Clinical research in psychedelic-assisted therapies is flourishing following the resumption of human trials exploring classic psychedelics and their therapeutic application to a range of mental health conditions. Translation from research to the clinic is underway in Australia and appears imminent in several other countries. Classic psychedelics function primarily as agonists of a subgroup of serotonin (5-HT) receptors but also act to varying degrees at other receptor and transporter systems. Some physiological responses to psychedelics may present risks to susceptible individuals that must be weighed against the potential neuropsychological benefits afforded by psychedelic therapies. Hence, an important rationale for eligibility criteria in clinical trials is to ensure participant safety by minimizing risks of adverse events. The analysis presented here focuses on physiological considerations associated with psychedelic therapies. We conducted a critical evaluation of medical exclusion criteria applied in clinical studies of psychedelic-assisted therapy listed on international clinical trials registries. The criteria were interrogated for their rationale and medical basis; informed by this analysis, the evolution of medical exclusion criteria over twenty-five years of psychedelic clinical research was considered. Finally, the applicability of medical exclusion criteria in psychedelic therapies is discussed in the context of hospital-based psychiatry as the global transition from clinical trials to clinical practice gathers pace.