Single-dose DMT reverses anhedonia and cognitive deficits via restoration of neurogenesis in a stress-induced depression model.
Rafael V Lima Da Cruz, Rêmullo B. G. De Miranda Costa, Gabriel M. De Queiroz, Tijana Stojanovic, Thiago C. Moulin, Richardson N. Leão
Translational Psychiatry January 29, 2026 DOI: 10.1038/s41398-026-03852-7 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Preclinical animal study Peer reviewed |
|---|---|
| Population | Male mice exposed to chronic unpredictable mild stress |
| Interventions | DMT fluoxetine |
| Dose | 30 mg/kg |
| Topics | Depression DMT Neuroplasticity |
| Citations | 2 |
| Key points | A single dose of DMT reversed depressive-like behavior and cognitive deficits in stressed male mice and enhanced adult-born granule cell integration, outperforming fluoxetine in most domains. |
Abstract
Major depressive disorder (MDD) remains a leading cause of disability worldwide, with current treatments limited by delayed onset and low efficacy. The serotonergic psychedelic N,N-dimethyltryptamine (DMT) has shown rapid antidepressant effects in early clinical studies, yet its mechanisms and efficacy remain poorly characterized in established models of depression. Here, we evaluated the effects of a single dose of DMT (30 mg/kg, i.p.) in male mice exposed to the Chronic Unpredictable Mild Stress (UCMS) paradigm, a robust mouse model recapitulating key features of MDD, including anhedonia and cognitive impairment. DMT administered after UCMS reversed depressive-like behavior and restored cognitive performance, outperforming chronic fluoxetine across most domains. When administered during the stress period, DMT mitigated anhedonic responses but did not rescue cognitive deficits, suggesting a long-lasting domain-specific efficacy. Exploratory assessments in anesthetized animals showed that DMT's behavioral and cellular benefits persisted under isoflurane, though the role of the psychedelic experience remains uncertain due to potential confounding effects of isoflurane not controlled for in our design. Histological analyses revealed that all DMT regimes significantly increased adult-born granule cell (abGC) integration and reduced the number of ectopically abnormally integrated abGCs. Together, our findings highlight the robust and multifaceted effects of DMT on behavior and neurogenesis, positioning it as a promising candidate for rapid-acting antidepressant strategies that target structural circuit repair.
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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A single dose of DMT reversed depressive-like behavior and cognitive deficits in stressed male mice and enhanced adult-born granule cell integration, outperforming fluoxetine in most domains.
Synthesized
Comparable studies
Other preclinical and animal studies on DMT for depression, most cited first.
| Study | Year | Design | Participants |
|---|---|---|---|
| Effects of N,N-Dimethyltryptamine on Rat Behaviors Relevant to Anxiety and Depression Adult male Sprague-Dawley rats | 2018 | Experimental study | |
| Immunomodulatory and behavioral effects of ayahuasca and N, N-dimethyltryptamine in a rat model of lipopolysaccharide-induced depression. Wistar rats | 2025 | Randomized controlled trial | n = 126 |
| N,N-dimethyltryptamine elicits antidepressant and anxiolytic effects in helpless mice: a comparative study with S-ketamine. Male helpless mice (single-housed and group-housed) | 2026 | Animal study | |
| 5-Methoxy-N,N-Dimethyltryptamine: Functional Safety Pharmacology and Video-EEG Assessment of a Short-Acting Serotonergic Psychedelic in Beagle Canines. Beagle dogs | 2026 | Preclinical animal study | n = 11 |