In this article, I discuss some of the implications of the transnational expansion of ayahuasca shamanism, which was traditionally found in Amazonia. This expansion has resulted in new transreligious ritual forms that although derived from Indigenous Amazonian traditions have developed their own characteristics. These ritual forms combine spiritual motivations with healing, making them harder to categorize in the way that religion is usually defined in Western cultures. I present what I see as the two major paradigms within which ayahuasca, and other psychedelics are used currently, namely the therapeutic and religious paradigms, and reflect on what they mean for the future of psychedelics and religion, particularly in the U.S. context. The religious and therapeutic paradigms seem to be enmeshed within the transnational spread of ayahuasca and its use in contexts such as shamanic tourism and informal ritual circles that have emerged in recent years. Although several stakeholders and scientists are working towards establishing the safety and therapeutic potential of psychedelics such as ayahuasca, the religious paradigm shows just as much promise as a road to legitimacy. However, given the compartmentalization between religious and therapeutic uses, it is likely that if a religious discourse as a path to legitimacy becomes more pronounced in the future, it cannot be within traditional religious frameworks. I discuss the limitations of the Christian-centric religious paradigm that dominates how religion is defined in Western cultures and argue that the transnational expansion of ayahuasca circles shows the emergence of a new paradigm combining transreligious elements and has the potential of reshaping the way religion or spirituality is conceptualized.