Impact of CYP2D6 Polymorphisms on the Pharmacokinetics of N,N-Dimethyltryptamine and Harmine via PBPK Modeling and Simulation
Gabriella de Souza Gomes Ribeiro, Pieter Annaert, Frederico Severino Martins, Tânia Marcourakis
Future Pharmacology June 23, 2026 DOI: 10.3390/futurepharmacol6030034 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Physiologically based pharmacokinetic modeling study Peer reviewed |
|---|---|
| Population | Simulated human phenotypes |
| Intervention | ayahuasca |
| Topics | 5-MeO-DMT DMT |
| Keywords | Harmine Pharmacokinetics Cmax Cyp2d6 Bioavailability Drug Pharmacology Enzyme Cytochrome p450 |
| Key points | CYP2D6 poor metabolizers showed substantially increased systemic exposure to DMT and harmine compared to normal metabolizers, while ultra-rapid metabolizers showed reduced exposure. |
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.
Comparable studies
Other experimental studies on 5-MeO-DMT, most cited first.
| Study | Year | Design | Participants |
|---|---|---|---|
| Short term changes in the proteome of human cerebral organoids induced by 5-MeO-DMT. Human cerebral organoids | 2017 | Experimental study | |
| Bufo alvarius: a potent hallucinogen of animal origin. Bufo alvarius toad venom | 1994 | Experimental study | |
| Prospective examination of synthetic 5-methoxy-N,N-dimethyltryptamine inhalation: effects on salivary IL-6, cortisol levels, affect, and non-judgment Volunteers | 2019 | Within-subjects experimental study | n = 11 |
| Unmasking of a neonatal somatovesical reflex in adult cats by the serotonin autoreceptor agonist 5-methoxy-N,N-dimethyltryptamine. Adult cats | 1990 | Experimental study | n = 10 |
| Studies on the Mechanism of Action of Monoamine Oxidase: Metabolism of N,N-Dimethyltryptamine and N,N-Dimethyltryptamine-N-Oxide | 1962 | Experimental study |
Citations in the library
Cites 6
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- A six-month prospective evaluation of personality traits, psychiatric symptoms and quality of life in ayahuasca-naïve subjects. Journal of Psychoactive Drugs September 1, 2009
- New World Tryptamine Hallucinogens and the Neuroscience of Ayahuasca Current Topics in Behavioral Neurosciences 2015
- Predicting drug–drug interactions between ayahuasca alkaloids and SSRIs using physiologically based pharmacokinetic modeling Frontiers in Molecular Biosciences February 18, 2026
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