Even modest increases in DMT exposure from ayahuasca may intensify serotonergic effects in individuals taking SSRI antidepressants, suggesting a clinically relevant interaction. The study provides a mechanistic and quantitative framework for assessing interaction risks between ayahuasca alkaloids and SSRIs, supporting clinical decision-making and harm-reduction strategies where controlled drug-drug interaction studies are not feasible.
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.