Psilocybin prevents chemotherapy-induced peripheral neuropathy through mitochondrial trafficking preservation

Chemotherapy-induced peripheral neuropathy (CIPN) is a common, disabling, and often irreversible complication of cancer treatment affecting many patients receiving platinum- or taxane-based regimens. Patients experience pain, cold sensitivity, numbness, and impaired touch sensation that can persist for years, frequently forcing dose reductions or discontinuation of otherwise life-saving therapy. The condition arises from injury to sensory nerves, mitochondrial dysfunction, loss of nerve endings in the skin, and maladaptive changes in central pain-processing circuits. Despite its enormous clinical burden, no proven preventive strategy exists.

Psilocybin is a naturally occurring compound found in certain mushroom species that activates serotonin 2A receptors. These receptors have been linked to neuronal plasticity and mitochondrial regulation, which indicates that psilocybin could protect the sensory nervous system from chemotherapy-induced injury. Because nerve damage, once established, is often irreversible, prevention is more tractable than treatment. We therefore asked whether psilocybin administered before chemotherapy could prevent neuropathy from ever developing and used a combination of mouse behavioral models, electrophysiology, live-cell imaging, molecular profiling, and human tissue analysis to define the underlying mechanisms.

In mouse models, just two doses of psilocybin given before chemotherapy prevented the development of pain hypersensitivity caused by neurotoxic chemotherapies, with protection maintained across up to six consecutive chemotherapy cycles and over the course of 8 months of follow-up. Critically, psilocybin also protected tumor-bearing mice without reducing tumor growth or altering immune cytokine levels. Using highly selective pharmacological tools, we showed that serotonin 2A receptor activation is both necessary and sufficient for this neuroprotection and that the effect does not require the hallucinogenic properties of psilocybin—a nonhallucinogenic serotonin 2A agonist conferred equivalent protection. Mechanistically, psilocybin acted through two complementary pathways: Peripherally, it preserved the structure and energy supply of distal sensory nerve endings, protecting tactile function and maintaining skin nerve fiber density; centrally, it normalized cortical electrical activity disrupted by chemotherapy. Using live imaging of mitochondria in freshly isolated human peripheral nerves from surgical patients and in human stem cell–derived sensory neurons, we found that psilocybin preserved the active transport of mitochondria along axons, the process by which nerve fibers distribute energy to their most distant, vulnerable endings. Chemotherapy halted this transport and depleted energy at distal nerve endings; psilocybin prevented both effects. Molecular studies traced this protection to a signaling cascade, the TrkB-Akt-PAK5-MAP2-KIF5B pathway, that supports mitochondrial transport along sensory axons. Human donor sensory neurons and patient skin biopsies independently confirmed that this serotonin 2A–mitochondrial trafficking network is conserved in human tissue.

Psilocybin prevents CIPN by activating serotonin 2A receptors on peripheral sensory neurons, preserving axonal mitochondrial transport and the local energy supply that nerve endings require for survival. This peripheral neuroprotective mechanism, previously unrecognized for psilocybin, acts in concert with the preservation of central cortical function. Given that no effective preventive treatment currently exists and psilocybin has an established clinical safety profile, these findings position psilocybin and related nonhallucinogenic serotonin 2A agonists as a first-in-class prophylactic strategy warranting clinical evaluation to prevent one of the most common and undertreated toxicities of cancer therapy.