BACKGROUND: Hallucinogen use for both recreational and medical purposes is rapidly increasing globally, raising concerns about potential adverse effects. This study examined the risk of incident mania or bipolar disorder (BD) diagnosis associated with having an emergency department (ED) visit or hospitalization involving hallucinogens.

METHODS AND FINDINGS: We used a population-based cohort study of all individuals aged 14-65 years with no baseline history of BD and registered in the Ontario Health Insurance Plan in Ontario, Canada, between 2008-2022. Incident mania (primary outcome) and incident BD (secondary outcome) were compared between individuals with acute care (an ED visit or hospitalization) involving hallucinogens and the general population using overlap propensity score weighted Cox proportional hazard models. Models were adjusted for age, sex, rural residence, income quintile, recent documentation of homelessness, and healthcare encounters for mental health or other substance use in the past five years. The study included 9,311,844 individuals of which 7,285 (0.08%) had acute care involving hallucinogens. Within 3-years of acute care involving hallucinogens, 1.43% (n = 104) of individuals had an incident episode of mania requiring acute care compared to 0.06% (n = 41) of individuals in the age-sex matched general population, a 25-fold increase in risk. After weighting, acute care for hallucinogens was associated with a 6-fold (weighted Hazard Ratio [HR] 5.97, 95% CI 3.29, 10.82) increase in risk of incident mania relative to individuals without hallucinogen acute care who had otherwise similar demographic and mental health histories. Associated increases were also observed for risk of an incident diagnosis of BD (HR 3.75 95%CI 2.49, 5.65, absolute proportion 2.50% versus 0.11%). The main limitation of the study is the risk associated with the exposure examined in this study may not generalize to the majority of people who use hallucinogens who do not require acute care.

CONCLUSIONS: These findings suggest the need for ongoing caution regarding hallucinogen use in individuals at risk of bipolar disorder. They also have potential implications for clinical practice, research, and public health policy, including substance regulation and targeted education for high-risk groups in the context of rising hallucinogen use.