Impact of CYP2D6 Polymorphisms on the Pharmacokinetics of N,N-Dimethyltryptamine and Harmine via PBPK Modeling and Simulation

CYP2D6 genetic variants substantially alter the body's exposure to the psychedelic brew ayahuasca's active compounds, N,N-dimethyltryptamine (DMT) and harmine (HRM). Using physiologically based pharmacokinetic modeling, poor metabolizers showed 53.3% higher area under the curve (AUC) and 40.5% higher peak concentration (Cmax) for DMT, with similar but smaller increases for HRM; ultra-rapid metabolizers showed reduced exposure to both. These results indicate that CYP2D6 polymorphisms contribute to interindividual variability in ayahuasca pharmacokinetics, with potential clinical implications.

Study at a glance

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.