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Less is more? Antidepressant effects of short-acting psychedelics

Neuropsychopharmacology volume 50, pages 875–876 (2025)Cite this article

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Long-acting psychedelics like psilocybin have demonstrated potential for rapid and sustained alleviation of depression symptoms [1]. However, psilocybin-based therapy is resource-intensive, requiring therapists to be present during extended dosing sessions alongside an integrative psychotherapy protocol. This may limit its scalability in clinical settings despite its proven efficacy. Alternatively, psychedelics with a quick onset (1–5 min) and short-duration (15–30 min) such as 5-methoxy-N,N-dimethyltryptamine (5-MeO-DMT) and N,N-dimethyltryptamine (DMT) are currently explored as more practical, cost-effective alternatives [2]. As a primer, dose escalations of vaporized 5-MeO-DMT, provided without integrative therapy, induced ultra-rapid (i.e., within 2 h) symptom relief in patients with treatment resistant depression (TRD) of whom a majority (87,5%, n = 7 out of 8) remained in full remission on day 7 [3]. In the present issue of Neuropsychopharmacology, Falchi-Carvalho et al. [4] report that subsequent inhalations of 15 and 60 mg DMT, spaced 90 min apart, also produced rapid and sustained antidepressant effects in 14 patients with TRD. At day 7 after treatment, response and remission rates were 85.7% and 57.1%, respectively. In many patients, the antidepressant effect of DMT persisted for at least three months, with response and remission rates reaching 57.1% and 35.7%, respectively.

These findings are particularly impressive when compared to the largest psychedelic trial on TRD, where a single 25 mg dose of psilocybin (n = 79) led to a 37% response rate and a 29% remission rate at three weeks, but the response rate declined to 20% by three months [1]. Moreover, the antidepressant effect of inhaled DMT occurred immediately within a day after dosing, as also evidenced by a strong drop in suicide ideation. This might be critical for achieving long term clinical stability as rapid antidepressant responses may reduce neurobiological harms from recurrent, enduring depression [5]. Yet, though these findings are very promising, it should also be noted that the antidepressant effect of inhaled DMT might be an overestimation of its actual effect size, as it was observed in an open-label trial without a proper control group. Patients enrolling in this DMT trial may have had high treatment expectations that contributed to strong placebo effects, potentially distorting the true impact of the treatment. To address this bias, future DMT trials should incorporate larger patient samples and include placebo and active control groups.

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References

  1. Goodwin GM, Aaronson ST, Alvarez O, Arden PC, Baker A, Bennett JC, et al. Single-Dose Psilocybin for a Treatment-Resistant Episode of Major Depression. N. Engl J Med. 2022;387:1637–48.

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  1. Faculty of Psychology and Neuroscience, Maastricht University, Maastricht, the Netherlands

    Johannes G. Ramaekers

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  1. Johannes G. Ramaekers
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Correspondence to Johannes G. Ramaekers.

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JGR is a scientific consultant to GH Research. GH Research was not involved in this manuscript.

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Ramaekers, J.G. Less is more? Antidepressant effects of short-acting psychedelics. Neuropsychopharmacol. 50, 875–876 (2025). https://doi.org/10.1038/s41386-025-02103-5

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