Psychosis-proneness may in part have a genetic basis. A number of recent studies illustrate how specific genetic factors moderate the effect of cannabis exposure on the risk for psychosis [91]. Catechol-O-methyltransferase (COMT) is the enzyme that degrades DA, epinephrine, and norepinephrine. COMT is critical in the breakdown of DA in the prefrontal cortex. A functional polymorphism of the COMT gene results in two common allelic variants, the valine (Val), and the methionine (Met) allele, associated with high versus low enzyme activity, respectively. Increased COMT activity associated with the Val allele may result in a combination of reduced DA neurotransmission in the prefrontal cortex (cognitive deficits) and subsequent increased levels of mesolimbic DA signaling (psychosis). In a longitudinal birth cohort study (n > 1,000), adolescents homozygous for the COMT Val108/158Met allele were most likely to exhibit psychotic symptoms or develop schizophrenia if they used cannabis [31]. Similarly, in a randomized, double-blind, placebo-controlled study, carriers of the Val allele were more sensitive to Δ9-THC-induced psychotomimetic and amnestic effects than Met carriers, but this was conditional on psychometric evidence of psychosis-proneness [94]. Unlike
