Is psilocybin therapy safe?

Is Psilocybin Therapy Safe?

Psilocybin therapy is not currently recommended for clinical use outside of research trials due to insufficient safety and efficacy data, significant risks including psychotic events and harmful behaviors without proper guidance, and potential for suicidal ideation in vulnerable populations. 1

Current Guideline Recommendations

The 2022 U.S. Department of Veterans Affairs and U.S. Department of Defense clinical practice guidelines explicitly recommend against the use of psilocybin for major depressive disorder treatment outside of clinical trials. 1 This recommendation is based on:

• Extremely limited evidence base: Only one small study with 27 participants (13 completing immediate treatment) was identified in their comprehensive literature review 1
• Inadequate long-term safety data: No established safety profile for repeated or maintenance use 1
• Resource-intensive requirements: Treatment requires 8-12 hours of continuous healthcare provider guidance and preparation 1

Specific Safety Concerns

Acute Risks During Treatment

Psychotic events and harmful behaviors represent the primary safety concern, particularly when patients do not receive appropriate guidance throughout the treatment process. 1 The risk is substantially elevated without:

• Proper patient preparation by trained healthcare providers 1
• Continuous monitoring during the 8-12 hour treatment session 1
• Structured psychotherapeutic support integrated with dosing 1

Suicidality Risk

Recent clinical trial data reveal concerning signals regarding suicidal ideation and self-injurious behaviors. 2 Specifically:

• Increased suicidal ideations were observed in psilocybin treatment arms 2
• Non-suicidal self-injurious behaviors occurred more frequently with psilocybin 2
• Risk appears concentrated in patients with prior history of suicidal ideation or suicide attempts 3

This contrasts sharply with the more established safety profile of esketamine, which has FDA approval and mandatory 2-hour post-treatment monitoring requirements. 1

Reported Adverse Events from Available Data

Most Common Physical Effects

When psilocybin has been studied in controlled settings, the following adverse events occur most frequently:

• Cardiovascular: Elevated blood pressure during sessions 3
• Gastrointestinal: Nausea and vomiting 3
• Neurological: Headaches, fatigue 3
• Psychological: Anxiety during sessions 3

Severity Assessment

Available data suggest that when administered under proper supervision (psilocybin-assisted therapy), most adverse effects are mild and transient. 2 However, this assessment comes with critical caveats:

• No deaths have been attributed to psilocybin in clinical trials reviewed 3
• Severe adverse events are uncommon in highly controlled research settings 2
• Heterogeneity in adverse event definitions, measurement, and reporting methods across studies limits confident safety conclusions 3

Why Current Evidence Is Insufficient

Study Quality Issues

The evidence base suffers from multiple methodological limitations:

• Small sample sizes: The guideline-cited study had only 13 completers in the active treatment group 1
• Lack of standardization: No consistent definitions for what constitutes an adverse event across psilocybin studies 3
• Variable monitoring protocols: Inconsistent methods for measuring and reporting safety outcomes 3
• Short follow-up periods: Limited data on long-term consequences 1

Comparison to Approved Alternatives

Unlike ketamine/esketamine which have:

• Risk Evaluation and Mitigation Strategy (REMS) requirements 1
• Mandatory pharmacy and healthcare setting certification 1
• Standardized 2-hour post-treatment monitoring 1

Psilocybin lacks any regulatory framework or established safety protocols for clinical use. 1

Potential for Dependence

The potential for dependence remains inadequately studied. 1 This represents a significant knowledge gap given that:

• Classical psychedelics were historically assumed to have low addiction potential
• Systematic evaluation of dependence risk has not been conducted in modern trials
• Long-term use patterns outside controlled settings are unknown

Clinical Context: When Safety Might Be Acceptable

The available research suggests psilocybin may have an acceptable benefit-risk profile only when:

1. Administered in highly controlled research settings with institutional review board oversight 4
2. Integrated with structured psychotherapeutic support throughout preparation, dosing, and integration phases 1, 4
3. Patients are carefully screened to exclude those with:
   • History of psychotic disorders 1
   • Active suicidal ideation or recent suicide attempts 3, 2
   • Inadequate social support for the intensive treatment process 1
4. Continuous monitoring is provided during the entire 8-12 hour session 1

Current Recommendation for Clinical Practice

Psilocybin should only be used within approved clinical trials until larger, well-designed randomized controlled trials with standardized safety monitoring establish its risk-benefit profile. 1 This recommendation applies equally to MDMA, cannabis, and other unapproved pharmacologic agents for psychiatric indications. 1

For patients inquiring about psilocybin therapy, clinicians should:

• Explain that current guidelines recommend against its use outside research 1
• Discuss established treatment alternatives with proven safety profiles
• Provide information about ongoing clinical trials if patients wish to participate in research 1
• Screen for and address any history of suicidality given the identified risk signals 3, 2

The field requires standardized adverse event definitions, consistent monitoring protocols, and larger sample sizes before psilocybin can be considered for routine clinical use. 3 Trials in veteran populations are currently underway and may provide more definitive safety data. 1