Keywords

hallucinogens; psychedelics; depression; anxiety; meta-analysis; suicidal ideation

Abstract

Background: Hallucinogens including psilocybin, lysergic acid diethylamide (LSD), ketamine, N,N-dimethyltryptamine (DMT) (as ayahuasca), have re-emerged as potential rapid-acting treatments for mood disorders. We conducted a meta-analysis of placebo-controlled trials evaluating their efficacy in depression and anxiety disorders. Methods: A systematic review identified 12 trials (Total ≈ 670) meeting inclusion criteria (randomized, placebo-controlled). Data on Cohen’s d and Hedges’ g effect sizes for depression- and anxiety-related outcomes were extracted. We computed pooled effect sizes (weighted by sample size and inverse variance), performed subgroup analyses by drug, diagnosis, follow-up duration, and outcome measure type, and assessed heterogeneity (I2, Q) and funnel plot asymmetry. Results: Hallucinogen-assisted therapy showed large antidepressant and anxiolytic effects overall. The pooled Hedges’ g was 0.79 for depression and 0.87 for anxiety outcomes, favoring hallucinogens over placebo. Psilocybin and ayahuasca produced consistently large reductions in depression (g≈1.0–1.2) (Goodwin et al., 2022) (Palhano-Fontes et al., 2019) and anxiety (g≈1.0–1.1) (Ross et al., 2016) (Palhano-Fontes et al., 2019) symptoms. LSD-assisted therapy yielded robust anxiolytic effects in patients with anxiety (g1.5) (Gasser et al., 2014), with more moderate effects on depressive symptoms (g0.7) (Holze et al., 2023). Ketamine had significant, rapid antidepressant effects in major depression (g0.5 at 24 hours) (Lapidus et al., 2014), and substantial anti-suicidal effects in acutely suicidal patients (e.g., MADRS-SI item, g>3) (Domany & McCullumsmith, 2021). Between-study heterogeneity was moderate to high (I^2≈45–67%). Subgroup analysis indicated larger effects in life-threatening illness-related distress (e.g., cancer-associated anxiety/depression, g1.2–1.4) and smaller effects in treatment-resistant depression (g~0.4–0.8). Follow-up duration influenced outcomes: psychedelic effects often persisted for weeks (Holze et al., 2023) (Ross et al., 2016), whereas ketamine’s effects waned by 12 weeks (Glue et al., 2024) without continued dosing. Mechanistically, classical psychedelics (LSD, psilocybin, DMT) likely act via 5-HT2A receptor agonism leading to enhanced neuroplasticity (Calder & Hasler, 2022), while ketamine’s effects involve glutamate-mediated synaptogenesis (BDNF–TrkB signaling) (Krystal et al., 2023). Conclusion: Hallucinogen-assisted therapies are associated with rapid, clinically meaningful reductions in depression and anxiety symptoms across diagnoses. Psilocybin and LSD, given with psychotherapy, showed durable benefits (weeks-months) (Holze et al., 2023) (Ross et al., 2016). Ketamine reliably produced acute antidepressant and anti-suicidal effects (Domany & McCullumsmith, 2021), though maintenance treatments are required for sustained remission. While results are encouraging, significant heterogeneity and potential publication bias were observed (funnel plots showed asymmetry). Further large-scale trials are warranted to confirm efficacy, address long-term outcomes, and optimize treatment protocols (e.g. dosing, psychotherapy integration). Keywords: hallucinogens, psychedelics, LSD, psilocybin, DMT, ketamine, depression, anxiety, meta-analysis, suicidal ideation

Thesis Completion Year

2025

Thesis Completion Semester

Spring

Thesis Chair

Schroeder, Kersten

College

College of Medicine

Department

Burnett School of Biomedical Sciences

Thesis Discipline

Neuroscience

Language

English

Access Status

Open Access

Length of Campus Access

None

Campus Location

Orlando (Main) Campus

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