Predicting drug-drug interactions between ayahuasca alkaloids and SSRIs using physiologically based pharmacokinetic modeling.

Introduction: Ayahuasca is a psychedelic preparation containing N,N-dimethyltryptamine (DMT) and the β-carboline harmine (HRM), a reversible monoamine oxidase A inhibitor that enables DMT oral bioavailability. The increasing concomitant use of ayahuasca with selective serotonin reuptake inhibitors (SSRIs) has raised concerns about potential pharmacokinetic and pharmacodynamic interactions, particularly because fluoxetine and paroxetine are strong CYP2D6 inhibitors and DMT and HRM undergo CYP-mediated metabolism. This study aimed to develop and validate physiologically based pharmacokinetic (PBPK) models to predict the impact of SSRI coadministration on the systemic exposure of DMT and HRM. Methods: PBPK models for DMT and HRM were developed and qualified using plasma concentration-time data from a controlled clinical study in which six volunteers received oral ayahuasca. Models for fluoxetine, norfluoxetine, and paroxetine were developed based on published clinical data and incorporated enzyme inhibition parameters to represent their inhibitory potential. Drug-drug interaction simulations were performed under acute and chronic SSRI dosing conditions. Results: Both fluoxetine and paroxetine increased HRM exposure and produced moderate increases in DMT systemic concentrations. These effects were consistent with CYP2D6 inhibition and enhanced monoamine oxidase A blockade. The simulations demonstrated that SSRI coadministration alters the pharmacokinetic profiles of ayahuasca alkaloids under both acute and chronic dosing scenarios. Discussion: The findings suggest a clinically relevant interaction between ayahuasca and SSRIs, as even modest increases in DMT exposure may intensify serotonergic effects in individuals receiving antidepressant therapy. This study provides a mechanistic and quantitative framework for assessing interaction risks between ayahuasca alkaloids and SSRIs, supporting clinical decision-making and harm-reduction strategies in contexts where controlled drug-drug interaction studies are not feasible.