Classic serotonergic psychedelics for mood and depressive symptoms: a meta-analysis of mood disorder patients and healthy participants
This meta-analysis of 12 randomised controlled trials (n = 257) found that classic serotonergic psychedelics (mainly psilocybin, with LSD and ayahuasca) produced moderate, significant improvements in acute mood in healthy volunteers and patients and significant reductions in depressive symptoms in patients at acute, medium (2–7 days) and longer-term (16–60 days) follow-ups. Despite concerns about unblinding and expectancy, the robust effect sizes, rapid onset and enduring effects support further double-blind, placebo-controlled clinical trials of these agents for negative mood and depression.
Authors
- Nathalia Galvão-Coelho
- Daniel Perkins
- Joseph Sarris
Published
Abstract
Rationale
Major depressive disorder is one of the leading global causes of disability, for which the classic serotonergic psychedelics have recently reemerged as a potential therapeutic treatment option.
Objective
We present the first meta-analytic review evaluating the clinical effects of classic serotonergic psychedelics vs placebo for mood state and symptoms of depression in both healthy and clinical populations (separately).
Results
Our search revealed 12 eligible studies (n = 257; 124 healthy participants, and 133 patients with mood disorders), with data from randomized controlled trials involving psilocybin (n = 8), lysergic acid diethylamide ([LSD]; n = 3), and ayahuasca (n = 1). The meta-analyses of acute mood outcomes (3 h to 1 day after treatment) for healthy volunteers and patients revealed improvements with moderate significant effect sizes in favor of psychedelics, as well as for the longer-term (16 to 60 days after treatments) mood state of patients. For patients with mood disorder, significant effect sizes were detected on the acute, medium (2–7 days after treatment), and longer-term outcomes favoring psychedelics on the reduction of depressive symptoms.
Conclusion
Despite the concerns over unblinding and expectancy, the strength of the effect sizes, fast onset, and enduring therapeutic effects of these psychotherapeutic agents encourage further double-blind, placebo-controlled clinical trials assessing them for management of negative mood and depressive symptoms.
Research Summary of 'Classic serotonergic psychedelics for mood and depressive symptoms: a meta-analysis of mood disorder patients and healthy participants'
Introduction
Earlier research has seen a resurgence of interest in classic serotonergic psychedelics — principally psilocybin, DMT (often via ayahuasca), LSD and mescaline — as potential treatments for depressive disorders. The background presented by Galvão-Coelho and colleagues notes limitations of conventional antidepressants (delayed onset, side-effects, and a high proportion of treatment-resistant cases) and highlights preclinical and clinical evidence that psychedelics act primarily via serotonin 2A receptor agonism and may produce rapid and enduring mood effects. The authors also outline safety considerations and prior trial activity, including open‑label studies and double‑blind trials in populations such as patients with life‑threatening cancer, and note regulatory interest (for example, FDA "breakthrough therapy" designation for psilocybin in 2019).
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Galvão-Coelho, N. L., Marx, W., Gonzalez, M., Sinclair, J., de Manincor, M., Perkins, D., & Sarris, J. (2021). Classic serotonergic psychedelics for mood and depressive symptoms: a meta-analysis of mood disorder patients and healthy participants. Psychopharmacology, 238(2), 341-354. https://doi.org/10.1007/s00213-020-05719-1
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