Not much is known from an ethnohistorical perspective about the use of psychoactive substances in southern Central America; it is mainly through the archeological record that their presence in the past has been inferred. This article reviews evidence for the use of mind-altering plants and mushrooms in the societies that inhabited the current Costa Rican territory during pre-Columbian times, and explores the cultural significance of this activity. Historical, ethnographic, archeological, and paleobotanical information was examined and integrated with the data obtained from the analysis of 46 artifacts with a presumed linkage to psychoactive drug use that were selected from an exhaustive search in the collections of the Museums of the Central Bank of Costa Rica and the National Museum of Costa Rica. Preliminary results suggest the consumption of tobacco (Nicotiana spp. L.), morning glory (Ipomoea spp. L.), cohoba [Anadenanthera peregrina (L.) Speg.], psychedelic fungi [Amanita muscaria (L.) Lam. and Psilocybe (Fr.) P. Kumm. species], as well as various alcoholic and invigorating beverages was present in ancient times. This use was likely connected to shamanistic healing practices, social–ceremonial events, and the ritual activities of people who held positions of religious and political importance within society.