Psilocybin as Transformative Fast‐Acting Antidepressant: Pharmacological Properties and Molecular Mechanisms
Makiath Adebo, Marie Laure Bonnet, Ons Laouej, Céline Defaix, Josephine C McGowan, Florence Butlen-Ducuing, Denis J David, Erwan Poupon, Laurent Tritschler, Alain M. Gardier
Fundamental and Clinical Pharmacology July 16, 2025 DOI: 10.1111/fcp.70038 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Review Peer reviewed |
|---|---|
| Interventions | Psilocybin Psilocin |
| Topics | Psilocybin |
| Keywords | Antidepressant Transformative learning Pharmacology Hallucinogen |
| Citations | 10 |
| Key findings | Psilocybin shows therapeutic potential for treatment-resistant depression, but its antidepressant mechanisms, particularly the role of 5-HT2A receptor activation, remain controversial. |
Abstract
ABSTRACT In the 1950s–60s, serotonergic psychedelic drugs were studied as potential adjuvants to psychotherapy to treat addiction and alcoholism. However, starting in the 70s, preclinical and clinical studies on psychedelics stopped for decades because legislation controlled its recreational use, citing their hallucinogenic and psychotomimetic effects, as well as their abuse potential. Amazingly, we are witnessing an impressive return of these drugs due to recent clinical trials suggesting a therapeutic potential of psychedelics, among them psilocybin, for treating patients with depression resistant to conventional antidepressant drugs. Yet, their underlying mechanisms of action remain incompletely elucidated. This review provides an update on seminal clinical trials using psilocybin, as well as preclinical work uncovering the pharmacological properties and experimental pharmacology of psilocybin and its active metabolite psilocin. These drugs are primarily serotonin 5‐HT 2A receptor (5‐HT2AR) agonists. Although there is a consensus that 5‐HT2AR activation mediates its psychedelic effects in human and rodent models of anxiety/depression, its role in psilocin's antidepressant effects remains controversial. This review also provides an overview of neurotransmitter systems, neuroplasticity, and neural circuits activated by psilocin. Further research in developing effective antidepressants for depression is prescient now more than ever, as according to the World Health Organization (WHO), depression will be the main cause of disability in 2030. Understanding the mechanisms through which psilocybin/psilocin would be an effective antidepressant is crucial to ultimately validate its therapeutic potential when combined with SSRIs/SNRIs in mood disorders.
Comparable studies
Other narrative reviews on psilocybin, most cited first.
| Study | Year | Design | Participants |
|---|---|---|---|
| Classic psychedelics: An integrative review of epidemiology, therapeutics, mystical experience, and brain network function. General population | 2019 | Integrative review | |
| The pharmacology of psilocybin | 2002 | Review | |
| Serotonin research: contributions to understanding psychoses | 2008 | Review | |
| Psychedelics, Meditation, and Self-Consciousness | 2018 | Review | |
| The abuse potential of medical psilocybin according to the 8 factors of the Controlled Substances Act | 2018 | Review |
Citations in the library
Cited by 9
- Psilocybin as a fast-acting and long-lasting antidepressant for adolescence: Proposing NeuroD1 as a biomarker of its long-term plasticity Biomedicine & Pharmacotherapy October 30, 2025
- With great power comes great responsibility: Promise and caution in the new psychedelic renaissance Brain Disorders September 23, 2025
- Psilocybin Treatment as an Adjunct to Cognitive Behavioral Therapy for Eating Disorders: Therapeutic Rationale & Considerations for Protocol Development. Behavioral Sciences March 6, 2026
- THE IMPACT OF SELECTED PSYCHOACTIVE SUBSTANCES - COCAINE, AMPHETAMINE, PSILOCYBIN, MDMA, AND KETAMINE - ON THE BODY IN PHYSICAL AND PSYCHOLOGICAL ASPECTS AND THEIR MAIN MECHANISMS OF ACTION: A NARRATIVE REVIEW International Journal of Innovative Technologies in Social Science September 28, 2026
- Psilocibin: Current Evidence, Safety Signals, and Challenges in Assessing Potential Multi-Organ Effects Biomedicines July 6, 2026
and 4 more in the library
Cites 100
- mTOR-Dependent Synapse Formation Underlies the Rapid Antidepressant Effects of NMDA Antagonists Science August 19, 2010
- Psilocybin produces substantial and sustained decreases in depression and anxiety in patients with life-threatening cancer: A randomized double-blind trial Journal of Psychopharmacology November 30, 2016
- Synaptic Dysfunction in Depression: Potential Therapeutic Targets Science October 4, 2012
- NMDAR inhibition-independent antidepressant actions of ketamine metabolites Nature April 24, 2016
- Psilocybin with psychological support for treatment-resistant depression: an open-label feasibility study. The Lancet Psychiatry May 17, 2016
and 95 more in the library