Examining the pharmacokinetic and pharmacodynamic interaction of N,N-dimethyltryptamine and harmine in healthy volunteers: Α factorial dose-escalation study.
Klemens Egger, Javier Jareño Redondo, Jovin Müller, Joëlle Dornbierer, John W Smallridge, Helena Aicher, Daniel Meling, Per Müller, Jonas Kost, Maxim Puchkov, Angela Äbelö, Erich Seifritz, Boris B. Quednow, Robin von Rotz, Milan Scheidegger, Dario Dornbierer
Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie March 1, 2025 DOI: 10.1016/j.biopha.2025.117908 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Single-blind, randomized, two-arm, factorial, dose-finding study Peer reviewed |
|---|---|
| Sample size | 16 |
| Population | Healthy participants (9 males, 7 females) |
| Intervention | DMT and harmine |
| Dose | 0-120 mg DMT, 0-180 mg harmine |
| Topics | Ayahuasca DMT 5-MeO-DMT |
| Keywords | Ayahuasca pharmahuasca Harmine Pharmacokinetics Psychedelics entheogens Hallucinogens Psychoactive substances Drug interactions Pharmacology pharmacodynamics |
| Citations | 14 |
| Key points | Harmine reduced DMT metabolism, while DMT altered harmine pharmacokinetics, producing dose-dependent subjective effects lasting 4-5 hours. |
Abstract
Ayahuasca, a traditional psychoactive Amazonian brew, usually contains N,N-dimethyltryptamine (DMT) and β-carboline (harmine, harmaline, tetrahydroharmine) monoamine oxidase inhibitors. However, the pharmacological interactions between these compounds remain incompletely understood. In this study, we developed an ayahuasca-inspired formulation containing DMT and harmine, aiming to systematically evaluate their pharmacokinetic and pharmacodynamic drug-drug interactions (DDI) across a range of dosage levels. We hypothesized that escalating harmine doses would enhance DMT bioavailability, increase its plasma half-life, and reduce the variability in DMT plasma concentrations between individuals. Additionally, we expected that harmine would attenuate the plasma levels of the main DMT metabolite, indole-3-acetic acid (3-IAA), while increasing levels of the secondary metabolite DMT-N-oxide (DMT-NO). This single-blind, randomized, two-arm, factorial, dose-finding study included 16 healthy participants (9 males, 7 females), each receiving six dose combinations (0-120 mg DMT, 0-180 mg harmine) administered via a microcarrier-based transmucosal delivery system. We then evaluated the pharmacokinetics of DMT and harmine and their main metabolites, subjective effects, autonomic responses, and the safety profile of the combined preparation. All DMT-harmine combinations reliably induced dose-dependent subjective effects lasting 4-5 h, with peak DMT and harmine levels (Cmax) reaching 33 ng/mL and 49 ng/mL, respectively. Tmax, the time to maximum concentrations, increased with dose escalation for both compounds. The interactions between DMT and harmine were not unidirectional, i.e., harmine reduced the metabolism of DMT, while DMT altered harmine pharmacokinetics. Our novel formulation demonstrated a favorable safety profile, supporting its potential for further testing in patients with various affective disorders.
Comparable studies
Other randomized controlled trials on 5-MeO-DMT, most cited first.
| Study | Year | Design | Participants |
|---|---|---|---|
| Dose-Response Study of N,N-Dimethyltryptamine in Humans Experienced hallucinogen users | 1994 | Double-blind, saline placebo-controlled, randomized study | n = 12 |
| Psychological Effects of (S)-Ketamine and N,N-Dimethyltryptamine (DMT): A Double-Blind, Cross-Over Study in Healthy Volunteers Healthy volunteers | 2005 | Double-blind crossover study | n = 9 |
| Differential tolerance to biological and subjective effects of four closely spaced doses of N,N-dimethyltryptamine in humans Experienced hallucinogen users | 1996 | Randomized controlled trial | n = 13 |
| Pharmacokinetics of N,N-dimethyltryptamine in Humans. Healthy adults | 2023 | Phase I component of a phase I/IIa randomised, double-blind, placebo-controlled, parallel-group, dose-escalation trial | n = 24 |
| Prepulse inhibition of the startle reflex and its attentional modulation in the human S-ketamine and N,N-dimethyltryptamine (DMT) models of psychosis Healthy volunteers | 2007 | Double-blind crossover study | n = 15 |
Citations in the library
Cited by 12
- Population pharmacokinetic-pharmacodynamic modeling of co-administered N,N-dimethyltryptamine and harmine in healthy subjects. Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie July 9, 2025
- Clinical pharmacology of ayahuasca: potential applications and future considerations Expert Review of Clinical Pharmacology October 3, 2025
- Meditation, psychedelics, and brain connectivity: A randomized controlled resting-state fMRI study of N,N-dimethyltryptamine and harmine in a meditation retreat. Imaging Neuroscience September 29, 2025
- DMT and harmala alkaloids: an exploratory study of oral Acacia based formulations in healthy volunteers. Frontiers in Psychiatry August 15, 2025
- Global Increases in Brain Glucose Metabolism Following Acute N,N-Dimethyltryptamine and Harmine Administration in Healthy Volunteers: An [¹⁸F]FDG-PET Study Research Square July 27, 2025
and 7 more in the library
Cites 29
- The Standardized Psychometric Assessment of Altered States of Consciousness (ASCs) in Humans Pharmacopsychiatry July 1, 1998
- Monoamine oxidase inhibitors in South American hallucinogenic plants: Tryptamine and β-carboline constituents of Ayahuasca Journal of Ethnopharmacology April 1, 1984
- Human Pharmacology of Ayahuasca: Subjective and Cardiovascular Effects, Monoamine Metabolite Excretion, and Pharmacokinetics Journal of Pharmacology and Experimental Therapeutics June 18, 2003
- Human Psychopharmacology of Hoasca, A Plant Hallucinogen Used in Ritual Context in Brazil The Journal of Nervous and Mental Disease February 1, 1996
- Subjective effects and tolerability of the South American psychoactive beverage Ayahuasca in healthy volunteers Psychopharmacology February 22, 2001
and 24 more in the library