The American journal of psychiatryJan 1, 2025

Advantages and Challenges of Very Fast-Acting Psychedelics for Treating Depression

Psychedelic Science Weekly Brief ↗PubMed ↗DOI ↗

Updated Feb 14, 2026

Abstract

Short interventions (15-30 min) with 5-methoxy-N,N-dimethyltryptamine (5-MeO-DMT) and N,N-dimethyltryptamine (DMT) are safe and well tolerated.

Both 5-MeO-DMT and DMT are associated with marked improvement in depression symptoms within 24 hours.
Improvements in depressive symptoms may last for at least 1 week following treatment.
Early clinical trials suggest these psychedelics could be effective with single day dosing regimens.
Both compounds primarily target serotonergic receptors, indicating a potential mechanism for their effects.
Challenges remain in understanding how to sustain the antidepressant response and optimize treatment delivery.

Simplified

Unlike classical antidepressants, psychedelics such as psilocybin have been shown to induce a rapid antidepressant response. In the wake of this development, interest has emerged in ultra-fast, short-acting psychedelics such as 5-methoxy-N,N-dimethyltryptamine (5-MeO-DMT) and N,N-dimethyltryptamine (DMT) with the expectation that these can produce rapid antidepressant effects following an intense but brief psychedelic intervention. The current paper reviews the clinical pharmacology of 5-MeO-DMT and DMT and their potential benefits and challenges in the treatment of depression. Both compounds display affinities for a variety of monoamine receptors and transporters, but mostly so for serotonergic (5HT) receptors, including 5HTand 5HT. Early clinical trials in small samples have shown that short interventions (15-30 min) with 5-MeO-DMT and DMT are safe and well tolerated and can induce marked improvement in symptoms of depression within 24 hours that sustain for at least 1 week. Data on long-term efficacy are currently scarce but do suggest a prolongation of the treatment response. Potential benefits of these treatments include flexible, single day dosing regimens, achievement of treatment efficacy independent from integrative therapy, and ease of clinical implementation. Future challenges include establishing the duration of the antidepressant effect and strategies on how to sustain the antidepressant response, optimization of treatment delivery parameters, and a mechanistic understanding of the clinical response. Acceptance of ultra-fast, short-acting psychedelics will depend on future randomized, placebo-controlled trials with a focus on replication, duration and maintenance of antidepressant efficacy in large patient samples. 1A2A

Funding

Competing interests

Dr. Ramaekers and Dr. Reckweg are scientific consultants to GH Research. GH Research was not involved in this manuscript. Dr. Mason reports no financial relationships with commercial interests.

PubMed

Advantages and Challenges of Very Fast-Acting Psychedelics for Treating Depression

Abstract

Funding

Competing interests

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Abstract

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