Background: Findings from contemporary clinical trials suggest that psychedelics are generally safe and may be effective in the treatment of various psychiatric disorders. However, less is known about the risks associated with psychedelic use outside of medically supervised contexts, particularly in populations that are typically excluded from participation in clinical trials.

Methods: Using a preregistered longitudinal observational research design with a purposive sample of US residents between 18 and 50 years old (N=21,990), we investigated associations between self-reported naturalistic psychedelic use and psychotic and manic symptoms, with emphasis on those with psychiatric histories of schizophrenia or bipolar I disorder.

Results: The follow-up survey was completed by 12,345 participants (56% retention), with 505 participants reporting psychedelic use during the 2-month study period. In covariate-adjusted regression models, psychedelic use during the study period was associated with increases in the severity of psychotic and manic symptoms. However, such increases were only observed for those who reported psychedelic use in an illegal context. While increases in the severity of psychotic symptoms appeared to depend on the frequency of use and the intensity of challenging psychedelic experiences, increases in the severity of manic symptoms appeared to be moderated by a personal history of schizophrenia or bipolar I disorder and the subjective experience of insight during a psychedelic experience.

Conclusions: The findings suggest that naturalistic psychedelic use specifically in illegal contexts may lead to increases in the severity of psychotic and manic symptoms. Such increases may depend on the frequency of use, the acute subjective psychedelic experience, and psychiatric history.