Importance: While psychedelic-assisted therapy has shown promise in the treatment of certain psychiatric disorders, little is known about the potential risk of psychotic or manic symptoms following naturalistic psychedelic use, especially among adolescents.

Question: Is there an association between psychedelic use and psychotic or manic symptoms in adolescents?

Findings: In a cross-sectional study of 16 255 adolescent twins, psychedelic use was significantly associated with lower rates of psychotic symptoms when adjusting for other drug use. Psychedelic use was significantly associated with more manic symptoms for individuals with a higher genetic vulnerability to schizophrenia or bipolar I disorder than for individuals with a lower genetic vulnerability.

Meaning: The findings suggest that psychedelic use may be associated with lower rates of psychotic symptoms but the association between psychedelic use and manic symptoms seems to be associated with genetic vulnerability.