Overview of Psychedelic Compounds in Adult Psychiatry
Current Clinical Status and Regulatory Position
Psychedelic compounds, including psilocybin and LSD, should NOT be used in routine adult psychiatric practice outside of approved clinical trials, as current guidelines explicitly recommend against their use due to extremely limited evidence, inadequate long-term safety data, and lack of established safety protocols. 1
The U.S. Department of Veterans Affairs and U.S. Department of Defense clinical practice guidelines specifically recommend against psilocybin for major depressive disorder treatment outside research settings, based on an evidence base consisting of only one small study with 27 participants. 1 Unlike FDA-approved alternatives such as ketamine/esketamine, which have Risk Evaluation and Mitigation Strategy (REMS) requirements and standardized safety protocols, psilocybin lacks any regulatory framework for clinical use. 1
Compounds Under Investigation
Classic Serotonergic Psychedelics
The primary compounds being studied include: 2, 3
- Psilocybin (from mushrooms)
- LSD (lysergic acid diethylamide)
- DMT (N,N-dimethyltryptamine)
- 5-MeO-DMT (5-methoxy-N,N-dimethyltryptamine)
- Mescaline
All function as serotonin 2A receptor agonists, though it remains unclear whether different receptor profiles contribute meaningfully to therapeutic potential. 2
Potential Psychiatric Applications (Research Only)
Depression and Anxiety
In controlled research settings with supportive environments, these compounds have shown immediate and significant antidepressant and anxiolytic effects lasting several months. 4 Seven studies with 130 patients demonstrated consistent symptom improvement in depression and anxiety disorders. 4 However, evidence remains strongest for psilocybin in depression, with other indications still relatively scarce. 2
Treatment-Resistant Conditions
Psychedelic-assisted therapy may represent a promising alternative for patients unresponsive to traditional treatments, though this remains investigational. 4
Critical Safety Concerns and Contraindications
Serious Psychiatric Risks
Psilocybin therapy carries significant risk of psychotic events and harmful behaviors, particularly when patients lack appropriate guidance throughout treatment. 1 Patients with history of psychotic disorders or active suicidal ideation must be excluded from treatment. 1
Cardiovascular and Physiological Effects
Microdosing studies reveal dose-dependent effects including: 5
- Increased blood pressure
- Increased heart rate
- Pupil changes
- Galvanic skin responses
- Autonomic changes 6
Common Adverse Effects
The most frequently reported side effects are typically mild, dose-dependent, and short-lived, including: 4, 5
- Transient anxiety
- Headaches
- Nausea
- Cognitive impairment
- Insomnia 6
- Physical discomfort 6
- Overstimulation 6
Approximately 6% of microdosers experience negative physiological effects. 6
Inadequately Studied Risks
The potential for dependence remains inadequately studied, representing a significant knowledge gap given the lack of systematic evaluation in modern trials. 1
Treatment Requirements (Research Settings Only)
Resource-Intensive Protocol
When administered in research settings, psychedelic therapy requires: 1
- 8-12 hours of continuous healthcare provider guidance during dosing sessions
- Extensive preparation sessions before dosing
- Structured psychotherapeutic support integrated with dosing
- Continuous monitoring throughout the entire session
- Psychological integration and after-care procedures 3
Necessary Infrastructure
Implementation requires redefinition of psychotherapeutic processes and new treatment infrastructure, including: 3
- Informed patient referral and co-treatment practices
- Rigorous screening protocols
- Specialized therapist training
- Structured patient communities for support
- Institutional review board oversight 1
Microdosing: A Separate Consideration
Definition and Practice
Microdosing involves taking sub-perceptual doses regularly (typically 10-20 μg LSD or equivalent psilocybin doses) to improve daily functioning, reduce anxiety, and enhance mood and cognition. 6, 5
Evidence Quality
Despite common anecdotal claims that microdosing is sub-perceptual, consistent evidence shows it does lead to changes in subjective awareness. 6 However, a systematic review of 44 studies from 1955-2021 found significant methodological limitations, with many studies excluded for not being peer-reviewed, wrong doses, or inadequate outcomes. 6
Reported Effects vs. Placebo
Self-rated intensity of drug effects was the only measure differentiating microdoses from placebo after controlling for expectation in self-blinded prospective studies. 6 This suggests substantial placebo effects may account for reported benefits. 6
Microdosing Safety Profile
Side effects are typically dose-dependent, mild, and short-lived, but include increased blood pressure, anxiety, and cognitive impairment. 5 Notably, 27.5% of affected respondents in surveys stopped taking conventional pain medication in favor of microdosing, raising concerns about discontinuation of evidence-based treatments. 6
Current Recommendation for Clinical Practice
Psychedelic compounds should only be used within approved clinical trials with institutional review board oversight until larger, well-designed randomized controlled trials with standardized safety monitoring establish their risk-benefit profile. 1
The acceptable benefit-risk profile exists only in highly controlled research settings with: 1
- Institutional review board oversight
- Integrated structured psychotherapeutic support
- Careful patient screening excluding psychotic disorders and active suicidal ideation
- Continuous monitoring during entire 8-12 hour sessions
Critical Pitfalls to Avoid
Do not recommend or prescribe psychedelics in routine practice, as they lack FDA approval, established safety protocols, and adequate long-term safety data. 1 The resource requirements (8-12 hours of continuous monitoring) make implementation outside specialized research settings impractical and potentially dangerous. 1
Do not assume microdosing is safe or effective based on anecdotal reports, as controlled studies show minimal differentiation from placebo when expectation is controlled. 6
Do not allow patients to discontinue evidence-based treatments in favor of self-administered psychedelics, as this represents a significant safety concern documented in survey studies. 6