The use of entheogens has been widely reported throughout the history of religious and mystical traditions and documented in various holy texts. These were employed as a complement to ritual and meditative practice, or as a form of worship and a means to interact with the divine. Examples of such use concerning the use of mind-altering substances can be found in the Elusynian mysteries or although debated in the Delphic Oracle. Many tribal and shamanic traditions use drugs derived from various plants such as San Pedro cactus and the internationally known Ayahuasca and finally, Tabernanthe Iboga. Entheogens such as Datura are used in Vajarana tantric traditions providing powerful mind alterations. The use of psychotropic substances is moreover documented in Judaism by Aryeh Kaplan. The Rastafari movement uses cannabis as a form of communion and in debating the passages of the Bible. In a more contemporary setting, the use of Ayahuasca is also employed by the relatively recently founded church of the Santo Daime for both therapeutic and spiritual development purposes. Finally, new religious movements such as the Neo-American Church consider the use of psychedelic drugs as a sacrament.

In some occasions the use of psychoactive substances is also employed by esoteric orders or individuals as a means to empower their ritual performance and facilitate the breaking of taboos such as the case of the experiments in the Abbey of Thelema. After decades of research being relegated to a select few and the cultural milieu attributed to controversial counter cultural groups, with the diffusion of healing rituals and spiritual experiences concentrating on the use of entheogens, the public attention towards the use of drugs associated with spirituality has significantly grown. Spiritual retreats to exotic locations are increasingly booked by corporations for teambuilding and the use of mind-altering substances linked to therapeutic reinterpretations of spirituality is growing constantly, especially in connection to their popularization through celebrities. The surge of interest in entheogens and other related substances presents new venues for scientific research in multiple fields.