This study investigates the associations between naturalistic psychedelic use and self-reported psychotic or manic symptoms in adolescents, using a genetically informative design. The research included a large sample of adolescent twins (n=16,255) assessed at ages 15, 18, and 24 years, focusing on psychedelic use at age 15. The primary outcomes were self-reported psychotic and manic symptoms, with lifetime psychedelic and other drug use also assessed. Key findings include: - Among participants who reported past psychedelic use (n=541), most also reported past use of other drugs. - After adjusting for other drug use, psychedelic use was associated with reduced psychotic symptoms (β=-0.79, 95% CI -1.18 to -0.41) and manic symptoms (β=-0.39, 95% CI -0.50 to -0.27). - There were statistically significant interactions between psychedelic use and genetic vulnerability to schizophrenia or bipolar I disorder for manic symptoms (β=0.17, 95% CI 0.01 to 0.32 and β=0.20, 95% CI 0.04 to 0.36, respectively). The study suggests that naturalistic psychedelic use may be associated with lower rates of psychotic symptoms among adolescents, while the association with manic symptoms depends on genetic vulnerability. These findings highlight the need for further research to understand the risks and benefits of psychedelic use, especially in individuals with a genetic predisposition to psychopathology.This study investigates the associations between naturalistic psychedelic use and self-reported psychotic or manic symptoms in adolescents, using a genetically informative design. The research included a large sample of adolescent twins (n=16,255) assessed at ages 15, 18, and 24 years, focusing on psychedelic use at age 15. The primary outcomes were self-reported psychotic and manic symptoms, with lifetime psychedelic and other drug use also assessed. Key findings include: - Among participants who reported past psychedelic use (n=541), most also reported past use of other drugs. - After adjusting for other drug use, psychedelic use was associated with reduced psychotic symptoms (β=-0.79, 95% CI -1.18 to -0.41) and manic symptoms (β=-0.39, 95% CI -0.50 to -0.27). - There were statistically significant interactions between psychedelic use and genetic vulnerability to schizophrenia or bipolar I disorder for manic symptoms (β=0.17, 95% CI 0.01 to 0.32 and β=0.20, 95% CI 0.04 to 0.36, respectively). The study suggests that naturalistic psychedelic use may be associated with lower rates of psychotic symptoms among adolescents, while the association with manic symptoms depends on genetic vulnerability. These findings highlight the need for further research to understand the risks and benefits of psychedelic use, especially in individuals with a genetic predisposition to psychopathology.