An appealing alternative to direct causation is that cannabis use precipitates psychosis in individuals with pre-existing vulnerabilities. In support of this hypothesis, Caspi and colleagues (63) examined whether individuals that carried the Valine (Val) allele of a missense polymorphism (rs4680) in the catechol-O-methyltransferase (COMT) gene are at heightened risk for developing psychotic disorders. COMT codes for an enzyme that is instrumental in the degradation of endogenous amines, including dopamine, which is well known to mediate the psychoactive effects of THC. Preliminary evidence supports the role of reduced enzymatic activity and slower dopamine metabolism in Val carriers (64). Furthermore, genetic (e.g. knock-out) and pharmacological attenuation of COMT activity has been noted to modify cannabis-induced effects on endophenotypes related to schizoprenia (e.g. sensorimotor gating (65)). In the Caspi et al study of 803 individuals, cannabis use prior to age 17 was examined as the activator of diathesis, as indexed by the Val158Met polymorphism in COMT to predict psychosis outcomes at age 26. For schizophreniform disorder, the odds-ratios reflecting the association with adolescent cannabis use were 10.9, 2.5 and 1.1 in the Val/Val,
