Examining the pharmacokinetic and pharmacodynamic interaction of N,N-dimethyltryptamine and harmine in healthy volunteers: Α factorial dose-escalation study

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).

Highlights

PKPD study with factorial design evaluates 7 DMT and harmine combinations.

Utilization of a novel transmucosal delivery system for precise dosing.

Clear dose-response relationship for DMT and harmine titration.

Novel formulation shows good safety and tolerability profile in healthy volunteers.

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 (C_max) reaching 33 ng/mL and 49 ng/mL, respectively. T_max, 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.

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Pharmaceutical formulation

The oromucosal formulation was manufactured by separate wet granulation of DMT succinate and harmine HCl with calcium phosphate (template inverted particle (TIP)) particles; Galvita AG, Basel, Switzerland; [20]) to yield TIP particles loaded with 25 % DMT or 25 % harmine. The DMT- and harmine-loaded TIP particles blends were then mixed in a turbula mixer to yield the seven different ratios used in this study (DMT:Harmine [mg]:[mg]; 0:120, 60:120, 90:120, 120:120, 120:0, 120:60, 120:90). Then, the blends were mixed with the superdisintegrant croscarmellose sodium (3 %), with the addition of sucralose (0.5 %), menthol (0.5 %), and peppermint flavor (0.5 %) for taste masking. The final blend was then compacted into fast-disintegrating orodispersible tablets. The final doses per tablet were one third of the target doses, enabling successive administration in three incremental steps (e.g., for the 120 mg DMT plus 120 mg harmine condition one tablet contained 40 mg of DMT and 40 mg of harmine). All dosage information for DMT and harmine refers to the freebase weight of DMT and harmine.

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, Examining the pharmacokinetic and pharmacodynamic interaction of N,N-dimethyltryptamine and harmine in healthy volunteers: Α factorial dose-escalation study, Biomedicine & Pharmacotherapy, Volume 184, 2025, 117908, ISSN 0753-3322, https://doi.org/10.1016/j.biopha.2025.117908.