Abstract 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 of using 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 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 50 studies from 34 reports published before April 20, 2023, 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 revealed various effects when psychedelics were combined with other drugs, including both attenuated and potentiated effects, as well as instances where no changes were observed. Except for a few case reports, no serious adverse drug events were described in the included studies. In-depth discussion of the results is presented, along with an exploration of the potential molecular pathways that underlie the observed effects.