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Original Investigation |

Shared Predisposition in the Association Between Cannabis Use and Subcortical Brain Structure

David Pagliaccio, PhD1; Deanna M. Barch, PhD2,3,4; Ryan Bogdan, PhD3; Phillip K. Wood, PhD5; Michael T. Lynskey, PhD6; Andrew C. Heath, DPhil2; Arpana Agrawal, PhD2
[+] Author Affiliations
1The Program in Neuroscience, Washington University in St Louis, St Louis, Missouri
2Department of Psychiatry, Washington University in St Louis, St Louis, Missouri
3Department of Psychology, Washington University in St Louis, St Louis, Missouri
4Department of Radiology, Washington University in St Louis, St Louis, Missouri
5Department of PsychologicalSciences, University of Missouri, Columbia
6Institute of Psychiatry, Psychology and Neuroscience, Department of Addictions, King’s College London, London, England
JAMA Psychiatry. 2015;72(10):994-1001. doi:10.1001/jamapsychiatry.2015.1054.
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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 (eg, ventral striatum) or at more severe levels of cannabis involvement and deserve further study.

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Figure 1.
Hypothetical Causal and Predispositional Effects

Three hypothetical patterns of results from the linear mixed model analyses are presented here. A, The hypothesis that cannabis causes alterations in brain volumes (depicted as reductions in volume) was tested with contrast 1. As denoted by the bar labeled contrast 1, this contrast tested for differences between exposed and unexposed members of pairs discordant for cannabis use. Finding smaller volumes among exposed members of these pairs compared with their siblings would support this causal hypothesis (pending replication with monozygotic twin pairs). B, Contrast 2 compares volumes for concordant exposed pairs with discordant pairs to test the hypothesis that brain volumes and cannabis use share familial/predispositional factors where concordant exposed pairs are at increased liability (both siblings are exposed vs only one), ie, graded liability. C, Contrast 3 compares volumes for the concordant unexposed pairs with all other groups to test the hypothesis that brain volumes and cannabis use share familial/predispositional factors but that liability does not differ by concordance vs discordance for use.

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Figure 2.
Left Amygdala Volume by Cannabis Exposure Group

Estimated marginal means (error bars indicate standard errors) for left amygdala volumes by cannabis exposure group are presented. The significant fixed effect of contrast 3 is denoted: concordant unexposed pairs showed larger volumes than all other groups.

aP < .05.

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