Genetic variation in the endocannabinoid system has been implicated in neural response during abstinence-related withdrawal and craving [101]. Specifically, during abstinence, rs2023239 (non-synonymous) heterozygotes have elevated reactivity to marijuana cues in OFC and ACC relative to A allele homozygotes. This elevated reactivity in corticostriatal regions critical for reward processing and the valuation of external stimuli may contribute to increased marijuana craving in rs2023239 heterozygotes following abstinence. Notably, a functional variant (rs324420) in FAAH, which codes for the fatty acid amide hydrolase enzyme that catabolizes endocannabinoids, was found to have independent and additive effects along with CNR1 [103••]. In addition to mediating neural activity in response to cues, CNR1 variants have also been linked to altered brain morphology. For example, Schacht et al. [104] found that heavy cannabis users have lower bilateral hippocampal volume than healthy controls, with the smallest volumes found in cannabis users with the rs2023239 G allele. Given that the hippocampus is a region critical in memory processing, these findings provide a putative mechanism underlying the association between heavy cannabis use and deficits in cognitive processes and learning [105].
