From the Guidelines
Psilocybin is not recommended for the treatment of depression due to limited evidence and potential risks, as stated in the 2022 U.S. Department of Veterans Affairs and U.S. Department of Defense clinical practice guideline 1.
Key Points
- The current evidence for psilocybin in treating depression is limited and primarily based on a single study with 27 participants 1.
- Psilocybin therapy requires careful preparation, psychological support during the experience, and integration therapy afterward to maximize benefits.
- The treatment is associated with potential risks, including psychotic events and harmful behaviors in patients who do not receive appropriate guidance throughout the treatment process 1.
- Other treatment options, such as cognitive behavioral therapy (CBT) and second-generation antidepressants, are recommended as first-line treatments for major depressive disorder (MDD) due to their similar efficacy and lower risks 1.
Considerations
- Psilocybin remains investigational for depression in most countries, with only limited approved use in specific clinical settings.
- The treatment is not recommended for individuals with psychotic disorders or family history of psychosis, and should only be administered by trained professionals in controlled environments.
- Further research is needed to fully understand the potential benefits and risks of psilocybin therapy for depression.
From the Research
Effectiveness of Psilocybin for Depression
The evidence suggests that psilocybin may be an effective treatment for depression, particularly for treatment-resistant depression.
- A study published in 2016 found that psilocybin was well tolerated and produced significant and sustained reductions in depressive symptoms in patients with treatment-resistant depression 2.
- A systematic review published in 2024 found that psilocybin may exert its antidepressant effects through various mechanisms, including changes to serotonin or glutamate receptor activity and increased synaptogenesis 3.
- A case report published in 2025 described a patient who experienced complete remission of depressive symptoms after receiving psilocybin treatment, highlighting the potential role of psilocybin in addressing treatment-resistant depression 4.
- A prospective 12-month follow-up study published in 2022 found that psilocybin-assisted treatment produced substantial and rapid antidepressant effects in patients with major depressive disorder, with large decreases in depressive symptoms observed at 1-, 3-, 6-, and 12-month follow-up 5.
- A review published in 2022 provided a comprehensive overview of the potential use of psilocybin in the treatment of depression and treatment-resistant depression, highlighting the efficacy and safety of psilocybin-assisted psychotherapy 6.
Key Findings
- Psilocybin has been found to produce significant and sustained reductions in depressive symptoms in patients with treatment-resistant depression.
- The mechanisms by which psilocybin exerts its antidepressant effects are not fully understood, but may involve changes to serotonin or glutamate receptor activity and increased synaptogenesis.
- Psilocybin-assisted treatment has been found to be well tolerated and safe, with no serious adverse events reported in clinical trials.
- The antidepressant effects of psilocybin-assisted treatment may be durable, with large decreases in depressive symptoms observed at 1-, 3-, 6-, and 12-month follow-up.
Study Limitations
- The current evidence is based on small-scale studies, and larger clinical trials are needed to fully establish the efficacy and safety of psilocybin-assisted treatment for depression.
- The mechanisms by which psilocybin exerts its antidepressant effects are not fully understood, and further research is needed to elucidate these mechanisms.
- Psilocybin is a controlled substance, and its use is subject to regulatory restrictions, which may limit its availability and accessibility as a treatment for depression.