Development of a physiologically based pharmacokinetic model of N,N-dimethyltryptamine, harmine, and their interactions from ayahuasca in rats and humans.
Naphat Wittayakarn, Yu-Mei Tan, Pattanachai Choomalaiwong, Samantha Chen, Daniel Hoer, Nilubon Thaoboonruang, Manupat Lohitnavy
Toxicological sciences : an official journal of the Society of Toxicology November 1, 2025 DOI: 10.1093/toxsci/kfaf118 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Physiologically based pharmacokinetic modeling Peer reviewed |
|---|---|
| Topics | Ayahuasca 5-MeO-DMT DMT |
| Keywords | Banisteriopsis caapi Psychotria viridis N,N-Dimethyltryptamine Harmine Physiologically based pharmacokinetics |
| Key points | The PBPK models reasonably predicted plasma concentrations of DMT and harmine across various dosing conditions, and simulations suggest that plasma concentration above a threshold may be more relevant for therapeutic effects than peak levels. |
Abstract
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 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 the 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.
Comparable studies
Other experimental studies on 5-MeO-DMT, most cited first.
| Study | Year | Design | Participants |
|---|---|---|---|
| Short term changes in the proteome of human cerebral organoids induced by 5-MeO-DMT. Human cerebral organoids | 2017 | Experimental study | |
| Bufo alvarius: a potent hallucinogen of animal origin. Bufo alvarius toad venom | 1994 | Experimental study | |
| Prospective examination of synthetic 5-methoxy-N,N-dimethyltryptamine inhalation: effects on salivary IL-6, cortisol levels, affect, and non-judgment Volunteers | 2019 | Within-subjects experimental study | n = 11 |
| Unmasking of a neonatal somatovesical reflex in adult cats by the serotonin autoreceptor agonist 5-methoxy-N,N-dimethyltryptamine. Adult cats | 1990 | Experimental study | n = 10 |
| Studies on the Mechanism of Action of Monoamine Oxidase: Metabolism of N,N-Dimethyltryptamine and N,N-Dimethyltryptamine-N-Oxide | 1962 | Experimental study |
Citations in the library
Cites 20
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- Ayahuasca: Psychological and Physiologic Effects, Pharmacology and Potential Uses in Addiction and Mental Illness Current Neuropharmacology March 2, 2018
and 15 more in the library