Ayahuasca has a variety of traditional uses, yet there is a growing global interest in its potential therapeutic benefits for mental health conditions. Novel approaches to psychotherapy are emerging to address the needs of ayahuasca users to prepare as well as to guide them in ‘integrating’ their powerful psychedelic experiences, yet there is little discussion on the ethical frameworks that may structure these therapeutic processes or the social and cultural assumptions that influence the assignment of ayahuasca as a medicine. Based on ethnographic fieldwork in San Martín and Loreto, Peru, I examine the varied social meanings and uses of ayahuasca in the Peruvian vegetalista tradition and the potential ethical tensions among curanderos, mental health practitioners, and ayahuasca retreat centres. Practitioners and ayahuasca centres are left with navigating globalized concepts of mental health and ethics while attempting to remain authentic to local ontologies of healing, care, and safety.