Classic serotonergic psychedelics for mood and depressive symptoms: a meta-analysis of mood disorder patients and healthy participants

Classic serotonergic psychedelics such as psilocybin, LSD, and ayahuasca may improve mood and reduce depressive symptoms more than placebo, with effects appearing within hours and lasting up to 60 days. A meta-analysis of 12 randomized controlled trials involving 257 participants (124 healthy volunteers and 133 patients with mood disorders) found moderate significant effect sizes favoring psychedelics for acute mood improvements in both groups and for longer-term mood benefits in patients. For patients with mood disorders, significant reductions in depressive symptoms were seen acutely, at 2–7 days, and at 16–60 days after treatment. Although unblinding and expectancy are concerns, the strength, speed, and durability of effects support further placebo-controlled trials.

Study at a glance

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.