This study investigates the association between naturalistic psychedelic use and self-reported psychotic or manic symptoms in adolescents using a genetically informative design. The study included 16,255 adolescent twins from the Swedish Twin Registry, assessed at ages 15, 18, and 24 years. Participants were asked about past use of psychedelics (LSD or psilocybin) and self-reported psychotic or manic symptoms. Among the participants, 541 reported past use of psychedelics, with most also reporting use of other drugs. After adjusting for substance-specific and substance-aggregated drug use, psychedelic use was associated with reduced psychotic symptoms in both linear regression analyses and co-twin control analyses. However, for manic symptoms, statistically significant interactions were found between psychedelic use and genetic vulnerability to schizophrenia or bipolar disorder. These findings suggest that, after adjusting for other drug use, naturalistic use of psychedelics 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 disorder. The study highlights the potential of genetically informative research designs to delineate the complex interplay between psychedelic use, genetic factors, and psychotic or manic symptoms. Future studies are needed to replicate these findings and extend them to other age groups, ideally with larger samples, longitudinal data, and more objective outcome measures. The study has limitations, including missing data, potential biases in self-reported outcomes, and the inability to exclude reverse causality. The findings should be interpreted with caution until they have been replicated in future studies.This study investigates the association between naturalistic psychedelic use and self-reported psychotic or manic symptoms in adolescents using a genetically informative design. The study included 16,255 adolescent twins from the Swedish Twin Registry, assessed at ages 15, 18, and 24 years. Participants were asked about past use of psychedelics (LSD or psilocybin) and self-reported psychotic or manic symptoms. Among the participants, 541 reported past use of psychedelics, with most also reporting use of other drugs. After adjusting for substance-specific and substance-aggregated drug use, psychedelic use was associated with reduced psychotic symptoms in both linear regression analyses and co-twin control analyses. However, for manic symptoms, statistically significant interactions were found between psychedelic use and genetic vulnerability to schizophrenia or bipolar disorder. These findings suggest that, after adjusting for other drug use, naturalistic use of psychedelics 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 disorder. The study highlights the potential of genetically informative research designs to delineate the complex interplay between psychedelic use, genetic factors, and psychotic or manic symptoms. Future studies are needed to replicate these findings and extend them to other age groups, ideally with larger samples, longitudinal data, and more objective outcome measures. The study has limitations, including missing data, potential biases in self-reported outcomes, and the inability to exclude reverse causality. The findings should be interpreted with caution until they have been replicated in future studies.