Recent research into so-called psychedelic substances, such as psilocybin, ketamine, and mescaline analogues, has been hailed as a “renaissance” heralding a “paradigm shift” in psychiatry. There is hope that psychedelic-assisted therapy will be made more available to address mental and substance use health problems through existing systems of medicalization and legalization. There are important relational and epistemic concerns that must be addressed, however, before we might begin stewarding this class of substances into the medical landscape in a responsible, evidence-based manner. In this paper, we draw on our ethnographic and clinical research observations to argue that the ontological and relational commitments of traditional medicine (ayahuasca-related healing) and randomized controlled trial (RCT) (ketamine-assisted psychotherapy) practices have important and revealing overlaps; together, they bring attention to ideal ways of working with these substances, as well as to ideal forms of healthcare more generally, with implications for reimagining our healthcare system from the ground up. As such, more is needed than a circumscribed shift to a new epistemological orientation (“paradigm”). We conclude by promoting ideals in alignment with our data and observations—relationality, inter-being, and epistemological fluidity—and by exploring how these ideals might reshape the medical landscape.