Many influential thinkers in the psychedelic movement that emerged in the West in the 1950s shared the view that psychedelic experiences culminate in “mystical experiences” of union. However, the recent “psychedelic renaissance” emphasizes biomedical, neurological, and psychotherapeutic explanations. These clinical, instrumental approaches overlook both new research on mysticism and many cultural realities and practices behind it. Analyzing key research on psychedelics and mysticism over the past three decades, this programmatic chapter investigates how cultural approaches may complement biomedical research and proposes the concept of mystical consciousness as a key. The chapter briefly illustrates such lines of inquiry with a case study on ayahuasca mysticism in Peruvian High Amazon. Drawing on a book written by an Indigenous curandero and a Western academic who work together, this case demonstrates how ayahuasca mysticism emerges as part of their respective cultural worlds and personal mystic journeys. Their views are grounded in an expanded Indigenous, ecological consciousness that recognizes the interconnectedness of all living things and the agency of human and nonhuman actors. Cultural approaches help map such hybrid modalities of mystical consciousness, which have until recently remained on the margins of modern mysticism.