The use of naturally occurring entheogens for cultural, religious, and therapeutic purposes is widely documented in traditional medicine practices of the Americas. Preliminary evidence suggests that the ritual use of such compounds in appropriately structured contexts, such as those offered in authentic Indigenous medicine practices and appropriately structured modern therapeutic adaptations, can provide beneficial effects for the treatment of substance use-related disorders, as well as various other psycho-emotional conditions. In an effort to making the benefits of entheogen assisted treatments more accessible for Indigenous communities, some of which have lost the access to these medicines, our team has supported Indigenous initiatives for the creation of a intercultural clinic in the Yaqui tribe in Sonora, Mexico, the Otomi tribe in the State of Mexico and the Bloodvein First Nations community in Manitoba Canada, where such entheogens of natural origin are applied in the context of traditional Indigenous medicine. These interventions are complemented by a multidisciplinary therapeutic program and community activities to treat substance use disorders and other mental health challenges. Using an observational study design the Entheogen Treatment Outcome Project (ENTOP) is in the process of community engagement, program implementation and evaluation of the effectiveness, safety and cultural implications of these applications. Preliminary results of this study will be presented, along with case studies and reflections of learnings from these pilot projects for further development of fields of intercultural medicine and psychedelic medicine.