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Pharmacology & Neurobiology Published by Dr. Elena Rostova (Ph.D. in Clinical Neurobiology & Somatosensory Systems) • 10 min read DOI: 10.1016/j.tips.2023.08.006

Microglial Polarization and Neuroinflammation: Immunomodulatory Mechanisms of 5-HT2A Agonists in Neurodegenerative Pathology

Executive Summary

While historically studied primarily for their psychoactive properties, classic psychedelics are potent systemic anti-inflammatory agents. Microglia, the resident immune cells of the central nervous system, express high densities of 5-HT2A receptors. Psilocin binding inhibits nuclear factor kappa B (NF-κB) transcription, dramatically suppressing pro-inflammatory cytokine expression (TNF-α, IL-1β, IL-6) and promoting neuroprotective M2 phenotype polarization.

1. The Neuroimmune Axis: Serotonin as a Master Immune Regulator

Chronic neuroinflammation is now recognized as a primary driver of major depression, anxiety, and cognitive decline. By dampening neurotoxic microglial activity, psilocybin creates a fertile cellular environment for Brain-Derived Neurotrophic Factor (BDNF) synthesis and synaptogenesis.

Primary Scientific Citations

  • Nau, F., et al. (2015). Serotonin 5-HT2A Receptor Activation Blocks TNF-α-Induced Inflammation in Primary Human Aortic Endothelial Cells. PLOS ONE • DOI: 10.1371/journal.pone.0139886
  • Flanagan, T. W., & Nichols, C. D. (2018). Psychedelics as Anti-Inflammatory Agents: Emerging Therapeutics for Immune-Mediated Disorders. International Review of Psychiatry • DOI: 10.1080/09540261.2018.1481850
Citation (APA 7th): Rostova, E. (2026). Microglial polarization and neuroinflammation: Immunomodulatory mechanisms of 5-HT2A agonists in neurodegenerative pathology. Mystic Toad Science Research Index, 1(28), 373-389.