Psilocybin and psilocin regulate microglial immunomodulation and support neuroplasticity via serotonergic and AhR signaling.
Salma Laabi, Claire LeMmon, Callie Vogel, Mariana Chacon, Víctor M. Jiménez
International Immunopharmacology June 26, 2025 DOI: 10.1016/j.intimp.2025.114940 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | In vitro study Peer reviewed |
|---|---|
| Population | Resting and LPS-activated microglia |
| Interventions | Psilocybin Psilocin |
| Topics | Psilocybin Neuroplasticity Serotonin |
| Keywords | 5-ht2a 5-ht2b 5-ht7 Ahr Bdnf Il-10 Microglia Tnf-α Trkb Neuroinflammation brain inflammation Psychedelics psilocybin Hallucinogens Entheogens Neuroimmunology Neurodegeneration |
| Citations | 15 |
| Key points | Psilocybin and psilocin suppress TNF-α and increase BDNF in activated microglia through 5-HT2A, 5-HT2B, 5-HT7, and TrkB signaling, with AhR selectively required for psilocin-induced BDNF upregulation. |
Abstract
Psilocybin, a serotonergic psychedelic, has demonstrated therapeutic potential in neuropsychiatric disorders. While its neuroplastic and immunomodulatory effects are recognized, the underlying mechanisms remain unclear. This study investigates how psilocybin and its active metabolite, psilocin, influence microglial inflammatory responses and neurotrophic factor expression through serotonergic and AhR signaling. Using in vitro models of resting and LPS-activated microglia, we evaluated the effects of psilocybin and psilocin on the expression of pro-inflammatory cytokines (TNF-α), anti-inflammatory cytokines (IL-10), and neuroplasticity-related markers (BDNF). Receptor-specific contributions were assessed using selective antagonists for 5-HT2A, 5-HT2B, 5-HT7, TrkB, and AhR. Psilocybin and psilocin significantly suppressed TNF-α expression and increased BDNF levels in LPS-activated microglia. These effects were mediated by 5-HT2A, 5-HT2B, 5-HT7, and TrkB signaling, while AhR activation was required for psilocin-induced BDNF upregulation but not TNF-α suppression. IL-10 levels remained unchanged under normal conditions but increased significantly when serotonergic, TrkB, or AhR signaling was blocked, suggesting a compensatory shift in anti-inflammatory pathways. Psilocybin and psilocin promote a microglial phenotype that reduces inflammation and supports neuroplasticity via receptor-specific mechanisms. Their effects on TNF-α and BDNF depend on distinct serotonergic and neurotrophic pathways, with AhR playing a selective role in psilocin's action. These findings clarify the receptor-mediated dynamics of psilocybin's therapeutic effects and highlight alternative anti-inflammatory pathways that may be relevant for clinical applications.
Comparable studies
Other preclinical and animal studies on neuroplasticity, most cited first.
| Study | Year | Design | Participants |
|---|---|---|---|
| Psychedelics promote neuroplasticity through the activation of intracellular 5-HT2A receptors In vitro and in vivo (rodent) models | 2023 | Experimental study | |
| Psychedelics promote plasticity by directly binding to BDNF receptor TrkB Mice | 2023 | Experimental study | |
| Effects of psilocybin on hippocampal neurogenesis and extinction of trace fear conditioning Mice | 2013 | Experimental study | |
| The alkaloids of Banisteriopsis caapi, the plant source of the Amazonian hallucinogen Ayahuasca, stimulate adult neurogenesis in vitro Progenitor cells from subventricular and subgranular zones of adult mice brains | 2017 | In vitro experimental study | |
| N,N-dimethyltryptamine compound found in the hallucinogenic tea ayahuasca, regulates adult neurogenesis in vitro and in vivo Mice | 2020 | In vitro and in vivo experimental study |
Citations in the library
Cited by 13
- Psychedelics and the Extracellular Matrix: Rewiring Neuroplasticity and Metaplasticity for Next-Generation Psychiatric Therapies Biological Psychiatry February 1, 2026
- Psychedelics in Multiple Sclerosis: Mechanisms, Challenges, and Prospects for Neuroimmune Modulation and Repair. Cells November 26, 2025
- Multianalytical Investigation of Psilocybe cubensis Mushrooms: Physicochemical Characterization and Biological Evaluation of Psilocybin and Psilocin Compounds ACS Omega September 15, 2025
- Psilocybin, From Ancestral Use to Therapeutic Potential: A Multidimensional Review of Its Pharmacological Basis and Current Perspectives Human Psychopharmacology: Clinical and Experimental September 1, 2026
- Current status and future prospects of research on psilocybin's regulation of neurotransmitters and their receptors related to the pathogenesis of tinnitus. Hearing research August 1, 2026
and 8 more in the library
Cites 51
- Psilocybin can occasion mystical-type experiences having substantial and sustained personal meaning and spiritual significance Psychopharmacology July 7, 2006
- Psilocybin with psychological support for treatment-resistant depression: an open-label feasibility study. The Lancet Psychiatry May 17, 2016
- Effects of Psilocybin-Assisted Therapy on Major Depressive Disorder JAMA Psychiatry November 4, 2020
- Psilocybin-assisted treatment for alcohol dependence: A proof-of-concept study Journal of Psychopharmacology January 13, 2015
- Psychedelics Promote Structural and Functional Neural Plasticity Cell Reports June 1, 2018
and 46 more in the library