Multilevel Mechanisms and Clinical Efficacy of Psilocybin in Depression Treatment: A Systematic Review
Xizhen Zhang, Xiaowen Zhang, Haiyu Zhang, Sheng Wei
International Journal of Molecular Sciences September 10, 2026 DOI: 10.3390/ijms27188052 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Systematic review Peer reviewed |
|---|---|
| Intervention | Psilocybin |
| Dose | 25 mg |
| Topics | Depression Psilocybin |
| Key findings | The authors propose that psilocybin's active metabolite psilocin may produce antidepressant effects via 5-HT2A receptor activation, BDNF-TrkB signaling, hippocampal neurogenesis, and default mode network remodeling. They report that single or limited doses, particularly 25 mg, rapidly and sustainably reduce treatment-resistant depression symptoms, with efficacy comparable or superior to escitalopram. |
Abstract
Depression, characterized by persistent low mood and anhedonia, represents a prevalent affective disorder imposing substantial medical and economic burdens. Current first-line antidepressants are limited by delayed onset and treatment resistance. Psilocybin (PSI) has re-emerged as a promising therapeutic agent with rapid, sustained antidepressant effects. This systematic review was conducted following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) 2020 guidelines and prospectively registered with International Prospective Register of Systematic Reviews (PROSPERO) (CRD420261425626). Comprehensive searches of PubMed, Web of Science, and ScienceDirect identified studies published between January 2021 and March 2026 that examined the antidepressant mechanisms and clinical efficacy of PSI. Of 949 records screened, 46 original studies were included. We synthesized evidence across the molecular, cellular, neural circuit, and clinical dimensions. Our findings suggest that psilocin, the active metabolite, may exert antidepressant effects through multilevel mechanisms, including 5-hydroxytryptamine receptor 2A (5-HT2a ) receptor activation, brain-derived neurotrophic factor (BDNF)-tropomyosin receptor kinase B(TrkB) signaling, hippocampal neurogenesis, and default mode network functional connectivity remodeling. Clinical trials confirm that single or limited-dose PSI (particularly 25 mg) rapidly and sustainably alleviates symptoms in treatment-resistant depression, with efficacy comparable or superior to that of escitalopram. This multilevel framework bridges mechanistic insights with clinical translation, supporting PSI as a novel therapeutic pathway for depression.
Comparable studies
Other systematic reviews and meta-analyses on psilocybin for depression, most cited first.
| Study | Year | Design | Participants |
|---|---|---|---|
| Therapeutic effects of classic serotonergic psychedelics: A systematic review of modern‐era clinical studies Patients with cancer- or illness-related anxiety and depression, major depressive... | 2020 | Systematic review | n = 188 |
| The experimental effects of psilocybin on symptoms of anxiety and depression: A meta-analysis People with elevated symptoms of anxiety and depression | 2020 | Meta-analysis | n = 117 |
| Psychedelics in the treatment of unipolar mood disorders: a systematic review Patients with broadly defined unipolar mood disorders | 2016 | Systematic review | n = 423 |
| Psychedelic therapy for depressive symptoms: A systematic review and meta-analysis. Participants in studies of psychedelic therapy for depressive symptoms (Major... | 2023 | Systematic review with meta-analysis | n = 14 |
| Serotonergic hallucinogens in the treatment of anxiety and depression in patients suffering from a life-threatening disease: A systematic review. Patients with life-threatening diseases and symptoms of anxiety or depression | 2018 | Systematic review | n = 445 |
Citations in the library
Cites 73
- Psilocybin with psychological support for treatment-resistant depression: an open-label feasibility study. The Lancet Psychiatry May 17, 2016
- Trial of Psilocybin versus Escitalopram for Depression New England Journal of Medicine April 14, 2021
- Single-Dose Psilocybin for a Treatment-Resistant Episode of Major Depression. New England Journal of Medicine November 3, 2022
- Psilocybin for treatment-resistant depression: fMRI-measured brain mechanisms. Scientific Reports October 13, 2017
- Single-Dose Psilocybin Treatment for Major Depressive Disorder JAMA August 31, 2023
and 68 more in the library