What are the safety and therapeutic uses of LSD (lysergic acid diethylamide) and psilocybin for conditions like treatment-resistant depression or anxiety?

LSD and Psilocybin: Safety and Therapeutic Uses

Based on the most recent high-quality guideline evidence, psilocybin and LSD should NOT be used for treatment of depression or anxiety outside of clinical trials, despite preliminary evidence suggesting potential benefit. 1

Current Guideline Recommendations

The 2022 U.S. Department of Veterans Affairs and U.S. Department of Defense Clinical Practice Guideline for Major Depressive Disorder explicitly recommends against the use of psilocybin, LSD, MDMA, cannabis, or other unapproved pharmacologic agents in settings outside clinical trials (Recommendation 35). 1

Rationale for Current Restriction

• Limited evidence base: The guideline review identified only 1 study of psilocybin with 27 participants, comparing immediate therapy versus an 8-week waiting period. 1
• Small sample size: Only 13 participants completed the immediate psilocybin group, though they showed significantly improved depressive symptoms at weeks 5 and 8. 1
• Insufficient safety data: Given the limited evidence related to psilocybin safety and efficacy, current use cannot be recommended. 1

Safety Concerns That Must Be Addressed

Acute Risks During Administration

Psilocybin and LSD carry specific risks that require intensive clinical management:

• Risk for psychotic events in patients who do not receive appropriate guidance throughout the treatment process 1
• Harmful behaviors if inadequate supervision is provided 1
• Potential for dependence (though this appears less concerning than other risks) 1
• Transient adverse effects including anxiety, dissociation, paranoia, confusion, headache, and nausea 2, 3

Clinical Requirements for Safe Administration

Therapeutic use of psilocybin requires extensive clinical infrastructure:

• Health care providers must help prepare and guide the patient through the entire treatment 1
• Treatment interventions typically last 8 to 12 hours, requiring prolonged clinical monitoring 1
• Supportive psychotherapy must be provided throughout the psilocybin treatment 1

Long-Term Safety Concerns

Chronic microdosing raises specific safety issues that remain unresolved:

• Chronic administration of serotonin 2B receptor agonists (which includes psychedelics) has been shown to cause valvular heart disease 1
• Commonly microdosed psychedelics activate the 5-HT2B receptor with high affinity 1
• Safety of long-term microdosing over many months or years has not been adequately studied 1
• While occasional ingestion of higher doses appears physiologically safe, the risks of chronic low-dose administration remain unknown 1

Preliminary Evidence of Potential Benefit

Depression and Anxiety

Recent research suggests possible therapeutic effects, but evidence remains preliminary:

• A 2024 phase IIb trial (n=198) showed 50% of participants experienced remission from generalized anxiety disorder after a single 100 μg dose of LSD 3
• In trials for anxiety and depression associated with life-threatening illnesses, 77% of participants demonstrated durable relief at 1 year post-treatment 3
• Both psilocybin and LSD have shown beneficial effects for treatment-resistant depression in small studies 4, 5
• Psilocybin and ayahuasca showed positive results in treatment-resistant depression in randomized controlled trials 4

Substance Use Disorders

Historical and contemporary data suggest potential for addiction treatment:

• Meta-analysis of mid-20th century RCTs showed single-dose LSD significantly improved alcohol use disorder (P < 0.0003) with an odds ratio of 1.96 3
• Evidence suggests possible roles for LSD and psilocybin in alcohol use disorders and for psilocybin in tobacco addiction 4, 5

Mechanism of Action

Therapeutic effects appear mediated through specific neurobiological pathways:

• Preponderant role of 5-HT2A receptor agonism 4
• Connectivity changes within the default mode network (DMN) and amygdala 4
• Low doses (LSD 10-20 mcg, psilocybin <1-3 mg) have subtle positive effects on cognitive processes including time perception, convergent and divergent thinking 6
• May induce cognitive flexibility that could decrease rumination in depression 6

Clinical Context and Future Directions

Current Status

Only one large-scale clinical trial (>50 participants) has been conducted on LSD in the contemporary era of psychedelic research. 3 Trials in veterans are currently underway and may provide more clarity on the utility of psilocybin in the future. 1

What Remains Unknown

• Patient selection criteria have not been established 3
• Optimal dosing strategy remains unclear 3
• Appropriate clinical follow-up guidelines need development 3
• Studies are heterogeneous in methods and have small sample sizes 4, 5

Common Pitfalls to Avoid

Do not:

• Use these agents outside of approved clinical trials or research settings 1
• Assume that preliminary positive results justify clinical use without proper infrastructure 1
• Underestimate the intensive clinical resources required for safe administration 1
• Ignore the potential for serious adverse events including psychosis, even if rare 2, 3

Bottom Line for Clinical Practice

Reserve ketamine/esketamine for patients who have failed or not tolerated previous therapies (these have more robust evidence and FDA approval for treatment-resistant depression). 1 For psilocybin and LSD, participation in properly designed clinical trials remains the only appropriate avenue for patient access until larger randomized controlled trials establish safety, efficacy, optimal dosing, and appropriate patient selection criteria. 1, 3