Single-dose DMT reverses anhedonia and cognitive deficits via restoration of neurogenesis in a stress-induced depression model

The authors of this study tested whether a single systemic dose of the serotonergic psychedelic N,N‑dimethyltryptamine (DMT) could reverse core depression‑like symptoms in a well‑validated mouse model of chronic stress and depression (Chronic Unpredictable Mild Stress, UCMS).

The goal was both behavioural and mechanistic: to assess effects on depressive behaviours (anhedonia and cognition) and on adult hippocampal neurogenesis, a structural plasticity process implicated in mood regulation.

“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.”

Notes

Rapid, robust antidepressant effects: DMT showed unusually fast and multifaceted reversal of core depressive phenotypes in an established animal model, suggesting rapid‑acting antidepressant potential beyond symptom suppression

Structural plasticity: By enhancing neurogenesis and proper circuit integration, DMT appears to address underlying structural brain deficits associated with stress‑induced depression rather than only modifying neurotransmitter levels

These preclinical results align with emerging clinical data on psychedelics in depression, highlighting neurogenesis and circuit repair mechanisms as promising translational targets for new treatments.

Lima da Cruz, R.V., Costa, R.B.G.d.M., de Queiroz, G.M. et al. Single-dose DMT reverses anhedonia and cognitive deficits via restoration of neurogenesis in a stress-induced depression model. Transl Psychiatry 16, 101 (2026). Read Paper

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