Psilocybin prevents chemotherapy-induced peripheral neuropathy through mitochondrial trafficking preservation

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Abstract
Chemotherapy-induced peripheral neuropathy (CIPN) is a disabling, often irreversible toxicity that affects millions of patients, limits life-saving cancer therapy, and lacks proven treatment. In this work, we show that as little as two doses of psilocybin before chemotherapy durably prevented the onset of CIPN across platinum- and taxane-based models, including repeated chemotherapy cycles, without impairing antitumor efficacy. Peripherally, psilocybin maintained tactile sensitivity and intraepidermal nerve fiber endings through axonal mitochondrial trafficking and distribution preservation, through the TrkB-Akt-PAK5-MAP2-KIF5B pathway and remobilization of syntaphilin-anchored mitochondria. Centrally, it normalized medial prefrontal cortical synaptic activity and cortical alpha and beta electroencephalography power. This stabilization of peripheral axonal energy balance establishes psilocybin as a first-in-class prophylactic agent for CIPN while also preserving central neural function. Given psilocybin’s established safety, these discoveries support clinical evaluation as a strategy to prevent CIPN.
Funding Information
  • National Institutes of Health (R37 1R37CA242006-01A1)
  • National Institutes of Health (5U19NS130608)
  • National Institutes of Health (R01NS132483)
  • National Institutes of Health (NIH/NCI R01CA286651)
  • National Institutes of Health (20-20-26-BORN)
  • National Institutes of Health (5P30CA045508-36)
  • U.S. Department of War (W81XWH-22-1-0871)
  • National Institute of Dental and Craniofacial Research (R01 DE032018)
  • Stiefel family Discovery award
  • Disruptive Science Moonshot award, MDACC
  • Cancer Early Detection Advanced Research Center, Knight Cancer Institute, Oregon Health and Science University (2023-1768)

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