Psilocybin-assisted therapy for depression

Psilocybin has shown promise in the treatment of depression, and research suggests that it may be helpful for individuals who have been diagnosed with treatment-resistant depression.

Treatment-resistant depression generally refers to depression that has not responded adequately to at least two standard antidepressant treatments.

Psilocybin may be useful in the treatment of depression as it is believed to:

  1. Increase serotonin levels: Psilocybin has been shown to increase serotonin levels in the brain, which is thought to improve mood. Serotonin is a neurotransmitter that regulates mood, appetite, and sleep, among other things. Low levels of serotonin are associated with depression, and increasing serotonin levels may help alleviate symptoms.

  2. Change brain activity: Psilocybin has been shown to change the activity of certain areas of the brain that are involved in mood regulation. Specifically, it reduces activity in the default mode network, which is responsible for self-reflection and rumination. Overactivity in this network has been linked to depression, and reducing activity in this network may help alleviate symptoms.

  3. Provide a new perspective: Psilocybin has been reported to provide individuals with a new perspective on their lives and their depression. This can be helpful in breaking negative thought patterns and providing a sense of clarity and purpose.

  4. Increase openness: Psilocybin has been shown to increase openness, which is a personality trait associated with creativity, imagination, and curiosity. Individuals with depression often have decreased openness, and increasing openness may help alleviate symptoms.

  5. Provide a sense of connection: Psilocybin has been reported to provide individuals with a sense of connection to themselves, others, and the world around them. This can be helpful in alleviating feelings of loneliness and isolation, which are common in depression.

Clinical Trial Results

In April 2021, the results of a trial conducted by researchers at Imperial College London showed that the antidepressant effects of psilocybin and escitalopram (a commonly prescribed SSRI to treat depression) were not significantly different.

In August 2024, a systematic review and meta-analysis, published in the British Medical Journal (BMJ), looked at 19 placebo-controlled studies of oral monotherapy with either psychedelics (psilocybin, lysergic acid diethylamide, MDMA and ayahuasca) or escitalopram (an antidepressant of the selective serotonin reuptake inhibitor class). In the meta-analysis, authors looked for changes in depressive symptoms from baseline. The study concluded: “Of the available psychedelic treatments for depressive symptoms, patients treated with high dose psilocybin showed better responses than those treated with placebo in the antidepressant trials.”

Research into psilocybin-assisted therapy for treatment-resistant depression has continued to accelerate in recent years, with several major clinical trials reporting encouraging outcomes.

In 2025, Compass Pathways announced positive results from the first Phase 3 clinical trial of COMP360 psilocybin therapy for treatment-resistant depression. Participants receiving a 25mg dose of psilocybin, alongside psychological support, showed a statistically significant and clinically meaningful reduction in depressive symptoms compared to placebo.

In early 2026, the company announced positive results from a second Phase 3 trial, again demonstrating significant improvements in depression scores. The trials also suggested rapid onset of effect, with some participants reporting improvement within days, and durable benefits lasting up to 26 weeks in some responders after only one or two supervised sessions.

These studies are particularly significant because treatment-resistant depression has historically been very difficult to treat successfully. The Phase 3 COMP360 program represents the most advanced clinical development program for a classic psychedelic therapy to date.

While these results remain subject to ongoing regulatory review, they have strengthened scientific and medical interest in psilocybin-assisted therapy as a potential new treatment approach for people who have not responded adequately to conventional antidepressants.

Important Note

Psilocybin-assisted therapy is not effective for everyone, and treatment sessions can sometimes be emotionally intense or psychologically challenging.

Psilocybin should only be used under the guidance of a trained healthcare professional in a safe and controlled environment.