Associations between cannabis use and the brain

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Recently published studies and an editorial examine associations between cannabis use and the brain. Cannabis, also known as marijuana, is a popular recreational drug and its legal status has been a source of enduring controversy.

In the first study, Dr David Pagliaccio, formerly of Washington University in St Louis, and now at the National Institute of Mental Health, Bethesda, Maryland, and co-authors analysed data from a group of twin/siblings (n=483 with 262 participants reporting ever using cannabis in their lifetime) to determine whether cannabis use was associated with brain volumes. The authors relied on interview, behavioural and neuro-imaging data.

To determine whether any significant differences could be attributed to pre-dispositional/familial or causal factors, brain volumes were compared across twin/sibling pairs. Among 241 twin/sibling pairs, 89 pairs were discordant (differing) for cannabis exposure, 81 pairs were concordant (in agreement) for cannabis exposure and 71 pairs were concordantly unexposed to cannabis. The authors found that among all 483 study participants, cannabis exposure was related to smaller left amygdala and right ventral striatum volumes. Volume differences were in the range of normal variation.

However, brain volumes did not differ between siblings discordant for cannabis exposure, according to the study. Both the exposed and unexposed siblings in pairs discordant for cannabis exposure showed smaller amygdala volumes relative to concordant unexposed pairs. “When using a simple index of exposure (ever vs never use), we found no evidence for the causal influence of cannabis exposure on amygdala volume.

Future work characterising the roles of causal and pre-dispositional factors underpinning neural changes at various degrees of cannabis involvement may provide targets for substance abuse policy and prevention programs,” the authors conclude.


In a another cannabis study, Dr Tomáš Paus, of the Rotman Research Institute, Toronto, and co-authors investigated whether the use of cannabis during early adolescence (by 16 years of age) was associated with variations in brain maturation as a function of genetic risk for schizophrenia, as assessed with a polygenic risk score.

The authors used observations from three study samples and a total of 1,577 participants had information about cannabis use, imaging studies of the brain and a polygenic risk score for schizophrenia. The authors report a negative association between cannabis use in early adolescence and cortical thickness in male participants with a high polygenic risk score.

“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 note.


In a related editorial, Dr David Goldman, of the National Institute on Alcohol Abuse and Alcoholism, Rockville, Maryland, writes: “Although siblings discordant for cannabis use were similar in brain structure, it would be wrong to conclude that it is safe to use cannabis or, as could be wrongly inferred from the French et al study, to conclude that it would be safe for people with the right genetic makeup or women, in particular, to use cannabis.”

Abstract 1
Importance: Prior neuroimaging studies have suggested that alterations in brain structure may be a consequence of cannabis use. Siblings discordant for cannabis use offer an opportunity to use cross-sectional data to disentangle such causal hypotheses from shared effects of genetics and familial environment on brain structure and cannabis use.
Objectives: To determine whether cannabis use is associated with differences in brain structure in a large sample of twins/siblings and to examine sibling pairs discordant for cannabis use to separate potential causal and predispositional factors linking lifetime cannabis exposure to volumetric alterations.
Design, Setting, and Participants: Cross-sectional diagnostic interview, behavioral, and neuroimaging data were collected from community sampling and established family registries from August 2012 to September 2014. This study included data from 483 participants (22-35 years old) enrolled in the ongoing Human Connectome Project, with 262 participants reporting cannabis exposure (ie, ever used cannabis in their lifetime).
Main Outcomes and Measures: Cannabis exposure was measured with the Semi-Structured Assessment for the Genetics of Alcoholism. Whole-brain, hippocampus, amygdala, ventral striatum, and orbitofrontal cortex volumes were related to lifetime cannabis use (ever used, age at onset, and frequency of use) using linear regressions. Genetic (ρg) and environmental (ρe) correlations between cannabis use and brain volumes were estimated. Linear mixed models were used to examine volume differences in sex-matched concordant unexposed (n = 71 pairs), exposed (n = 81 pairs), or exposure discordant (n = 89 pairs) sibling pairs.
Results: Among 483 study participants, cannabis exposure was related to smaller left amygdala (approximately 2.3%; P = .007) and right ventral striatum (approximately 3.5%; P < .005) volumes. These volumetric differences were within the range of normal variation. The association between left amygdala volume and cannabis use was largely owing to shared genetic factors (ρg = −0.43; P = .004), while the origin of the association with right ventral striatum volumes was unclear. Importantly, brain volumes did not differ between sex-matched siblings discordant for use (fixed effect = −7.43; t = −0.93, P = .35). Both the exposed and unexposed siblings in pairs discordant for cannabis exposure showed reduced amygdala volumes relative to members of concordant unexposed pairs (fixed effect = 12.56; t = 2.97; P = .003).
Conclusions and Relevance: In this study, differences in amygdala volume in cannabis users were attributable to common predispositional factors, genetic or environmental in origin, with little support for causal influences. Causal influences, in isolation or in conjunction with predispositional factors, may exist for other brain regions (ventral striatum) or at more severe levels of cannabis involvement and deserve further study.

Abstract 2
Importance: Cannabis use during adolescence is known to increase the risk for schizophrenia in men. Sex differences in the dynamics of brain maturation during adolescence may be of particular importance with regard to vulnerability of the male brain to cannabis exposure.
Objective: To evaluate whether the association between cannabis use and cortical maturation in adolescents is moderated by a polygenic risk score for schizophrenia.
Design, Setting, and Participants: Observation of 3 population-based samples included 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. Data analysis was performed from March 1 through December 31, 2014.
Main Outcomes and Measures: Cortical thickness derived from T1-weighted magnetic resonance images. Linear regression tests were used to assess the relationships between cannabis use, cortical thickness, and risk score.
Results: 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. Thus, in SYS male participants, cannabis use interacted with risk score vis-à-vis cortical thickness (P = .009); higher scores were associated with lower thickness only in males who used cannabis. Similarly, in the IMAGEN male participants, cannabis use interacted with increased risk score vis-à-vis a change in decreasing cortical thickness from 14.5 to 18.5 years of age (t137 = −2.36; P = .02). Finally, in the ALSPAC high-risk group of male participants, those who used cannabis most frequently (≥61 occasions) had lower cortical thickness than those who never used cannabis (difference in cortical thickness, 0.07 [95% CI, 0.01-0.12]; P = .02) and those with light use ( Conclusions and Relevance: Cannabis use in early adolescence moderates the association between the genetic risk for schizophrenia and cortical maturation among male individuals. This finding implicates processes underlying cortical maturation in mediating the link between cannabis use and liability to schizophrenia.

JAMA material
JAMA Psychiatry abstract 1
JAMA Psychiatry abstract 2
JAMA Psychiatry editorial

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