Neuropharmacology of halogenated DMT analogs: psychoplastogenic and antidepressant properties of 5-Br-DMT, a psychedelic derivative with low hallucinogenic potential
Pol Puigseslloses, Núria Nadal‐gratacós, Berta Fumàs, Carlos P. Modenutti, Eline Pottie, Juan Ortigosa, A. Pablo-Quesada, Clara Riera-Colomer, Miren Ettcheto, Xavier Berzosa, David Pubill, Christophe P Stove, Elena Escubedo, Raúl López‐arnau
Molecular Psychiatry October 21, 2025 DOI: 10.1038/s41380-025-03308-2 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Preclinical study Peer reviewed |
|---|---|
| Population | Mice |
| Intervention | 5-Br-DMT |
| Dose | 10 mg/kg, i.p. |
| Duration | Single administration |
| Topics | Neuroplasticity Serotonin DMT |
| Keywords | Antidepressant Neuropharmacology Psychopharmacology Reuptake inhibitor Hallucinogen Serotonin uptake inhibitors In vivo Receptor Prefrontal cortex Fluoxetine Psychotomimetic Hippocampus Serotonin transporter |
| Citations | 1 |
| Key points | 5-Br-DMT is a non-hallucinogenic psychoplastogen that produces rapid antidepressant effects in a mouse model of stress-induced depression. |
Abstract
Current first-line antidepressants, such as selective serotonin reuptake inhibitors (SSRI), often present a delayed onset of action and fail to effectively treat a large proportion of patients, leaving a gap in the treatment of mood disorders. Psychedelics have recently emerged as promising alternatives due to their ability to produce fast-acting antidepressant effects through neuroplastic adaptations, but their hallucinogenic properties remain a major obstacle to their widespread therapeutic use. In this study, we characterized a novel class of halogenated DMT derivatives-5-F-DMT, 5-Cl-DMT, and 5-Br-DMT-for their pharmacological activity, behavioral effects, and therapeutic potential. Using a combination of in vitro assays, in silico modeling, and in vivo behavioral and gene expression studies, we found that halogen substitution at the 5-position modulates receptor affinity and selectivity across key serotonin (5-HT) receptors (5-HT1A/2 A/2B/2CR) and transporter (SERT). Notably, 5-Br-DMT was found to activate 5-HT2AR but did not induce the head twitch response (HTR) in mice, suggesting non-hallucinogenic activity. Furthermore, 5-Br-DMT upregulated immediate early genes (IEGs) associated with neuroplasticity in the mouse prefrontal cortex and hippocampus (Arc, Egr-1, -2 and -3) and promoted dendritic growth in cortical neurons. In a mouse model of stress-induced depression, a single administration (10 mg/kg, i.p.) of 5-Br-DMT resulted in a significant reduction in depressive-like behavior, reflecting rapid antidepressant effects. Collectively, our results highlight 5-Br-DMT as a non-hallucinogenic psychoplastogen with antidepressant properties, supporting its potential as a prototypical candidate for further study. Moreover, the evaluation and biological characterization of the halogenated DMT derivatives offers valuable information on structure-activity relationships that may guide the design of future therapeutic compounds.
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
Cited by 2
- Chemical ecology and convergent evolution of natural hallucinogens: From ecological defense to conserved neural targets Proceedings of the National Academy of Sciences June 24, 2026
- Experience, plasticity, and context: Beyond single-level models of antidepressant action. Journal of Psychopharmacology August 17, 2026
Cites 49
- Psychedelics Promote Structural and Functional Neural Plasticity Cell Reports June 1, 2018
- Quality of Acute Psychedelic Experience Predicts Therapeutic Efficacy of Psilocybin for Treatment-Resistant Depression Frontiers in Pharmacology January 17, 2018
- Psilocybin induces rapid and persistent growth of dendritic spines in frontal cortex in vivo Neuron July 5, 2021
- The Subjective Effects of Psychedelics Are Necessary for Their Enduring Therapeutic Effects. ACS Pharmacology & Translational Science December 10, 2020
- A non-hallucinogenic psychedelic analogue with therapeutic potential. Nature 2021
and 44 more in the library