Pharmacokinetic interactions between monoamine oxidase A inhibitor harmaline and 5-methoxy-N,N-dimethyltryptamine, and the impact of CYP2D6 status.
Xi-Ling Jiang, Hong-Wu Shen, Donald E. Mager, Ai-Ming Yu
Drug Metabolism and Disposition May 1, 2013 DOI: 10.1124/dmd.112.050724 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Preclinical pharmacokinetic study Peer reviewed |
|---|---|
| Population | Wild-type and CYP2D6-humanized (Tg-CYP2D6) mice |
| Interventions | harmaline 5-MeO-DMT |
| Dose | harmaline 2, 5, 15 mg/kg; 5-MeO-DMT 2, 10 mg/kg |
| Topics | 5-MeO-DMT DMT |
| Keywords | Pharmacokinetics Drug interactions Drug metabolism Designer drugs |
| Citations | 29 |
| Key points | Harmaline inhibits both MAO-A and CYP2D6, leading to dose-dependent increases in systemic and brain exposure to 5-MeO-DMT and bufotenine, with higher harmaline doses paradoxically reducing bufotenine levels due to CYP2D6 inhibition. |
Abstract
5-Methoxy-N,N-dimethyltryptamine (5-MeO-DMT or street name "5-MEO") is a newer designer drug belonging to a group of naturally occurring indolealkylamines. Our recent study has demonstrated that coadministration of monoamine oxidase A (MAO-A) inhibitor harmaline (5 mg/kg) increases systemic exposure to 5-MeO-DMT (2 mg/kg) and active metabolite bufotenine. This study is aimed at delineating harmaline and 5-MeO-DMT pharmacokinetic (PK) interactions at multiple dose levels, as well as the impact of CYP2D6 that affects harmaline PK and determines 5-MeO-DMT O-demethylation to produce bufotenine. Our data revealed that inhibition of MAO-A-mediated metabolic elimination by harmaline (2, 5, and 15 mg/kg) led to a sharp increase in systemic and cerebral exposure to 5-MeO-DMT (2 and 10 mg/kg) at all dose combinations. A more pronounced effect on 5-MeO-DMT PK was associated with greater exposure to harmaline in wild-type mice than CYP2D6-humanized (Tg-CYP2D6) mice. Harmaline (5 mg/kg) also increased blood and brain bufotenine concentrations that were generally higher in Tg-CYP2D6 mice. Surprisingly, greater harmaline dose (15 mg/kg) reduced bufotenine levels. The in vivo inhibitory effect of harmaline on CYP2D6-catalyzed bufotenine formation was confirmed by in vitro study using purified CYP2D6. Given these findings, a unified PK model including the inhibition of MAO-A- and CYP2D6-catalyzed 5-MeO-DMT metabolism by harmaline was developed to describe blood harmaline, 5-MeO-DMT, and bufotenine PK profiles in both wild-type and Tg-CYP2D6 mouse models. This PK model may be further employed to predict harmaline and 5-MeO-DMT PK interactions at various doses, define the impact of CYP2D6 status, and drive harmaline-5-MeO-DMT pharmacodynamics.
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 20
- Serotonin toxicity of serotonergic psychedelics Psychopharmacology July 12, 2021
- Acute Biphasic Effects of Ayahuasca PLoS One September 30, 2015
- A narrative synthesis of research with 5-MeO-DMT. Journal of Psychopharmacology March 1, 2022
- Psychedelics: Alternative and Potential Therapeutic Options for Treating Mood and Anxiety Disorders Molecules April 13, 2022
- Drug–drug interactions involving classic psychedelics: A systematic review Journal of Psychopharmacology November 20, 2023
and 15 more in the library
Cites 20
- Human Pharmacology of Ayahuasca: Subjective and Cardiovascular Effects, Monoamine Metabolite Excretion, and Pharmacokinetics Journal of Pharmacology and Experimental Therapeutics June 18, 2003
- Clinical investigations of the therapeutic potential of ayahuasca: rationale and regulatory challenges. Pharmacology & Therapeutics May 1, 2004
- Clinical toxicology of newer recreational drugs Clinical Toxicology October 1, 2011
- Psychedelic 5-methoxy-N,N-dimethyltryptamine: metabolism, pharmacokinetics, drug interactions, and pharmacological actions. Current Drug Metabolism October 1, 2010
- A critical review of reports of endogenous psychedelic N, N-dimethyltryptamines in humans: 1955-2010. Drug Testing and Analysis 2012
and 15 more in the library