Cannabis, schizophrenia genetic risk, and psychotic experiences: a cross-sectional study of 109,308 participants from the UK Biobank.

Cannabis is known to produce acute, transient psychotic-like experiences. However, it is unclear whether cannabis disproportionately increases the risk of specific types of psychotic experiences and whether genetic predisposition influences the relationship between cannabis use and psychotic experiences. In this cross-sectional study of 109,308 UK Biobank participants, we examined how schizophrenia polygenic risk modulates the association between self-reported cannabis use and four types of self-reported psychotic experiences (auditory hallucinations, visual hallucinations, persecutory delusions, and delusions of reference). Cohort-wide, we found a strong, dose-dependent relationship between cannabis use and all four types of psychotic experiences, especially persecutory delusions. Cannabis users' psychotic experiences tended to be earlier-onset and cause greater distress than non-users', but were not more likely to lead to help-seeking. Participants with high schizophrenia polygenic risk scores showed stronger associations between cannabis use and auditory hallucinations, visual hallucinations, and delusions of reference, as well as psychotic experiences overall. For instance, cannabis ever-use was associated with 67% greater adjusted odds of delusions of reference among individuals in the top fifth of polygenic risk, but only 7% greater adjusted odds among the bottom fifth. Our results suggest that cannabis use is a predictive risk factor for psychotic experiences, including early-onset and distressing experiences. Individuals genetically predisposed to schizophrenia may be especially vulnerable to psychotic experiences as a result of using cannabis, supporting a long-postulated hypothesis. This study exemplifies the utility of population-scale biobanks for elucidating gene-by-environment interactions relating substance use to neuropsychiatric outcomes and points to the translational potential of using polygenic risk scores to inform personalized harm reduction interventions.