Molecular Mechanisms of Psilocybin and Implications for the Treatment of Depression
Susan Ling, Felicia Ceban, Leanna M.W. Lui, Yena Lee, Kayla M Teopiz, Nelson B Rodrigues, Orly Lipsitz, Hartej Gill, Mehala Subramaniapillai, Rodrigo B. Mansur, Kangguang Lin, Roger Ho, Joshua D. Rosenblat, David Castle, Roger S McIntyre
CNS Drugs November 17, 2021 DOI: 10.1007/s40263-021-00877-y (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Review Peer reviewed |
|---|---|
| Topics | Psilocybin Serotonin Depression |
| Keywords | Neurochemical Antidepressant Monoaminergic Hallucinogen Psychopharmacology Receptor Hippocampus |
| Citations | 123 |
| Key findings | Psilocybin's antidepressant and psychedelic effects are thought to involve modulation of the serotonergic system, primarily through agonism at 5-HT2A receptors, along with indirect effects on dopaminergic and glutamatergic systems and alterations in neural circuitry. |
Abstract
Therapeutic deficiencies with monoaminergic antidepressants invites the need to identify and develop novel rapid-acting antidepressants. Hitherto, ketamine and esketamine are identified as safe, well-tolerated rapid-acting antidepressants in adults with treatment-resistant depression, and also mitigate measures of suicidality. Psilocybin is a naturally occurring psychoactive alkaloid and non-selective agonist at many serotonin receptors, especially at serotonin 5-HT2A receptors, and is found in the Psilocybe genus of mushrooms. Preliminary studies with psilocybin have shown therapeutic promise across diverse populations including major depressive disorder. The pharmacodynamic mechanisms mediating the antidepressant and psychedelic effects of psilocybin are currently unknown but are thought to involve the modulation of the serotonergic system, primarily through agonism at the 5-HT2A receptors and downstream changes in gene expression. It is also established that indirect effects on dopaminergic and glutamatergic systems are contributory, as well as effects at other lower affinity targets. Along with the direct effects on neurochemical systems, psilocybin alters neural circuitry and key brain regions previously implicated in depression, including the default mode network and amygdala. The aim of this review is to synthesize the current understanding of the receptor pharmacology and neuronal mechanisms underlying the psychedelic and putative antidepressant properties of psilocybin.
Comparable studies
Other narrative reviews on psilocybin for depression, 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 | |
| Registered clinical studies investigating psychedelic drugs for psychiatric disorders. Registered clinical trials on clinicaltrials.gov evaluating psychedelics for... | 2021 | Review | n = 70 |
| Depression, Mindfulness, and Psilocybin: Possible Complementary Effects of Mindfulness Meditation and Psilocybin in the Treatment of Depression. A Review | 2020 | Review | |
| From psychiatry to neurology: Psychedelics as prospective therapeutics for neurodegenerative disorders | 2021 | Review | |
| Top Ten Tips Palliative Care Clinicians Should Know About Psychedelic-Assisted Therapy in the Context of Serious Illness. Palliative care clinicians and patients | 2022 | Review |
Citations in the library
Cited by 100
- Psilocybin therapy for females with anorexia nervosa: a phase 1, open-label feasibility study Nature Medicine July 24, 2023
- Psilocybin-assisted therapy for depression: A systematic review and meta-analysis. Psychiatry Research November 1, 2023
- Therapeutic use of psilocybin: Practical considerations for dosing and administration Frontiers in Psychiatry December 1, 2022
- Efficacy of psilocybin for treating symptoms of depression: systematic review and meta-analysis BMJ May 1, 2024
- Beyond the serotonin deficit hypothesis: communicating a neuroplasticity framework of major depressive disorder. Molecular Psychiatry December 1, 2024
and 95 more in the library
Cites 64
- Rapid and sustained symptom reduction following psilocybin treatment for anxiety and depression in patients with life-threatening cancer: a randomized controlled trial Journal of Psychopharmacology November 30, 2016
- 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
- Neural correlates of the psychedelic state as determined by fMRI studies with psilocybin Proceedings of the National Academy of Sciences January 23, 2012
- Psychedelics Promote Structural and Functional Neural Plasticity Cell Reports June 1, 2018
and 59 more in the library