This article reassesses what has been called ‘the puzzle of distribution’: why did some drugs rapidly emerge as global consumer goods in the era of the Columbian Exchange, whereas others remained restricted to regional centres of usage? I argue here that the early modern concept of transplantation allows us to approach the puzzle of distribution from a novel perspective. Early modern intoxicants were not disaggregated, free-floating commodities. Their consumption and trade took place within a larger constellation of social codes, cultural practices, ecologies, and built environments. Psychedelic compounds such as peyote and ayahuasca serve here as case studies for examining how the globalization of drugs involved far more than the transport of the substances themselves. Despite their centrality to numerous societies throughout the pre-Columbian Americas, the larger ‘assemblage’ of material cultures, cultural assumptions, and religious meanings that accrued around these substances made it difficult for them to follow the same paths as commodified drugs like cacao or tobacco.