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 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.
Comparable studies
Other preclinical and animal studies on 5-MeO-DMT, most cited first.
| Study | Year | Design | Participants |
|---|---|---|---|
| Psychedelic N,N-dimethyltryptamine and 5-methoxy-N,N-dimethyltryptamine modulate innate and adaptive inflammatory responses through the sigma-1 receptor of human monocyte-derived dendritic cells. Human primary monocyte-derived dendritic cells | 2014 | In vitro study | |
| Effects of N,N-Dimethyltryptamine on Rat Behaviors Relevant to Anxiety and Depression Adult male Sprague-Dawley rats | 2018 | Experimental study | |
| Hallucinogen-like actions of 5-methoxy-N,N-diisopropyltryptamine in mice and rats. Mice and rats | 2006 | Preclinical study | |
| Agonist Properties of N,N-Dimethyltryptamine at Serotonin 5-HT2A and 5-HT2C Receptors Rats and transfected fibroblasts | 1998 | Experimental study | |
| Subtypes of the 5-HT receptor mediating the behavioural responses to 5-methoxy-N,N-dimethyltryptamine in the rat Intact rats and rats depleted of monoamines with reserpine | 1985 | Experimental study |
Citations in the library
Cited by 6
- In vitro and in vivo metabolism of psilocybin’s active metabolite psilocin Frontiers in Pharmacology April 29, 2024
- Harnessing Pharmacogenomics in Clinical Research on Psychedelic‐Assisted Therapy Clinical Pharmacology & Therapeutics September 30, 2024
- Psychedelic Drugs in Mental Disorders: Current Clinical Scope and Deep Learning‐Based Advanced Perspectives Advanced Science March 20, 2025
- Liquid chromatography-tandem mass spectrometry-based pharmacokinetic and metabolic analysis of 4-bromo-2,5-dimethoxyphenethylamine and its metabolites in human plasma. Drug Metabolism and Disposition April 28, 2025
- Population pharmacokinetic-pharmacodynamic modeling of co-administered N,N-dimethyltryptamine and harmine in healthy subjects. Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie July 9, 2025
and 1 more in the library
Cites 8
- Rapid antidepressant effects of the psychedelic ayahuasca in treatment-resistant depression: a randomized placebo-controlled trial Psychological Medicine June 15, 2018
- Antidepressant Effects of a Single Dose of Ayahuasca in Patients With Recurrent Depression Journal of Clinical Psychopharmacology December 11, 2015
- Exploratory study of the dose-related safety, tolerability, and efficacy of dimethyltryptamine (DMT) in healthy volunteers and major depressive disorder. Neuropsychopharmacology September 1, 2022
- Metabolism and urinary disposition of N,N‐dimethyltryptamine after oral and smoked administration: a comparative study Drug Testing and Analysis July 28, 2014
- Metabolism and disposition of N,N‐dimethyltryptamine and harmala alkaloids after oral administration of ayahuasca Drug Testing and Analysis April 19, 2012
and 3 more in the library