Marijuana and the Brain: More Research, More Questions

Megan Brooks

August 27, 2015

How cannabis use might affect the brain of young people is the subject of two major studies published this week.

One study finds no significant effect of cannabis use on brain volume, but rather hints that the brains of users may be smaller to begin with.

The other study suggests that marijuana may alter brain structure in young men at high genetic risk of developing schizophrenia, which can be triggered by cannabis use.

Both studies were published online August 26 in JAMA Psychiatry.

In a related editorial, David Goldman, MD, of the National Institute on Alcohol Abuse and Alcoholism, Rockville, Maryland, cautions that it "would be wrong to conclude that it is safe to use cannabis" or that it "would be safe for people with the right genetic makeup or women, in particular, to use cannabis."

No Cause-and-Effect Conclusions

In the first study, researchers studied 483 twin/siblings aged 22 to 35 years, of whom 262 reported a history of cannabis use. On MRI, cannabis users had smaller left amygdala volume (roughly 2.3%; P = .007) and smaller right ventral striatum volume (about 3.5%; P < .005) than nonusers. These volumetric differences, however, were in the range of normal variation.

"Importantly," say the researchers, brain volumes did not differ between sex-matched siblings discordant for cannabis use (P = .35). Both exposed and unexposed siblings in pairs discordant for cannabis use showed reduced amygdala volumes relative to members of concordant unexposed pairs (P = .003).

"Our study shows that the relationship between a simple index of cannabis use (ever using it during one's lifetime) and amygdala volume is attributable to common predisposing factors, such as those shared by members of twin and sibling pairs," study investigator Arpana Agrawal, PhD, associate professor, Department of Psychiatry, Washington University School of Medicine in St. Louis, told Medscape Medical News.

She noted that although other studies have suggested causal effects of cannabis use on brain volumes, this study provides an alternative explanation for that association.

"We can conclude that factors that predispose individuals to use cannabis may also be associated with variations in their amygdala volume," Dr Agrawal explained. "These factors may be genetic or relate to early rearing environment, are shared by brothers and sisters, and influence both our likelihood of using cannabis and variations in amygdala volume. However, we cannot draw any definitive conclusions about causation nor infer what results might be seen when studying heavier, more involved levels of cannabis use and other regions of the brain."

In the second study, researchers asked whether cannabis use influences brain maturation differently in adolescents with low vs high genetic risk for schizophrenia, as estimated from 108 genetic locations identified by the Psychiatric Genomics Consortium.

"Note that all 1577 participants were recruited from the general population ― not selected because of their substance use or mental health. As such, it provides a snapshot of what might be going on in the brain of an average teenager," study investigator Tomáš Paus, MD, PhD, Tanenbaum Chair in Population Neuroscience, the Rotman Research Institute, and professor of psychology and psychiatry, University of Toronto, Ontario, Canada, told Medscape Medical News.

The researchers observed a negative correlation between cannabis use in early adolescence (by age 16 years) and cortical thickness in male participants with a high polygenic risk score. This was not the case for low-risk male participants or for the low- or high-risk female participants.

"Our findings suggest that cannabis use might interfere with the maturation of the cerebral cortex in male adolescents at high risk for schizophrenia by virtue of their polygenic risk score," the authors write.

Any Effect a "Serious Concern"

Dr Paus told Medscape Medical News, "Although we cannot make any cause-and-effect conclusions about the associations between cannabis use and brain maturation, it seems that cannabis- related differences are particularly pronounced in cortical regions with high density of cannabinoid receptor 1. This suggests that chemicals inhaled when smoking cannabis may have something to do with what we see.

"Whether or not this is the case, the fact that we observed the link between early cannabis use and brain maturation only in boys with high polygenic risk score tells us that the brains of these boys may be more susceptible to adverse experiences," Dr Paus said.

"Any effect on brain structure is a serious concern," writes Dr Goldman in his editorial. "If replicated, these genotype-mediated effects of cannabis use are of special concern in young men made vulnerable by genetic background."

Dr Goldman also notes that people using cannabis often and in potent forms are more apt to suffer negative consequences.

"Yet, data on the effects of heavy exposures are lacking, even as access to potent cannabis is becoming easier. The burden of cannabis' effects may fall more heavily on people who, because of genetic makeup or early life exposures, are at greatest risk for brain structural changes, psychosis or addiction. It is safer not to expose people to psychoactive drugs," Dr Goldman concludes.

Neither study had commercial funding. Several authors have disclosed relevant financial relationships, which are listed in the original articles.

JAMA Psychiatry. Published online August 26, 2015. Agrawal et al, abstract; Paus et al, abstract; Editorial

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