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

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.

Keywords: Ayahuasca; Depression; LSD; Mescaline; Placebo; Psilocybin.

Fig. 1

PRISMA flow diagram of systematic review and meta-analysis of classic serotonergic psychedelics for mood and depressive symptoms

Fig. 2

The effect size (SMD) of acute clinical effects of classic serotonergic psychedelic and placebo treatments on negative mood state in healthy volunteers and patients with mood disorders, shown as Hedges’ g with 95% confidence interval. Negative Hedges’ g indicates favor of psychedelics. Squares represent study effect sizes; open diamonds represent effect sizes of sub-group analyses by drug (lysergic acid diethylamide [LSD] or psilocybin); closed diamonds represent overall effect sizes for healthy volunteers (H) or mood disorder patients (P). The sizes of squares and diamonds are proportional to the SMD. Combined: polled LSD and psilocybin. d: day and h: hours. (c) The following instruments were grouped and the mean of SMD was used in analysis: Grob et al. (2011), Profile of Mood States (POMS) of 6 h and 1 day. Hasler et al. (2004), Adjective Mood Rating Scale (AMRS) of 4.5 h and 1 day. PANAS: Positive and Negative Affect. SE, standard error; l-IC, low confidence interval; u-CI, up confidence interval; I², heterogeneity across studies (%); Z, z value; p, p value

Fig. 3

Effect size (SMD) of acute, medium-term, and long-term clinical effects of classic serotonergic psychedelics vs placebo treatments on depressive symptoms of patients with mood disorders (P), shown as Hedges’ g with 95% confidence interval. A negative Hedges’ g indicates favor of psychedelics. Squares represent study effect sizes; open diamonds represent effect sizes of sub-group analyses by drug (psilocybin, lysergic acid diethylamide [LSD], and ayahuasca); closed diamonds represent overall effect sizes of each time-point (acute, medium term, and long term). The sizes of squares and diamonds are proportional to the SMD. Combined: pooled ayahuasca and psilocybin. Combined*: pooled LSD and psilocybin. d: day and h: hours. C: The score of the following instruments were grouped and the mean of SMD was used in analysis, for Ross et al. (2016) and Griffiths et al. (2016), Beck Depression Inventory (BDI) and Hospital Anxiety and Depression Scale (HADS); Palhano-Fontes et al. (2019), Hamilton Depression Rating Scale and Montgomery–Åsberg Depression Rating Scale (MADRS). SE, standard error; l-IC, low confidence interval; u-CI, up confidence interval; I², heterogeneity across studies (%); Z, z value; p, p value