It has long been speculated that psychedelic use could provoke the onset of psychosis, but there is little evidence to support this conjecture. Using a longitudinal research design with samples representative of the US and UK adult populations with regard to sex, age, and ethnicity (n = 9732), we investigated associations between psychedelic use and change in the number of psychotic symptoms during the two-month study period. In covariate-adjusted regression models, psychedelic use during the study period was not associated with a change in the number of psychotic symptoms unless it interacted with a personal or family history of bipolar disorder, in which case the number of symptoms increased, or with a personal (but not family) history of psychotic disorders, in which case the number of symptoms decreased. Taken together, these findings indicate that psychedelic use may affect psychotic symptoms in individuals with a personal or family history of certain disorders characterized by psychotic symptomatology.