Experiences of profound existential or spiritual significance can be triggered reliably through psychopharmacological means using psychedelic substances. However, little is known about the benefits of religious, spiritual, or mystical experiences (RSMEs) prompted by psychedelic substances, as compared with those that occur through other means. In this study, 739 self-selected participants reported the psychological impact of their RSMEs and indicated whether they were induced by a psychedelic substance. Experiences induced by psychedelic substances were rated as more intensely mystical (d = .75, p < .001), resulted in a reduced fear of death (d = .21, p < .01), increased sense of purpose (d = .18, p < .05), and increased spirituality (d = .28, p < .001) as compared with nonpsychedelically triggered RSMEs. These results remained significant in an expanded model controlling for gender, education, socioeconomic status, and religious affiliation. These findings lend support to the growing consensus that RSMEs induced with psychedelic substances are genuinely mystical and generally positive in outcome.