By University of Pennsylvania School of Medicine

Psilocybin appears to calm brain circuits that link physical pain with emotional distress, offering relief that lasts beyond the drug’s immediate effects.

By acting on the brain’s emotional and pain-processing centers, it could lead to safer, longer-lasting alternatives to opioids.
Breaking the Cycle of Pain and Depression

Researchers at Penn Medicine have uncovered how psilocybin, the main psychoactive ingredient in certain “magic mushrooms,” influences key brain circuits, offering potential new approaches for treating chronic pain and related mental health conditions.

Chronic pain affects more than 1.5 billion people globally and often intertwines with anxiety and depression, creating a feedback loop that worsens both physical and emotional suffering. The new research from the Perelman School of Medicine at the University of Pennsylvania, published in Nature Neuroscience, sheds light on how this cycle might be broken.

“As an anesthesiologist, I frequently care for people undergoing surgery who suffer from both chronic pain and depression. In many cases, they’re not sure which condition came first, but often, one makes the other worse,” said Joseph Cichon, MD, PhD, an assistant professor of Anesthesiology and Critical Care at Penn and senior author of the study. “This new study offers hope. These findings open the door to developing new, non-opioid, non-addictive therapies as psilocybin and related psychedelics are not considered addictive.”
Targeting the Brain’s Pain and Mood Hub

In experiments using mice with chronic nerve injury and inflammatory pain, scientists discovered that a single psilocybin dose eased both pain and depression-like behaviors caused by that pain, with the effects lasting for nearly two weeks. Psilocybin achieves this by subtly stimulating serotonin receptors (5-HT2A and 5-HT1A) in the brain. “Unlike other drugs that fully turn these signals on or off, psilocybin acts more like a dimmer switch, turning it to just the right level,” Cichon said.

To identify where these effects began, the team injected psilocin, the active compound formed when psilocybin is metabolized, into specific parts of the central nervous system. Using advanced fluorescent microscopy, which employs glowing dyes to track neuron activity, they observed spontaneous firing in pain-related neurons. When psilocin was introduced into the brain’s prefrontal cortex, specifically the anterior cingulate cortex (ACC), an area involved in processing both pain and emotion, the mice experienced similar pain and mood improvements to those seen when psilocybin was administered systemically.

Researchers also injected psilocin into the spinal cord, but it didn’t have the same calming effect. “Psilocybin may offer meaningful relief for patients by bypassing the site of injury altogether and instead modulating brain circuits that process pain, while lifting the ones that help you feel better, giving you relief from both pain and low mood at the same time,” said Cichon.