Psilocybin prevents chemotherapy nerve injury in preclinical models

Cold can hurt more than it should after chemotherapy. Numbness, loss of sensation and balance problems can join it when treatment damages peripheral nerves. At The University of Texas MD Anderson Cancer Center, researchers report that psilocybin given before chemotherapy prevented nerve injury in preclinical models, including after repeated treatment cycles.

The study was co-led by Moran Amit, M.D., Ph.D., professor of Head and Neck Surgery, and Patrick Dougherty, Ph.D., professor of Pain Medicine. In the models, as few as two doses prevented hypersensitivity to cold, protected sensory nerve endings and preserved touch sensation. The protection held across repeated treatment models using cisplatin, paclitaxel and docetaxel, without reducing chemotherapy’s antitumor activity.

The researchers traced the effect to 5-HT2A, a serotonin receptor pathway in the peripheral nervous system. Blocking it reversed the protection. A nonhallucinogenic compound that activates the same receptors produced protection similar to psilocybin, suggesting that the nerve benefit may not depend on the psychedelic experience itself.

The study also points to an energy problem inside injured nerves. Cisplatin depleted mitochondria — the structures that produce energy inside cells — and reduced their movement through nerve fibers. Psilocybin activated a signaling pathway that preserved this mitochondrial trafficking, helping maintain energy delivery at nerve endings.

In practice, the near-term change is a testable prevention strategy for people receiving chemotherapy, not a treatment established in patients. An upcoming phase 2 clinical trial, NeuroGuard (NCT07227909), is intended to evaluate psilocybin during chemotherapy in patients with multiple cancer types and determine whether the mechanism leads to clinically meaningful reductions in peripheral neuropathy.

The boundary is clear. These results come from preclinical models, while established chemotherapy-related nerve injury is often irreversible and current treatments offer limited benefits. The trial will have to show whether the protection seen in the laboratory can translate into better sensation, mobility and quality of life during cancer treatment.