This single-blind, randomized, two-arm, factorial, dose-finding study (n=16) investigates the pharmacokinetic and pharmacodynamic interactions between DMT and harmine in an ayahuasca-inspired (‘pharmahuasca’) formulation. Participants received six dose combinations (0–120 mg DMT, 0–180 mg harmine) via a transmucosal delivery system. Results show dose-dependent subjective effects lasting 4–5 hours, with peak plasma levels (Cmax) of 33 ng/mL for DMT and 49 ng/mL for harmine. Harmine increased DMT bioavailability and plasma half-life while altering its metabolism. The formulation demonstrated a favourable safety profile, supporting its potential for further clinical testing in affective disorders.
Abstract of Examining the pharmacokinetic and pharmacodynamic interaction of N,N-dimethyltryptamine and harmine in healthy volunteers
“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.”
Authors: Klemens Egger, Javier Jareño Redondo, Jovin Müller, Joëlle Dornbierer, John Smallridge, Helena D. Aicher, Daniel Meling, Per Müller, Jonas Kost, Maxim Puchkov, Angela Äbelö, Erich Seifritz, Boris B. Quednow, Robin von Rotz, Milan Scheidegger & Dario A. Dornbierer
Summary of Examining the pharmacokinetic and pharmacodynamic interaction of N,N-dimethyltryptamine and harmine in healthy volunteers
Ayahuasca is a traditional psychoactive brew originating from the Amazon, used for spiritual, therapeutic, and medicinal purposes. It typically contains two key components: N,N-dimethyltryptamine (DMT), a potent psychedelic compound, and β-carboline alkaloids such as harmine, harmaline, and tetrahydroharmine. These β-carbolines act as monoamine oxidase inhibitors (MAOIs), preventing the rapid breakdown of DMT in the digestive system and allowing it to exert its psychoactive effects when consumed orally. Despite its long history of use, the pharmacological interactions between these compounds remain incompletely understood, particularly in controlled scientific settings.
The study aimed to investigate these interactions by developing an ayahuasca-inspired formulation containing DMT and harmine. The primary goal was to systematically assess their pharmacokinetic (how the body absorbs, distributes, metabolises, and excretes the compounds) and pharmacodynamic (how the compounds affect the body) interactions across different dosage levels. The researchers hypothesised that increasing harmine doses would enhance the bioavailability of DMT, prolong its plasma half-life, and reduce interindividual variability in DMT plasma concentrations. They also predicted that harmine would modulate DMT metabolism by lowering the levels of its primary metabolite, indole-3-acetic acid (3-IAA), while increasing levels of a secondary metabolite, DMT-N-oxide (DMT-NO).
Additionally, the study sought to explore the subjective and physiological effects of different DMT-harmine dose combinations, as well as their overall safety profile. Given the increasing interest in ayahuasca and DMT for therapeutic applications, understanding these interactions is crucial for optimising potential clinical use while ensuring safety and consistency in psychedelic-assisted therapy.
Methods
Study Design and Participants
Find this paper
https://doi.org/10.1016/j.biopha.2025.117908
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Cite this paper (APA)
Egger, K., Redondo, J. J., Müller, J., Dornbierer, J., Smallridge, J., Aicher, H. D., ... & Dornbierer, D. A. (2025). Examining the pharmacokinetic and pharmacodynamic interaction of N, N-dimethyltryptamine and harmine in healthy volunteers: Α factorial dose-escalation study. Biomedicine & Pharmacotherapy, 184, 117908.
Study details
Compounds studied
DMT
Ayahuasca
Topics studied
Healthy Subjects
Neuroscience
Study characteristics
Original
Single-Blind
Within-Subject
Randomized
Bio/Neuro
Participants
16
Humans
Institutes
Institutes associated with this publication
Reconnect LabsReconnect Labs, a Swiss-based clinical-stage pharmaceutical company, is pioneering the development of Regenerative Therapeutics™ aimed at mental health, leveraging cutting-edge neuroscience and precision psychopharmacology.
Compound Details
The psychedelics given at which dose and how many times
DMT 0 - 120mg | 6x