Psilocybin could unlock new, non-addictive therapy for chronic pain management

US researchers have identified specific brain circuits affected by psilocybin, which may lead to new pain and mental health management options. The active compound found in some psychedelic mushrooms gently activates serotonin receptors, turning these signals “to just the right level.”

Mice with chronic nerve injury and inflammatory pain received a single dose of the compound. Psilocybin reduced pain and pain-induced anxiety and depression-like behaviors in these animals, with the benefits lasting almost two weeks.

“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,” says study senior author Joseph Cichon, M.D., Ph.D., and assistant professor of Anesthesiology and Critical Care at the University of Pennsylvania School of Medicine, US. 

“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.”

Identifying brain signals

The researchers injected psilocin into different parts of the central nervous system to determine where the effects on pain originated. Psilocin is the active substance into which the body converts psilocybin. 

To see how chronic pain neurons responded, the team used advanced fluorescent microscopy, a technology that uses glowing dyes to determine neuronal activity. 

The researchers injected psilocin directly into the brain’s prefrontal cortex (the anterior cingulate cortex), which processes pain and emotions. This injection provided the same pain relief and mood improvements as giving psilocybin to the whole body. 

Injecting psilocin into the spinal cord did not have the same calming effect. 

The researchers note that chronic pain affects over 1.5 billion people worldwide.“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,” suggests Cichon. 

Pain management

Research on psilocybin’s impact on mental health has shown promising results in improving depression-like symptoms. The researchers of the study in Nature Neuroscience note that chronic pain and mood dysfunction, depression, and anxiety are interconnected, creating a “vicious cycle that amplifies suffering and impairs quality of life.” 

According to the researchers, chronic pain affects over 1.5 billion people worldwide. 

“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,” says Cichon. 

“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.” 

Psilocybin benefits

The authors believe their findings may also inform therapies for other conditions involving dysregulated brain circuits, like addiction or post-traumatic stress disorder. However, more research is needed to determine psilocybin’s effectiveness. 

The research team aims to investigate optimal dosing strategies, long-term effects, and the brain’s ability to rewire itself to sustain 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 Neuroscience Ph.D. student in Cichon’s lab.

Meanwhile, researchers also call for better tracking of psilocybin-related issues as its use in the US rises, and there are more poison center calls on using the compound.  

Moreover, an analysis of 12 magic mushroom edibles on the US market revealed that these did not contain psilocybin, but several contained synthetic psychedelics.