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For millions of adults worldwide, nerve pain feels like a constant, inescapable electric shock. Standard medications often fall short, leaving patients desperate for relief. Now, scientists are looking to an unexpected source: the psychedelic compounds found in magic mushrooms.

A new study in mice suggests that a single dose of psilocybin — the psychoactive ingredient in magic mushrooms — can reduce nerve pain for up to a month. Even more remarkably, the drug appears to alter the brain’s circuitry, making gabapentin, a standard and widely prescribed painkiller, significantly more effective.

A Stubborn Kind of Pain

Neuropathic pain starts when nerves themselves are injured, often after surgery, trauma, diabetes, or other damage. Once it takes hold, the nervous system can behave like an alarm that keeps ringing after the danger has passed.

Researchers at the University of Reading used a mouse model called spared nerve injury. Scientists damage some branches of the sciatic nerve while leaving another intact, producing pain-like behaviors such as extreme sensitivity to touch.

After hypersensitivity had developed, the team gave mice psilocybin. A single dose reduced mechanical hypersensitivity in both male and female mice. In males, relief lasted up to 28 days after the injection. In female mice, the effect was also seen, though the measured duration was shorter.

The effect did not arrive immediately. It appeared about two hours after injection, then persisted well beyond the period when the drug itself would be expected to remain active.

The Gabapentin Surprise

Gabapentin is widely prescribed for nerve pain, but it often falls short. Not all patients respond well. The University of Reading noted that 30 to 50% of people with nerve pain do not get adequate relief from gabapentin alone.

The researchers first gave gabapentin while psilocybin was already reducing pain-like behavior. Together, the drugs produced stronger and longer-lasting relief than gabapentin alone.

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Then came the sharper test. The team gave mice psilocybin once, waited weeks until its own pain-relieving effect was no longer measurable, and then gave gabapentin. In mice previously treated with psilocybin, gabapentin relieved pain-like behavior for up to four days. In mice that had received saline instead, gabapentin’s effect was weaker and shorter.

“Millions of people live with nerve pain that their medication simply does not control well enough, and the medicines we do have can cause serious side effects or lead to addiction,” said Dr Maria Maiarú, senior author from the University of Reading, in a statement.

“What is exciting here is that psilocybin does not just reduce pain on its own. It appears to reset the brain’s pain networks in a way that makes existing treatments significantly more effective. For patients who have run out of options, that could be genuinely transformative.”

What a “Reset” Might Mean

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A reset does not mean psilocybin erases pain like a switch. It may make pain circuits more flexible.

Psilocybin acts partly through a serotonin receptor called 5-HT2A, which is also linked to psychedelic effects in the human brain. When the researchers blocked that receptor with another drug, psilocybin’s pain-relieving effect was substantially reduced.

The team also found that psilocybin given before nerve injury did not prevent mice from developing hypersensitivity. The compound seemed to act after chronic pain circuits had formed, rather than protecting the nervous system from injury in advance.

Psilocybin might one day serve as a primer, making existing pain medicines more effective, rather than replacing them.

For now, the work remains preclinical. Mice cannot describe pain, and researchers must infer it from behaviors such as paw withdrawal. Human pain is far more varied, tangled with sleep, mood, memory, and illness.

The study was published in the journal Communications Biology.