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

Abstract

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-StructuredAssessment 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 (ρ g ) and environmental (ρ e ) 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 (ρ g = −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 RELEVANCEIn 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.

Structural neuroimaging correlates of alcohol and cannabis use in adolescents and adults

“…This is consistent with our previous work suggesting that regionally specific differences between cannabis users and non-users are often inconsistent across studies and that some of the observed associations may actually be related to comorbid alcohol use [40]. The present results are also consistent with a recent study from a large consortium project that found no relationship between cannabis use and cortical GM ( N =466) [68] and a large twin study ( N =483) that found the association between cannabis use and GM volumes was explained by genetics rather than cannabis use [69]. While the analyses reported herein are consistent with the effects reported in studies with large sample sizes, future longitudinal studies will be important to clarify the effects of cannabis and alcohol use on brain structure.…”

Lifetime use of cannabis from longitudinal assessments, cannabinoid receptor (CNR1) variation, and reduced volume of the right anterior cingulate

“…However, these negative results may have been due to insufficient power to detect differences with small samples (Block et al, 2000; Jager et al, 2007; DeLisi et al, 2006; Gruber and Yurgelun-Todd, 2005; Medina et al, 2007; Medina et al, 2010). More recent morphological studies with larger samples have found reductions in volume in the anterior and posterior cingulum in patients with heavy use of cannabis and psychosis (Rapp et al, 2013), in the amygdala and hippocampus (Schacht et al, 2012; Cousijn et al, 2012; Gilman et al, 2014; Lorenzetti et al, 2015; Yücel et al, 2008; Pagliaccio et al, 2015), and in the nucleus accumbens (Gilman et al, 2014), along with the medial temporal cortex, temporal pole, parhippocampal gyrus, insula, and orbitofrontal cortex (Battistella et al, 2014, Filbey et al, 2014). Also, functional imaging effects have been reported for regular marihuana users with enhanced cue-elicited craving in the anterior cingulate gyrus, orbitofrontal cortex, and inferior frontal gyrus seen in association with variation in CNR1 SNP rs2023239 (Filbey et al, 2010).…”

“…One recent report found that cannabis use effects were not found when alcohol use was controlled for in statistical analyses (Weiland et al, 2015). In a large study of 483 participants, half of whom were exposed to cannabis, Pagliaccio et al (2015), reported that cannabis exposure was significantly related to reduction in left amygdala (2.3%) and ventral striatal (3.5%) volume. However, the authors interpret their findings as casting doubt on the assumption that cannabis is the causative agent in this volume reduction.…”

Legalizing marijuana

“…2,4 During periods of abstinence, milder cognitive and psychomotor impairments can persist for weeks in heavy users (average 11 joints per day for 10 years), 5 similar to the extended withdrawal effects seen following the chronic use of other substances. 6,7 Neurobiological differences in brain structure, 8 connectivity, 9 and function 10 have been tentatively identified, though some morphological differences, at least, might reflect pre-existing traits. 8 There is good evidence that cannabis has clinical efficacy for nausea, certain types of pain, and symptoms of multiple sclerosis, 11 but most other proposed indications are largely based on anecdotes, putting physicians in a difficult position (i.e., being asked to prescribe cannabis for conditions where the evidence remains poor).…”

“…6,7 Neurobiological differences in brain structure, 8 connectivity, 9 and function 10 have been tentatively identified, though some morphological differences, at least, might reflect pre-existing traits. 8 There is good evidence that cannabis has clinical efficacy for nausea, certain types of pain, and symptoms of multiple sclerosis, 11 but most other proposed indications are largely based on anecdotes, putting physicians in a difficult position (i.e., being asked to prescribe cannabis for conditions where the evidence remains poor). Among the greatest concerns are that cannabis use increases the risk for car accidents 12 and accelerates the onset of -perhaps even precipitates -schizophrenia.…”