N,N-dimethyltryptamine elicits antidepressant and anxiolytic effects in helpless mice: a comparative study with S-ketamine

A single dose of DMT produced antidepressant-like effects in mice comparable to S-ketamine in the short term, but with longer-lasting behavioural effects and additional anxiolytic-like benefits in preclinical tests.

In this new animal study Sousa-Silva et al. (2026) found that DMT produces rapid antidepressant-like effects in a mouse model of learned helplessness, with efficacy comparable to S-ketamine shortly after administration.

However, DMT showed longer-lasting behavioural benefits, persisting for several days, whereas ketamine’s effects were more short-lived.

Both compounds reduced depressive-like behaviour and prevented stress-induced anhedonia, but DMT additionally produced clear and sustained anxiolytic-like effects, which were more pronounced than those observed with S-ketamine. Overall, the study suggests that DMT may offer a broader and more durable antidepressant and anxiolytic profile than ketamine in preclinical models, though these findings are limited to animals and require human validation.

Key Highlights of the Study

• S-ketamine evoked fast-acting and long-lasting antidepressant effects in helpless mice.

• DMT rapidly and sustainably reversed helplessness and anhedonia in mice.

• DMT elicited anxiolytic actions in helpless mice with late onset.

Abstract

“N,N-dimethyltryptamine (DMT) is an naturally occurring indoleamine with hallucinogenic and antidepressant effects in humans. Here, we compared the effects of DMT and S-ketamine, a fast-acting antidepressant, in helpless mice. To induce helplessness, male single and group-housed mice were exposed to inescapable footshock stress; only helpless animals were subsequently treated with S-ketamine 10 or 30 mg/kg (ip), DMT 10 or 25 mg/kg (ip), or vehicle and tested in behavioral assays. In depressive-related behavioral tests, S-ketamine and DMT (both at 10 mg/kg), only in group-housed mice, 24 h after administration, reversed escape deficits and reduced escape latency in the learned helplessness model. In helpless single-housed mice, 5 days after drug administration, both compounds (at 10 mg/kg) prevented stress-induced anhedonia in the sucrose preference test.

In the tail suspension test, DMT (10 mg/kg) reduced immobility up to 8 days post-injection, whereas the effects of S-ketamine (30 mg/kg) lasted up to 30 h after injection. In anxiety-related behavioral tests, DMT (10 mg/kg), but not S-ketamine, reversed stress-induced hypolocomotion in the open field test, and increased exploration in open arms in the elevated plus-maze up to 5 days post-administration.

However, in the novelty-suppressed feeding behavior, at 8 days after drug administration, neither DMT nor S-ketamine altered mouse behavior. Collectively, DMT is as effective as S-ketamine in producing rapid and long-lasting antidepressant effects in helpless mice. Present data also suggest anxiolytic-like effects for DMT. Ultimately, main findings highlight the transdiagnostic therapeutic potential of DMT for stress-related disorders.”

Anne Nathalia de Sousa-Silva, Clarissa de Almeida Moura, Carina Ioná de Oliveira Torres, Vitória Barros Marques, Jayane M. do Nascimento Silva, Bruno Lobão-Soares, Sérgio Ruschi Silva, Nicole L. Galvão-Coelho, Fernanda Palhano-Fontes, Draulio Barros de Araújo, Edilson Dantas da Silva, Elaine C. Gavioli, N,N-dimethyltryptamine elicits antidepressant and anxiolytic effects in helpless mice: a comparative study with S-ketamine, Neuropharmacology, Volume 292, 2026, 110947, Read Paper

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