Predicting Drug–Drug Interactions Between Ayahuasca Alkaloids and SSRIs Using Physiologically Based Pharmacokinetic Modeling

Gabriella de Souza Gomes Ribeiro¹Beatriz Aparecida Passos Bismara Paranhos¹Fabiane Dörr¹Mauricio Yonamine¹Bianca Villanova²Lorena Terene Lopes Guerra²Adrieli Oliveira Raminelli²Jose Augusto Silva Reis²Caio Cesar de Paula²Anna Beatriz Vicentini Zacharias²Jaime Eduardo Hallak²Rafael Guimarães Dos Santos²Frederico Severino Martins^1*Tania Marcourakis^1*

• ¹University of São Paulo, São Paulo, Brazil
• ²Universidade de Sao Paulo Faculdade de Medicina de Ribeirao Preto, Ribeirao Preto, Brazil

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 This is a provisional file, not the final typeset article physiologically based pharmacokinetic (PBPK) models to predict the impact of SSRI coadministration on the systemic exposure of DMT and HRM. PBPK models for DMT and HRM were 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 from published clinical data and incorporated enzyme inhibition parameters to represent their inhibitory potential. After model qualification, drug–drug interaction simulations were performed under acute and chronic SSRI dosing conditions. Both SSRIs increased HRM exposure and produced moderate increases in DMT systemic concentrations, consistent with CYP2D6 inhibition and enhanced monoamine oxidase A blockade. These findings suggest a clinically relevant interaction, as even modest increases in DMT exposure may intensify serotonergic effects in individuals receiving antidepressant therapy. Altogether, this work provides a mechanistic, quantitative framework to assess 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.