Association between cannabis use disorder and schizophrenia stronger in young males than in females

Background Previous research suggests an increase in schizophrenia population attributable risk fraction (PARF) for cannabis use disorder (CUD). However, sex and age variations in CUD and schizophrenia suggest the importance of examining differences in PARFs in sex and age subgroups. Methods We conducted a nationwide Danish register-based cohort study including all individuals aged 16-49 at some point during 1972-2021. CUD and schizophrenia status was obtained from the registers. Hazard ratios (HR), incidence risk ratios (IRR), and PARFs were estimated. Joinpoint analyses were applied to sex-specific PARFs. Results We examined 6 907 859 individuals with 45 327 cases of incident schizophrenia during follow-up across 129 521 260 person-years. The overall adjusted HR (aHR) for CUD on schizophrenia was slightly higher among males (aHR = 2.42, 95% CI 2.33-2.52) than females (aHR = 2.02, 95% CI 1.89-2.17); however, among 16-20-year-olds, the adjusted IRR (aIRR) for males was more than twice that for females (males: aIRR = 3.84, 95% CI 3.43-4.29; females: aIRR = 1.81, 95% CI 1.53-2.15). During 1972-2021, the annual average percentage change in PARFs for CUD in schizophrenia incidence was 4.8 among males (95% CI 4.3-5.3; p < 0.0001) and 3.2 among females (95% CI 2.5-3.8; p < 0.0001). In 2021, among males, PARF was 15%; among females, it was around 4%. Conclusions Young males might be particularly susceptible to the effects of cannabis on schizophrenia. At a population level, assuming causality, one-fifth of cases of schizophrenia among young males might be prevented by averting CUD. Results highlight the importance of early detection and treatment of CUD and policy decisions regarding cannabis use and access, particularly for 16-25-year-olds.