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

Area of Science:

• Pharmacology
• Drug Metabolism
• Psychedelic Research

Background:

• Ayahuasca contains DMT and harmine, a MAO-A inhibitor.
• Increasing use of ayahuasca with SSRIs raises interaction concerns.
• SSRIs like fluoxetine and paroxetine inhibit CYP2D6, affecting DMT and harmine metabolism.

Purpose of the Study:

• Develop and validate PBPK models for DMT and harmine.
• Predict the impact of SSRI coadministration on ayahuasca alkaloid exposure.
• Assess pharmacokinetic and pharmacodynamic interactions.

Main Methods:

• Developed PBPK models for DMT and harmine using clinical data.
• Incorporated published data for fluoxetine, norfluoxetine, and paroxetine models.
• Simulated drug-drug interactions under acute and chronic SSRI dosing.

Main Results:

• Fluoxetine and paroxetine increased harmine exposure.
• Moderate increases in DMT systemic concentrations were observed.
• SSRI coadministration altered ayahuasca alkaloid pharmacokinetics.

Conclusions:

• Clinically relevant interaction between ayahuasca and SSRIs identified.
• Increased DMT exposure may intensify serotonergic effects.
• PBPK models provide a framework for assessing interaction risks.