Toxicokinetics and analytical toxicology of four N, N-dimethyltryptamine derivatives studied in human in vitro systems and in vivo by means of zebrafish embryos.
Gloria Daziani, Lea Wagmann, Matthias D. Kroesen, K Simon Wellenberg, Matthias Grill, Jennifer Herrmann, Jérémy Carlier, Francesco Paolo Busardò, Markus R Meyer
Archives of Toxicology September 21, 2026 DOI: 10.1007/s00204-026-04552-3 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | In vitro and in vivo metabolism study Peer reviewed |
|---|---|
| Population | Pooled human liver S9 incubations and zebrafish embryos |
| Interventions | DMT-Boc DMT-isopropylcarbamate DMT-pivaloylamide DMT-THP |
| Topics | 5-MeO-DMT DMT |
| Keywords | Metabolism New psychoactive substances Toxicokinetics Tryptamines |
| Key points | The four DMT derivatives are extensively metabolized, primarily through N-demethylation and hydroxylation, with CYP1A2, CYP2D6, and FMO3 as the most active phase I enzymes and MAO-A contributing to DMT-THP metabolism. DMT-Boc, DMT-isopropylcarbamate, and DMT-pivaloylamide had in vitro half-lives of 74 to 79 minutes, whereas DMT-THP exceeded 180 minutes, and all compounds showed plasma protein binding above 99 percent. The authors propose N,N-bis-demethylated, N-demethylated, and N-oxygenated metabolites plus parent compounds as consumption markers for clinical and forensic identification. |
Abstract
N,N-Dimethyltryptamine (DMT) is a naturally occurring substituted tryptamine used as a psychedelic drug for ritual purposes by various cultures. Derivatives were already found on the drug of abuse market, such as N1-tert-butoxycarbonyl-N,N-dimethyltryptamine (DMT-Boc). The aim of the current study was to investigate the toxicokinetics of DMT-Boc and three related DMT derivatives, by name DMT-isopropylcarbamate, DMT-pivaloylamide, and DMT-THP (N,N-dimethyl-2-[1-(oxan-2-yl)indol-3-yl]ethanamine). In vitro and in vivo metabolism studies with pooled human liver S9 incubations and zebrafish embryos were performed, respectively. Monooxygenase and monoamine oxidase (MAO) isozymes involved in the phase I metabolism were identified. In vitro metabolic stability and plasma protein binding (PPB) were evaluated. A total of 11 metabolites for DMT-Boc, 13 for DMT-isopropylcarbamate, eight for DMT-pivaloylamide and 16 for DMT-THP were identified using high-resolution tandem mass spectrometry. N-Demethylation and hydroxylation were the most relevant metabolic reactions. CYP1A2, CYP2D6, and FMO3 were identified as most active phase I isozymes and MAO-A contributed to DMT-THP metabolism. The in vitro half-lives of DMT-Boc, DMT-isopropylcarbamate, and DMT-pivaloylamide were calculated to be between 74 and 79 min, while that of DMT-THP was found to be > 180 min. All compounds showed high PPB (> 99%) indicating that co-consumption with other drugs might increase the DMT derivatives' toxicity. Combined in vitro and in vivo approaches provided a comprehensive metabolism overview. N, N-bis-Demethylated, N-demethylated and N-oxygenated metabolites along with parent compound were proposed as consumption markers in order to support clinical and forensic toxicologists to identify these substances in biosamples in case of suspected abuse.
In the evidence
This study is part of the evidence base for a synthesis in the library. Here is how each one recorded it.
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State of the evidence: DMT Unclear
Four DMT derivatives were extensively metabolized mainly via N-demethylation and hydroxylation, with CYP1A2, CYP2D6, and FMO3 most active and in vitro half-lives of 74 to over 180 minutes and plasma protein binding above 99 percent.
Synthesized
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
Cites 23
- The hallucinogenic world of tryptamines: an updated review. Archives of Toxicology August 1, 2015
- N, N-Dimethyltryptamine (DMT), an Endogenous Hallucinogen: Past, Present, and Future Research to Determine Its Role and Function Frontiers in Neuroscience August 6, 2018
- A fatal intoxication following the ingestion of 5-methoxy-N,N-dimethyltryptamine in an ayahuasca preparation. Journal of Analytical Toxicology 2005
- Dark Classics in Chemical Neuroscience:N,N-Dimethyltryptamine (DMT) ACS Chemical Neuroscience July 23, 2018
- N,N-Dimethyltryptamine attenuates spreading depolarization and restrains neurodegeneration by sigma-1 receptor activation in the ischemic rat brain. Neuropharmacology July 1, 2021
and 18 more in the library