Cannabis use at age 16 is associated with psychotic-like experiences (PLEs) even after accounting for genetic risk for schizophrenia, according to an analysis of 1740 European adolescents from the IMAGEN cohort and replicated in 1223 individuals from a Dutch cohort. Polygenic risk scores for schizophrenia predicted both cannabis use and PLEs, and cannabis use remained a significant predictor of PLEs in models including genetic risk. However, no evidence was found that genetic risk mediates or moderates the cannabis–psychosis link. The findings suggest cannabis use is a risk factor for PLEs independent of genetic vulnerability to schizophrenia.
A single dose of THC, the main psychoactive ingredient in cannabis, increases blood flow (perfusion) in brain regions linked to the salience network—the bilateral insula, medial superior frontal cortex, and left middle orbital frontal gyrus—while decreasing connectivity between that last area and the precuneus. The perfusion increase in the left insula correlated with subjective changes in perception and relaxation. Genetic variation in the COMT Val158Met genotype modulated these effects: only Val/Met heterozygotes showed increased perfusion in the executive network after THC, suggesting that prefrontal dopamine levels influence susceptibility to cannabis's acute effects.