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Beyond being one the most widely used psychoactive drugs in the world, cannabis has been identified as an environmental risk factor for psychosis. Though the relationship between cannabis use and psychiatric disorders remains controversial, consistent association between early adolescent cannabis use and the subsequent risk of psychosis suggested adolescence may be a particularly vulnerable period. Previous findings on gene by environment interactions indicated that cannabis use may only increase the risk for psychosis in the subjects who have a specific genetic vulnerability. The type 1 cannabinoid receptor (CB1), encoded by the  CNR1  gene, is a key component of the endocannabinoid system. As the primary endocannabinoid receptor in the brain, CB1 is the main molecular target of the endocannabinoid ligand, as well as tetrahydrocannabinol (THC), the principal psychoactive ingredient of cannabis. In this study, we have examined mRNA expression and DNA methylation of  CNR1  in human prefrontal cortex (PFC), hippocampus, and caudate samples. The expression of  CNR1  is higher in fetal PFC and hippocampus, then drops down dramatically after birth. The lifespan trajectory of  CNR1  expression in the DLPFC differentially correlated with age by allelic variation at rs4680, a functional polymorphism in the  COMT  gene. Compared with  COMT  methionine 158  carriers, Caucasian carriers of the  COMT  valine 158  allele have a stronger negative correlation between the expression of  CNR1  in DLPFC and age. In contrast, the methylation level of cg02498983, which is negatively correlated with the expression of  CNR1  in PFC, showed the strongest positive correlation with age in PFC of Caucasian carriers of  COMT  valine 158 . Additionally, we have observed decreased mRNA expression of  CNR1  in the DLPFC of patients with schizophrenia. Further analysis revealed a positive eQTL SNP, rs806368, which predicted the expression of a novel transcript of  CNR1  in human DLPFC, hippocampus and caudate. This SNP has been associated with addiction and other psychiatric disorders. THC or ethanol are each significantly associated with dysregulated expression of  CNR1  in the PFC of patients with affective disorder, and the expression of  CNR1  is significantly upregulated in the PFC of schizophrenia patients who completed suicide. Our results support previous studies that have implicated the endocannabinoid system in the pathology of schizophrenia and provided additional insight into the mechanism of increasing risk for schizophrenia in the adolescent cannabis users.

Cannabinoid receptor CNR1 expression and DNA methylation in human prefrontal cortex, hippocampus and caudate in brain development and schizophrenia