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Review
. 2025 May;18(5):263-280.
doi: 10.1080/17512433.2025.2515866. Epub 2025 Jun 11.

From molecules to meaning: unpacking the antidepressant mechanisms of psychedelic drugs

Victor Pablo Acero  1 , Taylor A Flatt  1   2   3 , Peter M Gooch  1   4 , Skylar J Gaughan  1   5 , Adam W Levin  1 , Alan K Davis  1   6   7
Affiliations
Free article
Review

From molecules to meaning: unpacking the antidepressant mechanisms of psychedelic drugs

Victor Pablo Acero et al. Expert Rev Clin Pharmacol. 2025 May.
Free article

Abstract

Introduction: Psychedelic compounds are emerging treatments for depression, capable of producing rapid and lasting symptom reduction after 1-2 administrations in the context of psychotherapy - a stark contrast to traditional antidepressants. Despite promising outcomes, the mechanisms underlying psychedelics' reported antidepressant effects remain poorly understood and are often framed in fragmented ways. Clarifying these mechanisms is crucial for guiding future research and clinical innovation with psychedelics.

Areas covered: This review critically examines current evidence on the mechanisms by which psychedelics may exert antidepressant effects. We highlight key mechanisms of action within biological, psychological, social, and spiritual domains that we believe are among the most compelling and deserving of further investigation. Throughout, we compare these mechanisms to those proposed for traditional antidepressants, identifying points of overlap and divergence.

Expert opinion: Although mechanistic research is valuable, an overemphasis on identifying discrete pathways may limit psychedelic science. Psychedelics likely work through complex, interwoven biological, psychological, and experiential processes that cannot be fully reduced to single mechanisms. Future research should move beyond frameworks and metrics used to validate conventional antidepressants to explore how suprapharmacological factors - set, setting, therapy modality, and integration - shape outcomes. Embracing this complexity is essential to realizing psychedelics' full therapeutic potential for depression.

Keywords: Psychedelic-assisted therapy for depression; psilocybin, LSD, DMT, ayahuasca, and 5-MeO-DMT for depression; psychedelic mechanism of action; psychedelic pharmacology; psychedelic transdiagnostic mechanisms; psychedelics for depression.

Plain language summary

Psychedelic drugs are being studied as new treatments for depression because they can reduce symptoms quickly and durably, sometimes after just one or two doses. However, scientists still do not fully understand how these drugs work to improve depression. In this review, we look at some of the most important ways psychedelics might help, including by improving function in brain networks, psychological flexibility, social wellbeing, and spiritual wellbeing. In discussing these mechanisms, we draw comparisons to traditional antidepressants like SSRIs, to highlight key differences in mechanisms and clinical outcomes. Although studying how psychedelics work is important, we argue that focusing too much on finding a single cause may limit progress. Psychedelics likely work through many combined effects that are hard to separate. Future research should explore not just how these drugs work biologically, but also how therapy, environment, and personal experiences shape treatment outcomes.

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