The magic mushroom compound psilocybin, which has had favorable results in two Phase 3 trials of depression and could be available as soon as 2027, has shown promise in rodents as a potential preventative for Chemotherapy‑Induced Peripheral Neuropathy (CIPN), a disabling pain condition caused by chemotherapy that affects about 30% to 50% of patients receiving chemotherapy.
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A 2014 review found that 68.1% of chemotherapy patients across 31 studies had CIPN when measured in the first month after chemotherapy, falling to 30% at six months or more. Common symptoms include persistent pain, burning dysesthesia, tingling, hypersensitivity, numbness and impaired dexterity. ASCO recommends duloxetine for the treatment of CIPN, although it is not approved for this indication, and studies have shown it only provides modest relief.
A new study from the MD Anderson Cancer Center in Houston published in Science this week investigated whether psilocybin could prevent CIPN.
CIPN is associated with mitochondrial dysfunction and distal axonal degeneration within the peripheral sensory pathways, according to the paper. Psilocybin increases neural plasticity through 5-HT2A signaling, and 5-HT2A receptors regulate mitochondrial biogenesis.
Cisplatin, a platinum chemotherapy used in head and neck, lung and ovarian cancers, arrests mitochondrial trafficking along peripheral sensory axons, cutting off the ATP supply that nerve endings need for survival. Psilocybin restarts trafficking by activating serotonin 2A receptors on the neurons.
Mitochondrial trafficking has been targeted before, though not through this receptor. The authors note that electrical stimulation and fluocinolone acetonide also restored the transport and prevented pain in paclitaxel and oxaliplatin models.
The study found that two 1 mg/kg doses of psilocybin before chemotherapy completely prevented the onset of mechanical hypersensitivity, one component of CIPN that causes pain from light touch, in mice. The researchers found no improvement with more doses.
The protection held across six monthly cisplatin cycles with more than eight months of follow-up, a durability the authors say has not previously been replicated in preclinical CIPN studies. Psilocybin protected mice given three different chemo drugs, cisplatin, paclitaxel and docetaxel.
The researchers found the same mechanism operating in human tissue. They cultured peripheral nerve samples from 29 surgical patients and exposed them to cisplatin in the lab, which stalled mitochondrial movement. They found that psilocybin pretreatment prevented that stall.
Tabernanthalog, a non-hallucinogenic 5-HT2A agonist, produced comparable protection without the hallucinogenic effect. Moran Amit, a senior author on the paper, filed a U.S. provisional patent application for the use of 5-HT2A receptor agonists for toxicity mitigation.
Mice that received cisplatin after tumor resection, without more psilocybin, developed hypersensitivity comparable to controls, suggesting that dosing will need to be repeated with every chemo cycle.
According to a paper published in Clinical Cancer Research in 2019, over 40 randomized controlled clinical trials have investigated preventative or therapeutic agents for CIPN, but none provided conclusive evidence of a clinically beneficial agent except duloxetine.
In a Phase 3 trial for the treatment, patients taking duloxetine for five weeks reported a mean decrease of 1.06 points in average pain on a 0-to-10 scale, compared with 0.34 for placebo. The difference between the two groups, 0.73 points, fell short of the 0.98-point threshold the trial’s authors had set as the minimum clinically important difference, though they argued the result was clinically meaningful on other grounds.
A Phase 2 trial to test psilocybin as a CIPN preventative in humans is estimated to start in November of this year.
Filed Under: Oncology, Preclinical testing, Psychiatric/psychotropic drugs
