Development of a Physiologically Based Pharmacokinetic Model of N,N-Dimethyltryptamine, Harmine, and Their Interactions from Ayahuasca in Rats and Humans.

Ayahuasca is a traditional Amazonian brew composed of Psychotria viridis, containing N,N-dimethyltryptamine (DMT), and Banisteriopsis caapi, which includes harmala alkaloids such as harmine. Ayahuasca can produce potent psychoactive effects primarily due to DMT, whose metabolism is inhibited by harmine via monoamine oxidase-A (MAO-A) enzymes. This inhibition increases DMT's systemic bioavailability, thereby allowing more DMT to reach the brain and intensify its psychedelic effects. Beyond its traditional psychoactive uses, ayahuasca has shown potential therapeutic benefits for mental health conditions such as depression, anxiety, and substance use disorders. To support better design of dosing regimens in both preclinical and clinical settings, we developed linked physiologically based pharmacokinetic (PBPK) models for DMT and harmine in rats and humans. The models account for multiple routes of administration (intraperitoneal, oral, intravenous, and buccal) and integrate harmine's inhibition of DMT metabolism in liver and lungs. Key absorption and metabolism parameters were optimized using published time-concentration data. The models reasonably predicted plasma concentrations of DMT and harmine across various dosing conditions. Simulation results offer insights into how the route of administration and co-administration with harmine influence exposure. The model also enables exploration of the dose metric driving the therapeutic effects, suggesting that plasma concentration above a threshold may be more relevant than peak levels. Overall, this PBPK model offers a mechanistic framework for guiding preclinical and clinical studies, supporting safer and more effective therapeutic use of ayahuasca and potentially other psychedelic compounds.