A Psychedelic Prevented Chemotherapy's Nerve Damage in Mice

The nerve fibers that report touch from a fingertip are among the longest cells in the body. Their working ends sit in the outer layer of the skin, and everything those ends need has to be carried out to them along the fiber. That includes the mitochondria that make the cell's energy, which travel the whole distance. Interrupt the delivery and the far tip starves first. That, roughly, is what several of the most useful chemotherapy drugs do.

The result has a clinical name, chemotherapy-induced peripheral neuropathy, and a familiar description: numb or burning hands and feet, a painful reaction to cold, a loss of fine sensation that can outlast the cancer treatment by years. By Nature's account, it reaches as many as 60% of people given platinum-based chemotherapy. Once it is established, the injury is often irreversible. When it gets bad enough, the remedy is to cut the chemotherapy back.

In a paper published in Science on 3 September, a group at MD Anderson Cancer Center co-led by Moran Amit and Patrick Dougherty reports that in mice, psilocybin, the compound in magic mushrooms, given ahead of chemotherapy, kept that injury from developing at all.

Prevention is the load-bearing word. The American Society of Clinical Oncology guideline that the paper itself cites is blunt about the gap: no agent is recommended for preventing this nerve damage. Duloxetine, an antidepressant, is the only drug with appropriate evidence for the established, painful form, and its benefit is limited. The authors' own claim is scoped to that gap: psilocybin, they write, is a "first-in-class prophylactic agent" for the condition. "There is an urgent need for treatments that prevent nerve injury without interfering with lifesaving chemotherapy," Amit, a surgical oncologist, said in MD Anderson's announcement of the work.

The paper's own phrase for the dose is "as little as two doses" before chemotherapy. That is the smallest schedule that worked, not the total the animals were given. In the longest experiment, Nature reported, the mice received two doses ahead of each of six rounds of chemotherapy across eight months. The protection held across cisplatin (one of the most widely used platinum-based chemotherapy drugs), paclitaxel and docetaxel, and the chemotherapy went on shrinking tumors while it did.

Then the mechanism, which is where the story stops being about a psychedelic and starts being about logistics. Cisplatin strips mitochondria out of nerve fibers and slows the ones left behind, according to MD Anderson's account of the work. Psilocybin acted on serotonin receptors of the 5-HT2A type, the same ones behind a psychedelic experience. It reached them out in the skin, on the sensory fibers themselves, rather than in the brain. From there, the team reports, a chain of signals ran to the motor proteins that walk mitochondria along a fiber, and freed mitochondria that had been anchored in place.

Two results turn that into a chain rather than a coincidence. Blocking the 5-HT2A receptor abolished the protection. And tabernanthalog, a non-hallucinogenic compound that activates the same receptors, protected the animals about as well. That is the finding with the longest reach, because it separates the neurology from the trip. Mitochondria failing to move was already a suspected route into this kind of nerve damage; the surprise is the drug that arrives there. "That's quite surprising. I wouldn't have expected psilocybin to regulate mitochondrial movement," Joe Cichon, a neuroanesthesiologist at the University of Pennsylvania who was not part of the study, told Nature.

Higher up, the paper reports changes too: in treated animals, activity in a region behind the forehead and the rhythm of the cortex's electrical activity stayed nearer normal. Science published a commentary on the work in the same issue, by a pharmacologist at the University of Reading. It is an assessment of the same data, not a second set of it: this is one laboratory and one paper, and no other group has repeated it.

Everything above is mice. Amit's group already runs trials of psilocybin-assisted psychotherapy for anxiety and depression in people with cancer, and the paper leans on that established safety record when it argues the nerve result is worth testing. What psilocybin does to the nerves of a person on chemotherapy, though, is unknown, and the trial meant to find out has not started. NeuroGuard, at MD Anderson, is due to begin in November with 83 people scheduled for platinum or taxane chemotherapy for breast, colorectal or head-and-neck cancer. Its schedule is not the mouse schedule: four supervised doses of 25 milligrams, two before chemotherapy and two during, set against standard care and against a dose small enough that a participant should feel nothing. What it counts first is how many people report their sensory symptoms a quarter worse than they started, twelve weeks in.