Medical Marijuana scientific papers - top picks for 2015

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 [one researcher's] 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.