Recent research published in communication biology A single dose of psilocybin, the active compound found in magic mushrooms, provides long-lasting relief from nerve pain and has been suggested to enhance the effectiveness of common painkillers. The results of this study show that psilocybin may change how the brain processes pain. This opens up a potential new approach for people with chronic pain who don’t respond to standard treatments.
Chronic pain affects millions of people around the world and often significantly reduces a person’s quality of life. Current treatments for nerve pain, known as neuropathic pain, tend to have negative side effects and carry the risk of addiction. Additionally, 30 to 50 percent of people receiving standard nerve pain treatments, such as gabapentin, do not experience adequate pain relief.
A research team from the University of Reading, University College London and Compass Pathfinder set out to explore alternative options for chronic pain management. They focused on psilocybin, a classic psychedelic substance known for altering perception and cognition. Previous clinical studies suggest that psilocybin has lasting effects on mood disorders by reorganizing brain networks and resetting maladaptive patterns of neural connectivity.
Chronic pain also involves changes in brain connectivity and structural changes that occur over time. The authors suspected that psilocybin might help rebuild these dysfunctional pain networks by changing their underlying organization. They designed an experiment to see if the compound could reduce pain on its own. They also wanted to observe whether gabapentin could improve gabapentin’s performance over a long period of time.
To test their idea, the scientists used 157 adult mice, including both males and females. They used a surgical procedure that partially severed certain nerves in the hind limbs, leaving one nerve intact to induce a state of chronic pain. This particular physical trauma precisely mimics nerve damage in humans due to surgery or diabetes, causing similar pain hypersensitivity.
After the mice became highly sensitive to pain, the researchers injected them with saline or synthetic psilocybin. They used two different dose levels to assess biological effects. Animals received either a standard dose of 1 milligram per kilogram of body weight or a lower dose of 0.3 milligrams per kilogram of body weight. The scientists confirmed that the drug reached the brain by observing specific head twitching movements that serve as a recognized sign of a psychedelic experience in rodents.
The research team used several specialized behavioral tests to assess pain sensitivity. They pressed a thin, graduated filament against the mouse’s foot to measure its sensitivity to static pressure. They also tested dynamic pain sensation by stroking their feet with a paintbrush. This mimics the human condition where light touch causes pain. In another test, they placed mice on a cold surface and observed their physical reactions to temperature changes.
To confirm that psilocybin was not simply sedating the mice so much that they were unable to respond to pain, the authors tracked the mice’s spontaneous behavior. They placed mice in an open arena and recorded how much the mice moved and explored. Scientists have found that it has no negative effect on the animals’ basic motor skills or general activity levels. This indicates that the reduction in pain response is real and not the result of a physical disorder.
The researchers found that a single dose of psilocybin reduced pain sensitivity in both male and female mice. In male mice, this analgesic effect lasted up to 28 days after injection. In female mice, the significant reduction in pain sensitivity lasted about a week. The compound also reduced the animals’ physiological signs of stress, as measured by decreased physical stress responses and increased body weight.
The research team also investigated whether repeated treatments were beneficial. They administered low doses of psilocybin once a week for three consecutive weeks. Scientists found that this repeated dosing schedule amplified and prolonged the pain relief effect compared to a single dose. This indicates that lower-dose regimens may be able to maintain therapeutic effects for even longer periods.
To understand how psilocybin exerts these effects, the authors gave some mice a drug called vorinanserin before administering psilocybin. Vorinanserin blocks specific serotonin receptors in the brain known as serotonin 2A receptors. When this receptor was blocked, the analgesic effects of psilocybin were significantly reduced. This provides evidence that serotonin 2A receptor activation is required for drugs that reduce neuralgia.
Interestingly, the research team found that injecting psilocybin 30 days before nerve injury surgery did not prevent the development of pain hypersensitivity. This suggests that the drug does not act as a defense against future pain. Instead, it appears to work by remodeling already dysfunctional brain networks. The therapeutic effect of this drug appears to depend on the presence of established maladaptive pain networks.
The scientists then tested how psilocybin interacted with gabapentin, a standard drug used worldwide for nerve pain in humans. They gave the mice gabapentin during the period when psilocybin’s direct analgesic effects were occurring. This combination produced significantly more potent and long-lasting analgesic effects than gabapentin alone. This indicates a synergistic effect when both drugs are activated simultaneously in the system.
In a secondary study, the authors administered gabapentin 55 days after the first psilocybin injection. By this point, the direct analgesic effects of psilocybin had completely disappeared. However, in mice previously given psilocybin, dramatic and long-lasting pain relief lasted up to 96 hours after gabapentin administration. Mice that received only saline injections had a much shorter and weaker response to gabapentin.
Researchers believe this sustained enhancement may be related to structural changes in the brain. They theorize that psilocybin increases the release of certain growth factors, such as brain-derived neurotrophic factor, which helps brain cells form new connections. This process of forming new connections may create a biological environment that allows traditional painkillers to work more effectively. The brain’s pain processing networks can be fundamentally altered over several weeks after a psychedelic experience.
Although these findings offer hope, there are also some limitations that should be considered. Animal pain models cannot fully capture the complex emotional and psychological aspects of chronic pain experienced by humans. This study should not be interpreted to mean that magic mushrooms automatically cure nerve pain. Self-medicating with uncontrolled substances carries risks and is not recommended as a substitute for professional medical care.
The study also observed differences in the duration of pain relief between male and female mice. The authors note the need to more fully characterize these potential sex differences. Additional research is needed to determine whether the extended duration seen in men also applies to other types of pain behaviors in women. How these biological sex differences affect human patients remains unclear.
Future research should investigate exactly how psilocybin causes these long-lasting changes at the cellular level. Scientists plan to investigate whether psilocybin can also enhance the effects of other common painkillers, such as morphine and certain antidepressants. Human clinical trials will be needed to determine whether these drug combinations are safe and effective. If successful, this approach could provide a new treatment for patients with treatment-resistant neuralgia.
The research paper, “Psilocybin improves neuropathic pain-like behavior and promotes gabapentin-mediated analgesia in mice,” was authored by Tatum Askey, Daniel Allen-Ross, Daniil Luzyanin, Reena Lasrado, Gary Gilmour, Stephen P. Hunt, Francesco Tamagnini, Maqsood Ahmed, Gary J. Stephens, and Maria Maiarú.
