Impact of CYP2D6 Polymorphisms on the Pharmacokinetics of N,N-Dimethyltryptamine and Harmine via PBPK Modeling and Simulation
Gabriella de Souza Gomes Ribeiro, Pieter Annaert, Frederico Severino Martins, Tânia Marcourakis
Future Pharmacology June 23, 2026 Peer reviewed DOI: 10.3390/futurepharmacol6030034 via OpenAlex
Summary
CYP2D6 enzyme polymorphisms significantly affect the pharmacokinetics of DMT and harmine in ayahuasca. Poor metabolizers experience a 53.3% increase in systemic exposure to DMT and a 40.5% increase in its peak concentration, while ultra-rapid metabolizers show reduced exposure to both compounds. This study emphasizes the importance of using physiologically based pharmacokinetic modeling to understand individual variations and potential clinical risks associated with these substances.
Study at a glance
| Design | physiologically based pharmacokinetic modeling |
|---|---|
| Population | not specified; focuses on metabolic phenotypes related to CYP2D6 |
| Key finding | Poor metabolizers of CYP2D6 have significantly increased systemic exposure to DMT and harmine compared to normal and ultra-rapid metabolizers. |
Abstract
Background/Objectives: In this study, we present an analysis of ayahuasca, a psychedelic preparation containing N,N-dimethyltryptamine (DMT) and β-carbolines, such as harmine (HRM), a reversible monoamine oxidase A (MAO-A) inhibitor that enables the oral bioavailability of DMT. CYP2D6 is a highly polymorphic enzyme associated with interindividual variability in drug exposure, but its influence on the pharmacokinetics of ayahuasca alkaloids remains poorly understood. Methods: Using physiologically based pharmacokinetic (PBPK) modeling, we simulated scenarios for poor (PM), normal (NM), and ultra-rapid (UM) metabolizers by adjusting CYP2D6 enzyme expression for each phenotype. Results: PMs showed increased systemic exposure to DMT (AUC +53.3%; Cmax +40.5%) and HRM (AUC +30.6%; Cmax +22.8%), while UMs exhibited reduced exposure to both compounds. Conclusions: These findings highlight the significant impact of CYP2D6 polymorphisms on the pharmacokinetics of DMT and HRM, reinforcing the value of PBPK modeling for predicting interindividual variability and potential clinical risks.