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

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.