ImportanceWhile 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.ObjectiveTo investigate associations between naturalistic psychedelic use and self-reported psychotic or manic symptoms in adolescents using a genetically informative design.Design, Setting, and ParticipantsThis study included a large sample of adolescent twins (assessed at age 15, 18, and 24 years) born between July 1992 and December 2005 from the Swedish Twin Registry and cross-sectionally evaluated the associations between past psychedelic use and psychotic or manic symptoms at age 15 years. Individuals were included if they answered questions related to past use of psychedelics. Data were analyzed from October 2022 to November 2023.Main Outcomes and MeasuresPrimary outcome measures were self-reported psychotic and manic symptoms at age 15 years. Lifetime use of psychedelics and other drugs was also assessed at the same time point.ResultsAmong the 16 255 participants included in the analyses, 8889 were female and 7366 were male. Among them, 541 participants reported past use of psychedelics, most of whom (535 of 541 [99%]) also reported past use of other drugs (ie, cannabis, stimulants, sedatives, opioids, inhalants, or performance enhancers). When adjusting for substance-specific and substance-aggregated drug use, psychedelic use was associated with reduced psychotic symptoms in both linear regression analyses (β, −0.79; 95% CI, −1.18 to −0.41 and β, −0.39; 95% CI, −0.50 to −0.27, respectively) and co-twin control analyses (β, −0.89; 95% CI, −1.61 to −0.16 and β, −0.24; 95% CI, −0.48 to −0.01, respectively). In relation to manic symptoms, likewise adjusting for substance-specific and substance-aggregated drug use, statistically significant interactions were found between psychedelic use and genetic vulnerability to schizophrenia (β, 0.17; 95% CI, 0.01 to 0.32 and β, 0.17; 95% CI, 0.02 to 0.32, respectively) or bipolar I disorder (β, 0.20; 95% CI, 0.04 to 0.36 and β, 0.17; 95% CI, 0.01 to 0.33, respectively).Conclusions and RelevanceThe findings in this study suggest that, after adjusting for other drug use, naturalistic use of psychedelic may be associated with lower rates of psychotic symptoms among adolescents. At the same time, the association between psychedelic use and manic symptoms seems to be associated with genetic vulnerability to schizophrenia or bipolar I disorder. These findings should be considered in light of the study’s limitations and should therefore be interpreted with caution.