A Critical Appraisal of Evidence on the Efficacy and Safety of Serotonergic Psychedelic Drugs as Emerging Antidepressants
Journal of Clinical Psychopharmacology – October 03, 2022
Source: OpenAlex
Summary
Psilocybin, a serotonergic hallucinogen, shows antidepressant promise for Major Depressive Disorder and distress when combined with psychotherapy. Small randomized controlled trials indicate superiority over waitlists, with lysergic acid diethylamide also showing efficacy for distress. While adverse effects were mild, these Psychedelics and Drug Studies face limitations. Expectancy theory highlights challenges in clinical trial design. Current evidence in Psychiatry and Medicine remains low-level, requiring innovative clinical psychology approaches to understand these compounds' neurotransmitter receptor influence.
Abstract
Abstract Purpose/Background There has been resurgence of interest in the therapeutic use of serotonergic (“classic”) psychedelics in major depressive disorder (MDD) and end-of-life distress. This commentary offers a critical appraisal of current evidence for antidepressant effects of classic psychedelics from contemporary clinical trials and highlights pitfalls that should be addressed before clinical translation. Methods/Procedures A narrative review was conducted to identify clinical trials of serotonergic psychedelics for the treatment of MDD and end-of-life distress. Trials published between January 1990 and May 2022 were identified on PubMed using combinations of search terms. Findings/Results Psilocybin, lysergic acid diethylamide, and ayahuasca have clinical trials to evaluate antidepressant effects. Two studies showed preliminary positive effects of single-dose ayahuasca for treatment-resistant depression. Similar results were seen in lysergic acid diethylamide for end-of-life distress. Small randomized clinical trials (RCTs) of psilocybin combined with psychotherapy showed superiority to waitlist controls and comparable efficacy and safety to an active comparator in MDD, with additional RCTs showing efficacy in end-of-life distress. Adverse events associated with psychedelics were reported as mild and transient. Small homogenous samples, expectancy bias, functional unblinding, and lack of consensus and standardization of psychotherapy are major limitations of all studies. Implications/Conclusions Given the methodological limitations of published RCTs, the evidence supporting the efficacy and safety of serotonergic psychedelics for depression is currently of low level. Future research should assess the role of expectancy and psychedelic effects in moderating and mediating treatment response. Innovative trial designs are needed to overcome functional unblinding. For now, psychedelics should remain experimental interventions used within clinical trials.