NEW preclinical research showed that the antidepressant effects of N,N-dimethyltryptamine (DMT) were rapid, robust, and superior to conventional antidepressant therapy in several domains in a validated model of depression.
Major depressive disorder (MDD) remains a leading global cause of disability, with many patients failing to respond adequately to existing treatments due to delayed onset and limited efficacy. The serotonergic psychedelic DMT has demonstrated fast-acting antidepressant potential in early clinical work, but its effects in established biological models of depression were not well defined.
DMT Antidepressant Effects in Chronic Stress
Researchers investigated the antidepressant effects of DMT in male mice exposed to the chronic unpredictable mild stress (UCMS) paradigm, a well-established model that recapitulated key features of MDD, including anhedonia and cognitive impairment. A single intraperitoneal dose of DMT (30 mg/kg) administered after UCMS exposure reversed depressive-like behaviours and restored cognitive performance, outperforming chronic fluoxetine treatment, a widely used selective serotonin reuptake inhibitor.
When administered during the stress period, DMT reduced anhedonic responses but failed to rescue cognitive deficits, indicating a timing-dependent and domain-specific effect. These findings were notable, as cognitive impairment often persists in patients with MDD despite symptomatic mood improvement.
Histological analyses revealed that all DMT treatment regimens significantly increased integration of adult-born granule cells within the hippocampus, while reducing the number of abnormally integrated ectopic cells. This pattern suggested enhanced structural circuit organisation and neuroplasticity, providing a potential mechanistic basis for the observed behavioural recovery.
Implications and Future Directions
Exploratory experiments conducted under isoflurane anaesthesia indicated that DMT’s behavioural and cellular benefits persisted in the absence of conscious psychedelic effects. However, because isoflurane itself has reported antidepressant properties, future studies using anaesthetics without known mood-related effects, alongside anaesthetic-only controls, will be necessary to clarify the role of consciousness in DMT’s action.
The authors also highlighted the need to define the dose–response relationship of DMT, particularly given prior reports of variable efficacy across dosing regimens in rodents. Improved understanding of DMT’s pharmacokinetic and pharmacodynamic properties across species will be essential to support translational development.
Further work should also focus on identifying the specific neural circuits and receptor pathways mediating the antidepressant effects of DMT, as well as assessing the durability of benefits following single or repeated dosing. As all experiments were conducted in male mice, validation in female subjects will also be critical to determine generalisability and potential sex-specific responses.
Reference
Lima da Cruz R.V et al. Single-dose DMT reverses anhedonia and cognitive deficits via restoration of neurogenesis in a stress-induced depression model. Transl Psychiatry. 2026; DOI:10.1038/s41398-026-03852-7.
