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 DOI: 10.3390/futurepharmacol6030034 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Physiologically based pharmacokinetic modeling study Peer reviewed |
|---|---|
| Population | Simulated human phenotypes |
| Intervention | ayahuasca |
| Topics | 5-MeO-DMT DMT |
| Keywords | Harmine Pharmacokinetics Cmax Cyp2d6 Bioavailability Drug Pharmacology Enzyme Cytochrome p450 |
| Key points | CYP2D6 poor metabolizers showed substantially increased systemic exposure to DMT and harmine compared to normal metabolizers, while ultra-rapid metabolizers showed reduced exposure. |
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.