Psilocybin for Depression and Anxiety: Current Evidence and Recommendations
Psilocybin is not recommended for treatment of depression or anxiety outside of clinical trials at this time, based on the 2022 VA/DoD guidelines which explicitly recommend against its use due to limited safety and efficacy data. 1
Guideline-Based Recommendation
The most authoritative guidance comes from the 2022 U.S. Department of Veterans Affairs and U.S. Department of Defense Clinical Practice Guideline for Major Depressive Disorder, which specifically addresses psilocybin:
The guideline explicitly recommends against the use of psilocybin, MDMA, cannabis, or other unapproved pharmacologic agents in settings outside clinical trials (Recommendation 35). 1
The evidence base at the time of guideline development consisted of only one small study with 27 participants comparing immediate versus delayed psilocybin treatment. 1
While that single study showed improved depressive symptoms at weeks 5 and 8 in the immediate treatment group (n=13), this was deemed insufficient evidence for clinical recommendation. 1
Safety Concerns That Drive This Recommendation
The VA/DoD guideline identifies specific risks that justify the recommendation against use:
Risk for psychotic events and harmful behaviors in patients who do not receive appropriate guidance throughout the treatment process. 1
Potential for dependence remains a concern. 1
Treatment requires intensive resources: health care providers must prepare and guide patients through 8-12 hour treatment sessions, making it impractical for routine clinical use. 1
Recent evidence from 2023 indicates increased suicidal ideations and non-suicidal self-injurious behaviors in some patients receiving psilocybin. 2
Emerging Research Evidence (Context Only)
While guidelines recommend against use, recent research provides context for ongoing investigation:
For Cancer-Related Anxiety and Depression:
The 2023 Society for Integrative Oncology-ASCO guideline notes psilocybin-assisted therapy is "promising" for existential anxiety and depression in cancer patients, but concludes the evidence is inconclusive based on only two small RCTs (51 and 29 participants). 1
A 2024 Cochrane review found psilocybin may reduce anxiety and depression in people with life-threatening diseases, but rated the evidence as low to very low certainty due to inability to maintain blinding and small sample sizes. 3
For Treatment-Resistant Depression:
A 2016 open-label feasibility study (12 patients) showed marked reduction in depressive symptoms at 1 week and 3 months, but this was uncontrolled and very small. 4
The 2024 update on psilocybin for treatment-resistant depression notes that phase 3 trials are underway, but current evidence remains preliminary. 5
Clinical Bottom Line
In real-world clinical practice, psilocybin should not be offered as a treatment option for depression or anxiety. 1 The evidence base is too limited, safety concerns are significant, and the intervention requires specialized settings and supervision that are not available in standard practice. 1
For patients with treatment-resistant depression who have failed standard therapies, ketamine or esketamine are the evidence-based alternatives that should be considered instead, though these are also reserved for patients who have not responded to or tolerated previous therapies. 1
Common Pitfall to Avoid:
Do not be swayed by media coverage or patient requests based on preliminary research. The VA/DoD guideline explicitly reviewed this evidence and determined it insufficient for clinical use. 1 Trials in veterans are currently underway and may provide more clarity in the future, but until then, psilocybin remains an investigational agent only. 1