Classic psychedelics, lysergic acid diethylamide, psilocybin, mescaline and N,N-dimethyltryptamine, are potent psychoactive substances that have been studied for their physiological and psychological effects. However, our understanding of the potential interactions and outcomes when these substances are used in combination with other psychoactive drugs is limited. This systematic review aims to provide a comprehensive overview of the current research on drug-drug interactions between classic psychedelics and other psychoactive drugs in humans. We conducted a thorough literature search using multiple databases, including PubMed, PsycINFO, Web of Science and other sources to supplement our search for relevant studies. A total of 8,487 records published before April 20, 2023, were screened, and studies involving human data describing potential interactions (as well as the lack thereof) between classic psychedelics and other psychoactive drugs were included. In total, we identified 34 reports from 50 studies, encompassing 31 studies on LSD, 11 on psilocybin, 4 on mescaline, 3 on DMT and 1 on ayahuasca. These studies provide insights into the interactions between classic psychedelics and a range of drugs, including antidepressants, antipsychotics, anxiolytics, mood stabilisers, recreational drugs and others. The findings reveal various effects when psychedelics are combined with other drugs, including both attenuated and potentiated effects, as well as instances where no changes were observed. With the exception of a few case reports, no significant adverse drug reactions were discovered in the studies included. In-depth discussions of the results are presented, along with an exploration of potential molecular pathways that underlie the observed effects.

JS and DP are directors of a not-for-profit research institute which has in the past received commercial funding to undertake psychedelic medicines research.

This study did not receive any funding.

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