Psilocybin targets brain circuits to relieve chronic pain and depression, study suggests

Researchers at Penn Medicine have identified specific brain circuits that are impacted by psilocybin—the active compound found in some psychedelic mushrooms—which could lead to new paths forward for pain and mental health management options.

Chronic pain affects more than 1.5 billion people worldwide and is often deeply entangled with depression and anxiety, creating a vicious cycle that amplifies suffering and impairs quality of life. The study from the Perelman School of Medicine at the University of Pennsylvania—published in Nature Neuroscience—offers new insight into ways to disrupt this cycle.

“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, Ph.D., 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 studies using mice with chronic nerve injury and inflammatory pain, researchers found that a single dose of psilocybin reduced both pain and pain-induced anxiety and depression-like behaviors, with those benefits lasting almost two weeks. Psilocybin acts by gently activating specific brain signals, called serotonin receptors (5-HT2A and 5-HT1A).

“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,” said Cichon.

To pinpoint where the effects originated, researchers injected psilocin—the active substance into which the body converts psilocybin—into different regions of the central nervous system.

The team used advanced fluorescent microscopy, a technique that uses glowing dyes to see and capture neuronal activity, to see chronic pain neurons spontaneously firing.

When psilocin was injected directly into the prefrontal cortex of the brain, specifically the anterior cingulate cortex (ACC), a part of the brain that processes pain and emotions, it provided the same pain relief and mood improvements as when psilocybin was given to the whole body.

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.

Results can drive future psilocybin research

Researchers believe the findings from this study could also inform therapies for other conditions involving dysregulated brain circuits, such as addiction or post-traumatic stress disorder. Cichon adds that more research is needed to determine the effectiveness of psilocybin.

“In my anesthesiology practice, I often see that both pain and mood symptoms can worsen following surgery due to the physiological and psychological stress imposed by the procedure. While psilocybin shows promise as a treatment for both pain and depression, it remains uncertain whether such therapies would be safe, effective, or feasible in the context of surgery and anesthesia,” adds Cichon.

The Penn team plans to investigate optimal dosing strategies, long-term effects, and the ability of the brain to rewire itself in sustaining these benefits in rodent models.

“While these findings are encouraging, we don’t know how long-lived psilocybin’s effects are or how multiple doses might be needed to adjust brain pathways involved in chronic pain for a longer-lasting solution,” adds Stephen Wisser, co-author and a Penn Neuroscience Ph.D. student in Cichon’s lab.