Psilocybin prevents chemotherapy-induced peripheral neuropathy via mitochondrial trafficking preservation

Peripherally, in freshly excised human peripheral nerves, psilocybin restored axonal mitochondrial distribution, cristae structure, and directional motility; mechanistically, psilocybin activation of the TrkB-Akt-PAK5-MAP2-KIF5 pathway and remobilization of syntaphilinanchored mitochondria led to enhanced survivability of human induced pluripotent stem cell derived sensory neurons treated with chemotherapy. These results establish psilocybin as a first in-class prophylactic agent for CIPN and uncover a mechanistic link between serotonergic signaling in the peripheral nervous system and cellular metabolic resilience that stabilizes distal axonal energetics while also preserving central neural function.

Given psilocybin’s established safety including in oncology settings, these discoveries support its urgent clinical evaluation as a transformative strategy to prevent CIPN.