This dissertation examines the history of psychedelics in the Americas by focusing on ayahuasca, a plant derivative native to the Amazonian lowlands that I describe as a “plant-being.” The project traces how a transnational network life and human scientists sought to transform ayahuasca from a sacred being into a scientific object and biomedical therapeutic from the 1850s to the present. Ayahuasca researchers relied extensively on the expertise of mestizo and Indigenous practitioners, especially those of Tukano, Ingano, and Shipibo ancestry, who held longstanding relations with ayahuasca. Ayahuasca’s unruly embeddedness in Amazonian human and non-human worlds—its invocations of demonic possession, production of powerful bodily and psychic responses, and mediation between material and ancestral worlds—prompted Western scientists to develop new epistemes, methods, and technologies. Late nineteenth-century naturalists established novel plant taxonomies, psychiatrists from the 1960s onwards reimagined phenomenological tests and research laboratories, and plant scientists and anthropologists of the late twentieth century conceptualized plant subjectivities. By telling a history of ayahuasca’s multiplicity, this dissertation demonstrates that the northwestern Amazon provided a unique ecological and social ecosystem for the continuous, if tumultuous, development of medico-scientific projects about sacred and psychedelic plants throughout the long twentieth century. Based on extensive archival research, oral histories, and ethnographic fieldwork in sites ranging from Brazil, Colombia, and Peru to the United States and the United Kingdom, this dissertation argues that ayahuasca and the scientific projects that sought to neatly define it often negotiated the epistemological and ontological boundaries of the category of “psychedelic.” Such forms of contention are situated amidst broader histories of colonial extraction and violence, enslavement and rebellion, the construction of modern nation-states, and shifting notions of race and indigeneity in the northwestern Amazon. At the same time, local and Native Amazonian ayahuasca practitioners leveraged the scientific study of these plants, in combination with their intimate knowledge of ayahuasca and related plant-beings, to assert their own sovereign environmental, epistemic, and political claims.