., 2011). …  there may be some argument that these are not adequate sample sizes for such an investigation

Beltramo M, de Fonseca F, Navarro M, Calignano A, Gorriti M, Grammatikopoulos G, Sadile A, Giuffrida A, Piomelli D. 2000. “Reversal of dopamine D(2) receptor responses by an anandamide transport inhibitor” J Neurosci 20(9): 3401-7

We characterized the pharmacological properties of the anandamide transport inhibitor N-(4-hydroxyphenyl)-arachidonamide (AM404) in rats and investigated the effects of this drug on behavioral responses associated with activation of dopamine D(2) family receptors

AM404 caused a mild and slow-developing hypokinesia that was significant 60 min after intracerebroventricular injection of the drug and was reversed by the CB1 cannabinoid receptor antagonist SR141716A

AM404 prevented the stereotypic yawning produced by systemic administration of a low dose of apomorphine, an effect that was dose-dependent and blocked by SR141716A. Furthermore, AM404 reduced the stimulation of motor behaviors elicited by the selective D(2) family receptor agonist quinpirole. Finally, AM404 reduced hyperactivity in juvenile spontaneously hypertensive rats, a putative model of attention deficit hyperactivity disorder. The results support a primary role of the endocannabinoid system in the regulation of psychomotor activity and point to anandamide transport as a potential target for neuropsychiatric medicines

Bénard G, Massa F, Puente N, Lourenco J, Bellocchio L, Soria-Gomez E, Matias I, Delamarre A, Metna-Laurent M, Cannich A, Hebert-Chatelain E, Mulle C, Ortega-Gutierrez S, Martin-Fontecha M, Klugmann M, Guggenhuber S, Lutz B, Gertsch J, Chaouloff F, Lopez-Rodriguez M, Grandes P, Rossignol R, Marsicano G. 2012. “Mitochondrial CB1 receptors regulate neuronal energy metabolism” Nat Neurosci 15(4): 558-64 add to dropbox

The mammalian brain is one of the organs with the highest energy demands, and mitochondria are key determinants of its functions. Here we show that the type-1 cannabinoid receptor (CB1) is present at the membranes of mouse neuronal mitochondria (mtCB1), where it directly controls cellular respiration and energy production. Through activation of mtCB1 receptors, exogenous cannabinoids and in situ endocannabinoids decreased cyclic AMP concentration, protein kinase A activity, complex I enzymatic activity and respiration in neuronal mitochondria. In addition, intracellular CB1 receptors and mitochondrial mechanisms contributed to endocannabinoid-dependent depolarization-induced suppression of inhibition in the hippocampus

The brain represents only 2% of the total body weight in mammals, but it consumes up to 20% of the body’s resting energy production

several reports have shown the intramitochondrial localization of potential downstream effectors of G protein signaling, such as soluble adenylyl cyclase, phosphodiesterase, and protein kinase A (PKA). Thus, cAMP can be produced in mitochondria, leading to activation of PKA and phosphorylation of mitochondrial proteins, eventually regulating mitochondrial respiration and energy production… mechanisms coupling mitochondrial activity and neuronal physiology, remain poorly understood

CB1 receptor signaling typically involves reduction of cAMP, and mitochondrial forms of adenylyl cyclase and protein kinase A (PKA) have been suggested to regulated complex I activity and mitochondrial respiration. Acute THC treatment decreased mitochondrial cAMP by approximately 30%

Brain mitochondria have substantial levels of endocannabinoid degrading activity

only the activation of intracellular CB1 receptors affects mitochondrial respiration of living cells

CB1 GPCR is present in a portion (approximately 30% in the hippocampus) of brain neuronal mitochondria

The open source program MitoProt II (ref 35) predicted the CB1 receptor protein to bear a 39.3% probability of mitochondrial localization. This theoretical value is much higher than that of many GPCRs and is comparable to the values of several known or recently identified mitochondrial proteins. … The proportion of CB1 receptors located on the mitochondrial membrane (approximately 15% of total cell CB1 receptors) might seem low. However, this expression accounts for up to 30% of mtCB1 dependent reduction of respiration in purified brain mitochondria.

Although a minimal amount (less than 10% of total cortical CB1 receptor proteins are expressed in glutamatergic neurons, many of the functions of the endocannabinoid system are exerted by this limited percentage of receptors. For instance, protection against excitotoxic seizures or the orexigenic properties of endocannabinoid signaling are mainly exerted by glutamatergic-neuron CB1 receptors

DSI is short-lasting (a few tens of seconds), likely due to efficient endogenous degradation of endocannabinoids. Conversely, drug applications (especially of lipphilic cannabinoids) are generally long-lasting, their duration depending only on pharmacokinetics properties of the drug, and might induce extra effects. From the spatial point of view, the moilization of endocannabinoids by depolarization and/or synaptic stimulation might be limited to specific cellular subdomains. Conversely, exogenous cannabinoids might display preference for other subdomains, thereby triggering different mechanisms. Finally, depolarization steps able to endogenously mobilize endocannabinoids might trigger other, so far unknown cellular events to favor additional means of endocannabinoid signaling, which would otherwise remain silent.

Berk M, Williams L, Jacka F, O’Neil A, Pasco J, Moylan S, Allen N, Stuart A, Hayley A, Byrne M, Maes M. 2013. “So depression is an inflammatory disease, but where does the inflammation come from?” BMC Medicine 11:200

A range of factors appear to increase the risk for the development of depression, and seem to be associated with systemic inflammation; these include psychosocial stressors, poor diet, physical inactivity, obesity, smoking, altered gut permeability, atopy, dental cares, sleep and vitamin D deficiency

the above mentioned sources of inflammation may play a role in other psychiatric disorders, such as bipolar disorder, schizophrenia, autism and post-traumatic stress disorder

There is now an extensive body of data showing that depression is associated with both a chronic low-grade inflammatory response, activation of cell-mediated immunity and activation of the compensatory anti-inflammatory reflex system (CIRS), characterized by negative immunoregulatory processes [1,2]. New evidence shows that clinical depression is accompanied by increased oxidative and nitrosative stress (O&NS) and autoimmune responses directed against O&NS modified neoepitopes [3,4].

cytokines induce depressive-like behaviors; in studies where healthy participants are given endotoxin infusions to trigger cytokines release, classical depressive symptoms emerge [7]. Exogenous cytokine infusions also cause the classical phenotypic behavioral and cognitive features of depression. As an exemplar, a quarter of the people given interferon for the treatment of hepatitis C develop emergent major depression [8,9]

remission of clinical depression is accompanied by a normalization of inflammatory markers [15], while lack of response is associated with persistently elevated levels of inflammatory markers [16]

These data beg the question

many inflammatory disorders (chronic obstructive pulmonary disease, cardiovascular disease (CVD) and autoimmune disorders) and neuroinflammatory disorders (multiple sclerosis and Parkinson’s disorder) and inflammatory conditions (hemodialysis and the postpartum period) may trigger clinical depression [17]. However, these factors are only present in a small percentage of the larger population of depressed individuals

Psychosocial stressors, including acute psychological trauma or more sub-chronic stressors, and early exposure to childhood trauma robustly increase the risk of developing clinical depression and mood symptoms, while impacting neuro-immune circuits

In humans, there is evidence that different types of psychosocial stressors may stimulate the pro-inflammatory cytokine network, including increases in IL-6 and TNFα [2528]. Maes et al. [28,29] were the first to report that stress-induced increases in IFNγ and stress-induced Th1 dominance were significantly correlated with stress-induced anxiety and distress. Thus, subjects with psychological stress-induced distress and anxiety showed significantly greater increases in IFNγ and lower IL-10 than those without distress and anxiety. Psychosocial stress is also accompanied by lowered levels of endogenous, anti-inflammatory compounds, for example, CC16 (uteroglobuline), which decreases the production of IFNγ [30]. Individuals showing stress-induced decreases in CC16 in the serum display higher stress-induced anxiety and distress, and an increased production of IFNγ during the stress condition [29,30]. Thus, stress-induced increases in pro-inflammatory and Th1-like cytokines may be mediated by lowered levels of endogenous anti-inflammatory compounds, such as CC16. Stress-induced production of pro-inflammatory cytokines, for example, TNFα and IL-6, and Th1-like cytokines, for example, IFNγ, are related to an increased number of leukocytes and neutrophils, and expression of immune cell activation markers, including CD2+CD26+ and CD2+HLADR, and different signs of an acute phase response [29]. This indicates that psychosocial stress-induced elevations in pro-inflammatory cytokines orchestrate stress-induced changes in peripheral blood immune cells, inflammatory reactions and neurobehavioral changes

psychosocial stressors and acute psychotrauma may trigger mood disorders in vulnerable subjects, for example, those with immune gene polymorphisms, lowered levels of pepdidases, including dipeptidylpeptidase and prolylendopeptidase, and those with increased inflammatory burden [31]

individuals experiencing stress in childhood resulting from maltreatment, abuse, social isolation and economic hardship are twice as likely to suffer chronic inflammation [32]. The detrimental impact of adversity on health in adulthood has also been demonstrated in US populations. Kiecolt-Glaser [33] found that childhood adversity can shorten the lifespan by 7 to 15 years, arguing that stress associated with abuse, death of a parent or parental relationship problems can lead to inflammation and premature cell aging, when compared with individuals who have not experienced such adversity. Miller et al. [34], in a further study focusing on depression outcomes, compared C-Reactive Protein (CRP) and IL-6 levels of women with and without history of childhood adversity; the former group was shown to have a greater likelihood of depression, recording higher levels of inflammation using these biomarkers. Studies exploring the influence of stress on other inflammatory diseases, such as CVD [35] and metabolic syndrome [36], have consistently shown similar trends

the association between childhood adversity and vulnerability to inflammatory disease cannot fully be explained by a prolonged period of stress initiated by such an event. Rather, it is possible that learned, maladaptive responses to stress occurring in early childhood are also employed later in adult life in response to stressors. Thus, stress in adulthood has become of increasing interest as an instrumental risk factor for disease onset

Slavich et al. [38] found that responses to social stress via neural activity lead to marked increases in inflammatory activity. Similarly, Emeny[39] found job strain to have a direct effect on inflammation, and to influence other risk factors for inflammation. Job strain is known as a risk factor for other inflammatory diseases, such as CVD, and more recently has been shown to be strongly associated with depression risk [40]. Indeed, it is clear that understanding modifiable risk factors related to stress (and lifestyle) may be an important step in the prevention of inflammatory diseases like depression

habitual or regular exercise protects against the development of new depressive illnesses [8284], and that physical inactivity during childhood is associated with an increased risk of depression in adulthood [85]

Acute exercise generates reactive oxygen species (ROS) [93] and inflammatory cytokines [94] that can transiently damage muscle cells, causing muscle fatigue, pain and inflammation. Contracting skeletal muscle produces a number of ‘myokines’, such as IL-6 [95], which impact systemically on lipid and glucose metabolism [96]. The pattern of inflammatory markers produced during acute exercise, characterized by a rapid elevation in levels of IL-6 that is quickly followed by induction of anti-inflammatory substances, including IL-1ra, IL-10 and soluble tumor necrosis factor receptor (sTNF-R) [97], differs markedly from that in other inflammatory conditions, such as sepsis. Recovery after the exercise-induced IL-6 spike dampens the inflammatory response and oxidative burst activity[98]. Chronic or regular exercise, therefore, down-regulates systemic inflammation via homeostatic adaptation [99]. Similarly, fitness and exercise reduces leptin [100], elevated levels of which are also implicated in the development of depression [101] and is the most evidence-based management strategy for insulin resistance [102]

Depression has also been shown to predispose to obesity in a bidirectional manner [112]. A recent meta-analysis of prospective cohort studies found obesity to increase the risk of later depression by 55%, while depression increased the risk of developing obesity by 58% [113]

Altered adipocyte function, fatty acid levels, leptin and hypothalamic pituitary adrenal (HPA) axis dysfunction and oxidative stress are hypothesized to play a crucial but synergistic role in obesity-associated inflammation [114]

Clinical depression has recently been shown to be accompanied by increased plasma levels of immunoglobulin (Ig) A and/or IgM directed against a number of gram negative bacteria, including Hafnia alvei, Pseudomonas aeruginosa,Morganella morganii, Proteus mirabilis, Pseudomonas putida, Citrobacter koseri and Klebsielle pneumoniae[138140]. All these gram negative bacteria belong to the normal gut flora [141,142]

An increased permeability of the gut wall may allow poorly invasive gram negative bacteria to translocate into the mesenteric lymph nodes (MLNs) and sometimes into the systemic circulation [148,149]. Consequently, in the systemic circulation, IgM and IgA responses are mounted against the LPS of the bacterial wall, while IgA responses may be mounted even when the bacteria do not reach the blood stream, but only translocate into the MLNs

IgE response to common allergen exposure, leading to the development of allergic symptoms, such as asthma, eczema or allergic rhinitis/hay fever is defined as atopy [157]. The prevalence of atopic disorders has been steadily increasing over the past few decades [158,159]. Interestingly, atopy and depression have recently been linked. Although methodologies differ among studies, it has been consistently reported that atopic disorders are associated with an increased risk of both clinical depression and depressive symptomatology in clinical settings [160163]. Population-based studies provide further support, showing a positive association between depression and atopic disorders [164168]

It is estimated that up to 80 to 90% of individuals who suffer from a MDD also experience sleep disturbances [194196]

Smith and Maes in 1995 launched the monocyte-T lymphocyte theory of schizophrenia, which considered that activation of immuno-inflammatory processes may explain the neurodevelopmental pathology related to gestational infections. Results of recent meta-analyses showed that schizophrenia is accompanied by activation of inflammatory and cell mediated pathways [234]. PTSD patients also show higher levels of pro-inflammatory cytokines, including IL-1[235], IL-6 [236,237] and TNFα [238]

he strong associations among schizophrenia and smoking [240], obesity [241], some atopic disorders [242], sleep disorders [243] and poor periodontal and oral health [244,245] may further contribute to the inflammatory burden in schizophrenia patients

Berman R, Cappiello A, Anand A, Oren D, Heninger G, Charney D, Krystal J. 1999. “Antidepressant effects of ketamine in depressed patients” Biological Psychiatry 47(4): 351-354

Bersani G, Orlandi V, Kotzalidis G, Pancheri P. 2002. “Cannabis and schizophrenia: impact on onset, course, psychopathology and outcomes” Eur Arch Psychiatry Clin Neurosci 252(2): 86-92

Family history positive for psychosis was more frequent in consumers, especially when consumption started before onset of schizophrenia. Subjects whose onset of schizophrenia preceded the beginning of cannabis abuse had more positive symptoms than those who started abuse before the onset of schizophrenia

had less negative symptoms than nonabusers

Beylin A, Shors T. 2003. “Glucocorticoids are necessary for enhancing the acquisition of associative memories after acute stressful experience” Horm Behav 43(1): 124-131

Exposure to acute stressful experience can enhance the later ability to acquire new memories about associations between stimuli. This enhanced learning is observed during classical eyeblink conditioning of both hippocampal-dependent and -independent learning. It can be induced within minutes of the stressful event and persists for days. Here we examined the role of the major stress hormones glucocorticoids in the enhancement of learning after stress

one injection of stress levels of corticosterone enhanced new learning within minutes but not new learning 24 h later

In the case of glucocorticoids, exogenous administration enhances some processes of learning (Sandi and Rose, 1997; Roozendaal and McGaugh, 1997b), whereas removal via adrenalectomy (ADX) has been associated with learning impairments (Conrad and Roy, 1995;Pugh et al., 1997; Vaher et al., 1994). In previous studies, we found a positive correlation between basal levels of glucocorticoids during training and acquisition of trace memories in male rats (Wood et al., 2001). The medullary substances epinephrine and norepinephrine have also been associated with enhanced performance on learning tasks, whereas antagonism of their receptors can be detrimental (Gamaro et al., 1997; Leon, 1998; Roozendaal et al., 1996)

stress-induced enhancement of conditioning can be mimicked by an acute exposure to glucocorticoids, but the effect does not persist, as it does after exposure to the acute tailshock stress

training with both delay and trace conditioning increases the observation of dendritic spines in area CA1 of the hippocampus (Leuner et al., 2002)

reports that glucocorticoids impair processes of retrieval and in some cases acquisition, at least during spatial navigation learning (de Quervain et al., 1998;Diamond and Rose, 1994; Kim et al., 2001; Kim and Diamond, 2002)

Bhattacharyya S, Atakan Z, Martin-Santos R, Crippa J, Kambeitz J, Prata D, Williams S, Brammer M, Collier D, McGuire P. 2012. “Preliminary report of biological basis of sensitivity to the effects of cannabis on psychosis: AKT1 and DAT1 genotype modulates the effects of d-9-tetrahydrocannabinol on midbrain and striatal function” Molecular Psychiatry 17: 1152-1155

Cannabis use can induce acute psychotic symptoms 1 and increase the long-term risk of schizophrenia2

The human DAT1 gene has a polymorphic 40 bp variable number of tandem repeats (VNTR) in the 3′ untranslated region (UTR), with several alleles ranging from 3 to 11 copies of the 40-bp repeats, the 9-repeat and 10-repeat alleles being the most common. The DAT1 3′ UTR VNTR modulates activity in the striatum 7,9 and midbrain, 9 and its 9-repeat allele is asso-ciated with higher synaptic dopamine levels than the 10-repeat counterpart. 10 AKT1 has recently been impli-cated in mediating the effects of cannabis on psycho-sis, 11 and variants of both genes have been linked with schizophrenia in genetic association studies.12–14

35 healthy volunteers who had minimal previous cannabis use

There was a main effect of DAT1 genotype (F1,31 = 7.46, P = 0.01; 9-repeat carriers > 10-repeat homo-zygotes) and a trend for a main effect of AKT1 genotype (F 1,31 =3.42, P = 0.07; G homozygotes > heterozygotes) on the increase in psychotic symptoms induced by d-9-THC. There was also an interaction (F1,31 =4.49, P = 0.04) between the effects of the DAT1 and AKT1 genotypes on the symptomatic effect of d-9-THC; the increase in symptoms was greater in individuals who were G homozygotes of AKT1 rs1130233 and also carriers of the 9-repeat allele of the DAT1 3′ UTR VNTR (hereafter referred to as GG/9-repeat carrier; n =7), relative to those that were not

During encoding, following placebo, indi-viduals who were G homozygotes of AKT1 and carriers of the 9-repeat allele (DAT1 3 ‘ UTR VNTR) showed strong striatal activation, whereas there was a little response in the REST. d9 THC markedly attenuated the striatal activation in GG/9-repeat carrier individuals, but had a minimal effect in the REST group. Similarly, during the recall condition, following placebo, subjects who were homozygotes for the G allele of AKT1 and carriers of the 9-repeat allele for the DAT1 3’UTR VNTR showed strong activation in the midbrain, whereas there was only a modest response in the REST. Administration of d9-THC led to deactivation in the midbrain in GG/9-repeat carrier individuals, but had little effect on the response in the REST group

there were no significant interactions between d9-THC and genotype on task performance

the more d9-THC attenuated striatal and midbrain activation, the greater the severity of the psychotic symptoms

Blaauw E, Arensman E, Kraaij V, Winkel F, Bout R. 2002. “Traumaatic life events and suicide risk among jail inmates: the influence of types of events, time period and significant others” J Trauma Stress 15(1): 9-16

Relationships between traumatic life events and suicide risk were studied in two samples of jail inmates with a low (N = 216) and a high (N = 51) suicide risk. Although nonsuicidal inmates reported a high prevalence of traumatic life events, suicidal inmates reported even higher prevalence rates. Suicidal inmates reported more episodes of sexual abuse, physical maltreatment, emotional maltreatment, abandonment, and suicide attempts by significant others. They also had experienced more traumatic life events during childhood, later life, and detention

Black, C. 2013. The Flight of the Eagle: A Strategic History of the United States. Signal.

Describing the United States in 2013: “its justice system was corrupt and oppressive and produced 6 to 12 times the per capita number of incarcerated people as other prosperous democracies, on behalf of a war on drugs that is an exercise in hypocrisy and futility in which America has been more decisively defeated than in any war it actually waged. A rogue prosecutocracy terrorizes the country; it wins 99.5 per cent of its cases, 97 percent without a trial, so stacked is the judicial deck and withered the guarantees of individual liberties in the Bill of Rights. Forty-eight million Americans have a criminal record and there is minimal general recognition of the evils of this system.”

Blair R. 2001. “Neurocognitive models of aggression, the antisocial personality disorders, and psychopathy” J Neurol Neurosurg Psychiatry 71: 727-731

Impairments in executive emotional systems (the somatic marker system or the social response reversal system) are related to reactive aggression shown by patients with “acquired sociopathy” due to orbitofrontal cortex lesions

“Acquired sociopathy” was a term introduced to characterise persons who, after acquired lesions of the orbitofrontal cortex, fulfil the DSM-III diagnostic criteria for “sociopathic disorder”, an antecedent of APD.2

Individuals with acquired sociopathy following orbitofrontal cortex lesions are a relatively homogeneous population; they present solely with reactive aggression even if the lesion occurs early in life

it is damage to the orbitofrontal cortex, rather than any other region of the frontal or posterior cortex, which places the patient at greatest risk of presenting with reactive aggression.17

The instrumental antisocial behaviours shown by the developmental psychopath are a consequence of inability to socialise due to an impairment in the capacity to form associations between emotional unconditioned stimuli (particularly distress cues) and conditioned stimuli (specifically representations of transgressions). If the person is raised in a social environment (for example, poverty) where there are advantages for engaging in antisocial behaviour, they may engage in this behaviour but will not experience aversion to the distress of their victims. Because of the heterogeneity in the populations of those with CD and APD, different cases are likely to correspond to either a developmental form of acquired sociopathy (and some cases may reflect trauma) or developmental psychopathy itself

Blanco C, Hasin D, Wall M, Florez-Salamanca F, Hoertel N, Wang S, Kerridge B, Olfson M. 2016. “Cannabis use and risk of psychiatric disorders Prospective evidence from a US National Longitudinal Study” JAMA Psychiatry  doi:10.1001/jamapsychiatry.2015.3111

We used multiple regression and propensity score matching to estimate the strength of independent associations between cannabis use at wave 1 and incident and prevalent psychiatric disorders at wave 2. Psychiatric disorders were measured with a structured interview (Alcohol Use Disorder and Associated Disabilities Interview Schedule–DSM-IV). In both analyses, the same set of wave 1 confounders was used, including sociodemographic characteristics, family history of substance use disorder, disturbed family environment, childhood parental loss, low self-esteem, social deviance, education, recent trauma, past and present psychiatric disorders, and respondent’s history of divorce

34 653 respondents (14 564 male [47.9% weighted]; mean [SD] age, 45.1 [17.3] years), cannabis use in wave 1 (2001-2002), which was reported by 1279 respondents, was significantly associated with substance use disorders in wave 2 (2004-2005) (any substance use disorder: odds ratio [OR], 6.2; 95% CI, 4.1-9.4; any alcohol use disorder: OR, 2.7; 95% CI, 1.9-3.8; any cannabis use disorder: OR, 9.5; 95% CI, 6.4-14.1; any other drug use disorder: OR, 2.6; 95% CI, 1.6-4.4; and nicotine dependence: OR, 1.7; 95% CI, 1.2-2.4), but not any mood disorder (OR, 1.1; 95% CI, 0.8-1.4) or anxiety disorder (OR, 0.9; 95% CI, 0.7-1.1)

Although the cross-sectional association between cannabis use and psychiatric disorders has been consistently documented,12,13 longitudinal studies evaluating the association of cannabis use with incident psychiatric disorders have yielded mixed results.14– 16 Some studies have reported that cannabis use is associated with increased risk of onset of depression,16– 19 anxiety,14,17,19 bipolar disorder,16 substance use disorders,20 and psychosis,21,22 while others have not replicated these findings.14– 16,23 Discrepancies may be partly explained by a focus on varying age ranges,14,15,17– 19,23– 25 geographic locations,18,23– 25 males vs females,15 or number and type of mental disorders evaluated.14– 19,23– 26

Confounders from the childhood tier included family history of SUDs (lifetime history of alcohol or drug use disorders in the biological parents or siblings), parental loss (parent’s divorce or death of at least 1 parent before the participant was 18 years old), and vulnerable family environment (parental absence or separation from a biological parent before age 18 years). The confounders for the early-adolescence tier included low self-esteem (dichotomous; scored 1 if respondents believed they were not as good, smart, or attractive as most other people), age at onset of anxiety disorders (with childhood onset before age 18 years), and social deviance (assessed as the number of conduct disorder or antisocial personality disorder behaviors in which the respondent engaged before age 15 years; range, 0-33). Confounder in the late-adolescence tier included educational level (in years), number of personality disorders, and number of Axis I disorders with onset before age 18 years. Confounders in the adulthood tier included history of divorce, history of SUD (alcohol use disorder, nicotine dependence, and drug use disorder other than cannabis use disorders), and social deviance (measured as the number of antisocial personality disorder behaviors in which the individual engaged after age 15 years but prior to the wave 1 assessment)

In the full sample of 34 653 respondents (14 564 male [47.9% weighted]; mean [SD] age, 45.1 [17.3] years), the 1279 individuals with cannabis use (772 male [66.4% weighted]; mean [SD] age, 29.9 [10.7] years) had greater odds of most risk predictors examined except age and history of divorce, which were lower among individuals with cannabis use, and educational level and nonwhite race/ethnicity, which did not differ across groups (eTable 1 in the Supplement). Among the individuals with cannabis use, 345 (28.4% weighted) had cannabis abuse in the past year and 99 (7.7%) had cannabis dependence in the past year

in unadjusted analyses in the full population, cannabis use was associated with increased prevalence and incidence of a broad range of psychiatric disorders. However, after adjusting for several covariates that predicted cannabis use, multiple regression analysis and propensity score matching converged in indicating that cannabis use was associated only with increased prevalence and incidence of alcohol and drug use disorders, including nicotine dependence

The new results also help reconcile discrepant findings from prior studies by suggesting that most of the association of cannabis use with non-SUD psychiatric disorders is explained by differences in the distribution of confounders between cannabis users and nonusers.14,15,17– 19,23– 25 In addition, our findings support a dose-response association between cannabis use and the risk of SUDs.16,17

our study does not establish a causal association between cannabis use and new onset of disorders because of the possibility of residual confounding, particularly confounders that may vary over time across survey waves.

Our study indicates that cannabis use is associated with increased prevalence and incidence of substance use disorders. These adverse psychiatric outcomes should be taken under careful consideration in clinical care and policy planning.

Blázquez C, Chiarlone A, Bellocchio L, Resel E, Pruunsild P, Garcia-Rincon D, Sentner M, Timmusk T, Lutz B, Galve-Roperh I, Guzman M. 2015. “The CB1 cannabinoid receptor signals striatal neuroprotection via a PI3K-Akt/mTORC1/BDNF pathway” Cell Death Differ 22(1): 1618-1629

CB1 receptor engagement protects striatal cells from excitotoxic death via the phosphatidylinositol 3-kinase/Akt/mammalian target of rapamycin complex 1 pathway, which, in turn, (2) induces brain-derived neurotrophic factor (BDNF) expression through the selective activation of BDNF gene promoter IV, an effect that is mediated by multiple transcription factors

Block R, Wittenborn J. 1984. “Marijuana effects on semantic memory: verification of common and uncommon category members” Psychological Reports 55: 503-512

Marijuana did not alter the normal difference in reaction time between common and uncommon examples of categories, suggesting that effects of marijuana on associations do not derive directly from underlying, general alterations of semantic memory retrieval. Marijuana’s effects were not influenced by the demands on memory retrieval or by providing advance information relevant to the required decisions, suggesting memory retrieval was not impaired by this dose of marijuana.

Block R, O’Leary D, Ehrhardt J, Augustinack J, Ghoneim M, Arndt S, Hall J. 2000. “Effects of frequent marijuana use on brain tissue and composition” Neuroreport 11(3): 491-6

in 18 current, frequent, young adult marijuana users and 13 comparable, non-using controls… no differences in grey or white matter. Lower ventricular CSF in MJ users

Bloomfield M, Morgan C, Egerton A, Kapur S, Curran H, Howes O. 2014. “Dopaminergic function in cannabis users and its relationship to cannabis-induced psychotic symptoms” Biol Psychiatry 75(6): 470-8

These findings indicate that chronic cannabis use is associated with reduced dopamine synthesis capacity and question the hypothesis that cannabis increases the risk of psychotic disorders by inducing the same dopaminergic alterations seen in schizophrenia

Bola J, Lehtinen K, Cullberg J, Ciompi L. 2009. “Psychosocial treatment, antipsychotic postponement, and low-dose medication strategies in first-episode psychosis: a review of the literature” Psychosis 1(1): 4-18

Five studies were ineludcd (N=261). each reporting modestly better long-term outcomes than initial medication treatment. resulting in a composite smallmedium effect-size advantage (r .= 0.17). In addition, 27-43% of experimental patients were not receiving anti psychotics at the two- or three-year follow-up

Bola J, Mosher L. 2003. “Treatment of acute psychosis without neuroleptics: two-year outcomes from the Soteria Project” Nervous and Mental Disease 191(4): 219-229

Newly diagnosed DSM-II schizophrenia subjects were assigned consecutively (1971 to 1976, N 79) or randomly (1976 to 1979, N 100) to the hospital or Soteria and followed for 2 years

Completing subjects with schizophrenia exhibited a large effect size benefit with Soteria treatment (.81 SD, p .02), particularly in domains of psychopathology, work, and social functioning. Soteria treatment resulted in better 2-year outcomes for patients with newly diagnosed schizophrenia spectrum psychoses, particularly for completing subjects and for those with schizophrenia. In addition, only 58% of Soteria subjects received antipsychotic medications during the follow-up period, and only 19% were continuously maintained on antipsychotic medications.

Bolla K, Eldreth D, Matochik J, Cadet J. 2005. “Neural substrates of faulty decision-making in abstinent marijuana users.” Neuroimage 26(2):480-92 in dropbox

A dose-related association was found between increased MJ use and lower IGT performance and alterations in brain activity. The MJ group showed greater activation in the left cerebellum and less activation in the right lateral orbitofrontal cortex (OFC) and the right dorsolateral prefrontal cortex (DLPFC). When the MJ group was divided into Moderate (8-35 joints/week) and Heavy users (53-84 joints/week), the Heavy MJ group showed less activation in the left medial OFC and greater activation in the left cerebellum than the Moderate group. similar between the Moderate MJ users and Control… very heavy users of MJ have persistent decision-making deficits and alterations in brain activity

Bonnet A, Marchalant Y. 2015. “Potential therapeutic contributions of the endocannabinoid system towards aging and Alzheimer’s Disease” Aging Dis 6(5): 400-405

Alzheimer’s disease (AD) is the most common neurodegenerative disease and accounts for the majority of diagnosed dementia after age 60. It is estimated to currently affect between 20 and 30 million people worldwide with an incidence of the disease between 3 and 30% over the age of 60

Currently available drugs do not reverse or stop the progression of the disease

important feature of AD’s pathology is the presence of a chronic inflammatory component

A lot of the studies have focused on microglial cells, but it is now clear that microglial cells are assisted by astrocytes and endothelial cells [18] to maintain a chronic inflammatory state of the brain

elevated levels of inflammatory factors (such as IL-6 and C-reactive protein notably) could be found in the plasma of AD patients long before clinical onset of the disease [23,24]

Several reports over the last two decades demonstrate the potential benefits from the modulation of the ECS over amyloid β and Tau hyper-phosphorylation

most studies looking at the modulation of neuroinflammation using cannabinoids have mainly focused on CB2 receptors as they are mostly expressed on microglial cells. Studies mentioned earlier [58,68,69,71] have observed reduction in microglial activation and pro-inflammatory cytokines following infusion of Aβ in rodents

ur work demonstrated the anti-inflammatory potential using WIN-55,212-2 chronically on chronic neuroinflammation in young and aged rats [54,56,77] as well the neurogenic and cognitive effect of WIN-55,212-2 in aged animals [55]. Our data suggested that the anti-inflammmatory effect of WIN-55,212-2 could be due to its activity on TRPV1 receptors and its neurogenic effects linked to both CB1 and CB2 receptor

Boos H, Aleman A, Cahn W, Hulshoff H, Kahn R. 2007. “Brain volumes in relatives of patients with schizophrenia” Arch Gen Psychiatry 64:297-304 – in dropbox

smaller brain volumes in schizophrenia, with more pronounced reductions in the hippocampus and amygdala

estimated heritability of 80% including interaction between the genes and environment

This meta-analysis integrated the results of 25 MRI stud-ies that compared brain volumes of 1065 nonpsychotic first-degree relatives of patients with schizophrenia with those of 1100 healthy control subjects. The results indicate that brain volumes in relatives of patients with schizophrenia differ from those of healthy control subjects, with effect sizes in the small to moderate range. The largest effect is found in hippocampal volume (d = 0.31), with relatives of patients having smaller volumes than healthy control subjects. In addition, total gray matter volume (d = 0.18) and third-ventricle (d = 0.21) volume are smaller in relatives compared with healthy control subjects. Although total brain and white matter volume did not differ significantly in relatives compared with healthy controls, both structures showed a trend toward significance (P = .06 and P = .07, respectively). The analysis that compared patients with schizophrenia with first-degree relatives showed smaller hippocampal volumes in the patients (d = 0.43)

brain abnormalities in schizophrenia are related (in part) to the risk of developing the disease and that these brain changes may therefore predate the clinical onset of the disorder

lower performance in relatives of patients compared with healthy control sub-jects was reported on several cognitive domains, includ-ing verbal and declarative memory, executive function-ing, and attention. Interestingly, Sitskoorn et al 62 found that the largest effect size was obtained for verbal memory (d = 0.54), being significantly worse in relatives of pa-tients than in healthy subjects

decreased verbal memory is one of the most robust neuropsychological findings in schizo-phrenia. 60 Deficits in verbal memory have generally been associated with smaller (left) hippocampal volume, 65 as is also the case in patients with schizophrenia 66,67 and their relatives. 17,26 In the present meta-analysis, the effect size was considerably larger for the left than for the right
hippocampus. This finding is consistent with findings from lesion and functional MRI studies in healthy subjects, suggesting more involvement of the left hippo-campus in encoding and recognition of verbal as opposed to visual or pictorial material

Obstetric complications such as hypoxia are known to result in smaller brain vol-umes, affecting the hippocampus profoundly. 21,72,73 Smaller hippocampal volumes have also been associated with brain injury 65,74,75 and stress 65,76 and have been found not only in schizophrenia but also in several other psychiatric dis-orders, such as major depression, posttraumatic stress dis-order, obsessive-compulsive disorder, and borderline per-sonality disorder. 65 An important function of the hippocampus and amygdala is the regulation of the hy-pothalamic-pituitary-adrenal axis, which plays a role in stress processing. This regulation may be altered be-cause of a genetic predisposition. In depression, the hy-pothalamic-pituitary-adrenal axis is strongly activated and
the adrenal cortex hypersecretes glucocorticoids such as cortisol. Although less pronounced, considerable hypo-thalamic-pituitary-adrenal activation is also found in schizophrenia. 77 On the basis of earlier animal experi-ments, overexposure to cortisol during prolonged peri-ods of stress is expected to damage the brain, particu-larly the hippocampus. Sapolsky et al 77 provided evidence in rats that chronic stress, with the concomitant in-crease in corticoid levels, causes loss of neurons in the hippocampus and subsequent deficits in memory func-tion and cognition. In patients with depression, this glu-cocorticoid cascade has also been presumed to result in decreased hippocampal volume, 78 possibly explained by apoptosis. 79 Both apoptosis and  neurogenesis have been shown to occur in the hippocampus. 80 Thus, smaller hip-pocampal volumes in patients with schizophrenia and their first-degree relatives might also be the result of stress-related processes in the brain. 81

slightly elevated rates of obstetric complications are found not only in patients with schizophrenia but also in their nonpsychotic first-degree relatives. 82,83 As reported by Can-non et al,
83 most of these relatives exposed to obstetric complications did not develop schizophrenia

Van Erp et al 9 examined siblings of pa-tients with schizophrenia and found that hippocampal volumes differed stepwise with each increase in genetic predisposition to schizophrenia and that hippocampal vol-umes of patients exposed to fetal hypoxia were smaller than those who were unexposed, whereas no such rela-tionship was observed within the healthy control sub-jects. They suggested that carrying susceptibility genes for schizophrenia makes one vulnerable to perinatal dam-age, especially in the hippocampus

structures other than those that have been evaluated in this meta-analysis may also be affected in relatives of patients with schizophrenia

the possibility that some of the effects found in this meta-analysis were caused by confounding factors such as sex and age cannot be ruled out

Borgwardt S, McGuire P, Aston J, Gschwandtner U, Pfluger M, Stieglitz R-D, Radue E-W, Riecher-Rossler A. 2008. “Reductions in frontal, temporal and parietal volume associated with the onset of psychosis” Schizophrenia Research 106: 108-114 add to dropbox

Which volumetric abnormalities are related to psychotic illness, as opposed to vulne rability to psychosis is unclear

n = 20). Over the following 3 years, 10 subjects developed psychosis and 10 did not. Subjects were re-scanned af ter the ons et of psychosis or at the end of follow-up if they did not become psychotic… In subjects who developed psychosis there were longitudinal volume reductions in the orbitofrontal, superior frontal, inferior temporal, medial and superior parietal cortex, and in the cerebellum

longitudinal reductions in regional gray matter volume also occur in chronic patients ( Cahn et al., 20 02; Ho et al., 20 03; Kasai et al., 20 03; Kubicki et al., 20 02; Mathalon et al., 20 01; Sporn et al., 20 03; Wood et al., 20 01)

Bossong M, Berckel B, Boellaard R, Zuurman L, Schuit R, Windhorst A, van Gerven J, Ramsey N, Lammertsma A, Kahn R. 2009. “Δ9-Tetrahydrocannabinol Induces Dopamine Release in the Human Striatum” Neuropsychopharmacology 34: 759-766

Miniscule finding among general absence of finding exaggerated and made to sound like proof of addictiveness, because Bossong is a lying weasel of a scientist

“This is the first study demonstrating THC-induced dopamine release in the human striatum… The ability of THC to induce dopamine release in the human striatum suggests that THC shares addictive properties with other drugs of abuse.”

Bossong - dopamine increase from THC

whereas amphetamine (Drevets et al, 2001;Martinez et al, 2003, 2007), cocaine (Schlaepfer et al, 1997), alcohol (Boileau et al, 2003), and nicotine (Brody et al, 2004, 2006) cause reductions in dopamine D2/D3receptor availability in the range of 10–30%, we found a relatively modest THC-induced decrease of 3.4 and 3.9% in the ventral striatum and the precommissural dorsal putamen

THC inhalation reduces [11C]raclopride binding in the ventral striatum and the precommissural dorsal putamen but not in other striatal subregions. This is consistent with an increase in dopamine levels in these regions

As THC was dissolved in 100 vol% alcohol and the solvent was used as placebo, we cannot exclude that the inhalation of alcohol has caused dopamine release. However, this is very unlikely, as only 200μl alcohol was administered

THC plasma concentrations in this study were comparable with or even higher than those obtained after smoking of high-potency cannabis

it is unlikely that striatal dopamine release immediately after THC administration has been much larger than the modest levels of 3.4–3.9%

Thus, elevated striatal dopamine release after the use of cannabis may explain how cannabis use contributes to the development and pathophysiology of schizophrenia

in animals, it has been demonstrated that cannabinoid substances such as Δ9-tetrahydrocannabinol (THC), the main psychoactive component in cannabis (Gaoni and Mechoulam, 1964), also stimulate striatal dopamine neurotransmission (for review see Tanda and Goldberg, 2003; Lupica et al, 2004; Gardner, 2005). Cannabinoids enhance neuronal firing of mesolimbic dopamine neurons (French, 1997; French et al, 1997; Gessa et al, 1998) and elevate striatal dopamine levels (Ng Cheong Ton et al, 1988; Chen et al, 1990; Tanda et al, 1997; Malone and Taylor, 1999; Fadda et al, 2006), both through activation of cannabinoid CB1 receptors (French, 1997; French et al, 1997;Tanda et al, 1997; Gessa et al, 1998; Malone and Taylor, 1999). However, whether THC affects the human striatal dopamine system is currently unknown

Nine healthy male subjects gave informed consent for this study. Seven volunteers completed the study procedure. One subject was excluded because of positive urine drug screening on the first study day. Another subject did not complete the second scanning session because of anxiety… All subjects were familiar with the effects of cannabis. Two subjects used cannabis less than once a month, one subject three times a month, three subjects twice a month and one subject used cannabis once a week. They all showed negative urine screening at both study days

There were no significant changes in equilibrium levels of striatal activity, expressed by percentage change of activity concentration over time, between placebo (−0.10±0.16% per min) and THC (−0.12±0.08% per min) sessions (p=0.633). In addition, the slope (ie change over time during scanning) of the ratio between striatum and cerebellum [11C]raclopride concentrations was not significantly different between sessions (−0.0011±0.0030 and −0.0010±0.0025 for placebo and THC sessions, respectively; p=0.967)

[11C]Raclopride concentrations were not significantly different between placebo and THC sessions in both whole blood (0.59±0.25 and 0.61±0.28kBq/g, respectively;p=0.717) and plasma (1.02±0.42 and 1.06±0.43kBq/g, respectively; p=0.687), normalized to the effectively injected dose. In addition, the fraction of parent[11C]raclopride was not significantly different (p=0.191) between placebo (80.4±5.6%) and THC (77.5±4.3%).

significantly reduced in the ventral striatum and the precommissural dorsal putamen after inhalation of THC compared to placebo

No significant associations between measures of dopamine release and behavioral, subjective or physiological effects were demonstrated.

Bossong M, Niesink R. 2010. “Adolescent brain maturation, the endogenous cannabinoid system and the neurobiology of cannabis-induced schizophrenia” Progress in Neurobiology 92: 370-385 in dropbox

Central argument of the paper is based on the assumption that marijuana increases glutamate signalling, for which no evidence is provided, and evidence that it does the opposite is brushed off, because Bossong is a lying weasel of a scientist

Bossong - Overpruning

Bossong's Folly

implies a toxic substance affecting the central nervous system during a critical period, resulting in irreversible structural changes. These changes subsequently cause psychopathological effects. It is assumed that D 9-tetrahydrocannabinol (D 9-THC, henceforth mentioned as THC), the main psychoactive substance in cannabis, is the neurotoxic substance and that adolescence is the critical period. The interference of THC with a maturational process in the brain of adolescents is supposed to induce structural and functional changes.

From the results of the literature search, it can be postulated that THC adversely affects normal physiological maturational processes during adolescence. Usually, the interaction of endoge-nous cannabinoids with the CB1 receptor is critically involved in brain maturation through its regulating role in the release of glutamate. Through its action on CB1 receptors, THC can interfere
with this normal physiological process, resulting in disturbed glutamate release, subtle neurotoxic effects and subsequent structural defects. Since maturation of the prefrontal cortex (PFC) is one of the most important processes during adolescence, THC may predominantly affect the maturation of specific neurocircuitries within this brain region

Brain development is an organized and highly dynamic multistep process, which is genetically determined, epigenetically directed and environmentally influenced (Tau and Peterson, 2010)

From childhood to adolescence, development shifts from producing a large number of neurons to creating efficient neuronal pathways. This efficiency is thought to be achieved by synaptic refinement, the process by which some connections between brain cells are pruned and eliminated, and ‘‘useful’’ neurons, synapses and dendrites are selected and preserved for the adult brain (Katz and Shatz, 1996; Cohen-Cory, 2002; Whitford et al., 2007; Purves et al., 2008; Luna, 2009)

Recent studies focusing on the development of the social brain support evidence that adolescence also represents a period of significant social development

For information from the outside world, cortical areas sub-serving high-order behavior completely depend on subcortico-cortical connections. Animal studies, specifically studies in rodents, suggest unique anatomical and functional changes during adolescence. An intact innervation of the cortex from subcortical structures during this time period appears to be a prerequisite for the proper maturation of specific cortical areas. Thus, lesions in neurons connecting subcortical structures, such as the amygdale and hippocampus, with the prefrontal cortex before adolescence lead to specific structural and behavioral changes at the end of adolescence and in adulthood. Such lesions studies have been proposed as good animal models for neurodevelopmental psycho-pathological disorders, such as schizophrenia (Bouwmeester et al., 2002; Lipska, 2004; Tseng et al., 2009 )

Deprivation of complex stimuli in vulnerable periods, such as rearing in an impoverished environment ( Benefiel et al., 2005 ) and social isolation ( Hall, 1998), results in permanent disturbances in adult behavior, disturbances that seem to be mediated by defects in the neural circuitry within the PFC (Card et al., 2005 ). Deprivation studies also have shown that social play behavior, the first form of non-mother directed social behaviors displayed by most adolescent mammals, is essential for appropriate social, cognitive and sexual development ( Vanderschuren et al., 1997)

the development of complex functions involves cascades of sensitive periods affecting different levels of processing at different ages (Knudsen, 2004). Although stimuli from the cognitive, social and emotional domain are thought to be important for appropriate brain maturation during adolescence, it does not exclude an important role for this type of stimuli during critical or sensitive periods during infancy and childhood. For example, social contacts with parents has shown to be important for brain plasticity early in life (Helmeke et al., 2009; Musholt et al., 2009), whereas social contacts with peers are thought to be important for brain development during adolescence (Leussis and Andersen, 2008)

Transient blockade of the CB1 receptor, for example by exposure to exogenous cannabinoids such as THC (1), disrupts the protective effect of the endogenous cannabioid system (2), thereby causing an excess of glutamate (3) and consequently too great an influx of Ca2+ (4) in the postsynaptic neuron. This causes a disturbance of the LTP/LTD balance, which may lead to pruning of the postsynaptic part of the synapse and possibly of the postsynaptic dendritic arbors. The ultimate result might be a disturbance in local neuronal circuitry

overactivation of ionotropic glutamate receptors can induce either apoptosis or necrosis through excessive Ca2+ influx, a process known as excitotoxicity (Mody and MacDonald, 1995; Olney, 2003). This is illustrated by the fact that the immature brain is more sensitive to the excitotoxic effects of glutamate than the adult brain ( Ikonomidou et al., 1999; Olney et al., 2000 ). Because the immature NMDA receptor is more sensitive to glutamate, the probability to induce such excessive concentrations of postsynap-tic intracellular Ca2+ is increased during the critical period. Excitotoxicity may disturb the normal maturational processes by the formation of aberrant cortical connections (Olney, 2003). Thus, binding of glutamate to the NMDA receptor will have greater consequences during the critical period than outside this phase.

A comprehensive neuroanatomical analysis of CB1 receptors and endogenous cannabinoids during specific critical periods within particular areas of the frontal cortex is currently lacking

The research that has been done in vulnerable people concerns studies in people diagnosed with subclinical symptoms ( Henquet et al., 2004 ). In fact, these people already suffered from a subclinical prodromal syndrome at the time that the exposure to cannabis took place

in this model, a dose–time–effect relationship is responsible for the toxic effect of cannabis during late postnatal development. This is possibly also one of the main reasons why not everyone who used cannabis during adolescence will develop a permanent psychosis. Lower exposure will result in a less serious, probably sub-threshold effect

Most of the research on the neurobiological basis of schizophrenia is monodisciplinary and the same applies to the study of the action and function of endogenous cannabinoids, although both require a multidisciplinary approach

Bossong M, van Hell H, Jager G, Kahn R, Ramsey N, Jansma J. 2013. “The endocannabinoid system and emotional processing: a pharmacological fMRI study with Δ9-Tetrahydrocannabinol” European Neuropsychopharmacology 23(12): 1687-1697 in dropbox

THC) on brain function related to emotional processing in 11 healthy subjects… Performance and brain activity during matching of stimuli with a negative (‘fearful faces’) or a positive content (‘happy faces’) were assessed after placebo and THC administration. After THC administration, performance accuracy was decreased for stimuli with a negative but not for stimuli with a positive emotional content
These results suggest that administration of THC shifts the brain’s bias for stimuli that have a negative impact towards a bias for stimuli that have a positive impact.

a defect in endocannabinoid neurotransmission could contribute to the abnormal emotional reactions as seen in patients with a major depression

As emotional responses such as anxiety and fear are associated with increased glutamate and diminished GABA neurotransmission (Millan, 2003), the reduced negative emotional bias as demonstrated in the current study may be the result of a THC-induced reinstatement of the balance between both neurotransmitter systems (Ruehle et al., 2012)

We did not find significant effects of THC on amygdala activity. Possibly, the subjective anxiety-like effects of THC administration may have specifically masked THC-induced effects on the response of the amygdala, as it has been shown that particularly amygdala activity may be involved in the subjective response to pharmacologically induced anxiety (Eser et al., 2009). This view is supported by results of Fusar-Poli et al. (2009)), who showed strong subjective anxiety-like effects of THC, but no significant effects of THC administration on the amygdala response

Bossong M, Jansma J, van Hell H, Jager G, Kahn R, Ramsey N. 2013. “Default mode network in the effects of Δ9-Tetrahydrocannabinol (THC) on Human Executive Function” PLoS One 8(7): e70074

Decreases in contentedness and calmness may be related to THC administration in an MRI environment, as they were not shown in a previous study using Positron Emission Tomography (PET) [34]

THC-induced impairment of task performance as shown in the present study is expected to result in increased effort to maintain good performance levels, most likely reflected as elevated CES activity. However, THC did not affect CES activity during performance of the task.

Previous studies have reported reduced activity in the CES in psychiatric disorders such as ADHD [58],[59] and schizophrenia [60], [61], an effect that is likely related to impaired task performance [61]. One explanation for the apparent discrepancy with the current findings could be that performance deficits as shown in our study after THC are moderate compared to those of psychiatric patients. For example, decreased CES activity in schizophrenia patients in the study of Salgado-Pineda et al. [60] was associated with a 33% reduction in the mean percentage of correctly identified targets

Higher COMT activity, resulting in reduced prefrontal dopamine neurotransmission, has been associated with significantly greater deactivation of the posterior cingulate cortex of healthy volunteers [64] and reduced deactivation in the medial prefrontal cortex of both healthy subjects and schizophrenia patients …  Interestingly, individuals with increased COMT activity appear to have stronger responses to THC administration in terms of acute psychotic effects and cognitive impairments [67]

nicotine administration decreased DMN activity at rest in non-smokers [70], improved cognitive withdrawal symptoms of abstinent smokers through modulation of functional connectivity within the DMN and of inverse coupling between default mode and central executive brain networks [71], and enhanced visuospatial attention by deactivating DMN nodes including posterior cingulate cortex and angular gyrus in minimally deprived smokers [15]

neither brain activity nor behavioral effects were significantly correlated with reported cannabis use (data not shown)

non-specific THC-induced changes on cerebral blood flow may have confounded our results [72]

this study shows that THC administration results in less deactivation in the DMN during an executive function task, an effect that is correlated with task performance. These results suggest an important role for the eCB system in both DMN modulation and executive function. The association of the eCB system with DMN modulation may be relevant for psychiatric disorders associated with executive function deficits, such as schizophrenia and ADHD, as well as for neurological disorders such as Alzheimer’s disease

Bossong M, Jansma J, Bhattacharyya S, Ramsey N. 2014. “Role of the endocannabinoid system in brain functions relevant for schizophrenia: an overview of human challenge studies with cannabis or delta9-tetrahydrocannabinol (THC)” Progress in Neuro-Psychopharmacology & Biological Psychiatry 52: 53-69 in dropbox

Pattern in text of “Schizophrenia involves significant impairment of X; studies showed THC does not impair X, but alters activity during the task in a strikingly different pattern than the alterations in schizophrenia; altogether they show similarity” My working hypothesis remains that Bossong is a lying, weasel of a scientist. X = increase in dopamine signalling, memory impairment, executive function, emotional processing, response inhibition, auditory and visual processing. How does this bullshit get published?

“administration of… THC… reduces most cognitive functions” (Bossong is a lying weasel of a scientist)

the incidence of schizophrenia is relatively low (10-22 per 100,000), its prevalence is relatively high (0.3-0.7 per 100) due to the chronic nature of the illness (McGrath, 2008)

One of the most robust pathophysiological features of schizophrenia is an increase in striatal dopamine function. … dopamine enhancing drugs are able to induce direct psychotic effects (Angrist and van Kammen, 1984; Lieberman et al, 1987)… PET and SPECT neuroimaging sturides have consistently shown increased dopamine neurotransmission and elevated dopamine synthesis capacity in the striatum of patients with schizophrenia (for reviews Abi-Dargham, 2004; Howes 2009)

THC induces strong behavioral and physiological effects which are not associated with a large magnitude of dopamine release in the striatum

cognitive impairments are considered a core feature of the illness (Elvvag and Goldberg 2000; Gold 2004; Green 1996)

in two extensive meta-analyses, most prominent deficits during encoding of information were found in prefrontal areas of patients, including right medial, superior and middle frontal gyrus, as well as bilateral inferior frontal gyrus (Achim and Lepage 2005; Ragland 2009)

areas that showed significantly increased activity in schizophrenia patients during encoding included left precentral gyrus, middle temporal gyrus and postcentral gyrus, right parahippocampal gyrus, and anterior cingulate (Ragland, 2009), suggesting that general deficits in cognitive control may strongly contribute to memory impairment in schizophrenia (Andrews 2006; Ragland 2009; Segarra 2008)

Many neuropsychological studies investigating the impact of a challenge with cannabis or THC on memory paradigms consisting of encoding and recall conditions have shown an absence of effect, despite robust subjective and physiological responses (Block, 1984; Chait, 1994; Darley, 1977; Hart, 2001,2002, 2010; McDonald, 2003). Recall of information learned before cannabis use is also generally not affected (Abel, 1971; Darley, 1973; Dornbush, 1974). However, effects of cannabis or THC on memory performance have been reported in the free recall of information that is previously learned under the influence of cannabinoids (Curran, 2002; D’Souza, 2004; Liem-Moolenaar, 2010; Miller, 1978; Miller, 1976; Miller, 1977a,b; Miller 1979; see for reviews Ranganathan and D’Souza; Schoeler and Bhattacharyya, 2013; Zuurman, 2009). This suggets that cannabinoids may specifically influence encoding but not recall of information

a normal decrease in activity in the parahippocampal gyrus that was present over repeated encoding blocks during placebo was no longer evident after THC administration. THC also eliminated the linear reduction in activity in the anterior cingulate and bilateral medial prefrontal cortex that was shown over recall conditions. … overall task performance was unaffected… THC also attenuated bilateral striatal activity across repeated recall blocks, and its effect in the ventral striatum was directly correlated with the severity of THC-induced psychotic symptoms (Bhattacharyya, 2009)

One possibility is that subjects with higher dopamine levels show a more inefficient encoding of information after THC administration, which may be compensated by increased midbrain activity during recall to maintain normal task performance

schizophrenia patients exhibited increases in activity in left pre- and postcentral gyrus and temporal cortex during encoding, and reductions in bilateral thalamus and cerebellum during recall (Achim and Lepage, 2005; Ragland, 2009), effects that were not seen after THC administration [followed by some irrelevent excuses of why differences may exist]

Deficits in working memory, which is the ability for short-term storage and manipulation of information (Baddeley, 1986) are a persistent and disabling feature of schizophrenia that may underlie many cognitive impairments and symptoms… schizophrenia patients often exhibit a reduced load-dependent increase in brain activity, together with enhanced brain activity for tasks with low working memory load. This has been shown in a network of working-memory related brain areas, including bilateral dorsolateral prefrontal cortex, inferior parietal gyrus, basal ganglia, thalamus and anterior cingulate (Callicott 2000; Jansma 2004; Johnson 2006; Manoach 1999, 2000; Potkin 2009)

THC administration enhanced activity for low working memory loads, and reduced the linear relationship between working memory load and activity in a network of working-memory related brain regions and in the left dorsolateral prefrontal cortex, inferior temporal gyrus, inferior parietal gyrus and cerebellum… performance accuracy after THC was only reduced for oderately high working memory loads

working memory inefficiency was demonstrated in the left cerebellum and inferior temporal gyrus after THC administration but not in schizophrenia patients… differences in study design most likely account for the variation in results

Neuroimaging studies with schizophrenia patients have shown reduced activity in the central executive system, mainly in prefrontal and parietal areas, during perfromance of executive function tasks such as the CPT (Gur, 2007; Hong, 2011; Kiehl, 2005; Salgado-Pineda, 2004; Volz, 1999; Weiss, 2007), and effect that was related to impaired task performance

schizophrenia patients exhibit an inability to deactivate the default mode network during performance of executive function paradigms (Garrity, 2007; Hasenkamp, 2011; Pomarol-Clotet, 2008; Schneider, 2011; Whitfield-Gabrieli, 2009; see for reviews Broyd, 2009; Whitfield-Gabrieli and Ford, 2012)

A number of neuropsychological studies have reported no effects of cannabis or THC administration on continuous performance paradigms (Casswell, 1975; Curran, 2002; D’Souza, 2004; Vachon, 1974; Weil, 1968; Wilson, 1994)… decreased performance after cannabis or THC has been reported on more challenging continuous performance paradigms (Hunault, 2009; Sharma and Moskowitz, 1974). Tasks used in these studies are difficult cognitive tasks with a low memory component, typically relying on fast processing of information

Bossong 2013: task performance impaired after THC administration, reflected in both an increase in false alarms and a reduction in detected targets, associated with reduced deactivation in a set of brain regions linked to the default mode network, including posterior cingulate cortex and angular gyrus, correlated with lower performance after THC. Regions that were activated by the continuous performance task, notably bilateral prefrontal and parietal cortices, did not show effects of THC. [in the study, it was noted that the effect was moderate compared to psychiatric subjects, subjects given THC were less calm and more distracted by the fMRI environment, and that changes in cerebral blood flow likely confounded the results, none of which is mentioned here]

Reduced performance on executive function paradigms [NOT ESTABLISHED] after cannabis or THC may be associated with a failure to deactivate teh default mode network rather than effects on activity in the central executive system (Bossong, 2013). … resting state fMRI study showed that THC administration decreased functional connectivity between the posterior cingulate cortex and a network of brain regions collectively referred to as the left dorsal visual stream, thought to be involved in attentional processes (Klumpers, 2012). These findings are in line with impairments in capacity to deactivate the default mode network during performance of executive function paradigms as exhibited by schizophrenia patients (Broyd, 2009; Whitfield-Gabrieli and Ford, 2012)

Acute THC administration did not affect brain activity patterns in the central executive system… in contrast with reduced activity in the central executive system of schizophrenia patients during performance of executive function tasks (Gur, 2007; Salgado-Pineda, 2004).

One explanation for this apparent discrepancy could be that performance deficits as shown in the study by Bossong and colleagues (9% decrease in the mean percentage of correctly identified targets) are moderate compared to those of schizophrenia subjects. For example, decreased activity in the central executive system of schizophrenia patients in the study of Salgado-Pineda (2004) was associated with a 33% reduction in the mean percentage of correctly identified targets. Another possibility is that the ability to detect erroneous responses is impaired in schizophrenia patients, but not after THC administration, as diminished capacity for error monitoring is associated with reduced activity in the central executive system (Klein, 2007; Ridderinkhof, 2004)

Abnormalities in emotional processing are among the most important characteristics of schizophrenia, with significant consequences for social functioning and subjective well-being of patients (Aleman and Kahn, 2005; Pinkham, 2003). Individuals with schizophrenia have deficits in facial affect perception, which are present throughout the course of the disorder, and which are stronger for the perception of negative than positive emotions (Edwards, 2002; Mandal, 1998; Pinkham, 2003)… a large network of brain regions regulates processing of emotions, including [amygdala], orbital frontal cortex, prefrontal cortex, anterior cingulate, and occipital and temporal lobes (Fusar-Poli, 2009; Phillips, 2008). Schizophrenia patients exhibit reduced activity in this network when emotional stimuli are compared to similar but neutral stimuli (Gur, 2002; Aleman and Kahn, 2005) which is due to increased activity to neutral stimuli in schizophrenia (Hall, 2008; Holt, 2006; Surguladze, 2006). … schizophrenia patients activate areas related to processing of emotions in response ton netural stimuli to a stronger extent than normal subjects, consistent with the theory that schizophrenia may be characterized as a state of aberrant assignment of salience to otherwise insignificant stimuli (Kapur, 2003).

Only one neuropsychological study examined the acute effects of THC on processing of emotions (Ballard, 2012)… THC significantly reduced recognition of threatening stimuli (fear and anger), but did not affect ratings of emotional scenes… reduced activity in amygdala to threatening stimuli with no difference on task performance found by Phan, 2008.

When threatening stimuli were compared to neutral stimuli, THC administration increased activity in the left precuneus and reduced activity in the right inferior frontal gyrus, right superior temporal gyrus and left medial frontal gyrus, without effects on task performance (Fusar-Poli, 2009b)… in 2010 failed to show any effects of THC administration on effective connectivity etween the amygdala and the anterior cingulate cortex

studies in unmedicated schizophrenia patients have consistently demonstrated attenuated activity in the ventral striatum during reward anticipation (Esslinger, 2012; Juckel, 2006; Nielsen, 2012a; Schlagenhauf, 2009)

Eleven recreational cannabis users showed similar behavioral resposnes to reward during THC and placebo… THC attenuated the brain response during reward feedback in a network of areas involved in the processing of feedback including the bilateral inferior temporal gyrus, left inferior parietal gyrus and right superior frontal gyrus. Brain activity during the anticipation of reward was not affected. (van Hell, 2012)

Jansma (2013) compared activity in the ventral striatum and the caudate putamen during anticipation and feedback of reward after THC inhalation (6 mg) between subjects with a nicotine addiction (N=10) and healthy controls (N=11) (matched on cannabis use). In the absence of any other differences between the two groups, THC administration induced a significantly different effect on activity in the ventral striatum during reward anticipation: subjects with a nicotine addiction exhibited a significant reduction in activity after THC, not present in healthy controls

Schizophrenia has been associated with impaired response inhibition for decades (Frith, 1979)… attenuated activity in patients known to be involved in this cognitive task including bilateral dorsolateral prefrontal cortex (Arce, 2006; Ford, 2004; Rubia, 2001), anterior cingulate cortex (Arce, 2006; Rubia, 2001), right inferior frontal gyrus (Kaladjian, 2007), bilateral superior and inferior parietal gyrus (Ford, 2004) and right striatum (Vink, 2006)… abnormalities also in bilateral superior temporal gyrus (Ford, 2004)

In the absence of THC-induced effects on reaction time or inhibition errors, activity was reduced in right inferior frontal gyrus, bilateral anterior cingulate gyrus and precuneus, and increased in right (para)hippocampal gyrus, right superior temporal gyrus and left posterior cingulate gyrus (Borgwardt, 2008). In an extension of this study, THC showed significantly stronger [than absent?] effects on inhibition errors in the group of participants with psychotic symptoms, accompanied by different effects of THC between groups on activity in the left parahippocampal gyrus, bilateral middle temporal gyrus and right fusiform gyrus (increased in right middle temporal, decreased in other areas) (Atakan, 2013)

The aberrant processing of salience is thought to be a fundamental factor underlying psychosis (Kapur, 2003)… patients exhibited a diffuse pattern of decreased activity during processing of novel auditory stimuli, with the strongest reductions in bilateral inferior parietal lobe, bilateral caudate/thalamus, left postcentral gyrus, right posterior cingulate gyrus and left inferior temporal gyrus (Kiehl, 2005). Gur (2007) showed decreased activity in bilateral cuneus and left middle occipital gyrus, but increased activity in bilateral inferior parietal lobule, right middle and inferior frontal gyrus, and left fusiform gyrus during visual processing of novel stimuli. Jensen (2008) showed increased activity in right ventral striatum, middle cingulate cortex, thalamus, prefrontal cortex and hippocampus in response to neutral condition in motivational salience task

THC administration reduced the response latency to standard stimuli relative to oddball stimuli… attenuated activity in right caudate and putamen, increased activity in right prefrontal cortex during oddball processing. Effect of THC in right caudate was negatively correlated with both the severity of THC-induced psychotic symptoms and the effect on response latency

Hallucinations are one of the main clinical features of schizophrenia and can occur in any sensory modality, although auditory and visual hallucinations are most common (Allen, 2008). Elevated activity in the auditory and visual processing pathways has consistently been shown when patients are experiencing auditory and visual hallucinations, respectively (Allen, 2008; Bossong and Allen, in press). In response to external speech, patients exhibit strong reductions in activity in the superior temporal gyrus, althouh decreases in other area (bilateral middle frontal gyrus, right insula, left putamen) and increases (right middle temporal gyrus, left inferior parietal lobule, anterior cingulate cortex) have also been reported (Copolov, 2003; Woodruff, 1997)

THC decreased activation relative to placebo in bilateral superior temporal gyrus and right middle temporal gyrus when subjects listened passively to words read. The attenuation of temporal activation by THC was associated with increase in psychotic symptoms. During viewing of a visual checkerboard, THC reduced activity in regions of the occipital lobe (left middle occipital gyrus, right cuneus, bilateral lingual gyrus), increased in right middle occipital gyrus, bilateral lingual gyrus (Winton-Brown, 2011)

“Similarities in brain function between healthy volunteers after THC administration and schizophrenia patients provide an argument for the role of the endocannabinoid system in symptoms of schizophrenia”

Significant decreases in alertness may be associated with activity changes related to cognitive brain functions discussed in this review paper

Bossong M, Mehta M, van Berckel B, Howes O, Kahn R, Stokes P. 2015. “Further human evidence for striatal dopamine release induced by administration of ∆9-tetrahydrocannabinol (THC): selectivity to limbic striatum” Psychopharmacology (Berl) 232(15):2723-9

THC administration induced a significant reduction in [(11)C]raclopride binding in the limbic striatum (-3.65 %, from 2.39 ± 0.26 to 2.30 ± 0.23, p = 0.023). This is consistent with increased dopamine levels in this region. No significant differences between THC and placebo were found in other striatal subdivisions

This finding suggests limited involvement of the endocannabinoid system in regulating human striatal dopamine release and thereby challenges the hypothesis that an increase in striatal dopamine levels after cannabis use is the primary biological mechanism underlying the associated higher risk of schizophrenia.

[MV: I’d previously accused Bossong of dishonesty for claiming that marijuana has effects on dopamine “similar to other drugs of abuse,” even though his results show the effect to be smaller by an order of magnitude. Finally he admits that this effect cannot explain the association with psychosis. If he will also admit that THC does not block cannabinoid receptors or produce elevated glutamate signalling, I might take him off my shit list. His speculations have emboldened anti-pot critics despite the lack of empirical support. Here he finally admits a lack of empirical support for at least one part of that]

Boulanger L. 2009. “Immune proteins in brain development and synaptic plasticity” Neuron 64(1): 93-109

The MHCI is a large family of proteins that are expressed on the surface of most nucleated cells in the body. Cell-surface MHCI presents peptides derived from intracellular proteins for immune surveillance, permitting immune recognition of foreign (“nonself”) antigens generated by transplanted, infected, and cancerous tissues

Neurons themselves express immune proteins, but they can also be affected by secreted and cell-surface immune proteins produced by infiltrating immune cells (e.g., lymphocytes), microglia (the resident CNS macrophage), and other resident neuroglia (e.g., astrocytes, oligodendrocytes). Indeed, although neurons can produce tumor necrosis factor- (TNF)- α, glia are the source of the endogenous TNFα that affects synaptic scaling

Interleukin- (IL-) 6 and IL-6 receptor mRNAs are also coexpressed in neurons and are developmentally regulated in rat brain, with highest levels of both detected in adult hippocampus (Gadient and Otten, 1994)

TNFα can promote the cell surface accumulation of AMPA-type glutamate receptors (AMPARs) in hippocampal neurons in vitro. Since AMPARs carry the majority of excitatory glutamatergic current at resting membrane potentials, this TNFα-mediated increase in cell surface AMPARs should regulate synaptic transmission, and indeed, exogenous TNFα rapidly induces an increase in the frequency and amplitude of miniature excitatory postsynaptic currents (mEPSCs) in hippocampal neurons in vitro (Beattie et al., 2002 and Stellwagen et al., 2005)

In addition to its regulation of the properties of excitatory connections, MHCI was recently identified in a screen for targets of the transcription factor Npas4, which controls the number of inhibitory GABA-releasing synapses that contact excitatory neurons (Lin et al., 2008). However, it remains unknown if MHCI affects the establishment, maintenance, or function of GABAergic connections. A number of proinflammatory cytokines, including IL-1β (Zeise et al., 1992) and TNFα (Stellwagen et al., 2005), have been shown to regulate inhibitory synaptic transmission

endogenous MHCI in the adult hippocampus inhibits LTP and either permits or promotes LTD. A component of many MHCI immunoreceptors, CD3ζ, is also required for LTD and limits LTP in the adult hippocampus (Huh et al., 2000) (Figure 3B)

Since TNFα is a proinflammatory cytokine and can regulate MHCI expression, any effects TNFα may have on plasticity could potentially be mediated by changes in MHCI. In fact, several other proinflammatory cytokines, including interleukin- (IL-) 6 (Bellinger et al., 1995, Li et al., 1997 and Tancredi et al., 2000), IL-1β (Cunningham et al., 1996 and Katsuki et al., 1990), IL-2 (Tancredi et al., 1990), IL-18 (Curran and O’Connor, 2001), IL-8 (Xiong et al., 2003), and interferon-α and -β (D’Arcangelo et al., 1991 and Mendoza-Fernandez et al., 2000), also inhibit hippocampal LTP, consistent with the possibility they may converge on a common pathway. Although exogenous IL-6 inhibits LTP in hippocampal slice, IL-6 levels are dramatically upregulated by LTP induction in vivo (Balschun et al., 2004 and Jankowsky et al., 2000), and application of an anti-IL-6 antibody 90 min after tetanus prolonged LTP and improved long-term memory (Balschun et al., 2004)

In hippocampal neurons in vitro, chronic, long-term reduction of excitatory synaptic activity (e.g., with tetrodotoxin [TTX]) normally causes an increase in synaptic transmission, while a chronic increase in activity (e.g., by application of picrotoxin, a blocker of GABAA-mediated inhibition) causes a decrease in synaptic transmission. These changes keep the activity of networks relatively constant in the face of ongoing acute plasticity, keeping excitation and inhibition in balance and preventing runaway excitation that can lead to epileptic activation and excitotoxicity (Turrigiano, 2008)

MHCI is bidirectionally regulated by changes in activity, with increases in activity adding to the normal constitutive expression of MHCI. In contrast, TNFα may be released in response to a drop in activity ( Stellwagen and Malenka, 2006)

while TNFα is required for scaling up of excitatory synapses, other factors are responsible for scaling them down ( Stellwagen and Malenka, 2006)

Accumulating evidence indicates that the same molecules can perform both immunological and neurological functions in a single organism. It will be important to determine how these distinct functions coexist, and the pressures they exert on one another. Shared molecular machinery could help coordinate neuronal and immune responses of the disparate systems in which these proteins function, linking changes in the timing and magnitude of the two responses. It also increases the risk of potentially pathological molecular crosstalk. Given that the precisely tuned functioning of the immune system and the nervous system are both critical for survival, adaptations may have arisen to minimize such crosstalk, which if unchecked could promote autoimmunity, hamper efforts to fight off infections or cancer, or induce major motor or cognitive impairments. One speculative idea is that the immune privilege of the brain, long taken to be evidence that neurons lack key immune proteins, is instead necessary to preserve the distinct neuronal functions of these proteins. In this model, rather than being evidence of a lack of immune proteins, CNS immune privilege is the opposite: a specialization that is due to the expression and functional importance of immune proteins in normal brain development and plasticity

Bovasso G. 2001. “Cannabis abuse as a risk factor for depressive symptoms” American Journal of Psychiatry 158(12): 2033-2037

Participants (N=1,920) in the 1980 Baltimore Epidemiologic Catchment Area (ECA) study who were reassessed between 1994 and 1996 as part of a follow-up study

those who reported no depressive symptoms at baseline (N=849) and those with no diagnosis of cannabis abuse at baseline (N=1,837)

In participants with no baseline depressive symptoms, those with a diagnosis of cannabis abuse at baseline were four times more likely than those with no cannabis abuse diagnosis to have depressive symptoms at the follow-up assessment, after adjusting for age, gender, antisocial symptoms, and other baseline covariates. In particular, these participants were more likely to have experienced suicidal ideation and anhedonia during the follow-up period. Among the participants who had no diagnosis of cannabis abuse at baseline, depressive symptoms at baseline failed to significantly predict cannabis abuse at the follow-up assessment

underscore the importance of cannabis abuse prevention rather than treatment

Boys A, Marsden J, Strang J. 2001. “Understanding reasons for drug use amongst young people: a functional perspective” Health Education Research 16(4): 457-469

364 young poly-drug users recruited using snowball-sampling methods (345 cannabis users)

functions most endorsed for cannabis use were to `RELAX’ (96.8%), become `INTOXICATED’ (90.7%), `ENHANCE ACTIVITY’ (72.8%), `DECREASE BOREDOM’ (70.1%), `SLEEP’ (69.6%), FEEL BETTER’ (69.0%) after effects of other substances 64.6, stop worrying 57.7

Used [substance] to… Cannabis (n =345) Amphetamines (n = 160) Ecstasy (n =357) LSD (n =58) Cocaine (n =168) Alcohol (n =312)
aAbbreviations for these items shown in brackets are used in the text of this paper.
i–vIndication of rank according to item scores on Likert scales.
Make yourself feel better when down or depressed (FEEL BETTER)a 69.0 43.1 48.4 20.7 61.9 69.9
Help you `keep going’ on a night out with friends (KEEP GOING) 35.9 95.6i 91.1i 58.6iv 84.5i 66.7iv
Help you feel elated or euphoric (ELATED/EUPHORIC) 46.1 60.6iv 77.7iii 72.4ii 57.1iv 51.3
Just get really stoned or intoxicated (INTOXICATED) 90.7ii 55.0v 68.2v 77.6i 66.1iii 89.1i
Help you lose weight (LOSE WEIGHT) 23.1 7.0 6.0
Help you enjoy the company of your friends (ENJOY COMPANY) 66.4 58.1 63.1 58.6v 61.3v 74.0iii
Help you to relax (RELAX) 96.8i 13.1 29.9 17.2 28.6 82.7ii
Help you feel more confident or more able to talk to people in a social situation (INCREASE CONFIDENCE) 36.5 53.1 42.0 10.3 66.1 70.2v
Improve the effects of other substances (IMPROVE EFFECTS) 44.3 37.5 27.4 29.3 26.2 41.0
Help ease the after effects of other substances (AFTER EFFECTS) 64.6 11.9 8.3 3.4 12.5 35.9
Help you to stay awake (STAY AWAKE) 7.5 91.3ii 72.0iv 50.0 69.0ii 10.6
Help you lose your inhibitions (LOSE INHIBITIONS) 28.1 41.9 49.7 36.2 41.1 51.0
Enhance feelings when having sex (ENHANCE SEX) 27.8 31.9 63.1 25.9 52.4 32.1
Help you stop worrying about a problem (STOP WORRYING) 57.7 22.5 32.5 15.5 41.7 55.1
Help make something you were doing less boring (DECREASE BOREDOM) 70.1v 45.6 36.3 44.8 53.6 60.6
Help you to sleep (SLEEP) 69.6iv 30.4
Help you to concentrate or to work or study (WORK) 20.9 29.4 3.2 1.7 6.0 6.4
Enhance an activity such as listening to music or playing a game or sport (ENHANCE ACTIVITY) 72.8iii 66.2iii 79.6ii 72.4iii 60.7 51.6
Total number of items in the scale 17 17 17 16 17 17
Chronbach’s α for scale items 0.78 0.74 0.76 0.73 0.78 0.84
Mean total number of different functions endorsed for use of [substance] (range) 9.0 (0–17) 7.8 (0–16) 8.0 (0–16) 5.9 (0–15) 7.9 (0–17) 8.8 (0–17)

Braakman M, Kortmann F, van den Brink W. 2009. “Validity of ‘post-traumatic stress disorder with secondary psychotic features’: a review of the evidence” Acta Psychiatr Scand 119(1): 15-24

Twenty-four comparative studies were included. These studies indicate that PTSD-SP is a syndrome that comprises PTSD-symptoms followed in time by the additional appearance of psychotic features. The psychotic features are not confined to episodes of re-experiencing, but remain present continuously. PTSD-SP seems to have some biological features differentiating it from schizophrenia and PTSD, e.g. there are differences in smooth pursuit eye movement patterns, concentrations of corticotropin-releasing factor and dopamine beta-hydroxylase activity

Bradley A, Dinan T. 2010. “Review: A systematic review of hypothalamic-pituitary-adrenal axis function in schizophrenia: implications for mortality” Journal of Psychopharmacology 24: 91 in dropbox

Brandt C, Eichele T, Melle I, Sundet K, Server A, Agartz I, Hugdahl K, Jensen J, Andreassen O. 2014. “Working memory networks and activation patterns in schizophrenia and bipolar disorder: comparison with healthy controls” British Journal of Psychiatry 204: 290-298 in dropbox

patients with schizophrenia (n = 100) and bipolar disorder (n = 100) and a healthy control group (n = 100) performed a 2-back working memory task while fMRI data were acquired

Similar working memory networks were activated in all groups. However, in three out of nine networks related to the experimental task there was a graded response difference in fMRI signal amplitudes, where patients with schizophrenia showed greater activation than those with bipolar disorder, who in turn showed more activation than healthy controls

In both disorders the impairment is stable over time and across different clinical states, is relatively resistant to treatment and contributes to poor functional outcome.5

dorsolateral (Brodmann areas (BAs) 9/46) and ventrolateral (BAs 44/45/47) prefrontal cortex, premotor cortex (BAs 6/32) and parietal cortex (BAs 7/40) in both hemispheres.15,16 The last three components were deactivations in regions consistent with the main sites of the default mode network.29

no disease-specific network or compensatory region was detected

brain activation of people with schizophrenia and healthy controls may be represented by different, but overlapping, inverted U-curve shapes of activation.31,32 According to such a model, patients will show stronger activation than controls even if task difficulty is low

The three components that showed group differences were all in frontal and parietal brain regions consistent with the well-known working memory network

Breetvelt E, Boks M, Numans M, Selten J, Sommer I, Grobbee D, Kahn R, Geerlings M. 2010. “Schizophrenia risk factors constitute general risk factors for psychiatric symptoms in the population” Schizophr Res 120(1-3): 184-90

general population sample of 4894 subjects (mean age 39 years, 45% men) from the Utrecht Health Project

Participants with non-clinical psychotic symptoms had an 89% probability of concomitant depressive, anxiety or phobic anxiety symptoms, compared to 11% in participants without psychotic symptoms. The risk profiles for non-clinical psychotic symptoms and other psychiatric symptoms were largely similar. Non-Dutch ethnicity was most strongly associated with non-clinical psychotic symptoms. Adjusting for other psychiatric symptoms did not increase the specificity of the risk factors

Socio-demographic risk factors for non-clinical psychotic symptoms in the general population are also risk factors for other psychiatric symptoms

Bremner J, Southwick S, Darnell A, Charney D. 1996. “Chronic PTSD in Vietnam combat veterans: course of illness and substance abuse” Am J Psychiatry 153(3): 369-75

substance use increased in parallel with PTSD symptoms; alcohol, marijuana, heroin, and benzodiazepines reported to make PTSD symptoms better, while cocaine made symptoms in the hyperarousal category worse

Bremner J, Vythilingam M, Vermetten E, Southwick S, McGlashan T, Nazeer A, Khan S, Vaccarino L, Soufer R, Garg P, Ng C, Staib L, Duncan J, Charney D. 2003. “MRI and PET study of deficits in hippocampal structure and function in women with childhood sexual abuse and posttraumatic stress disorder” Am J Psychiatry 160 (5): 924-32

women with sexual abuse and PTSD (N=10) 16% smaller hippocampus than PTSD- abuse+ (N=12), 19% smaller than abuse- (N=11)

Breslau N, Davis G, Schultz L. 2003. “Posttraumatic stress disorder and the incidence of nicotine, alcohol and other drug disorders in persons who have experienced trauma” Arch Gen Psychiatry 60(3): 289-294

The prospective and retrospective data show an increased risk for the onset of nicotine dependence and drug abuse or dependence in persons with PTSD, but no increased risk or a significantly (P=.004) lower risk (for nicotine dependence, in the prospective data) in persons exposed to trauma in the absence of PTSD, compared with unexposed persons

Breslau N, Anthony J. 2007. “Gender differences in the sensitivity to posttraumatic stress disorder: an epidemiological study of urban young adults” Journal of Abnormal Psychology 116(3): 607-611

Qualifying events occur more often among men than among women, though the gender gap (i.e., male excess) tends to be small except for assaultive violence (e.g., shot/stabbed, badly beaten up, mugged/threatened with a weapon, raped), which occurs far more often among men (Breslau, Kessler, Chilcoat, et al., 1998; Breslau, Wilcox, et al., 2004)

Of the total sample of 1,698 young adults, 82.5% (n 1,401; 87.2% of men and 78.4% of women) were exposed to one or more DSM–IV qualifying traumatic events. The mean number of traumatic events was 4.8 (6.1 per male respondent and 3.7 per female respondent)

Among men, the conditional probability of PTSD varied little by (a) whether the worst event involved assaultive violence (7.2% vs. 7.7%)

among women, the conditional probability of PTSD following an assaultive violence event was markedly higher than following a nonassaultive event, 24.3% versus 6.9%

Britton J, Phan K, Taylor S, Fig L, Liberzon I. 2005. “Corticolimbic blood flow in posttraumatic stress disorder during script-driven imagery.” Biol Psychiatry. 57(8): 832-40

PTSD patients had greater rostral anterior cingulate (rACC) deactivation

Brodbeck J, Matter M, Page J, Moggi F. 2007. “Motives for cannabis use as a moderator variable of distress among young adults.” Addict Behav 32(8): 1537-45

2031 young Swiss adults; only cannabis users with coping motives showed lower mental health, greater pathology, more distress, and more life events than non-users whereas those with predominantly social reasons for use were not more distressed than non-users

Our results suggest that secondary prevention for cannabis users should target especially young adults with coping motives for use

Brook D, Brook J, Zhang C, Cohen P, Whiteman M. 2002. “Drug use and the risk of major depressive disorder, alcohol dependence and substance use disorders” Arch Gen Psychiatry 59(11): 1039-1044

community-based sample of 736 adults (50% female) from upstate New York, the subjects were interviewed at the mean ages of 14, 16, 22, and 27 years

Adolescent and young adult tobacco use was significantly associated with an increased risk of alcohol dependence and substance use disorders at a mean age of 27 years, but not with new episodes of major depressive disorder. Earlier alcohol use significantly predicted later major depressive disorder, alcohol dependence, and substance use disorders in the late 20s, as did early marijuana use and other illicit drug use. Except for the effect of tobacco use on major depressive disorder, early drug use was significantly related to later psychiatric disorders, even after statistically controlling for age, sex, parental educational level, family income, and prior episodes of major depressive disorder and substance use disorders

Marijuana use during childhood and early adolescence (OR, 1.18; 95% CI, 1.04-1.33; P<.05), middle and late adolescence (OR, 1.23; 95% CI, 1.06-1.43; P<.05), and the early 20s (OR, 1.41; 95% CI, 1.21-1.65; P<.001) also showed substantial effects on later MDD, alcohol dependence, and SUDs

the study provides evidence that drug use precedes MDD and alcohol dependence, and is not merely a consequence of these disorders

the similarity of the ORs between drug use and psychiatric disorders (1.2-1.4) suggests the homogeneity of their mechanisms, which may arise from unmeasured common underlying factors

a decrease in youth substance use may be accompanied by a corresponding decrease in later psychiatric disorders

Brown G, Craig T, Harris T, Handley R, Harvey A. 2007. “Development of a retrospective interview measure of parental maltreatment using the Childhood Experience of Care and Abuse (CECA) instrument — a life-course study of adult chronic depression -1” J Affect Disord 103(1-3): 205-15

adverse maternal behaviour emerges as of critical importance for the link with adult chronic depression. Maternal lack of affection (‘neglect’) and maternal rejection (’emotional abuse’) form the core of an index of parental maltreatment, and it is concluded that persistent rejection, particularly from a mother, appears to be the core experience of importance

Broyd S, Demanuele C, Debener S, Helps S, James C, Sonuga-Barke E. 2009. “Default-mode brain dysfunction in mental disorders: a systematic review” Neuroscience and Biobehavioral Reviews 33: 279-296 in dropbox

Marcus Raichle first coined the term ‘default-mode’ in relation to resting state brain function ( Raichle et al., 2001 )

attenuation of the ventral MPFC occurred with tasks involving judgments that were self-referential, while activity in the dorsal MPFC increased for self-referential stimuli, suggesting the dorsal MPFC is associated with introspective orientated thought ( Gusnard et al., 2001).

the DMN is characterised by very low frequency neuronal oscillations providing temporal synchrony between functionally specific and diverse brain regions (Sonuga-Barke and Castellanos, 2007)

Should only the task-negative network be termed the DMN and contrasted with the task-positive network? Or should both task-positive and task-negative networks be regarded as elements of the DMN? … we use the DMN term to describe the task-negative network specifically. We use the term Low Frequency Resting State Networks (LFRSN) to describe both the task-positive and task-negative networks.

The human brain then, is never really ‘at rest’, but rather an orchestra of distinct functional networks in dynamic concert

PCC appears to serve an important adaptive function and is implicated in broad-based continuous sampling of external and internal environments ( Raichle et al., 2001), the attenuation of which during transition from rest facilitates focused attention during task-specific activity (Eichele et al., 2008; Raichle et al., 2001). Moreover, modulation of the PCC during working-memory tasks (Greicius et al., 2003 ), reduced activation at rest (Greicius et al., 2004 ), susceptibility to atrophy in Alzheimer’s disease patients (Buckner et al., 2005), and reduced connectivity with anterior DMN regions in attention deficit/ hyperactivity disorder (ADHD) participants ( Castellanos et al., 2008; Uddin et al., 2008a ) suggests that this region may be implicated in working memory dysfunction. Finally, PCC and retrosplenial cortex are also associated with the processing of emotionally salient stimuli, and may play a role in emotional processing related to episodic memory (Maddock, 1999)

MPFC is thought to mediate a dynamic interplay between emotional processing and cognition functions which map on to the ventral and dorsal regions, respectively ( Gusnard et al., 2001; Raichle et al., 2001; Simpson et al., 2001). Ventral MPFC is heavily interconnected with other limbic structures such as amgydala, ventral striatum and hypothalamus, which Gusnard and colleagues suggest may indicate a role in relation to the mediation of visceromotor aspects of emotional information gathered from external and internal sources ( Gusnard et al., 2001; Gusnard and Raichle, 2001). Both PCC/precuneus and MPFC are associated with introspective processes such as self-referential and emotional processing, and are attenuated when attention is directed toward external events ( Gusnard and Raichle, 2001)

In view of the lack of association between alpha and resting state brain activity, Laufs et al. (2003b) hypothesise that alpha may act as a baseline for specific brain structures associated with the
attentional system, and more specifically the task-positive net-work ( Laufs et al., 2006 ). In contrast, Mantini et al. (2007) reported positive correlations between beta (13–30 Hz) and alpha (8–13 Hz) with the PCC, precuneus, bilateral superior frontal gyrus and the MFG

The results ofMeltzer et al. (2007) and Scheeringa et al. (2008) suggest that the DMN may operate within the theta frequency such that decreased DMN activation is associated with increased theta power during goal-directed activity

low frequency electromagnetic activity is notoriously difficult to study. Interference to the low frequency fluctuations in the BOLD signal may arise from low frequency cycles in respiration and cardiac activity, and the related body and head movements may obscure EEG and MEG signals. Variations in respiration ( 0.03 Hz) correlate highly with fluctuations in the DMN ( <0.1 Hz), with overlap between regions within the DMN and areas significantly affected by changes in respiration (Birn et al., 2006, 2008)

The ability to maintain attentional focus and resist distraction or lapses of attention is conventionally considered to underlie higher order top–down control… two groups have suggested that the DMN may represent a mechanism underlying deficient top–down attentional control (Mason et al., 2007; Sonuga-Barke and Castellanos, 2007). Both perspectives predict that attentional lapses during goal-directed action may be a result of interference arising from spontaneous, and most likely self-referential, thought

Spontaneous low frequency activity in the task-negative compo-nent of the default-mode network which is routinely attenuated during goal directed tasks, can under certain circumstances (e.g. suboptimal motivational states or in individuals with attention disorders) persist into or remerge during periods of task-related active processing to such an extent that it competes with task-specific neural processing and creates the context for periodicattentional intrusions/lapses and cyclical deficits in performance; the temporal signatures of task-negative fluctuations being mirrored in patterns of attention and performance ( Sonuga-Barke and Castellanos, 2007, p. 981)

lapses in attention will be caused by intrusions of introspective thought which produce increased variability in task performance

The notion of wandering minds provides another possible theory of attentional lapses during task performance, and it is conceivable that generalised deficits in attention and cognitive control may well coincide with an increased incidence of stimulus-independent thought or mind wandering and the intrusion of increased activity in the DMN

In a group of schizophrenic patients, Zhou et al. (2007) reported significantly increased resting state connectivity in the task-positive network and DMN in the patient group,  alongside significantly increased anti-correlations between the networks. These results were more specifically associated with bilateral dorsal MPFC, inferior temporal gyrus, and lateral parietal region in the DMN; and right dorsal lateral PFC and bilateral insula and orbital frontal gyrus in the task-positive network. The authors argue that the increased anti-correlations reflect increased antagonism and excessive competition between the networks, and most likely contribute to the over-mentalising and deficit in attentional control symptomatic of schizophrenia. More interest-ingly, reduced anti-correlations were evident between the right dorsal premotor cortex and the PCC and bilateral parietal region of the DMN and suggest that the right dorsal premotor cortex may be instructive in mediating the anti-correlation between the DMN and task-positive networks (Zhou et al., 2007 )

resting state BOLD fMRI scans revealed a reduced anti-correlation in an ADHD population relative to controls, thought to relate to attentional lapses and performance variability sympto-matic of this disorder (Castellanos et al., 2008)

Kennedy and Courchesne (2008) report no significant anti-correlations in a sample of individuals with autism spectrum disorder (ASD). This patient group did not show any abnormal patterns of connectivity in the task-positive network, but did show reduced connectivity in the DMN mainly associated with the MPFC

Hahn et al. (2007) reported nicotine to increase deactivation within the DMN for task-specific cues, indicating increased preparation and improvements in attentional control ( Hahn et al., 2007)

excessive rivalry between the functions subserved by the networks and associated neural processing, will be accompanied by cyclical fluctuations in attention and deficits in goal-directed action. Generally, this will manifest as an attentional deficit

In Alzheimer’s disease, connectivity between the right hippocampus and many component regions of the DMN, including the dorsal MPFC, ventral ACC, middle temporal gyrus (MTG) and the right PCC is reduced ( Wang et al., 2006), and likely relates to a dysfunction of working memory and attentional processes. Similarly, although one study has reported increased resting state functional connectivity within the DMN in adoles-cents with ADHD (Tian et al., 2006 ), more commonly, aberrant functional connectivity between the anterior (e.g. MFPC and superior frontal gyrus) and posterior (e.g. PCC/precuneus) compo-nents of the DMN is observed ( Castellanos et al., 2008; Uddin et al., 2008a )

in schizophrenia, increased connectivity between the DMN and other resting state networks suggests greater depen-dence on other resting state networks, most likely associated with increased distraction due to hallucinations and delusional experiences (Jafri et al., 2008 ). Moreover, increased connectivity within the DMN and task-positive network in schizophrenic patients at rest implies that these individuals are susceptible to over-mentalising and excessive alertness to the external environ-ment, respectively (Zhou et al., 2007 )

aberrant increases in connectivity will likely manifest in delusional experience, over ardent mentalising, and attentional lapses due to the disproportionate involvement and interaction between the DMN and associated networks

n schizophrenia, positive symp-tom severity was correlated with increased deactivation in the MFG, precuneus, and the left MTG in an oddball task (Garrity et al., 2007), while impaired self-monitoring processes and stimulus-independent thought have been associated with abnormal low frequency resting state connectivity (Bluhm et al., 2007; Liang et al., 2006 ). In autism however, atypical or reduced self-referential, affective and introspective thought is associated with low activation of the DMN in the resting state. Additionally, atypical emotional processing in autism is notable by the absence of any functional activation of the medial orbital frontal component of the DMN during the processing of emotional compared with neutral words in a Stroop task (Kennedy et al., 2006). Indeed, reduced task-induced deactivation of the DMN during a number-word Stroop task has been associated with greater social impairment in participants with autism (Kennedy et al., 2006 ). More specifically, reduced DMN connectivity in autism is associated with the MPFC

In depressed patients, the subgenal cingulate is a prominent region within the DMN and related to the length of depressive episode, while noticeably absent in the DMN of control partici-pants (Greicius et al., 2007 ). Further, in this patient group increased connectivity between the DMN and the thalamus is argued to reflect increased interaction between the thalamus and subgenal cingulate due to increased emotional processing, at the expensive of executive functions (Greicius et al., 2007 ). In patients with anxiety disorders, reduced deactivation of MPFC and increased deactivation of the PCC is thought to be indicative of increased levels of anxiety (MPFC) and emotional processing (PCC) of task-specific threat words

reduced connectivity between MPFC and PCC regions of the DMN is associated with aging, and the anterior region of the DMN is correlated with cognitive decline. In Alzheimer’s patients, the hippocampus features as a prominent node within the DMN and shows reduced connectivity with other DMN regions

greater deactivation in the MFG, precuneus, and the left MTG were correlated with positive symptoms of schizophrenia (Garrity et al., 2007 )

increased connectivity between the DMN and other resting state networks using spatial ICA, has been hypothesised to reflect distraction and hallucinatory experiences of schizophrenic patients (Jafri et al., 2008). … reduced deactivation of ACC was suggested to be associated with reduced attentional control

subgenual cingulate was found to contribute disproportionally to the connectivity of the DMN in this patient group, with increases in connectivity associated with depression refractoriness, or the length of the current depressive episode (Greicius et al., 2007). There was also increased functional connectivity in the thalamus during rest. Greicius et al. (2007) suggest that increased
connectivity in ‘affective’ regions may detrimentally affect connectivity in regions associated with cognitive processing such as the dorsal anterior cingulate (Greicius et al., 2007)

no difference in the deactivation of the DMN was evident between a group of anxiety patients or controls when emotionally neutral words were alternated with rest. In contrast, when threat words were alternated with emotionally neutral words, anxiety patients demonstrated reduced deactiva-tion of the MPFC and increased deactivation of the PCC relative to controls ( Zhao et al., 2007)

it has been postulated that a deficit in the mirror neuron network is associated with DMN dysregulation in autism, suggesting that this disorder may arise from an atypical processing of self and relationship with others (Iacoboni, 2006 )

increased functional connectivity with dorsal ACC was observed for bilateral dorsal ACC, bilateral thalamus, bilatertal cerebellum, bilateral insula and bilateral brain stem in the ADHD compared to control group… the ADHD group showed less negatively correlated functional activity in the ACC, MFG and superior temporal gyrus… may indicate a relationship between working
memory deficits and attentional lapses in ADHD (Castellanos et al., 2008)… adult ADHD and control groups did not differ on global measures of DMN homogeneity, although significantly reduced network homogene-ity in the posterior regions of the DMN, particularly the precuneus was observed in the ADHD group (Uddin et al., 2008a)

Burstein S, Hunter S. 1995. “Stimulation of anandamide biosynthesis in N-18TG2 neuroblastoma cells by delta 9-tetrahydrocannabinol (THC)” Biochem Pharmacol 49(6): 855-8


Butters J. 2002. “Family stressors and adolescent cannabis use: a pathway to problem use” J Adolesc 25(6): 645-54

those reporting family disruption (e.g.,from death or divorce) 79% more likely to use cannabis; of those who were already using cannabis, … family disruption were 87% more likely to progress to problem use.

van Buuren M, Gladwin T, Zandbelt B, van den Huevel M, Ramsey N, Kahn R, Vink M. 2009. “Cardiorespiratory effects on default-mode network activity as measured with fMRI” Human Brain Mapping 30: 3031-3042 in dropbox

The default-mode network (DMN) consists of areas showing more activation during rest than during a task

The goal of this study is to investigate whether BOLD signal changes within the DMN can be explained by CR effects

CR effects were present within the frequency-range of the DMN and were located in areas of the DMN, but equally so in other areas. After removal of CR effects, deactivation and resting-state connectivity between the areas of the DMN remained significant. In addi-tion, DMN deactivation was still modulated by task demand. The same CR correction method did remove activation in task-related areas. We take these results to indicate that the BOLD signal within the DMN cannot be explained by CR effects alone and is possibly related to some form of cognitive neuronal processing

Functional imaging studies typically investigate brain function by identifying areas showing increased activation during a task as compared to rest or baseline. However, some areas in the brain are more active during rest [Binder et al., 1999; Mazoyer et al., 2001; Shulman et al., 1997]. To-gether, these areas are called the default-mode network (DMN) and include the posterior cingulate (PCC), the medial prefrontal cortices and the lateral posterior cortices (Brodmann area 39) [Fox et al., 2005; Greicius et al., 2003; Raichle et al., 2001]

the cardiac and respiratory cycle cause signal changes in brain areas near major vessels and the ventricles, and motion artifacts near the edges of the brain [Bhattacharyya and Lowe, 2004; Dagli et al., 1999; Glover et al., 2000; Hu et al., 1995]. In addition, fluctuations in heart rate (HR), heart rate variability (HRV) and respiration volume are related to BOLD signal changes in grey matter areas not located near large vessels [Birn et al., 2006; Critchley et al., 2003; Shmueli et al., 2007; Wise et al., 2004]

correcting for CR effects resulted in both reduced BOLD signal changes during the task (Fig. 5A,B) and reduced resting-state connectivity in the DMN and the task-positive network (Table III) (i.e. areas that showed more activation during the task compared to rest). However, even after applying a strict method to cor-rect for CR effects, BOLD signal changes within the DMN
during the task as well as resting-state connectivity between the areas of the DMN remained significant. In addition, DMN deactivation was still modulated by the amount of effort or attention required to perform the task

the proportion of variance explained by factors modeling CR effects was higher within the task-positive network compared to DMN

BOLD signal changes within the DMN were correlated with EEG power within the alpha and beta band [Mantini et al., 2007]

This study confirmed that part of the BOLD signal within the DMN originates from confounding effects of cardiorespiratory processes

Cabral G. 2001. “Marijuana and Cannabinoids: Effects on Infections, Immunity, and AIDS” Journal of Cannabis Therapeutics 1(3/4): 61-85

Cabral G, Raborn E, Griffin L, Dennis J, Marciano-Cabral F. 2008. “CB2 receptors in the brain: role in central immune function” Br J Pharmacol 153(2): 240-251

Recently, it has been recognized that the cannabinoid receptor CB2 may play a functionally relevant role in the central nervous system (CNS). This role is mediated primarily through microglia, a resident population of cells in the CNS that is morphologically, phenotypically, and functionally related to macrophages. These cells also express the cannabinoid receptor CB1. The CB1 receptor (CB1R) is constitutively expressed at low levels while the CB2 receptor (CB2R) is expressed at higher levels and is modulated in relation to cell activation state. The relatively high levels of the CB2R correspond with microglia being in ‘responsive’ and ‘primed’ states, suggesting the existence of a ‘window’ of functional relevance during which activation of the CB2R modulates microglial activities. Signature activities of ‘responsive’ and ‘primed’ microglia are chemotaxis and antigen processing, respectively. The endocannabinoid 2-arachidonylglycerol has been reported to stimulate a chemotactic response from these cells through the CB2R. In contrast, we have shown in vivo and in vitro that the exogenous cannabinoids delta-9-tetrahydrocannabinol and CP55940 inhibit the chemotactic response of microglia to Acanthamoeba culbertsoni, an opportunistic pathogen that is the causative agent of Granulomatous Amoebic Encephalitis, through activation of the CB2R

CB1R is G-protein coupled as evidenced by inhibition of adenylyl cyclase (Howlett et al., 1986), inhibition of N-type calcium channels (Mackie and Hille, 1992) and increased binding of non-hydrolyzable GTPγS in the presence of cannabinoids (Sim et al., 1996)

Transcripts (that is, mRNAs) for the CB1R and CB2R have been found in spleen and tonsils (Munro et al., 1993; Galiègue et al., 1995) and other immune tissues (Munro et al., 1993; Bouaboula et al., 1996). However, in all cases reported to date, levels of message for the CB2R in immune cells exceed those for the CB1R. The distribution pattern of levels of CB2R mRNA displays major variation in human blood cell populations with a rank order of B lymphocytes>natural killer cells≫monocytes>polymorphonuclear neutrophils>CD8 lymphocytes>CD4 lymphocytes (Galiègue et al., 1995)

The presence of the CB2R primarily within immune cells suggests a role for this receptor in the activities attributed to these cells. However, CB1R also may be involved in cannabinoid-mediated modulation of select immune functions (Stefano et al., 1996; Sinha et al., 1998; Waksman et al., 1999)

palmitoylethanolamide, an analogue of anandamide that does not bind the CB2R, causes a reduction of pain associated with inflammatory response (Calignano et al., 1998; Jarai et al., 1999) that is blocked by the CB2R antagonist ((1S-endo)-5-(4-Chloro-3-methylphenyl)-1-((4-methylphenyl)methyl)-N-(1,3,3-trimethylbicyclo(2.2.1)hept-2-yl)-1H-pyrazole-3-carboxamide (SR144528). The nuclear peroxisome proliferator-activated receptor-alpha (PPAR-α) has been reported as the mediator of the anti-inflammatory actions of this lipid amide (Lo Verme et al., 2005a, 2005b)

Microglia migrate and proliferate during and after injury and inflammation (Leong and Ling, 1992; Kreutzberg, 1995, 1996; Benveniste, 1997a). Once activated, they produce various cytokines including interleukin (IL)-1, IL-6 and tumour necrosis factor-α (Giulian et al., 1986; Reid et al., 1993; Benveniste, 1997b), and express major histocompatability complex (MHC) class I and II antigens and the complement receptor, CD11/CD18 complex.  Microglia, also, are phagocytic and, upon activation, can process antigens and exert cytolytic functions. Paradoxically, these cells not only play a role in host defense and tissue repair in the CNS (Streit et al., 1988; Perry, 1990), but also have been implicated in nervous system disorders, such as Multiple Sclerosis (MS) (Matsumoto et al., 1992), Alzheimer’s disease (Rogers et al., 1988), Parkinson’s disease (McGeer et al., 1988) and acquired immune deficiency syndrome (AIDS) dementia (Dickson et al., 1991; Merrill and Chen, 1991; Spencer and Price, 1992). Neural histological features of AIDS dementia complex include diffuse leukoencephalopathy of the white matter, which is accompanied by severe loss of myelin and sparing of fibres (Kleihues et al., 1985) Discrete areas of demyelination with hypertrophied astrocytes, which also contain microglia, blood-derived macrophages and multinucleated giant cells, are observed. The multinucleated giant cells have been reported to constitute syncytia of macrophages or microglia, which are productively infected with the human immunodeficiency virus type 1 (HIV1) and are a histopathological hallmark of subacute encephalitis in HIV1-infected brains (Koenig et al., 1986; Michaels et al., 1988) and spinal cords (Eilbott et al., 1989; Maier et al., 1989). Thus, it has been proposed that in AIDS dementia, macrophages and microglia are the predominant cell types, which are infected and produce HIV1 (Koyanagi et al., 1987; Kure et al., 1990)

The CB2R is not detected in ‘resting’ cells, is present at high levels in ‘responsive’ and ‘primed’ cells, and is identified at greatly diminished levels in ‘fully’ activated cells. In contrast, the CB1R is present in microglia at relatively low levels and is expressed constitutively in relation to cell activation state

since the kinetics of CB1R and CB2R expression by microglia are distinctive, activation of the two receptors by endogenous and/or exogenous cannabinoids may result in disparate functional outcomes

fully’ activated microglia are not susceptible to cannabinoid-mediated action that is linked to the CB2R

Waksman et al. (1999) reported that the production of inducible nitric oxide (iNO), a potent inflammatory mediator that is released from microglia and macrophage-like cells upon their ‘full’ activation, was inhibited by cannabinoids in a mode that was linked, at least in part, to the CB1R

Puffenbarger et al. (2000) extended these studies on the effects of cannabinoids on ‘fully’ activated microglia and indicated that the inhibition of the inducible expression of pro-inflammatory cytokines was exerted through a non-CB1, non-CB2 receptor process

Exposure of neonatal rat cortical microglia to THC resulted in reduced amounts of lipopolysaccharide-induced mRNAs for IL-1α, IL-1β, IL-6 and tumour necrosis factor-α. Of these cytokine mRNAs, the response of that for IL-6 was exquisitely sensitive to THC treatment… when methanandamide, the non-hydrolyzable analogue of anandamide, was tested, its ability to inhibit cytokine mRNA expression was comparable to that of THC

Stefano et al. (1998) reported that acute exposure to anandamide resulted in transformation of macrophages from an amoeboid and motile state to that of a rounded and non-motile conformation. These investigators proposed that the transforming events were linked to the CB1R since the CB1R-selective antagonist SR141716A blocked the transformation

The chemotactic response of mouse macrophages to formal-methionyl-leucine-phenylalanine also has been shown to be decreased by CBD (Sacerdote et al., 2005), a cannabinoid that binds weakly to the CB2R. The CB2R antagonist SR144528 prevented this decrease, suggesting a functional linkage to the cognate receptor

Walter et al. (2003) found that the endocannabinoid 2-arachidonylglycerol (2-AG) triggered migration of microglia and that the CB2R was involved in this effect

Franklin and Stella (2003) suggested that CB2Rs and ‘abnormal-CBD-sensitive’ receptors regulated the migration of microglial-like cells. Stella and co-workers extended these studies and showed that P2X7 ionotropic receptors played a key role in controlling the production of 2-AG by microglia (Witting et al., 2004). Recently, Raborn et al. (in press) demonstrated that THC and CP55940 mediated inhibition of mouse peritoneal macrophage chemotaxis to the chemokine RANTES/CCL5 and that this event was linked to the CB2R.

cannabinoids act through the CB2R to alter macrophage migration with exogenous cannabinoids, such as THC exerting inhibitory effects and endocannabinoids such as 2-AG eliciting an opposite stimulatory effect

the CB2R may be a constituent element of a network of G-protein-coupled receptor signal transductional systems, inclusive of chemokine receptors, that act coordinately to modulate macrophage migration

THC impaired the ability of a macrophage hybridoma to function as an antigen-presenting cell based on its ability to secrete IL-2 upon stimulation of a soluble protein antigen-specific helper T-cell hybridoma… CB2 activation on macrophages

CB2R as playing a relevant functional role in the early inflammatory process by macrophages and macrophage-like cells, namely chemotaxis and antigen-processing functional attributes of these cell types when in ‘responsive’ and ‘primed’ states. Since microglia constitute a resident population of macrophages in the brain, exhibit phenotypic and functional properties of macrophages, and express the CB2R at maximal levels when in ‘responsive’ and ‘primed’ states, a ‘window’ of functional relevance for the CB2R comparable to that for macrophages at peripheral sites may be operative

Mice treated with THC exhibited higher mortalities from infection with Acanthamoebaas compared to similarly infected vehicle control mice (Marciano-Cabral et al., 2001)

The CB2R, but not the CB1R, agonist inhibits chemotaxis of microglia

It is postulated that bioactive lipid mediators thus generated include the endocannabinoid 2-AG that serves to drive chemotaxis by autocrine and/or paracrine activation of the CB2R. The exogenous cannabinoid THC may inhibit this chemotactic response by superimposing a signal transductional activation of the CB2R. That is, THC could inhibit the synthesis and/or release of 2-AG or, alternatively, by virtue of its relative long half-life as compared to that of 2-AG, preclude this endocannabinoid from ligating to the CB2R

Alzheimer’s disease, Parkinson’s Disease, MS, amyotrophic lateral sclerosis and HIV-associated dementia. The pathological hallmark of these diseases is chronic inflammation induced by persistent cell activation and elicitation of proinflammatory mediators (that is, NO, cytokines and chemokines). Studies have shown that microglia and microglia-derived cells are the major cell types responsible for this neuroinflammation

During activation, microglia upregulate an array of cell-surface receptors that may be critical in microglial regeneration and/or degeneration of the CNS. Included among these are immunoglobulin (Ig) superfamily receptors, complement receptors, toll-like receptors, cytokine/chemokine receptors, opioid receptors and cannabinoid receptors. Microglia have been found to express both the CB1R and CB2R in vitro (Carlisle and Cabral, 2002; Carrier et al., 2005) and to produce the endocannabinoids 2-AG as well as anandamide in lesser quantities (Carrier et al., 2004)… Activation of the CB2R on these cells appears to promote migration and proliferation. Walter et al. (2003) demonstrated that 2-AG induced migration of microglia and that this occurred through the CB2R and abnormal-CBD-sensitive receptors

Fernandez-Ruiz et al. (2007), using a variety of neurodegenerative disease models, reported the expression of the CB2R in microglia, astrocytes and neuron sub-populations. This expression of the CB2R in vivo apparently is attributed, in large measure, to microglia. In several neurodegenerative diseases, upregulation of microglial CB2R has been observed (Zhang et al., 2003; Benito et al., 2005, 2007; Maresz et al., 2005; Yiangou et al., 2006; Ashton et al., 2007)

It has been proposed that the role of the CB2R in immunity in the CNS is primarily that of anti-inflammatory (Carrier et al., 2005)

Cabral G, Griffin-Thomas L. 2009. “Emerging role of the CB2 cannabinoid receptor in immune regulation and therapeutic prostpects” Expert Rev Mol Med 11: e3

CB2 may serve as a selective molecular target for therapeutic manipulation of untoward immune responses including those associated with a variety of neuropathies that exhibit a hyperinflammatory component

Campolongo P, Roozendaal B, Trezza V, Hauer D, Schelling G, McGaugh J, Cuomo V. 2009. “Endocannabinoids in the rat basolateral amygdala enhance memory consolidation and enable glucocorticoid modulation of memory.” Proc Natl Acad Sci U S A 106(12): 4888-93

basolateral amygdala modulates consolidation of emotionally arousing memories, involving glucocorticoids. CB1 agonists enhance, and antagonists impair, retention of avoidance training if injected into rat BLA after training. Antagonist blocks corticosterone memory enhancement

Campos A, Ferreira F, Guimaraes F, Lemos J. 2010. “Facilitation of endocannabinoid effects in the ventral hippocampus modulates anxiety-like behaviors depending on previous stress experience” Neuroscience 167(2): 238-46

AM404 (5-50 pmol) microinjection promoted an anxiogenic-like effect in non-stressed rats but decreased anxiety in stressed animals

Cardno A, Gottesman I. 2000. “Twin studies of schizophrenia: from bow-and-arrow concordances to Star Wars Mx and functional genomics” American Journal of Medical Genetics 97 (1): 12-17;2-U/abstract

concordance rates of 41–65% in monozygotic (MZ) pairs and 0–28% in dizygotic (DZ) pairs, and heritability estimates of approximately 80–85%

Carey C, Agrawal A, Zhang B, Conley E, Degenhardt L, Heath A, Li D, Lynskey M, Martin N, Montgomery G, Wang T, Bierut L, Hariri A, Nelson E, Bogdan R. 2015. “Monoacylglycerol lipase (MGLL) polymorphism rs604300 interacts with childhood adversity to predict cannabis dependence symptoms and amygdala habituation: evidence from an endocannabinoid system-level analysis” J Abnorm Psychol 124(4): 860-77

Significant interactions with CSA emerged for MGLL at the gene level (p = .009), and for rs604300 within MGLL (ΔR2 = .007, p < .001), the latter of which survived SNP-level Bonferroni correction and was significant in an additional sample with similar directional effects (N = 859; ΔR2 = .005, p = .026). Furthermore, in a third sample (N = 312), there was evidence that rs604300 genotype interacts with early life adversity to predict threat-related basolateral amygdala habituation, a neural phenotype linked to the eCB system and addiction (ΔR2 = .013, p = .047). Rs604300 may be related to epigenetic modulation of MGLL expression. These results are consistent with rodent models implicating 2-arachidonoylglycerol (2-AG), an endogenous cannabinoid metabolized by the enzyme encoded by MGLL, in the etiology of stress adaptation related to cannabis dependence

Carracedo A, Gironella M, Lorente M, Garcia S, Guzman M, Velasco G, Iovanna J. 2006. “Cannabinoids induce apoptosis of pancreatic tumor cells via endoplasmic reticulum stress-related genes” Cancer Res 66: 6748

Pancreatic adenocarcinomas are among the most malignant forms of cancer… the fourth leading cause of cancer death in the United States and the fifth in the Western world overall

cannabinoid receptors are expressed in human pancreatic tumor cell lines and tumor biopsies at much higher levels than in normal pancreatic tissue

cannabinoid administration (a) induced apoptosis, (b) increased ceramide levels, and (c) up-regulated mRNA levels of the stress protein p8. These effects were prevented by blockade of the CB2 cannabinoid receptor or by pharmacologic inhibition of ceramide synthesis de novo

Cannabinoids also reduced the growth of tumor cells in two animal models of pancreatic cancer. In addition, cannabinoid treatment inhibited the spreading of pancreatic tumor cells. Moreover, cannabinoid administration selectively increased apoptosis and TRB3 expression in pancreatic tumor cells but not in normal tissue. In conclusion, results presented here show that cannabinoids lead to apoptosis of pancreatic tumor cells via a CB2 receptor and de novo synthesized ceramide-dependent up-regulation of p8 and the endoplasmic reticulum stress–related genes ATF-4 and TRB3

cannabinoids exert a strong inhibitory effect on the spreading of pancreatic tumor cells not only to adjacent locations such as spleen but also to distal tissues such as liver, diaphragm, stomach, and intestine, thus suggesting that these agents may also decrease the propagation of pancreatic tumor cells.

Although the pancreatic tumor biopsies and cell lines analyzed expressed both CB1 and CB2 cannabinoid receptors, our findings indicate that the CB2 receptor is the one that plays a major role in the proapoptotic effect of cannabinoids in these cells

CB2 receptor is involved in the antitumoral effect of cannabinoids in gliomas ( 9, 19), skin carcinomas ( 11), lymphomas ( 18), and prostate carcinomas ( 30)

p8 and ATF-4 up-regulation mediates cannabinoid-induced apoptosis via induction of the proapoptotic protein TRB3 ( 29, 31)

cannabinoid treatment does not seem to activate this pathway in normal pancreas or spleen, suggesting that these agents may activate the endoplasmic reticulum stress proapoptotic pathway selectively in tumor cells

Carrey N, Butter H, Persinger M, Bialik R. 1995. “Physiological and cognitive correlates of child abuse” J Am Acad Child Adolesc Psychiatry 34(8): 1067-75 in dropbox

Verbal and Full Scale IQ scores were inversely related to the severity of abuse that had been experienced. When these variables were used in a discriminant function analysis, children were assigned to the correct group 86% of the time

abuse as delaying cognitive development and inhibiting physiological responsiveness to the environment — 13 full scale IQ gap between abused and reference group

Carrion V, Weems C, Eliez S, Patwardhan A, Brown W, Ray R, Reiss A. 2001. “Attenuation of frontal asymmetry in pediatric posttraumatic stress disorder” Biol Psychiatry 50(12): 943-51

Casadio P, Fernandes C, Murray R, Di Forti M. 2011. “Cannabis use in young people: The risk for schizophrenia” Neuroscience and Biobehavioral Reviews 35: 1779-1787 add to dropbox

Until recently, the main types of cannabis available on the “street” were marijuana (grass) and resin (hash) but in recent years a more potent variant termed sinsemilla or skunk has become available in many countries

repeated use of cannabis produces a prolonged and excessive stimulation of the CB1 receptor and disrupts the system

polymorphisms in the AKT1 gene could be involved in cannabis induced psychosis possi-bly through a mechanism of cannabinoid-regulated AKY1/GSK-3 signalling downstream of the dopamine D2 receptor

Other environmental risk factors can also be important. Harley et al. (2010) in studying the effects of childhood trauma, confirmed that cannabis use and childhood trauma were independently asso-ciated with the risk of psychotic symptoms (only cannabis use: OR = 1.9, 95% CI = 0.04–16.5, p = 0.55; only trauma: OR = 2.6, 95% CI = 0.25–14.6, p = 0.23; trauma and cannabis use: OR = 20.9, 95% CI = 2.3–173.5, p = 0.00), but that the joint presence of these two risk factors increased the likelihood of psychotic symptoms in ado-lescence to a much greater extent than would be expected if each risk factor were working independently.

predisposition for psychosis at baseline did not significantly predict cannabis use at follow-up, thus refuting the self-medication hypothesis

Possible explanations for the greater risk in those who start cannabis use early include:
– This association reflects an increased propensity of young peopel with psychotic experiences to commence cannabis use (reverse causality);
– Higher cumulative exposure to cannabis of early users;
– Increased vulnerability to THC during critical phases of brain maturation, such as in early puberty, is reflected in a specific association between psychotic experiences and young inital age of THC exposure

The ability of THC to induce dopamine release in the striatum suggests that THC shares addictive properties with other drugs of abuse, as dopamine has a central role in their rewarding effects, but the increase was modest compare to that obtained with other drugs like cocaine, nicotine or alcohol

While cannabis does not have long term adverse effects for the majority of users, it is clear from studies of psychosis that some individuals are more vulnerable to its effects than others, and that the degree of cannabis exposure and age of first use amplify the harmful effects of cannabis

Caspi A, Moffitt T, Cannon M, McClay J, Murray R, Harrington H, Taylor A, Arseneault L, Williams B, Braithwaite A, Poulton R, Craig I. 2005. “Moderation of the effect of adolescent-onset cannabis use on adult psychosis by a functional polymorphism in the catechol-O-methyltransferase gene: longitudinal evidence of a gene X environment interaction” Biol Psychiatry 57(1): 1117-27

functional polymorphism in the catechol-O-methyltransferase (COMT) gene moderated the influence of adolescent cannabis use on developing adult psychosis. Carriers of the COMT valine158 allele were most likely to exhibit psychotic symptoms and to develop schizophreniform disorder if they used cannabis. Cannabis use had no such adverse influence on individuals with two copies of the methionine allele

Casswell, S. 1975. “Cannabis intoxication: effects of monetary incentive on performance, a controlled investigation of behavioural tolerance in moderate users of cannabis” Perceptual and Motor Skills 41: 423-434

Dose-related impairment was found on four of the five tasks, supporting previous findings of cannabis-induced impairment of short-term memory, goal-directed behavior and choice reaction times. Results for three of the tasks suggested that the performance of the motivated subjects was Less affected by the drug than was the performance of the nonmotivated subjects

Both behaviour and experiences while intoxicated have been shown experimentally to be influenced by non-pharmacological factors. Jones demonstrated the importance of the subjects’ expectations and the interpersonal situation in which the drug is taken, for the subjective effects experienced. Experimental manipulation of subjects’ expectancies about the potency of the cannabis they smoked has also resulted in significantly different performance levels following a moderate dose of cannabis (Carlin, Bakker, Halpern, & Post, 1972 )

Users report that they have some control over the degree to which they are involved in the subjective effects and can ‘come down’ and perform normally when necessary (Le Dain Report, 1972). This suggests that the subject’s motivation in experimental investigations of behavioural tolerance to cannabis effects is of crucial importance. It may be unrealistic to assume that incentive to perform the required tasks will be intrinsic to the usual experimental situation, whereas the necessary incentive may be intrinsic to self-set goals during intoxication

Twenty-four of the volunteer subjects were experienced users of cannabis (median frequency of use was three times per wk. and median length of use was 3 yr.), and 24 were non-users all of whom were experienced cigarette smokers and thus able to inhale smoke. Half of each group of 24 was assigned to the motivated group and half to the non-motivated group. The four groups did not differ significantly in mean age, education, and use of alcohol and prescription drugs. Each group contained seven males and five females, five university graduates and seven subjects without university education

cigarettes containing 700 mg of active leaf material, 300 mg of active leaf, or 700 mg of placebo material were smoked. The total leaf content of all cigarettes was 700 rng and in the low dose, placebo and leaf material were thoroughly mixed [MV: leaf? Did they not know that the flowers are the good part?]

it was estimated that the high dose cigarette delivered approximately 4 mg A9-THC and the lower dose delivered approximately 2 mg

Digit Symbol Substitation Task.-A three-way analysis of variance on scores showed a significant (9 < 0.001) dose-related decrement in performance following the administration of cannabis.

Meyer, et al. ( 197 1) allowed ad lib. smoking of cannabis (average dose was 3.6 mg A9-THC) and found mild but non-significant effects on the performance of both casual and heavy users

A third investigation (Miller, Hansteen, Adamec, & Lehmann, 1972) which found no impairment on digit subsritution following a dose and method of administration comparable to the present study did not measure performance until 1% to 2 hr. after smoking

Weil, ed al., while unable to make a definitive comparison, described their naive subjects as ‘grossly impaired’ following the high dose of cannabis (18 mg of ~9-THC was smoked) whereas the chronic users improved slightly after the same dose. Jones ( 1971 ) similarly found no significant change in the performance of frequent users after smoking cannabis containing 9 mg h9-THC

Continuogs Performance Task.-The data obtained from this task were not suitable for parametric analysis. Using the Friedman two-way analysis by ranks (Siegel, 1956), performance by all groups showed no significant effects of drug treatment on either errors of omission or errors of commission… agrees with the results of Weil, et al. ( 1968) who found no cannabis-induced impairment in their naive subjects on this task with or without strobe light distraction. The attention required for adequate performance was not impaired by cannabis

During the early phase of intoxication, in the relatively stimulating circumstances of this experimental administration, and when only short periods of sustained attention are required, socially relevant doses of cannabis seem to induce the “confusion” type of error rather than lapses in attention and are similar in this respect ro the effects of LSD and barbiturates (Mirsky & Kornetsky, 1964). However, lapses in attention may occur more frequently following cannabis consumption during longer lasting vigilance tasks (Moskowitz, Sharma, & Schapero, 1972; Casswell & Marks, 1973a). The relatively long response time allowed in the continuous performance task (1 sec.) will obscure very brief attention lapses induced by cannabis

Goal-directed Serial Alternation nnd Serial Subtraction Tasks A three-way analysis of variance on the transformed serial alternation scores gave a significant (p < 0.05 ) effect of dose on performance, no effect of prior experience with the drug and no statistically significant effect of motivation

None of the differences between the scores of the non-motivated subjects in the placebo condition and the scores of the motivated subjects after smoking cannabis, was statistically significant on either goal-directed serial alternation or serial subtraction

The groups with the best initial baseline performance, i.e., subjects with a university education and males, are those who when motivated are best able to avoid the dose-related impairment found in other groups

greater level of impairment of the motivated subjects in the placebo condition on the most complex of the tasks used in this study, the goal-directed serial alternation. The incentive, in the absence of the counteracting effect of cannabis, has apparently raised the level of arousal beyond the optimum for efficient performance.

This increased inconsistency substantiates the suggestion that cannabis-induced perceptual deficits result from brief lapses of attention (Moskowitz, 1973)

The results of this investigation suggest that when incentive is provided, some cannabis-intoxicated subjects are able to avoid the usual level of impairment in performance of tasks involving short-term memory and goal-directed behaviour. No support was found for the hypothesis that this is true for the moderate users of cannabis to a greater degree than the previously naive subjects

Casswell - cognitive effects of marijuana and motivation

Ceccarini J, De Hert M, Van Winkel R, Peuskens J, Bormans G, Kranaster L, Enning F, Koethe D, Leweke F, Van Laere K. 2013. “Increased ventral striatal CB1 receptor binding is related to negative symptoms in drug-free patients with schizophrenia” Neuroimage 79: 304-12

Compared to CON, there was a significant increase of CB1 receptor binding in SCZ patients in the nucleus accumbens, insula, cingulate cortex, inferior frontal cortex, parietal and mediotemporal lobe. Furthermore, in the SCZ-F group only, CB1 receptor binding was negatively correlated to negative symptoms and to depression scores, especially in the nucleus accumbens

Centonze D, Battistini L, Maccarrone M. 2008. “The endocannabinoid system in peripheral lymphocytes as a mirror of neuroinflammatory diseases” Curr Pharm Des 14(23): 2370-42

During immuno-mediated attack of the brain, activation of endocannabinoids represents a protective mechanism, aimed at reducing both neurodegenerative and inflammatory damage through various and partially converging mechanisms that involve neuronal and immune cells

we discuss the appealing working hypothesis that the presence of type-1 cannabinoid receptors on the luminal side, and that of type-2 cannabinoid receptors on the abluminal side of the blood-brain barrier, could drive a unidirectional transport of AEA in the luminal –> abluminal direction (i.e., from blood to brain), thus implying that blood may be a reservoir of AEA for the brain. On this basis, it can be expected that an unbalance of the endogenous tone of AEA in the blood may sustain a similar unbalance of its level within the brain, as demonstrated in Huntington’s disease, Parkinson’s disease, multiple sclerosis, attention-deficit/hyperactivity disorder, schizophrenia, depression and headache

Chait L, Perry J. 1994. “Acute and residual effects of alcohol and marijuana, alone and in combination, on mood and performance” Psychopharmacology 115: 340-349 add to dropbox

Fourteen male and female subjects were each studied under four conditions: alcohol alone~ marijuana alone, alcohol and marijuana in combination, and no active treatment. Mood and performance assessments were made during acute intoxication and twice the following day (morning and mid-afternoon). Acutely, each drug alone produced moderate levels of subjective intoxication and some degree of behavioral impairment. The drug combination produced the greatest level of impairment on most tasks and “strong” overall subjective ratings. There were few significant interactions between the two drugs, indicating that their effects tended to be additive. Only weak evidence was obtained for subjective or behavioral effects the day after active drug treatments… this study provided little evidence that moderate doses of alcohol and marijuana, consumed either alone or in combination, produce behavioral or subjective impairment the following day

14 subjects (10 males, 4 females) ranged in age from 21 to 34 years (mean = 24.5). All but four reported use of marijuana on at least 100 occasions (lifetime). At the time of participation, subjects reported drinking an average of 7 alcoholic drinks per week (range, 2–12) and smoking marijuana an average of 4 times a month (range, 1-16). Four of the 14 subjects also smoked tobacco cigarettes; all smoked less than a pack a day.

All subjects received four puffs of active marijuana and one alcoholic drink during the practice session

Four treatment conditions were scheduled on the overnight sessions: alcoholic beverage and active marijuana (AM), alcoholic beverage and placebo marijuana (AP), placebo beverage and active marijuana (PM), and placebo beverage and placebo marijuana (PP). Each subject was tested once under each condition and the order of treatments was counterbalanced across subjects… sessions were scheduled 1 week apart on the same day of the week. Subjects were tested in pairs, but treatment condition varied for each member of a pair. Both subjects and experimenter were blind to the treatment conditions

They arrived at 5 P.M. and ate dinner (Fig. 1). At 6:30 P.M. subjects left the CRC and were brought to a room in a separate area of the hospital where behavioral testing and drug administration took place. Subjects were returned to the CRC at 11:45 P.M. Nursing staff ensured that subjects were in their rooms with lights out by midnight, and that subjects were awakened at 7:30 the following morning. Subjects were allowed 30 min to wash and dress before behavioral testing began (about 8 A.M.). Eating, smoking, and coffee drinking were not allowed, however, until after the morning testing was completed. Subjects were tested once more in the afternoon at 3:00 P.M. Subjects were discharged at 4 P.M. Both the morning and afternoon testing were conducted in the same room as the evening testing

Pre-rolled marijuana cigarettes were supplied by the National Institute on Drug Abuse (NIDA). The delta-9-THC contents of the cigarettes were 0.0% (placebo) or 3.6% (active)

95% ethanol in diet tonic water and lime juice. The content (v/v) of the ptacebo beverage was 1% ethanol (as a taste mask), 4% lime juice, and 95% tonic, while the content of the alcoholic beverage was 10% ethanol, 4% lime juice, and 86% tonic. Drink volume was adjusted for gender and body weight so that the dose for the alcohol conditions was 0.6 g/kg for males and 0.5 g/kg for females. Drink volume was 540 ml/70 kg for males and 450 ml/70 kg for females. The beverages were served cold in 1 1 plastic containers

The effect of active marijuana on heart rate varied considerably across subjects, from no increase at all to a 56 bpm increase. Neither placebo marijuana nor alcohol significantly altered heart rate, and there was no interaction between marijuana and alcohol

The only significant effect for ratings of drug liking was a main effect of Marijuana [F(1, 13) = 9.9, P < 0.01]. Subjects rated liking active marijuana (mean = 64.4) more than placebo (mean = 51.3

The POMS was insensitive to the drug treatments, Mthough five of the eight scales did show significant main effects of Time, reflecting more negative mood and greater fatigue as the evening progressed, regardless of drug condition

Four of the VAS scales were sensitive to the drug treatments (Fig. 2). Ratings of “high” were increased only by marijuana [Marijuana x Time: F(4; 52) = 17.5, P < 0.0001] whereas ratings of “drunk” were increased only by alcohol [Alcohol x Time: F(4, 32)= 8.7, P = 0.0005]. With active marijuana, “high” ratings peaked after the first drug administration and showed little further increase after the second drug administration. In contrast, ratings of “drunk” continued to increase throughout the evening when alcohol was given. Ratings of”stimutated” were increased by both drugs [Alcohol x Time: F(4, 52) = 3.4, P < 0.025; Marijuana x Time: F(4, 52) = 3.4, P < 0.05]. Marijuana, but not alcohol, also resulted in higher ratings of”hungry” [Marijuana x Time: F(4, 52) = 6.4, P < 0.005]. Interestingly, the effects of marijuana on “hungry” ratings showed a different time course from the effects of the drug on “high,” with “hungry” ratings peaking later in the session (Fig. 2)

Chait - high drunk stimulated hungry

Both drugs affected time production [Alcohol x Target Interval: F(2, 24) = 9.7, P < 0.01; Marijuana x Target Interval: F(2, 24) = 4.2, P < 0.05]. As shown in Fig. 3, the two drugs produced opposite effects – alcohol administration resulted in subjects producing time intervals longer than the targets (overproduction), whereas marijuana administration occasioned underproduction. When the two drugs were given in combination, (AM condition) the effects canceled each other out, resulting in no effect.

Chait - Time Production

Standing steadiness. Only alcohol impaired performance on this task [Alcohol x Time: F(1, 13) = 9.9, P < 0.01]. The mean score (time summed for both legs) dropped from 57.7 s before drug to 45.9 s after drug.
DSST. Alcohol impaired performance on all measures of DSST performance: number attempted [Alcohol x Time: F(1, 13) = 23.3, P < 0.0005], number correct [Alcohol x Time: F(1, 13) = 22.3, P < 0.0005], and percentage correct [Alcohol x Time: F(1, 13) = 7.2, P < 0.025]. Number correct decreased from a mean of 43.9 before alcohol to 37.4 after, while mean percentage correct decreased from 96.5 to 91.1. Marijuana affected only percentage correct [Marijuana x Time: /7(1, 13) = 8.3, P < 0.025], which declined from a mean of 96.t to 91.3.
Backward digit span. Only alcohol affected this task [Alcohol x Time: F(1, 13) = 29.0, P < 0.0001]. The average span was 6.5 digits before alcohol, compared with 5.1 digits after alcohol.
Logical reasoning. No significant drug effects were obtained on this task.
Divided attention. There were no effects of the drug treatments on either hit rate or mean reaction time for responding to the primary target. Alcohol increased errors in estimating the number of occurrences of the secondary target [Alcohol x Time: F(1, 13) = 7.3, P < 0.025], from a mean of 1.0 errors before drug to 1.6 errors after drug. Marijuana increased false alarm responses (responding to the secondary target as if it were the primary target) from 0.9 to 1.6, before and after drug, respectively [Marijuana x Time: F(1, 13)= 5.9, P < 0.05].
Free recall. Only alcohol affected this task, producing a decrement in the number of words recalled from a mean of 9.3 before drug to 6.6 after drug [Alcohol x Time: F(t, 13) = 23.5, P < 0.0005]

Sleep questionnaire. Three of the four factors measured by the LSEQ showed significant drug-related effects (Table 1). Subjects rated it easier to get to sleep (GTS) after both drugs [Alcohol: F(1, 13) — 15.8, P < 0.0025; Marijuana: F(1, 13) = 6.4, P < 0.025]. For ratings of quality of sleep (QOS), a significant Alcohol x Marijuana interaction was obtained [F(1, 13) — 4.9, P < 0.05]. As Table 1 indicates, this interaction was due to higher ratings of sleep quality when alcohol and marijuana were administered alone, but relatively lower ratings after the drug combination. Finally, behavior following wakefulness (BFW) scores were decreased by Alcohol [F(1, 12) = 7.4, P < 0.025], indicating subjects felt more tired and clumsy

The present study yielded little evidence for next-day effects after any of the active drug treatments.

none of the apparent after-effects obtained in our previous studies was replicated here… In our first study (Chait et al. 1985) we found increased scores on the A and BG scales of the ARCI, and overproduction on the time production task, the morning after active marijuana. In the second study (Chait 1990), we observed underproduction on the time production task, impaired performance on backward digit span, and slowing of reaction time on the divided attention task the morning after active marijuana… type I errors.

One effect of marijuana that did replicate here, although not strictly speaking a next-day effect, was its effect on subjective sleep: in both the present and the previous study in which the LSEQ was used (Chait 1990) active marijuana increased subject ratings of ease of getting to sleep (Table 1); the mean increases in the two studies were of comparable magnitude (12-15 units).

ur failure to find significant behavioral impairment the day after this dose of alcohol is not surprising, since most studies that have reported impairment the day after drinking used doses higher than 1.2 g/ kg (Seppala et al. 1976; Myrsten et al. 1980), and some studies using higher doses found no reliable evidence of impairment (Takala et al. 1958)

During the evening sessions, heart rate increased more after marijuana smoking during the first compared with the second smoking period. Similarly, ratings of “high” increased sharply after the first, but not the second smoking period (Fig. 2). Since CO boost did not differ between the two smoking periods, these results provide strong evidence for acute tolerance to these effects of marijuana, a phenomenon that has been observed by others (Coc- chetto et al. 1981; Perez-Reyes et al. 1981).

inability to show marijuana-induced increases in hunger in at least some of these prior studies (Chait et al. 1985, 1988a,b; Zacny and Chait 1989, t991; Zacny and de Wit 1989, 1991; Chait and Zacny 1992) may have been because the effect is delayed, not reaching a peak until 1 h after smoking.

moderate doses of these two commonly used substances have little effect on mood or performance the day after use, and that at least equal attention should be paid to time of day as an important influence upon human behavior

Chakraborty A, Anstice N, Jacobs R, LaGasse L, Lester B, Wouldes T, Thompson B. 2015. “Prenatal exposure to recreational drugs affects global motion perception in preschool children” Nature: Scientific Reports 5: 16921

Global motion perception was measured in one hundred and forty-five 4.5-year-old children who had been exposed to different combinations of methamphetamine, alcohol, nicotine and marijuana prior to birth and 25 unexposed children. Self-reported drug use by the mothers was verified by meconium analysis. We found that global motion perception was impaired by prenatal exposure to alcohol and improved significantly by exposure to marijuana. Exposure to both drugs prenatally had no effect

Demographically the cohort was 52.5% European, 36.5% Māori and 11% other. The children had been exposed to a range of different drugs: 75.2% to nicotine, 56.4% to alcohol, 44.2% to methamphetamine and 40% to marijuana. The majority of children (81.3%) had been exposed to multiple drugs. Twenty-five children (15%) had no drug exposure and provided a non-drug exposed comparison group

Only alcohol and marijuana exposure had independent effects on global motion perception after controlling for the effects of multiple drug exposure, verbal IQ, ethnicity, habitual visual acuity, stereoacuity, and sex. Children who were exposed prenatally to alcohol had elevated (worse) motion coherence thresholds (Fig. 1A) whereby global motion perception was significantly poorer (t163 = −2.26, p = 0.002) than that of children not exposed to alcohol (alcohol exposed, n = 95: 59 ± 21% motion coherence threshold vs alcohol non-exposed, n = 70: 50 ± 23%). Unexpectedly, children exposed to marijuana had significantly lower (better) motion coherence thresholds (Fig. 1B) (t163 = 3.52, p = 0.001) than those of children not exposed to marijuana [marijuana exposed, n = 67: 46 ± 20% vs marijuana non-exposed, n = 98: 63 ± 25%]. A significant interaction between the effects of alcohol exposure and marijuana exposure on motion coherence thresholds was also present (Fig. 1C, F1,114 = 7.7, p = 0.006), whereby exposure to marijuana in the absence of alcohol was associated with improved global motion perception (mean motion coherence threshold = 34 ± 11%, n = 20), which was significantly lower (better) (t41 = 4.42, p < 0.001) than that of children who had not experienced prenatal drug exposure (mean motion coherence threshold = 58 ± 23%, n = 25). However global motion perception for children exposed to both marijuana and alcohol (mean motion coherence threshold = 53 ± 24%, n = 48) was no different (t70 = −0.28, p = 0.39) from that of children who had no drug exposure (mean motion coherence threshold = 58 ± 23%, n = 25)

visual acuity (measured with habitual refractive correction if worn), stereoacuity, and verbal IQ (measured with Wechsler Preschool and Primary Scale of Intelligence-III) were unaffected by drug exposure in this group of children

More frequent maternal use of marijuana (Fig. 2a) during pregnancy and more joints smoked per occasion (Fig. 2b) were associated with lower motion coherence thresholds, indicating better global motion perception. The opposite of this was true for children (n = 46) exposed to alcohol

none of the children in this study had been diagnosed with foetal alcohol syndrome. This suggests that prenatal exposure to levels of alcohol that are not sufficient to induce foetal alcohol syndrome can still impair the cortical processing of visual information as assessed using a behavioural measure of global motion perception

interesting possibility that prenatal marijuana exposure may improve dorsal stream function but impair ventral stream function. Alternatively, the detrimental effects of marijuana on visual processing reported in previous studies may reflect impairments at the level of visual attention, visual memory, or response inhibition rather than visual perception [MV: or may be artifacts of bad study designs and confounding by other factors]

Marijuana neutralizes the effect of nicotine in an animal model of addiction54

Chang L, Yakupov R, Cloak C, Ernst T. 2006. “Marijuana use is associated with a reorganised visual-attention network and cerebellar hypoactivation” Brain 129(5): 1096-1112

24 chronic MJ users, 12 abstinent, 12 active; 19 age-, sex- and education-matched controls age of first marijuana use was 14.7 ± 0.4 (12–16) years for the THC(−) subjects and 15.5 ± 0.9 (9–20) years for the THC(+)

decreased activation in the right prefrontal, medial and dorsal parietal, and medial cerebellar regions, but greater activation in various frontal, parietal and occipital brain regions during the visual-attention tasks

Active marijuana users, with positive urine tests for THC, showed greater activation in the frontal and medial cerebellar regions than abstinent

earlier age of first use and greater estimated cumulative dose of THC exposure were related to lower BOLD signals in the right prefrontal region and medial cerebellum

CES-depression scale 6.90 ± 0.98 9.42 ± 1.92 12.67 ± 2.71 0.08*

“minimal depressive symptoms”

smoke 27.9 days per month,  6047 ± 2908 joints

THC(+) marijuana user group showed better performance on the response reversal/visual scanning tests and a trend for faster reaction times on the choice reaction task

Marijuana users performed better while tracking 2 balls, but not when tracking 3 or 4

Chavarría-Siles I, Contreras-Rojas J, Hare E, Walss-Bass C, Quezada P, Dassori A, Contreras S, Medina R, Ramírez M, Salazar R, Raventos H, Escamilla MA. 2008. “Cannabinoid receptor 1 gene (CNR1) and susceptibility to a quantitative phenotype for hebephrenic schizophrenia” Am J Med Genet B Neuropsychiatr Genet 147(3):279-84

subjects with schizophrenia who had an elevated lifetime dimensional score for negative and disorganized symptoms, which we used as a proxy for “hebephrenia.”

we found association of these hebephrenic subjects and the (AAT)n-repeat marker of the CNR1 (multi-allelic P = 0.0368). Our hypothesis that an association with the (AAT)n-repeat marker of CNR1 would not be found with the more general type of schizophrenia was also confirmed. Schizophrenic subjects with prominent lifetime scores for disorganization and negative symptoms (dimension for hebephrenia) are associated with the CNR1 gene and present a type of symptomatology that resembles chronic cannabinoid-induced psychosis

Cheetham A, Allen N, Whittle S, Simmons J, Yucel M, Lubman D. 2012. “Orbitofrontal volumes in early adolescence predict initiation of cannabis use: a 4-year longitudinal and prospective study” Biol Psychiatry 71(8): 684-92

Although these changes are frequently attributed to the neurotoxic effects of cannabis, it is possible that some abnormalities might predate use and represent markers of vulnerability

Smaller orbitofrontal cortex volumes at age 12 years predicted initiation of cannabis use by age 16 years. The volumes of other regions (amygdala, hippocampus, and anterior cingulate cortex) did not predict later cannabis use

Chen X, Williamson V, An S-S, Hettema J, Aggen S, Neale M, Kendler K. 2008. “Cannabinoid Receptor 1 Gene Association with Nicotine Dependence” Arch Gen Psychiatry 65(7): 816-824

Chhatwal J, Davis M, Maguschak K, Ressler K. 2005. “Enhancing cannabinoid neurotransmission augments the extinction of conditioned fear” Neuropsychopharmacology 30(3):516-24

CB1 antagonist rimonabant (SR141716A) prior to extinction training led to significant, dose-dependent decreases in extinction
CB1 agonist WIN 55,212-2 did not appear to affect extinction, administration of AM404, an inhibitor of eCB breakdown and reuptake, led to dose-dependent enhancements in extinction
AM404-treated animals showed decreased shock-induced reinstatement of fear; could not be attributed to alterations in the expression of conditioned fear, locomotion, shock reactivity, or baseline startle, as these parameters seemed unchanged by AM404
coadministration of rimonabant with AM404 blocked this enhancement

eCB modulators may be therapeutically useful as adjuncts for exposure-based psychotherapies such as those used to treat Post-Traumatic Stress Disorder and other anxiety disorders

de Chiara V, Errico F, Musella A, Rossi S, Mataluni G, Sacchetti L, Siracusano A, Castelli M, Cavasinni F, Bernardi G, Usiello A, Centonze D. 2010. “Voluntary exercise and sucrose consumption enhance cannabinoid CB1 receptor sensitivity in the striatum” Neuropsychopharmacology 35(2): 374-387

Running wheel and sucrose consumption have rewarding and reinforcing properties in rodents, and share many neurochemical and behavioral characteristics with drug addiction… . We found that cannabinoid CB1 receptor-mediated presynaptic control of striatal inhibitory postsynaptic currents was remarkably potentiated after these environmental manipulations…  the sensitivity of glutamate synapses to CB1 receptor stimulation was unaltered, as well as that of GABA synapses to the stimulation of presynaptic GABAB receptors

the upregulation of cannabinoid transmission induced by wheel running or sucrose had a crucial role in the protective effects of these environmental manipulations against the motor and synaptic consequences of stress

Chiu Y-C, Egner T. 2015. “Inhibition-induced forgetting: when more control leads to less memory” Psychological Science 26(1): 27-38

hypothesis that inhibition-induced forgetting occurs when response inhibition shunts attentional resources from perceptual stimulus encoding to action control.

Chiurchiù V, Leuti A, Maccarrone M. 2015. “Cannabinoid signaling and neuroinflammatory diseases: a melting pot for the regulation of brain immune responses” Journal of Neuroimmune Pharmacology 10(2): 268-280

Cannabis sativa-derived phytocannabinoids, as well as synthetic cannabinoids, are endowed with significant immunoregulatory and anti-inflammatory properties, both in peripheral tissues and in the CNS, through the activation of cannabinoid receptors. In this review, the immunomodulatory effects of cannabinoid signaling on the most relevant brain immune cells will be discussed. In addition, the impact of cannabinoid regulation on the overall integration of the manifold brain immune responses will also be highlighted, along with the implication of these compounds as potential agents for the management of neuroinflammatory disorders

Choi J, Jeong B, Rohan M, Polcari A, Teicher M. 2009. “Preliminary evidence for white matter tract abnormalities in young adults exposed to parental verbal abuse.” Biol Psychiatry 65(3):227-34

Three WM tract regions had significantly reduced FA: 1) arcuate fasciculus in left superior temporal gyrus, 2) cingulum bundle by the posterior tail of the left hippocampus, and 3) the left body of the fornix.

Across groups, FA in region 1 correlated with verbal IQ and verbal comprehension index. Fractional anisotropy in region 2 was inversely associated with ratings of depression, dissociation, and limbic irritability. Fractional anisotropy in region 3 was inversely correlated with ratings of somatization and anxiety.

Chuchawankul S, Shima M, Buckley N, Hartmann C, McCoy K. 2004. “Role of cannabinoid receptors in inhibiting macrophage costimulatory activity” Int Immunopharmacol 4(2): 265-78

THC decreased costimulation provided by peritoneal cells elicited with polystyrene beads and thioglycollate, but the drug had no influence with macrophages elicited with thioglycollate alone. Bead administration induced CB2 mRNA expression in macrophages, while CB1 mRNA was not detected. Although inhibition was associated with functional heat-stable antigen, a costimulatory molecule, on macrophages, THC exposure did not alter cell surface heat-stable antigen expression. Inhibition by THC and anti-heat-stable antigen antibody was not additive suggesting the inhibitory mechanisms may overlap… CB1-selective antagonist SR141716A completely reversed, and CB2-selective antagonist SR144528 partially blocked THC’s inhibition

High affinity synthetic agonist CP55,940, but not partial agonist THC, impaired costimulation by macrophages from mice lacking CB2 receptor

Churchwell J, Lopez-Larson M, Yurgelun-Todd D. 2010. “Altered frontal cortical volume and decision making in adolescent cannabis users” Front Psychol 1: 225

fails to control for trauma which separately found same effect; small sample size, and two outliers produce the correlation between low MoPFC and age of first use; Axis I diagnoses excluded but CA had subclinical levels of pathology and were not asked about why they were using

no significant correlations between right moPFC volume and several measures of cannabis use, total moPFC volume was positively associated with age of first use

18 cannabis abusing adolescents (CA; 2 female and 16 male subjects; mean age, 17.7 years; range 16–19 years), and 18 healthy controls (HC; 6 female and 12 male subjects; mean age, 17.2 years; range 16–19 years)

cannabis abusing adolescents have decreased right moPFC volume compared to controls, p = 0.01, d = 0.92, CI0.95 = 0.21, 1.59

total moPFC volume was positively correlated with age of first use r (18) = 0.49, p < 0.03

Morphogenesis of the prefrontal cortex has been associated with an enhanced capacity to temporally organize action plans and choices as a means of reaching goals

decreased right moPFC cortical volume was also shown to be associated with increased observed impulsivity in a sample of adolescent males (Boes et al., 2009)

exclusionary criteria: (1) presence of any current Axis I disorder other than cannabis abuse (for the cannabis group); (2) presence of a serious medical illness, including diabetes; (3) presence of a neurological disorder; (4) history of head trauma resulting in loss of consciousness requiring hospital evaluation; (5) history of ECT treatment; (6) estimated IQ < 85 (based on measures of verbal fluency and academic history); (7) claustrophobia or metal implanted within the body

Cannabis abusing subjects in the present study performed somewhat better on the verbal fluency test (M = 45.8, SD = 9.5) than healthy controls (M = 37.5, SD = 8.7)

no correlation between tetrahydrocannabinol metabolite values and BIS scores, suggesting that active levels did not influence BIS responding

Hamilton Anxiety Rating Scale (HAM-A; HC, M = 1.27, SD = 1.93; CA, M = 2.0, SD = 2.66) or depression as assessed with the Hamilton Depression Rating Scale (HAM-D; HC, M = 0.77, SD = 1.43; CA, M = 2.11, SD = 3.07)

Cichewicz D, Haller V, Welch S. 2001. “Changes in opioid and cannabinoid receptor protein following short-term combination treatment with delta(9)-tetrahydrocannabinol and morphine” J Pharmacol Exp Ther 297(1): 121-7

upregulation of CB1 in spinal cord. Coadministration of THC and morphine blocks development of morphine tolerance without reducing antinociceptive effects

Cloitre M, Stolbach B, Herman J, van der Kolk B, Pynoos R, Wang J, Petkova E. 2009. “A developmental approach to complex PTSD: childhood and adult cumulative trauma as predictors of symptom complexity” J Trauma Stress 22(5): 399-408

Childhood cumulative trauma but not adulthood trauma predicted increasing symptom complexity in adults. Cumulative trauma predicted increasing symptom complexity in the child sample. Results suggest that Complex PTSD symptoms occur in both adult and child samples in a principled, rule-governed way and that childhood experiences significantly influenced adult symptoms

Cloitre M, Garvert D, Weiss B, Carlson E, Bryant R. 2014. “Distinguishing PTSD, Complex PTSD, and Borderline Personality Disorder: A latent class analysis” Eur J Psychotraumatol. 5

spectrum of diagnoses moving from PTSD to CPTSD and BPD


the following symptoms were highly indicative of placement in the BPD rather than the CPTSD class: (1) frantic efforts to avoid real or imagined abandonment, (2) unstable and intense interpersonal relationships characterized by alternating between extremes of idealization and devaluation, (3) markedly and persistently unstable self-image or sense of self, and (4) impulsiveness. Given the gravity of suicidal and self-injurious behaviors, it is important to note that there were also marked differences in the presence of suicidal and self-injurious behaviors with approximately 50% of individuals in the BPD class reporting this symptom but much fewer and an equivalent number doing so in the CPSD and PTSD classes (14.3 and 16.7%, respectively)

The focus of treatment for BPD concerns reduction of life-interfering behaviors such as suicidality and self-injurious behaviors, a reduction in dependency on others and an increase in an internalized and stable sense of self (e.g., Dialectical Behavior Therapy, Linehan, 1993). In contrast, treatment programs for CPTSD focus on reduction of social and interpersonal avoidance, development of a more positive self-concept and relatively rapid engagement in the review and meaning of traumatic memories (e.g., Cloitre et al., 2006)

Cluny N, Keenan C, Reimer R, Le Foll B, Sharkey K. 2015. “Prevention of diet-induced obesity effects on body weight and gut microbiota in mice treated chronically with Δ9-tetrahydrocannabinol” PLoS One  DOI: 10.1371/journal.pone.0144270

THC reduced weight gain, fat mass gain and energy intake in DIO but not lean mice. DIO-induced changes in select gut microbiota were prevented in mice chronically administered THC. THC had no effect on locomotor activity or whole gut transit in either lean or DIO mice

Chronic THC treatment reduced energy intake and prevented high fat diet-induced increases in body weight and adiposity; effects that were unlikely to be a result of sedation or altered gastrointestinal transit. Changes in gut microbiota potentially contribute to chronic THC-induced actions on body weight in obesity

Coccaro E, McCloskey M, Fitzgerald D, Phan K. 2007. “Amygdala and orbitofrontal reactivity to social threat in individuals with impulsive aggression” Biological Psychiatry 62(2): 168-178

Relative to controls, individuals with IED exhibited exaggerated amygdala reactivity and diminished OFC activation to faces expressing anger. Extent of amygdala and OFC activation to angry faces were differentially related to prior aggressive behavior across subjects. Unlike controls, aggressive subjects failed to demonstrate amygdala-OFC coupling during responses to angry faces

These findings provide evidence of amygdala-OFC dysfunction in response to an ecologically-valid social threat signal (processing angry faces) in individuals with a history of impulsive aggressive behavior

Cohen R, Grieve S, Hoth K, Paul R, Sweet L, Tate D, Gunstad J, Stroud L, McCaffery J, Hitsman B, Niaura R, Clark C, McFarlane A, Bryant R, Gordon E, Williams L. 2006. “Early life stress and morphometry of the adult anterior cingulate cortex and caudate nuclei” Biol Psychiatry 59(10): 975-82

Participants with greater than two ACEs had smaller ACC and caudate nuclei than those without ACEs

Cole S, Hawkley L, Arevalo J, Sung C, Rose R, Cacioppo J. 2007. “Social regulation of gene expression in human leukocytes” Genome Biol 8(9): R189

The present study analyzed genome-wide transcriptional activity in people who chronically experienced high versus low levels of subjective social isolation (loneliness) to assess alterations in the activity of transcription control pathways that might contribute to increased adverse health outcomes in social isolates

Promoter-based bioinformatic analyses showed under-expression of genes bearing anti-inflammatory glucocorticoid response elements (GREs; p = 0.032) and over-expression of genes bearing response elements for pro-inflammatory NF-κB/Rel transcription factors (p = 0.011). This reciprocal shift in pro- and anti-inflammatory signaling was not attributable to differences in circulating cortisol levels, or to other demographic, psychological, or medical characteristics. Additional transcription control pathways showing differential activity in bioinformatic analyses included the CREB/ATF, JAK/STAT, IRF1, C/EBP, Oct, and GATA pathways

impaired transcription of glucocorticoid response genes and increased activity of pro-inflammatory transcription control pathways provide a functional genomic explanation for elevated risk of inflammatory disease in individuals who experience chronically high levels of subjective social isolatio

Cole J, Toga A, Hojatkashani C, Thompson P, Costafreda S, Cleare A, Williams S, Bullmore E, Scott J, Mitterschiffthaler M, Walsh N, Donaldson C, Mirza M, Marquand A, Nosarti C, McGuffin P, Fu C. 2010. “Subregional hippocampal deformations in major depressive disorder.” J Affect Disord 126(1-2): 272-7

Both right (P=0.001) and left (P=0.005) hippocampal volumes were reduced in patients relative to healthy controls (n=37 patients and n=37 controls), while only the right hippocampus (P=0.016) showed a reduced volume in a subgroup of first-episode depression patients

Compton M, Furman A, Kaslow N. 2004. “Preliminary evidence of an association between childhood abuse and cannabis dependence among African American first-episode schizophrenia-spectrum disorder patients” Drug Alcohol Depend 76(3):311-6

Schizophrenics with comorbid cannabis dependence reported greater childhood physical and sexual abuse than schizophrenics without cannabis dependence

Compton M, Furman A, Kaslow N. 2004. “Lower negative symptom scores among cannabis-dependent patients with schizophrenia-spectrum disorders: preliminary evidence from an African American first-episode sample” Schizophr Res 71(1): 61-4

those with cannabis dependence had significantly lower Positive and Negative Syndrome Scale negative subscale scores compared to those without cannabis dependence. The two groups did not differ on postive and general psychopathology subscale scores

Compton M, Kelley M, Ramsay C, Pringle M, Goulding S, Esterberg M, Stewart T, Walker E. 2009. “Association of pre-onset cannabis, alcohol and tobacco use with age at onset of prodrome and age at onset of psychosis in first-episode patients” American Journal of Psychiatry 166(11): 1251-1257

Whereas classifying participants according to maximum frequency of use prior to onset (none, ever, weekly, or daily) revealed no significant effects of cannabis or tobacco use on risk of onset, analysis of change in frequency of use prior to onset indicated that progression to daily cannabis and tobacco use was associated with an increased risk of onset of psychotic symptoms

progression to daily use resulted in a much larger increased relative risk of onset of psychosis in females than in males

12-month prevalence estimates of use and misuse of cannabis were 29% and 19%, respectively, and lifetime use and misuse estimates were 42% and 23%, respectively

In patients with first-episode psychosis, reported rates of cannabis misuse have ranged from 15% to 65% (311) , rates of alcohol misuse from 27% to 43% (9 , 1115) , and rates of daily cigarette smoking from 50% to 75% (11 , 13 ,16)

one critique of the literature is that the possible influence of cannabis use on prodromal symptoms has not been explored

family history in first-degree relatives was present in only 13.4% of participants, making it difficult to estimate those effects with any reasonable certainty

large percentage of daily cannabis users (40.6%) and daily tobacco users (44.1%) but relatively few daily alcohol users (7.9%)

no significant effects of cannabis or tobacco use on risk of onset of psychotic symptoms but showed an effect of weekly and daily alcohol use on age at onset of psychosis

progression to daily use was associated with a larger increased relative risk for onset of psychosis in female patients (hazard ratio=5.154) than in male patients (hazard ratio=3.359) male patients with no history of use and those with ever or weekly use had higher hazard ratios than the female comparison groups (2.250 compared with 1.000, and 2.329 compared with 2.049, respectively), which was expected, although the male and female patients were not significantly different at those levels. However, for daily users, the hazard ratio was 3.359, compared with 5.154, indicating a reversal of the pattern of findings (higher in female patients)

increased use of cannabis by those imminently approaching the onset of psychotic symptoms is also a reasonable interpretation of these data

Conrad C. 2008. “Chronic stress-induced hippocampal vulnerability: the glucocorticoid vulnerability hypothesis” Rev Neurosci 19(6): 395-411

The hippocampus, a limbic structure important in learniJng and memory, is particularly sensitive to chronic stress and to glucocorticoids

a chronic stress history, which includes repeated elevation of glucocorticoids, may make the hippocampus vulnerable to potential injury

glucocorticoids can compromise the hippocampus by producing dendritic retraction, a reversible form of plasticity that includes dendritic restructuring without irreversible cell death. Conditions that produce dendritic retraction are hypothesized to make the hippocampus vulnerable to neurotoxic or metabolic challenges

A racing heart and high blood pressure triggered by epinephrine to maximize blood flow is critical for assisting in escaping the stressor, but a persistent racing heart and high blood pressure increases the risk of heart failure and arteriosclerosis. Elevated glucocorticoids are essential for the redistribution of energy resources, but the long-term elevation of glucocorticoids starves some tissues of necessary resources and hinders immune function, increasing the susceptibility to disease

Guinea pigs injected daily with glucocorticoids for four weeks exhibited brain damage in the hypothalamus and hippocampus /4

the hippocampus provides negative feedback to the HPA axis, with hippocampal stimulation and lesions causing decreases and increases in HPA axis activity, respectively /36,40,43,58,85

glucocorticoids secreted during periods of stress desensitize the hippocampus to further glucocorticoid exposure by downregulating glucocorticoid receptors, an effect that is self-correcting and therefore reversible. At some point, however, the downregulation of glucocorticoid receptors precipitates further hypersecretion of glucocorticoids until permanent hippocampal cell loss occurs. This irreversible hippocampal damage was proposed to make the hippocampus irreversibly insensitive to further glucorticoid elevations, creating a feed-forward cycle of elevated glucocorticoids and continued hippocampal destruction as an individual ages. While elegant, the glucocorticoid cascade hypothesis had some inconsistencies /see 2/. The purpose of this review is to discuss the seemingly inconsistent findings concerning the effects of prolonged elevation of glucocorticoids on hippocampal health and to discuss the interpretation that a chronic stress history, which includes repeated elevation of glucocorticoids, may make the hippocampus vulnerable to potential injury

acute stress and the concurrent elevation of glucocorticoids exacerbated damage to the hippocampus caused by neurochemical or metabolic challenges. Glucocorticoids enhance hippocampal damage following neurotoxin insult /kanic acid, also known as 3-acetyl-pyridine, 125,126/, or metabolic challenge /hypoxia, 156/, /hypoglycemia, 156/, /ischemia, 124/. Glucocorticoids can aggravate hippocampal damage when steroid titers are elevated just prior to, during, or immediately after the neurotoxic challenge /122

Down-regulating the HPA axis with repeated glucocorticoid injections to produce low glucocorticoid titers during a hypoxia/ischemia challenge helps to protect against hippocampal damage /72

a damaged hippocampus makes itself even more susceptible to a metabolic challenge than a healthy hippocampus, creating a downward spiral of increased chances of potentiated hippocampal damage with each metabolic episode and this risk increases with age

Only chronic stress, but not acute stress, exacerbated IBO-induced CA3 damage, which confirmed that waiting several days following the end of the last day of restraint permitted glucocorticoid elevations from the last restraint session to subside

Rats exposed repeatedly to the same chronic stress stimulus (homotypic stressor) begin to habituate to that stimulus and show attenuated HPA axis responses. In contrast, rats exposed repeatedly to the same chronic stress stimulus and then presented with a novel stressful stimulus (heterotypic stressor) exhibit potentiated HPA axis responses to the novel stimulus

stress/glucocorticoid-induced hippocampal changes include decreasing neurogenesis /62,108,115/, altering dendritic spine density /97,153,155/, hindering synaptic plasticity /62,115/, impeding long-term potentiation /105/, changing the inhibitory and excitatory tone /62,102,112/, downregulating GR /69,170/, and reducing dendritic complexity /70,82,167

hippocampal CA3 dendritic retraction lasts for at least four days following the end of chronic stress /27,164

chronic stress alters the larger apical region in males as opposed to the smaller basal region in females /49/ with evidence of ovarian hormones being neuroprotective /90/. We found that chronic stress exacerbated IBO-induced CA3 damage in males, but not females /28

dendritic retraction may be an adaptive response to reduce the exposure of CA3 neurons to glucocorticoidinduced glutamate elevation… CA3 dendritic retraction corresponds with impaired spatial ability… neurons that retract dendrites may be unable to respond adequately to an unexpected metabolic challenge, leading to exacerbated hippocampal damage… CA3 dendritic retraction is proposed to be a relatively low-risk, temporary neuroplastic response to combat the immediate looming threat of elevated glutamate

hippocampal dendritic retraction produced by chronic stress in rodents and reduced hippocampal volumes observed in Cushing’s disease, MDD, and PTSD are dynamic and have the capacity to recover… A consistent characteristic of these conditions is that symptom severity correlates with hippocampal size, which shows plasticity by improving with treatment

glucocorticoids appear to be problematic when they are either too high (Cushing’s disease or MDD) or too low (PTSD), but only high levels of glucocorticoids are traditionally thought to reduce hippocampal volumes

animal literature shows that reduced glucocorticoids via adrenalectomy causes neural degeneration within the hippocampal dentate gyrus, /2224,140/, which can be detected by volumetric measures /23/. Consequently, glucocorticoids can reduce hippocampal volume and plasticity when their levels are either too high or low… inverted U-shaped function

subthreshold metabolic events that are benign to the hippocampus of a healthy individual may be harmful to people with Cushing’s disease, MDD, PTSD or a history of chronic stress

the theory of Cognitive Reserve is used to explain the finding that individuals with more mental activity develop better, more elaborate neuronal connections that can withstand a greater amount of pathological damage before succumbing to disease /66,151/. Individuals engaging in intellectually-stimulating activities throughout their lives maintain their cognitive abilities when others begin to show cognitive decline /1,132,139

housing rats in enriched environments to provide opportunities for social interactions, exercise, and novel visual stimulation prevents the detrimental effects of chronic stress on hippocampal function /171

Copeland W, Keeler G, Angold A, Costello E. 2007. “Traumatic events and posttraumatic stress in childhood.” Arch Gen Psychiat 64:577-584

Higher levels of ADHD, conduct disorder and violence during childhood predicted higher levels of cannabis use

Corlew R, Brasier D, Feldman D, Philpot B. 2008. “Presynaptic NMDA receptors: newly appreciated roles in cortical synaptic function and plasticity” Neuroscience 14(6): 609-625


Cornelius J, Kirisci L, Reynolds M, Clark D, Hayes J, Tarter R. 2009. “PTSD contributes to teen and young adult cannabis use disorders” Addictive Behaviors 35(2):91-94

“PTSD contributes to the etiology of CUD among teenagers making the transition to young adulthood beyond the effects of deviant peers, the TLI (Transmissible Liability Index, a measure of risk for SUD), and demographic factors.”

Cornelius J, Aizenstein H, Hariri A. 2010. “Amygdala reactivity is inversely related to level of cannabis use in individuals with comorbid cannabis dependence and major depression” Addict Behav 35(6): 644-646

a higher level of cannabis use was consistently associated with a lower level of amygdala reactivity across all subjects (matched pairs t=2.70, df=5, p<0.05, two-tailed). These findings are consistent with the reports by Phan et al. (Phan et al., 2008) and Hariri et al. (Hariri et al., 2009) suggesting that cannabinoids have an inhibitory effect on threat-related amygdala reactivity.

major depression and anxiety disorders have … increased reactivity of the amygdala (Drevets 2003), while treatment with antidepressant medications… reduce the reactivity (activation) of the amygdala in subjects with major depression

Cornwall M. 2002. “Alternative Treatment of Psychosis: A Qualitative Study of Jungian Medication-Free Residential Treatment at Diabasis”

(a) psychosis is not a unitary phenomenon; (b) for at least some people, it is both a purposive developmental process and an experience with strong transpersonal and archetypal elements; and (c) given the right kind of support, such people can come through the experience “healed.”

Participants were strongly critical of the medical model, which Diabasis sought to supplant, but also expressed retrospective criticisms of Diabasis itself

I both observed and facilitated many dramatic recoveries of people in acute psychosis

studies published over the last few decades (e.g. Bola, 1998; Dabrowski & Aronson, 1964; Goldberg, Klerzman, & Cole, 1965; Karon, 1983; Menninger, 1959, 1999; Matthews, Roper, Mosher, & Menn, 1979; Silverman, 1978; Sullivan, 1953) have presented evidence that some people experiencing acute psychotic episodes, when allowed to undergo the psychotic process in a supportive, medication-free setting, can go on to lead rewarding lives, rather than becoming chronic mental patients

for a period of eight years, our therapists were called to the psychiatric emergency screening ward of the hospital whenever somebody without a prior history of psychiatric hospitalization presented with psychotic symptoms. Since we accepted all first break clients, not all of them could have been Brief Reactive

participants treated with medication at Agnews had roughly the same rate of recidivism as the national average in mental hospitals (73%), while the placebo group showed only 8% recidivism

when the Agnews State Hospital Research Department sought to publish the findings, their article was rejected by four major psychiatric journals, despite being approved for publication by the peer review panels assembled by each of the journals. Eventually published in 1978 in International Pharmacopsychiatry, it received little attention in the United States (John Perry, personal communication, January 20, 1998)

Soteria study “has been treated as if it never existed” and described “25 years of swimming upriver against the prevailing biological zeitgeist” (Mosher and Bola, 2000, p. 68)

psychodynamic, existential, humanistic, and transpersonal orientations

Jung (1953, 1960)

for recent annotated bibliographies of studies that demonstrate the brain-damaging effects of neuroleptics, see Mosher (n.d.) and Support Coalition International (1999)

Laing 1967: “true sanity entails, in one way or another, the dissolution of the normal ego, that false self competently adjusted to our alienated social reality; the emergence of the “inner” archetypal mediators of divine power, and through this death a rebirth, and the eventual re-establishment of a new kind of ego-functioning, the ego now being the servant of the divine, no longer its betrayer (p. 145)”

Gestalt Therapy, shamanism, communication theory, and Taoism

Cortes-Briones J, Cahill J, Skosnik P, Mathalon D, Williams A, Sewell R, Roach B, Ford J, Ranganathan M, D’Souza D. 2015. “The psychosis-like effects of Δ9-Tetrahydrocannabinol are associated with increased cortical noise in healthy humans” Biological Psychiatry 78: 805-813 add to dropbox

The acute, dose-related effects of Δ9-THC on Lempel-Ziv complexity and signal power were studied in humans (n 5 24) who completed 3 test days during which they received intravenous Δ9-THC (placebo, .015 and .03 mg/kg) in a double-blind, randomized, crossover, and counterbalanced design

Δ9-THC increased neural noise in a dose-related manner. Furthermore, there was a strong positive relationship between neural noise and the psychosis-like positive and disorganization symptoms induced by Δ9-THC, which was independent of total signal power. Instead, there was no relationship between noise and negative-like symptoms. In addition, Δ9-THC reduced total signal power during both active drug conditions compared with placebo, but no relationship was detected between signal power and psychosis-like symptoms

Complex mental processes such as perception, language, emotion, and memory rely on the integrity of long-range functional networks formed by ensembles of brain areas (nodes) processing information in a coordinated manner(1 , 2)

converging lines of evidence from structural (diffusion tensor imaging) and functional (functional magnetic resonance imaging [fMRI], electroencephalogram [EEG], and magneto-encephalogram [MEG]) studies have shown abnormal neural connectivity in schizophrenia, which has been related to the presence and intensity of psychotic symptoms ( 3 –9 )

Information is transmitted from one node to another through a medium (e.g., a cable) as part of a signal (e.g., an electromagnetic wave), which is composed by information and random noise. The latter is a sum of random activity and interference caused by other signals travelling through the same medium. According to information theory, the upper limit of the total amount of undistorted (error-free) information per unit of time that can be carried by a signal is limited by: 1) the bandwidth (in Hz), 2) the total power, and 3) the amount of random activity or noise of the signal ( 10–13). Thus, keeping the bandwidth and the total power of a signal constant, the higher the level of noise, the lower the amount of information that can be carried by the signal without distortion. Increased noise may, therefore, disrupt the coordinated activity between nodes, resulting in the disruption of information processing

growing evidence from EEG, MEG, and neuro-imaging studies suggesting increased randomness/noise in the brain activity of schizophrenia patients ( 14–19). A number of studies have shown increased intertrial (random) variability in the latency and amplitude of evoked responses measured in the EEG of schizophrenia patients ( 14, 16–18,20). Furthermore, measures developed to characterize the uncertainty (entropy) or randomness of signals have revealed increased levels of randomness in the EEG and MEG of schizophrenia patients (21–23), which are higher during periods of exacerbation of psychosis (22). While there may be limitations to the existing EEG and MEG literature, recent fMRI data provide further support to the hypothesis that noise is increased in schizo-phrenia ( 19).

schizophrenia patients show increased baseline activity, especially in the gamma band, and an inverse relationship between prestimulation and poststi-mulation gamma activity (43). These findings suggest that at least part of the task-related abnormalities observed in schizophrenia may be associated with the presence of aber-rant brain activity during the prestimulation period

3 test day, randomized, double-blind, placebo-controlled, crossover study, subjects received Δ9-THC (vehicle [ethanol], .015 mg/kg or .03 mg/kg) over 10 minutes by intravenous route. The sample included subjects with and without recent cannabis exposure (within the last 30 days) and excluded cannabis-naïve and cannabis-dependent subjects

there was a significant effect of drug condition on signal power (Wald w22 5 8.004, pAdj 5 .036), which disappeared after controlling for LZC (Wald w22 5 2.236, pAdj ..1). Three HB-adjusted pairwise comparisons performed on the data before controlling for LZC revealed significantly lower power for the .03 mg/kg and .015 mg/kg doses compared with placebo (both pAdj 5 .029) but no difference between the .03 mg/kg and .015 mg/kg doses (pAdj . .1)

regression of LZC on signal power revealed a significant inverse relationship between both variables

significant effect of drug condition for the PANSS positive, disorganization and negative symptoms factors. The nine HB-adjusted pairwise comparisons showed significantly higher scores for the 0.03 mg/kg and 0.015 mg/kg doses compared with placebo and for the .03 mg/kg dose compared with the .015 mg/kg dose

Animal studies have revealed that cannabinoids acutely reduce the spectral power of LFP oscillations by increasing the randomness (reducing the synchronization) of the activity of populations of neurons rather than reducing the activity of individual neurons. The increased randomness would reduce the neurons’ capacity to form temporally coordinated ensembles, leading to a reduction of LFP spectral power (28, 29)

bandwidth of the signals was kept constant (99.5 Hz) across conditions by filtering

In the cerebral cortex and hippocampus, CB1Rs are located on the axon terminals of cholecystokinin-expressing gamma-aminobutyric acidergic interneurons… it has been proposed that cholecystokinin cells enhance the signal-to-noise ratio of neural oscillations (like a noise filter) through a CB1R-mediated mechanism (63–65)

whether our findings apply to resting state activity or to activity associated with expectancy during the prestimulation will need to be determined in future studies

a consequence of using the median as the threshold is that low-range frequencies are preferentially represented in the resulting binary data ( Supplement 1 ). Even though the median-crossing approach is widely used, alternate approaches [e.g., ( 68)] that better represent the entire frequency spectrum should be explored

At doses that produced increases in psychosis-like effects, Δ9-THC increased neural noise (LZC) measured in the EEG of humans in a dose-dependent manner. Furthermore, increases in neural noise were positively related with Δ9-THC-induced psychosis-like, but not negative-like, effects

if psychotic symptoms are a result of brain dysconnectivity related to an abnormal increase of neural noise, interventions directed toward reducing noise may have therapeutic potential

Costello E, Copeland W, Shanahan L, Worthman C, Angold A. 2013. “C-Reactive Protein and substance use disorders in adolescence and early adulthood: a prospective analysis” Drug Alcohol Depend 133(2): 712-717

The acute phase protein C-reactive protein (CRP) is a marker of systemic inflammation (Volanakis, 2001;Black et al., 2004) that is associated with chronic and costly diseases, including cardiovascular and metabolic disease (Raison et al., 2006; Shah et al., 2009; Miller et al., 2011) and with shortened life expectancy (Crimmins and Finch, 2006)

Once established, elevated CRP appears to be fairly stable across time (Macy et al., 1997).

A U-shaped cross-sectional relationship between CRP and alcohol consumption is widely documented (e.g., Albert et al., 2003; Imhof et al., 2001; Pai et al., 2006), but most in studies, including these, alcohol users showing abuse or dependence have elevated CRP

In inflammatory conditions, cannabinoids have long been used to reduce pain in rheumatoid arthritis and Crohn’s disease, and may protect against diabetes (Rajavashisth et al., 2012)

in these analyses we controlled for factors known from the literature to be associated with higher CRP levels (Davey Smith et al., 2005; Benson et al., 2009; Skinner et al., 2010; Elovainio et al., 2006a): age, low socioeconomic status, obesity, psychotropic medications, other medications and some psychiatric disorders

In the simple models without covariates, higher CRP levels at the previous wave predicted a higher likelihood of any cannabis use, but not alcohol use or nicotine use. It predicted abuse or dependence of any drug, and specifically cannabis abuse/dependence and nicotine dependence. When the covariates were added, any abuse/dependence and nicotine dependence remained significant, and there was a trend for cannabis use and abuse/dependence to be predicted by CRP (p<.1)

Only one form of SUD – nicotine use – predicted higher levels of CRP. Significant covariates were age and having a diagnosis of depression

the bivariate cross-sectional associations were much stronger between CRP level and most forms of SUD than they were between CRP and other psychiatric disorders

a recent analysis of the NHANES data (Rajavashisth et al., 2012) found that the prevalence of elevated C reactive protein (>0.5 mg/dl) was significantly less among past or current users than among non-marijuana users, suggesting support for the idea that cannabis is anti-inflammatory

Once other factors were entered into the models, the predictive relationships from CRP to cannabis use and addiction became non-significant

Population studies have consistently shown that there is no clear cut-point between “normal” and elevated levels of CRP (Kushner et al., 2010). In these analyses we excluded values above 10 mg/L (1.5% of all observations) as likely to signal current physical illness. Using the standard definition of “elevated” CRP as >3mg/L, 89.2% of GSMS observations were lower than this, compared with, for example, 62% of about 9,000 subjects (mainly adults) from the 1999–2002 National Health and Nutrition Examination Survey (Woloshin and Schwartz, 2005). Thus, this young and fairly healthy sample may not show effects seen in older or clinical samples.

Cota D. 2008. “The role of the endocannabinoid system in the regulation of hypothalamic-pituitary-adrenal axis activity” J Neuroendocrinol 20 suppl 1:35-8

previous pharmacological studies using plant-derived or synthetic cannabinoids have implied a stimulating action on the HPA axis … endogenous cannabinoid … inhibiting the release of both adrenocorticotrophic hormone and glucocorticoids

endocannabinoids have been found to mediate the nongenomic glucocorticoid-induced inhibition of the release of corticotrophin-releasing factor within the paraventricular nucleus of the hypothalamus

Cottler L, Nishith P, Compton WM 3rd. 2001. “Gender differences in risk factors for trauma exposure and post-truamatic stress disorder among inner-city drug abusers in and out of treatment” Compr Psychiatry 42(2): 111-7

Although more women than men met criteria for DSM-III-R PTSD, there were no gender differences on endorsement for a traumatic event. Adult antisocial behavior, affective disorder, schizophrenia, other anxiety disorder and polysubstance use predicted exposure to an event, whereas, only schizophrenia and other anxiety disorder predicted PTSD. In men, drug use preceded the exposure to an event, while in women, the onset age for both drug use and exposure to an event were nearly identical

Cougle J, Bonn-Miller M, Vujanovic A, Zvolensky M, Hawkins K. 2011. “Posttraumatic stress disorder and cannabis use in a nationally representative sample” Psychol Addict Behav 25(3): 554-8

large representative survey of adults (N = 5,672) from the United States (Kessler et al., 2004)

PTSD diagnoses were associated with increased odds of lifetime history of cannabis use as well as past year daily cannabis use. Lifetime, but not current, PTSD diagnosis also was uniquely associated with increased risk for any past year cannabis use. Additional analyses revealed that the relations between PTSD (lifetime and current) and lifetime cannabis use remained statistically significant when adjusting for co-occurring anxiety and mood disorders and trauma type frequency

Couper K, Blount D, Riley E. 2008. “IL-10: the master regulator of immunity to infection” Journal of Immunology 180(9): 5771-5777

IL-10 is an anti-inflammatory cytokine. During infection it inhibits the activity of Th1 cells, NK cells, and macrophages, all of which are required for optimal pathogen clearance but also contribute to tissue damage

IL-10 can act directly on CD4+ T cells, inhibiting proliferation and production of IL-2, IFN-γ, IL-4, IL-5 and TNF-α (5, 8, 9)

Irrespective of the source of IL-10, its effects are similar in all of the infections that have been studied: IL-10 suppresses macrophage and DC function, thereby limiting Th1 and Th2 effector responses (Table I). Nevertheless, the impact of IL-10 is clearly determined by the timing and site of its production, and these are both likely to be affected by which cells are making IL-10. Moreover, because IL-10 production by one cell population can affect the ability of other cells to make IL-10, there is the potential for IL-10-producing cells to regulate each other.

the ability of Th1 cells to coproduce IL-10 and IFN-γ may favor simultaneous pathogen clearance and suppression of downstream pathologies; examples include T. gondii, malaria, and leishmaniasis (17, 37,64, 68)

both Th1 and Th2 cells are now known to mediate inflammation and tissue damage as well as pathogen killing. Anti-inflammatory functions, in contrast, are now known to rest with populations of regulatory cells that may be myeloid or lymphoid in origin and can include fully mature, classical Th1 or Th2 cells that produce IL-10 as a negative feedback mechanism to limit their own response. More than any other cytokine, IL-10 is an essential component of this regulatory response in almost all infections

Cousijn J, Wiers R, Ridderinkhof K, van der Brink W, Veltman D, Goudriaan A. 2012. “Grey mater alterations associated with cannabis use: results of a VBM study in heavy cannabis users and healthy controls.” Neuroimage 59(4): 3845-51 in dropbox

Regional grey matter volume in the anterior cerebellum was larger in heavy cannabis users. Within the group of heavy cannabis users, grey matter volume in the amygdala and hippocampus correlated negatively with the amount of cannabis use or dependence. No associations were found between white matter volume and measures of cannabis use or dependence.

Coutinho A, Chapman K. 2011. “The anti-inflammatory and immunosuppressive effects of glucocorticoids, recent developments and mechanistic insights” Mol Cel Endocrinol 335(1): 2-13

Cui M, Yang Y, Yang J, Zhang J, Han H, Ma W, Li H, Mao R Xu L, Hao W, Cao J. 2006. “Enriched environment experience overcomes the memory deficits and depressive-like behavior induced by early life stress”

Curran H, Brignell C, Fletcher S, Middleton P, Henry J. 2002. “Cognitive and subjective dose-response effects of acute oral Delta 9-tetrahydrocannabinol (THC) in infrequent cannabis users” Psychopharmacology (Berl) 164(1): 61-70

Delta(9)-THC 15 mg impaired performance on two explicit memory tasks at the time of peak plasma concentration (2 h post-drug). At the same time point, performance on an implicit memory task was preserved intact

In several tasks, delta(9)-THC increased both speed and error rates, reflecting “riskier” speed-accuracy trade-offs. Subjective effects were also most marked at 2 h but often persisted longer, with participants rating themselves as “stoned” for 8 h. Participants experienced a strong drug effect, liked this effect and, until 4 h, wanted more oral delta(9)-THC. No effects of delta(9)-THC were found 24 or 48 h following ingestion indicating that the residual effects of oral delta(9)-THC are minimal

Crane N, Schuster R, Fusar-Poli P, Gonzalez R. 2012. “Effects of cannabis on neurocognitive functioning: recent advances, neurodevelopmental influences, and sex differences” Neuropsychol Rev 23:117-137

the neurobehavioral effects of cannabis use have been intensely studied over several decades and summarized in numerous published reviews (Crean et al. 2011; Ferraro 1980; R. Gonzalez et al. 2002; R. Gonzalez 2007; I. Grant et al. 2003; Iversen 2003; Jager and Ramsey 2008; Pope et al. 1995; Ranganathan and D’Souza 2006; Schweinsburg et al. 2008; Solowij and Battisti 2008; Solowij and Pesa 2010; Wert and Raulin 1986). However, many of these reviews conclude that the findings for several neurocognitive domains are equivocal

Several review articles have been written on acute cannabis intoxication and neuropsychological functioning (Crean et al. 2011; R. Gonzalez 2007; Ferraro 1980;Ranganathan and D’Souza 2006; Solowij and Pesa 2010), with equivocal findings for most neurocognitive domains other than aspects of episodic memory – the autobiographical memory of specific events, situations, and experiences (Tulving 2001). … More recent studies also suggest that acute THC intoxication seems to impair retrieval-based memory of new material, but evidence regarding the effects of THC on other neuropsychological domains remained mixed (R. Gonzalez 2007; Ranganathan and D’Souza 2006). For instance, a recent review of cannabis’ effects on executive functioning suggests that THC administration adversely affects inhibition, impulsivity, and working memory, but not verbal fluency, and findings are mixed for decision-making, risk-taking, and aspects of attention (Crean et al. 2011)

Data from the past five years is consistent with previous studies, generally showing acute administration of THC to impair episodic memory, including immediate (D’Souza et al. 2008a; D’Souza et al. 2008b; Dumont et al. 2011;Morrison et al. 2009) and delayed recall (D’Souza et al. 2008a; D’Souza et al. 2008b); procedural memory (Dumont et al. 2011); and associative learning and memory (Ballard et al. 2012) among occasional and regular cannabis users as well as non-users. Evidence indicates there may be a dose-dependent relationship between amount of intravenous THC and impairments in total free and delayed verbal recall, but not delayed cued or recognition recall (D’Souza et al. 2008b)

In studies of visuospatial memory, THC impaired accuracy in regular cannabis users (Weinstein et al. 2008a; Weinstein et al. 2008b). On the other hand, others report no effect from THC on visuospatial memory (Anderson et al. 2010), associative memory (Bossong et al. 2012a), or verbal episodic memory (Sugarman et al. 2011). Hart and colleagues (2010) also found that THC administration did not affect overall performance on a task of verbal episodic memory in regular cannabis users, but participants performed more poorly on a recognition task suggesting a deleterious impact of cannabis on retrieval-based memory

Most studies document impairments in attention and concentration following administration of small (i.e., 2.5mg) and large (i.e., 0.5 mg/kg) doses of THC in cannabis users and non-users compared to placebo administration (Anderson et al. 2010; D’Souza et al. 2008a; D’Souza et al. 2008b; Hunault et al. 2009; Ramaekers et al. 2009; Ramaekers et al. 2011;Theunissen et al. 2011), with some evidence for a dose-dependent relationship between amount of THC smoked and degree of impairment (Hunault et al. 2009). However, two studies found no differences in performance on measures of auditory selective attention and concentration in regular cannabis users after smoking cannabis standardized to 20mg THC (O’Leary et al. 2007) or on a measure of sustained attention in occasional cannabis users after ingesting 15mg THC (Sugarman et al. 2011) compared to placebo. Impairments in working memory have been observed following acute administration of vaporized THC (Bossong et al. 2012b), oral THC (D’Souza et al. 2008a; Dumont et al. 2011), smoked cannabis containing different doses of THC (Hart et al. 2010), and intravenous THC (Morrison et al. 2009)

THC has been found to impair healthy young adults’ performance on a reasoning task (but not a verbal fluency task; Morrison et al. 2009) and significantly increased total errors and nonpreservative errors in regular cannabis users on a task of abstract reasoning (Weinstein et al. 2008a; Weinstein et al. 2008b). Additionally, problems with cognitive flexibility have been reported after smoking cannabis standardized to different doses of THC compared to a placebo condition (Anderson et al. 2010). In contrast, most current evidence suggests that acute intoxication does not negatively impact decision-making or risk-taking in occasional, regular, or heavy cannabis users (D’Souza et al. 2008a; Ramaekers et al. 2009; Ramaekers et al. 2011; Vadhan et al. 2007; Weinstein et al. 2008a; Weinstein et al. 2008b), but it may slow decision-making (Vadhan et al. 2007). Some contradictory evidence does exist. Whereas a previous study demonstrated increasing levels of cannabis intoxication were associated with more risky responses in occasional cannabis users (Lane et al. 2005), a recent study found THC may actually reduce risk-taking behaviors in healthy young adults (Rogers et al. 2007)

Similar to the findings for decision-making and risk taking, studies examining inhibition, motor impulsivity, and psychomotor control (these domains are invariably linked and generally defined as behavior involving rapid reactions to internal and external stimuli; Moeller et al. 2001) are mixed. THC was found to negatively influence inhibitory control, as evidenced by increased stop reaction time and decreased accuracy of responses in occasional and heavy cannabis users during a stop signal task in two studies (Ramaekers et al. 2009; Theunissen et al. 2011), but THC administration, three hours after placebo alcohol administration, did not have an effect on inhibition or motor impulsivity in heavy cannabis users on the same task in another study (Ramaekers et al. 2011). Given the motor components inherent in the aforementioned tasks, it is worth considering that some studies find THC to impair psychomotor performance (D’Souza et al. 2008a; Hunault et al. 2009; Ramaekers et al. 2009), but several others do not (Dumont et al. 2011; O’Leary et al. 2007; Ramaekers et al. 2011). Interestingly, Ramaekers and colleagues (2009) found THC administration impaired psychomotor control in occasional cannabis users, but not in heavy cannabis users, suggesting a potential tolerance effect.Hunault and colleagues (2009) found THC to significantly decrease response time and increase errors in a dose-dependent manner in heavy cannabis users on a motor control task

Borgwardt and colleagues (2008) administered 10mg THC, 600 mg CBD, or placebo capsules to 15 men with minimal cannabis exposure (<15 times in life) on three separate occasions in a double-blind, within-subject design. In this study, and across several other investigations using the same sample, participants’ performance was unaffected by THC or CBD on measures of inhibition, verbal memory, accuracy of gender discrimination, and visual and auditory processing (Bhattacharyya et al. 2009; Bhattacharyya et al. 2010; Borgwardt et al. 2008; Fusar-Poli et al. 2009; Winton-Brown et al. 2011). In contrast, Roser and colleagues (2009) found combined THC and CBD, but not THC alone, impaired psychomotor control in 24 occasional cannabis users who were administered a combination of 10mg THC and 5.4mg CBD, 10mg THC alone, or a placebo pill on three separate visits in a double-blind, cross-over design

Morgan and colleagues (2010)found 22 cannabis users with low cumulative levels of CBD (as evidenced from hair analysis) demonstrated poorer performance on immediate and delayed episodic memory (but not verbal and category fluency) compared to 22 users with higher cumulative CBD exposure when both groups were intoxicated. The same group showed that daily cannabis users who had higher cumulative THC exposure demonstrated poorer performance on measures of immediate and delayed episodic memory, as well as source memory, compared to daily cannabis users with lower cumulative THC exposure when participants were intoxicated (Morgan et al. 2011). However, there were no differences in episodic memory and source memory performance between the 54 occasional cannabis users regardless of the cumulative THC exposure. On the other hand, both daily and occasional cannabis users with CBD present in hair analysis displayed better recognition memory than users without CBD present when all individuals were intoxicated (Morgan et al. 2011).

although no neurocognitive differences were found, THC and CBD had opposite effects of brain activation patterns in the striatum during verbal recall, in the hippocampus during inhibition, in the superior temporal cortex during auditory processing, in the occipital cortex during visual processing, and in the amygdala while subjects viewed fearful faces when compared to placebo (Bhattacharyya et al. 2010).

Some suggest residual effects (i.e., after several hours to several days of abstinence) and long-term effects (i.e., after several weeks of abstinence and beyond), while others find no clear evidence for residual or long-term neuropsychological deficits among cannabis users across several domains (Crean et al. 2011; R. Gonzalez et al. 2002; R. Gonzalez 2007; I. Grant et al. 2003; Pope et al. 1995; Schweinsburg et al. 2008; Solowij and Battisti 2008; Solowij and Pesa 2010; Wert and Raulin 1986). As found in the acute intoxication studies, the evidence is mixed for most domains other than episodic memory, which remains adversely impacted for up to 28 days following abstinence (R. Gonzalez 2007; I. Grant et al. 2003; Solowij and Battisti 2008)

Regular adolescent cannabis users who have been abstinent between 12 hours and 21 days demonstrate poorer immediate (Hanson et al. 2010;Harvey et al. 2007; Solowij et al. 2011) and delayed recall (Harvey et al. 2007; Solowij et al. 2011), as well as impaired recognition (Solowij et al. 2011). However, one of these studies found no difference in recognition between regular and occasional cannabis users (Harvey et al. 2007). After longer periods of abstinence (28 days), Tapert and colleagues (2007) found adolescent cannabis users made more recall intrusions than controls, while other studies found no differences between groups on any measure of episodic memory (Jacobsen et al. 2007; Mahmood et al. 2010; Medina et al. 2007a). Recently abstinent adult cannabis users also demonstrate poorer immediate (Battisti et al. 2010b; R. Gonzalez et al. In press;Hadjiefthyvoulou et al. 2011; Korver et al. 2010; Nestor et al. 2008; Wagner et al. 2010; Yucel et al. 2008) and delayed recall (R. Gonzalez et al. In press; Wadsworth et al. 2006; Yucel et al. 2008), but have intact recognition (R. Gonzalez et al. In press; Nestor et al. 2008; Wadsworth et al. 2006). Although this is not invariably the case, as some studies report intact immediate (Chang et al. 2006; Gruber et al. 2011;Wadsworth et al. 2006) and delayed recall (Chang et al. 2006; Gruber et al. 2011) among cannabis users. Other evidence suggests that recall performance is negatively associated with amount of past year (Jager et al. 2007) and lifetime cannabis use (Indlekofer et al. 2009; Jager et al. 2007; P. Murphy et al. 2011;Solowij et al. 2011), duration of cannabis use (Solowij et al. 2011; Wadsworth et al. 2006), frequency of cannabis use, and age of first cannabis use (Solowij et al. 2011).

Adolescent cannabis users who were abstinent between 12 to 24 hours demonstrated intact associative learning (Harvey et al. 2007; Jager et al. 2010). After longer periods of abstinence (28 days), adolescent cannabis users exhibited deficits on a story memory task (Medina et al. 2007a), but had intact visuospatial memory (Mahmood et al. 2010; Medina et al. 2007a; Schweinsburg et al. 2010). In recently abstinent adult cannabis users, some studies report visuospatial memory deficits (Hermann et al. 2007; McHale and Hunt 2008), but others do not (Chang et al. 2006; Gruber et al. 2011). Amount of lifetime cannabis use did not predict visuospatial memory in a community sample of recently abstinent polydrug users (Indlekofer et al. 2009). Recently abstinent adult cannabis users have demonstrated intact associative learning (Fisk and Montgomery 2008) and semantic memory (Wadsworth et al. 2006). Evidence for prospective memory deficits is split with one study reporting deficits (Montgomery et al. 2012) and another no deficits (Hadjiefthyvoulou et al. 2011)

Several studies cite impairments in attention and concentration in recently abstinent adolescent cannabis users (Abdullaev et al. 2010; Hanson et al. 2010; Harvey et al. 2007; Lane et al. 2007). After at least 21 days of abstinence, complex attention continues to be impaired in adolescent cannabis users (Hanson et al. 2010; Jacobsen et al. 2004; Medina et al. 2007a; Tapert et al. 2007), with evidence of a dose-dependent relationship with amount of lifetime use (Medina et al. 2007a). Conversely, others reported that after 45 days of abstinence, selective and divided attention was intact in adolescent cannabis users (Jacobsen et al. 2004). Recently abstinent adult cannabis users also demonstrated impairments in attention and concentration in several studies (Hermann et al. 2007; Indlekofer et al. 2009;Scholes and Martin-Iverson 2009; Scholes-Balog and Martin-Iverson 2011; Wadsworth et al. 2006), which persisted for several hours to one week of abstinence. However, a few studies report no impairments among adult cannabis users when the time of last cannabis use was either unknown (J. Grant et al. 2011;Korver et al. 2010) or after at least 4 hours to approximately 38 months of abstinence (Chang et al. 2006)…

Adolescent regular cannabis users who are abstinent demonstrated poorer working memory compared to controls after 3 and 13 days, during a challenging task that required active manipulation of items (Hanson et al. 2010), but not after 8 days, during a more simple matching task (Jager et al. 2010) … Harvey and colleagues (2007) found regular adolescent cannabis users performed more poorly on spatial working memory than occasional cannabis users and amount of cannabis use was one of the strongest predictors of poorer spatial working memory. The evidence is also mixed regarding the persistence of working memory deficits among adolescents after abstinence, with some studies reporting deficits after 28 days (Jacobsen et al. 2004; Jacobsen et al. 2007), whereas others do not (Hanson et al. 2010; Padula et al. 2007; Schweinsburg et al. 2008; Schweinsburg et al. 2010). In contrast to studies with adolescent samples, most studies report intact working memory among recently abstinent adult cannabis users (Becker et al. 2010; Chang et al. 2006; Fisk and Montgomery 2008; J. Grant et al. 2011; Gruber et al. 2011; Jager et al. 2006; Looby and Earleywine 2010; Piechatzek et al. 2009; Scholes and Martin-Iverson 2010)… in a longitudinal study, working memory performance remained intact among recently abstinent current cannabis users, former cannabis users, and controls over a period of eight years (Tait et al. 2011). On the other hand, frequency of cannabis use was negatively correlated with working memory performance among abstinent cannabis users (Wadsworth et al. 2006) and among polysubstance users (Fernandez-Serrano et al. 2010)

one recent study examined verbal fluency in a sample of adolescent cannabis users and found it to be impaired after 28 days of abstinence (Tapert et al. 2007). Studies of recently abstinent adult cannabis users report deficits in verbal fluency after 8-24 hours since last use (Korver et al. 2010; Mason et al. 2012;McHale and Hunt 2008) and after 15 days of abstinence (Fernandez-Serrano et al. 2010). However, others report intact verbal fluency after a few hours to a week since last cannabis use (Chang et al. 2006; Fisk and Montgomery 2008; Gruber et al. 2011; Piechatzek et al. 2009). Of note, recently abstinent adult cannabis users have also been reported to demonstrate deficits in text comprehension (Huestegge et al. 2010)

Poorer cognitive flexibility has been reported among adolescent cannabis users abstinent for approximately 8 hours compared to controls (Lane et al. 2007), but not between recently abstinent occasional and regular adolescent cannabis users (Harvey et al. 2007). After at least 23 days of abstinence, adolescent cannabis users appear to evidence intact cognitive flexibility (Medina et al. 2007a). As with adolescent cannabis users, abstinent adult cannabis users also demonstrated impairments in cognitive flexibility (Fontes et al. 2011a, 2011b; J. Grant et al. 2011; Mason et al. 2012). Similarly, planning and reasoning were poorer among adult cannabis users who were abstinent for at least 5 days compared to controls (Montgomery et al. 2012). Furthermore, amount of lifetime cannabis use predicted worse performance on a reasoning task for adult polysubstance users who were abstinent for at least 15 days (Fernandez-Serrano et al. 2010)

Compared to findings from acute investigations, recently abstinent adult cannabis users show more consistent deficits in decision-making and risk-taking (J. Grant et al. 2011;Vaidya et al. 2012; Wesley et al. 2011), even after 15 days of abstinence (Fernandez-Serrano et al. 2010).Fridberg and colleagues (2010) also reported impairments in decision-making among cannabis users, and through using computational modeling they found these impairments were likely due to cannabis users’ decreased sensitivity to losses and increased sensitivity to immediate gains. However, others have not observed such deficits (Boggio et al. 2010; Hermann et al. 2009; Martin-Soelch et al. 2009). In our own studies, cannabis users and non-users, who were matched on various potential comorbidities, performed equivalently on measures of decision-making and risk-taking (R. Gonzalez et al. In press). However, we found that decision-making performance (but not performance on measures of episodic memory or other measures associated with impulsive behavior) is related to more DSM-IV cannabis use dependence symptoms among cannabis users (R. Gonzalez et al. In press)

recently abstinent adolescent cannabis users, regular and non-regular users showed no difference in inhibition or psychomotor control (Harvey et al. 2007). After 28 days of abstinence, adolescent cannabis users demonstrated intact inhibition and motor impulsivity (Tapert et al. 2007). Yet, after at least 23 days of abstinence, adolescent cannabis users had impairments in psychomotor performance compared to controls, and there was a negative, dose-dependent association between performance and lifetime cannabis use episodes (Medina et al. 2007a). In recently abstinent adult cannabis users, some studies report impairments in inhibition and motor impulsivity (Battisti et al. 2010a; Clark et al. 2009; Cunha et al. 2010; Fontes et al. 2011a, 2011b; Scholes and Martin-Iverson 2010), with some evidence for a dose-dependent relationship between amount of past 30 day use and performance (Cunha et al. 2010; Piechatzek et al. 2009). However, many other studies report no differences in performance between recently abstinent adult cannabis users and controls (Aharonovich et al. 2008; Becker et al. 2010;Cane et al. 2009; Chang et al. 2006; Fernandez-Serrano et al. 2010; Fontes et al. 2011b; R. Gonzalez et al. In press; J. Grant et al. 2011; Gruber et al. 2011; Hermann et al. 2007; Hester et al. 2009; Roberts and Garavan 2010; Scholes and Martin-Iverson 2010)

one investigation finding deficits in psychomotor control across several measures among adult cannabis users abstinent for 12 hours (King et al. 2011), but others suggesting intact psychomotor control in recently abstinent cannabis users (Chang et al. 2006; Korver et al. 2010; Wadsworth et al. 2006) and after 28 days of abstinence (Pillay et al. 2008)

there is some evidence indicating cannabis may exert neuroprotective effects among heavy alcohol using adolescents (Jacobus et al. 2009; Mahmood et al. 2010; Medina et al. 2007b; Schweinsburg et al. 2011), alcohol-dependent adults (Nixon et al. 1998), and methamphetamine-dependent adults (R. Gonzalez et al. 2004)

rats exposed to synthetic cannabinoids or THC during adolescence experience impaired working memory during adulthood (O’Shea et al. 2004; O’Shea et al. 2006; Rubino et al. 2009a; Rubino et al. 2009b). These impairments have been correlated with less active synapses in the prefrontal cortex (Rubino et al. 2009a), as well as shorter dendrites and reduced spine densities in the hippocampus, suggesting enduring neurobiological consequences of early cannabis exposure (Rubino et al. 2009b). The heightened vulnerability of younger brains is highlighted by the fact that the same amount of THC exposure that led to decreased working memory performance in adolescent rats had no effect in adult rats (Quinn et al. 2008). However, some have suggested that heavy THC administration during adolescence may be needed to produce significant and persistent impairments in working memory (Realini et al. 2009). With regards to learning, impairments with synthetic cannabinoid administration during late adolescence were reported, but these resolved after a prolonged period of abstinence (Abush and Akirav 2012). Conversely, rats exposed to chronic doses of THC during adolescence, but not during late adolescence, evidenced deficits in learning during adulthood (Harte and Dow-Edwards 2010). There may be a critical time during adolescence when cannabis use may have the most negative effects. When taken together, these studies suggest that cannabis use during adolescence may have a more significant and lasting impact on neurocognition than if cannabis use is initiated during adulthood.

those who initiate use before 15 to 17 years of age demonstrate more pronounced deficits in visual attention (Ehrenreich et al. 1999), verbal fluency (Gruber et al. 2011; Pope et al. 2003), inhibition (Fontes et al. 2011a; Gruber et al. 2011; Pope et al. 2003), and other aspects of executive functioning (Fontes et al. 2011a) as compared to those who initiate use later on. Further, episodic memory was poorer in those with an earlier onset of cannabis use in two studies (Pope et al. 2003; Solowij et al. 2011); however, another study failed to find this effect (Gruber et al. 2011). Poorer performance on measures of inhibition (Battisti et al. 2010a; Gruber et al. 2011) and impulsivity (Solowij et al. 2012) have also been associated with earlier age of onset. Moreover, Gruber and colleagues (2012) reported that early-onset users made more errors and showed greater disruptions in brain activation patterns than late-onset users during an inhibition task. On the other hand, others have reported no differences between early and late-onset cannabis users (and healthy controls) on measures of working memory and attention (Ehrenreich et al. 1999; Gruber et al. 2011; Pope et al. 2003), as well as on a task of visuospatial memory (Gruber et al. 2011)

Females’ total brain size peaks between 10 and 11 years of age, while males’ total brain size peaks at about 14 to 15 years of age (Lenroot et al. 2007). Similarly, females’ prefrontal cortex gray matter volume peaks 1 to 2 years earlier than in males (Giedd et al. 1999). Therefore, if cannabis use is initiated in early to mid-adolescence, it is possible that males may be more vulnerable to neurobehavioral disturbances, especially functional and/or structural disruptions in the prefrontal cortex, compared to females

nimal studies citing greater CB1 receptor density among males across several brain regions (Burston et al. 2010; Mateos et al. 2011; Reich et al. 2009; Rubino et al. 2008) Whereas males either maintain or lose some CB1 binding sites in later adulthood (i.e., 45 to 70 years of age), adult female brains show increases in CB1 receptor density across the lifespan, eventually surpassing that of males (Van Laere et al. 2008)

Furthermore, adolescent females evidence greater CB1 desensitization after exposure to THC in the prefrontal cortex, hippocampus, striatum, amygdala, and midbrain (Burston et al. 2010; Rubino et al. 2008). Given that endocannabinoid signaling plays a crucial role in establishing normal sex differences in the brain (Viveros et al. 2012)

Acute THC administration disrupted learning in adolescent female, adolescent male, and adult female rats, but did not disrupt learning in adult male rats (Cha et al. 2007). Chronic doses of THC administration did not affect learning in either adolescent or adult male and female rats (Cha et al. 2007), but others found that male rats evidenced worse novel object recognition than female rats (Mateos et al. 2011). In contrast, female rats administered chronic THC during adolescence perform worse on an object location task than female controls, while no differences emerged among male rats (Mateos et al. 2011). Although both male and female rats demonstrated deficits in spatial working memory after exposure to THC in adolescence (O’Shea et al. 2004; O’Shea et al. 2006; Rubino et al. 2009a; Rubino et al. 2009b), this exposure in adulthood had long-term impairments on memory in male rats, but not in female rats (O’Shea et al. 2004; O’Shea et al. 2006). Thus, cannabis use during adolescence may produce sex-specific alterations in neurodevelopment

evidence from animal studies suggest exogenous cannabinoids, like THC, have the ability to significantly alter pituitary function (L. Murphy et al. 1991a; L. Murphy et al. 1991b; Wenger et al. 1999) and may inhibit the HPG axis (L. Murphy et al. 1990; L. Murphy et al. 1994;L. Murphy et al. 1999; Steger et al. 1980; Steger et al. 1983), thereby dysregulating key motivational systems involved in drug-seeking behavior

estrogen reduces the inhibitory effect of cannabinoids on HPG function (Scorticati et al. 2003; Scorticati et al. 2004). Furthermore, hormones play a key role in structural and functional changes in the endocannabinoid system, evidenced by fluctuations in endocannabinoid receptor (especially CB1) density across the estrus cycle (Bradshaw et al. 2006; S. Gonzalez et al. 2000; Rodriguez de Fonseca et al. 1994)  Moreover, human studies have demonstrated that, during the follicular phase of the menstrual cycle (when estradiol is high and progesterone is low), females are more responsive to the effects of stimulants, such as cocaine (Sofuoglu et al. 1999) and nicotine (Newman 2009; Perkins et al. 2000)

females enter treatment for marijuana use disorders significantly sooner (i.e., after fewer years of use) and after less cumulative cannabis use compared to males (Hernandez-Avila et al. 2004). This may be due to various differences in the pharmacologic effects of THC in males and females

female rats preferentially metabolize THC to its most highly active metabolite, while male rats metabolize THC to multiple compounds (Narimatsu et al. 1991). Moreover, physiological data shows that when smoking a second cigarette, females have less tachycardia than males (Cocchetto et al. 1981)

females may feel greater hedonic reinforcement from cannabis compared to males, and that ovarian hormones (such as estrogen and progesterone) may facilitate stronger learned associations between drug effects and drug-related stimuli (Fattore et al. 2007)

it is possible that females may be more vulnerable to the negative effects of cannabis

Males often perform better than females on measures of decision-making (Bolla et al. 2004; Overman et al. 2004;Reavis and Overman 2001), spatial processing, and psychomotor performance (Gur et al. 2012); whereas females perform better on measures of verbal memory (Kramer et al. 1988), visual recognition, attention, and reasoning abilities (Gur et al. 2012)

35 male and 35 female cannabis users did not demonstrate differential effects of smoked THC (joints with either 0% THC or 2.9% THC) in performance on measures of visuospatial processing, time estimation, and cognitive flexibility (Anderson et al. 2010)

Rogers and colleagues (2007) found no sex differences in risk-taking performance between 7 male and 8 female cannabis users after administration of either 0mg or 5mg THC. Surprisingly, spatial working memory was enhanced in females (n= 7), but not in males (n=12) after 0mg or 8.5mg of sublingual THC (Makela et al. 2006)

in all five sessions of a finger tapping task, males (n= 12) had faster left-hand tapping than females (n= 12) after 10mg THC administration and for two sessions after THC and CBD combined administration (10mg THC and 5.4mg CBD), despite no differences in baseline performance (Roser et al. 2009). In summary, preliminary evidence suggests there may be little or no sex-specific effects of acute THC administration on neurocognition

females who used cannabis heavily (i.e., median frequency of use was 29 out of the past 30 days) performed worse than light users (i.e., median frequency of use was 1 out of the past 30 days) on a visuospatial task – no differences were found between heavy and light male cannabis users, nor were any sex differences found on task of attention and inhibition (Pope et al. 1997). More recently, male cannabis users evidenced impairments on psychomotor performance (Clark et al. 2009; King et al. 2011) and visuospatial organization (King et al. 2011) compared to male healthy controls, but no differences were observed between cannabis-using females and their non-using counterparts (Clark et al. 2009; King et al. 2011) among male (n= 44) and female (n = 25) young adult cannabis users (unpublished). Specifically, more lifetime cannabis use was associated with poorer decision-making performance for male cannabis users, but not female cannabis users. In contrast, more lifetime cannabis use was negatively associated with episodic memory performance in both male and female cannabis users. Other studies report no interaction effects of sex and cannabis use on episodic memory (Solowij et al. 2011; Tait et al. 2011) or working memory (Tait et al. 2011)

After 28 days of abstinence, female adolescent chronic cannabis users had larger right amygdala volumes compared to female adolescent healthy controls, while there was no difference in amygdala volumes among adolescent male chronic cannabis users and controls (McQueeny et al. 2011). Female adolescent chronic cannabis users also evidenced larger prefrontal cortex volumes than female controls, whereas males showed the opposite pattern relative to a male control group (Medina et al. 2009). In this sample, smaller prefrontal cortex volume was associated with better executive functioning among the cannabis users, but larger prefrontal cortex volume was associated with better executive functioning among the controls

We suggest that a specific focus on pre-existing neurobehavioral factors and sex-differences, as well as their complex interactions, will be fruitful in understanding the subjective liability to the neurocognitive effects of cannabis.

Crippa J, Zuardi A, Martin-Santos R, Bhattacharyya S, Atakan Z, McGuire P, Fusar-Poli P. 2009. “Cannabis and anxiety: a critical review of the evidence” Hum. Psychopharmacol Clin Exp 24: 515-523 add to dropbox

Cannabis can cause an acute and short-lasting episode of anxiety, which often resembles a panic attack, in those who are not habitual users… About 20-30% of users show brief acute anxiety reactions after smoking the drug (Hollister, 1986; Thomas, 1996). Such symptoms usually occur when the drug is used at high doses aand are more common in drug-naive subjects and in novel or stressful environmental situations (Manzanares et al, 2004)

consistently described in experimental studies in man (D’Souza et al ., 2004; Gregg et al ., 1976; Naliboff et al ., 1976; Zuardi et al ., 1982) and in many case reports (Deaset al ., 2000; Moran, 1986)

anxiety reactions and panic attacks appear to result in aversion to further use of the drug, as these symptoms are one of the most common reasons given for the cessation of cannabis use. These individuals are also less likely to be come regular users (Thomas, 1996)

cannabis can exacerbate existing anxiety symptoms, precipitate recurence of an acute episode and counteract the effects of anxiolytic medication (Szuster et al, 1988)

Factors associated with the risk of anxiety induced by cannabis use: Individual and genetic vulnerability Personality traits Gender Frequency of use Dose and quantity consumed Proportions and concentration of cannabinoids History of previous episode Presence of anxiety disorders/symptoms Basal anxiety levels Abstinence states Environment and context of use

In contrast, long-term users typically report that cannabis use is associated with a reduction in anxiety. Relaxation and relief from tension remain the most common effects of using cannabis and the most common reasons for using the drug (Boys et al, 1999; Hathaway, 2003; Reilly et al, 1998).

Frequent cannabis users appear to have higher levels of anxiety than non-users without these necessarily representing an anxiety disorder. In a study with people who regularly used cannabis for at least 10 years, 21% of the subjects had high levels of anxiety (Reilly et al, 1998)

Troisi: severity of anxiety symptoms increased progressively with increasing cannabis use and higher levels of anxiety were observed in those who reported abuse or dependence on the drug

Dorard (2008) confirmed that cannabis dependence in adolescents is related to increased psychological distress and anxiety levels. Similar result was found in two indigenous communities in the northern territory of Australia (Clough et al., 2005). The authors found that the severity of symptoms within the ‘anxiety-dependency’ cluster in cannabis users increased as their level of cannabis use increased

particularly evident among women, as observed in cannabis-dependent individuals arrested for marijuana-related offending behaviour (Feeney et al ., 2005). State anxiety level was also one of the main predictors of increased severity of cannabis use (Spalletta et al ., 2007), while the marijuana use increased the risk for anxiet y symptoms and catastrophic thinking (Zvolensky et al ., 2006b)

a considerable number of subjects developed anxiety disorders before the first symptoms of cannabis dependence suggesting that some of them may have been using cannabis as a self-prescribed anxiolytic medication (Agosti et al., 2002). In line with this hypothesis a recent study observed that social anxiety disorder is an independent risk factor for cannabis dependence (Buckner et al ., 2008)

authors of this study found that the age of onset of panic attacks was significantly earlier among the subjects with both conditions than for individuals with panic attack with no cannabis use (Zvolensky et al ., 2006a)

Strike et al . (2003) verified that 13% of individuals dependent on cannabis who sought treatment had a history of previous anxiety disorder. Similarly, Swadi and Bobier (2003) verified that 63% of patients hospitalized with an anxiety disorder presented with a comorbid substance abuse disorder, especially cannabis. On the other hand, suffering from an anxiety disorder seems to be one of the most important reasons for cannabis users to seek psychiatric treatment

An-xiety is one of the main manifestations of the cannabis withdrawal syndrome (Bonn-Miller et al., 2007; Haney, 2005). Its onset is typically between the second and sixth day and lasts from 4 to 14 days (Budney et al ., 2004). The severity and duration of these effects are comparable to those of tobacco and other withdrawal syndromes… The most promising demonstration of suppression of symptoms of cannabis withdrawal was observed through the use of oral D9-THC (from 30 to 90 mg/day), which decreased both symptoms and cravings. At this dose
it did not produce intoxication and induced only minimal adverse effects (Budney et al ., 2007; Haney et al ., 2004)

[MV: 90 mg THC is a LOT… “did not produce intoxication”?]

Several cases of agoraphobia (Moran, 1986) and panic disorder (Dannon et al ., 2004; Langs et al ., 1997) induced by cannabis use have been previously described. Some authors have also speculated that cannabis use may be associated with enduring anxiety symptoms, as these clinical observations parallel data from animal studies (O’Shea et al ., 2004, 2006).

It was observed that frequent cannabis use in adolescent females doubled the chances of their subsequently presenting with anxiety and depressive conditions, with daily cannabis use increasing the risk fourfold (Patton et al ., 2002). As depression did not predict higher cannabis use in later life, this seems unlikely to reflect self-medication with cannabis for these symptoms; consistent with an earlier report (McGee et al., 2000). These findings have been replicated by a recent study which followed up a cohort of 3239 Australian young adults from birth to the age of 21 years. After controlling for confounding factors, those who started using cannabis before the age of 15 years and used it frequently at 21 years were more likely to report symptoms of an anxiety disorder in early adulthood (Hayatbakhsh et al., 2007). However, contrasting results were observed in a large longitudinal study that focused on the vulnerability factors in adolescent substance use (Windle and Wiesner, 2004). These contrasting findings were further supported by a recent study which investigated whether cannabis use predicted the first incidence of mood and anxiety disorders in 6000 adults during a 3-year follow-up period. Use of cannabis at baseline predicted a modest increase in the risk of a first episode of major depression and a stronger increase in the risk of a first episode of bipolar disorder. Although there was an association noted between cannabis use and anxiety disorders, it did not survive after controlling for confounding factors (Van Laaret al ., 2007)

the combination of cognitive-behavioural therapy and pharmacotherapy was not effective for the treatment of panic or social phobia symptoms among occasional cannabis users (Brickeret al ., 2007)

a causal relationship between cannabis use and long-term anxiety disorders remains dubious (Gilder et al., 2006; Windle and Wiesner, 2004). For instance, if cannabis use were to have been responsible for the precipitation of anxiety disorders, one would have expected an increase in the number of people presenting with these disorders in recent years, as the prevalence and extent of cannabis use has increased in recent times (Boydell et al ., 2006; Iversen, 2003)

Cuthbert B, Insel T. 2013. “Toward the future of psychiatric diagnosis: the seven pillars of RDoC” BMC Med 11: 126

Current diagnostic systems for mental disorders rely upon presenting signs and symptoms, with the result that current definitions do not adequately reflect relevant neurobiological and behavioral systems – impeding not only research on etiology and pathophysiology but also the development of new treatments

Dallman M. 2007. “Modulation of stress responses: how do we cope with excess glucocorticoids” Exp Neurol 206(2): 179-182

Circulating glucose is increased with an abundant supply for the potential need for fighting or fleeing, as is arterial blood pressure; the immune system is prevented from over-responding to acute bacterial threats; contextual brain-generated behaviors are enhanced by both increased attention and drive (13). Thus, the glucocorticoids engage many of the body systems for optimal responses to acute challenge

persistently elevated glucocorticoid concentrations are far too much of a once good thing

there appears to be a host of mechanisms that allow strong damping of the HPA responses

“habituation” to (homotypic) stressors … with repetition the HPA response diminishes markedly, thus limiting the overall exposure to glucocorticoids experienced by the animal during repeated bouts of the same stimulus… the HPA system maintains, or even augments its responsivity to new (heterotypic) stimuli

all indices of activity are diminished after repetition. Corticotropin-releasing factor (CRF) and vasopressin(AVP) synthesis is decreased as is consequent ACTH and corticosterone secretion (6) … c-Fos staining, shows a reduced number of excited cells, and that the responsive CRF neurons are more ventrally located in the nuclei (20)

neurotoxin lesions of the posterior midline paraventricular thalamus, known as the neuroendocrine thalamus, abrogated habituation to repeated stressors… habituation appears to be mediated by the corticosteroids, since injection of a combination of mineralocorticoid- and glucocorticoid receptor antagonists into the paraventricular thalamus before each of the repeated restraint bouts also blocked the acquisition of habituation

Amygdalar CRF synthesis and secretion is stimulated by glucocorticoid activity in amygdalar cells (3, 1517) and CRF activity appears to be essential for the engagement of the chronic stress response network (4, 14)

reduction in plasma AVP is highly correlated with the reduction in corticosterone, and that injection of an AVP-neutralizing antiserum reduced corticosterone in water-deprived but not ad lib drinking rats

the splanchnic neural innervation of adrenocortical cells is of key importance in upregulation of adrenal sensitivity to ACTH diurnally (9) and to the response to water deprivation (19)

It seems likely that there is a similar mechanism in place under those conditions to rapidly relieve the organism of excessive corticosterone secretion once the stimulus is relieved. Limiting the increased corticosterone burden through a variety of mechanisms is physiologically important, and should serve to prolong life and more normal function under conditions of chronic challenge

van Dam D, van Nierop M, Viechtbauer W, Velthorst E, van Winkel R, GROUP investigators, Bruggeman R, Cahn W, de Haan L, Kahn R, Meijer C, Myin-Germeys I, van Os J, Wiersma D. 2014. “Childhood abuse and neglect in relation to the presence and persistence of psychotic and depressive symptomatology” Psychological Medicine 17: 1-15 in dropbox

patients ( n = 1119), their siblings ( n = 1057) and a control group ( n = 589)

more childhood trauma is associated with more severe psychopathology; stronger association for abuse and positive psychotic symptoms, no specific symptom association for neglect

D’Andrea W, Ford J, Stolbach B, Spinazzola J, van der Kolk B. 2012. “Understanding Interpersonal Trauma in Children: Why We Need a Developmentally Appropriate Trauma Diagnosis” American Journal of Orthopsychiatry 82(2): 187-200 in dropbox

Children exposed to interpersonal victimization often meet criteria for psychiatric disorders other than posttraumatic stress disorder (PTSD) … a wide range of symptoms is common in victimized children … in the current psychiatric nosology, multiple comorbid diagnoses are necessary—but not necessarily accurate—to describe many victimized children, potentially leading to both under-treatment and overtreatment

worldwide, approximately one third of children are estimated to experience physical abuse; approximately one in four girls and one in five boys experience sexual victimization

fewer than a quarter of children in treatment for trauma-related psychopathology with the National Child Traumatic Stress Network meet criteria for PTSD

Comorbidity is the rule: 40% of children with any trauma history have at least one other mood, anxiety, or disruptive behavior disorder diagnosis; this is exacerbated by exposure to
increasing numbers of types of traumatic stressors. … chronicity, physical violation, and betrayal of trust also determine risk and severity of posttraumatic symptoms and impairment, but a greater breadth of types of victimization is particularly influential in the development of multifaceted and severe symptoms

place at risk of chronic and severe coexisting problems with emotion regulation, impulse control, attention and cognition, dissociation, interpersonal relationships, and attributions

Although it may appear obvious that child maltreatment results in negative outcomes, current literature has remained fragmented; studies are conducted by islands of researchers who may not collaborate or integrate (e.g., experimental psychologists, epidemiologists, developmental psychologists, and clinicians)

the range of maltreatment, interpersonal violence, abuse, assault, and neglect experiences encountered by children and adolescents, including familial physical, sexual, emotional abuse and incest; community-, peer-, and school-based assault, molestation, and severe bullying; severe physical, medical, and emotional neglect; witnessing domestic violence; as well as the impact of serious and pervasive disruptions in caregiving as a consequence of severe caregiver mental illness, substance abuse, criminal involvement, or abrupt separation or traumatic loss

affective symptoms … exposed to interpersonal violence include lability, anhedonia, flat or numbed affect, explosive or sudden anger, and incongruous or inappropriate affect. Behavioral expressions of affect regulation may include withdrawal, self-injury, aggression, oppositional behavior, substance use, or other compulsive behavior. Behavioral dysregulation may represent affective overload as well as attempts to dispel, reduce, or recover from negative affect states

maltreated children are either hypersensitive or avoidant in response to negative emotional stimuli or are likely to interpret positive emotions as ambiguous

dissociation may take the form of inattention and impulsivity in traumatized children

domestic (esp interparental) violence increases risk and severity of internalizing, externalizing, relational, academic and vocational, and legal problems

maltreatment, sexual abuse, parental verbal abuse, and harsh corporal punishment have been found to be associated with numerous structural and functional alterations in the brain and neuroendocrine systems. Maltreated children have been found to have volumetric reductions in the corpus callosum left neocortex, hippocampus, and amygdala (Teicher et al., 2003). Young adult women who experienced sexual abuse, compared to matched controls, had reduced hippocampal volumes if the abuse occurred in early childhood or preadolescence, reduced corpus callosum volumes if the abuse occurred in middle childhood, and reduced prefrontal cortex volumes if the abuse occurred in adolescence (Andersen et al., 2008)

studies comparing women diagnosed with PTSD, depression, borderline personality disorder, and dissociative identity disorder who had childhood sexual abuse histories versus matched controls found evidence of reduced hippocampal (and in some cases, amygdalar) volumes (Bremner, Vithilingham, Vermetten, Southwick, et al., 2003; Schmahl, Vermetten, Elzinga, & Bremner, 2003; Vermetten, Sch-mahl, Lindner, Loewenstein, & Bremner, 2006; Vythilingam et al., 2002)

Women with childhood sexual abuse histories also have been shown to have reduced gray matter in the visual cortices (Tomoda, Navalta, Polcari, Sadato, & Teicher, 2009)

Harsh corporal punishment associated with reduced gray matter volumes in the medial and dorsolateral prefrontal cortices and anterior cingulate (Tomoda, Suzuki, et al., 2009)

Taylor et al. (2006) found that children who experienced harsh or cold parenting showed decreased amygdala activation during an emotion observation task and a strong relationship between amygdala activation and right ventrolateral prefrontal cortical areas during an emotion labeling task, which indicates poor inhibition of the amygdala

Young children who experienced abuse had lower cortisol than peers (King et al., 2001; Linares et al., 2008). women with childhood sexual abuse…  similar neuroendocrine abnormalities (Bremner, Vermetten, & Kelley, 2007; Bremner, Vithilingam, Anderson, et al., 2003; Bremner, Vythilingam, Vermetten, et al., 2003).

The continued practice of applying multiple distinct comorbid diagnoses to traumatized children defies the cardinal rule of parsimony, obscures etiological clarity, and runs the danger of relegating trauma-informed treatment to only one disorder (PTSD) that is experienced by only a small fraction of traumatized children who are in psychiatric treatment

Dalton V, Long L, Weickert C, Zavitsanou K. 2011. “Paranoid schizophrenia is characterized by increased CB1 receptor binding in the dorsolateral prefrontal cortex” Neuropsychopharmacology 36(8): 1620-1630

paranoid SCZ having 22% higher levels of CB1R binding compared with the control group

Danese A, Moffitt T, Pariante C, Ambler A, Poulton R, Caspi A. 2008. “Elevated inflammation levels in depressed adults with a history of childhood maltreatment” Arch Gen Psychiatry 65(4): 409-415

Although depression was associated with high hsCRP (RR=1.45; 95%CI=1.06;1.99), this association was significantly attenuated and no longer significant when the effect of childhood maltreatment was taken into account. Individuals with current depression and childhood maltreatment history were more likely to show high hsCRP levels than controls (N=27; RR=2.07; 95%CI=1.23;3.47). In contrast, individuals with current depression only showed a non-significant elevation in risk (N=109; RR=1.40; 95%CI=0.97;2.01). Results generalized to the inflammation factor. The elevated inflammation levels in depressed+maltreated individuals were not explained by correlated risk factors, such as depression recurrence, low socioeconomic status in childhood or adulthood, poor health, or smoking

Danielson C, Amstadter A, Dangelmaier R, Resnick H, Saunders B, Kilpatrick D. 2009. “Trauma-related risk factors for substance abuse among male versus female young adults” Addict Behav 34(4): 395-399

1,753 young adults who participated in the 7−8 year follow-up telephone-based survey to the original National Survey of Adolescents. … 29.1% met criteria for substance abuse

exposure to specific traumatic events indeed increases risk for SUDs among young men. This is in contrast to much of the previous literature that has found that trauma exposure increases risk for SUDs among young women, but not young men. One possible explanation for this contrast is the inclusion of introductory narratives and behaviorally specific measurement of traumatic event history in the current study, which may have captured greater numbers of trauma-exposed young men than previous studies and provided a larger sample within which to examine the relation between such traumatic event history and SUDs

young adult women who have been sexually assaulted are at greater risk for alcohol abuse than men who have been sexually assaulted. Thus, gender may moderate the relation between alcohol abuse and SA

Dantzer R, O’Conner J, Freund G, Johnson R, Kelley K. 2008. “From inflammation to sickness and depression: when the immune system subjugates the brain” Nat Rev Neurosci 9(1): 46-56

In response to a peripheral infection, innate immune cells produce pro-inflammatory cytokines that act on the brain to cause sickness behaviour. When activation of the peripheral immune system continues unabated, such as during systemic infections, cancer or autoimmune diseases, the ensuing immune signalling to the brain can lead to an exacerbation of sickness and the development of symptoms of depression in vulnerable individuals

Darley C, Tinklenberg J, Roth W, Hollister L, Atkinson R. 1973. “Influence of marihuana on storage and retrieval processes in memory” Memory & Cognition 1(2): 196-200 add to dropbox

oral dose of marihuana extract calibrated to 20 mg of THC… One hour later. all Ss were administered delayed recall, recognition, and order tests on the first set of words, Presentation of another set of 10 lists followed. and there were immediate recall and delayed recall, recognition. and order t<:5!S on these words. Performance of drug and placebo Ss did not differ significantly for any of the first delayed tests. However. the performance of drug Ss was poorer than that of placebo Ss on immediate recall, delayed recall, and delayed recognition of the second set of lists. We concluded that retrieval of information relevant to the occurrence or nonoccurrence of an event was not affected by marihuana intoxication. Storage difficulties probably account for memory deficits due to the drug. and these difficulties appear to occur in the process of transferring information from short- term to long-term memory

The Ss were 48 adult males, all of whom were moderate(not more than once per week) social users of marihuana

Previous studies (Tinklenberg et al. 1970; Melges et aI, 1970: Abel. 1971a, b) have shown that marihuana intoxication causes decrements in the performance of certain memory tasks

Oral doses of the active drug were administered in the form of brownies containing NIMH marihuana extract calibrated to 20 mg of d9-tetrahydrocannibinol (THC)… required to fast for at least 8 h before the administration of the dose

it is important to ensure that the two groups did not differ by chance on the initial recall task

it is evident that not only is overall performance equal for the two groups, but probability of recall is virtually identical at each serial position

absence of differences between drug and placebo groups on delayed recall and recognition suggests that marihuana intoxication does not influence the retrieval of items stored in memory before drug intoxication. At least this is the case for the retrieval of information about whether or not a given item had been a member of a study list

Serial position curves for the immediate recall tests on the second set of lists are presented in the left panel of Fig. 2. The shapes of the curves are strikingly similar for the two groups, but performance for drug Ss is depressed for nearly all serial positions.

Drug and placebo Ss differ significantly in both delayed recall (placebo = .16, drug = .11, t(40) = 2.05, P < .05] and delayed recognition [placebo = .63, drug = .53, t(40) = 2.34, P < .05] . It is interesting to note that the groups differ even for terminal list positions in delayed recognition, even though the immediate and delayed recall curves converged for these items. On the second order-information test, the drug Ss again were less accurate in their estimates than were the placebo Ss. Meanabsolute deviations were 3.10 for the drug group and 2.97 for the placebo group. However,the difference between groups was not significant [t(40) = 1.08, p > .20] , and the fact that the mean values are based on different numbers of observations for the two groups (because of the different levels of delayed recognition performance) makes it difficult to interpret the result

Abel (1971a, b) performed a series of experiments using a procedure similar to that used here,and he found that marihuana intoxication had no effect uponrecall of previously stored information. However, performance on a delayed yes-no recognition test was adversely affected by the drug

if we are willing to conclude from the first part of the experiment that marihuana does not influence retrieval, then the differences observed in the second part of the experiment mustbe interpreted as being due to differential storage in the drug and placebo groups. Stated otherwise, marihuana has a decremental effect on the storage phase of memory, but has no effect on the retrieval stage

the apparent convergence in Fig. 2 of the immediate recall curves over terminal positions may indicate how storage isaffected bymarihuana. The recencyeffect for immediate recall can be explained as resulting from the near -perfect retrieval of terminal list items from short-term memory (Atkinson & Shiffrin, 1968, 1971). If it is the case that terminal items are in short-term memory at the time of test, then the fact that performance of drug and placebo groups for these items is similar may mean that drug Ss enterinformation into short-term memory as well as do placebo Ss

The results presented here indicate that during marihuana intoxication, Ss are not deficient in their ability to retrieve information which had been stored in memory before ingestion of the drug. In contrast, marihuana does affect storage processes so that information processed during intoxication is not remembered as well. It appears that marihuana does not influence the likelihood of entering information into short-term memory, but rather its transfer to a longer-term memory

Darley C, Tinklenberg J, Roth W, Vernon S, Kopell B. 1977. “Marijuana effets on long-term memory assessment and retrieval” Psychopharmacology 52, 239-241 add to dropbox

The ability of 16 college-educated male subjects to recall from long-term memory a series of common facts was tested during intoxication with marijuana extract calibrated to 0.3 mg/kg delta-9- tetrahydrocannabinol and during placebo conditions… cookies

Marijuana had no effect on recall or recognition performance… During both marijuana and placebo conditions, subjects could accurately predict their recognition memory performance

indicates that retrieval of non-experimentally-presented information from the long-term memory store is unaffected by marijuana. These data are consistent with previous findings that marijuana has no effect upon recall of word lists (Abel, 1971; Darley et al., 1973; Dornbush, 1974) or textual material (Miller et al., 1972) experimentally presented prior to drug intoxication

Our results suggest that subjects’ predictions of their own future memory task performance may be as accurate during marijuana intoxication as when they are unintoxicated

Davison S, Leese M, Taylor P. 2001. “Examination of the screening properties of the personality diagnostic questionnaire 4+ (PDQ-4+) in a prison population” J Pers Disord 15(2): 180-94

There is a high prevalence of personality disorder in most prison populations. Many pass through the system undiagnosed

the prevalence of BPD was 45.7 percent by one measure, and, on the second, 47.4 percent

Day A, Metrik J, Spillane N, Kahler C. 2013. “Working memory and impulsivity predict marijuana-related problems among frequent users” Drug Alcohol Depend 131(0): 171-174

104 marijuana smokers marijuana use at least 2 days a week in the past month and at least weekly in the past 6 months, and self-reported ability to abstain from marijuana for 24 hours without withdrawal. Exclusion criteria were: intent to quit or receive treatment for cannabis abuse, use of other illicit drugs, pregnancy, nursing, past month affective or panic disorder, psychotic or suicidal state assessed by psychiatric interview, contraindicated medical issues by physical exam and BMI > 30, and smoking more than 20 tobacco cigarettes per day

Participants reported using marijuana a mean of 2.03 (SD = 1.22) times a day on 71.86% (SD = 22.02%) of the past 60 days (about 5 days per week). There were 44 tobacco cigarette smokers (42.3%), who smoked 4.08 cigarettes (SD = 3.77) per day. The 100 current drinkers drank 8.5 (SD=7.88) drinks per week consuming an average of 4.34 drinks (SD=2.44) on a drinking day

Although marijuana is the most commonly used illicit substance in the US, only a small portion of users go on to develop dependence, suggesting that there are substantial individual differences in vulnerability to marijuana-related problems among users. Deficits in working memory and high trait impulsivity are two factors that may place marijuana users at increased risk for experiencing related problems

Lower working memory, as measured by Trail Making Test B, but not short-term memory capacity, predicted more marijuana-related problems. Higher trait impulsivity scores were independently associated with greater number of problems

Participants most frequently reported that marijuana caused them “to procrastinate” (53% of the sample) and “to have a lower energy level” (42.6%). No participants reported that marijuana had caused them to lose a job, and 1% reported experiencing medical problems as a result of marijuana. The remaining 18 problems were reported by between 2 and 37% of participants

The current study did not examine motives or expectancies related to marijuana use, which have been shown to mediate the relation between use and subsequent problems (Mirin, 1971; Patrick et al., 2011;Simons et al., 1998)… negative expectancies about marijuana use have been shown to mediate the link between impulsivity and marijuana use (Vangsness et al., 2005), and as such, future studies might examine the role of motives expectancies in determining the link between impulsivity, executive functioning, use, and problems

Dean B, Sundram S, Bradbury R, Scarr E, Copolov D. 2001. “Studies on [3H]CP-55940 binding in the human central nervous system: regional specific changes in density of cannabinoid-1 receptors associated with schizophrenia and cannabis use” Neuroscience 103(1): 9-15

measured CB1R in dorsolateral prefrontal cortex (Brodmann’s area 9), caudate–putamen and areas of the temporal lobe from schizophrenic and control subjects; some used cannabis close to death. increase in the CB1R binding density in the dorsolateral prefrontal cortex from subjects with schizophrenia (mean±S.E.M.: 142±9.9 vs 119±6.6 fmol/mg estimated tissue equivalents; P<0.05) independent of recent cannabis ingestion. increase in density of CB1R in caudate–putamen from subjects who had recently ingested cannabis (151±9.0 vs 123±7.2 fmol/mg estimated tissue equivalents; P<0.05) that was independent of diagnoses.

De Bellis M, Keshavan M, Shifflett H, Iyengar S, Beers S, Hall J, Moritz G. 2002. “Brain structures in pediatric maltreatment-related posttraumatic stress disorder: a sociodemographically matched study” Biol Psychiatry 52(11): 1066-78

subjects with PTSD had smaller intracranial, cerebral, and prefrontal cortex, prefrontal cortical white matter, and right temporal lobe volumes and areas of the corpus callosum and its subregions (2, 4, 5, 6, and 7), and larger frontal lobe cerebrospinal fluid (CSF) volumes. The total midsagittal area of corpus callosum and middle and posterior regions remained smaller in subjects with PTSD, whereas right, left, and total lateral ventricles and frontal lobe CSF were proportionally larger

gender by group effect demonstrated greater lateral ventricular volume increases in maltreated males

larger prefrontal lobe cerebrospinal fluid volumes and smaller midsagittal area of the corpus callosum subregion seven (splenium)

De Bellis M, Kuchibhatla M. 2006. “Cerebellar volumes in pediatric maltreatment-related posttraumatic stress disorder.” Biol Psychiatry 60(7):697-703

Unadjusted means of the left, right, and total cerebellum were smaller in the PTSD group

De Bellis M, Spratt E, Hooper S. 2011. “Neurodevelopmental biology associated with childhood sexual abuse” J Child Sex Abuse 20(5): 548-587

Child maltreatment appears to be the single most preventable cause of mental illness and behavioral dysfunction in the US: disrupted development -> delays/deficits/failures of multisystem achievements in motor, emotional, behavioral, language, psychosocial, social, and cognitive skills

discussion of PTSD diagnosis, sub-clinical measures, differences in children

in clinically referred, PTSD incidence from sexual abuse range from 42% to 90% (Dubner & Motta, 1999; Lipschitz, Winegar, Hartnick, Foote, & Southwick, 1999; McLeer, Callaghan, Henry, & Wallen, 1994), from witnessing domestic violence from 50% to 100% (for domestic homicide; Pynoos & Nader, 1989), and from physical abuse to as high as 50% (Dubner & Motta, 1999; Green, 1985; Pynoos & Nader, 1989). few studies have assessed PTSD in non-clinically referred maltreated children. Famularo, Fenton and Kinscherff (1993) reported a 39% incidence rate of PTSD within eight weeks of abuse or neglect disclosure. About a third of the PTSD subjects re-examined from the original sample continued to meet PTSD criteria at two year follow-up (Famularo, Fenton, Augustyn, & Zuckerman, 1996). McLeer and colleagues (1998) reported prevalence rates of PTSD of 36.3%

Even if childhood trauma does not result in childhood PTSD, it increases the risk for adult PTSD (Bremner, Southwick, Johnson, Yehuda, & Charney, 1993; Widom, 1999) and health problems (Dube, Felitti, Dong, Giles, & Anda, 2003)

combat-related PTSD studies suggest that there is increased sensitivity of the locus ceruleus/SNS/catecholamine system, even in PTSD-

Elevated levels of corticotrophin releasing hormone (CRH) or factor (CRF); increased cortisol in children, decreased in adults.

sexually abused girls manifest a dysregulatory disorder of the HPA axis associated with hyporesponsiveness of the pituitary (ACTH) to exogenous CRH and normal overall cortisol secretion to CRH challenge

prepubertal abuse: larger pituitary. Pubertal/post-pubertal: smaller pituitary

Low serotonin function is associated with suicidal and aggressive behaviors  In primate studies of chronic stress, serotonin levels decrease in the prefrontal cortex (Fontenot, Kaplan, Manuck, Arango, & Mann, 1995)

impaired immune, incl involution of the thymus and stress-induced lymphopenia

severe stress of sexual abuse may lead to suppression of the mechanisms (T suppressor cells) that actively suppress the autoantibody-producing lymphocytes (B lymphocytes) and may thus increase the incidence of positive antinuclear antibody titers in these sexually abused girls

medial prefrontal hyporesponsivity, amygdalar hyperresponsivity in PTSD.

monkeys were found to have a reduction in the midsagittal size of the corpus callosum, in parallel to a decrease in white (but not grey) matter volume in the prefrontal and parietal cortices

Teicher et al. (1997) early childhood trauma had reduction in the middle portion of the corpus callosum in children at psychiatric facilities with histories of trauma, including abuse or neglect, as compared to psychiatric controls (greater in males)

44 maltreated children and adolescents with PTSD and 61 age- and sex-matched controls, De Bellis (1999) decreased total midsagittal area of the corpus callosum and enlarged right, left, and total lateral ventricles in PTSD (males smaller CC, trend for smaller total brain) intracranial volume was decreased by 7% and total brain volume by 8% in PTSD subjects compared to controls; worse the earlier that abuse. PTSD symptoms correlated positively with ventricular volume

attenuation of frontal lobe asymmetry in children with maltreatment-related PTSD Carrion and colleagues (2001)

boys appear to be more sensitive to abuse in terms of brain development

maltreated children and adolescents with PTSD have lower NAA/creatine ratios suggests loss of neuronal integrity in the anterior cingulate region of the medial prefrontal cortex

maltreated subjects with PTSD had significantly larger, mainly right-sided, superior temporal gyrus grey matter volumes

intellectual ability (low IQ) may be due to child abuse. intellectual impairments leading to poor school performance (NationalResearchCouncil, 1993;Trickett & McBride-Chang, 1995), have been consistently reported in abused children not evaluated for PTSD (Augoustinos, 1987; Azar, Barnes, & Twentyman, 1988;Kolko, 1992; NationalResearchCouncil, 1993; Trickett & McBride-Chang, 1995). Negative correlations between Verbal IQ score and severity of abuse were observed (Carrey, Butter, Persinger, & Bialik, 1995). Perez & Widom (1994) reported lower IQ and reading ability in a large sample of adult survivors of child maltreatment

On average, children exposed to high levels of domestic violence had IQ scores eight points lower than children who were not exposed Koenen and colleagues (2003)

Decoster J, van Os J, Myin-Germeys I, De Hert M, van Winkel R. 2012. “Genetic variation underlying psychosis-inducing effects of cannabis: critical review and future directions” Current Pharmaceutical Design 18: 5015-5023

the relationship between cannabis use, cog-nition and psychosis is unclear

recent meta-analyses reported better cognition in cannabis-using patients [39, 40]. Several explanations for superior cognitive abilities in cannabis-using patients have been put forward, including possible neuroprotective effects of cannabis in individuals develop-ing psychotic symptoms [41] and a selective mechanism of causal contribution of cannabis, such that persons with less neurocognitive impairment make a transition to psychotic disorder

at the level of cognition, the evidence for differential sensitivity to cannabis associated with pre-existing liability is relatively inconsistent, for both the acute as well as the longer-term effects

greater reduction of grey matter density in cerebral regions known to have a high density of cannabinoid receptors (CB1R) in canna-bis-using patients [47-50], although this was not always found [51]. Ambiguous results were reported with regard to the effect of cannabis use on white matter integrity [47, 52]

COMT is an enzymatic inactiva-tor of dopamine and other mono-amines and is essential for dopa-mine signalling in the prefrontal cortex. The Val allele is associated with a 40% higher enzyme activity [58, 59]… interactions between cannabis and COMT showed greater variation, even with opposite directions in different analyses [66] [57-65]

It is disappointing that even the most studied gene-cannabis interaction (COMT Val158Met), has never been the subject of a true attempt at replication. It should be noted that the (negative) studies by Zammit and colleagues came closest to the original study design, in terms of phenotype under study [62] or in terms of the prospective design [66]

Defer N, Best-Belpomme M, Hanoune J. 2000. “Tissue specificity and physiological relevance of various isoforms of adenylyl cyclase” Renal Physiology 279 (3): F400-F416

forty years after its discovery by Earl Sutherland, cAMP is still the archetypal “second messenger.” But the cAMP signaling pathway, once considered to be simple and straightforward, has become very complex indeed

mong the large diversity of the AC isoforms, some are widely expressed, such as AC2, AC4, and AC6, whereas others are more specifically expressed, for example AC1 in tissues of neural origin and AC5 in heart and striatum

AC1 is abundant in the dentate gyrus of the hippocampus and the cerebral cortex (189), the highest expression of AC3 is exhibited in the olfactory neuroepithelium (188), whereas the important area for AC8 expression is the hypothalamus (16,102), where it is the only Ca2+/calmodulin-stimulated isoform (110,187, 188)

All AC activities are inhibited by high, nonphysiological concentrations of Ca2+ in the submillimolar range, possibly by competition with magnesium

AC1 does function as a good coincidence detector, and this is well demonstrated in the pineal gland (170), where AC1 is activated by norepinephrine via both the β-AR (through Gsα) and the α1-AR (through Ca2+ release), to increase cAMP formation and ultimatelyN-acetyl transferase and melatonin synthesis

AC8 is also a major isoform in the brain although it has also been found in testis (36, 63) and lung (115). In the brain, it is mainly present throughout (16, 102, 115), especially in the cortex, cerebellum, brain stem, hypothalamus, hippocampus, and olfactory bulb. The specific localization in hypothalamic nuclei suggests a role in neuroendocrine function whereas its specific increase in some regions of the brain, and especially in the locus cœruleus during morphine administration and withdrawal, points to a role in drug dependence (87, 103)

It is interesting to note that another type of cyclase, AC9, is expressed to a high level in the brain

Acute administration of morphine or opioids causes a decrease of AC activity via the Gi pathway, and chronic administration leads to the classic states of tolerance and dependence (122)

After 6 days of treatment with Δ-9 tetrahydrocannabinol, followed by the administration of the antagonist, mice exhibit several somatic signs (wet-dog shakes, facial rubbing, ataxia, hunched posture, mastication) that could be interpreted as being part of a withdrawal syndrome. Interestingly, the same animals exhibit a 100% increase in the basal, forskolin-, and Ca2+/calmodulin-stimulated AC activity in the cerebellum (rich in CB1 receptors) but not in the cortex or the striatum (70).

In most cell culture systems, acute exposure to ethanol treatment has been found to potentiate the receptor-mediated cAMP synthesis. In contrast, chronic exposure often causes a decrease in cAMP production. Parsian et al. (127) have observed that basal and fluoride-stimulated platelet AC activity of alcoholic patients have lower value than in control subjects (127)

In human platelets, the major AC isoform expressed is AC7

Degenhardt L, Hall W, Lynskey M. 2002. “Alcohol, cannabis and tobacco use among Australians: a comparison of their associations with other drug use and use disorders, affective and anxiety disorders, and psychosis.” Addiction 96(11): 1603-1614

nationally representative sample of 10 641 Australian adults

after controlling for demographics, neuroticism and other drug use, cannabis was not associated with anxiety or affective disorders. Alcohol dependence and tobacco use remained associated with both of these indicators of mental health

Degenhardt L, Hall W, Lynskey M. 2003. “Exploring the association between cannabis use and depression.” Addiction 98(11): 1493-1504

causation unclear… cannabis use makes, at most, a modest contribution to the population prevalence of depression.

little evidence of an increased risk of later cannabis use among people with depression and hence little support for the self-medication

Degenhardt L, Hall W, Lynskey M. 2003. “Testing hypotheses about the relationship between cannabis use and psychosis” Drug Alcohol Depend 71(1):37-48

There was a steep rise in the prevalence of cannabis use in Australia over the past 30 years and a corresponding decrease in the age of initiation of cannabis use. There was no evidence of a significant increase in the incidence of schizophrenia over the past 30 years. Data on trends the age of onset of schizophrenia did not show a clear pattern. Cannabis use among persons with schizophrenia has consistently been found to be more common than in the general population. Cannabis use does not appear to be causally related to the incidence of schizophrenia

Deiana S. 2013. “Medical use of cannabis. Cannabidiol: a new light for schizophrenia?” Drug Test Anal 5(1): 46-51

Behavioural and neurochemical models suggest that CBD has a pharmacological profile similar to that of atypical anti-psychotic drugs and a clinical trial reported that this cannabinoid is a well-tolerated alternative treatment for schizophrenia.

DeLisi L, Bertisch H, Szulc K, Majcher M, Brown K, Bappal A, Ardekani B. 2006. “A preliminary DTI study showing no brain structural change associated with adolescent cannabis use.” Harm Reduct J 3: 17

cannabis use began prior to the age of 18 and consisted of use more than 21 times in any single year; no evidence of atrophy in any relevant regions

Demirakca T, Sartorius A, Ende G, Meyer N, Welzel H, Skopp G, Mann K, Hermann D. 2011. “Diminished gray matter in the hippocampus of cannabis users: Possible protective effects of cannabidiol” Drug and Alcohol Dependence 114 242-245

gray matter (GM) concentration and volume of the hippocampus were measured in 11 chronic recreational cannabis users and 13 healthy controls, and correlated with THC and CBD from hair analyses

Cannabis users showed lower GM volume located in a cluster of the right anterior hippocampus (P uncorr = 0.002; effect size Cohen’sd = 1.34). In a regression analysis an inverse correlation of the ratio THC/CBD with the volume of the right hippocampus (P uncorr p < 0.001, Cohen’s d = 3.43) was observed. Furthermore Cannabidiol correlated positively with GM concentration (unmodulated VBM data), but not with GM volume (modulated VBM) in the bilateral hippocampus

Cannabis was used for 5.4 years in an average daily dose of 0.27 g… Cannabis users were more likely to smoke tobacco cigarettes ( n = 6 versus n = 1) and consumed more alco-hol (21.4 g/day = about 1.5 drinks/day) than controls (4.2 g/day)

Group comparison of GM tissue composition or concentra-tion (unmodulated data) revealed no differences between healthy controls and cannabis users in whole brain or in hippocam-pal ROI

endocannabinoids promote oligoden-drocyte progenitor survival ( Molina-Holgado et al., 2002) and control axonal growth by inducing chemorepulsion or collapse of axonal growth cones ( Berghuis et al., 2007 ). Cannabionoid-1 (CB-1) receptor activation increases astroglial progenitor proliferation and differentiation in vitro, and neural progenitor proliferation and astrogliogenesis are decreased in adult CB1-deficient mice ( Aguado et al., 2006 )

Our results are limited by the small sample size and that volume differences did not survive a correction for the number of voxels in the hippocampus

Demuth D, Molleman A. 2006. “Cannabinoid signalling” Life Sciences 78: 549-563 add to dropbox

numerous studies have now shown that the signalling pathw ays utilised by cannabinoid receptors are a great deal more diverse than originally established

concentrations of cannabinoids that produced a profound sedation and inhibition of locomotor activity in mice did not reduce CB1 receptor binding by radioisotopes in the cerebellum and hippocampus (Gifford et al., 2002). This suggests that the occupancy of the CB1 receptor necessary for the behavioural effects of cannabinoids is very low

The CB1 cannabinoid receptor is a member of the rhodopsin subfamily of GPCRs. Cannabinoid agonists interact with the receptor within the pore formed within the trans membrane helical cluster (Mukhopadhyay et al., 2002). The three cytosolic loops and a putative fourth loop formed by palmitoylation at the juxtamembrane C-terminal region contribute to the activation of G proteins. The proxi mal CB1 receptor intracellular C- terminal domain (am ino aci ds 401 – 417) is critical f or G protein coupling and the distal C-terminal tail domain (amino acids 418 – 472) modulates the magni tude and kinetics of signal transduction ( Nie and Lewis, 2001)

Brain regions in which cannabinoids are effective inhibitors of adenylyl cyclase are those most densely populated with cannabinoid binding sites. Thus, cannabinoid-mediated inhibition of cAMP as been demonstrated in slices of rat hippocampus, striatum, cerebral cortex and cerebellum (Bidaut-Russell et al., 1990)

Nine distinct isozymes of adenylyl cyclase have been identified, which can be categorised into six distinct classes based on sequence and functional similarities (Patel et al, 2001): (a) AC type I (AC-I) is found mainly in brain, is stimulated by Ca2+/calmodulin and is inhibited by G beta gama subunits and by G i alpha; (b) AC-VIII is found only in brain and is only stimulated by Ca2+/calmodulin; (c) AC-II, AC-IV and AC-VII are activated by G beta gamma, providing that G s alpha is present; (d) AC-V and AC-VI are highly expressed in brain and heart, and they are inhibited by g i alpha and low levels of Ca2+; (2) AC-III is stimulated by a high concentration of Ca2+/calmodulin in the presence of G alpha s; (f) AC-IX is expressed at high levels in skeletal muscle and brain and, as yet, is found to be affected by G alpha s only

Monkey kidney COS-7 cells, expressing exogenous CB1 receptors, were transfected with each adenylyl cyclase isoform in turn and stimulated with the cannabinoid agonists HU-210 and WIN 55,212-2. AC-I, V, VI and VIII were shown to be inhibited by, whereas types II, IV and VII were stimulated by, CB1 receptor activation

the globus pallidus contains mRNA encoding for AC-II (Furuyama et al, 1993), an area of the brain where CB1 activation has been shown to induce an increase in cAMP accumulatin (Maneuf and Brotchie, 1997)

CB1 receptors have been shown to link positively to MAP kinase… human astrocytoma and CHO cells, expressing CB1 receptors, HU-210 and CP 55,940 activated a p42/p44 MAP kinase… in CHO cells was linked to the activation of a Na+/H+ exchanger (NHE-1), a transporter involved in multiple cellular functions such as intracellular pH regulation and control of cell volume (Bouaboula et al., 1999). In vivo, acute administration of d9-THC induces a progressive and transient activation of p42/p44 MAP kinase in rat dorsal striatum and nucleus accumbens Valijent et al., 2001), as well as in murine hippocampus (Derkinderen et al., 2003), striatum and cerebellum (Rubino et al., 2004). Blocked by CB1 antagonist… CP 55,940, WIN 55,212-2, anandamide and 2-AG have also been shown to stimulated p38 MAP kinase in rat and murine hippocampus

studies in primary rat astrocyte cultures showed that d9-THC and HU-210 increased glucose metabolism, phospholipid metabolism and glycogen synthesis through the activation of MAP kinase (Sanchez et al, 1998b)

Anandamide… acts via CB1 receptors to inhibit N-type VOCCs leading to a decrease in Ca2+ influx… inhibited Q-type Ca2+ currents in AtT-20 pituitary tumour cells expressing exogenous CB1 receptor… studies in rat cortical and cerebellar brain slices showed that anandamide inhibited P/Q-type Ca2+ fluxes

Activation of CB1 receptors by WIN 55,212-2 (nanomolar concentrations) inhibited only a fraction (17%) of the whole-cell CA2+ current, even though more than half of this current is carried by N- and P/Q-type Ca2+ channels (Shen and Thayer, 1998)… at micromolar concentrations the effects of WIN 55,212-2 are not mediated by CB1 receptors, which may suggest a direct effect of cannabinoids on Ca2+ channels. The inhibitory effect of cannabinoids on N-type Ca2+ channels in the hippocamus is in accordance with the observations of Wilson, 2001 who demonstrated that WIN 55,212-2 was unable to mimic depolarisation-induced suppression of inhibition in rat hippocampal slices pretreated with conotoxin

L-type Ca2+ channels can also be regulated via CB1 receptor stimulation

T-type Ca2+ channels transfected in HEK 293 and CHO cells and endogenously expressed in NG108-15 cells were inhibited by anandamide (Chemin et al, 2001) not mimicked by synthetic cannabinoids or blocked by antagonist

In cultured hippocampal neurons WIN 55,212-2 increased voltage-dependent A-type outward K+ currents (IsubA) (Deadwyler et al., 1995) and decreased voltage-independent D-type outward K+ currents (IsubD or delay current) (Mu et al., 1999) in a concentration-dependent, SR 141716A= and PTX sensitive manner. A cannabinoid-mediated reduction in cAMP/PKA was the mechanism shown to activate IsubA (Hampson 1995) and inhibit IsubD. It was proposed that phosphorylation of the K+ channel inactivated IsubA and therefore a decrease in PKA would act to reverse this process

in cerebellar granule and COS-7 cells anandamide inhibited the acid-sensitive background K+ channel TASK-1 (Maingret et al., 2001)

Nicholson et al (2003) demonstrated the ability of anandamide and WIN 55,212-2 to inhibit voltage dependent Na+ channels (activated by veratridine) in mouse synaptosomes. The cannabinoids also blocked teh veratridine-induced release of neurotransmitters from sypatosomes including GABA and glutamate. CB1 antagonst AM 251 did not attenuate sodium channel inhibition

In cultured human arterial endothelial cells anandamide evoked an increase in Ca2+i in an SR 141716A-sensitive manner… coupled to the production of NO… also in human umbilical endothelial cells only marginally blocked by SR, insensitive to PTX and blocked by caffeine suggesting a release of Ca2+ from caffeine-sensitive intracellular stores. Anandamide also significantly increased NO synthase activity… suggest that CB1 dependent and independent increases of Ca2+i and subsequent NO production may account for some of the vasodilator actions of anandamideit can be envisaged that Ca2+ release from intracellular stores in excitable cells can be inhibitory through activation of Ca2+ dependent K+ channels, leading to hyperpolarisation. This then would preevnt the activation of VDCC and large Ca2+ influx

Treatment of human prostate epithelial PC-3 cells with either THC or methanandamide activated the PI3K/PKB pathway, which in turn induced translocation of Raf-1 to the membrane and phosphorylation of p42/p44 MAP kinase… blocked by CB2 antagonist

cannabinoid-mediated reduction of MAP kinase may inhibit IL-2 production

on sensory neurons TRPV1 channel opening causes Ca2+ influx and neurotransmitter release… anandamide is thought to activate TRPV1 by binding to sites on the cytosolic side… Anandamide has also been shown to activate TRPV1 receptors in rat hippocampal slices

Nemeth (2003) investigated the effects of different concentrations of anandamide on neuropeptide release from sensory neurons of the rat trachea, which express both CB1 and TRPV1 receptors. Low concentrations of anandamide (10 microM) inhibited peptide release… high concentrations (50-100 microM) increased the release of peptides and this response was inhibited by capsazepine

cannabinoid mediated inhibition of 5-HT3 currents… cannabinoids do not interact directly with the agonist binding site of the 5-HT3 receptor, but may instead act allosterically at a 5-HT3 modulatory site

when the CB1 receptor component was blocked, anandamide but not d9-THC produced a stimulatory effect on NMDA-induced Ca2+ responses including rat cortical, cerebellar and hippocampal slices

cannabinoids may be able to modulate the activity of nAChRs in a cannabinoid receptor-independent manner

Denson TF, Earleywine M. 2006. “Decreased depression in marijuana users” Addictive Behaviour 31(4):738-42

” Despite comparable ranges of scores on all depression subscales, those who used once per week or less had less depressed mood, more positive affect, and fewer somatic complaints than non-users. Daily users reported less depressed mood and more positive affect than non-users. The three groups did not differ on interpersonal symptoms. Separate analyses for medical vs. recreational users demonstrated that medical users reported more depressed mood and more somatic complaints than recreational users, suggesting that medical conditions clearly contribute to depression scores and should be considered in studies of marijuana and depression. These data suggest that adults apparently do not increase their risk for depression by using marijuana.”

Denson T, Earleywine M. 2008. “Self-reported use of alcohol, marijuana, and hard drugs and aggression: a structural equation modeling analysis of an internet survey of long-term marijuana users” Journal of Aggression, Maltreatment and Trauma 16(2): 164-180

Although alcohol use and hard drug history were found to predict aggressive behavior, marijuana use did not

consistent with the majority of research that has shown no relationship between marijuana use and aggression

Deykin E, Buka S. 1997. “Prevalence and risk factors for posttraumatic stress disorder among chemically dependent adolescents” Am J Psychiatry 154(6): 752-7

297 adolescents aged 15-19 years who met the DSM-III-R criteria for dependence on alcohol or other drugs and who were receiving treatment

The lifetime prevalence of PTSD was 29.6% (24.3% for males and 45.3% for females), and the current prevalence was 19.2% (12.2% for males and 40.0% for females)

The lifetime prevalence of PTSD among these chemically dependent adolescents is five times that reported for a community sample of adolescents

De Petrocellis L, Ligresti A, Moriello A, Allara M, Bisogno T, Petrosino S, Stott C, Di Marzo V. 2011. “Effects of cannabinoids and cannabinoid-enriched Cannabis extracts on TRP chennels and endocannabinoid metabolic enzymes” British Journal of Pharmacology 163: 1479-1494

Diazgranados N, Ibrahim L, Brutsche N, Newberg A, Kronstein P, Khalife S, Kammerer W, Quezado Z, Luckenbaugh D. 2010. “A randomized add-on trial of an n-methyl-d-aspartate antagonist in treatment resistant bipolar depression” Arch Gen Psychiatry 67(8): 793-802


Dickerson S, Gable S, Irwin M, Aziz N, Kemeny M. 2009. “Social-evaluative threat and proinflammatory cytokine regulation: an experimental laboratory investigation” Psychol Sci 20(10): 1237-1244

stimulated production of the proinflammatory cytokine tumor necrosis factor-α (TNF-α) increased from baseline to poststressor in the social-evaluative threat condition, but was unchanged in the non-SET condition. Further, the increases in TNF-α production correlated with participants’ cognitive appraisals of being evaluated. Additionally, the ability of glucocorticoids to shut down the inflammatory response was decreased in the SET condition. These findings underscore the importance of social evaluation as a threat capable of eliciting proinflammatory cytokine activity and altering its regulation.

Dill D, Chu J, Grob M, Eisen S. 1991. “The reliability of abuse history reports: a comparison of two inquiry formats.” Compr Psychiatry 32(2):166-9

nearly all reports of abuse histories obtained in the intake interview were consistent with later reports obtained in the survey. However, findings of no abuse history obtained in the intake format were frequently inconsistent with reports obtained in the survey, which were twice as frequent as intake reports.

Diseth T. 2006. “Dissociation following traumatic medical treatment procedures in childhood: a longitudinal follow-up” Dev Psychopathol 18(1): 233-51

three groups of patients with congenital anomalies were examined longitudinally. At first admission, adolescents (ages 10-20, mean 15) with anorectal anomalies (n = 14), adolescents with Hirschsprung disease (n = 14), and hospitalized controls (n = 14)

Anal dilatation, an invasive medical treatment procedure performed daily by the parents the first 4 years, was correlated with the frequency and severity of persisting dissociative symptomatology. The procedure was the only significant predictor of A-DES and SDQ-20 scores, and one of two significant predictors of DES scores

impact of early traumatic exposure on child development in the absence of parental malevolence, and on later dissociative outcome in adolescence and adulthood

A trauma may be so intense and complex that the child’s mind is unable to process the events as a whole experience. The cognitive schemas are lacking, the level of affect is too high, and the traumatic experiences may become split off from conscious control. Dissociation (ie, a fragmentation of the experience) occurs. According to DSM-IV, pathological dissociation in children refers to a developmental “disruption in the usually integrated functions of consciousness, memory, identity, or perception of the environment” with psychological dissociative symptoms such as amnesia, depersonalization, derealization, fragmentation, absorption, and identity confusion. Children with dissociative failure may also have somatic symptoms that reflect somatoform dissociative phenomena such as sensory losses, loss of motor control, general paralysis, and alterations of vision, hearing, taste and smell (Nijenhuis, Spinhoven, Van Dyck, Van der Hart, & Vanderlinden, 1996)

strong association between a history of early, chronic abuse, and extensive dissociative experienecs in adults (Chu, 1999; Lange 1999), adolescents and children (Brunner, 2000; Kisiel, 2001). This research emphasizes the importance of age of onset, severity, chronicity; that is, the number of developmetal periods during which trauma was experienced, and the number of subtypes of the trauma experience

children may experience specific life-saving medical procedures and treatment, such as bone marrow transplanatation and chemotherapy, as traumatic

The early onset, daily, repetitive, long-lasting and invasive anal treatment procedure performed by the parents for years proved to be associated with the frequency and severity of mental health problems and dissociative symptoms. Duration… was the only significant predictor of both dissociative and mental health outcomes in adolescence, was still the only significant predictor of somatoform dissociative outcome in adults, and was one of two significant predictors of psychogical dissociative outcome in adults… similar to those indicative of a strong relationship between sexual and physical abuse and dissociation in children and adolescents (Kisiel, 2001; Nijenhuis, 1996)

chronicity Kendall-Tackett 1993

medical procedures are cited as traumatic events more often than any other disease-related traumatic event (Stuber, 2003)

at median of 7 months, children with HD were kept restrained and tied in bed for 5 days after an operation involving crushing clamps in the anorectum. In one-third of the HD children, a second procedure was performed at the average age of 1.5 years. The short-term, nonrepetitive restraints of teh child was reported by parents to be unpleasant for the child and parents alike, but no significant dissociative problems were reported as adolescents or adults. In children with ARA, anal dilatations were performed once or twice daily by the parents until the children reached an average age of 4 years. The parents reported taht the treatment had a traumatic effect on the children, causing power struggles and engendering parental guilt as a result of the discomfort and even pain inflicted on the child. Both the procedure itself and the children’s reactions to it may have affected the attitude of the parents and the parent-child relationship

the most severe traumatic experiences are those inflicted by the persons who were expected to be protectors… one aspect of the risk entailed by anal dilatation may be the absence of the sensitive and protective interaction between the parents and young child. The development of these executive functions requires maturation of the frontal lobes from the end of the first year (Glaser, 2000)

previous findings of low global self-esteem, school competence, and social acceptance in ARA adolescents compared with adolescents with other chronic physical disorders (Aasland, 1999). Also supported by the discovery of significant differences in A-DES, DES, SDQ-20 and IES scores in this sample between those who had anal dilatation up to 2.5 years of age and those who were treated with the procedure for more than 2.5 years

adult patients can better cope with their experiences of the traumatic treatment procedure, but for the adolescent, the experience is still so recent that coping is not yet possible

Treatment involving years of anal dilatation as a routine treatment procedure has no been brought to an end.

There is still much ignorance or, at best, discussions, about dissociative disorders in general. The criticism against today’s perception of dissociative disorders has focused on these disorders as iatrogenic and epidemic. … this study eliminates any doubt about whether repeated, long-term traumatization performed by caregivers has a long-lasting impact on the children’s development

Dixon L, Haas G, Welden P, Sweeney J, Frances A. 1990. “Acute effects of drug abuse in schizophrenia patients: clinical observations and patients’ self-reports” Schizophrenia Bulletin 16(1): 69-79

Though drug abuse may exacerbate psychotic symptoms, abused drugs may also lead to transient symptom reduction in subgroups of schizophrenic patients. Some patients report feeling less dysphoric, less anxious, and more energetic while intoxicated

If rational treatment strategies are to be designed, it is necessary to develop empirical and theoretical foundations to understand why schizophrenic patients abuse psychoactive drugs

Negrete et al. (1986) evaluated 137 schizophrenic outpatients and found that cannabis users had significantly more delusional and hallucinatory activity than nonusers. Heavy cannabis users showed the most symptomatology. Bernhardson and Gunne (1972) found that in 7 of the 14 patients whose psychosis predated cannabis use, cannabis abuse produced a further psychotic deterioration; cannabis did not appear to exert any effect on the remaining 7 patients.

clinical observations of drug-abusing schizophrenic inpatients are likely to overrepresent exacerbations and underrepresent benefits, since the study population is a relapsing one, and adverse effects are more likely to come to clinicians’ attention

Hekimian and Gershon (1968) reported that in their sample of eight cannabis users, of whom six had a predrug and postdrug diagnosis of schizophrenia, five reported a “favorable subjective response” to cannabis. Knudsen and Vilmar (1984) presented descriptions of 10 schizophrenic patients medicated with neuroleptics of whom 7, they contended, used cannabis to reverse neurolepric effects. For example, one patient reported that cannabis allowed her to “regain experiences blotted out by medication.” Knudsen and Vilmar described patients’ experiences with cannabis in detail; responses were characterized by an initial feeling of being “inspired,” “relaxed,” “energized,” or “active,” followed by an exacerbation of symptoms and feeling “bad,” “aggressive,” or “splitting of thoughts.”

Alcohol, cannabis, and cocaine were the drugs abused commonly enough for meaningful results to be obtained. The large majority of substance-abusing patients felt that all three drugs decreased depression (table 1). In contrast, reported effects on anxiety, energy, and psychotic symptoms differed for the three drugs. For example, drug-abusing patients reported that cannabis and alcohol decreased anxiety but that cocaine made them more anxious

dysphoria, anxiety, desire for socialization, and possibly the anergia associated with negative symptoms may impel schizophrenic patients to abuse drugs.

Is psychosis just an unwanted side effect of illicit drug use, or an intended effect?

a way of understanding the popularity of cannabis abuse is that cannabis, in addition to its reported acute antidepressant effects (common to cocaine and alcohol), was perceived to have desirable anxiolytic and activating effects

although evidence may suggest that schizophrenic patients self-medicate negative symptoms, negative symptoms presumably diminish the patients’ capacities to seek and obtain drugs. Thus, patients with the most severe negative symptoms would be unlikely to abuse drugs

dysphoria may be the final common pathway to drug abuse

Do Y, McKallip R, Nagarkatti M, Nagarkatti P. 2004. “Activation through cannabinoid receptors 1 and 2 on dendritic cells triggers NF-KB-dependent apoptosis: novel role for endogenous and exogenous cannabinoids in immunoregulation” Journal of Immunology 173(4): 2372-2382

Addition of Δ9-tetrahydrocannabinol (THC), a major psychoactive component found in marijuana or anandamide, an endogenous cannabinoid, to DC cultures induced apoptosis in DCs. DCs expressed CB1 and CB2 receptors and the engagement of both receptors was necessary to trigger apoptosis. Treatment with THC induced caspase-2, -8, and -9 activation, cleavage of Bid, decreased mitochondrial membrane potential, and cytochrome c release, suggesting involvement of death-receptor and mitochondrial pathways. DCs from Bid-knockout mice were sensitive to THC-induced apoptosis thereby suggesting that Bid was dispensable. There was no induction of p44/p42 MAPK, p38 MAPK, or stress-activated protein/JNK pathway in THC-treated DCs. However, THC treatment induced phosphorylation of IκB-α, and enhanced the transcription of several apoptotic genes regulated by NF-κB. Moreover, inhibition of NF-κB was able to block THC-induced apoptosis in DCs. Lastly, in vivo treatment of mice with THC caused depletion of splenic DCs

Dorahy M, Corry M, Shannon M, Macsherry A, Hamilton G, McRobert G, Elder R, Hanna D. 2009. “Complex PTSD, interpersonal trauma and relational consequences: findings from a treatment-receiving Northern Irish sample” J Affect Disord 112(1-3): 71-80

Complex PTSD is associated with PTSD but when present should be considered a superordinate diagnosis

Dorard G, Berthoz S, Phan O, Corcos M, Bungener C. 2008. “Affect dysregulation in cannabis abusers” Eur Child Adolsc Psychiatry 17: 274-282

32 cannabis abusers (CA) and 30 healthy controls completed a battery of self-reports measuring depression (BDI-13), anxiety (STAI-Y), alexi-thymia (TAS20; BVAQ-B), anhe-donia (PAS; SAS), and sensation seeking (SSS)… more than half of the CA reported at least one other non-drug or alcohol comorbid diagnosis. The most commmon were mood and anxiety disorders. CA subjects scored significantly higher on all affective dimensions except alexithymia total scores; however, they had greater scores for the two subscales measuring difficulties in identifying feelings

CA subjects were more likely to experience high levels of trait anxiety, physical anhedonia and sensation seeking than the controls.

puts emphasis on the importance of substance use prevention as early as middle school

various studies have demon-strated that daily or even regular cannabis use can massively affect cognitive abilities and motivation, and in turn ultimately impede educational achieve-ment, social adjustment, and emotional reactivity

recruited in the Centre Emergence — Espace Tolbiac addiction unit of the Institut Mutualiste Montsouris, Paris… the patients’ treatment started on request of the patients’ parents (56%), the patient him/herself (28%), the justice (12%) or a physician (4%)

Exclusion criteria were mental retardation, organic brain disease, chronic or severe somatic disorder with possible effect on psychological state, psychotic disorder, inability to read or fill out the questionnaires or refusal to participate

Among the CA group, 5 (15.6%) were in middle school (14-15 years old), 6 (18.8%) were in vocational school (14-18 years old) and 3 (9.4%) were in university (18 years old and more)

control group recruited among students attending a scholar drug use prevention program

8 CA subjects (26.7%) had comorbid current major depression, one had past major depressive episode, 6 had comorbid dysthymia over the previous 2 years, 3 had past hypomania, and 2 had past mania. Regarding anxiety disorders, 2 CA subjcts presented lifetime panic attack, 2 had current agoraphobia, 2 had current social phobia, and 6 had a generalized anxiety disorder over the previous 6 months. 18 met DSM-IV criteria for comorbid alcohol abuse, and 3 had alcohol dependence.

foremost drives for cannabis consumption were to achieve: a feeling of detachment (50%), relaxation and anxiety sedation (37.5%), and euphoria (12.5%)

Age of first use 13.3 +/- 1.3, max joints per day 15.3 +/- 8.5, current joints per day 4.9 +/- 3.1 days alcohol use per month 9.6 +/- 10.1, alcohol per day of use 4.1 +/- 2.5, cigarettes per day 12.3 +/- 7.6

Nine subjects had experienced ecstasy, 8 had used shrooms, 4 cocaine, 3 LSD, 3 sedatives, tranquilizers or pain relievers without medical prescription

25% of CA and 6.7% of controls had a severe depressive symptomatology, 37.5% of CA and 16.7% of controls had a moderate depressive symptomatology, 28.1% of CA and 23.3% of controls had a mild depressive symptomatology, and 9.$% of CA and 53.3% of controls had no depressive symptomatology… 40.6% of CA and 24.1% of controls categorized as alexithymic, 37.5% of CA and 48.3% of controls were intermediate, and 21.9% of CA and 27.6% of controls were non-alexithymic

Although the SSS total score and subscores were not correlated with the cannabis use modalities, we observed a positive correlation between the SSS total score and the number of days of alcohol use on the previous month and the age of first tobacco use

an 85% psychiatric comorbidity rate has been assessed through the cannabis abusers’ sample, when excluding psychotic patients.

Although causality linkage could not be established in this cross sectional study, rates and levels of depressive and anxiety symptomatology of the CA subjects suggest a specific association between cannabis dependence and mood disorders and symptoms

the fact that CA subjects’ motivation for cannabis use was mainly detachment and anxiety sedation, togetehr with the finding of a high prevalence of lonely cannabis and alchol use, might give some additional support to the self-medication model… higher physical anhedonia and sensation seeking scores of the CA

the sample’s representativeness is questionable

Dube SR, Felitti VJ, Dong M, Chapman DP, Giles WH, Anda RF. 2003. “Childhood abuse, neglect, and household dysfunction and the risk of illicit drug use: the adverse childhood experiences study.” Pediatrics 111(3):564-72

“the effects of adverse childhood experiences transcend secular changes such as increased availability of drugs, social attitudes toward drugs, and recent massive expenditures and public information campaigns to prevent drug use. … [adverse childhood experiences] seem to account for one half to two third of serious problems with drug use”

The attributable risk fractions as a result of ACEs for each of these illicit drug use problems were 56%, 64%, and 67%, respectively.

Durkee C, Sarlls J, Hommer D, Momenan R. 2013. “White Matter Microstructure Alterations: A Study of Alcoholics with and without Post-Traumatic Stress Disorder.” PLOS ONE  doi: 10.1371/journal.pone.0080952 in dropbox

Harris et al. [19], lower FA in alcoholics in the right superior longitudinal fascicles II and III, orbitofrontal cortex white matter, and cingulum bundle associated with lower working memory. Pfefferbaum et al. [20] showed that the greatest white matter abnormalities in alcoholics compared to healthy controls were observed in the frontal forceps, internal and external capsules, fornix, and longitudinal fasciculus, and that these were correlated with poorer performance on psychomotor speed tests. Other white matter regions typically implicated in alcoholism are the frontal and limbic pathways, centrum semiovale, and corpus callosum [11,2024], with the genu of the corpus callosum and other more anterior white matter structures often found to be more compromised than posterior structures [20,25]

Durrant J, Ensom R. 2012. “Physical punishment of children: lessons from 20 years of research” CMAJ 184(12): 1373-1377 in dropbox

Shift in public policy and perspective since 1990; physical punishment now widely recognised as unacceptable

Physical punishment increases aggression; reduction in harsh discipline was followed by reduced aggression

a range of mental health problems in children, youth and adults, including depression, unhappiness, anxiety, feelings of hopelessness, use of drugs and alcohol, and general psychological maladjustment

These relationships may be mediated by disruptions in parent–child attachment resulting from pain inflicted by a caregiver,30,31 by increased levels of cortisol32 or by chemical disruption of the brain’s mechanism for regulating stress.33 Researchers are also finding that physical punishment is linked to slower cognitive development and adversely affects academic achievement.

Driessen M, Herrmann J, Stahl K, Zwaan M, Meier S, Hill A, Osterheider M, Petersen D. 2000. “Magnetic resonance imaging volumes of the hippocampus and the amygdala in women with borderline personality disorder and early traumatization” Arch Gen Psychiatry 57(12):1115-22

patients with BPD had nearly 16% smaller volumes of the hippocampus (P<.001) and 8% smaller volumes of the amygdala (P<.05) than the healthy controls. The results for both hemispheres were nearly identical

hippocampal volume negatively correlated with extent and duration of self-reported early traumatization only when BPD and control subjects were considered together. Levels of neuropsychological functioning were associated with the severity of depression but not with the volumes of the hippocampus.

Edwards C, Skosnik P, Steinmetz A, Vollmer J, O’Donnell B, Hetrick W. 2008. “assessment of forebrain-dependent trace eyeblink conditioning in chronic cannabis users” Neuroscience Letters 439: 264-268 add to dropbox

While CB1 knockout mice exhibit striking impairments on a cerebellar-dependent task called delay eyeblink conditioning (dEBC), these animals demonstrate intact forebrain-dependent trace EBC (tEBC)… 13 heavy cannabis users and 13 cananbis naive controls completed a tEBC procedure… exhibited similar rates of conditioned responding compared to controls in the acquisition and extinction phase. Consistent with reports of overt attentional abnormalities, the cannabis group exhibited decreased N100 ERP amplitudes to teh tone CS that were unrelated to mean levels of conditioning across blocks during the acquisition phase

Skosnik demonstrated that chronic cannabis users are similarly impaired on the dEBC procedure (as knockout mice, as shown by Kishimoto and Kano)

All inclusion criteria, clinical interviews, drug use assessment, experimental stimuli, procedures and data processing methods are identical to those employed by Skosnik, with the exception of the 500 ms trace period

minimum 1 joint per week, 24hr abstinence, no DSM-IV axis I or II diagnosis except cannabis abuse or dependence

mean 6.7 joints per week, 44 per month, 228 ppast six months, age of onset 15.46, years of use 3.2, alcoholic drinks per week 5, cigarettes per day 1.6 (4.25) (no alcohol or cigarette use by controls)

covarying for alcohol consumption on % CRs did not alter the sig-nificant main effect of group, and a Pearson correlation between the reported average number of cigarettes smoked per day within the cannabis and the mean % CRs yielded a non-significant relationship, r(13) = .11, p =.73

The total awareness score did not differ between the groups… Nor were the scores significantly associated with change in percent CRs across the acquisition phase… group rates of extinction did not differ

N100 amplitudes were significantly smaller in the cannabis group (mean = −5.23, S.D. = 2.68) compared to the control group (mean = −8.27, S.D. = 3.81) ( F(1, 24) = 5.25, p = .031, d = .92; seeFig. 1B). N100 latencies, however, did not differ between the cannabis group (mean = 128.22, S.D. = 16.99) and the control group (mean = 129.39, S.D. = 12.92) ( F(1, 24) = .04, p = .85, d = .08)

the rate of cigarette smoking, within the cannabis group, was significantly associated with N100 latency ( r(25) = −.71, p = .01)

tEBC appears to recruit a broader forebrain network including the anterior cingulate, dorsolateral prefrontal cortex, hippocampus, caudate, and sensory cortex in order to properly encode the trace interval

the present N100 finding differs from the results of a recent study assessing dEBC in cannabis users in which no differences in the N100 to the CS were identified

Ehlers C, Slutske W, Lind P, Wilhelmsen K. 2007. “Association between single nucleotide polymorphisms in the cannabinoid receptor gene (CNR1) and impulsivity in southwest California Indians” Twin Res Hum Genet 10(6): 805-11

Ehrenreich H, Rinn T, Kunert H, Moeller M, Poser W, Schilling L, Gigerenzer G, Hoehe M. 1999. “Specific attentional dysfunction in adults following early start of cannabis use.” Psychopharmacology (Berl) 142(3):295-301

Of the potential predictors of test performance within the user group, including present age, age of onset of cannabis use, degree of acute intoxication (THC+THCOH plasma levels), and cumulative toxicity (estimated total life dose), an early age of onset turned out to be the only predictor, predicting impaired reaction times exclusively in visual scanning. Early-onset users (onset before age 16; n = 48) showed a significant impairment in reaction times in this function, whereas late-onset users (onset after age 16; n = 51) did not differ from controls (n = 49).

Ehrhart J, Obregon D, Mori T, Hou H, Sun N, Bai Y, Klein T, Fernandez F, Tan J, Shytle R. 2005. “Stimulation of cannabinoid receptor 2 (CB2) suppresses microglial activation” J Neuroinflammation 2: 29

Activated microglial cells have been implicated in a number of neurodegenerative disorders, including Alzheimer’s disease (AD), multiple sclerosis (MS), and HIV dementia. It is well known that inflammatory mediators such as nitric oxide (NO), cytokines, and chemokines play an important role in microglial cell-associated neuron cell damage. Our previous studies have shown that CD40 signaling is involved in pathological activation of microglial cells. Many data reveal that cannabinoids mediate suppression of inflammation in vitro and in vivo through stimulation of cannabinoid receptor 2 (CB2)

selective stimulation of cannabinoid receptor CB2 by JWH-015 suppressed IFN-γ-induced CD40 expression. In addition, this CB2 agonist markedly inhibited IFN-γ-induced phosphorylation of JAK/STAT1. Further, this stimulation was also able to suppress microglial TNF-α and nitric oxide production induced either by IFN-γ or Aβ peptide challenge in the presence of CD40 ligation. Finally, we showed that CB2 activation by JWH-015 markedly attenuated CD40-mediated inhibition of microglial phagocytosis of Aβ1–42 peptide. Taken together, these results provide mechanistic insight into beneficial effects provided by cannabinoid receptor CB2 modulation in neurodegenerative diseases

Ligation of CD40 on microglial cells leads to the production of TNF-α and other unidentified neurotoxins [1113]

In the normal brain, microglial cells display a quiescent phenotype, including low CD40 expression [14]. However, upon insult to the brain, microglial cells become highly activated, altering their phagocytic and antigen-presentation functions [15] as well as the production of cytokines [13]. Mounting evidence implicates microglial CD40 as contributing to the initiation and/or progression of several neurodegenerative diseases [15]

the treatment of cultured microglial cells with THC, CP55940 and JWH-015 significantly inhibited CD40 expression induced by IFN-γ

stimulation of CB2 decreases CD40 expression on primary cultured microglial cells

CB2 protein is detected in primary cultured microglial cells, and is also markedly increased following the challenge with IFN-γ

either IFN-γ /CD40L or Aβ1–42/CD40L increased the secretion of the pro-inflammatory molecules TNF-α and NO, as indicated in Figure Figure5A5A and and5B.5B. However, when CB2 is stimulated by the presence of JWH-015, these pro-inflammatory molecules were significantly reduced

increased numbers of CD40-positive microglial cells as well as increased CD40L expression on astrocytes in AD [53,54]

Aβ peptide can synergize with the IFN-γ signaling pathway to induce microglial CD40 expression and subsequent neurotoxicity [28]

CB2 agonist JWH015 inhibits IFN-γ-induced microglial CD40 expression by opposing JAK/STAT1 pathway activation

Eldreth D, Matochik J, Cadet J, Bolla K. 2004. “Abnormal brain activity in prefrontal brain regions in abstinent marijuana users” Neuroimage 23(3): 914-20 in dropbox

25-day abstinent, heavy marijuana users (n = 11), and a matched comparison group (n = 11); no deficits in performance on modified Stroop

hypoactivity in the left perigenual anterior cingulate cortex (ACC) and the left lateral prefrontal cortex (LPFC) and hyperactivity in the hippocampus bilaterally

El-Gabalawy H, Guenther L, Bernstein C. 2010. “Epidemiology of immune-mediated inflammatory diseases: incidence, prevalence, natural history and comorbidities” J Rheumatol Suppl 85: 2-10

Immune-mediated inflammatory diseases (IMID) present a group of common and highly disabling chronic conditions that share inflammatory pathways. Several incidence and prevalence studies of IMID during the past decades have reported a considerable variation of the disease occurrence among different populations. Overall, the estimated prevalence of IMID in Western society is 5%-7%

Elsey J, Coates A, Lacadie C, McCrory E, Sinha R, Mayes L, Potenza M. 2015. “Childhood trauma and neural responses to personalized stress, favorite-food and neutral-relaxing cues in adolescents” Neuropsychopharmacology doi:10.1038/npp.2015.6

Relative to the low-trauma-exposed group, high-trauma-exposed adolescents displayed an increased activation of insula, anterior cingulate, and prefrontal cortex in response to stress cues. Activation in subcortical structures, including the hippocampus, was inversely correlated with subjective anxiety in the high- but not the low-trauma-exposed group. The high-trauma-exposed group displayed hypoactivity of cerebellar regions in response to neutral/relaxing cues. No group differences were observed in response to favorite-food cues

Elvevåg B, Goldberg T. 2000. “Cognitive impairment in schizophrenia is the core of the disorder” Crit Rev Neurobiol 14(1): 1-21

we argue that various cognitive deficits are enduring features of the schizophrenia illness, that they are not state-related and are not specific to subtypes of the illness, and, more specifically, that working memory and attention are characteristically impaired in patients with schizophrenia, irrespective of their level of intelligence. Last, we conclude that problems in these cognitive domains are at the very core of the dysfunction in this disease

Elzinga B, Bremner J. 2001. “Are the neural substrates of memory the final common pathway in posttraumatic stress disorder (PTSD)?” Journal of Affective Disorders 70: 1-17 in dropbox

Elzinga - memory table

the noradrenergic stress-system is involved in enhanced encoding of emotional memories, sensitization, and fear conditioning, by way of its effects on the amygdala

two types of memory disturbances have been identified in traumatized individuals; intrusive memories and impoverished memory functioning

patients with PTSD develop serious distortions in the way they process information

trauma provides highly salient information that does not fit into preexisting schema’s or models of the world (Foa et al., 1989; Brewin et al., 1996)

PTSD is not only characterized by intrusive memories, but is also associated with general deficits in declarative memory, fragmentation of memories (both autobiographical and trauma-related), and trauma-related amnesia. Even though intrusions and amnesia may appear to be opposite phenomena these may instead be interrelated processes in that the occupancy with intrusive memories may interfere with, and thus reduce, memory processing of other material

Vietnam veterans with combat-related PTSD scored significantly lower (almost 50%) on the Weschsler Memory Scale (WMS) (Bremner et al., 1993a)

More than 30% of adults who had been sexually abused as children either failed to report or were amnesic for the event many years later (Williams, 1994)

subjects with high scores on dissociative and imaginative capacities appeared to be more prone to create false memories

Women with abuse-related PTSD had a higher frequency of false recognitions of critical lures then women with abuse histories without PTSD, non-abused non-PTSD women, or men without abuse or PTSD (Bremner, 2000)

Thus, PTSD-patients may be more prone for the creation of false memories, not so much because they are more suggestible, but because of their general memory deficits, leaving more room for elaboration

Dissociation is defined as a disruption in the usually integrated functions of consciousness, memory, identity or perception of the environment… dissociative reactions, such as rerealisation or depersonalisation, may impede memory encoding, so that traumatic memories can not be stored properly

amnesia and related dissociative symptoms at the time of trauma are associated with a long-term increase in psychopathology (Bremner et al., 1992; Marmar et al., 1994; Shalev et al., 1996; Bremner and Brett, 1997a)

Adrenaline has a short-term effect to strengthen memory traces, while cortisol has a more long-term effect to inhibit the laying down of memory traces

The noradrenergic system is responsible for rapid responses to stress, including the fight or flight response. Chronic stress is associated with increased firing of noradrenaline neurons in the brainstem and potentiated release of noradrenaline in the brain with subsequent stressors. (Bremner et al., 1996b) The noradrenergic system strengthens the formation of memory traces associated with emotional events.

memory enhancing effects of emotionally arousing events are mediated by the activation of b-adrenergic activity within the amygdala complex (Cahill and McGaugh, 1998)

when retrieval of a traumatic event is accompanied by adrenaline release, this may further strengthen the traumatic memory trace. A positive feedback loop may then result in deeply engraved memories, which are clinically expressed as intrusive recollections and flashbacks that are difficult to erase

lactate or yohimbine, substances that activate the noradrenergic system, induced intrusive memories and flashbacks in combat veterans with PTSD, besides other PTSD-symptoms including emotional numbing, and panic attacks (Southwick et al., 1993).

Noradrenaline appears to have opposite actions at alpha-1 and alpha-2 receptors; noradrenaline can impair PFC function through its actions at post-synaptic alpha-1 adrenergic receptors, whereas actions at alpha-2 receptors may improve performance. Since noradrenaline has higher affinity for alpha-2 than for alpha-1 receptors, low levels of noradrenaline release may engage alpha-2 receptors, whereas higher concentrations may engage alpha-1 receptors, resulting in impaired PFC function, including impaired working memory and response inhibition (Arnsten, 1998)

medial PFC dysfunction may be partially responsible for the failure to extinguish fear

Because of its glucocorticoid (GC) receptor sites, the hippocampus is the primary site of feedback for GC regulation keeping cortisol levels within physiological range. This makes the hippocampus particularly sensitive to stress

hipocampal atrophy may provide an explanation for the general memory deficits of PTSD patients

a differential effect was found between procedural and declarative memory: cortisol did impair declarative, but not procedural, memory (Kirschbaum et al., 1996; Lupien et al., 1997; Newcomer et al., 1999)

memory dysfunction as a core element of PTSD. While witnessing a traumatic event two stress reactions may occur. As a first rapid reaction, (nor)adrenaline is secreted. This may strengthen emotional memory traces, and enhance fear conditioning. Since the retrieval of traumatic memories is often accompanied by enhanced levels of adrenaline, this may further engrave the traumatic memory each time that it is retrieved. … Dysfunction of the medial PFC, a structure that normally inhibits the activation of the amygdala, may further enhance the effects of amygdala function, thereby increasing the emotional valence and the frequency of intrusive memories.

Cortisol may result in acute (but reversible) hippocampal dysfunction, an thus in verbal, declarative memory deficits, such as trauma-related amnesia, while leaving non-hippocampus mediated memory processes unaffected. Chronic cortisol secretion may eventually result in a permanent loss or atrophy of hippocampal cells. … dysfunction or atrophy of the hippocampus may also underlie distortions and fragmentations of trauma memories

Lack of self-esteem has been found to correlated with cortisol response in a stress task (Pruessner, 1999)

In animal models, adrenal activity has been related more to “defense” reactions, whereas cortisol is more associated with “defeat” (Henry and Stephens, 1977)

it must be stressed that… reconstructed memories are dependent on the emotions and needs of the context in which they are retrieved (Schacter, 1995)

Emeny R, Lacruz M, Baumert J, Zierer A, von Eisenhart Rothe A, Autenrieth C, Herder C, Koenig W, Thorand B, Ladwig K. 2012. “Job strain associated CRP is mediated by leisure time physical activity: results from the MONICA/KORA study” Brain Behav Immun 26(7): 1077-84

High job strain was reported by half (n = 482, 50.7%) of the study participants. While workers with high job strain were more likely to have adverse workplace conditions (competition with coworkers, job dissatisfaction and insecurity), sleeping problems, depressive symptoms, a Type A personality, and be physically inactive, no differences in cardiometabolic risk factors were detected. A strong and robust association between job strain and C-reactive protein (CRP) was observed in age and sex adjusted models, as well as models adjusted for classic coronary heart disease risk factors (β = 0.39, p = 0.006 and β = 0.27, p = 0.03, respectively). Adjustment for physical activity abrogated this effect (β = 0.23, p = 0.07), and a mediating effect of physical activity on stress-associated inflammation was demonstrated (p = 0.04)

Endo T, Sugiyama T, Someya T. 2006. “Attention-deficit/hyperactivity disorder and dissociative disorder among abused children” Psychiatry Clin Neurosci 60(4): 434-8

39 abused child inpatients in Aichi Japan. 59% dissociative disorder, 18% diagnosed ADHD, 71% of whom dissociative disorder. 67% met ADHD criteria, but only 27% prior to child abuse. Those with dissociative disorder increased apparent ADHD.

England T, Hind W, Rasid N, O’Sullivan S. 2015. “Cannabinoids in experimental stroke: a systematic review and meta-analysis” J Cereb Blood Flow Metab 35(3): 348-58

In all, 144 experiments (34 publications) assessed CBs on infarct volume in 1,473 animals. Cannabinoids reduced infarct volume in transient (SMD -1.41 (95% CI -1.71), -1.11) P<0.00001) and permanent (-1.67 (-2.08, -1.27), P<0.00001) ischemia and in all subclasses: endocannabinoids (-1.72 (-2.62, -0.82), P=0.0002), CB1/CB2 ligands (-1.75 (-2.19, -1.31), P<0.00001), CB2 ligands (-1.65 (-2.09, -1.22), P<0.00001), cannabidiol (-1.20 (-1.63, -0.77), P<0.00001), Δ(9)-tetrahydrocannabinol (-1.43 (-2.01, -0.86), P<0.00001), and HU-211 (-2.90 (-4.24, -1.56), P<0.0001). Early and late neuroscores significantly improved with CB use (-1.27 (-1.58, -0.95), P<0.00001; -1.63 (-2.64, -0.62), P<0.002 respectively) and there was no effect on survival. Statistical heterogeneity and publication bias was present, median study quality was 4 (range 1 to 6/8). Overall, CBs significantly reduced infarct volume and improve functional outcome in experimental stroke

Englund A, Morrison P, Nottage J, Hague D, Kane F, Bonaccorso S, Stone J, Reichenberg A, Brenneisen R, Holt D, Feilding A, Walker L, Murray R, Kapur S. 2012. “Cannabidiol inhibits THC-elicited paranoid symptoms and hippocampal-dependent memory impairment” J Psychopharmacol 27: 19 add to dropbox

There is a wide inter-individual variation in PANSS positive scores following THC and, as a group, positive symptoms are modest compared with acute schizophrenia. In ear -lier studies approximately 35–50% of healthy participants showed changes of ≥3–4 points (D’Souza et al. 2004; Morrison et al.,  2009)

In the placebo group, PANSS posi-tive scores, (mean±sd) increased by 2.4 (±3.1) points following  THC, compared with 1.2 (±1.8) in the CBD group, a non-signifi -cant difference ( t =1.5, p =0.15) Clinically significant positive symptoms following THC, defined as an increase in PANSS positive scores of ≥ 3 points, were more common in the group pre-treated with placebo (11 of 26 cases) compared with the group pre-treated with CBD (3 of 22 cases), ( χ 2=4.74, p<0.05) (Table 3)

Energetic arousal decreased in the CBD group following the administration of CBD (p<0.01), whereas subsequent decreases following THC were not significant ( p=0.13)

Following THC, immediate recall was 2.9 (±5.3) and 3.6 (±4.5) items fewer in the CBD and placebo groups,  respectively, compared with baseline

pre-treatment with CBD inhibited THC-induced paranoia and inhibited the detrimental effects of THC on episodic memory. In addition, CBD decreased the pro -portion of participants who experienced clinically significant acute THC psychosis… CBD (in so far as it was administered here) does not completely abolish THC-induced positive psychotic symptoms.

Here there were marked performance deficits post-THC in three tests which require pre-frontal resources: immediate recall, digit-span forward and digit-span back. CBD did not appear to attenuate THC-induced deficits in any of the three tasks. This contrasted with the protective effect of CBD on delayed recall and paranoid symp -toms. It is also notable that THC-induced impairment in delayed recall and THC-induced paranoia were correlated, and it is feasible that both measures load onto a common factor

Etkin A, Wager T. 2007. “Functional neuroimaging of anxiety: a meta-analysis of emotional processing in PTSD, Social Anxiety Disorder, and Specific Phobia” Am J Psychiatry 164(10): 1476-1488

Etkin - hypoactivation and hyperactivation in anxiety disorders

Patients with any of the three disorders consistently showed greater activity than matched comparison subjects in the amygdala and insula… similar pattern was observed during fear conditioning in healthy subjects… only patients with PTSD showed hypoactivation in the dorsal and rostral anterior cingulate cortices and the ventromedial prefrontal cortex—structures linked to the experience and regulation of emotion

Despite some shared key features, anxiety disorders also differ in a number of fundamental ways. Symptoms of hypervigilance and hyperarousal, dissociation, emotional numbing, and reexperiencing phenomena (nightmares and flashbacks) are particularly characteristic of PTSD (1). These symptoms are not observed during normal fear conditioning, suggesting that PTSD involves either different or more profound emotional dysregulation than other anxiety disorders

Hypoactivations (comparison subjects > patients) were seen only in PTSD, specifically in the inferior occipital gyrus, ventromedial prefrontal cortex, rostral anterior cingulate cortex, parahippocampal gyrus, lingual gyrus, dorsal amygdala and anterior hippocampus, orbitofrontal cortex, putamen, middle occipital gyrus, dorsomedial prefrontal cortex, dorsal anterior cingulate cortex, and mid-cingulate

for the thalamus, hypoactivity was observed more frequently than hyperactivity in PTSD patients in relation to matched comparison subjects (left thalamus: p=0.004; right thalamus: p=0.06; data not shown). Thalamic hypoactivity was also more commonly seen in PTSD than either social anxiety disorder or specific phobia

we observed significant negative coactivation between the dorsal or rostral anterior cingulate cortex and the amygdala or insula, indicating that hypoactivation of frontal regions was associated with hyperactivation in limbic and perilimbic regions (see Figure 1B

Hypoactivation of the dorsal amygdala, containing the central nucleus, may be relevant for the autonomic blunting associated with emotional numbing or dissociation in PTSD (74). Hypoactivation of the anterior hippocampus may be important for both declarative memory (75) and regulation of the hypothalamic-pituitary-adrenal axis (76, 77), both of which are perturbed in PTSD (78,79)

amygdala activity strongly habituates to repeated presentation of emotional stimuli (48, 82, 83), which may result in below-baseline levels of activity (48, 82). Although such habituation favors elimination of patient-comparison subject differences rather than hypoactivity (84), it suggests that greater attention should be paid to the time course of amygdala effects

while each of the three disorders involves an excessive fear component, PTSD is a more complex disorder in which the fear part per se is only one element. Thus, PTSD symptoms may be more attributable to dysfunctional emotion regulation systems, whereas the symptoms of social anxiety disorder and specific phobia may be more readily described as intense states of fear

emotion regulation has been investigated using tasks that instruct subjects to deliberately decrease their emotional responses using distraction, reappraisal, suppression, or detachment strategies (95100). These studies consistently point to involvement of the lateral prefrontal cortex, a locus of executive control for nonemotional stimuli (99, 101). A different picture emerges when one considers “reflexive” forms of emotion regulation, in which the generation and/or modulation of emotion is based on an individual’s expectations about stimuli but without any self-reflective focus on the emotions themselves or the explicit goal of regulating them

Etkin et al. (102) recently found that monitoring of emotional conflict was associated with dorsomedial prefrontal activation, whereas resolution of emotional conflict was associated with rostral anterior cingulate cortex increases and amygdala decreases, consistent with its top-down inhibition. Extinction of conditioned fear also involves increased activity in the rostral anterior cingulate cortex and ventromedial prefrontal cortex and decreased activity in the amygdala (54). Likewise, rostral anterior cingulate cortex activation and amygdala decreases have been observed during placebo anxiolysis (103), and placebo-induced increases in mu-opioid activity have been found in the rostral anterior cingulate cortex, the ventromedial prefrontal cortex, and the amygdala while the subject was experiencing pain (104). Based on these data, we have previously proposed that emotional control processes mediated by the rostral anterior cingulate cortex/ventromedial prefrontal cortex may reflect an individual’s emotional coping or resilience mechanisms (102), which normally function in absence of explicit task instructions to regulate emotion

Our meta-analysis demonstrated robust hypoactivations in PTSD in the rostral anterior cingulate cortex and ventromedial prefrontal cortex but failed to show alterations in the lateral prefrontal cortex. Thus, we propose that hypoactivation of the rostral anterior cingulate cortex and ventromedial prefrontal cortex in patients with PTSD reflects a deficit in reflexive emotion regulation processes occurring in the absence of self-reflection about emotion or deliberate attempts at emotional control and is reflected clinically in emotional dysregulation symptoms and anxiety generalization. A reflexive emotion regulation deficit may thus encompass and extend beyond a fear extinction deficit in PTSD, as has been proposed previously (42,105). The work on the rostral anterior cingulate cortex and the ventromedial prefrontal cortex in humans parallels animal data showing that ventromedial prefrontal cortex lesions in rats impair the ability of these animals to extinguish learned fear (106). Electrical stimulation of this region, which has direct inhibitory projections to the amygdala (107, 108), facilitates fear extinction (109). Although the ventromedial prefrontal cortex in rodents is not an exact homologue of the human rostral anterior cingulate cortex and the ventromedial prefrontal cortex, the shared roles of these areas in fear extinction suggest some degree of analogous function (105) and support a translational approach to anxiety

Unlike the regulatory roles proposed for the rostral anterior cingulate cortex and ventromedial prefrontal cortex, activity in the dorsomedial prefrontal cortex and adjacent dorsal anterior cingulate cortex seems to relate to emotional experience (59) or awareness (110). These regions are activated by emotional conflict (102), track levels of emotional arousal (111), correlate with autonomic activity (112, 113), and respond in anticipation of an aversive event (96), among related functions. Thus, inasmuch as the dorsomedial prefrontal cortex and dorsal anterior cingulate cortex function in the experience of negative emotion, hypoactivation of these regions in PTSD may be related to a decrease in the experience or impact of negative emotion. Because these regions may help recruit rostral anterior cingulate cortex emotion regulation mechanisms (102), dysfunction of the dorsomedial prefrontal cortex and dorsal anterior cingulate cortex may indirectly further contribute to emotional dysregulation in PTSD. Likewise, hypoactivation of the thalamus may relate to decreased processing of sensory information and thereby decreased experience of negative emotion, as suggested previously (40, 72), although the thalamus also plays diverse roles in cortical-cortical interactions

control over the stressor promotes resilience (114116)

perceived controllability during a trauma is related to the severity of subsequent PTSD symptoms (117)

Eubanks L, Rogers C, Beuscher A, Koob G, Olson A, Dickerson T, Janda K. 2006. “A molecular link between the active component of marijuana and Alzheimer’s disease pathology” Mol Pharm 3(6): 773-777

Δ9-tetrahydrocannabinol (THC), competitively inhibits the enzyme acetylcholinesterase (AChE) as well as prevents AChE-induced amyloid β-peptide (Aβ) aggregation, the key pathological marker of Alzheimer’s disease

Ewijk H, Heslenfeld D, Zwiers M, Buitelaar J, Oosterlaan J. 2012. “Diffusion tensor imaging in attention deficit/hyperactivity disorder: A systematic review and meta-analysis” Neuroscience and Biobehavioural Reviews 36: 1093-1106 in dropbox

Ewijk H, Heslenfeld D, Zwiers M, Faraone S, Luman M, Hartman C, Hoekstra P, Franke B, Buitelaar J, Oosterlaan J. 2014. “Different Mechanisms of White Matter Abnormalities in Attention-Deficit/Hyperactivity Disorder: A Diffusion Tensor Imaging Study” Journal of the American Academy of Child & Adolescent Psychiatry 53(7): 790-799 in dropbox

Fachner J. 2003. “Jazz, improvisation and a social pharmacology of music.” Music Therapy Today 4(3)

Fagan S, Campbell V. 2013. “The influence of cannabinoids on generic traits of neurodegeneration.” British Journal of Pharmacology 2014: 171; 1347-1360 in dropbox

“mechanisms that underlie their neurodegenerative components have been elucidated; namely neuroinflammation, excitotoxicity, mitochondrial dysfunction and reduced trophic support… application of phytocannabinoids and synthetic cannabinoids have been investigated. Signalling from the CB1 and CB2 receptors are known to be involved in the regulation of Ca 2+ homeostasis, mitochondrial function, trophic support and inflammatory status, respectively, while other receptors gated by cannabinoids such as PPAR γ, are gaining interest in their anti-inflammatory properties. Through multiple lines of evidence, this evolutionarily conserved neurosignalling system has shown neuroprotective capabilities and is therefore a potential target for neurodegenerative disorders”

Fanous A, Gardner C, Walsh D, Kendler K. 2001. “Relationship between positive and negative symptoms of schizophrenia and schizotypal symptoms in nonpsychotic relatives” Arch Gen Psychiatry 58(7): 669-673

Positive and negative symptoms in schizophrenia predict corresponding schizotypal symptoms in relatives. This provides evidence that these schizophrenic symptom factors (1) are etiologically distinct from each other and (2) occur on an etiological continuum with their personality-based counterparts.

Positive schizotypy comprises ideas of reference, illusions, and magical thinking, while negative schizotypy includes poor rapport, aloofness, and guardedness.21

Overall, negative symptoms had statistically significant relationships with more schizotypy factors than did positive symptoms. This coheres with the general notion that negative symptoms have greater familial, and possibly genetic, bases than do positive symptoms. Evidence suggesting this is their association with greater family history,37 worse premorbid functioning,38– 40 and greater longitudinal stability.41– 43 Furthermore, the phenomenological resemblance between positive schizotypal symptoms such as magical thinking and illusions on one hand, and positive schizophrenic symptoms on the other, appears to be less than that between negative symptoms of schizotypy21 and schizophrenia.14

The effect sizes (regression slopes) of the analyses did not change substantially when the definition of proband affection was broadened to include nonschizophrenic psychotic disorders, while significance levels increased substantially. This supports the spectrum concept of schizophrenia—that several disorders share with schizophrenia the same underlying liability.47– 50

Fassbender C, Zhang H, Buzy W, Cortes C, Mizuiri D, Beckett L, Schweitzer J. 2009. “A lack of default network suppression is linked to increased distractibility in ADHD” Brain Research 1273: 114-128 in dropbox

greater variability was associated with a failur e to deactivate vent romedial PFC with increasing task difficulty. T-tes ts on brain activation betwee n participan ts wit h ADHD with low versus high IIV implicated a similar region so that high variability was associated w ith greater acti vity in this region. These data provide support for the theory that incre ased distractibility in at least
some participants with ADHD may be due to an inability to sufficiently suppress activity in the defaul t attention network in respons e to increasing task difficulty

ADHD is a disorder typically character-ized by high degrees of intra-individual variability (IIV) in reaction time (RT) (e.g., Castellanos et al., 2005; Leth-Steensen et al., 2000)

The ADHD subjects evidenced decreases in connectiv-ity between the posterior cingulate/precuneus and task-active regions such as dorsal ACC but also other default network regions such as ventromedial PFC

a reduction in power in very low frequency oscillations electrodes consistent with default network regions was found in young adults with greater numbers of ADHD symptoms, particularly symptoms relating to inattention (Helps et al., 2008). Low frequency oscillations in resting state fMRI data have previously been found to reflect interactions in the default attention network
(De Luca et al., 2006)

The default attention network is a group of regions located along the brain’s medial wall, which are active during non-cognitively demanding paradigms and have been associated with task-irrelevant thought processes, mind wandering, and attention to the outside environment or one’s own mental state (Gusnard et al., 2001b; Shulman et al., 1997)

Inability to sufficiently suppress activity in the default network during a cognitively demanding paradigm may lead to less focus on the task at hand and more vulnerability to distraction from the external environment or one’s own internal non-task-related thoughts ( Weissman et al., 2006)

normally adaptive state of periodically attend-ing to potential novel events in the environment (subserved by the default attention network) can become maladaptive and interfere with ongoing task-related processes…  if activation in the default network surpasses a particular threshold, there is a potential for competition with task-specific attention processes, leaving the individual open to attention lapses and decrements in performance. Castellanos et al. (Sonuga-Barke and Castellanos, 2007 ; Castellanos et al., 2008) purport this as a m odel for attention deficits in ADHD with inattention stemmin g f rom a n i mbala nce between suppressing the default network and activating task-appro-priate regions

However, contrary to Castellanos et al. (Castellanos et al., 2008; Uddin et al., 2008 ) finding of dysfunction in the posterior cingulate in ADHD, we found no differences in patterns of deactivation in this region between ADHD and HC children in either the simpler AT task or the more cognitively dema nding VS AT. This held tr ue fo r b ot h t he post erior cingulate region defined by the HC group and that defined by the ADHD group. Group differences were only found in medial PFC. As can be seen in Fig. 2, although both groups tended to increase deactivation from AT to VSAT in three regions in medial PFC/ACC, the ADHD group failed to suppress activity in these regions to the same degree as their HC peers

those with greater RT variability d uring the VSAT also tend ed to di splay l ess deactivation in the ventromedial PFC during the working memory task

study examining default network activity revealed attenuated levels of activation in medial PFC, ACC and poster-ior cingulate in children compared to adults (Marsh et al., 2006). This finding was interpreted as being due to greater auto-maticity of performance on the baseline task in adults leading to an incr ease in task-irr elevan t t hou ghts co mpar ed t o children

Although Castellanos et al. (2008)suggest that the region of the default network incorporating posterior cingulate extend-ing into precuneus may be a core of dysfunction in ADHD participants responsible for increased variability, we found no suggestion of any difference between ADHD and HC partici-pants in this region

In children, proximal regions tend to be interconnected more than in adults, whereas distal regions, such as medial PFC/rostral ACC and posterior cingulate, tend to be less interconnected (Fair et al., 2007 ). Default network structure in adolescents is thought to lie somewhere between that of children and adults, with shorter range connections being progressively broken and longer range connections being formed (Fair et al., 2007)

it could be argued that only five of the children with ADHD are driving our results… It may be that the default network hypothesis is applicable to at least a large subgroup of individuals with ADHD

Felitti V, Anda R, Nordenberg D, Williamson D, Spitz A, Edwards V, Koss M, Marks J. 1998. “Relationship of Childhood Abuse and Household Dysfunction to Many of the Leading Causes of Death in Adults: The Adverse Childhood Experiences (ACE) Study” American Journal of Preventative Medicine 14:245-258 in dropbox

“smoking, which is medically and socially viewed as a ‘problem’ may, from the perspective of the user, represent an effective immediate solution that leads to chronic use. … incomplete understanding of the possible benefits of health risk behaviors leads them to be viewed as irrational and having solely negative consequences”

Fattore L, Melis M, Fadda P, Pistis M, Fratta W. 2010. “The endocannabinoid system and nondrug rewarding behaviours” Experimental Neurology 224: 23-36 in dropbox

rewarding behaviours activate the same brain circuits that mediate the postiive reinforcing effects of drugs

we focus first on the role of the endocannabinoid system in the modulation of neural activity and synaptic functions in brain regions that are involved in natural and nonnatural rewards (namely, the ventral tegmental area, striatum, amygdala and prefrontal cortex)

marijuana and cannabinoids, in general, are potent modulators of the central mechanisms that underlie not only drug (Fattore et al, 2007a, 2008) but also nondrug rewarding behaviours

Felitti V, Anda R. 2009. “The relationship of adverse childhood experiences to adult medical disease, psychiatric disorders and sexual behaviour: implications for healthcare” chapter in The Hidden Epidemic: The Impact of Early Life Trauma on Health and Disease Cambridge University Press. ISBN-13: 978-0521880268 in dropbox

1/3 had 0 ACEs, 1/6 had 4 ACEs, 1/9 had 5 ACEs 54% of current depression can be attribute to ACEs; males with an 6 ACEs 4,600% more likely to inject drugs than 0 ACE male

“It’s hard to get enough of something that almost works” “the attempted solution rather than the core problem is being addressed”

strong relationship of ACE Score to coronary disease, after correcting for all the conventional risk factors like smoking, cholesterol

Fellner J, Walsh S, Roth K, Smart, M. 2000. “Punishment and Prejudice: Racial Disparities in the War on DrugsHuman Rights Watch 12(2)

Fennig S, Horesh N, Aloni D, Apter A, Weizman A. 2005. “Life events and suicidality in adolescents with schizophrenia” Eur Child Adolesc Psychiatry 14(8): 454-60

number of negative events differentiates from non-schizophrenics, but not suicidal from non-suicidal. Ratio negative to other life events does: suicidal 74%, nonsuicidal 57%

Fergusson D, Horwood L. 1997. “Early onset cannabis use and psychosocial adjustment in young adults.” 92(3): 279-96 in dropbox

those who used by age 16, esp frequent users more likely to come from socially disadvantaged backgrounds, experienced family adversity as children, formed affiliations with substance using or delinquent peers in adolescence, reported poorer attachments with parents, had more adjustment problems by the age of 16. Early onset users had significantly higher rates of later substance use, juvenile offending, mental health problems, unemployment and school dropout

Fergusson D, Swain-Campbell N, Horwood L. 2003. “Arrests and convictions for cannabis related offences in a New Zealand birth cohort” Drug Alcohol Depend  70(1):53-63

Over a quarter of those using cannabis more than 400 times were arrested or convicted (5.1% of total users, who are more than two thirds of the cohort). Males and Maori overrepresented. Of those arrested/convicted, 95% either increased use or continued with same level of use subsequent to arrest.

Fergusson D, Horwood L, Ridder E. 2005. “Tests of causal linkages between cannabis use and psychotic symptoms” Addiction 100: 354-366 in dropbox

Fernández-López D, Martinez-Orgado J, Nunez E, Romero J, Lorenzo P, Moro M, Lizasoain I. 2006. “Characterization of the neuroprotective effect of the cannabinoid agonist WIN-55212 in an in vitro model of hypoxic-ischemic brain damage in newborn rats” Pediatr Res 60(2): 169-73

WIN55212 afforded robust neuroprotection in the forebrain slices exposed to OGD, by acting on glutamatergic excitotoxicity, TNF-alpha release, and iNOS expression; this neuroprotective effect seemed to be mediated by CB1 and CB2 receptors

Ferrer B, Asbrock N, Kathuria S, Piomelli D, Giuffrida A. 2003. “Effects of levodopa on endocannabinoid levels in rat basal ganglia: implications for the treatment of levodopa-induced dyskinesias” Eur J Neurosci 18(6): 1607-14

In intact animals, systemic administration of levodopa increased anandamide concentrations throughout the basal ganglia via activation of dopamine D1/D2 receptors… a deficiency in endocannabinoid transmission may contribute to levodopa-induced dyskinesias and that these complications may be alleviated by activation of CB1 receptors

Filbey F, Aslan S, Calhoun V, Spence J, Damaraju E, Caprihan A, Segall J. 2014. “Long-term effects of marijuana use on the brain” PNAS 111(47): 16913-16918

findings remain inconclusive

[MV: the finding of decreased FA from chronic use was mainly driven by the two longest using subjects]
Filbey - FA and chronic marijuana use

The results showed that compared with controls, marijuana users had significantly less bilateral orbitofrontal gyri volume, higher functional connectivity in the orbitofrontal cortex (OFC) network, and higher structural connectivity in tracts that innervate the OFC (forceps minor) as measured by fractional anisotropy (FA). Increased OFC functional connectivity in marijuana users was associated with earlier age of onset

Although some have reported decreases in regional brain volume such as in the hippocampus, orbitofrontal cortex, amygdala, and striatum (712), others have reported increases in amygdala, nucleus accumbens, and cerebellar volumes in chronic marijuana users (1315). However, others have reported no observable difference in global or regional gray or white matter volumes in chronic marijuana users (16, 17)

110 participants consisting of 62 nonusing controls and 48 marijuana users… included if they currently use marijuana regularly (at least four times per week) over the last 6 mo (confirmed via positive THC-COOH urinalysis) [from table 1, half of users were considered dependent]

the IQ of the marijuana users was significantly lower than the control group (P < 0.05)

quantitatively, marijuana users had significantly higher connectivity in all four nodes (i.e., bilateral OFC and bilateral temporal lobe) compared to the control group

earlier age of onset leads to higher functional connectivity of the bilateral OFC. Finally, there was an inverse correlation between the left temporal lobe functional connectivity and problems related with marijuana use, such that the greater the functional connectivity of the left temporal cortex to bilateral OFC, the lower the total score on MPS

inverse relationship between bilateral OFC gray matter volume and problems related to marijuana use. That is, the lower the OFC gray matter volume in these participants, the higher their MPS total scores

We did not find that the causal variable (i.e., marijuana use) was significantly correlated with the mediator variable (i.e., OFC gray matter volume, OFC/temporal functional connectivity, and FA/RD of forceps minor) and outcome variable (i.e., IQ). We, therefore, suggest that the path from marijuana use to neural abnormalities to decreases in IQ is more complex and, perhaps, include other mediators such as environmental (i.e., age of onset) and/or genetic factors.

a prospective study also found that smaller OFC volumes at 12 y of age predicted initiation of marijuana use at 16 y of age (30)

these OFC abnormalities may reflect preexisting pathophysiology related to vulnerability to marijuana abuse and dependence

Greater FA has been suggested to reflect better myelination and/or intact axons (42).

FA difference between the groups in the forceps minor was driven by lower RD, suggesting greater myelination in the marijuana users

Greater FA has also been reported in alcohol users (44, 45), which was posited to reflect a premorbid vulnerability for accelerated PFC myelin maturation in those at risk for alcohol use disorders

DTI is sensitive to increased tissue water resulting in decreased FA as a result of inflammation; therefore, it is possible that any antiinflammatory effects of cannabis would lead to greater FA. Lastly, it is also possible that the effects of cannabis (i.e., CBD) may be beneficial to white matter in terms of regulation of mitochondrial activity, antioxidant processes, and modulation of clearance processes that protect neurons on the molecular level (46)

greater functional connectivity was associated with earlier onset of regular use, whereas chronic marijuana use showed lower structural connectivity (i.e., FA)

Fink M. 1976. “Effects of acute and chronic inhalation of hashish, marijuana, and delta 9-tetrahydrocannabinol on brain electrical activity in man: evidence for tissue tolerance” Ann N Y Acad Sci 282: 387:98

The EEG effects of enhanced alpha activity, decreased beta activity, and decreased mean frequency are dose dependent, both in intensity and in duration. The behavioral measures, particularly self-ratings of euphoria (“high” or “mastura”) and heart rate, are also dose dependent and interrelated with the EEG measures. Tolerance to the cerebral, heart rate, and behavioral effects of repeated inhalations of delta 9-THC are demonstrable in chronic users and also in short-term (21-day) experimental administration studies… No differences in incidence of abnormal EEG records were found between long-term heavy hashish users and controls. Taken in conjunction with the neurologic, echo-EEG, and psychopathologic data in these men, we failed to define a syndrome of persistent brain damage as a result of hashish use, although persistent adaptational changes are noted in the development of tissue tolerance.

Finkelhor D, Hotaling G, Lewis I, Smith C. 1990. “Sexual abuse in a national survey of adult men and women: prevalence, characteristics and risk factors.” Child Abuse Negl 14:19-28

27% of women and 16% of men had been sexually abused

Finkelhor D, Ormrod R, Turner H. 2009. “Lifetime assessment of poly-victimization in a national sample of children and youth” Child Abuse & Neglect 33 403-411

Nearly 80% of the children and youth victimized; mean lifetime victimizations 3.7, median 2.6. Number highly predictive of current distress symptoms. Best linear prediction weights: child maltreatment 4, sexual assault 3, other victimizations 1. propose classifying poly-victims as those 10% with the highest scores for each age threshold

Fishbein M, Gov S, Assaf F, Gafni M, Keren O, Sarne Y. 2012. “Long-term behavioral and biochemical effects of an ultra-low dose of Δ9-tetrahydrocannabinol (THC): neuroprotection and ERK signaling” Exp Brain Res 221(4): 437-48

We have previously reported that a single injection of an ultra-low dose of delta-9-tetrahydrocannabinol (THC; the psychoactive ingredient of marijuana) protected the brain from pentylenentetrazole (PTZ)-induced cognitive deficits when applied 1-7 days before or 1-3 days after the insult… we expanded the protective profile of THC by showing that it protected mice from cognitive deficits that were induced by a variety of other neuronal insults, including pentobarbital-induced deep anesthesia, repeated treatment with 3,4 methylenedioxymethamphetamine (MDMA; “ecstasy”) and exposure to carbon monoxide. The protective effect of THC lasted for at least 7 week… long-lasting (7 weeks) modifications of extracellular signal-regulated kinase (ERK) activity in the hippocampus, frontal cortex and cerebellum of the mice. The alterations in ERK activity paralleled changes in its activating enzyme MEK and its inactivating enzyme MKP-1. Furthermore, a single treatment with the low dose of THC elevated the level of pCREB (phosphorylated cAMP response element-binding protein) in the hippocampus and the level of BDNF (brain-derived neurotrophic factor) in the frontal cortex. These long-lasting effects indicate that a single treatment with an ultra-low dose of THC can modify brain plasticity and induce long-term behavioral and developmental effects in the brain

Fisher H, Jones P, Fearon P, Craig T, Dazzan P, Morgan K, Hutchinson G, Doody G, McGuffin P, Leff J, Murray R, Morgan C. 2010. “The varying impact of type, timing and frequency of exposure to childhood adversity on its association with adult psychotic disorder” Psychological Medicine 40: 1967-1978 in dropbox

Psychosis cases were three times more likely to report severe physical abuse from mother that commenced prior to 12 years of age, even after adjustment for other significant forms of adversity and demographic confounders

Associations with maternal neglect and childhood sexual abuse disappeared after adjusting for maternal physical abuse and antipathy. Paternal maltreatment and other forms of adversity were not associated with psychosis nor was there evidence of a dose-response effect

Given the hypothesised key role of mother-child attachment bonds in psychological wellbeing (Bowlby, 1951, 1977), evidence from cohort studies of mothers’ perceptions and care of the child being related to adult schizophrenia (Jones et al., 1994; McNeil et al., 2009; Myhrman et al., 1996), and the greater absence of fathers in the childhoods of individuals with psychosis (Agid et al., 1999; Morgan et al., 2007) it seems plausible to hypothesise that abuse perpetrated by mothers will also have a greater association with psychotic disorders

the vast majority of psychosis cases (86%) and controls (93%) in this study did not report maternal physical or emotional abuse

If comparisons are restricted to the largest previous study of first-episode psychosis patients (Neria et al., 2002), then the rates reported in the current study are slightly lower for physical abuse (21.6% vs. 14.0-15.2%) but fairly similar for sexual abuse (15.0% vs. 18.2%)

the prevalence of physical and sexual abuse reported by healthy controls in this study (5.4-12.3% and 13.1%, respectively) is similar to that found in a recent UK general population survey (May-Chahal & Cawson, 2005: 7-14% physical, 11% sexual)

it is possible that previous associations between sexual abuse and psychosis may have been inflated by overlap with physical abuse

Higher rates of psychotic symptoms have also been found in those exposed to emotional forms of abuse (Colins et al., 2009; Sommer et al., 2008)

the importance of the mother in the psychological development of the child has long been advocated as she is usually the main attachment figure in infancy (Bowlby, 1951, 1977)

it is also plausible that stronger effects in childhood are just a proxy for more prolonged abuse or higher risk of exposure to other adverse experiences

other potentially predictive forms of childhood adversity were not measured, such as bullying, psychological abuse, domestic violence and family discord (see Bebbington et al., 2004; Campbell & Morrison, 2007; Kelleher et al., 2008; Lataster et al., 2006; Rosenberg et al., 2007)

Fisher H, Craig T, Fearon P, Morgan K, Dazzan P, Lappin J, Hutchinson G, Doody G, Jones P, McGuffin P, Murray R, Leff J, Morgan C. 2011. “Reliability and comparability of psychosis patients’ retrospective reports of childhood abuse” Schizophrenia Bulletin 37(3): 546-553 in dropbox

high levels of concurrent validity were demonstrated with the Parental Bonding Instrument were demonstrated with the Parental Bonding Instrument (antipathy:rs = 0.350–0.737, P < .001; neglect:rs = 0.688– 0.715, P < .001), and good convergent validity was shown with clinical case notes (sexual abuse: k 5 0.526, P < .001; physical abuse: k = 0.394, P < .001). Psychosis patients’ reports were also reasonably stable over a 7-year period (sexual abuse: k = 0.590, P < .01; physical abuse: k = 0.634, P < .001; antipathy: k = 0.492, P < .01; neglect: k = 0.432, P < .05). Additionally, their reports of childhood abuse were not associated with current severity of psychotic symptoms (sexual abuse: U = 1768.5, P = .998; physical abuse: U = 2167.5, P = .815; antipathy: U = 2216.5, P = .988; neglect: U = 1906.0, P 5 .835) or depressed mood (sexual abuse: x2 = 0.634, P 5 .277; physical abuse: x2 = 0.159, P = .419; antipathy: x2 = 0.868, P = .229; neglect: x2 = 0.639, P 5 .274). These findings provide justification for the use in future studies of retrospective reports of childhood abuse obtained from individuals with psychotic disorders

Flinn M, Nepomnaschy P, Muehlenbein M, Ponzi D. 2011. “Evolutionary fuctions of early social modulation of hypothalamic-pituitary-adrenal axis development in humans.” Neurosci Biobehav Rev 35(7): 1611-29

difficult family environments and traumatic social events are associated with temporal elevations of cortisol, suppressed reproductive functioning and elevated morbidity. The long-term effects of traumatic early experiences on cortisol profiles are complex and indicate domain-specific effects, with normal recovery from physical stressors, but some heightened response to negative-affect social challenge

Folsom D, Hawthorne W, Lindamer L, Gilmer T, Bailey A, Golshan S, Garcia P, Unützer J, Hough R, Jeste D. 2005. “Prevalence and risk factors for homelessness and utilization of mental health services among 10,340 patients with serious mental illness in a large public mental health system” Am J Psychiatry 162(2): 370-6

The prevalence of homelessness was 15%. Homelessness was associated with male gender, African American ethnicity, presence of a substance use disorder, lack of Medicaid, a diagnosis of schizophrenia or bipolar disorder, and poorer functioning. Latinos and Asian Americans were less likely to be homeless. Homeless patients used more inpatient and emergency-type services and fewer outpatient-type services

Ford J, Hawke J, Alessi S, Ledgerwood D, Petry N. 2007 “Psychological trauma and PTSD symptoms as predictors of substance dependence treatment outcomes” Behav Res Ther 45(10): 2417-31

affect dysregulation, dissociation, and disturbed interpersonal functioning; C-PTSD predicts poor outcome, PTSD predicts improved outcome

Ford J, Elhai J, Connor D, Frueh B. 2010. “Poly-victimization and risk of posttraumatic, depressive, and substance use disorders and involvement in delinquency in a national sample of adolescents” J Adolesc Health 46(6): 545-52

poly-victimized youths’ risk of delinquency cannot be fully accounted for by posttraumatic stress disorder, depression, or substance use problems

Di Forti M, Marconi A, Carra E, Fraietta S, Trotta A, Bonomo M, Bianconi F, Gardner-Sood P, O’Conner J, Russo M, Stilo S, Marques T, Mondelli V, Dazzan P, Pariante C, David A, Gaughran F, Atakan Z, Iyegbe C, Powell J, Morgan C, Lynskey M, Murray R. 2015. “Proportion of patients in south London with first-episode psychosis attributable to use of high potency cannabis: a case control study” in dropbox

Study uses loaded, inaccurate and stigmatising terminology such as “skunk-like” to refer to good quality bud (skunk is one breed among thousands, but British media has seized on it because it sounds uglier than, say, “girl scout cookies” or “tickle kush”) and ignores the real reasons why schizophrenics use marijuana, rejecting self-medication on the grounds that it doesn’t reduce positive symptoms, when it’s in fact used to reduce negative symptoms. A bad-faith propaganda piece from King’s College London, which nevertheless contains some interesting data

Patients with first-episode psychosis were no more likely than were controls to report a lifetime history of ever having used cannabis, but were more likely to use cannabis every day and to mostly use high-potency (skunk-like) cannabis

among cannabis users, the mean duration of use did not differ between patients with first-episode psychosis and controls (table 2). On average, both groups started using cannabis in their mid-teens

individuals who had ever used cannabis were not at increased risk of psychotic disorder compared with those who had never used cannabis (n=775)  Individuals who started using cannabis at ages younger than 15 years had modestly, but significantly, increased risk of psychotic disorders compared with those who never used cannabis (table 3). People who used cannabis or skunk every day were both roughly three times more likely to have a diagnosis of a psychotic disorder than were those who never used cannabis (table 3)

Individuals who mostly used low-potency (hash-like) cannabis occasionally (p=0·493), at weekends (p=0·102), or daily (p=0·626) had no increased likelihood of psychotic disorders compared with those who never used cannabis (figure 2)

If causality is assumed, this finding suggests that skunk alone was responsible for the largest proportion of new cases (24%) of psychotic disorder in the study population, an effect driven by its high prevalence among patients with first-episode psychosis who used cannabis (218 [53%] of 410 patients)

The presence of cannabidiol might explain our results, which showed that hash users do not have any increase in risk of psychotic disorders compared with non-users, irrespective of their frequency of use

South London has one of the highest recorded incidence rates of psychosis in the UK. Boydell and colleagues showed that the incidence of schizophrenia had doubled since 1965, and that one possible contribution to this was the increase in cannabis use among individuals who developed schizophrenia. In the present study, we identified an increased estimate for the PAF accounted for by cannabis (24%) compared with previous studies, which  reported PAFs of 6·2% in Germany, 8% in New Zealand, and 13·3% in Holland. This finding could be caused by, not only the greater use of cannabis, but also the greater use of high-potency (skunk-like) cannabis in south London than in these other countries in earlier periods [so the zero increase from any cannabis use, which can be made to look like 24% increase from high-THC cannabis use because schizophrenics prefer high THC cannabis because it more effectively treats negative symptoms, is the causal factor explaining why the incidence DOUBLED? Psychiatrists at King’s College London evidently are not strong on arithmetic]

That people who already have prodromal symptoms would choose a type of cannabis that is high in THC and has little cannabidiol (such as skunk), which might exacerbate their symptoms, rather than a cannabidiol-containing type (such as hash), would seem counterintuitive [if you ignore why they use it]

urgent need to develop public education to inform young people about the risks of high-potency cannabis

Foti D, Kotov R, Guey L, Bromet E. 2010. “Cannabis use and the course of schizophrenia: 10-year follow-up after first hospitalization” Psychiatryonline 167(8): 987-993

authors assessed 229 patients with a schizophrenia spectrum disorder five times: during the first admission and 6 months, 2 years, 4 years, and 10 years later

lifetime rate of cannabis use was 66.2%, and survival analysis revealed that lifetime use was associated with an earlier onset of psychosis. The rates of current use ranged from 10% to 18% across assessments

Mixed-effects logistic regression revealed that changes in cannabis use were associated with changes in psychotic symptoms over time even after gender, age, socioeconomic status, other drug use, antipsychotic medication use, and other symptoms were controlled for. Structural equation modeling indicated that the association with psychotic symptoms was bidirectional

A recent review of 53 treatment studies found that the average 12-month prevalence of cannabis use was 29.2% among patients with psychosis (1), compared with 4.0% in the general U.S. population (2)

Some individuals with schizophrenia report using cannabis to relieve symptoms or medication side effects (11 – Dixon). Also, some cross-sectional studies have reported that cannabis use is associated with less severe negative and disorganized symptoms (12 – Bersani)

On the other hand, other cross-sectional data indicate that cannabis users have more severe psychotic symptoms than nonusers (13, 14)

lower severity of psychotic symptoms predicted cessation of cannabis use, whereas higher severity was associated with an increased likelihood of use at the next assessment. Likewise, cannabis use predicted an increase in severity of psychotic symptoms

we cannot rule out the possibility that some individuals used cannabis to obtain relief from disorganized symptoms (11, 12), but in this sample a more robust association was found with psychotic symptoms. This suggests that individuals with schizophrenia who use cannabis are not more severely ill overall but suffer specifically from more severe psychotic symptoms.

Frank M, Baratta M, Sprunger D, Watkins L, Maier S. 2007. “Microglia serve as a neuroimmune substrate for stress-induced potentiation of CNS pro-inflammatory cytokine responses” Brain Behav Immun 21(1): 47-59

microglia are the primary immune effector cell in the CNS… The present results suggest that stress can activate microglia, thereby sensitizing the pro-inflammatory reactivity of microglia to immunogenic stimuli

Franklin A, Parmentier-Batteur S, Walter L, Greenberg D, Stella N. 2003. “Palmitoylethanolamide increases after focal cerebral ischemia and potentiates microglial cell motility” J Neurosci 23(21): 7767-75

FCI greatly increases palmitoylethanolamide (PEA), only moderately increases anandamide [arachidonylethanolamide (AEA)], and does not affect 2-arachidonoylglycerol levels. We also found that PEA potentiates AEA-induced microglial cell migration, without affecting other steps of microglial activation, such as proliferation, particle engulfment, and nitric oxide production

French L, Gray C, Leonard G, Perron M, Pike B, Richer L, Seguin J, Veillette S, Evans J, Artiges E, Banaschewski T, Bokde A, Bromberg U, Bruehl R, Buchel C, Cattrell A, Conrod P, Flor H, Frouin V, Galliant J, Garavan H, Gowland P, Heinz A, Lemaitre H, Martinot J-L, Nees F, Orfanos D, Pangelinan M, Poustka L, Rietschel M, Smolka M, Walter H, Whelan R, Timpson N, Schumann G, Smith G, Pausova Z, Paus T. 2015. “Early cannabis use, polygenic risk score for schizophrenia, and brain maturation in adolescence” JAMA Psychiatry 72(10): 1002-1011 add to dropbox

initial analysis in 1024 adolescents of both sexes from the Canadian Saguenay Youth Study (SYS) and follow-up in 426 adolescents of both sexes from the IMAGEN Study from 8 European cities and 504 male youth from the Avon Longitudinal Study of Parents and Children (ALSPAC) based in England. A total of 1577 participants (aged 12-21 years; 899 [57.0%] male) had (1) information about cannabis use; (2) imaging studies of the brain; and (3) a polygenic risk score for schizophrenia across 108 genetic loci identified by the Psychiatric Genomics Consortium

Across the 3 samples of 1574 participants, a negative association was observed between cannabis use in early adolescence and cortical thickness in male participants with a high polygenic risk score. This observation was not the case for low-risk male participants or for the low- or high-risk female participants

2011 European School Survey Project on Alco-hol and Other Drugs,3 a mean lifetime prevalence of canna-bis use among high school students aged 15 to 16 years was 17%, with large variations across the 36 participating coun-tries (eg, 19% in Germany, 25% in the United Kingdom, and 39% in France). The 2014 Monitoring the Future survey4 has reported a lifetime prevalence of cannabis use of 35.8% among youth aged 15 to 16 years living in the United States in 2013

steeper slopes of age-related increases in white matter and decreases in (cortical) gray matter in male compared with female adolescents.13,14 These sex differences in the dynamics of brain maturation during adolescence may be of particular importance with regard to vulnerability of the male brain to external factors, such as cannabis exposure, during this period of development

SYS sample 1024 adolescents comes from the Saguenay Lac-Saint-Jean region of Quebec, Canada… first replication sample consisted of 504 male youth recruited from the Avon Longitudinal Study of Parents and Children (ALSPAC)20 based in England… second replication sample consisted of 426 adolescents recruited in 8 European cities in the context of the IMAGEN Study

SYS sample classified adolescents as ever or never used cannabis. In ALSPAC and IMAGEN address the latter question using original data on the number of occasions of cannabis use by 16 years of age

cortical thickness is a useful metric for capturing the cumu-lative effects of various experiential factors on cortical neu-robiological features, especially neuropil (ie, dendrites, glial cells) and capillary densities

we have related regional variations in the group differ-ences (users vs nonusers) in thickness across 34 cortical regions to those in the expression of the cannabinoid receptor 1 gene ( CNR1 [NCBI Entrez Gene 1268]) derived from the Allen Brain Atlas in the same regions.26 This atlas provides postmortem measurements of gene expression obtained in 6 adult brains (1269 cortical samples were used to calculate an aver-age for each of the 34 regions). We used CNR1 expression as a proxy of the cannabinoid type 1 receptor density to evaluate whether the extent of the relationship between cannabis use and cortical thickness varies as a function of this receptor’s density in the cerebral cortex, thus testing for the level of specificity in this relationship

French - cortical thickness by cannabis ever by genetic risk decile for schizophrenia

The Schizophrenia Working Group of the Psychiatric Genomics Consortium found that the top decile (based on the top 108 loci) contained about 3 times more cases of schizophrenia than the bottom decile (mean odds ratio across 39 samples, 3.21)

French - ALSPAC French - IMAGEN French - SYS

the largest group differences between those who never and ever used cannabis were found in regions that showed high CNR1 expression(eg,entorhinal and anterior cingulate cortex)

Observational studies such as ours cannot attribute causality to the observed relationships. Even the longitudinal de-sign does not rule out the possibility that individuals with a particular developmental trajectory may be more likely to experiment with cannabis rather than the cannabis exposure affecting the trajectory

Unlike the SYS and IMAGEN samples, the high-risk male participants in the ALSPAC sample do not show a difference in cortical thickness between those who never and ever used cannabis; only the high-frequency users do. We can only speculate that, with a given sample size, the association between less frequent cannabis use and cortical thickness is less robust and, therefore, sensitive to other (confounding) effects that may accumulate with age

The overall volume of cortical gray matter and cortical thickness decrease with age in typi-cally developing male adolescents. 13,14 Our longitudinal findngs suggest that cannabis exposure might accelerate such processes, including cortical thinning, in male adolescents with a high polygenic risk score. A profound thinning of cortical gray matter was observed during adolescence in patients with childhood-onset schizophrenia (onset of symptoms by 12 years of age)31,32 and, to a much lesser extent, in their nonpsychotic siblings.33

Rising levels of testosterone during male adolescence and the associated high dynamics in the neurobiological features underlying cortical maturation may represent a risk factor with regard to other external (eg, cannabis) and/or internal eg, genetic risk) perturbations. Furthermore, limited evidence supports the possible effects of testosterone on potentiating the action of cannabinoid type 1 receptor agonists on presynaptic inhibition of excitatory inputs in vitro57 and on transcriptional upregulation of the CNR1 gene.58,59

In this report, the polygenic risk score for schizophrenia calculated with the genome-wide significant SNPs ( P <5×10−8) showed an association with cortical thickness. This association was not in evidence when we calculated the score with the 24 727 nominally significant SNPs ( P < .05)(eTable4 in the Supplement ). Nevertheless, the latter score is superior to the former in predicting liability to schizophrenia.17

we speculate that the moderating in-fluence of cannabis use on the association between the ge-netic risk for schizophrenia and cortical thickness may repre-sent a combination of reduced experience-related brain plasticity taking place on the background of testosterone-associated decreases in cortical gray matter

Fried P, Watkinson B, James D, Gray R. 2002. “Current and former marijuana use: preliminary findings of a longitudinal study of effects on IQ in young adults.” CMAJ 166(7):887-91 in dropbox

IQ difference scores showed decrease of 4.1 points in current heavy users (more than 5 joints/week) ( p < 0.05); gains in IQ for light current users (5.8), former users (3.5) and non-users (2.6)

potentially confounding variables: socioeconomic status (incl family income and parental education); the subject’s education level (years of education); age and sex of the subject; mother’s age at the time of birth; maternal use of cigarettes, marijuana and alcohol during pregnancy; use of tobacco and alcohol and exposure to secondhand marijuana smoke.

no predictive relation with the IQ difference score was found for the self-reported period of marijuana use or the estimated total number of joints smoked

lack of a negative impact among the former heavy users; they had smoked avg 5793 joints over 3.2 years (mean of 37 joints per week); the current heavy users had smoked, on average, an estimated 2386 joints over 3.1 years (mean of 14 joints per week)

Fried P, Watkinson B, Gray R. 2005. “Neurocognitive consequences of marihuana–a comparison with pre-drug performance.” Neurotoxicol Teratol 27(2):231-9

current regular heavy users did significantly worse than non-users in overall IQ, processing speed, immediate, and delayed memory; former marihuana smokers did not show any cognitive impairments

there is considerable consensus that gross cognitive impairment is not evident in chronic users compared to irregular or non-users following lengthy abstinence periods [13,29,3 6,40,42]

Ottawa Prenatal Prospective Study (OPPS) was initiated in 1978 with the primary objective of examining the effects on offspring of soft drugs used during pregnancy. In this predominantly middle class, low risk sample, approximately 160 children have been administered neuropsychological tests yearly to age 7 and once during each of the 9-12, 13-16, and 17-21 year intervals… in the present study, data from the 9-12 year testing (pre-teen) were used as pre-drug performance measures for the 17-21 year testing (young adult)… of the 152 subjects who have been tested between 17 and 21, 121 were available who had also been tested at 9-12

Additional exclusions were one subject on ritalin, one subject because of amphetamine use, an LSD user, an uncooperative subject, three cases with a positive urinalysis for cannabinoid metabolites coupled with a negative self-report, and one previous regular user who had quit for several months but began regular use a few weeks before testing. The final sample comprised 113 subjects, 50 females and 63 males. None smoking marihuana regularly at the 9-12 year testing. Of the 113 subjects, 10 had tried between 9 and 12: 1 from the control group and 2, 6, and 1 from the current light, current heavy, and former user group, respectively

Potential confounds considered were SES variables (family income, parental education), maternal use of alcohol, cigarettes, and marihuana during pregnancy, age and sex of subject, young adult’s cigarette and alcohol use, and DSM positive criteria for any of the following DSM-IV Axis I disorders: generalized anxiety, major depression, dysthymic disorder, attention deficit/hyperactivity disorder, conduct disorder, oppositional defiant disorder, alcohol dependence and abuse.

Although on average, current and former marihuana useing groups showed more positive DSM criteria than the comparison group, the frequency of positive diagnoses for each of the disorders considered was low

After controlling for pre-use performance, the current heavy use group had lower mean scores in Immediate Memory and General (delayed) Memory as well as the Processing Speed Index, a composite score contributing to overall IQ

former users smoked 2203 joints on average, compared to 1884 in current heavy users and 122 in current light. 9.6 cigarettes per day in heavy current group, and 8.8 maternal joints per week (1.5-2.1 in other groups)

After controlling for pre-drug performance , no relation-ships were found between current marihuana use and working memory [48] , Verbal IQ [47] , the Peabody Picture Vocabulary Test (PPVT) [44] , the Category Test [44] , or the TOVA attention tasks [26]

Processing Speed Index was associated with current heavy marihuana use after, but not before, pre-drug performance control. Conversely, both the PPVT and Category Test were associated with current heavy marihuana use before, but not after, pre-drug performance control

Self-reports of marihuana usage in each of the 7 days previous to testing, when individually correlated with relevant outcomes, did not reveal stroner negative associations with more recent exposure… no significant differences between former heavy and comparison group on any of the cognitive outcomes were noted

former user group started regular use slightly younger (14.3 years) than the current heavy users (15 years), and consumed a total of approximately 5000 joints compared with 2000 for the current users

deficits in visual information proces sing are largely independent of competency in visual attention as demonstrated both by the low correlations between the visual attention task and the Processing Speed Index in the present work as well as with Wechsler ’s report of only low to moderate correlations between several measures of attention and the Visual Processing composite score [49] .

The absence of a negative impact among the former heavy users in the present report is all the more striking as they initiated their regular habits at a younger age than the curren users (14 vs 15 years)… the cognitive impairments among the current heavy users and the recovery of function among the heavy, former users do not appear to have clinical underpinnings

the absence of significant cognitive differences between the former users and the control group suggests that residual marihuana-associated deficits observed among current users are transient phenomena and that regular, heavy use does not produce irreversible, neurocognitive effects

Frohlich J, Van Horn J. 2014. “Reviewing the ketamine model for schizophrenia” J Psychopharmacol 28: 287 in dropbox

Frolich - ketamine hypothesis of schizophrenia

Frolich - NMDA blocked by ketamine

striatal regions suffer from hyperdopaminergia, while prefrontal cortical regions suffer from hypodopaminergia (Howes and Kapur, 2009; Lau et al., 2013)

Schizophrenic hypofrontality is hypothesized to lessen tonic dopamine release, and phasic dopamine release is in turn increased as a homeostatic compensation mechanism (Grace, 1991)

single photon emission computed tomography (SPECT) imaging of healthy subjects shows a strong ( r =0.96) correlation between negative symptoms and ketamine-induced changes in the binding of a [123I]CNS-1261 radiotracer to NMDARs (Stone et al., 2008)

dysfunctional role of cortico-limbocortico-thalamic circuitry in schizophrenia (Tsai and Coyle, 2002)

NMDAR is rarely considered a glycine receptor because it is glutamate that is released from the presynaptic terminal, with micromolar background levels of glycine sufficing for channel activation

Although findings have been mixed, many studies report a positive correlation between levels of dynorphins, endogenous kappa receptor ligands, in the cerebrospinal fluid of schizophrenia patients and psychotic symptoms (Tejeda et al., 2012)

ketamine and other uncompetitive NMDAR antagonists have a net positive effect on excitatory transmission by inducing excessive release of glutamate (Kim et al., 2011; Rowland et al., 2005; Stone et al., 2012) and acetylcholine (Giovannini et al., 1994; Hasegawa et al., 1993)

reduced levels of a protein linked to NMDAR function and working memory (Karlsgodt et al., 2011), dystrobrevin-binding-protein-1 (dysbindin)

the gene encoding dysbindin, and GRIN2B (Li and He, 2007a), the gene encoding the NR2B subunit of NMDAR, have been associated with schizophrenia

The growth factor neuregulin-1 (NRG1), its receptor, erbB4, and the scaffold protein known as postsynaptic  density protein of 95 kDa (PSD-95); NRG1 inhibits prefrontal cortical NMDAR in humans, and schizophrenics have increased interactions between erbB4 and PSD-95 (Hahn et al., 2006)

D-amino acid oxidase (DAAO) is an enzyme that degrades D-serine by oxidation. Several single nucleotide polymorphisms (SNPs) in DAAO have been linked to schizophrenia (Chumakov et al., 2002). Additionally, G72 (also known as D-amino acid oxidase activator: DAOA) and G30, overlapping genes that interact with DAAO, have SNPs associated with schizophrenia (Li and He, 2007b: 30; Shinkai et al., 2007)

supplementing antipsychotic medication with D-serine alleviates the negative (p=0.02; pooled effect size (ES)=0.48), cognitive (p=0.007; ES=0.42), and total ( p=0.02; ES=0.4) symptoms of schizophrenia (Tsai and Lin, 2010)

significant reductions in all psychiatric groups (schizophrenic, depressive, and bipolar) for GRIN1 mRNA encoding the NR1 subunit of NMDAR in the dentate gyrus. Unique to the schizophrenia cohort was the left-lateralization of this finding (Law and Deakin, 2001)

enhanced sensitivity to the dopaminergic effects of amphetamine challenge is also characteristic of schizophrenia patients, as revealed by PET and SPECT imaging (Breier et al., 1997; Laruelle et al., 1996)

increased glutamate release, induced by ketamine, explains observed frontal deactivation (Deakin et al., 2008)

a PET study of schizophrenia patients reported fewer functional interactions between brain regions than controls, including reduced correlations between activation of anterior and posterior regions and between thalamic and cortical regions (Volkow et al., 1988)

Anatomical networks in patients are more sparsely connected when analyzed both in terms of axonal connectivity and cortical thickness (an indirect measure of the former) (Bassett et al., 2008; Wang et al., 201 1; Zalesky et al., 201 1). Resting-state
functional networks in patients show reduced connection density (“clustering”), fewer “hub” regions with very high interconnectivity, and reduced efficiency (“small-worldness”) of connections (Lynall et al., 2010)

(DMN), a set of brain regions deactivated by cognitive tasks and forming a functional module in resting state functional networks observed with fMRI (Sporns, 2012), has increased connectivity in schizophrenia patients. What is more, the extent of
strengthened connectivity within the DMN is correlated with the severity of psychiatric symptoms (Whitfield-Gabrieli et al., 2009)

TMS-evoked waves of excitation propagate longer and farther in schizophrenia patients than controls (Frantseva et al., 2012)

Postmortem studies of PFC tissue from schizophrenic patients reinforce the above findings by revealing reduced numbers of GABAer gic interneurons expressing GAD67 (Hashimoto et al., 2003; Volk et al., 2000), parvalbumin (Hashimoto et al., 2003), and GABA transporter-1 (GAT-1) mRNA (Volk et al., 2001). PFC chandelier cells, GABAergic neurons that regulate pyramidal cell output, have lower axon cartridge (terminal array) density in schizophrenia patients (Pierri et al., 1999)

several lines of evidence converge to implicate the thalamic reticular nucleus in the pathology of schizophrenia (Ferrarelli and Tononi, 2011)

increased global based connectivity of six clusters are associated with positive symptoms, whereas constant or decreased GBC in the dorsal and medial striatum and thalamus is associated with negative symptoms (Driesen et al., 2013)

while gamma oscillations in schizophrenia are often reduced, increases have also been observed (Bucci et al., 2007). Like resting-state GBC, decreases are often associated with negative symptoms and increases are often associated with positive symptoms (Figure 3) (Baldeweg et al., 1998; Bucci et al., 2007; Kehrer et al., 2008; Spencer et al., 2008: 2)

cognitive control induced modulation of prefrontal gamma band activity, correlated with cognitive control demand and task performance in healthy controls, is not observed in schizophrenia patients (Cho et al., 2006)

N-back tests of working memory induce excessive frontal gamma band activity in schizophrenia patients, whose performance is worse than that of healthy controls (Barr et al., 2010, 2011). One might draw a crude analogy between the schizophrenic PFC and an overworked engine: frontal networks in schizophrenia appear inflexible and inefficient, thus serving as weaker substrates for working memory

patients have higher absolute gamma synchrony relative to controls (Williams et al., 2009) Cortical networks in schizophrenia appear rigid and inflexible, as judged from their gamma band activity

a heartbeat that is too regular is linked to cardiac pathologies such as congestive heart failure (Ho et al., 2011; Norris et al., 2008; Poon and Merrill, 1997)

schizophrenia patients’ oscillations in lower frequencies bands include both abnormal increases and decreases in power during both induced and resting oscillations (Uhlhaas and Singer, 2011)

NMDAR antagonists that are nonspecific or specific to the NR2A subunit increase gamma power in rat cortex, whereas antagonists specific to other NMDAR subunits have weak effects (Kocsis, 2012)

the general theta-to-gamma shift observed in schizophrenia is replicated using ketamine (Ehrlichman et al., 2009). Ketamine also increases the power of 20–29 Hz oscillations in the beta band in the association cortex and PFC, a finding likely compatible with increased frontal and parietal resting beta oscillations in schizophrenia patients with auditory hallucinations (Lee et al., 2006; Mulert et al., 2011; Roopun et al., 2008)

Fu Q, Heath A, ZBucholz K, Nelson E, Goldberg J, Lyons M, True W, Jacob T, Tsuang M, Eisen S. 2002. “Shared genetic risk of major depression, alcohol dependence, and marijuana dependence: contribution of antisocial personality disorder in men” Arch Gen Psychiatry 59(12): 1125-32

Genetic effects on ASPD accounted for 38%, 50%, and 58% of the total genetic variance in risk for MD, AD, and MJD, respectively … after controlling for ASPD, genetic correlations of MD with AD and with MJD not statistically significant

Fu C, Williams S, Brammer M, Suckling J, Kim J, Cleare A, Walsh N, Mitterschiffthaler M, Andrew C, Pich E, Bullmore E. 2007. “Neural responses to happy facial expressions in major depression following antidepressant treatment” Am J Psychiatry 164(4): 599-607

Impairments in the neural processing of happy facial expressions in depression were evident in the core regions of affective facial processing, which were reversed following treatment. These data complement the neural effects observed with negative affective stimuli

Fusar-Poli P, Crippa JA, Bhattacharyya S, Borgwardt SJ, Allen P, Martin-Santos R, Seal M, Surguladze SA, O’Carrol C, Atakan Z, Zuardi AW, McGuire PK. 2009. “Distinct effects of {delta}9-tetrahydrocannabinol and cannabidiol on neural activation during emotional processesing.” Arch Gen Psychiatry 66(1):95-105 in dropbox

“Delta9-Tetrahydrocannabinol increased anxiety, as well as levels of intoxication, sedation, and psychotic symptoms, whereas there was a trend for a reduction in anxiety following administration of CBD”

Fusar-Poli P, Allen P, Bhattacharyya S, Crippa JA, Mechelli A, Borgwardt S, Martin-Santos R, Seal ML, O’Carrol C, Atakan Z, Zuardi AW, McGuire P. 2010. “Modulation of effective connectivity during emotional processing by Delta 9-tetrahydrocannabinol and cannabidiol” International Journal of Neuropsychopharmacology 13(4):421-32

“BMS identified a model with driving inputs entering via the anterior cingulate and forward intrinsic connectivity between the amygdala and the anterior cingulate as the best fit. CBD but not Delta 9-THC disrupted forward connectivity between these regions during the neural response to fearful faces”

Fuster D, Cheng D, Allensworth-Davies D, Palfai T, Samet J, Saitz R. 2014. “No detectable association between frequency of marijuana use and health or healthcare utilization among primary care patients who screen positive for drug use” J Gen Intern Med 29(1): 133-9

All 589 participants reported recent drug use: marijuana 84 % (29 % daily, 55 % less than daily), cocaine 25 %, opioid 23 %, other drugs 8 %; 58 % reported exclusive marijuana use. Frequency of marijuana use was not significantly associated with emergency department use {adjusted odds ratio [AOR] 0.67, [95 % confidence interval (CI) 0.36, 1.24] for daily; AOR 0.69 [95 % CI 0.40,1.18] for less than daily versus no use}, hospitalization [AOR 0.79 (95 % CI 0.35, 1.81) for daily; AOR 1.23 (95 % CI 0.63, 2.40) for less than daily versus no use], any comorbidity [AOR 0.62, (95 % CI 0.33, 1.18) for daily; AOR 0.67 (95 % CI 0.38, 1.17) for less than daily versus no use] or health status (adjusted mean EuroQol 69.1, 67.8 and 68.0 for daily, less than daily and none, respectively, global p = 0.78).

Gaffal E, Cron M, Glodde N, Tuting T. 2013. “Anti-inflammatory activity of topical THC in DNFB-mediated mouse allergic contact dermatitis independent of CB1 and CB2 receptors” Allergy 68(8): 994-1000

Topical THC application effectively decreased contact allergic ear swelling and myeloid immune cell infiltration not only in wild-type but also in CB1/2 receptor-deficient mice. We found that THC (1) inhibited the production of IFNγ by T cells, (2) decreased the production of CCL2 and of IFNγ-induced CCL8 and CXL10 by epidermal keratinocytes and (3) thereby limited the recruitment of myeloid immune cells in vitro in a CB1/2 receptor-independent manner

Topically applied THC can effectively attenuate contact allergic inflammation by decreasing keratinocyte-derived pro-inflammatory mediators that orchestrate myeloid immune cell infiltration

Galea S, Ahern J, Resnick H, Kilpatrick D, Bucuvalas M, Gold J, Vlahov D. 2002. “Psychological sequelae of the September 11 terrorist attacks in New York City” N Engl J Med 346(13): 982-7

Among 1008 adults interviewed, 7.5 percent reported symptoms consistent with a diagnosis of current PTSD related to the attacks, and 9.7 percent reported symptoms consistent with current depression (with “current” defined as occurring within the previous 30 days). Among respondents who lived south of Canal Street (i.e., near the World Trade Center), the prevalence of PTSD was 20.0 percent. Predictors of PTSD in a multivariate model were Hispanic ethnicity, two or more prior stressors, a panic attack during or shortly after the events, residence south of Canal Street, and loss of possessions due to the events. Predictors of depression were Hispanic ethnicity, two or more prior stressors, a panic attack, a low level of social support, the death of a friend or relative during the attacks, and loss of a job due to the attacks.

Galve-Roperh I, Aguado T, Palazuelos J, Guzman M. 2008. “Mechanisms of control of neuron survival by the endocannabinoid system” Curr Pharm Des 14(23): 2279-88

Thus, CB(1) receptor activation has been shown to protect neurons from acute brain injury as well as in neuroinflammatory conditions and neurodegenerative diseases

Cannabinoid neuroprotective activity relies on the inhibition of glutamatergic neurotransmission and on other various mechanisms, and is supported by the observation that the brain overproduces endocannabinoids upon damage. Coupling of neuronal CB(1) receptors to cell survival routes such as the phosphatidylinositol 3-kinase/Akt and extracellular signal-regulated kinase pathways may contribute to cannabinoid neuroprotective action. These pro-survival signals occur, at least in part, by the cross-talk between CB(1) receptors and growth factor tyrosine kinase receptors. Besides promoting neuroprotection, a role for the endocannabinoid system in the control of neurogenesis from neural progenitors has been put forward. In addition, activation of CB(2) cannabinoid receptors on glial cells may also participate in neuroprotection by limiting the extent of neuroinflammation

Galynker I, Cai J, Ongseng F, Finestone H, Dutta E, Serseni D. 1998. “Hypofrontality and negative symptoms in major depressive disorder” J Nucl Med 39(4):608-12

Major depressive disorder (MDD) group had significantly lower rCBF in the frontal cortex and cinglulate gyrus due to differences in dorsolateral prefrontal cortex bilaterally (right F = 7.69, p = 0.01; left F = 8.41, p = 0.01) in the right orbitofrontal cortex (F = 6.79, p = 0.02) and in the cingulate gyrus (F = 5.34, p = 0.03). The MDD group also had lower rCBF in the posterior cortical structures (MANOVA, p = 0.072) due to decreased perfusion in the right parietal cortex (F = 7.54, p = 0.01). negative correlations between the SANS total score and rCBF in both the left dorsolateral prefrontal cortex (Pearson’s correlation coefficient r = .-67, p < 0.05) and the left anterior temporal cortex (r = -0.71, p < 0.01) in MDD patients. Additionally, there were positive correlations between HRSD scores and rCBF in the left anterior temporal (r = 0.71, p < 0.01), left dorsolateral prefrontal (r = 0.70, p < 0.01), right frontal (r = 0.82, p < 0.01) and right posterior temporal (r = 0.74, p < 0.01) cortices. Hypofrontality/decreased perfusion correlates with negative symptoms

Ganon-Elazar E, Akirav I. 2012. “Cannabinoids prevent the development of behavioral and endocrine alterations in a rat model of intense stress” Neuropsychopharmacology 37(2): 456-466

WIN (0.5 mg/kg) administered intraperitoneally 2 or 24 h (but not 48 h) after SPS prevented the trauma-induced alterations in IA conditioning and extinction, ASR potentiation, and HPA axis inhibition

(i) there may be an optimal time window for intervention treatment with cannabinoids after exposure to a highly stressful event, (ii) some of the preventive effects induced by WIN are mediated by an activation of CB1 receptors in the BLA, and (iii) cannabinoids could serve as a pharmacological treatment of stress- and trauma-related disorders.

Ganzel B, Casey B, Glover G, Voss H, Temple E. 2007. “The Aftermath of 9/11: Effect of Intensity and Recency of Trauma on Outcome” Emotion 7(2): 227-238

More than three years after the terrorist attacks, bilateral amygdala activity in response to viewing fearful faces compared to calm ones was higher in people who were within 1.5 miles of the World Trade Center on 9/11, relative to those who were living more than 200 miles away

This activity mediated the relationship between group status and current symptoms of posttraumatic stress disorder. In turn, the effect of group status on both amygdala activation (fearful vs. calm faces) and current symptoms was statistically explained by time since worst trauma in lifetime and intensity of worst trauma, as indicated by reported symptoms at time of the trauma. These data are consistent with a model of heightened amygdala reactivity following high-intensity trauma exposure, with relatively slow recovery.

increased activity in the amygdala is the most consistently observed neural correlate of PTSD as probed with emotional faces, with some evidence that this activation is localized to subregions of the amygdala and is associated with alterations in medial prefrontal activity.
increased amygdala activation predicted increased current symptoms

Garcia-Bueno B, caso J, Leza J. 2008. “Stress as a neuroinflammatory condition in brain: damaging and protective mechanisms”  Neurosci Biobehav Rev 32(6): 1136-51

Several neuropsychiatric diseases are related with stress (posttraumatic stress disorder, major depressive disorder, anxiety disorders, schizophrenia) and stress exposure modifies the onset and evolution of some neurological diseases (neurodegenerative diseases). It is accepted that brain inflammatory responses contribute to cell damage during these illnesses

pro-inflammatory response in the brain and other systems mainly characterized by a complex release of several inflammatory mediators such as cytokines, prostanoids, free radicals and transcription factors

Genetic Risk and Outcome in Psychosis (GROUP) Investigators. 2011. “Evidence that familial liability for psychosis is expressed as differential sensitivity to cannabis an analysis of patient-sibling and sibling-control pairs” Arch Gen Psychiatry 68(2): 138-147

a sibling-based design may aid in teasing apart moderation (genetic control of sensitivity to the psychotomimetic effects of cannabis) from mediation (genetic control of exposure to cannabis)

Both patients and siblings displayed higher rates of cannabis use, suggesting that some of the apparent differential sensitivity to the psychotomimetic effects of cannabis may in fact represent a mechanism of psychotic disorder liability contributing not only to sensitivity for cannabis but also to the tendency to start using cannabis (gene-environment correlation).50 However, the results of the cross-sibling, cross-trait analyses examining whether cannabis use and psychosis liability were associated with each other across siblings did not support a gene-environment correlation. This is in agreement with a previous study examining this issue51 and with genetic epidemiology findings indicating that cannabis use in (early) adolescence—the relevant timing of exposure with regard to psychotic disorder52—is influenced by environmental rather than genetic factors.53 Thus, it is likely that the findings reflect, at least in part, moderation of the psychotomimetic effects of cannabis by familial liability to psychotic disorder.

Similarly, cannabis use assessed by urinalysis increased the sibling correlation by an approximate factor of 10 for positive symptoms and a factor of 2 (not statistically significant) for negative symptoms (Table 5).

An important issue revealed by this study is that while the relative effect sizes of differential sensitivity were high, absolute effect sizes, for example, of cannabis on schizotypy in unaffected siblings, were small

differential sensitivity to cannabis was demonstrated in the form of greater response to recent cannabis use in individuals at higher-than-average risk for psychotic disorder and related disorders

George K, Saltman L, Stein G, Lian J, Zurier R. 2008. “Ajulemic acid, a nonpsychoactive cannabinoid acid, suppresses osteoclastogenesis in mononuclear precursor cells and induces apoptosis in mature osteoclast-like cells” J Cell Physiol 214(3): 714-20

Oral administration of ajulemic acid (AjA), a cannabinoid acid devoid of psychoactivity, prevents joint tissue injury in rats with adjuvant induced arthritis

Reduction by AjA of both monocyte growth and osteoclast formation was associated with apoptosis, assayed by annexin V and propidium iodide staining, and caspase activity. The anti-osteoclastogenic effects of AjA did not require the continuous presence of AjA in the cell cultures. Based on these findings, we propose that AjA or other nonpsychoactive synthetic analogs of Cannabis constituents may be useful therapy for diseases such as RA and osteoporosis in which bone resorption is a central feature.

Gerritsen L, Velzen L, Schmaal L, van der Graaf Y, van der Wee N, van Tol M-J, Penninx B, Geerlings M. 2015. “Childhood maltreatment modifies the relationship of depression with hippocampal volume” Psychological Medicine 45(16): 3517-3526

262 participants from the Netherlands Study of Depression and Anxiety (NESDA) (mean age 37 years, 32% male) and 636 participants from the SMART-Medea study (mean age 61 years, 81% male)

In both cohorts CM was not significantly associated with hippocampal volume. After pooling the data MDD was associated with smaller hippocampal volume (B = −138.90 mm3, p = 0.05) and the interaction between MDD and CM reached significance (p = 0.04); in participants with CM, MDD was related to smaller hippocampal volume (NESDA: B = −316.8 mm3, p = 0.02; SMART: B = −407.6, p = 0.046), but not in participants without CM (p > 0.05)

Gertsch J, Leonti M, Raduner S, Racz I, Chen J-Z, Xie X-Q, Altmann K-H, Karsak M, Zimmer A. 2008 “Beta-caryophyllene is a dietary cannabinoid” Proc Natl Acad Sci U S A 105(26): 9099-9104

Although the CB1 receptor is responsible for the psychomodulatory effects, activation of the CB2receptor is a potential therapeutic strategy for the treatment of inflammation, pain, atherosclerosis, and osteoporosis. Here, we report that the widespread plant volatile (E)-β-caryophyllene [(E)-BCP] selectively binds to the CB2 receptor (K i = 155 ± 4 nM) and that it is a functional CB2 agonist

common constituent of the essential oils of numerous spice and food plants and a major component inCannabis

Upon binding to the CB2receptor, (E)-BCP inhibits adenylate cylcase, leads to intracellular calcium transients and weakly activates the mitogen-activated kinases Erk1/2 and p38 in primary human monocytes. (E)-BCP (500 nM) inhibits lipopolysaccharide (LPS)-induced proinflammatory cytokine expression in peripheral blood and attenuates LPS-stimulated Erk1/2 and JNK1/2 phosphorylation in monocytes. Furthermore, peroral (E)-BCP at 5 mg/kg strongly reduces the carrageenan-induced inflammatory response in wild-type mice but not in mice lacking CB2 receptors, providing evidence that this natural product exerts cannabimimetic effects in vivo. These results identify (E)-BCP as a functional nonpsychoactive CB2 receptor ligand in foodstuff and as a macrocyclic antiinflammatory cannabinoid in Cannabis

Giaconia R, Reinherz H, Hauf A, Paradis A, Wasserman M, Langhammer D. 2000. “Comorbidity of substance use and post-traumatic stress disorders in a community sample of adolescents” Am J Orthopsychiatry 70(2): 253-62

A study of 384 18-year-old adolescents living in the community demonstrated a frequent co-occurrence of substance use disorders and post-traumatic stress disorder. Multiple pathways appeared to lead to this comorbidity, which was associated with widespread psychological impairment that might have serious developmental consequences

Giacoppo S, Galuppo M, Pollastro F, Grassi G, Bramanti P, Mazzon E. 2015. “A new formulation of cannabidiol in cream shows therapeutic effects in a mouse model of experimental autoimmune encephalomyelitis” Daru 23: 48

topical 1 % CBD-cream may exert neuroprotective effects against EAE, diminishing clinical disease score (mean of 5.0 in EAE mice vs 1.5 in EAE + CBD-cream), by recovering of paralysis of hind limbs and by ameliorating histological score typical of disease (lymphocytic infiltration and demyelination) in spinal cord tissues. Also, 1 % CBD-cream is able to counteract the EAE-induced damage reducing release of CD4 and CD8α T cells (spleen tissue localization was quantified about 10,69 % and 35,96 % of positive staining respectively in EAE mice) and expression of the main pro-inflammatory cytokines as well as several other direct or indirect markers of inflammation (p-selectin, IL-10, GFAP, Foxp3, TGF-β, IFN-γ), oxidative injury (Nitrotyrosine, iNOS, PARP) and apoptosis (Cleaved caspase 3)

It is known that when orally given, due to a marked first-pass effect, CBD bioavailability ranges between values of 13 and 19 % [37], hence the oral route is not ideal for the therapeutic delivery of CBD

1 % CBD-cream treatment acts counteracting leukocyte infiltration and microglial activation and improving neuroinflammation status. Hystopathology of spinal cord samples supported this view showing a marked remyelination following 1 % CBD-cream treatment

As expected we found increased levels of proinflammatory mediators including IL-1β, TNF-α, IL-6, IFN-γ and TGF-β in spinal cord from EAE mice. Remarkably, 1 % CBD-cream treatment significantly attenuates the expression of all these inflammatory markers and also regulates immune tolerance by increasing the production of antinflammatory cytokines, like IL-10. This confirms that CBD was able to decrease TNF-α, IL-2 and IFN-γ release from activated splenocytes and macrophages as reported in other studues [4749]

it’s probably that all these mediators are produced by Th17 cells, that play a key role in in autoimmune neuroinflammation and EAE development [50]. Also, it is generally considered that Th17-mediated inflammation is characterized by neutrophil recruitment into the CNS and neurons killing. In this context, mainly IFN-γ seems to have a pathological role in the development of this autoimmune disease [51]. Our results show that the MOG-induced EAE causes significant increases in IFN-γ expression. 1 % CBD-cream administration, significantly diminished the expression of this cytokine

To verify if treatment with CBD can modulate the production of Treg cells, we evaluated the expression of the transcription factor Foxp3, as an indirect marker of Treg. In accordance with a previous study [52], we confirmed a clear engagement of Treg cells during EAE, while treatment with CBD-cream is able to deplete Foxp3 positive cells. This leads to think that the immune system response is somehowe restrained by topic application of 1 % CBD-cream in EAE affected mice in correlation with a lower degree of autoimmune cells activity in these animals. Also, it is possible that 1 % CBD-cream stimulates Th0 cell to develop into a Treg phenotype

we demonstrated that CBD reduces the expression of iNOS and nitrotyrosine in tissues from EAE treated mice, suggesting that this compound, at least in part, may be responsible for the reduction of cytokines production, that in turn counteract the rise of iNOS levels and the downstream cascade of events triggered by the inflammatory process, reducing thus oxidative stress

CBD has the capability to interfere with EAE-induced neuronal apoptotic death, attenuating, or even preventing the activation of cellular molecular mechanisms triggered by severe damage

Gil T, Calev A, Greenberg D, Kugelmass S, Lerer B. 1990. “Cognitive functioning in post-traumatic stress disorder” Journal of Traumatic Stress 3(1):29-45 in dropbox

“intelligence of PTSD patients and psychiatric controls was average and had deteriorated significantly by the time of current testing. not secondary to alcohol, drug abuse, or head injury. The results suggest a cognitive impairment in post-traumatic patients.”

13 point drop from premorbid IQ

Gilbert G, Kim H, Waataja J, Thayer S. 2007. “Delta9-tetrahydrocannabinol protects hippocampal neurons from excitotoxicity” Brain Res 1128(1): 61-9

Excitotoxic neuronal death underlies many neurodegenerative disorders. Because cannabinoid receptor agonists act presynaptically to inhibit glutamate release, we examined the effects of Win 55212-2, a full agonist at CB(1) receptors, and Delta(9)-tetrahydrocannabinol (THC), a partial agonist, on the survival of neurons exposed to an excitotoxic pattern of synaptic activity

Win 55212-2 (100 nM) and THC (100 nM) significantly reduced 0.1 mM [Mg(2+)](o)-induced cell death by 77 +/- 11% and 84 +/- 8%, respectively… the protection afforded by THC was not significantly different from that produced by Win 55212-2, suggesting that attenuation without a complete block of excitatory activity is sufficient for neuroprotection

When cultures were pretreated for 24 h with Win 55212-2 (100 nM) or THC (100 nM), inhibition of 0.1 mM [Mg(2+)](o)-induced toxicity was significantly reduced to 39 +/- 19% and 45 +/- 13%, respectively. Thus, desensitization of CB(1) receptors diminishes the neuroprotective effects of cannabinoids

Gilbertson M, Shenton M, Ciszewski A, Kasai K, Lasko N, Orr S, Pitman R. 2002. “Smaller hippocampal volume predicts pathologic vulnerability to psychological stress” Nature Neuroscience 5:1242-1247

Disorder severity in PTSD patients who were exposed to trauma was negatively correlated with the hippocampal volume of both the patients and the patients’ trauma-unexposed identical co-twin

Gill J, Luckenbaugh D, Charney D, Vythilingam M. 2010. “Sustained elevation of serum interleukin-6 and relative insensitivity to hydrocortisone differentiates posttraumatic stress disorder with and without depression” Biol Psychiatry 68(11): 999-1006

Only subjects with PTSD + MDD exhibited higher, overnight serum IL-6 levels compared with individuals with PTSD – MDD (p < .01) and healthy control subjects (p < .001). Peak overnight IL-6 levels positively correlated with severity of PTSD (r = .56, p < .01) and depressive symptoms (r = .54, p < .01)

Giuffrida A, Parsons L, Kerr T, Fonseca F, Navarro M, Piomelli D. 1999. “Dopamine activation of endogenous cannabinoid signaling in dorsal striatum” Nat Neurosci 2(4): 358-63

Neural activity stimulated the release of anandamide, but not of other endogenous cannabinoids such as 2-arachidonylglycerol. Moreover, anandamide release was increased eightfold over baseline after local administration of the D2-like (D2, D3, D4) dopamine receptor agonist quinpirole, a response that was prevented by the D2-like receptor antagonist raclopride

The endocannabinoid system therefore may act as an inhibitory feedback mechanism countering dopamine-induced facilitation of motor activity

Giuffrida A, Leweke F, Gerth C, Schreiber D, Koethe D, Faulhaber J, Klosterkotter J, Piomelli D. 2004. “Cerebrospinal anandamide levels are elevated in acute schizophrenia and are inversely correlated with psychotic symptoms” Neuropsychopharmacology 29: 2108-2114 in dropbox

CSF anandamide levels are eight-fold higher in antipsychotic-naive first-episode paranoid schizophrenics (n-47) than healthy controls  (n=84), dementia patients (n=13) or affective disorder patients (n=22) … absent in schizophrenics treated with typical antipsychotics (n=37) but not in those treated with atypical antipsychotics (n=34)

in nonmedicated acute schizophrenics, CSF anandamide is negatively correlated with psychotic symptoms. These results suggest that anandamide elevation in acute paranoid schizophrenia may reflect a compensatory adaptation to the disease state

In contrast to the elevation observed with anandamide, CSF levels of OEA were identical in antipsychotic-naı ¨ve schizophrenics and control subjects (controls, 1.011 7 0.136 pmol/ml, n ¼ 81; antipsychotic-naı ¨ve schizophrenics, 1.11670.217 pmol/ml, n ¼ 37,P ¼ 0.624, Kruskal–Wallis test), while CSF levels of PEA were lower in antipsychotic-naı¨ve

Previous studies have suggested that anandamide release in the brain may serve as an inhibitory feedback signal countering dopamine activation of motor behavior (Giuf-frida et al , 1999; Beltramo et al , 2000). We hypothesized therefore that anandamide might also serve as a homeo-static function in acute schizophrenia, in which exaggerated dopaminergic transmission has been documented (Abi-Dargham et al , 2000; Meyer-Lindenberg et al , 2002)

CSF anandamide levels were negatively correlated with PANSS scores (PANSS-T: cumulative value for all symptom complexes; PANSS-P: positive symptoms; PANSS-N: negative symptoms; and PANSS-G: general symptoms) (Figure 2) (PANSS-T: rS ¼0.452, P ¼ 0.001; PANSS-P:r S ¼0.347; P ¼ 0.017; PANSS-N: r S ¼0.409, P ¼ 0.004; PANSS-G: r S ¼0.426, P ¼ 0.003; n ¼ 47)

history of cannabis use in the group of healthy controls and antipsychotic-naı¨ve schizophrenics was comparable to some extent and no overall effect of cannabis use on the primary end point of this study was observed

the elevation in anandamide concentration was unlikely to be caused by a generalized alteration in lipid signaling, which is hypothesized to occur in schizophrenia (Horrobin 1998), because the levels of two closely related analogs of anandamide, OEA and PEA, were not increased in schizophrenics

D2-like receptors initiates anandamide synthesis in limbic and motor areas of the rat brain (Giuffrida et al , 1999; Ferrer et al, 2003)

Phar-macological experiments in the rat have suggested that anandamide release may serve as an inhibitory feedback signal countering dopamine activation of motor behavior (Giuffrida et al , 1999; Beltramo et al , 2000). The negative correlation of CSF anandamide with psychopathological symptoms in acute, antipsychotic-naı¨ve paranoid schizo-phrenics suggests that anandamide might play a similar adaptive role in acute schizophrenia

it is important to point out results from a Phase III clinical trial, which suggests that the CB1 antagonist rimonabant (SR141716A) has no therapeutic effect in schizophrenia and schizoaffec-tive disorders (Arvanitis et al , 2002)

Glass C, Saijo K, Winner B, Marchetto M, Gage F. 2010. “Mechanisms underlying inflammation in neurodegeneration” Cell 140(6): 918-934

Although inducers of inflammation may be generated in a disease-specific manner, there is evidence for a remarkable convergence in the mechanisms responsible for the sensing, transduction, and amplification of inflammatory processes that result in the production of neurotoxic mediators

Sustained inflammation resulting in tissue pathology implies persistence of an inflammatory stimulus or a failure in normal resolution mechanisms

Although some inflammatory stimuli induce beneficial effects (e.g., phagocytosis of debris and apoptotic cells), and inflammation is linked to tissue repair processes, uncontrolled inflammation may result in production of neurotoxic factors that amplify underlying disease states

Roles of TLR2 and TLR4 have recently been established in the pathogenesis of several chronic inflammatory diseases in animal models, and specific TLR4 polymorphisms are associated with several human age-related diseases, including atherosclerosis, type 2 diabetes, and rheumatoid arthritis, raising the question of whether these receptors also contribute to inflammatory programs associated with neurodegenerative disease (Balistreri et al., 2009) (TLR= toll-like receptor)

purinergic receptors are expressed on microglia and astrocytes and are capable of responding to ATP released from cells following cell death, traumatic injury, or ischemia (Di Virgilio et al., 2009). Microglia and astrocytes also express a number of so-called “scavenger receptors” that have been demonstrated to be involved in the uptake of a number of substrates, including oxidized proteins, lipids, and apoptotic cells, and that may also contribute to cell signaling (Husemann et al., 2002).

TLRs couple to signaling adaptor systems that are defined by the MyD88 and TRIF signal adaptor proteins, resulting in activation of downstream kinases including IkB kinases and MAP kinases. These in turn control the activities of multiple, signal-dependent transcription factors that include members of the NF-κB, AP-1, and interferon regulator factor (IRF) families. These factors work in a combinatorial manner to regulate hundreds of genes, depending on the target cell that is activated

To bring about an effective immune response, the initial detection of a microbial pathogen must be amplified to recruit additional cells to sites of infection, induce antimicrobial activities, and initiate the development of adaptive immunity. Important subsets of highly induced genes thus include cytokines (e.g., TNF-α, IL-1β) that are amplifiers of the program of inflammation and chemokines (e.g., MCP-1) that serve to recruit additional immune cells. In addition, genes that encode proteins with antimicrobial activities (e.g., iNOS) are induced, as are genes that influence substrate metabolism, protein synthesis, cell motility, phagocytosis, intracellular killing, and antigen presentation. The generation of reactive oxygen species (ROS), e.g., through the NADPH oxidase system, is an important antimicrobial mechanism but also exemplifies a system that can result in collateral damage to tissue

Microglia appear to be the major initial sensors of danger or stranger signals recognized by TLR4, and they secrete inflammatory mediators such as TNF-α and IL-1β that can act on astrocytes to induce secondary inflammatory responses (Saijo et al., 2009). Microglia are thus likely to play critical roles in establishing and maintaining inflammatory responses in the context of neurodegenerative diseases.

The distinct pathways for production of inducers of inflammation—such as Aβ, α-synuclein, mutant SOD1, and myelin peptide mimetic—and the specific anatomical locations at which these processes occur are likely determinants of the specific pathologicial features of each disease. Remarkably, however, once inducers are generated, there appears to be considerable convergence in the sensor, transducer, and effector mechanisms that lead to amplification of inflammatory responses, neurotoxicity, and neuronal death. Activation of innate immune cells in the CNS, such as microglia and astrocytes, is one of the universal components of neuroinflammation (Figures 14). In particular, TLRs and other pattern recognition receptors expressed on microglia are likely to play significant roles in initiating inflammatory responses that are further amplified by astrocytes. Similarly, signal transduction pathways downstream of these receptors that regulate the activities of the transcription factors NF-κB and AP-1 appear to play general roles in mediating the production of amplifiers and effector molecules, such as cytokines (e.g., TNF-α, IL-1β, and IL-6), ROS, and NO. Several of these factors could be general neurotoxic factors for all of the neurodegenerative diseases discussed above. However, the marked involvement of the adaptive immune system clearly distinguishes MS from AD, PD, and ALS, although T cells do seem to play a neuroprotective role in ALS

Although inhibition of neuroinflammation may not alter the underlying cause of disease, it may reduce the production of factors that contribute to neurotoxicity, thereby resulting in clinical benefit

Glocker E, Kotlarz D, Klein C, Shah N, Grimbacher B. 2011. “IL-10 and IL-10 receptor defects in humans” Ann N Y Acad Sci 1246: 102-7

Inflammatory bowel disease (IBD), which includes Crohn’s disease (CD) and ulcerative colitis (UC), is chronic in nature and is characterized by abdominal pain, diarrhea, bleeding, and malabsorption. It is considered a complex multigenic and multifactorial disorder that results from disturbed interactions between the immune system and commensal bacteria of the gut. Recent work has demonstrated that IBD with an early-onset within the first months of life can be monogenic: mutations in IL-10 or its receptor lead to a loss of IL-10 function and cause severe intractable enterocolitis in infants and small children. Both IL-10 and IL-10 receptor deficiency can be successfully treated by hematopoietic stem cell transplantation

Golub Y, Kaltwasser S, Mauch C, Herrmann L, Schmidt U, Holsboer F, Czisch M, Wotjak C. 2011. “Reduced hippocampus volume in the mouse model of Posttraumatic Stress Disorder” Journal of Psychiatric Research 45(5): 650-659

Exposure to a brief inescapable foot shock led to a volume reduction in both left HPC and right central amygdala two months later. This volume loss was mirrored by a down-regulation of growth-associated protein-43 (GAP43) in the HPC. Enriched housing decreased the intensity of trauma-associated contextual fear, independently of whether it was provided before or after the shock. Beyond that, enriched housing led to an increase in intracranial volume, including the lateral ventricles and the hippocampus, and to an up-regulation of GAP43 as revealed by MEMRI and Western blot analysis, thus partially compensating for trauma-related HPC volume loss and down-regulation of GAP43 expression

Gonzalez R, Swanson JM. 2012. “Long-term effects of adolescent-onset and persistent use of cannabis.” Proc Natl Acad Sci 109(40):15970-15971.

past findings differ in two important ways from those reported by Meier et al.: they suggest that detrimental effects of cannabis may be specific to some neurocognitive functions (rather than general) and that cannabis-associated deficits may recover with abstinence (rather than persist)

nonregular users (50.6% of the total) showed no decline in IQ or neuropsychological performance — to whom do Meier’s findings apply?

de Graaf R, Radovanovic M, van Laar M, Fairman B, Degenhardt L, Aguilar-Gaxiola S, Bruffaerts R, Girolamo G, Fayyad J, Gureje O, Haro J, Huang Y, Kostychenko S, Lepine J-P, Matschinger H, Mora M, Neumark Y, Ormel J, Posada-Villa J, Stein D, Tachimori H, Wells J, Anthony J. 2010. “Early Cannabis Use and Estimated Risk of Later Onset of Depression Spells: Epidemiologic Evidence from the Population-based World Health Organization World Mental Health Survey Initiative”  American Journal of Epidemiology

Association of before 17 cannabis with after 17 depression of 1.5. Controlling for childhood conduct problems reduces association to nonsignificance

The influences of family and parenting factors and childhood trauma were not studied; their confounding effects could be studied in future research

Grant I. 2003. “Non-acute (residual) neurocognitive effects of cannabis use: A meta-analytic study.” Journal of the International Neuropsychological Society 9(5):679-689

“alteration in learning and forgetting domains, lack of effect in other six… our results indicate that there might be decrements in the ability to learn and remember new information in chronic users, whereas other cognitive abilities are unaffected… small magnitude of these effect sizes suggests that they may have an acceptable margin of safety”

The results of our meta-analytic study failed to reveal a substantial, systematic effect of long-term, regular cannabis consumption on the neurocognitive functioning of users who were not acutely intoxicated. For six of the eight neuro-cognitive ability areas that were surveyed, the confidence intervals for the average effect sizes across studies over-lapped zero in each instance, indicating that the effect size could not be distinguished from zero

The two exceptions were in the domains of learning and forgetting. Here when we averaged across the 11 studies that had the most rigor-ous inclusion 0 exclusion criteria and the best designs, the effect size for learning was 2 .21 99%CI ( 2 .39, 2 .022) indicating a very small but discernible negative effect. This effect was slightly larger when all 15 studies were included [2 .24 99%CI (2 .41, 2 .064)]. Similarly, in the domain of forgetting (failure to recall or recognize) the average effect size was 2 .27 99%CI (2 .49, 2 .044), again suggesting a very small but measurable decrement

The “real life” impact of such a small and selective effect is questionable. In addition, it is important to note that most users across studies had histories of heavy long-term cannabis consumption. Therefore, these findings are not likely to generalize to more limited administration of cannabis compounds

another factor that may have contributed to the small ten-dency towards worse performance in the cannabis-using group might be attributable to what Pope et al. have called “residual effects.”

In nearly all instances, heavier can-nabis users were asked to abstain for a period of hours or days before testing. Therefore, many of them could have been at risk for “residual effects” or “abstinence phenom-ena,” which might have contributed to slight decrements in their performance. Given this likelihood, it is even more surprising that our meta-analytic study revealed so few effects

many studies had insufficient information about potential confounding fac-tors. These factors included recency of last cannabis expo-sure, extent of exposure to other drugs of abuse, presence of confounding neuropsychiatric factors (e.g., depression, anxiety, personality disorders, etc.), or other neuromedical risks that can independently affect brain function

It was surprising to find such few and small effects given that most of the potential biases inherent in our analy-ses actually increased the likelihood of finding a cannabis effect

Specifically, our use of a fixed effects model re-sulted in smaller confidence intervals for the effect sizes we computed, thus facilitating the discovery of statistically sig-nificant between-group differences. Moreover, many of the confounds inherent in the studies included in our analyses made it more likely for the cannabis using group to demon-strate poorer performance on neuropsychological tests than controls, irrespective of cannabis consumption. Finally, meta-analytic studies are generally criticized for including only investigations that have been published in peer-reviewed journals, because studies that report statistically significant findings are more likely to be published. This “file-drawer” bias can result in an underrepresentation of studies that did not find statistically significant results, therefore also in-creasing the likelihood of generating statistically significant effect sizes

Inspecting the effect sizes for neurocognitive domains by study, we noted that one study examining users in India (class-IV caste) of bhang and charas appeared to be a distant outlier

Grant - Forgetting Grant - Attention Grant - abstraction executive Grant - verbal language Grant - Reaction time Grant - perceptual motor Grant - Motor Grant - Learning

Grant B, Cho S, Goldstein R, Huang B, Stinson F, Saha T, Smith S, Dawson D, Pulay A, Pickering R, Ruan W. 2008. “Prevalence, correlates, disability and comorbidity of DSM-IV Borderline Personality Disorder: results from the wave 2 national epidemiologic survey on alcohol and related conditions” J Clin Psychiatry 69(4): 533-545

Prevalence of lifetime BPD was 5.9% (99% CI: 5.4–6.4). There were no differences in the rates of BPD among men (5.6%, 99% CI: 5.0–6.2) and women (6.2%, 99% CI: 5.6–6.9)

Prevalence of BPD in the general population is much greater than previously recognized, equal prevalent among men and women, and associated with considerable mental and physical disability, especially among women

Grant J, Lynskey M, Madden P, Nelson E, Few L, Bucholz K, Statham D, Martin N, Heath A, Agrawal A. 2015. “The role of conduct disorder in the relationship between alcohol, nicotine and cannabis use disorders” Psychological Medicine 45: 3505-3515  add to dropbox

Multivariate quantitative genetic analyses were conducted using data from 9577 individuals, including 3982 complete twin pairs and 1613 individuals whose co-twin was not interviewed (aged 24 – 37 years) from two Australian twin samples. Analyses examined the genetic correlation between alcohol dependence, nicotine dependence and cannabis abuse/dependence and the extent to which the correlations were attributable to genetic in fluences shared with conduct disorder

Additive genetic (a2 = 0.48– 0.65) and non-shared environmental factors explained variance in substance use dis-orders… ll substance use disorders were in fluenced by shared genetic factors (rg= 0.38– 0.56), with all genetic overlap between substances attributable to genetic in fluences shared with conduct disorder. Genes in fluencing individual sub-stance use disorders were also signi ficant, explaining 40– 73% of the genetic variance per substance

There is substantial evidence that similar genetic fac-tors in fl uence liability to multiple substance use disor-ders (e.g. Kendleret al. 2003a , 2007; Rhee et al. 2006; Young et al. 2006; Xian et al. 2008; Sartor et al. 2010; Palmeret al.2013)

results indicating the absence of a residual genetic correlation between alcohol and cannabis dependence when accounting for genetic overlap with antisocial personality disorder have also been noted in adult Vietnam era males (Fu et al. 2002). Other studies suggest that this shared liability extends to additional aspects of externalizing behavior, including novelty seeking and non-substance-related behavioral disinhibition (Krueger et al. 2002; Hicks et al.2011)

Alcohol initiation was endorsed by almost 99% of the respondents, with 89% of the sample reporting having consumed at least fi ve drinks in a 24-h period and 26% of those having consumed 55 drinks in a 24-h period reporting a lifetime history of AD. Over 88% of respondents had tried cigarettes, with 33% of initiators having a history of ND. Cannabis initiation was endorsed by 63% of respon-dents, with 28% of initiators having a history of CAD

the genetic correlation across substances was entirely attributable to genes shared with conduct disorder

Kendler et al .( 2007) noted that substance-specifi c genetic variance ranged from 3% for cocaine to 91% for caffeine abuse/dependence symptoms

Our results are consistent with previous reports (Fu et al. 2002; Kendler et al. 2003b ; Button et al. 2006; Hicks et al. 2011) showing that alcohol and drug de-pendence tend to share an appreciable proportion of their genetic liability with conduct and antisocial per-sonality disorder

a signifi cant proportion of the genetic variance in ND (40%), AD (73%), and CAD (47%) was substance-speci fi c

Greer G, Grob C, Halberstadt A. 2014 “PTSD symptom reports of patients evaluated for the New Mexico medical cannabis program” Journal of Psychoactive Drugs 46(1): 73-77

Greer - Cannabis reduction in PTSD symptoms

Greater than 75% reduction in CAPS symptom scores were reported when patients were using cannabis compared to when they were not

In one unpublished, open-label pilot study, smoked medical cannabis containing 23% tetrahydrocannabinol (THC) and less than 1% cannabidiol was administered to 29 male Israeli combat veterans with PTSD, with instructions to smoke it daily (Mashiah 2012). The baseline score on the Clinician Administered Posttraumatic Scale for DSM-IV (CAPS) was 98 for the entire group, and post-treatment scores in three subgroups after four to 11 months of treatment ranged from 54 to 60

Criterion B (core symptom cluster of re-experiencing), which decreased from 29.5 ± 6.4 to 7.3 ± 5.9 (F(1,79) = 734.98, p < 0.0001); Criterion C (numbing and avoidance), which decreased from 38.2 ± 8.4 to 8.7 ± 8.0 (F(1,79) = 783.73, p < 0.0001); and Criterion D (hyperarousal), which decreased from 31.0 ± 6.2 to 6.6 ± 6.0 (F(1,79) = 910.79,p < 0.0001)

Some degree of intentional or unintentional exaggeration of symptom differences on the part of the patients is likely, and some unintentional bias on the part of the psychiatrist conducting the evaluations is possible

variability in scores with cannabis use was relatively high, with the standard deviation being almost equal to the mean total scores and the scores of the three symptom clusters. If patients had consistently reported frequent and severe symptoms without cannabis and almost no symptoms with cannabis in order to make sure they qualified for the Program, one would expect less variability in the cannabis scores. Finally, the relatively consistent reporting of low or “0” scores on Criterion C3 without cannabis (see Table 1) is another indication that most patients were not malingering by exaggerating their no-cannabis scores for every single symptom in order to qualify for the program

Because only patients who reported benefit from cannabis in reducing their PTSD were studied, no conclusions can be drawn as to what proportion or type ofPTSD patients would benefit from treatment with cannabis or its constituents

Grella C, Joshi V. 2003. “Treatment processes and outcomes among adolescents with a history of abuse who are in drug treatment” Child Maltreat 8(1): 7-18

N = 803, physical and/or sexual abuse was reported by 59% of the girls and 39% of the boys; physically abused adolescents less likely to stay abstinent after treatment

Griffith-Lendering M, Wigman J, Prince van Leeuwen A, Huijbregts S, Huizink A, Ormel J, Verhulst F, van Os J, Swaab H, Vollebergh W. 2013. “Cannabis use and vulnerability for psychosis in earl adolescence–a TRAILS study” Addiction 108(4): 733-40 add to dropbox

A large prospective population study of Dutch adolescents [the TRacking Adolescents’ Individual Lives Survey (TRAILS) study].Participants A total of 2120 adolescents with assessments at (mean) age 13.6, age 16.3 and age 19.1

ignificant associations (r = 0.12–0.23) were observed between psychosis vulnerability and cannabis use at all assessments. Also, cannabis use at age 16 predicted psychosis vulnerability at age 19 (Z = 2.6, P < 0.05). Further-more, psychosis vulnerability at ages 13 (Z = 2.0, P < 0.05) and 16 (Z = 3.0, P < 0.05) predicted cannabis use at, respectively, ages 16 and 19

there is increasing evidence for stability or continuity (from adoles-cence onwards) of psychosis symptoms [23–25]

confounding variables such as socio-economic status (SES), parental psychopathology and use of other substances

exclusion criteria were: (i) adolescent’s inability of participating because of intellectual disability or a serious physical illness or handicap; and (ii) Dutch-speaking parent or parent surrogate not available, and not feasible to administer a part of the measurements in the parent’s own language. Of all subjects who were approached (n = 3145), 6.7% were excluded

Using categories no use (i), one to two times (ii), three to six times (iii) and seven times or more (v) resulted in the best Tukey solutions for T2, T3 and T4

Vulnerability for psychosis at T2 predicted cannabis use at T3… cannabis use measured at T2 did not predict psychosis vulnerability measured at T3

vulnerability for psychosis at T3 predicted cannabis use at T4… cannabis use measured at T3 significantly predicted psy-chosis vulnerability measured at T4

With respect to self-medication, it has been hypothesized specifically that individuals with psychosis symptoms use cannabis to improve their mood or to control one’s feelings, boredom, social motives, improving sleep, anxiety and agitation, although some studies indicate that individuals with psy-chosis symptoms use cannabis for similar reasons as the general population as well, i.e. ‘to get high’, relax and have fun [10,11,46]

a cascading model would fit the temporal associations between cannabis use and psy-chosis vulnerability best, particularly because associations between cannabis use and psychosis vulnerability became stronger at later assessments

it may be argued that the choice of potential confounders could have been more refined. For example, the genetic variation associated with psychosis vulnerability and substance use could manifest itself in (impairments in) certain (dopamine or serotonin-dependent) cognitive abilities that could have been assessed as well

Gruber A, Pope H. 2002. “Marijuana use among adolescents” Pediatr Clin North Am 49(2): 389-413

More than half of US adolescents will experiment with marijuana. Of those who try marijuana more than once, approximately one third will subsequently use marijuana regularly, although most will have stopped by their late 20s.

Gruber S, Yurgelun-Todd D. 2005. “Neuroimaging of marijuana smokers during inhibitory processing: a pilot investigation” Brain Res Cogn Brain Res 23(1):107-18

chronic marijuana abusers in Stroop demonstrated significantly lower anterior cingulate activity in focal areas of the anterior cingulate cortex and higher midcingulate activity relative to controls, although both groups were able to perform the task within normal limits. Normal controls also demonstrated increased activity within the right dorsolateral prefrontal cortex (DLPFC) during the interference condition, while marijuana smokers demonstrated a more diffuse, bilateral pattern of DLPFC activation

DTI measures in frontal regions, which include the genu and splenium of the corpus callosum and bilateral anterior cingulate white matter regions, showed no between group differences in fractional anisotropy (FA), a measure of directional coherence within white matter fiber tracts, but a notable increase in trace, a measure of overall isotropic diffusivity in marijuana smokers compared to controls

Gruber S, Rogowska J, Yurgelun-Todd D. 2009. “Altered affective response in marijuana smokers: an FMRI study” Drug Alcohol Depend 105: 139-153

Despite no between-group differences on clinical or demographic measures, smokers demonstrated a relative decrease in both anterior cingulate and amygdalar activity during masked affective stimuli compared to controls, who showed relative increases in activation within these regions during the viewing of masked faces

none of the chronic, heavy marijuana subjects were acutely intoxicated or “high” at the time of the scan and had been abstinent for a minimum of 12–16 hours, and are therefore not likely to reflect acute effects of the drug

Gruber S, Silveri M, Dahlgren M, Yurgelun-Todd. 2011. “Why so impulsive? White matter alterations are associated with impulsivity in chronic marijuana users” Exp Clin Psychopharmacol 19: 231-242

significant reductions in left frontal FA in MJ smokers associated with impulsivity

Fifteen adult chronic, heavy MJ smokers who had smoked at least 3,000 joints in their lifetime, average age of onset of 14.9 years, smoked an average of 25.5 joints per week, used at least four of last 7 days and tested positive for cannabinoids and 15 non-MJ smoking control subjects who were age, sex, and education matched; twice as much alcohol use in MJ group (9.6 days in last month compared to 4)

Axis I pathology excluded by Structured Clinical Interview for DSM-IV

Gruber S, Sagar K, Gahlgren M, Racine M, Lukas S. 2012. “Age of onset of marijuana use and executive function” Psychology of Addictive Behaviors 26(3): 496-506

Thirty-four chronic, heavy MJ smokers separated into early and late onset groups, and 28 non-MJ smoking controls completed a battery of neurocognitive measures

As hypothesized, MJ smokers performed more poorly than controls on several measures of executive function. Age of onset analyses revealed that these between-group differences were largely attributed to the early onset group, who were also shown to smoke twice as often and nearly 3 times as much MJ per week relative to the late onset smokers

Exposure to MJ during a period of neurodevelopmental vulnerability, such as adolescence, may result in altered brain development and enduring neuropsychological changes

Gruber S, Dahlgren M, Sagar K, Gonenc A, Lukas S. 2014. “Worth the wait: effects of age of onset of marijuana use on white matter and impulsivity” Psychopharmacology (Berl) 321(8): 1455-1465

Twenty-five MJ smokers and 18 healthy controls… MJ smokers had to have reported smoking a minimum of 2,500 times, used MJ at least 5 out of the last 7 days, tested positive for urinary cannabinoids, and met DSM-IV criteria for MJ abuse or dependence

divided into early onset (regular use prior to age 16) and late onset (age 16 or later) groups

MJ smokers exhibited significantly reduced fractional anisotropy (FA) relative to controls, as well as higher levels of impulsivity. Earlier MJ onset was also associated with lower levels of FA. Interestingly, within the early onset group, higher impulsivity scores were correlated with lower FA, a relationship that was not observed in the late onset smokers

no Axis I pathology was present other than MJ use in the smoking group

Comparisons of early and late onset smokers revealed no significant differences in patterns of MJ use between the two groups. However, it is of note that early onset smokers smoked slightly more often (smokes/week; 18.76 vs. 15.51) and more than twice as much MJ per week (grams/week; 14.65 vs. 6.66) as late onset smokers [MV: how the fuck is 14.65 grams per week not significantly different than 6.66 grams per week?]

when the MJ-smoking group was separated into those with early vs. late onset, it appeared that these relationships were driven almost exclusively by the early onset smokers, as higher impulsivity scores on all BIS subscales were significantly associated with lower FA in both the left and right genu of early onset smokers

decreased white matter integrity is associated with higher levels of impulsivity, specifically among individuals who initiated MJ use prior to age 16

higher concentrations of cannabinoid receptors in neural fiber tracts during adolescence may therefore represent a period of specific vulnerability to the effects of MJ use on white matter microstructure

Study findings may therefore be specific to individuals who do not endorse the more negative effects of marijuana use (i.e., psychological issues, inability to stop or cut down on use, withdrawal effects) and to those who do not meet for dependence, despite frequent, heavy use

it remains unclear whether the reductions in FA in MJ smokers noted in the present study are the result of demyelination or damage to white matter, delayed or altered brain developmental patterns in MJ smokers, and if they precede or are the result of MJ use

Gunduz-Cinar O, MacPherson K, Cinar R, Gamble-George J, Sugden K, Williams B, Godlewski G, Ramikie T, Gorka A, Alapafuja S, Nikas S, Makriyannis A, Poulton R, Patel S, Hariri A, Caspi A, Moffitt T, Kunos G, Holmes A. 2013. “Convergent translational evidence of a role for anandamide in amygdala-mediated fear extinction, threat processing and stress-reactivity.” Molecular Psychiatry 18(7): 813-23.

FAAH inhibition reduces fear in rats given extinction training; effect prevented by injection of CB1 antagonist. Found genetic variances in FAAH influence stress-reactivity

Gupta M. 2013. “Review of somatic symptoms in post-traumatic stress disorder” Int Rev Psychiatry 25(1): 86-99

Post-traumatic stress disorder (PTSD) is associated with both (1) ‘ill-defined’ or ‘medically unexplained’ somatic syndromes, e.g. unexplained dizziness, tinnitus and blurry vision, and syndromes that can be classified as somatoform disorders (DSM-IV-TR); and (2) a range of medical conditions, with a preponderance of cardiovascular, respiratory, musculoskeletal, neurological, and gastrointestinal disorders, diabetes, chronic pain, sleep disorders and other immune-mediated disorders

cardiovascular disease, especially hypertension, and immune-mediated disorders

PTSD is associated with limbic instability and alterations in both the hypothalamic- pituitary-adrenal and sympatho-adrenal medullary axes, which affect neuroendocrine and immune functions, have central nervous system effects resulting in pseudo-neurological symptoms and disorders of sleep-wake regulation, and result in autonomic nervous system dysregulation. Hypervigilance, a central feature of PTSD, can lead to ‘local sleep’ or regional arousal states, when the patient is partially asleep and partially awake, and manifests as complex motor and/or verbal behaviours in a partially conscious state

Gur R. 1999. “Is schizophrenia a lateralized brain disorder?” Schizophrenia Bulletin 25: 7-10

laterality hypotheses of schizophrenia were proposed more than two decades ago (Gruzelier and Venables 1974; Flor-Henry 1976; Gur 1977, 1978) and have since been tested using increasingly powerful neurobehavioral, neuroanatomic, and neurophysiologic methods

the question of whether schizophrenia is characterized by dysfunction of one or the other hemisphere is simplistic and needs to be reformulated

Patients with schizophrenia from a large prospective sample show meager indication of lateralized disturbances in sensory processing and motor speed. They do, however, have more language than spatial deficits, implicating relative left hemispheric dysfunction in regions needed for complex cognitive behavior. Laterality effects in performance were mediated by sex differences, and the results underscore the importance of examining sex differences in laterality research

One may vacillate, after reading this diverse set of contributions, between being overwhelmed by the amount of data that have converged on the issue of laterality in schizophrenia and feeling some exasperation at the paucity of solid answers for questions that seem quite rudimentary

Haj-Dahmane S, Shen R. 2014. “Chronic stress impairs α1-adrenoceptor-induced endocannabinoid-dependent synaptic plasticity in the dorsal raphe nucleus” Journal of Neuroscience 34(44): 14560-14570

Alpha 1-adrenergic receptors (α1-ARs) control the activity of dorsal raphe nucleus (DRn) serotonin (5-HT) neurons and play crucial role in the regulation of arousal and stress homoeostasis

in the control condition, activation of α1-ARs induced an inward current and long-term depression (LTD) of glutamate synapses of DRn 5-HT neurons. The α1-AR LTD was initiated by postsynaptic α1-ARs but mediated by a decrease in glutamate release. The presynaptic expression of the α1-AR LTD was signaled by retrograde endocannabinoids (eCBs)

chronic exposure to restraint stress profoundly reduced the magnitude of α1-AR LTD but had no effect on the amplitude of α1-AR-induced inward current. Chronic restraint stress also reduced the CB1 receptor-mediated inhibition of EPSC and the eCB-mediated depolarization-induced suppression of excitation. Collectively, these results indicate that chronic restraint stress impairs the α1-AR LTD by reducing the function of presynaptic CB1 receptors and reveal a novel mechanism by which noradrenaline controls synaptic strength and plasticity in the DRn. They also provide evidence that chronic stress impairs eCB signaling in the DRn, which may contribute, at least in part, to the dysregulation of the stress homeostasis

Hamilton I, Lloyd C, Hewitt C, Godfrey C. 2013. “Effect of reclassification of cannabis on hospital admissions for cannabis psychosis: a time series analysis” International Journal of Drug Policy 25(1): 151-156

There was a significantly increasing trend in cannabis psychosis admissions from 1999 to 2004. However, following the reclassification of cannabis from B to C in 2004, there was a significant change in the trend such that cannabis psychosis admissions declined to 2009. Following the second reclassification of cannabis back to class B in 2009, there was a significant change to increasing admissions.

Hampson AJ, Grimaldi M, …, Wink D. 1998. “Cannabidiol and delta-9-tetrahydrocannabinol are neuroprotective antioxidants.” Proc Natl Acad Sci. 95(14):8268-8273

Han J, Liu Z, Ren W, Zhang X. 2011. “Counteractive effects of cannabinoid and nicotine-addictive behavior” Neuroreport 22(4): 181-4

Our recent results suggest that cannabinoid exposure induces conditioned place preference (CPP) through facilitated induction of synaptic long-term depression at dopamine circuitry of the midbrain ventral tegmental area (VTA). Here, we show that chronic nicotine exposure also induces CPP, but facilitates the induction of synaptic long-term potentiation in the VTA. Coadministration of cannabinoid and nicotine leads to a blockade of facilitated long-term depression and long-term potentiation induction in these neurons and elimination of CPP. These findings point to counteractive effects of cannabinoid and nicotine-addictive behavior through opposite changes in synaptic plasticity of dopamine circuitry of the VTA

Haughey H, Marshall E, Schacht J, Louis A, Hutchison K. 2008. “Marijuana withdrawal and craving: influence of the cannabinoid receptor 1 (CNR1) and fatty acid amide hydrolase (FAAH) genes” Addiction 103(10): 1678-1686

Glutamate toxicity reduced by cannabidiol and THC; also were shown to prevent hydroperoxide-induced oxidative damage as well as or better than other antioxidants in a chemical (Fenton reaction) system and neuronal cultures. Cannabidiol was more protective against glutamate neurotoxicity than either ascorbate or α-tocopherol, indicating it to be a potent antioxidant. may be useful for treatment of oxidative neurological disorders such as cerebral ischemia. also protective against calcium-signalling mediated forms of neurotoxicity

Heifets B, Castillo P. 2009. “Endocannabinoid signaling and long-term synaptic plasticity” Annual Review of Physiology 71: 283-306 – in dropbox

we review the major molecular and cellular mechanisms underlying eCB-LTD, as well as the potential physiological relevance of this widespread form of synaptic plasticity

Activation of the CB1R, and subsequent long-term reduction of transmitter release at the same synapse, defines eCB-LTD

CB1Rs can engage a wide range of effector molecules, in-cluding (but not limited to) voltage-dependent Ca2+ channels (VDCCs), K+ channels, pro-tein kinase A (PKA), and mitogen-activated protein kinase (MAPK) (recently reviewed in Reference 14)

eCB-LTD induction typically begins with a transient increase in activity at glutamatergic afferents and a concomitant release of eCBs from a target (postsynaptic) neuron (Figure 1 ). eCBs then travel backward (retrogradely) across the synapse, activating CB1Rs on the presy-naptic terminals of either the original afferent (homosynaptic eCB-LTD) or nearby afferents (heterosynaptic eCB-LTD

In addition to mGluR-I, metabotropic dopamine (type 2; D2), muscarinic acetylcholine (type 1/3; M 1 /M3), serotonin (type 2; 5-HT2), orexin, and chole-cystokinin receptors are all effective stimuli for eCB release… D2 stimulate the formation of AEA rather than 2-AG… are required for corticostriatal eCB-LTD… a role for AEA in this process

D2Rs may directly stimulate eCB release from medium spiny neurons, or, as recently suggested, D2Rs may exert an indirect effect on eCB release via cholinergic interneurons in dorsal striatum. However, a recent study has shown that the presence or absence of D2Rs on MSNs determines whether eCB-LTD can be induced at an afferent glutamatergic synapse, owing to a D2R-mediated facilitation of eCB release

the requirement for coincident activation of CB1Rs and presynaptic activity provides an additional mechanism to ensure synapse specificity such that only active fibers undergo eCB-LTD

Sj ¨ostrom et al. (26) postulated that coincident activa-tion of presynaptic NMDA and CB1 receptors is required for the induction of eCB-t-LTD.

CB1R agonists alone do not trigger long-term plasticity without co-incident presynaptic activity

heterosynap-tic eCB-LTD at excitatory synapses in the im-mature hippocampus is likely due to a CB1R-dependent reduction of presynaptic excitability through activation of K+ channels at presynaptic fibers

Interestingly, brain-derived neurotrophic factor (BDNF), which may be re-leased from strongly activated presynaptic sites, appears to prevent the induction of homosy-naptic eCB-LTD. presumably, an interaction between the CB1R and TrkB (the high-affinity receptor for BDNF) at active presynaptic terminals leads to the blockade of CB1R signal-ing

LTD is a leading model to explain the synap-tic weakening that occurs at cortical synapses after a period of sensory deprivation

Long-term changes in synaptic strength are also believed to underlie associative memory forma-tion in hippocampus and amygdala… eCBs and CB1Rs were specifically required for extinguishing an established fear or spatial memory but were not needed to acquire these types of memories

Heinrichs R, Zakzanis K. 1998. “Neurocognitive deficit in schizophrenia: a quantitative review of the evidence” Neuropsychology 12(3): 426-45

Moderate to large raw effect sizes (d > .60) were obtained for all 22 neurocognitive test variables, and none of the associated confidence intervals included zero. The results indicate that schizophrenia is characterized by a broadly based cognitive impairment, with varying degrees of deficit in all ability domains measured by standard clinical tests

de Heredia F, Gomez-Martinez S, Marcos A. 2012. “Obesity, inflammation and the immune system” Proc Nutr Soc 71(2): 332-8

Obesity shares with most chronic diseases the presence of an inflammatory component, which accounts for the development of metabolic disease and other associated health alterations… Obesity, like other states of malnutrition, is known to impair the immune function, altering leucocyte counts as well as cell-mediated immune responses… an altered immune function contributes to the pathogenesis of obesity… there is a positive feedback loop between local inflammation in adipose tissue and altered immune response in obesity, both contributing to the development of related metabolic complications

Ho B-C, Andreasen N, Ziebell S, Pierson R, Magnotta V. 2011. “Long-term antipsychotic treatment and brain volumes” Arch Gen Psychiatry 68(2): 128-137

During longitudinal follow-up, antipsychotic treatment reflected national prescribing practices in 1991 through 2009. Longer follow-up correlated with smaller brain tissue volumes and larger cerebrospinal fluid volumes… More antipsychotic treatment was associated with smaller gray matter volumes. Progressive decrement in white matter volume was most evident among patients who received more antipsychotic treatment. Illness severity had relatively modest correlations with tissue volume reduction, and alcohol/illicit drug misuse had no significant associations when effects of the other variables were adjusted.

Hoffman A, Oz M, Yang R, Lichtman A, Lupica C. 2007. “Opposing actions of chronic Δ9-tetrahydrocannabinol and cannabinoid antagonists on hippocampal long-term potentiation” Learn Mem 14(1-2): 63-74

Although cannabinoids acutely reduce glutamate release and block hippocampal long-term potentiation (LTP), a potential substrate for learning and memory, the consequences of prolonged exposure to Δ9-THC for hippocampal function are poorly understood


Δ9-THC also blocked HFS-LTP after 3 d, but not 1 d of treatment. The complete blockade of LTP persisted for 3 d after the last Δ9-THC injection, and full reversal of the LTP deficit was not observed up to 14 d following Δ9-THC withdrawal. The cannabinoid antagonist AM251 (2 mg/kg), administered before each Δ9-THC injection prevented the blockade of LTP, and 7-d treatment with AM251 alone significantly increased the level of LTP. Chronic Δ9-THC also produced tolerance to the inhibition of synaptic GABA, but not glutamate release by the agonist WIN55,212-2

cannabinoid-induced impairment of hippocampal LTP was reversed via the facilitation of NMDA receptor function by either the depolarization of CA1 pyramidal neurons or by removing Mg2+ from the extracellular space (Misner and Sullivan 1999). This suggested that the blockade of LTP by cannabinoid agonists resulted from a decrease in the probability of glutamate release via presynaptic receptors (Misner and Sullivan 1999)

the relationship between presynaptic axon fiber volley and fEPSP amplitudes in slices obtained from 7-d vehicle- and 7-d Δ9-THC-treated rats was examined. There was no effect of chronic Δ9-THC on this relationship (Fig. 2A), suggesting that synaptic strength was not altered by the chronic treatment.

the consequences of chronic Δ9-THC exposure were not mediated by ongoing pharmacological actions of this cannabinoid agonist following its accumulation in tissue, but rather through more enduring neurobiological changes in hippocampal function brought about through repeated exposure to the drug

cannabinoid receptor antagonists do not acutely alter HFS-LTP, and that endogenous cannabinoids released during HFS (Stella et al. 1997) are not likely involved in the initiation or maintenance of HFS-LTP

Chronic exposure to Δ9-THC does not alter NMDA receptor function, but reduces paired pulse facilitation of AMPA-mediated EPSCs

in contrast to GABAergic synapses (see below), the inhibitory effect of WIN55,212-2 on glutamatergic fEPSPs was not altered by chronic Δ9-THC

Harder V, Morral A, Arkes J. 2006. “Marijuana use and depression among adults: Testing for causal associations” Addiction 101(10): 1463-72

marijuana users 1.4 times as likely to be depressed. Dropped to 1.1 after adjustment for risk factors

Hariri A, Gorka A, Hyde L, Kimak M, Halder I, Ducci F, Ferrell R, Goldman D, Manuck S. 2009. “Divergent Effects of Genetic Variation in Endocannabinoid Signaling on Human Threat- and Reward-Related Brain Function” Biol Psychiatry 66(1): 9-16

Carriers of FAAH 385A, associated with reduced enzyme and, possibly, increased eCB signaling, had decreased threat-related amygdala reactivity but increased reward-related ventral striatal reactivity in comparison to C385 homozygotes. Similar divergent effects of FAAH C385A genotype were manifest at the level of brain-behavior relationships. 385A carriers showed decreased correlation between amygdala reactivity and trait anxiety but increased correlation between ventral striatal reactivity and delay discounting, an index of impulsivity.

Harkness K, Bruce A, Lumley M. 2006. “The role of childhood abuse and neglect in the sensitization to stressful life events in adolescent depression” J Abnorm Psychol 115(4): 730-41

Consistent with hypotheses, adolescents with a history of childhood abuse and/or neglect reported a lower level of threat of stressful life events prior to episode onset than that reported by those without… his effect was robust when controlling for level of chronic difficulties, which was higher in those with childhood abuse and/or neglect. The authors suggest that childhood abuse and/or neglect may be an important risk factor that sensitizes individuals to the effects of acute independent life events

Harrison G, Gunnell D, Glazebrook C, Pake K, Kwiecinski R. 2001. “Association between schizophrenia and social inequality at birth: case-control study” British Journal of Psychiatry 179: 346-350

Those both born in “deprived area” and to social class IV-V father had odds ratio of 8.1 for developing schizophrenia

Harrow M, Jobe T. 2013. “Does long-term treatment of schizophrenia with antipsychotic medications facilitate recovery?” Schizophr Bull 39(5): 962-965

Antipsychotic medications are viewed as cornerstones for both the short-term and long-term treatment of schizophrenia

antipsychotic medications are viewed as the cornerstone of treatment, in both the short-term and the long-term treatments of patients with schizophrenia

Prolonged use of antipsychotic medications is viewed as a key factor in treatment for schizophrenia, but there is very little systematic evidence for the long-term benefits of antipsychotics. There is even some longitudinal data suggesting the opposite

within the first 6–10 months after discontinuation, 25%–55% of schizophrenia patients discontinued from antipsychotics relapse

patients with schizophrenia not on antipsychotics for a prolonged period do not show this tendency to relapse when they remain unmedicated

when vulnerable patients are treated with antipsychotics for a prolonged period, this increases their chances of relapsing if they subsequently discontinue

The discontinuation effect includes the potential of medication-generated buildup, prior to discontinuation, of supersensitive dopamine receptors, or the buildup of excess dopamine receptors, or supersensitive psychosis, as indicated by multiple studies by Seeman14 and others13 of dopamine-blocking agents using animal models

“breakthrough supersensitivity during ongoing antipsychotic treatment undermines treatment efficacy.”

“… nothing is known about the effects of antipsychotic drugs compared to placebo after three years.”

a sample of schizophrenia patients who were treated continuously with antipsychotics over 15-year and 20-year periods have shown considerable psychopathology and few sustained periods of recovery

the sample of schizophrenia patients who were untreated for many years showed significantly better outcomes than did those on antipsychotics

Other longitudinal studies have found similar results. This includes important longitudinal studies such as the Vermont studies of C. Harding20,21 and the Chestnut Lodge Study.22 In Canada, the Alberta Hospital Studies of Bland (1978) found similar results. Overseas the longitudinal studies of M. Bleuler (1978) led to his commenting about relapses for many schizophrenia patients treated with antipsychotics. The important World Health Organization (WHO) Study and the Determinants of Outcome of Severe Mental Disorders (DOSMED) Study by Edgerton and Cohen found better outcomes in many developing countries where only a small percentage of schizophrenia patients were treated with antipsychotics

Other evidence, also from longitudinal studies, suggest that long-term outcome for schizophrenia in the modern era is not much better than it was 60–80 years ago.23,24 In regard to relapses, our own evidence indicates that many schizophrenia patients who have not been treated with antipsychotic medications for prolonged periods show a low rate of relapse over the next 5-year period

Harley M, Kelleher I, Clarke M, Lynch F, Arseneault L, Connor D, Fitzpatrick C, Cannon M. 2010. “Cannabis use and childhood trauma interact additively to increase the risk of psychotic symptoms in adolescence” Psychological Medicine 40: 1627-1634 in dropbox

both cannabis use and childhood trauma were significantly associated with risk of experiencing psychotic symptoms. However, the presence of both childhood trauma and early cannabis use significantly increased the risk for psychotic symptoms beyond the risk posed by either risk factor alone, indicating that there was a greater than additive interaction between childhood trauma and cannabis use

childhood trauma was reported in 11.3% of participants interviewed. Those adolescents who had experienced childhood trauma were almost five times more likely to use cannabis… also five times more likely to develop psychotic symptoms

Hart C, van Gorp W, Haney M, Foltin R, Fischman M. 2001. “Effects of acute smoked marijuana on complex cognitive performance” Neuropsychopharmacology 25: 757-765

Although the ability to perform complex cognitive operations is assumed to be impaired following acute marijuana smoking, complex cognitive performance after acute marijuana use has not been adequately assessed under experimental conditions… Although marijuana significantly increased the number of premature responses and the time participants required to complete several tasks, it had no effect on accuracy on measures of cognitive flexibility, mental calculation, and reasoning… acute marijuana smoking produced minimal effects on complex cognitive task performance in experienced marijuana users

Marijuana increased premature responding and the amount of time needed to complete several MicroCog tasks, including the immediate recall, tic-tac, clocks, and mental calculation tasks. Nevertheless, accuracy on these and other cognitive tasks were unaltered after marijuana administration

psychomotor performance was only subtly affected by smoked marijuana: following high Δ9-THC concentration cigarettes, participants exhibited a decrement in performance only during the immediate recall task, while performance on a tracking task was markedly improved

The most salient cognitive effect from the present investigation was the finding that premature responses were increased after volunteers smoked the high Δ9-THC concentration cigarette

more complex cognitive performance is only minimally affected following acute marijuana smoking.

heavy marijuana smokers show less cognitive impairment following acute marijuana administration (Meyer et al. 1971; Rickles et al. 1973;Cohen and Rickles 1974)

marijuana use history plays less of a role in subjective ratings and heart rate responses than it does on cognitive performance after smoking a single marijuana cigarette

Hart C, Ilan A, Gevins A, Gunderson E, Role K, Colley J, Foltin R. 2010. “Neurophysiological and cognitive effects of smoked marijuana in frequent users” Pharmacol Biochem Behav 96(3): 333-41

electroencephalographic (EEG) signals were recorded as daily marijuana users performed additional tests of immediate working memory and delayed episodic memory, before and after smoking marijuana

Overall performance accuracy was not significantly altered by marijuana, although the drug increased response times during task performance and induced a response bias towards labeling “new” words as having been previously seen in the verbal episodic memory task. Marijuana reduced slow wave evoked potential amplitude in the episodic memory task and decreased P300 amplitude and EEG power in the alpha band in the spatial working memory task

van der Hart O, Nijenhuis E, Steele K. 2005. “Dissociation: an insufficiently recognized major feature of complex posttraumatic stress disorder” J Trauma Stress 18(5): 413-23

The role of dissociation in (complex) posttraumatic stress disorder (PTSD) has been insufficiently recognized for at least two reasons: the view that dissociation is a peripheral, not a central feature of PTSD, and existing confusion regarding the nature of dissociation… traumatization essentially involves some degree of division or dissociation of psychobiological systems that constitute personality. One or more dissociative parts of the personality avoid traumatic memories and perform functions in daily life, while one or more other parts remain fixated in traumatic experiences and defensive actions. Dissociative parts manifest in negative and positive dissociative symptoms that should be distinguished from alterations of consciousness. Complex PTSD involves a more complex structural dissociation than simple PTSD

Hartung B, Schwender H, Roth E, Hellen F, Mindiashvili N, Rickert A, Ritz-Timme S, Grieser A, Monticelli F, Daldrup T. 2015. “The effect of cannabis on regular cannabis consumers’ ability to ride a bicycle” Int J Legal Med DOI 10.1007/s00414-015-1307-y add to dropbox

repetitive practical cycling tests and medical examinations were carried out before and after inhalative consumption of cannabis. A maximum of three joints with body weight -adapted THC con-ent (300 μ g THC per kg body weight) could be consumed by each test subject. Fourteen regular cannabis-consuming test subjects were studied (12 males, 2 fe-males). In summary, only a few driving faults were observed even under the influence of very high THC concentrations. A defined THC concentration that leads to an inability to ride a bicycle cannot be presented

Cannabis-related e ffects o n simulated driving p er for-mances did regularly not show relevant impairments of motor behavior, and it is assumed that documented deficits are relat-ed to attention or perception [ 5, 6]

THC consumpti on in doses up to 300 μ g per kilogram body weight is considered to cause relevant cognitive and psychomotor impairments comparable to 0.5 g/l BAC [10]. F u r t he rm o r e, T H C c on ce nt ra ti on s o f 7–10 ng/ml THC in se-rum are thought to evoke comparable impairments to 0.5 g/l BAC. THC serum concentrations below 10 ng/ml should not increase the risk of a traffic accident [ 11 ].

regularly consumed amounts of cannabis varied between approximately 1g per week and 1g per day

exclusion criteria were pregnancy, acute illnesses, history of s ub-st an c e ab us e , int ak e o f ps yc ho a ct i ve med i c a tio n, r ar e consumption of cannabis, and positive urine screening for drugs other t ha n cannabis

Dutch medical cannabis ( Cannabis flos: B edrocan, 22 % dronabinol, <1.0 % cannabidiol; supplier: Dutch Ministry of Health, Welfare and Sport, Office of Medicinal Cannabis, P.O. Box 16114, NL-2500 BC The Hague) was imported for the trials (import authorization no. E5304/2014) with allowance from the German Federal Opium Agency

The consumption of the cannabi s cigarettes w as stan-dardized. Each joint c ontained 300 μ gofTHCperkilo-gram of body weight. The test persons were instruct ed to cons ume the joints in the following way: 4-s i nhalat ion, 10-s holdi ng breath, and 15-s exhalation. A m aximum of three joints could be c onsumed

opthamalogical: The average time required t o r ead the 50-wor d t ext l in-early d i d not significan tly differ befo r e and a f ter t he cons umption of cannabi s… The median time needed
to touch the i nvestigator ’s fingertip 10 times also remained constant and was between 10 and 11 s . The median amplitude of fusion dec reas ed immediately after cannabis c onsumption (Fig. 2a, b) a nd increased again wi th fall ing T HC concent rat ion r esp. CIF. No st at isti cal significances were observed. I t s eems that the simulta-neous influence of amphetamine/MDMA hinders the de-crease i n the amplitude of fusion

t h er e i s n o i nc r e as e i n t h e nu m b er o f d em e ri ts after the cannabi s consumption. While the median de-merits in the CIF groups below 10 a nd above 30 is 8 (Fig. 4b), the m edian demerits decreased from 9 to 8 only when the THC concentrations serve a s a basis. There w ere no s ignificant differences between the THC groups (p =0.81)

The study is limited by the small, male-dominated test group, by the fact that four test persons showed positive results for amphetamine/MDMA, and by the fact that only one test person showed a THC concentration below the limit of detection when the study began. However, the age and gender of the test persons are representative of the group of persons who are regularly found driving under the influence of cannabis products

Some test persons w ith THC concentra-ti ons a bove 100 ng/ ml parti al ly rode t hei r b icycles in a way t hat was not more suspicious than the way the test persons r ode their bicycles during the initial r ides

de Havenon A, Chin B, Thomas K, Afra P. 2011. “The secret “Spice”: an undetectable toxic cause of seizure” Neurohospitalist 1(4): 182-186

“Spice” is an umbrella term for a variety of synthetic cannabinoid products whose inhalation has been associated with an increasing number of toxic side effects resulting in emergency department visits. These side effects (including psychosis, tachyarrhythmia, and seizures) are not typically seen with marijuana (Cannabis sativa) use. We report 2 patients with no prior history of neurological disease that experienced their first generalized tonic–clonic seizure after smoking Spice.

Havens J, Gudino O, Biggs E, Diamond U, Weis J, Cloitre M. 2012. “Identification of Trauma Exposure and PTSD in Adolescent Psychiatric Inpatients: An Exploratory Study” J Trauma Stress 25(2): 171-178

large discrepancy between rates of probable PTSD identified through standardized assessment and during the emergency room psychiatric evaluation (28.6% vs. 2.2%). Adolescents with probable PTSD had greater clinical severity and service utilization, an increased likelihood of being diagnosed with bipolar disorder (27.5% vs. 9.2%) and being prescribed antipsychotic medications (47.5% vs. 27.6%)

Only one patient out of 40 (2.5%) who met criteria for probable PTSD received an admission diagnosis of PTSD

Without knowledge about exposure to a traumatic event, it is virtually impossible to evaluate re-experiencing symptoms… symptoms of avoidance of thoughts and reminders

if the youth or their family does not spontaneously disclose exposure to a traumatic event or if the evaluating clinician does not systematically assess exposure to trauma, it will be impossible to obtain information about these central aspects of PTSD

Hayakawa K, Mishima K, Hazekawa M, Sano K, Irie K, Orito K, Egawa T, Kitamura Y, Uchida N, Nishimura R, Egashira N, Iwasaki K, Fujiwara M. 2008. “Cannabidiol potentiates pharmacological effects of Delta(9)-tetrahydrocannabinol via CB(1) receptor-dependent mechanism” Brain Res 1188: 157-64

CB1 upregulation enhanced by combining CBD and THC

Heim C, Newport DJ, Heit S, Graham YP, Wilcox M, Bonsall R, Miller AH, Nemeroff CB. 2000 “Pituitary-adrenal and autonomic responses to stress in women after sexual and physical abuse in childhood.” JAMA 284(5):592-7

Women with childhood abuse exhibited increased pituitary-adrenal and autonomic responses to stress compared with controls. effect particularly robust in women with current symptoms of depression and anxiety.

more than 6-fold greater ACTH response to stress

Heim C, Newport J, Bonsall R, Miller A, Nemeroff C. 2001. “Altered pituitary-adrenal axis responses to provocative challenge tests in adult survivors of childhood abuse” Am J Psychiatry 158(4):575-81

Abused women without major depressive disorder exhibited greater ACTH responses to CRF administration, whereas abused women with major depressive disorder and depressed women without early life stress demonstrated blunted ACTH responses.

sensitization of the anterior pituitary and counterregulative adaptation of the adrenal cortex in abused women without major depressive disorder. On subsequent stress exposure, women with a history of childhood abuse may hypersecrete CRF, resulting in down-regulation of adenohypophyseal CRF receptors and symptoms of depression and anxiety

The seeming discrepancy between greater ACTH responses to psychosocial stress and blunted ACTH responses to CRF stimulation in abused women with major depression may reflect the involvement of corticolimbic pathways and enhanced hypothalamic releasing activity (CRF and other releasing factors), thus overriding receptor down-regulation.

Henquet C, Krabbendam L, Spauwen J, Kaplan C, Lieb R, Wittchen H-U, van Os J. 2004. “Prospective cohort study of cannabis use, predisposition for psychosis, and psychotic symptoms in young people.” BMJ 330

cannabis use was much stronger in those with any predisposition for psychosis at baseline (23.8% adjusted difference in risk, 95% confidence interval 7.9 to 39.7, P = 0.003) than in those without (5.6%, 0.4 to 10.8, P = 0.033

Henquet C, Krabbendam L, Spauwen J, Kaplan C, Lieb R, Wittchen H-U, van Os J. 2005. “Prospective cohort study of cannabis use, predisposition for psychosis, and psychotic symptoms in young people” BMJ 330(7481): 11

after adjustment for age, sex, socioeconomic status, urbanicity, childhood trauma, predisposition for psychosis at baseline, and use of other drugs, tobacco, and alcohol, cannabis use at baseline increased the cumulative incidence of psychotic symptoms at follow up four years later (adjusted odds ratio 1.67, 95% confidence interval 1.13 to 2.46). The effect of cannabis use was much stronger in those with any predisposition for psychosis at baseline (23.8% adjusted difference in risk, 95% confidence interval 7.9 to 39.7, P = 0.003) than in those without (5.6%, 0.4 to 10.8, P = 0.033). The risk difference in the “predisposition” group was significantly greater than the risk difference in the “no predisposition” group (test for interaction 18.2%, 1.6 to 34.8, P = 0.032). There was a dose-response relation with increasing frequency of cannabis use

Henquet C, Murray R, Linszen D, van Os J. 2005. “The environment and schizophrenia: the role of cannabis use” Schizophr Bull 31(3): 608-612

although a relative risk of around 2.0 is not a very large effect size, cannabis use is extremely prevalent in young people

although effect sizes were reduced, the effect of cannabis persisted after adjustment for factors such as age, sex, social class, ethnic group, family history of psychiatric illness, urbanicity, and use of other drugs

Henquet C, Rosa A, Krabbendam L, Papiol S, Fananas L, Drukker M, Ramaekers J, van OS. 2006. “An Experimental Study of Catechol-O-Methyltransferase Val158Met Moderation of |[Delta]|-9-Tetrahydrocannabinol-Induced Effects on Psychosis and Cognition” Neuropsychopharmacology 31(12): 2748-57

Carriers of the Val allele were most sensitive to |[Delta]|-9-THC-induced psychotic experiences, but this was conditional on prior evidence of psychometric psychosis liability. |[Delta]|-9-THC impacted negatively on cognitive measures. Carriers of the Val allele were also more sensitive to |[Delta]|-9-THC-induced memory and attention impairments compared to carriers of the Met allele. Experimental effects of |[Delta]|-9-THC on cognition and psychosis are moderated by COMT Val158Met genotype, but the effects may in part be conditional on the additional presence of pre-existing psychosis liability. The association between cannabis and psychosis may represent higher order gene-environment and gene-gene interactions

COMT Valine (Val) allele, the relative risk to develop psychotic illness after cannabis exposure was 10.9, whereas in individuals homozygous for the COMT Methionine (Met) allele, this risk was only 1.1

THC impacted on cognition and psychosis outcomes, but there was evidence that this was conditional on other variables

the differential sensitivity to THC associated withCOMT genotype was in part conditional on additional evidence of psychosis liability, as Val carriers with evidence of psychometric psychosis liability experienced more THC-induced transient psychotic symptoms compared to Val carriers without these additional measures of liability

Higher activity of COMT in the prefrontal cortex, associated with the Val allele, may produce a selective decrease in tonic dopamine subcortically, thus initiating an activation of phasic dopamine transmission. The Met allele, associated with low-activity COMT, is thought to decrease phasic and increase tonic dopamine transmission subcortically (Bilderet al, 2004). Phasic dopamine may be important for flexibility of neuronal activation, whereas tonic dopamine may play a critical role in cognitive stability

we did not replicate differences in THC sensitivity between patients and controls

evidence for differential THC sensitivity was found, restricted to subjects with the Val|[sol]|Val genotype

the hypothesis of higher-order interactions is nevertheless necessary to explain the epidemiological observation that only a small minority of those exposed to cannabis develop a severe psychosis outcome (Henquet et al, 2005b)

liability to schizophrenia may in part consist of a developmentally mediated limitation in the capacity to modulate stress-related increased activity of meso-limbic dopamine neurons (Lieberman et al, 1997).COMT genotypes may be relevant in this regard

Henquet C, Di Forti M, Morrison P, Kuepper R, Murray R. 2008. “Gene-environment interplay between cannabis and psychosis” Schizophrenia Bulletin 34(6): 1111-1121 in dropbox

Cannabis use is considered a contributory cause of schizophrenia and psychotic illness. However, only a small proportion of cannabis users develop psychosis.Henquet - psychosis and risk exposure, abuse and cannabis

Evidence suggests that mechanisms of gene-environment interaction are likely to underlie the association between cannabis and psychosis… multiple variations within multiple genes together with other environmental factors (eg, stress) may interact with cannabis to increase the risk of psychosis

In patients with an established psychotic disorder, cannabis use is associated with more and earlier relapses and poorer psychosocial functioning but perhaps surprisingly also with less negative and affective symptoms

it is manifestly obvious that only a small proportion of cannabis users develop psychosis

Herman J, Perry J, van der Kolk B. 1989. “Childhood trauma in borderline personality disorder” Am J Psychiatry 146(4): 490-5

Subjects with borderline personality disorder (N = 21) or borderline traits (N = 11) and nonborderline subjects with closely related diagnoses (N = 23)

Significantly more borderline subjects (81%) gave histories of such trauma, including physical abuse (71%), sexual abuse (68%), and witnessing serious domestic violence (62%); abuse histories were less common in those with borderline traits and least common in the subjects with no borderline diagnosis

Herting M, Schwartz D, Mitchell S, Nagel B. 2010. “Delay discounting behavior and white matter microstructure abnormalities in youth with a family history of alcoholism” Alcoholism: Clinical and Experimental Research 34(9): 1590-1602 in dropbox

lower FA in the left inferior longitudinal fasciculus and the right optic radiation statistically mediated the relationship between FH status and slower RTs on the delay discounting task… FHP youth showed a trend toward greater impulsive decision making, possibly representing an inherent personal characteristic that may facilitate substance use onset and abuse in high-risk youth

Hester R, Nestor L, Garavan H. 2009. “Impaired error awareness and anterior cingulate cortex hypoactivity in chronic cannabis users” Neuropsychopharmacology 34(11): 2450-2458

Sixteen active chronic cannabis users and 16 control participants were administered a Go/No-go response inhibition task during event-related fMRI data collection

Higher depression scores than controls, more use of alcohol, lifetime joints: 11628.8 ± 5993.4, cannabis abstinence 38.0 ± 47.7, cannabis withdrawal 9.3 ± 2.2 — no reference to abstinence status within text, only within Table 1. Text misleadingly refers to “active” use.

Cannabis users’ inhibitory control performance was equivalent to that of the control group, but the former demonstrated a significant deficit in awareness of commission errors. Cannabis users demonstrated a diminished capacity for monitoring their behaviour that was associated with hypoactivity in the ACC and right insula. In addition, increased levels of hypoactivity in both the ACC and right insula regions were significantly correlated with error awareness rates in the cannabis group (but not controls)

Deficits in error detection have also been found to relate to clinical symptoms, including the debilitating symptoms of loss of insight (Lysaker et al, 1998), perseverative behaviour (Frith, 1987) and delusions of alien control in schizophrenia (Frith and Done, 1989), and poor clinical outcomes (e.g., inability to maintain independent living (Seltzer et al, 1997))

diminished error-related anterior cingulate cortex (ACC) activity in a range of clinical conditions, including schizophrenia (Alain et al, 2002; Carter et al, 2001; Turken et al, 2003), major depression (Steele et al, 2007), and drug addiction (Forman et al, 2004; Kaufman et al, 2003)

The hypoactive error-related ACC response observed in the cannabis group is consistent with similar diminished responses in schizophrenia (Alain et al, 2002; Bates et al, 2002; Carter et al, 2001; Kerns et al, 2005; Laurens et al, 2003; Turken et al, 2003), major depression (Steele et al, 2007), ADHD (Liotti et al, 2005; Rubia et al, 2005) and various drug dependent samples (e.g., cocaine (Kaufman et al, 2003), methamphetamine (London et al, 2005), heroin (Forman et al, 2004), alcohol (Ridderinkhof et al, 2002))

Cannabis users showed less deactivation in the left middle frontal gyrus (BA 10) and right putamen during unaware errors when compared to their aware errors, whereas control participants showed no difference in these regions. The opposite pattern was observed in the right cerebellum, with control participants demonstrating significantly less activity (deactivation) during unaware errors when compared to aware, whereas the cannabis group showed no difference. Common to both groups was the differentiation of aware from unaware errors by greater activity in the right insula, bilateral IPL and right middle frontal cortices, as well as significantly less deactivation in the right middle occipital cortex

higher levels of cannabis craving were associated with poorer error awareness rates

Studies with cannabis users have demonstrated a consistent pattern of increased activity in prefrontal and parietal regions

may indeed precede use and constitute a risk factor for prolonged cannabis use

Hickman M, Vickerman P, Macleod J, Lewis G, Zimmit S, Kirkbride J, Jones P. 2009. “If cannabis caused schizophrenia — how many cannabis users may need to be prevented in order to prevent one case of schizophrenia? England and Wales caculations” Addiction 104(11): 1856-61

NNP for heavy cannabis and schizophrenia ranged from 2800 [90% confidence interval (CI) 2018-4530] in those aged 20-24 years to 4700 (90% CI 3114-8416) in those aged 35-39. In women, mean NNP for heavy cannabis use and schizophrenia ranged from 5470 (90% CI 3640-9839) in those aged 25-29 to 10 870 (90% CI 6786-22 732) in 35-39-year-olds. Equivalent mean NNP for heavy cannabis use and psychosis were lower, from 1360 (90% CI 1007-2124) in men aged 20-24 and 2480 (90% CI 1408-3518) in women aged 16-19. The mean and median number of light cannabis users that would need to be prevented in order to prevent one case of schizophrenia or psychosis per year are four to five times greater than among heavy users.

Hill A, Williams C, Whalley B, Stephens G. 2012. “Phytocannabinoids as novel therapeutic agents in CNS disorders” Pharmacol Ther 133(1): 79-97

The Cannabis sativa herb contains over 100 phytocannabinoid (pCB) compounds and has been used for thousands of years for both recreational and medicinal purposes

Δ(9)-tetrahydrocannabinol (Δ(9)-THC) as the primary mediator of the psychoactive, hyperphagic and some of the potentially therapeutic properties of ingested cannabis…  research focus has recently widened to include other pCBs including cannabidiol (CBD), cannabigerol (CBG), Δ(9)tetrahydrocannabivarin (Δ(9)-THCV) and cannabidivarin (CBDV)

Disorders that could be targeted include epilepsy, neurodegenerative diseases, affective disorders and the central modulation of feeding behaviour

Hill M, Gorzalka B. 2004. “Enhancement of anxiety-like responsiveness to the cannabinoid CB1 receptor agonist HU-210 following chronic stress” European Journal of Pharmacology 499: 291-295 in dropbox

Results demonstrated that in unstressed animals [rats], a low dose of HU-210 induced an anxiolytic response, whereas a high dose induced an anxiogenic response. In stressed animals both the low and high doses of HU-210 induced anxiogenic responses… chronic stress enhances either cannabinoid receptor responsivity or one of the interacting systems implicated in emotional states

Hill M, Hillard C, Bambico F, Patel S, Gorzalka B, Gobbi G. 2009. “The therapeutic potential of the endocannabinoid system for the development of a novel class of antidepressants” Trends in Pharmacological Sciences 30(9): 484-493

Substantial evidence has accumulated implicating a deficit in endocannabinoid in the etiology of depression; accordingly, pharmacological augmentation of endocannabinoid signaling could be a novel target for the pharmacotherapy of depression

facilitation of endocannabinoid neurotransmission evokes both antidepressant and anxiolytic effects

enhancement of endocannabinoid signaling can enhance serotonergic and noradrenergic transmission; increase cellular plasticity and neurotrophin expression within the hippocampus; and dampen activity within the neuroendocrine stress axis

Hill M, Kumar S, Filipski S, Iverson M, Stuhr K, Keith J, Cravatt B, Hillard C, Chattarji S, McEwen B. 2013. “Disruption of fatty acid hydrolase activity prevents the effects of chronic stress on anxiety and amygdalar microstructure.” Molecular Psychiatry 18(10): 1125-35

Chronic restraint stress in rats increases FAAH and reduces AEA in the amygdala. All stress induced changes in amygdalar structure and function were absent in mice deficient in FAAH.

Hirvonen J, Goodwin R, Li C-T, Terry G, Zoghbi S, Morse C, Pike V, Volkow N, Huestis M, Innis R. 2012. “Reversible and regionally selective downregulation of brain cannabinoid CB1 receptors in chronic daily cannabis smokers” in dropbox

Hirvonen - nonregulationHirvonen - downregulation

downregulation correlated with years of cannabis smoking and was selective to cortical brain regions. After ~4 weeks of continuously monitored abstinence from cannabis on a secure research unit, CB1 receptor density returned to normal levels

Hohmann A, Suplita R, Bolton N, Neely M, Fegley D, Mangieri R, Krey J, Walker J, Holmes P, Crystal J, Duranti A, Tontini A, Mor M, Tarzia G, Piomelli D. 2005. “An endocannabinoid mechanism for stress-induced analgesia” Nature 435(7045): 1108-12 in dropbox

Blockade of cannabinoid CB(1) receptors in the periaqueductal grey matter of the midbrain prevents non-opioid stress-induced analgesia. 2-AG and anandamide enzyme blockers (MAGL and FAAH) enhance stress-induced analgesia

stress triggers the formation of both 2-AG and anandamide in the midbrain, but these two endocannabinoids are released with strikingly dissimilar time-courses (2-AG: marked increase 2 min after shock termination, baseline 15 min later; anandamide: peak 7-15 min after shock, persisting but weakening at 25 min)

Holderith N, Nemeth B, Papp O, Veres J, Nagy G, Hajos N. 2011. “Cannabinoids attenuate hippocampal γ oscillations by suppressing excitatory synaptic input onto CA3 pyramidal neurons and fast spiking basket cells” J Physiol 589(20): 4921-34

van Holst R, Schilt T. 2011. “Drug-related decrease in neuropsychological functions of abstinent drug users” Curr Drug Abuse Rev 4(1): 42-56 – add to dropbox

All substances of abuse, except cannabis, were associated with sustained deficits in executive functioning, especially inhibition. In addition, verbal memory decrements were consistently found in cocaine, (meth)amphetamines and ecstasy users, but not in heroin or cannabis users

There was little evidence for sustained cognitive impairments in adult abstinent cannabis users

a metaanalysis of studies up to 2002 demonstrated no significant detrimental effects of cannabis on neuropsychological functions [75] (Grant)

The short-term effects of cannabis on cognitive functions consist of deficits in attention, working memory, verbal fluency and cognitive flexibility [76]. These deficits are also found in frequent cannabis users after seven days of abstinence [77]… One methodological limitation of these studies is that there was no control for other psychiatric disorders, which could explain some of the differences between cannabis users and controls

although the focus on studies requiring two weeks of abstinence is needed to rule out acute toxification effects, this criterion could also introduce a selection bias. It is conceivable that participants, who are able to refrain from drug use for two weeks or more, actually would like to stop using the substance (as it’s difficult to get non-treatment seekers willing to stop for that long). Moreover, those who are able to remain abstinent might have better executive functions. Conversely, those who want to stop or cut down use might be the people who experience particularly adverse outcomes after drug use. Second, because of the crosssectional nature of most studies, it is impossible to determine whether the identified deficits are a consequence of drug use, or are related to pre-existing vulnerabilities, or a combination of both

Hopper J, Frewen P, van der Kolk B, Lanius R. 2007. “Neural correlates of reexperiencing, avoidance and dissociation in PTSD: symptom dimensions and emotion dysregulation in responses to script-driven trauma imagery” J Trauma Stress 20(5): 713-25

reexperiencing severity associated with right anterior insula activity, negatively with right rostral anterior cingulate cortex (rACC). Avoidance correlated negatively with rACC and subcallosal anterior cingulate activity. dissociation correlated positively with activity in the left medial prefrontal and right superior temporal cortices, and negatively with the left superior temporal cortex

Horder J, Cowen P, di Simplicio M, Browning M, Harmer C. 2009. “Acute administration of the cannabionid CB1 antagonist rimonabant impairs positive affective memory in healthy volunteers” Psychopharmacology (Berl) 205(1): 85-91

A single dose of rimonabant did not alter subjective mood. However, rimonabant selectively reduced incidental recall of positive self-relevant adjectives, an effect contrary to that seen following the administration of antidepressants. There were no effects of rimonabant on the other measures of emotional processing

Horder J, Browning M, di Simplicio M, Cowen P, Harmer C. 2012. “Effects of 7 days of treatment with the cannabinoid type 1 receptor antagonist, rimonabant, on emotional processing” J Psychopharmacol 26(1): 125-32

Previously, we showed that a single dose of rimonabant produced a negative bias on an emotional word memory task, in the absence of subjective mood effects… In comparison with placebo, rimonabant induced a negative bias on a memory recognition task without producing a change in subjective mood. This raises the possibility that the depressogenic effects of rimonabant may be linked to emotional memory biases

Houston J, Murphy J, Shevlin S, Adamson G. 2011. “Cannabis use and psychosis: revisiting the interactive role of childhood sexual abuse.” Psychol Med 41:2339-2348 in dropbox

cannabis consumption was predictive of psychosis diagnosis in a bivariate model; within a multivariate model that included childhood sexual abuse, the effect of cannabis use was attenuated and not statistically significant. multivariate analysis revealed non-consensual sex in childhood… over six times [odds ratio (OR) 6.10] more likely to have diagnosis of psychosis compared with those who had not experienced this trauma.”

Howes O, Kapur S. 2009. “The Dopamine Hypothesis of Schizophrenia: Version III — The Final Common Pathway” Schizophr Bull 35(3): 549-562

Huang H, Gundapuneedi T, Rao U. 2012. “White Matter Disruptions in Adolescents Exposed to Childhood Maltreatment and Vulnerability to Psychopathology.” Neuropsychopharmacology 2012: 37, 2693-2701 in dropbox

adolescents exposed to childhood maltreatment had lower FA values in left and right superior longitudinal fasciculi, right cingulum bundle projecting to the hippocampus, left inferior fronto-occipital fasciculus, and splenium of the corpus callosum compared with controls. observed white matter disruptions SLF-L, SLF-R, and CGH-R associated with vulnerability to unipolar depression and/or substance abuse

effect in right cingulum bundle projecting to hippocampus discriminates between those who went on to develop substance use disorder and those who did not

Hui C, Morcillo C, Russo D, Stochl J, Shelley G, Painter M, Jones P, Perez J. 2013. “Psychiatric morbidity, functioning and quality of life in young paeople at clinical high risk for psychosis” Schizophr Res 148(1-3): 175-180

The presence of co-morbid moderate or severe depressive and anxiety symptoms was common in our sample of young people at enhanced risk for psychosis

Growing evidence is indicating that psychosis may lie on a continuum, with mild psychotic symptoms or psychotic-like experiences at one end and schizophrenia and related psychotic disorders at the other (Kendler et al., 1996; van Os et al., 2001; Dhossche et al., 2002; Johns et al., 2004; van Os et al., 2009). Recent studies including population-based samples also suggest that nearly 80% of the adolescents who report psychotic-like symptoms may have at least one other psychiatric disorder (Kelleher et al., 2012a, 2012b). Furthermore, co-presence of psychotic symptoms in adolescents and young adults with disorders of anxiety and depression appears to be more prevalent than previously considered, and an etiological and functionally relevant feature (Wigman et al., 2012)

60 help-seeking individuals, aged 16–35, referred to CAMEO Early Intervention in Psychosis Service from February 2010 to September 2012 met criteria for HR, according to the Comprehensive Assessment of At Risk Mental States (CAARMS) (Yung et al., 2005). From this assessment, HR individuals were divided into three groups based on whether they were mainly characterised by: i) vulnerability traits (family history of psychosis in first degree relative plus significant drop in functioning levels within past 12 months), ii) attenuated psychotic symptoms, or iii) brief limited intermittent psychotic symptoms (BLIPS). In our sample, all individuals fulfilled criteria for the attenuated psychotic symptoms’ group. Seven individuals (11.7%) also qualified for the vulnerability traits’ group. Intake exclusion criteria included: i) acute intoxication or withdrawal associated with drug or alcohol abuse or any delirium, ii) confirmed intellectual disability (Wechsler Adult Intelligence Scale — tested IQ < 70), or iii) prior total treatment with antipsychotics for more than one week

mean age of 20.7 years (SD = 3.4)… Gender was nearly evenly split between male (n = 55; 52.4%) and female (n = 50; 47.6%)… Less HR individuals achieved higher education degrees (p = 0.001) compared to healthy volunteers, and more HR individuals were single (p = 0.033). A significant proportion of HR individuals were on antidepressant or/and anxiolytic medication (41.7%) at the time of their first contact with CAMEO

MINI DSM-IV diagnoses for 55 of the 60 HR individuals. 38 (69.1%) had more than one DSM-IV psychiatric diagnosis, mainly within the affective and anxiety diagnostic spectra. Primary diagnoses for this group were ranked as follows: major depressive episode, current or recurrent (n = 26; 47.3%) > social phobia (n = 7; 12.7%) = generalised anxiety disorder (n = 7; 12.7%) > obsessive compulsive disorder (n = 5; 9.1%) > bipolar disorder, type II (n = 2; 3.6%) > panic disorder (n = 1; 1.8%) = posttraumatic stress disorder (n = 1; 1.8%). Six HR individuals (10.9%) did not fulfil enough criteria for a DSM-IV Axis I diagnosis

HR individuals had a 72.0% endorsement in suicidal thoughts or intention, as measured with item 9 of BDI-II, whereas only 9.1% of healthy volunteers had positive response in this item (p < 0.001)… 41 HR individuals (85.4%) suffered moderate or severe anxiety symptoms

Approximately 80% of HR individuals had experienced at least one obsessive symptom. Among those who had any obsession or compulsion, the mean of YBOCS total severity score was significantly higher in HR individuals than healthy volunteers (20.1 ± 5.8 vs. 5.3 ± 1.5, p < 0.001), suggesting moderate and subclinical severity respectively

After more than one year of follow-up for each individual at HR in our sample, only 6 (10%) made a transition into FEP. We obtained MINI DSM-IV diagnoses at baseline for 5 of them. 4 had an initial diagnosis of major depression, current or recurrent, and one did not fulfil enough criteria for a DSM-IV mental disorder

HR subjects had poorer functioning, with much lower scores in GAF symptoms and disability than healthy volunteers (45.4 ± 8.9 vs. 86.6 ± 3.8 and 48.6 ± 9.4 vs. 86.7 ± 3.6, respectively, both with p < 0.001), suggesting that individuals with HR mental states suffered serious psychiatric symptoms and any serious impairment in social, occupational or academic functioning. Higher unemployment rate was found in the HR group (37.7% vs. 17.8%, p = 0.029). HR individuals also reported poorer quality of life (3.8 ± 1.0 vs. 5.6 ± 0.6, p < 0.001)

psychotic experiences among young adolescents appear to follow a dose–responseKell pattern in the prediction of a wide variety of future psychopathology (Kelleher et al., 2012a, 2012b)

Our findings highlight the lack of specificity and predictive value of psychotic symptoms and carry important implications for clinicians and researchers in the field of psychosis. Psychotic experiences appear to be common, not only among those patients who suffer from a psychotic illness, but also from other disorders such as depression and anxiety (Wigman et al., 2012)

traumatic events in childhood could eventually manifest as psychotic-like symptoms in the context of non-psychotic psychiatric disorders (Kelleher et al., 2013)

Hungund B, Vinod K, Kassir S, Basavarajappa B, Yalamanchili R, Cooper T, Mann J, Arango V. 2004. “Upregulation of CB1 receptors and agonist-stimulated [35S]GTPbold italic gammaS binding in the prefrontal cortex of depressed suicide victims” Molecular Psychiatry 9: 184-190

Upregulation of CB1receptor density (Bmax) of 24% observed in brains of depressed suicides compared with matched controls. 38% increase in CB1R immunoreactivity. 45% greater CB1 receptor stimulated protein binding in dorsolateral prefrontal cortex

Decreased CB1 receptor binding in neurodegenerative diseases related to extrapyramidal function has been reported.17 Alterations in the serotonergic (for a review see, Arango et al18) and adrenergic19 receptors in the pathophysiology of depression and suicidal behavior are well documented. Recently, Dean et al,20reported increased CB1 receptor density in dorsolateral prefrontal cortex (DLPFC) in schizophrenia.

The average density (Bmax) of CB1 receptor in DLPFC of normal control subjects was 493.3plusminus52.7 fmol/mg protein

opiates signaling was found to be 20-fold more efficient than cannabinoid signaling.32 CB1 receptor signaling functions as a subtle, fine-tuning mechanism for cells; high density of receptors makes the CB1 receptor highly sensitive to agonists; however, the poor coupling efficiency ensures that overactivation of the system will not occur

Dowlatshahi et al,33 found decreased cAMP signaling in the brain of depressed suicides; sensitization of cannabinoidergic signaling may lead to the decreased cAMP content of the cell as these receptors are negatively coupled to AC

Aged rats exhibited a marked decrease in CB1receptors and its mediated [35S]GTPitalic gammaS binding sites in rat brain.34 we also observed reduced receptor density with increasing age in normal control subject 15,16

only three patients had medications or alcohol at the time of death and no psychoactive drugs were detected in the remaining patients

CB1 receptor activation suppresses neurotransmitter release by inhibiting a calcium-dependent step in vesicle release,41 decreasing the local release of synaptic vesicles42,43,44

The pharmacological manipulation of endocannabinoid system may serve as a new therapeutic target in the treatment of depression

Huizink A, Ferdinand R, Ormel J, Verhulst F. 2006. “Hypothalamic-pituitary-adrenal axis activity and early onset of cannabis use” Addiction 101(11):1581-8

The early onset group had lower cortisol levels 30 minutes after awakening than the late onset group (OR = 0.93, 95% CI: 0.86-0.99). Furthermore, compared to non-users, the early and late onset cannabis users had higher levels of cortisol at 8 p.m

Hutchison K, Haughey H, Niculescu M, Schacht J, Kaiser A, Stitzel J, Horton W, Filbey F. 2008. “The Incentive Salience of Alcohol, Translating the Effects of Genetic Variant in CNR1” Arch Gen Psychiatry 65(7): 841-850

Hyman S, Sinha R. 2009. “Stress-Related Factors in Cannabis Use and Misuse: Implications for Prevention and Treatment” J Subst Abuse Treat 36(4): 400-413

cannabis is commonly used as a stress-coping strategy. Negative life events, trauma, and maladaptive coping related to consumption. Cannabis use for stress-coping purposes was most evident when examining chronic as compared with experimental use

72% of daily cannabis users reported smoking to relax or relieve tension, 36% to escape from problems, 29% to alleviate anger or frustration, 28% to get through the day Johnston and O’Malley (1986)

Green, Kavanagh, and Young (2004): those with psychosis using cannabis to positively alter their mood (36% and 42%), to cope with negative affect (27% and 29%), and for social activity reasons (38% and 29%). Those without using cannabis to relax (34% and 43%), and for social activity reasons (49% and 51%).

stressful life circumstances, especially those that occur early in life, may elevate distress, increase sensitivity to stress, and set individuals on a trajectory toward experimental cannabis use and a more severe course of addiction … cannabis use may be most likely in stress-vulnerable individuals as it supplies immediate stress-relief with relatively little effort

Iannetti G, Wise R. 2007. “BOLD functional MRI in disease and pharmacological studies: room for improvement?” Magnetic Resonance Imaging 25: 978:988 in dropbox

BOLD fMRI does not measure neural activity directly, but relies on a cascade of physiological events linking neural activity to the generation of MRI signal. However, most of the disease and pharmacological studies performed so far have interpreted changes in BOLD fMRI as bbrain activation,Q ignoring the potential confounds that can arise through drug- or disease-induced modulation of events downstream of the neural activity

necessary improvements consist of (1) the inclusion of one or more control tasks, and (2) the recording of physiological parameters during scanning and subsequent correction of possible between-group differences. Second-line,highly recommended important aim to make the results of a patient or drug BOLD study more interpretable and include the assessment of (1) baseline brain perfusion, (2) vascular reactivity, (3) the inclusion of stimulus-related perfusion fMRI and (4) the recording of electrophysiological responses to the stimulus of interest. Finally, third-line, desirable improvements consist of the inclusion of (1) simultaneous EEG–fMRI, (2) cerebral blood volume and (3) rate of metabolic oxygen consumption measurements and, when relevant, (4) animal studies investigating signalling between neural cells and blood vessels

Insel, T. 2010. “Rethinking schizophrenia” Nature 486: 187-193 in dropbox

Insel - grey matter density

A century ago we had large public institutions for serious mental illness, tuberculosis and leprosy. Of these three, today only mental illness, especially schizophrenia, remains unchanged in prevalence and disability

those with serious mental illness were three times more likely to be found in the criminal justice system than in hospitals

Although both conventional and atypical antipsychotics reliably reduce delusions and hallucinations, they have not enhanced functional recovery (for example, employment) for people with schizophrenia. One explanation is that the disability of schizophrenia is largely due to cognitive deficits, such as problems with attention and working memory, which these drugs fail to improve

Although schizophrenic psychosis usually emerges between ages 18–25, several longitudinal population-based studies indicate that problems are evident much earlier. For instance, a recent report from a 45-year follow up of a Copenhagen birth cohort demonstrated that adults with schizophrenia have a history of delayed maturation including delayed developmental milestones in the first year 40 . Data from the Dunedin birth cohort, consist-ent with many previous studies 41, indicated that IQ is reduced early and persistently in children destined to develop schizophrenia 42 These precur-sors of schizophrenia are subtle and non-specific, but the consistency of the finding supports the hypothesis that psychosis does not emerge from a completely healthy brain

Maternal malnutrition during famine 50,51 , infections in the second trimester52 , perinatal injury53 and cytokine exposure 54 have all been associated with subsequent increased risk for schizophrenia

291 adolescents followed for 2.5 years reported that the prodrome represented a 405-fold increase in risk (rela-tive to the general population) and that a combination of three factors (for example, genetic risk with recent functional decline, unusual thought content, and either suspicion/paranoia or reduced social func-tioning) resulted in a positive predictive power for conversion to psychosis of 74–81%

Results from single-site trials of atypical antipsychotics 81 , antidepressants 82, lithium83 and cognitive behaviour therapy 84 have had, at best, modest effects in reducing symptoms or preventing conversion to psychosis

It is now clear that negative symptoms (loss of will, anhedonia, poverty of thought) and cognitive deficits (reduced working memory, poor cognitive control) are core features of the disorder that account for much of the long-term morbidity and poor functional outcomes 87

In 2010, smoking and obesity are epidemic among people with schizophrenia, with estimates of nicotine dependence ranging from 58–90% (ref. 95) and metabolic syndrome (obesity, hyperlipidemia, hyperglycemia and hypertension) present in 40% (ref. 96)

Institute of Medicine. 2009. “Preventing Mental, Emotional and Behavioral Disorders Among Young People: Progress and Possibilities” The National Academies Press

cost related to ELA ~$247 billion

Ito Y, Teicher M, Glod C, Harper D, Magnus E, Gelbard H. 1993. “Increased prevalence of electrophysiological abnormalities in children with psychological, physical and sexual abuse” Journal of Neuropsychiatry 5:401-408 in dropbox

27 nonabused, 22 psychologically abused, 55 physical/sexual abuse (within which 38 “unequivocal abuse of substantial severity”)

Abnormal EEG in 26.9% of nonabused, 54.4% of early trauma, 42.9% with psychological abuse, 59.6% in total physical/sexual abuse sample, 71.9% in subsample with definite serious abuse

Majority of abnormalities in frontal, temporal and anterior regions. 2.7 to 3.1 fold greater prevalence of EEG abnormalities localized to frontotemporal and anterior regions than not abused. Mostly left. In non-abused, left abnormalities rare; in abused, left 2.5 more likely abnormal than right. Psychological abuse possibly specific to left temporal. In physical/sexual abuse, increae in prevalence of frontotemporal, and less evidence of left-localisation.

Left-hemisphere deficit indexed by substantially better visual-spatial ability than verbal ability

Recall of traumatic childhood memory shifts cortical activity from left-sided to right-sided; degree of shift correlates with severity of abuse

Irish L, Kobayashi I, Delahanty D. 2009. “Long-term Physical Health Consequences of Childhood Sexual Abuse: A Meta-Analytic Review” Journal of Pediatric Psychology 35(5): 450-461

53% of patients with functional (non-organic) GI disorders have a history of CSA compared with 37% of those with organic disorders (Drossman,1995).

pain, cardiopulumonary symptoms, obesity, gynecologic health, GI health, general health lack of regular exercise

although abused girls increased body mass at a steeper rate than non-abused girls, the groups did not significantly differ in BMI until early adulthood

differences larger in clinical samples than in community samples

Ishiguro H, Horiuchi Y, Ishikawa M, Koga M, Imai K, Suzuki Y, Morikawa M, Inada T, Watanabe Y, Takahashi M, Someya T, Ujike H, Iwata N, Ozaki N, Onaivi ES, Kunugi H, Sasaki T, Itokawa M, Arai M, Niizato K, Iritani S, Naka I, Ohashi J, Kakita A, Takahashi H, Nawa H, Arinami T. 2010. “Brain cannabinoid CB2 receptor in schizophrenia” Biol Psychiatry 67(10): 974-82

increased risk of schizophrenia for people with low CB2 receptor function

R63 allele of rs2501432 (R63Q) (p = .001), the C allele of rs12744386 (p = .005) and the haplotype of the R63-C allele (p = 5 x 10(-6)) were significantly increased among 1920 patients with schizophrenia compared with 1920 control subjects in the combined population. A significantly lower response to CB2 ligands in cultured CHO cells transfected with the R63 allele compared with those with Q63, and significantly lower CB2 receptor mRNA and protein levels found in human brain with the CC and CT genotypes of rs12744386 compared with TT genotype were observed. AM630 exacerbated MK-801- or methamphetamine-induced disturbance of prepulse inhibition and hyperactivity in C57BL/6JJmsSlc mice

Jackowski A, Douglas-Palumberi H, Jackowski M, Win L, Schultz R, Staib L, Krystal J, Kaufman J. 2008. “Corpus callosum in maltreated children with PTSD: A diffusion tensor imaging study” Psychiatry Res 162(3): 256-261 in dropbox

the maltreated children had reduced FA in the medial and posterior regions of the CC

Jackowski A, Perera T, Abdallah C, Garrido G, tang C, Martinez J, Mathew S, Gorman J, Rosenblum L, Smith E, Dwork A, Shungu D, Kaffman A, Gelernter J, Coplan J, Kaufman J. 2011. “Early-life stress, corpus callosum development, hippocampal volumetrics, and anxious behavior in male nonhuman primates” Psychiatry Res 192(1): 37-44

Male bonnet monkeys (Macaca radiata) were subjected to the Variable Foraging Demand (VFD) early stress paradigm as infants

VFD rearing was associated with smaller CC size, CC measurements were found to correlate with fearful behavior in adulthood, and ex-vivo CC assessments showed high consistency with earlier MRI measures. Region of Interest (ROI) hippocampus and whole brain voxel- based morphometry assessments were also completed and VFD rearing was associated with reduced hippocampus and inferior and middle temporal gyri volumes

smaller mid-sagittal cross-sectional area of corpus callosum observed in VFD-reared animals (F1,17=5.43, P <0.032; VFD: 90.0 mm2 ± 11.9; non-VFD: 98.4 mm2 ± 14.6) VBM of total CC volume found no significant main effect
smaller left but not right hippocampal volume in VFD (F1,17=8.21, P < 0.01; VFD: 0.43 cm3 ± 0.04; non-VFD: 0.46 cm3 ± 0.02)

animals were exposed briefly to a masked intruder and fearful responses were scored: emotional responsivity measure correlated significantly with the ROI CC assessments (R=-0.74, P < 0.01) larger mid-sagittal CC = lower intruder stress

Over 80% (5/6) of the VFD subjects with one or two “s” alleles had smaller CC cross-sections… no genotype effect observed for left or right hippocampal volume

Primates who carried at least one “s” allele had smaller volumes of cuneus bilaterally, left fusiform gyrus, and right intraparietal sulcus. Moreover, greater volumes of right amygdala, right striatum, bilateral middle temporal gyrus, right superior temporal gyrus, and right inferior frontal gyrus volumes were observed in the primates with one or two “s” alleles

gender differences in the CC (Bachmann et al., 2003; Suganthy et al., 2003) and the gender-by-early stress effect on the CC (Coe et al., 2002; see Table 3)

medial and posterior portions of the CC contain interhemispheric projections from the auditory cortices, posterior cingulate, insula, and somatosensory and visual cortices to a lesser extent. It also includes connections from the inferior parietal lobe to the contralateral inferior parietal lobe, superior temporal sulcus, cingulate, retrosplenial cortex, and parahippocampal gyrus (Pandya and Seltzer, 1986). Several of the regions with interhemispheric projections through the medial and posterior CC have connections with prefrontal cortical areas, and are involved in circuits that mediate the processing of emotional stimuli and various memory functions — core disturbances associated with a history of early trauma

In rodents, early-life stress seems to affect the hippocampus though the effects are seen only in adulthood and not during development (Andersen and Teicher, 2004)

Human studies which showed an association between childhood adverse events and small hippocampal size in adults (Bremner et al., 1997; Stein et al., 1997; Driessen et al., 2000; Vythilingam et al., 2002) but not in children (De Bellis et al., 1999; Carrion et al., 2001; De Bellis et al., 2001; De Bellis, 2002; Tupler and De Bellis, 2006; Woon and Hedges, 2008)

Preclinical studies of the effects of stress suggest a minimum of four mechanisms by which hippocampal atrophy may result from stress: dendritic atrophy, synaptic remodeling (synaptic overproduction and pruning), increased neuronal death, and decreased rates of neurogenesis (Sapolsky et al., 1985; Watanabe et al., 1992; Gould and Cameron, 1996; Sapolsky, 1996; Andersen and Teicher, 2004)

Reductions in middle and inferior temporal gyri were also noted in association with VFD rearing. The middle temporal gyrus and inferior temporal gyrus subserve language and semantic memory processing, visual perception, and multimodal sensory integration (Onitsuka et al., 2004)

Jacobus J, McQueeny T, Bava S, Schweinsburg B, Frank L, Yang T, Tapert S. 2009. “White matter integrity in adolescents with histories of marijuana use and binge drinking” Neurotoxicol Teratol 31(6): 349-355

42 adolescents (ages 16−19) classified as controls, binge drinkers, or binge drinkers who are also heavy marijuana users

Significant between group differences were found in FA in eight white matter regions (ps ≤ .016) between the binge drink-only group and controls, including superior corona radiata, inferior longitudinal fasciculus, inferior fronto-occipital fasciculus, and superior longitudinal fasciculus. Interestingly, in 4 of these same regions, binge drinkers who are also heavy marijuana users had higher FA than binge drinkers who did not use marijuana (ps < .05). MD did not differ between groups

Jacobus J, Thayer R, Trim R, Bava S, Frank L, Tapert S. 2013. “White matter integrity, substance use, and risk taking in adolescence” Psychol Addict Behav 27(2): 431-442

Altered white matter integrity in mid-adolescence was hypothesized to predict subsequent risk taking behaviors 1.5 years later

Adolescent substance users (predominantly alcohol and marijuana, n=47) and demographically similar non-users (n=49)

In substance using youth (n=47), lower white matter integrity at baseline in the fornix and superior corona radiata predicted follow-up substance use (ΔR2 =10–12%, ps < .01), and baseline fornix integrity predicted follow-up delinquent behaviors (ΔR2 = 10%, p < .01) 1.5 years later. Poorer fronto-limbic white matter integrity was linked to a greater propensity for future risk taking behaviors among youth who initiated heavy substance use by mid-adolescence. Most notable were relationships between projection and limbic system fibers and future substance use frequency

While internalizing behaviors have been described as internal emotional states that are “overcontrolled,” externalizing is suggested as “undercontrol,” (Achenbach & Rescorla, 2001; Achenbach & Edelbrock, 1978)

the tendency to engage in some degree of risk taking and novelty seeking can increase opportunities for success and social status (Spear, 2010)

cross-sectional study suggests a link between more coherent white matter in superior/anterior corona radiata fiber tracts and increased engagement in substance use-related risk taking behaviors (Berns, Moore, & Capra, 2009); however this finding is in the opposite directions of neurodevelopmental models of adolescent risk taking and therefore warrants further investigation

Jacobus J, Squeglia L, Bava S, Tapert S. 2013. “White matter characterization of adolescent binge drinking with and without co-occurring marijuana use: A 3-year investigation” Psychiatry Res 214(3): 374-381

controls with consistently minimal substance use, n = 16; teens who gradually increase their heavy episodic drinking n = 17, and continuous binge drinkers with heavy marijuana use, n = 21

chronic alcohol use has been consistently associated with abnormalities in white matter volume and integrity (Kril et al., 1997; Pfefferbaum et al., 2000; Pfefferbaum and Sullivan, 2005; Pfefferbaum et al., 2006)

more alcohol use over 1.5 year follow-up was associated with poorer white matter at follow-up (decreased FA), controlling for marijuana use and baseline white matter health (Bava et al., 2013). Together, findings suggest that deleterious effects might be more attributable to binge drinking than marijuana, as preliminary studies suggest that cannabis may have a lesser effect on white matter development during adolescence (Delisi et al., 2006) and may actually serve a neuroprotective role in attenuating the negative effects of heavy alcohol use on white matter integrity during this critical maturation period (Jacobus et al., 2009)

As existing white matter studies from our laboratory and others are largely cross-sectional, it is unclear if differences between substance users and controls predated the onset or escalation of alcohol and marijuana use, or emerged as a result of substance use

we hypothesized that adolescents who engage in both heavy drinking and/or marijuana would demonstrate poorer white matter integrity compared to controls with minimal substance use histories by late adolescence/early adulthood. We found evidence to support this hypothesis in 15 white matter clusters, including association fiber tracts (e.g., superior longitudinal fasciculus, uncinate fasciculus), projection fiber tracts (e.g., regions of the corona radiata), and interhemispheric tracts (e.g., splenium, genu)… most clusters showed significantly decreased FA from baseline to 3-year follow-up

poorer global neurocognitive performance, as measured by a change from 18-month follow-up to 3-year follow-up was related to poorer white matter integrity within a large white matter tract connecting frontal and parietal brain regions (i.e., superior longitudinal fasciculus) at approximately 20 years of age

we did not see substantial differences in white matter integrity between our two user groups, or correlations between neuropsychological performance and substance use severity (e.g., lifetime drinking occasions, marijuana occasions)

at 18-month follow-up, adolescents who engaged in binge drinking demonstrated better global cognitive performance than their marijuana-using counterparts, but this was no longer observed at the 3-year follow-up

We have also seen alterations in macrostructural integrity (e.g., cortical thickness, (Squeglia et al., 2012b) and functional brain activation patterns (Schweinsburg et al., 2011) in teens with similar alcohol use profiles, as well as declines in cognitive status (Squeglia et al., 2009; Mahmood et al., 2010). In a previous investigation, Jacobus et al. (2009), we found that adolescent alcohol users (approximately 17 years old) demonstrated poorer white matter integrity compared to not only matched controls, but to heavy marijuana users with similar levels of alcohol use

it remains surprising that our marijuana users do not show a marked decrease in tissue integrity compared to the binge drinkers given their consistent and heavy co-occurring use

Jacobson S, Kelleher I, Harley M, Murtagh A, Clarke M, Blanchard M, Connolly C, O’Hanlon E, Garavan H, Cannon M. 2010. “Structural and functional brain correlates of subclinical psychotic symptoms in 11-13 year old schoolchildren” Neuroimage 49(2): 1875-85

11 school-going, non-treatment seeking children aged 11-13 who were at symptomatic risk for psychosis (AR) and 14 healthy control children aged 11-12 without subclinical psychotic symptoms (CON)

fMRI results showed reduced activity in the AR group within right frontal and bilateral temporal cortex for response inhibition and reduced activity within the anterior cingulate, insula and middle frontal gyrus for error-related processing (p<.05, corrected). VBM analysis revealed GM increases in the AR group within middle and superior temporal gyri, angular gyrus, orbitofrontal gyrus and GM decrease within the inferior temporal gyrus (p<.05, corrected). DTI analysis identified WM decreases in the AR group along the inferior fronto-occipital fasciculus, cingulum and inferior longitudinal fasciculus (p<.05, corrected)

Jager G, Kahn R, Van Den Brink W, Van Ree J, Ramsey N. 2006. “Long-term effects of frequent cannabis use on working memory and attention: an fMRI study” Psychopharmacology (Berl) 185(3): 358-68 in dropbox

ten frequent cannabis users (after 1 week of abstinence) less hippocampi activation in MJ users, no structural differences

Jager G, Van Hell H, De Win M, Kahn R, Van Den Brink W, Van Ree J, Ramsey N. 2007. “Effects of frequent cannabis use on hippocampal activity during an associative memory task.” Eur Neuropsychopharmacol 17(4):289-97

Cannabis users and controls performed equally well during the working memory task and the selective attention task, greater activity in the left superior parietal cortex in the cannabis users

Jansen, K. 2004. Ketamine: Dreams and Realities MAPS

Ketamine binds to receptors (called PCP receptors for historical reasons) inside tunnels and causes a blockage. The outer end of the tunnel is attached to a glutamate receptor (called an NMDA receptor) on the cell surface… A natural tunnel blocker will protect the brain from damage while generating a state of being that also holds the flood of overwhelming anxiety at bay. The NDE may be beneficial for the physical brain as well as having the potential for a positive mental outcome. The benefit may be even greater where the forces of the psyche give the person a strong message to “go back” in terms of a mythological drama, and tell them that it is not their time to go. This might be the final expression of the deep drive in the mind to survive

Jaycox L, Ebener P, Damesek L, Becker K. 2004. “Trauma exposure and retention in adolescent substance abuse treatment” J Trauma Stress 17(2): 113-21

212 adolescents upon admission to long-term residential drug treatment… 71% trauma exposed, 29% of which PTSD+. Trauma-exposed PTSD- left treatment sooner than nonexposed

Jean-Gilles L, Gran B, Constantinescu C. 2010. “Interaction between cytokines, cannabinoids and the nervous system” Immunobiology 215(8): 606-10

Cytokines play important roles in neuroinflammation and neurodegeneration… Activation of the cannabinoid system is associated with therapeutic effects that may be mediated by the down-regulation of cytokine expression. Here we review the findings from studies on the reciprocal regulation of the immune and cannabinoid systems, which is based on functional as well as anatomical connections

Jenko K, Hirvonen J, Henter I, Anderson K, Zoghbi S, Hyde T, Deep-Soboslay A, Innis R, Kleinman J. 2012. “Binding of a tritiated inverse agonist to cannabinoid CB1 receptors is increased in patients with schizophrenia” Schizophr Res 141(2-3): 185-188

The specific binding of [3H]MePPEP to CB1 receptors was 20% higher in patients with schizophrenia than in controls

Jia W, Hegde V, Singh N, Sisco D, Grant S, Nagarkatti M, Nagarkatti P. 2006. “Δ9-Tetrahydrocannabinol-Induced Apoptosis in Jurkat Leukemia T Cells Is Regulated by Translocation of Bad to Mitochondria” Mol Cancer Res 4: 549

Plant-derived cannabinoids, including Δ9-tetrahydrocannabinol (THC), induce apoptosis in leukemic cells, although the precise mechanism remains unclear

THC down-regulated Raf-1/mitogen-activated protein kinase/ERK kinase (MEK)/ERK/RSK pathway leading to translocation of Bad to mitochondria. THC also decreased the phosphorylation of Akt. However, no significant association of Bad translocation with phosphatidylinositol 3-kinase/Akt and protein kinase A signaling pathways was noted when treated cells were examined in relation to phosphorylation status of Bad by Western blot and localization of Bad to mitochondria by confocal analysis. Furthermore, THC treatment decreased the Bad phosphorylation at Ser112 but failed to alter the level of phospho-Bad on site Ser136 that has been reported to be associated with phosphatidylinositol 3-kinase/Akt signal pathway. Jurkat cells expressing a constitutively active MEK construct were found to be resistant to THC-mediated apoptosis and failed to exhibit decreased phospho-Bad on Ser112 as well as Bad translocation to mitochondria. Finally, use of Bad small interfering RNA reduced the expression of Bad in Jurkat cells leading to increased resistance to THC-mediated apoptosis. Together, these data suggested that Raf-1/MEK/ERK/RSK-mediated Bad translocation played a critical role in THC-induced apoptosis in Jurkat cells

John O, Gross J. 2004. “Healthy and unhealthy emotion regulation: personality processes, individual differences, and life span development” J Pers 72(6): 1301-33

we review experimental findings showing that reappraisal has a healthier profile of short-term affective, cognitive, and social consequences than suppression. In the second section, we review individual-difference findings, which show that using reappraisal to regulate emotions is associated with healthier patterns of affect, social functioning, and well-being than is using suppression. In the third section, we consider issues in the development of reappraisal and suppression and provide new evidence for a normative shift toward an increasingly healthy emotion regulation profile during adulthood (i.e., increases in the use of reappraisal and decreases in the use of suppression).

Johns A. 2001. “Psychiatric effects of cannabis” British Journal of Psychiatry 178: 116-122

From New Zealand, a sample of 1000 people aged 18-25 were asked to complete a self-administered questionnaire on cannabis use and related problems (Thomas, 1996). Those respondents who admitted using cannabis (38%) were asked about mental health consequences; of these, 22% reported panic attacks or anxiety. Women were twice as likely as men to report these symptoms. Troisi et al (1998) used urine tests on Italian draftees to identify 133 men who used only cannabis. All individuals with a pre-existing psychosis or severe personality disorder had been excluded. An adjustment disorder with depressed mood was found in 16%, major depression in 14%, and dysthymia in 10.5%. The severity of these symptoms was dose-related. No acute psychotic symptoms were reported. Reilly et al (1998) describe the adverse effects found among 268 cannabis users who had taken the drug for at least 10 years, and who continued to smoke about two refers a day. The most common adverse effects were feelings of anxiety, paranoia or depression (21%), tiredness and low motivation (21%)

Peralta & Cuesta (1992) reported that cannabis had no significant effect on positive symptoms of schizophrenia, but it did attenuate negative symptoms.

Subjects were asked about episodes of violence in the previous year (i.e. hitting a partner, bruising a child, fighting, using a weapon in a fight while drinking). Of the 191 respondents with cannabis abuse or dependence, 19.25% (risk ratio 9.4) had been violent compared with 12.69% (risk ratio 6.2) of those with schizophrenia or schizophreniform disorder and 24.57% (risk ratio 11.9) of those with alcohol abuse or dependence. Here, the risk is expressed relative to the 2.05% who were violent among those of the sample population who showed no psychiatric disorder

Andreasson et al (1987) of 45 570 Swedish conscripts, of whom 9.4% had used cannabis and 1.7% were ‘high consumers’ having used more than 50 times. Fifteen-year follow-up data were drawn from national registers of deaths and psychiatric cases. Compared with non-users, the relative risk of schizophrenia was 2.4 in the group that reported use of cannabis at least once, rising to 6.0 among heavy users. Nearly half (430/730) of these high consumers had a psychiatric diagnosis other than psychosis on conscription; controlling for this reduced the relative risk to 2.9. The authors suggest that cannabis consumption is a ‘ life-event stressor’ for individuals vulnerable to schizophrenia. Hall et al (1994) offer a number of alternative explanations. There is a large temporal gap between self-reported cannabis use on conscription and the development of schizophrenia over 15 years, and no data as to whether the cannabis use continued during this time. Drugs other than cannabis could have been taken at any time after conscription.

It should also be noted that as only 49 of the 274 conscripts with schizophrenia had ever tried cannabis, then this drug may only be relevant to a minority of cases. Furthermore, Jablensky et al (1992) demonstrate a striking uniformity in the incidence of schizophrenia in cultures with very different rates of cannabis consumption.

McGuire et al (1994). In this study, 23 patients with psychosis and with cannabis in their urine were gender-matched with 46 drug-free controls with psychosis, and the lifetime risk of psychiatric disorder among all the first-degree relatives was ascertained. The cannabis-positive subjects had a significantly greater (7.1%) familial risk of schizophrenia than controls (0.7%), suggesting that the development or recurrence of acute psychosis in the context of cannabis use may be associated with a genetic predisposition to schizophrenia.

Johns L, Cannon M, Singleton N, Murray R, Farrell M, Brugha T, Bebbington P, Jenkins R, Meltzer H. 2004. “Prevalence and correlates of self-reported psychotic symptoms in the british population” British Journal of Psychiatry 185(4): 298-305

8580 respondents aged 16–74 years were interviewed

5.5% endorsed one or more items on the PSQ. Factors independently associated with psychotic symptoms were cannabis dependence, alcohol dependence, victimisation, recent stressful life events, lower intellectual ability and neurotic symptoms. Male gender was associated with paranoid thoughts, whereas female gender predicted hallucinatory experiences

n the US National Comorbidity Survey, 28% of individuals endorsed psychosis-screening questions although the rate of clinician-defined psychosis was only 0.7% (Kendler et al, 1996). In the Dunedin birth cohort, 25% of the sample at age 26 years reported at least one delusional or hallucinatory experience that was unrelated to drug use or physical illness, but only 3.7% actually fulfilled criteria for schizophreniform disorder (Poulton et al, 2000). Data on psychotic symptoms were collected as part of the Dutch NEMESIS study (van Os et al, 2000). This representative general population sample of 7076 men and women was interviewed using the Composite International Diagnostic Interview (CIDI), which contains 17 core positive psychosis items; 17.5% of the sample scored at least one on any type of positive psychosis rating but only 2.1% received a DSM–III–R (American Psychiatric Association, 1987) diagnosis of non-affective psychosis. Together, these findings suggest that only a small part of the total phenotypic continuum of psychosis is represented by clinically verified and defined cases…  It is likely that variation in prevalence rates across studies is partly a consequence of the different instruments used (number and type of questions asked)

Individuals were 3.5 times as likely (95% CI 2.9–4.5) to experience one or more psychotic symptoms if they scored above 12 on the CIS–R, were almost three times as likely (95% CI 2.0–4.4) if they were dependent on cannabis and were just under 2.5 times as likely (95% CI 1.3–3.9) if they were dependent on any other drug (with or without cannabis). Experience of victimisation and alcohol dependence were also strongly associated with psychotic symptoms (OR=2.0, 95% CI 1.7–2.6; OR=1.8, 95% CI 1.3–2.4, respectively). After controlling for interrelationships between all the variables, young age, non-White ethnic group, urban residence and recent drug use were no longer associated significantly with psychotic symptoms

we cannot determine the direction of the relationship between cannabis dependence and psychotic symptoms from these data… risk was specific to cannabis use, as opposed to the use of other drugs. The association between alcohol dependence and psychotic symptoms may be related to the occurrence of withdrawal symptoms

The association between non-White ethnic group and psychotic symptoms in this study was no longer significant after controlling for other factors, including victimisation and stressful life events. Although it has been reported that Black and ethnic minority patients with psychosis do not experience more life events than do White British patients, they do perceive these events as more threatening (Gilvarry et al, 1999)

experiences of victimisation may lead individuals to believe that they are vulnerable and to view other people and the world as hostile and threatening; and stressful events may then trigger symptoms. Janssen et al (2003) found that perceived discrimination was associated longitudinally with onset of delusional ideation

Johnson K, Bonn-Miller M, Leyro T, Zvolensky M. 2009. “Anxious arousal and anhedonic depression symptoms and the frequency of current marijuana use: testing the mediating role of marijuana-use coping motives among active users” J Stud Alcohol Drugs 70(4): 543-550

After controlling for daily cigarette smoking rate, alcohol consumption, and gender, anxious arousal symptoms, but not anhedonic depression symptoms, were significantly and uniquely associated with the frequency of marijuana use. In addition, coping motives for marijuana use mediated the relation between anxious arousal symptoms and the frequency of current marijuana use.

Jones D, Knosche T, Turner R. 2013. “White matter integrity, fiber count, and other fallacies: the do’s and don’ts of diffusion MRI” 73: 239-54

Juon H-S, Fothergill K, Green K, Doherty E, Ensminger M. 2011. “Antecedents and consequences of marijuana use trajectories over the life course in an African American population” Drug Alcohol Depend 118(2-3): 216-223

five marijuana trajectories for men (n=455) and four trajectories for women (n=495) were identified extending from adolescence to young adulthood (age 32). We labeled the four trajectory groups similar for men and women “abstainers,” “adolescent only users,” “early adulthood decliners,” and “persistent users.” We named the unique fifth group for men “late starters.”

Although African American youth consistently use marijuana less than white youth (Johnston et al., 2006; Wallace, 1999), the rates among African American adults equal or exceed those of white adults, suggesting a “crossover effect” (Geronimus et al., 1993;National Institute on Drug Abuse, 2002)

In prior work, we have found that first grade children who did not perform well in school were more likely to use drugs later as adolescents (Kellam et al., 1980; Ensminger et al., 1982). Specifically, first grade children rated by teachers as having aggressive behavior or the combination of shy and aggressive behavior were more likely to use alcohol, cigarettes, and marijuana in adolescence and early adulthood (Ensminger et al., 2002). Later in the life course, other social fields, such as family formation and employment, become more prominent, and lack of involvement in these fields relates to later life onset (Green et al., 2010)

ur research is also guided by social control theory (Hirschi, 1969), which explains that those who are strongly bonded to important social institutions are less likely to engage in deviant behavior

Schulenberg et al. (2005) showed that their six marijuana trajectories were related to differences in parental education, religion, high school grades, and employment. Windle and Wiesner (2004), using a white sample, found that their “high chronic” group compared less favorably to the other four trajectory groups on delinquency, academic performance, drug-using friends, and stressful life events

Childhood classroom behaviors were predictors for marijuana trajectories with male later starters(OR=2.13) more likely to be aggressive than abstainers and female adolescent only users (OR=2.51) more likely to be shy than abstainers. Abstainers did not differ on childhood factors from persistent users orearly adult decliners for either men or women

bstainers were more likely to finish high school compared to persistent users(OR=1.88 for men; OR=2.30 for women) and to male early adult decliners (OR=2.60). Female persistent users were more likely to have low adolescent family involvement than abstainers (OR=2.00)

For males in general, those in the three groups with more problematic use (early adult decliners, late starters, and persistent users) were more likely to have a substance use disorder, be incarcerated, never marry, and have high levels of MDD. The male persistent users were at highest risk overall. For females, those in the persistent user group were also at highest risk, with higher levels of substance use disorder, incarceration, and MDD. Interestingly, females in the adolescent only group had the second highest level of MDD, which is intriguing as they would be expected to have fewer mental health problems than those who continue using marijuana into adulthood.

we do not know if the depression influenced trajectory membership, resulted from membership, or merely correlated with the marijuana trajectory

Kaffman A. 2009. “The Silent Epidemic of Neurodevelopmental Injuries” Biol Psychiatry 66(7): 624-626 in dropbox

(licking and grooming in rats protects against hyperactivation of hippocampal corticosterone) because Low LG have lower levels of GR in their hippocampus, they show elevated and prolonged levels of corticosterone when stressed, compared with transient corticosterone release in High LG. once established, this pattern of DNA methylation is highly stable and persists throughout the animal’s life.

Offspring of High LG dams are less fearful, show decreased stress reactivity, and perform better on several hippocampal-dependent tasks compared with offspring raised by Low LG dams

a 2009 report from the Institute of Medicine estimated the cost related to ELA at $247 billion annually (1), which is similar in magnitude to the estimated costs for all cancers combined. Interestingly, however, we spend only $.05 on research related to psychopathology of ELA compared with $2 spent on cancer research for each $100 of their respective costs (12)

Kamprath K, Plendl W, Marsicano G, Deussing J, Wurst W, Lutz B, Wotjak C. 2009. “Endocannabinoids mediate acute fear adaptation via glutamatergic neurons independently of corticotropin-releasing hormone signalling” Genes Brain Behav 8(2): 203-11

Kamprath K, Romo-Parra H, Haring M, Gaburro S, Doengi M, Lutz B, Pape H-C. 2011. “Short-term adaptation of conditioned fear responses through endocannabinoid signalling in the central amygdala” Neuropsychopharmacology 36(3): 652-663

CB1 is expressed in the CeA of mice and that CB1 in the CeA mediates short-term synaptic plasticity, namely depolarization-induced suppression of excitation (DSE) and inhibition (DSI). CB1 antagonist AM251 increased both excitatory and inhibitory postsynaptic responses in CeA neurons. Local application of AM251 in the CeA in vivo resulted in an acutely increased fear response in an auditory fear conditioning paradigm. Upon application of AM251 in the basolateral nucleus of the amygdala (BLA) in an otherwise identical protocol, no such acute behavioral effects were detected, but CB1 blockade resulted in increased fear responses during tone exposures on the subsequent days. Moreover, we observed that the efficacy of DSE and DSI in the CeA was increased on the day following fear conditioning, indicating that a single tone-shock pairing resulted in changes in endocannabinoid signaling in the CeA

Kanayama G, Rogowska J, Pope H, Gruber S, Yurgelun-Todd D. 2004. “Spatial working memory in heavy cannabis users: a functional magnetic resonance imaging study” Psychopharmacology (Berl) 176(3-4):239-47 in dropbox

12 long-term heavy cannabis users, 6-36 h after last use
Recent cannabis users displayed greater and more widespread brain activation than normal subjects when attempting to perform a spatial working memory task  greater dorsolateral prefrontal recruitment

little or no significant correlation with subjects’ years of education, verbal IQ, lifetime episodes of cannabis use, or urinary cannabinoid levels at the time of scanning.

Kaplan H, Tolle G, Yoshida T. 2006. “Substance use-induced diminution of violence: a countervailing effect in longitudinal perspective” Criminology 39(1): 205-224

cannabis use in adolescence associated with less violence later on

Kaplan B, Springs A, Kaminski N. 2008. “The profile of immune modulation by cannabidiol (CBD) involves deregulation of nuclear factor of activated T cells (NFAT)” Biochem Pharmacol 76(6): 726-737

e demonstrated previously that CBD suppressed interleukin-2 (IL-2) production from phorbol ester plus calcium ionophore (PMA/Io)-activated murine splenocytes. Thus, the focus of the present studies was to further characterize the effect of CBD on immune function. CBD also suppressed IL-2 and interferon-γ (IFN-γ) mRNA expression, proliferation, and cell surface expression of the IL-2 receptor alpha chain, CD25

CBD also suppressed activator protein-1 (AP-1) and nuclear factor of activated T cells (NFAT) transcriptional activity, which are critical regulators of IL-2 and IFN-γ. Furthermore, CBD suppressed the T cell-dependent anti-sheep red blood cell immunoglobulin M antibody forming cell (anti-sRBC IgM AFC) response. Finally, using splenocytes derived from CB1-/-/CB2-/- mice, it was determined that suppression of IL-2 and IFN-γ and suppression of the in vitro anti-sRBC IgM AFC response occurred independently of both CB1 and CB2. However, the magnitude of the immune response to sRBC was significantly depressed in CB1-/-/CB2-/- mice. Taken together, these data suggest that CBD suppresses T cell function and that CB1 and/or CB2 play a critical role in the magnitude of the in vitro anti-sRBC IgM AFC response.

Karagianis J, Novick D, Pecenak J, Haro J, Dossenbach M, Treuer T, Montgomery W, Walton R, Lowry A. 2009. “Worldwide-schizophrenia outpatient health outcomes (W-SOHO): baseline characteristcs of pan-regional observational data from more than 17,000 patients” International Journal of Clinical Practice 63(11): 1578-1588

50% (range 41–59%) of patients taking antipsychotics exhibited extrapyramidal symptoms at baseline, and 62% (34–67%) of patients reported sexual dysfunction in the previous month. On average, only 19% (16–23%) of patients were in paid employment and as many as 69% were living in dependent housing

Outcomes were significantly better in “developing” countries than in “developed” countries, possibly due to differences in treatment

Karl A, Schaefer M, Malta L, Dorfel D, Rohleder N, Werner A. 2006. “A meta-analysis of structural brain abnormalities in PTSD” Neurosci Biobehav Rev 30(7): 1004-31

smaller hippocampal volumes in PTSD, group differences moderated by MRI methodology, PTSD severity, medication, age and gender. Trauma-exposed PTSD- showed smaller bilateral hippocampal. smaller left amygdala volumes in PTSD compared to both healthy and trauma-exposed controls, and significantly smaller anterior cingulate cortex compared to trauma-exposed controls. Pediatric samples with PTSD exhibited significantly smaller corpus callosum and frontal lobe volumes compared to controls, no group differences in hippocampal volume. (1) hippocampal volumetric differences covary with PTSD severity; (2) hippocampal volumetric differences do not become apparent until adulthood; and (3) PTSD is associated with abnormalities in multiple frontal-limbic system structures

Kathuria S, Gaetani S, Fegley D, Valino F, Duranti A, Tontini A, Mor M, Tarzia G, La Rana G, Calignano A, Giustino A, Tattoli M, Palmery M, Cuomo V, Piomelli D. 2003. “Modulation of anxiety through blockade of anandamide hydrolysis” Nat Med 9(1): 76-81

in rats FAAH inhibitors exhibit benzodiazepine-like properties in the elevated zero-maze test and suppress isolation-induced vocalizations. These effects are accompanied by augmented brain levels of anandamide and are prevented by CB1 receptor blockade

Kato M, Ohno-Shosaku T, Hashimotodani Y, Uchigashima M, Watanabe M. 2009. “Endocannabinoid-mediated control of synaptic transmission” Physiological Reviews 89(1): 309-380

Marijuana and other derivatives of the plant Cannabis sativa have been used for thousands of years for their therapeutic and mood-altering properties.

blocking the endocannabinoid system suppresses the extinction of aversive memory (330), relearning of the water maze test (540), cerebellum-dependent eyeblink conditioning (277), drug addiction (323), feeding behavior (407), a certain form of stress-induced analgesia (232), and the recovery of neurobehavioral function after brain injury (411)

CB1 polymorphisms have been reported to link to obesity-related phenotypes (173, 448), hebephrenic schizophrenia (78, 530), childhood attention deficit/hyperactivity disorder (429), and depression in Parkinson’s disease (20)

High levels of [3H]CP55,940 binding are observed in innermost layers of the olfactory bulb, hippocampus (particularly high in the dentate molecular layer and the CA3 region), lateral part of the striatum, target nuclei of the striatum (i.e., globus pallidus, entopeduncular nucleus, substantia nigra pars reticulata), and cerebellar molecular layer. Moderate levels are noted in other forebrain regions and a few nuclei in the brain stem and spinal cord. They include the cerebral cortex (higher in the frontal, parietal, and cingulated areas than other cortical areas), septum, amygdala (nucleus of lateral olfactory tract), hypothalamus (ventromedial hypothalamus), lateral subnucleus of interpeduncular nucleus, parabrachial nucleus, nucleus of solitary tract (caudal and commissural portions), and spinal dorsal horn. The thalamus, other nuclei in the brain stem, and spinal ventral horn are low in ligand binding

CB1 mRNA is expressed in medium spiny neurons and parvalbumin-positive interneurons within the striatum, and in cerebellar granule cells, basket cells, and stellate cells within the cerebellar cortex. In contrast, nonuniform expression reflecting the presence of a few cell types expressing high CB1 mRNA is found in the cerebral cortex, hippocampus, and amygdala. In these regions, strong expression is seen in cholecystokinin (CCK)-positive interneurons, whereas no expression in parvalbumin-positive ineterneurons and generally low expression in principal (or excitatory) neurons are noted

CB1 is preferentially targeted to presynaptic elements (Figs. 1 and 2). As a result, regional distributions of CB1 mRNA and immunoreactivity sometimes dissociate. This is particularly conspicuous when CB1 is predominantly expressed in projection neurons. For example, medium spiny neurons are the output neurons in the striatum, and very intense CB1immunoreactivity is detected in the target regions rather than within the striatum CB1 immunoreactivity is strong along the striatonigral and striatopallidal pathways as well as in substantia nigra pars reticulata and the globus pallidus (Fig. 1A) (342), in both of which CB1mRNA is not expressed

inhibitory synapses generally have higher levels of CB1 than excitatory synapses among CB1-expressing synapses within given neural regions… the density of CB1immunogold labeling on inhibitory synaptic elements is higher than excitatory synapses by 30 times for hippocampal CA1 pyramidal cells (Fig. 2), six times for cerebellar Purkinje cells, and three to four times for striatal medium spiny neurons (267, 528)

CB2 is found in microglial cells, not in astrocytes (13, 387), and is upregulated in response to chronic pain (27, 325, 387, 578)

CB1 activation inhibits adenylyl cyclase or cAMP production in many preparations

In neurons or CB1-transfected cells, application of a cannabinoid agonist activates A-type (198) and inwardly rectifying K+ channels (313) and inhibits N- and P/Q-type Ca2+ channels (524) and D- and M-type K+ channels (365, 466)

neurotransmitters reported to be controlled by the CB1 receptor include glutamate (297), GABA (502), glycine (247), acetylcholine (176), norepinephrine (241), dopamine (61), serotonin (374), and CCK (