N, N-dimethyltryptamine forms oxygenated metabolites via CYP2D6 - an in vitro investigation.
Emma Eckernäs, Alicia Macan-Schönleben, Moa Andresen-Bergström, Sofia Birgersson, Kurt-Jürgen Hoffmann, Michael Ashton
Xenobiotica; the fate of foreign compounds in biological systems December 1, 2023 DOI: 10.1080/00498254.2023.2278488 via PubMed
Summary
AI-generated from the abstractThe psychedelic compound DMT is metabolized primarily by monoamine oxidase A, but other pathways are poorly understood. This work investigated cytochrome P450 (CYP) enzymes in DMT metabolism by incubating DMT with recombinant human CYP enzymes and human liver microsomes, then analyzing metabolites with high-resolution mass spectrometry. DMT was rapidly metabolized by CYP2D6, while stable with all other tested CYP enzymes. Metabolism in human liver microsomes was reduced by harmine and SKF-525A but not quinidine, likely due to residual MAO-A activity. CYP2D6 incubations produced mono-, di-, and tri-oxygenated metabolites, probably from hydroxylation on the indole core. The findings may affect safety for ayahuasca use in slow CYP2D6 metabolizers or with CYP2D6 inhibitors.
Study at a glance
| Characteristics | In vitro experimental study Peer reviewed |
|---|---|
| Population | Recombinant human CYP enzymes and human liver microsomes |
| Intervention | DMT |
| Topics | 5-MeO-DMT DMT |
| Keywords | N n-dimethyltryptamine Cytochrome p450 Human liver microsomes In vitro metabolism Psychedelics hallucinogens |
| Citations | 6 |
| Key finding | CYP2D6 rapidly metabolizes DMT, forming oxygenated metabolites, while other CYP enzymes do not. |
Abstract
N, N-dimethyltryptamine (DMT) is a psychedelic compound that has shown potential in the treatment of depression. Aside from the primary role of monoamine oxidase A (MAO-A) in DMT metabolism, the metabolic pathways are poorly understood. Increasing this understanding is an essential aspect of ensuring safe and efficacious use of DMT.This work aimed to investigate the cytochrome 450 (CYP) mediated metabolism of DMT by incubating DMT with recombinant human CYP enzymes and human liver microsomes (HLM) followed by analysis using high-resolution mass spectrometry for metabolite identification.DMT was rapidly metabolised by CYP2D6, while stable with all other investigated CYP enzymes. The metabolism of DMT in HLM was reduced after inclusion of harmine and SKF-525A whereas quinidine did not affect the metabolic rate, likely due to MAO-A residues present in HLM. Analysis of the CYP2D6 incubates showed formation of mono-, di- and tri-oxygenated metabolites, likely as a result of hydroxylation on the indole core.More research is needed to investigate the role of this metabolic pathway in vivo and any pharmacological activity of the proposed metabolites. Our findings may impact on safety issues following intake of ayahuasca in slow CYP2D6 metabolizers or with concomitant use of CYP2D6 inhibitors.