An attractive candidate gene system for the links between cannabis use, depression and suicide is the endogenous cannabinoid system. In particular, the gene encoding the cannabinoid receptor 1 (CNR1) to which endocannabinoids and THC bind, is an excellent target. There is well-documented evidence for the role of the endocannabinoid system in the regulation of mood, particularly in the context of stress adaptation for which it interfaces with the Hypothalamic-Pituatary-Adrenal axis (84; 85). For instance, rodents administered a cannabinoid receptor 1 (CB1) antagonist engage in more depressive and anhedonic behaviors upon administration of chronic mild and unpredictable stress (86). In humans as well, clinical trials for the anti-obesity medication Rimonabant, also a CB1 antagonist, found a high rate of serious adverse events related to suicidality that consequently led to its discontinuation (87; 88). In addition, studies have documented that variants in CNR1 in conjunction with stress exposure are related to low mood (89; 90). While THC binds to CB1 to exert its psychotropic effects, and this is well documented in rodent models, human association studies with variants in CNR1 have yielded equivocal findings (10).
