Discovery and In Vitro Characterization of SPL028: Deuterated N,N-Dimethyltryptamine.
Marie Layzell, Peter Rands, Meghan Good, Zelah Joel, Rick Cousins, Tiffanie Benway, Ellen James, Carol Routledge
ACS Medicinal Chemistry Letters September 14, 2023 DOI: 10.1021/acsmedchemlett.3c00143 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Preclinical study Peer reviewed |
|---|---|
| Intervention | D2-DMT |
| Topics | 5-MeO-DMT DMT |
| Keywords | Psychedelics Drug development Mental health treatment Pharmaceutical research |
| Citations | 6 |
| Key points | Deuteration at the α-carbon of DMT yields D2-DMT, which has a longer half-life and comparable receptor binding affinity to DMT. |
Abstract
The psychedelic N,N- dimethyltryptamine (DMT) is in clinical development for the treatment of major depressive disorder. However, when administered via intravenous infusion, its effects are short-lived due to rapid clearance. Here we describe the synthesis of deuterated analogues of DMT with the aim of prolonging the half-life and decreasing the clearance rate while maintaining similar pharmacological effects. The molecule with the greatest degree of deuteration at the α-carbon (N,N-D2-dimethyltryptamine, D2-DMT) demonstrated the longest half-life and intrinsic clearance in hepatocyte mitochondrial fractions when compared with DMT. The in vitro receptor binding profile of D2-DMT was comparable to that of DMT, with the highest affinity at the 5-HT1A, 5-HT2A, and 5-HT2C receptors. D2-DMT was therefore the preferred candidate to consider for further evaluation.
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 5
- A Brief Historical Overview of Psychedelic Research. Biological Psychiatry: Cognitive Neuroscience and Neuroimaging May 1, 2024
- Evaluation of the Indazole Analogs of 5-MeO-DMT and Related Tryptamines as Serotonin Receptor 2 Agonists. ACS Medicinal Chemistry Letters February 8, 2024
- Modification of natural tryptamines for the treatment of neuropsychiatric diseases Journal of Psychopharmacology October 4, 2025
- Serotonin 2A receptor binding, functional activity, and in vitro metabolism of two trideuteromethoxy 2C-B isotopologues. Naunyn-Schmiedeberg's Archives of Pharmacology June 18, 2026
- Safety, pharmacokinetics, and pharmacodynamics of intravenously administered deuterated N,N-dimethyltryptamine (CYB004) in healthy volunteers. Journal of Psychopharmacology September 3, 2026
Cites 26
- Effects of Psilocybin-Assisted Therapy on Major Depressive Disorder JAMA Psychiatry November 4, 2020
- Evidence for 5-HT2 involvement in the mechanism of action of hallucinogenic agents. Life Sciences December 17, 1984
- The Hallucinogen N,N -Dimethyltryptamine (DMT) Is an Endogenous Sigma-1 Receptor Regulator Science February 13, 2009
- Efficacy and safety of psilocybin-assisted treatment for major depressive disorder: Prospective 12-month follow-up Journal of Psychopharmacology February 1, 2022
- Neural correlates of the DMT experience assessed with multivariate EEG. Scientific Reports November 19, 2019
and 21 more in the library