Single psilocybin dose provides lasting relief from pain and depression

Psilocybin is a natural psychedelic compound found in certain mushrooms that affects mood and perception. In a new study, researchers found that a single dose of psilocybin quieted chronic pain and depression-like behavior within 24 hours.

The benefits persisted for at least 12 days, even though the original injuries were still visible.

Evidence points to the anterior cingulate cortex as the control center, a brain region that processes emotion and pain. The effect also depends on a careful retuning of serotonin receptors.

These receptors sit on nerve cells, respond to serotonin, and help regulate mood and pain. The change did not come from numbing nerves in the injured paw or the spine of the mice used in this study.

Psilocybin may aid chronic depression

The work comes from Joseph Cichon at the University of Pennsylvania’s Perelman School of Medicine, whose team set out to test whether one intervention could lift pain and mood together.

They asked where in the nervous system the change begins and which signals need to be adjusted.

Chronic pain is not rare, and it is not only physical. In 2021, an estimated 51.6 million adults in the United States lived with chronic pain, according to a CDC report. Depression and anxiety often travel with that pain and make it harder to treat.

Study senior author Joseph Cichon is an assistant professor of anesthesiology and critical care.

“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 Cichon.

Behavioral changes recorded in mice

The researchers created two forms of long-lasting pain, one from a sciatic nerve injury and the other from a strong inflammatory irritant, a chemical that causes swelling and pain in tissues, placed in the paw.

Both groups became very sensitive to touch and showed reliable measures of low mood and anxiety.

One psilocybin injection, at 0.5 milligrams per kilogram, normalized pain sensitivity within a day. Those behavioral changes stayed stable for the next 12 days of monitoring.

The team also mapped the day-to-day link between pain severity and mood scores. Mice with more allodynia, an abnormal sensitivity to touch, showed more anxiety and despair, and both improved together after treatment.

Psilocybin changed the brain

Activity recordings in the anterior cingulate cortex showed neurons firing about 40 percent faster than normal in the chronic pain state.

When the researchers locally applied psilocin, the active chemical that psilocybin turns into inside the body, to this cortical area, that overactivity dropped back to baseline within minutes.

Injecting psilocin into the spinal cord near the injured nerves did not help. The brain site mattered, and the cortex was the lever.

Independent evidence already puts the anterior cingulate at the center of the emotional side of pain.

A recent review, a scholarly summary of existing research on a topic, highlights its role in linking sensation to affect and in shaping pain-driven anxiety.

How serotonin signals were tuned

The mechanistic tests focused on 5-HT2A and 5-HT1A receptors, two distinct serotonin-sensitive switches in the brain that regulate emotion, sleep, and pain perception. Blocking either one before psilocybin erased both the pain relief and the mood benefits.

Turning one receptor fully on with standard agonists, drugs that activate specific receptors, did not replicate what psilocybin did.

Full 5-HT2A activation increased activity in already overactive circuits, while full 5-HT1A activation gave only modest analgesia or pain relief, without clear mood change.

Psilocybin’s effect emerged when both receptors were nudged, not maxed out.

“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.

Why psilocybin’s action matters

The work shows that relief came from quieting a hyperactive cortical hub rather than fixing nerves at the injury site. That is consistent with the idea that chronic pain reshapes brain circuits and that mood and pain share those circuits.

It also explains why the same dose could help both symptoms at once. When the overactive hub settled down, mood-related behaviors and mechanical sensitivity both normalized.

This cortical view matches prior human and animal data that tie the anterior cingulate to the unpleasantness of pain.

It helps clarify why some treatments that hit the periphery, meaning the nerves and tissues outside the brain and spinal cord, fall short when pain becomes entrenched.

Can psilocybin ease long-lasting pain?

The mouse data line up with clinical findings that psilocybin can shift mood states quickly in people with depression.

In a phase 2 randomized trial, a single 25 milligram oral dose lowered depression scores more than a 1 milligram control over three weeks. Early patient studies are now testing whether psilocybin can ease long-lasting pain itself.

One clinical trial is exploring effects in fibromyalgia, a chronic disorder marked by widespread pain and fatigue; a condition marked by heightened pain sensitivity and disrupted sleep.

None of this says people should self-medicate. The dosing, setting, screening, and follow-up in research are deliberate, and safety questions need careful answers in controlled studies.

Further testing is needed

Rodent models, standardized animal systems used to test human-like conditions, do not capture the social and psychological layers that shape human pain.

The observation window here was 12 days after dosing for behavior and 40 days for injury checks, so durability beyond that is unknown.

Sex differences were examined, though some assays, or laboratory tests, had small groups for those comparisons.

Adverse effects were not a focus in these experiments, so safety in chronic use remains to be defined. The receptor story is still being refined.

Pharmacology work shows psilocin engages multiple serotonin sites, while assays indicate partial agonist actions at 5-HT2A with activity at 5-HT1A as well. But the exact balance that produces lasting relief will need human data.

Future of psilocybin research

The study reinforces a simple but often overlooked point. Chronic pain is a brain circuit problem as much as it is a nerve or tissue problem.

Targeting those circuits may allow treatments that help with pain and mood together. That goal will require cautious trials, realistic expectations, and learning who benefits most and when.

The study is published in the journal Nature Neuroscience.

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