Psilocybin prevents chemotherapy-induced peripheral neuropathy in preclinical models, paving the way for a Phase 2 trial
核心洞察
Researchers at UT MD Anderson Cancer Center found that psilocybin given before chemotherapy prevented chemotherapy-induced peripheral neuropathy (搜索) across several preclinical models, even after repeated treatment cycles.
The neuroprotective effect is mediated through serotonin 5-HT2A receptors, which preserve mitochondrial trafficking and energy delivery to nerve endings without interfering with chemotherapy's antitumor activity.
Blocking the 5-HT2A pathway reversed the protection, while a non-hallucinogenic compound activating the same receptors produced similar neuroprotection, suggesting a first-in-class preventive approach.
In a breakthrough study, researchers at The University of Texas MD Anderson Cancer Center discovered that psilocybin given before chemotherapy prevented the onset of nerve injury in preclinical models, even after repeated treatment cycles. The findings, published in Science and co-led by Moran Amit, M.D., Ph.D., professor of Head and Neck Surgery, and Patrick Dougherty, Ph.D., professor of Pain Medicine, uncover a previously unrecognized neuroprotective role of serotonin receptors and position psilocybin as a first-in-class intervention for the prevention of chemotherapy-induced peripheral neuropathy (搜索).
"There is an urgent need for treatments that prevent nerve injury without interfering with lifesaving chemotherapy," Amit said. "These findings offer important insights into how psilocybin may protect nerves before damage occurs, rather than treating symptoms after they become persistent. At UT MD Anderson, we are actively exploring the multiple facets of psychedelics to pursue interventions that improve the lives of our patients."
The burden of chemotherapy-induced peripheral neuropathy
Chemotherapy is a common treatment that is beneficial for many cancer types, but it can also damage normal cells, including nerves. This peripheral neuropathy, or nerve injury, can result in many of the side effects associated with chemotherapy, such as pain, increased sensitivity to cold, numbness and loss of sensation, all of which can persist beyond treatment. Some patients may also experience changes that impact their balance or ability to continue life-saving treatments, significantly impacting their quality of life. Established nerve injury often is irreversible, and existing treatments offer limited benefits.
A neuroprotective mechanism through 5-HT2A receptors
Psilocybin is a naturally occurring psychedelic compound currently under investigation for neuropsychiatric and neurological disorders. In this study, the researchers used several preclinical models to examine the effects of psilocybin on nerves and evaluate whether it could be used to prevent peripheral neuropathy after chemotherapy.
The researchers discovered that psilocybin directly affects the peripheral nervous system through serotonin 5-HT2A receptors. In preclinical models, as few as two doses of psilocybin given before chemotherapy prevented hypersensitivity to cold, protected sensory nerve endings and preserved touch sensation while also maintaining chemotherapy's antitumor activity. These results were consistent even when models were given repeated chemotherapy cycles with cisplatin, paclitaxel and docetaxel.
Blocking the 5-HT2A pathway reversed these neuroprotective effects, while using a non-hallucinogenic compound that activates the same receptors produced similar protection to psilocybin.
Preserving mitochondrial trafficking
Additionally, researchers found that cisplatin depleted mitochondria — the structures that produce energy inside cells — and reduced their movement inside nerve fibers. Further, psilocybin activated a specific signaling pathway that preserved mitochondrial trafficking after chemotherapy, maintaining adequate energy levels at the nerve endings.
"Psilocybin does more than reduce pain signals by protecting the nerves, themselves, through energy delivery," Dougherty said. "This neuroprotective effect could help patients withstand the stress of chemotherapy, maintaining sensation, mobility and quality of life during treatment and long into survivorship."
The mechanism appears tied to how energy-producing mitochondria move through nerve cells. Chemotherapy attacks "microtubules," which are structures in nerve cells that help transport mitochondria like a "railroad system," Amit explained. With psilocybin, cells were able to maintain mitochondria's movement along this "railroad."
A serendipitous discovery
The discovery was something of an accident. One of Amit's colleagues noticed that mice that had been given psilocybin avoided nerve damage after chemotherapy, but Amit did not believe it at first. "Do it again," he recalled telling her. "So she did, again and again and again."
"We did it so many times with tumor, without tumor, different types of chemotherapy. And consistently, we did not see the development of neuropathy, whether we gave those animals just one cycle or even six consecutive cycles," Amit said. "This is unparalleled."
Next steps: a Phase 2 clinical trial
These preclinical findings are the basis for an upcoming Phase 2 clinical trial (NeuroGuard, NCT07227909) evaluating psilocybin during chemotherapy in patients with multiple cancer types to determine whether the mechanisms observed in this trial translate to clinically meaningful reductions in peripheral neuropathy. Other ongoing trials, led by Amit, currently are examining the effects of psilocybin-assisted psychotherapy for patients with anxiety and/or depression.
For now, the results are limited to mice and cellular models in the lab. However, the researchers say they have good reason to believe the process will translate to humans. Anecdotally, the team has heard of chemotherapy patients who enrolled in psilocybin trials for other reasons and have said they have seen improvement in nerve-related symptoms, too.
These studies are part of UT MD Anderson's Cancer Neuroscience Program, a comprehensive initiative that examines the interactions between cancer and the nervous system, taking a multidisciplinary approach to enhance patient quality of life.