Chemotherapy-induced peripheral neuropathy (CIPN) can cause pain and sensory disturbances and, in severe cases, may require dose reductions or discontinuation of cancer treatment. Effective treatments are unavailable. A new study published in Science found promising preclinical data suggesting that psilocybin may protect sensory nerves from the neurotoxic effects of several chemotherapeutic agents.

Effective preventive treatment for CIPN is still lacking, and existing symptoms have limited treatment options. Lead author Mario Heles, MD, from The University of Texas MD Anderson Cancer Center in Houston, and colleagues therefore investigated whether psilocybin could protect against chemotherapy-induced nerve damage. The researchers evaluated its neuroprotective effects in preclinical models of platinum and taxane chemotherapy. Psilocybin is a serotonergic compound known primarily for its psychedelic effects and potential use in psychiatric disorders.

Speaking with Science Media Center Germany, Wolfgang Löscher, MD, PhD, professor and head of the Neuromuscular Unit, EMG and EP-laboratory at the Department of Neurology, Innsbruck Medical University in Innsbruck, Austria, said, “What is new and surprising is that psilocybin acts not only centrally but also directly on peripheral sensory nerves, where it stabilizes the local energy supply by regulating the distribution of mitochondria. This discovery reveals a previously unknown, new neuroprotective mechanism against CIPN.”

“If these results are confirmed in humans, this would be the first successful prevention of chemotherapy-induced peripheral neuropathy,” he added. Given the prevalence and potentially severe consequences of CIPN, he considered this a potentially important advance in oncology.

When Cancer Affects Nerves

CIPN is one of the most clinically debilitating adverse effects of neurotoxic chemotherapy. Typical symptoms include pain, burning dysesthesia, cold allodynia, tingling, and numbness. These symptoms can persist for long periods and may become severe enough to require dose reduction or discontinuation of cancer treatment.

CIPN can occur in up to 60% of patients receiving platinum-based chemotherapy. No established pharmacologic preventive treatment is currently available, and existing symptoms can generally be treated only to a limited extent.

Two Doses Protect Mice

In a cisplatin mouse model, a single prophylactic dose of psilocybin shortened the duration of mechanical hypersensitivity but did not completely prevent it. In contrast, two doses administered before chemotherapy completely prevented mechanical hypersensitivity in the model studied.

This protective effect persisted after repeated chemotherapy. The animals underwent up to six cycles of cisplatin and were followed for more than 8 months. Protection was also observed in models using paclitaxel and docetaxel.

Neuroprotection persisted in mice with tumors. The authors found no evidence in these models that psilocybin affected tumor growth or caused relevant changes in the systemic cytokines examined.

The protective effect also appears to depend on the specific chemotherapy regimen used. When cisplatin was administered again after tumor resection without repeated psilocybin prophylaxis, the previously observed protection was lost. This finding suggests a cycle-specific preventive effect instead of a permanent protective mechanism.

Psilocybin Preserves Axonal Energy

A key strength of this study was the detailed analysis of the underlying mechanism. Mitochondrial dysfunction and damage to distal sensory axons play important roles in CIPN. In particular, long axons depend on the transport of mitochondria to areas where energy is required.

Cisplatin disrupted this transport. Psilocybin did not restore damaged mitochondria to normal function. Reduced mitochondrial respiratory capacity and impaired membrane potential were not restored. Instead, mitochondrial transport and distribution along the axon were preserved. Consequently, adenosine triphosphate remained available, particularly in neurites.

The key finding, therefore, was not a global increase in mitochondrial energy production but the preservation of energy supply in particularly vulnerable distal nerve segments.

The axonal distribution of mitochondria was also better preserved with psilocybin treatment. Electron microscopy provided additional evidence that the mitochondrial structure was preserved.

Mechanism Replicated in Human Tissue

This study was not limited to mouse models. The researchers also worked with human-induced sensory neurons and freshly harvested peripheral nerves from surgical patients.

In human sensory neurons, pretreatment with psilocybin reduced cisplatin-induced shortening and structural simplification of neurites. Blocking the serotonin 2A receptor (5-HT2A) eliminated this protective effect.

Live-imaging experiments using freshly isolated human peripheral nerves also provided evidence supporting this mechanism. Cisplatin significantly impaired mitochondrial motility in these nerves. Pretreatment with psilocybin better preserved mitochondrial transport. This finding replicated the key elements of the mechanism observed in mice in human tissue.

5-HT2A as a Switch

The 5-HT2A receptor appears to play a central role in the mechanism. The researchers detected the receptor not only in the central nervous system but also in the peripheral sensory nerves. Blocking 5-HT2A with ketanserin or the more selective antagonist volinanserin reversed the protective effect of psilocybin. According to the authors, protection to a signaling cascade, the TrkB-Akt-PAK5-MAP2-KIF5B pathway, supports mitochondrial transport along the sensory axons. KIF5B is a kinesin family member 5B motor protein heavy chain that actively drives the outward movement of mitochondria toward the cell periphery along microtubules.

These findings suggest a mechanistic link between serotonergic signaling and the preservation of axonal energy supply.

Neuroprotection Without Psychedelia

The researchers treated the mice with tabernanthalog, a non-hallucinogenic 5-HT2A agonist. In the model studied, tabernanthalog provided protection against mechanical hypersensitivity, similar to that observed with psilocybin. However, another finding may be particularly relevant for future drug development.

Therefore, the neuroprotective effect does not appear to depend on psychedelic effects. If this mechanism is confirmed in humans, it may be possible to develop drugs that activate the protective signaling pathway without producing a psychedelic state.

Promising but Preliminary

“The results are promising, even though there is still a long way to go before its effectiveness in humans can be confirmed,” Löscher said. Because psilocybin has already been studied in human clinical trials, he considered testing it for CIPN to be feasible in principle. However, the appropriate dose remains unclear, and the doses used in mice cannot be directly applied to humans.

Löscher also considered a clinical efficacy trial feasible because validated methods are available to assess neuropathic pain and nerve damage. Given the lack of effective pharmacologic prevention, he proposed a prospective, randomized, placebo-controlled, double-blind trial to determine whether the treatment can prevent chemotherapy-induced neuropathy.

Importantly, the current study provides preclinical evidence, not evidence of efficacy in patients with cancer. Findings from human cells and ex vivo nerve tissue support the biological plausibility of the mechanism but do not replace clinical trials.

This story was translated from Medscape’s German edition.