Psychedelic drug calms hyperactive brain cells linked to chronic pain

A single dose of the psychedelic compound psilocybin can rapidly relieve both chronic pain and the symptoms of anxiety and depression that often accompany it. The drug achieves this dual effect by calming hyperactive brain circuits associated with these linked conditions. The research was published in Nature Neuroscience.

Chronic pain rarely exists in isolation. People who suffer from persistent physical pain often develop mood disorders like anxiety and depression. These conditions can feed into one another, making the pain feel worse and making the depression harder to treat. Standard medical treatments usually address the physical pain and the mood symptoms separately, often with limited success.

Researchers suspect these conditions share an underlying physical root in the brain. Brain scans of individuals with chronic pain and depression often show abnormal activity in the anterior cingulate cortex. This region of the brain helps process emotions and the unpleasantness of pain.

Psilocybin is the primary psychoactive ingredient found in magic mushrooms. Once ingested, the body converts it into an active molecule called psilocin. Psilocin binds to serotonin receptors in the brain, which are the same receptors targeted by many standard antidepressant medications.

Recent clinical trials have shown that psilocybin can provide lasting relief for severe depression. Separate observations suggest it might also help with chronic nerve pain. University of Pennsylvania researchers Joseph Cichon, Ahmad Hammo, and Stephen Wisser wanted to see if a single treatment could target the shared brain circuits of both conditions at the same time.

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To study this, the research team first established chronic pain in laboratory mice using two different methods. One group of mice received a minor surgical nerve injury to simulate long-lasting nerve pain. Another group received a specialized injection in their paw to create persistent inflammatory pain.

After a few weeks, both groups of mice displayed severe sensitivity to a light physical touch. They also began to show behaviors that researchers use to gauge anxiety and depression in rodents. For example, they spent less time exploring open, exposed areas, and they showed less motivation to keep moving when placed in water.

The researchers then gave the mice a single systemic injection of psilocybin. The next day, the mice showed a complete reversal of their physical pain sensitivity. Their mood-related behaviors also returned to normal baseline levels. This restorative effect lasted for at least twelve days, which was the end of the testing period.

To verify that the psilocybin was actually relieving the negative experience of pain, the team used a behavioral test involving two connected rooms. The mice were given psilocybin in one specific room and a plain saline solution in the other.

When given the freedom to choose, the mice with chronic pain strongly preferred to spend time in the room where they had received psilocybin. Healthy mice without pain did not show this preference. This indicates that the mice associated the environment with the relief of their discomfort.

Pain signals travel from the body, up the spinal cord, and into the brain. The researchers needed to find out exactly where the drug was acting to provide relief. They injected psilocin directly into the lower spinal cords of a group of mice with nerve pain. This local spinal treatment did not improve the animals’ pain or mood behaviors.

Next, they injected the psilocin directly into the anterior cingulate cortex of the brain. This direct brain application rapidly reversed both the physical pain sensitivity and the signs of depressed mood. This result suggests that the drug works by altering networks in the higher brain centers rather than blocking pain signals at the spinal level.

To observe this brain activity in real time, the team used a technique called two-photon calcium imaging. This allowed them to look at individual brain cells in the anterior cingulate cortex of awake mice.

They found that mice with chronic pain had abnormally high levels of spontaneous cellular activity in this brain region. When the researchers applied psilocin to the area, it rapidly suppressed this erratic hyperactivity. The overactive cells quieted down to match the activity levels seen in healthy mice.

Psilocin interacts with several types of serotonin receptors, specifically ones known as 5-HT2A and 5-HT1A. To figure out which receptors were responsible for the healing effect, the team gave the mice drugs that block these specific receptors before administering the psilocybin.

Blocking either the 5-HT2A receptor or the 5-HT1A receptor completely stopped the psilocybin from working. The mice remained in pain and continued to show depressed behaviors. This demonstrates that psilocybin requires access to both of these serotonin receptor types simultaneously to initiate its healing effects.

In pharmacology, a full agonist is a drug that turns a receptor on completely. A partial agonist, like psilocin, only turns it on partially. The researchers tested what would happen if they used different drugs to fully activate the 5-HT2A and 5-HT1A receptors in the mice.

Activating these receptors fully, even at the same time, failed to replicate the broad therapeutic effects of psilocybin. The mice did not experience the same comprehensive relief from pain and mood issues. The researchers suspect that the partial activation provided by psilocin creates a specific, balanced modulation of brain cells that full activation cannot achieve.

While these animal studies offer a detailed look at brain circuitry, mice are not humans. Brain structures and the subjective experience of pain differ between species. It is not yet known if the specific dosage that provided relief in mice will translate safely and effectively to human patients.

The researchers tracked the mice for twelve days after the single dose. It remains unseen exactly how long the pain relief might last beyond that window.

Future studies will need to explore how this brief chemical intervention translates into long-term physical changes in the brain. The authors suggest that calming the hyperactive brain cells might allow the brain to physically rewire itself, breaking the cycle of chronic pain and depression over time.

The study, “Single-dose psilocybin rapidly and sustainably relieves allodynia and anxiodepressive-like behaviors in mouse models of chronic pain,” was authored by Ahmad Hammo, Stephen Wisser, and Joseph Cichon.