Indolethylamine N-Methyltransferase Deletion Impacts Mouse Behavior without Disrupting Endogenous Psychedelic Tryptamine Production.
Cassandra J. Hatzipantelis, Lindsay P. Cameron, Min Liu, Seona D Patel, Hannah N Saeger, Anna M M Vernier, Yara A Khatib, Brandon J Willis, Louise Lanoue, Oliver Fiehn, David E. Olson
ACS Chemical Neuroscience October 15, 2025 DOI: 10.1021/acschemneuro.5c00384 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Experimental study with genetic knockout model Peer reviewed |
|---|---|
| Population | Mice |
| Topics | DMT |
| Keywords | Inmt N,N-Dimethyltryptamine Temt Bufotenine Indolethylamine n-methyltransferase Psychedelic Thioether s-methyltransferase |
| Key findings | INMT knockout did not decrease endogenous psychedelic levels in mice, indicating alternative biosynthetic pathways for these compounds. |
Abstract
Exogenously administered psychedelics produce both rapid and long-lasting effects on neuroplasticity and behavior, but it is currently unclear if endogenously produced psychedelics can elicit similar effects. There have been relatively few studies on the role of endogenous psychedelics in health and disease, perhaps owing to the difficulty in quantifying their levels and manipulating their production. Here, we describe highly sensitive mass spectrometry-based analytical methods for quantifying endogenous psychedelics in mice, and we disclose a genetic mouse model lacking indolethylamine N-methyltransferase (INMT), an enzyme believed to play a critical role in the production of endogenous psychedelics and previously characterized as a thioether S-methyltransferase. We found that INMT knockout (KO) does not produce any major abnormalities in reproduction or growth, but it does impact a range of mouse behaviors across several distinct domains. However, INMT KO did not result in an obvious decrease in endogenous psychedelic levels, suggesting that psychedelics might be produced by alternative biosynthetic pathways in rodents.
Comparable studies
Other preclinical and animal studies on DMT, most cited first.
| Study | Year | Design | Participants |
|---|---|---|---|
| The Hallucinogen N,N -Dimethyltryptamine (DMT) Is an Endogenous Sigma-1 Receptor Regulator Mice and cell lines | 2009 | Experimental study | |
| Correlation between the potency of hallucinogens in the mouse head-twitch response assay and their behavioral and subjective effects in other species. C57BL/6J mice | 2020 | Experimental study with dose-response experiments | |
| 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 | |
| Inhibitory effect of chlorpromazine on the syndrome of hyperactivity produced by l‐tryptophan or 5‐methoxy‐N,N‐dimethyltryptamine in rats treated with a monoamine oxidase inhibitor Rats | 1971 | Experimental study | |
| Effects of N,N-Dimethyltryptamine on Rat Behaviors Relevant to Anxiety and Depression Adult male Sprague-Dawley rats | 2018 | Experimental study |
Citations in the library
Cites 28
- Psychedelics Promote Structural and Functional Neural Plasticity Cell Reports June 1, 2018
- Classic psychedelics: An integrative review of epidemiology, therapeutics, mystical experience, and brain network function. Pharmacology & Therapeutics May 1, 2019
- Psychedelics promote neuroplasticity through the activation of intracellular 5-HT2A receptors Science February 16, 2023
- Psychedelics reopen the social reward learning critical period Nature June 14, 2023
- The neural basis of psychedelic action. Nature Neuroscience October 24, 2022
and 23 more in the library