Population pharmacokinetic-pharmacodynamic modeling of co-administered N,N-dimethyltryptamine and harmine in healthy subjects.
Angela Äbelö, John W Smallridge, Robin von Rotz, Dario Dornbierer, Klemens Egger, Michael Ashton, Milan Scheidegger
Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie July 9, 2025 DOI: 10.1016/j.biopha.2025.118329 (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) |
| Interventions | buccal DMT harmine |
| Dose | 0-120 mg DMT, 0-180 mg harmine |
| Topics | DMT 5-MeO-DMT |
| Keywords | Pharmacodynamics Pharmacokinetics Psychedelics Harmine-DMT Interaction Alter Enhances Influences Availability Sustained - DMT Psychedelic research investigated Sophisticated model Participants Doses - DMT Personalized dosing Psychedelic's effects |
| Citations | 3 |
| Key points | Harmine markedly enhanced DMT bioavailability and prolonged its absorption, resulting in higher and more sustained plasma concentrations, and potentiated subjective psychedelic effects at higher DMT doses. |
Abstract
N,N-dimethyltryptamine (DMT) is a psychedelic compound commonly co-administered with the monoamine oxidase inhibitor harmine in ayahuasca-inspired formulations. However, the impact of harmine on DMT pharmacokinetics (PK) and pharmacodynamics (PD) remains insufficiently characterized. In this single-blind, randomized, two-arm, factorial, dose-finding study, 16 healthy participants (9 males, 7 females) received six combinations of buccal DMT (0-120 mg) and harmine (0-180 mg) via a microcarrier-based transmucosal delivery system. Plasma concentrations and subjective intensity ratings of psychedelic effects were collected and analyzed using nonlinear mixed-effects modeling in NONMEM. A one-compartment model with delayed absorption, incorporating three transit compartments, best described the PK of DMT. Allometric scaling based on body weight improved the model fit, revealing significant interindividual variability in clearance and bioavailability. Harmine markedly enhanced DMT bioavailability and prolonged its absorption, resulting in higher and more sustained plasma concentrations. The relationship between DMT plasma concentrations and subjective drug effect intensity was captured by a sigmoidal maximum effect model, which demonstrated considerable variability in individual sensitivity to psychedelic effects. Model-based simulations showed a clear dose-dependent increase in subjective intensity for both DMT and harmine, with a potentiating effect observed at higher DMT doses when combined with escalating harmine doses. These findings provide a comprehensive population PK/PD framework that elucidates how harmine influences DMT exposure and subjective effects. By quantifying key sources of variability, this work provides a proof-of-concept approach applied to a specific population and dosing regimen, which lays the foundation for more precise, personalized dosing strategies in psychedelic-assisted therapy.
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 3
- Registered Clinical Trials of Ayahuasca and DMT: A Scoping Review. Clinical Pharmacology & Therapeutics July 1, 2026
- Brain-body integromics of the ayahuasca experience. Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie June 1, 2026
- Development of a physiologically based pharmacokinetic model of N,N-dimethyltryptamine, harmine, and their interactions from ayahuasca in rats and humans. Toxicological sciences : an official journal of the Society of Toxicology November 1, 2025
Cites 27
- Rapid antidepressant effects of the psychedelic ayahuasca in treatment-resistant depression: a randomized placebo-controlled trial Psychological Medicine June 15, 2018
- Global Street Food: la cocina de la calle Diseño interior 2009
- Constructing drug effects: A history of set and setting Drug Science, Policy and Law 2017
- Changes in global and thalamic brain connectivity in LSD-induced altered states of consciousness are attributable to the 5-HT2A receptor Elife October 25, 2018
- Monoamine oxidase inhibitors in South American hallucinogenic plants: Tryptamine and β-carboline constituents of Ayahuasca Journal of Ethnopharmacology April 1, 1984
and 22 more in the library