Background: In recent years, both meditation and psychedelics have attracted rapidly increasing scientific interest. While the current state of evidence suggests the promising potential of psychedelics, such as psilocybin, to enhance meditative training, it remains equivocal whether these effects are specifically bound to psilocybin or if other classical psychedelics might show synergistic effects with meditation practice. One particularly promising candidate is N,N-dimethyltryptamine (DMT), an active ingredient of ayahuasca.

Aim: This study aims to investigate the effect of the psychedelic substance DMT, combined with the monoamine oxidase inhibitor harmine (DMT-harmine), on meditative states, compared to meditation with a placebo.

Method: Forty experienced meditators (18 females and 22 males) participated in a double-blind, placebo-controlled study over a 3-day meditation retreat, receiving either placebo or DMT-harmine. Participants’ levels of mindfulness, compassion, insight, and transcendence were assessed before, during, and after the meditation group retreat, using psychometric questionnaires.

Results: Compared to meditation with a placebo, meditators who received DMT and harmine self-attributed greater levels of mystical-type experiences, non-dual awareness, and emotional breakthrough during the acute substance effects and, when corrected for baseline differences, greater psychological insight 1 day later. Mindfulness and compassion were not significantly different in the DMT-harmine group compared to placebo. At 1-month follow-up, the meditators who received DMT and harmine rated their experience as significantly more personally meaningful, spiritually significant, and well-being-enhancing than the meditators who received placebo.

Conclusion: Investigating the impact of DMT-harmine on meditators in a naturalistic mindfulness group retreat, this placebo-controlled study highlights the specific effects of psychedelics during meditation.

Trial registration: ClinicalTrials.gov identifier NCT05780216.