Overcoming the clinical challenges of traditional ayahuasca: a first-in-human trial exploring novel routes of administration of N,N-Dimethyltryptamine and harmine.
Dario Dornbierer, Laurenz Marten, Jovin Mueller, Helena Aicher, Michael J Mueller, Martina I. Boxler, Michael Kometer, Davor Kosanic, Robin von Rotz, Maxim Puchkov, Thomas Kræmer, Hans-Peter Landolt, Erich Seifritz, Milan Scheidegger
Frontiers in Pharmacology 2023 DOI: 10.3389/fphar.2023.1246892 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Open-label within-subject study Peer reviewed |
|---|---|
| Sample size | 10 |
| Population | Healthy male subjects |
| Interventions | DMT harmine |
| Topics | Ayahuasca DMT 5-MeO-DMT |
| Keywords | Psychedelics/entheogens/hallucinogens Drug-delivery/formulations/administration Ayahuasca/DMT/Harmine Pharmaceutical-innovation/drug-development |
| Citations | 32 |
| Registration | NCT04716335 |
| Key points | Combined buccal/intranasal administration of harmine and DMT yielded improved pharmacokinetic profiles with reduced variations in systemic exposure and fewer gastrointestinal side effects compared to oral capsules. |
Abstract
Recently, the Amazonian plant medicine "ayahuasca"-containing the psychedelic compound N,N-dimethyltryptamine (DMT) and numerous β-carboline alkaloids, such as harmine-has been suggested to exhibit beneficial effects in patients with affective and other mental health disorders. Although ayahuasca ingestion is considered safe, its pharmacokinetics/pharmacodynamics and tolerability profile pose some challenges and may limit the clinical applicability in vulnerable patient populations. While overdosing and the admixture of intolerable plant constituents may explain some of the common adverse reactions, the peroral route of administration may represent another relevant source of gastro-intestinal intolerabilities and unpredictable pharmacokinetics across users. To overcome these challenges, the present work aimed at creating ayahuasca-analogue formulations with improved pharmacokinetics and tolerability profiles. To this end, we developed peroral formulas and compared them with parenteral formulas specifically designed to circumvent the gastro-intestinal tract. In more detail, peroral administration of a capsule (containing purified DMT and harmine) was tested against a combined administration of an oromucosal harmine tablet and an intranasal DMT spray at two dose levels in an open-label within-subject study in 10 healthy male subjects. Pharmacokinetic and pharmacodynamic profiles were assessed by means of continuous blood sampling, vital sign monitoring, and psychometric assessments. Common side effects induced by traditional herbal ayahuasca such as nausea, vomiting, and diarrhea were significantly attenuated by our DMT/harmine formulations. While all preparations were well tolerated, the combined buccal/intranasal administration of harmine and DMT yielded substantially improved pharmacokinetic profiles, indicated by significantly reduced variations in systemic exposure. In conclusion, the combined buccal/intranasal administration of harmine and DMT is an innovative approach that may pave the way towards a safe, rapid-acting, and patient-oriented administration of DMT/harmine for the treatment of affective disorders. Clinical Trial Registration: clinicaltrials.gov, identifier NCT04716335.
Comparable studies
Other non-randomized and open-label trials on 5-MeO-DMT, most cited first.
Citations in the library
Cited by 30
- Potential therapeutic effects of an ayahuasca-inspired N,N-DMT and harmine formulation: a controlled trial in healthy subjects. Frontiers in Psychiatry 2023
- Neurobiological research on N,N-dimethyltryptamine (DMT) and its potentiation by monoamine oxidase (MAO) inhibition: from ayahuasca to synthetic combinations of DMT and MAO inhibitors. Cellular and Molecular Life Sciences September 10, 2024
- A Phase 1 single ascending dose study of pure oral harmine in healthy volunteers. Journal of Psychopharmacology October 1, 2024
- Meditating on psychedelics. A randomized placebo-controlled study of DMT and harmine in a mindfulness retreat Journal of Psychopharmacology September 27, 2024
- Examining the pharmacokinetic and pharmacodynamic interaction of N,N-dimethyltryptamine and harmine in healthy volunteers: Α factorial dose-escalation study. Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie March 1, 2025
and 25 more in the library
Cites 25
- A Randomized Trial of an N-methyl-D-aspartate Antagonist in Treatment-Resistant Major Depression Archives of General Psychiatry August 1, 2006
- REBUS and the Anarchic Brain: Toward a Unified Model of the Brain Action of Psychedelics Pharmacological Reviews June 20, 2019
- Single-Dose Psilocybin for a Treatment-Resistant Episode of Major Depression. New England Journal of Medicine November 3, 2022
- Rapid antidepressant effects of the psychedelic ayahuasca in treatment-resistant depression: a randomized placebo-controlled trial Psychological Medicine June 15, 2018
- Antidepressant effects of a single dose of ayahuasca in patients with recurrent depression: a preliminary report Brazilian Journal of Psychiatry March 1, 2015
and 20 more in the library