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 (opens in new tab)
Study at a glance
AI-extracted from the abstract| 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 Entheogens Drug metabolism biotransformation Metabolic pathways DMT N Liver enzymes |
| Citations | 6 |
| Key findings | 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.