A Critical Appraisal of Evidence on the Efficacy and Safety of Serotonergic Psychedelic Drugs as Emerging Antidepressants: Mind the Evidence Gap.
Nicole Ledwos, Joshua D. Rosenblat, Daniel M. Blumberger, David Castle, Roger S McIntyre, Benoit H. Mulsant, Muhammad Ishrat Husain
Journal of Clinical Psychopharmacology DOI: 10.1097/jcp.0000000000001608 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Narrative review Randomized Peer reviewed |
|---|---|
| Interventions | Psilocybin Lysergic acid diethylamide Ayahuasca |
| Topics | Psychedelic-assisted therapy Serotonin |
| Keywords | Mental health treatment Clinical research Depression treatment Psychiatric medicine |
| Citations | 16 |
| Key findings | The evidence supporting the efficacy and safety of serotonergic psychedelics for depression is currently of low level due to methodological limitations in published randomized clinical trials. |
Abstract
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. 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. 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. 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.
Comparable studies
Other narrative reviews on serotonin, most cited first.
Citations in the library
Cited by 14
- Psilocybin for treatment-resistant depression without psychedelic effects: study protocol for a 4-week, double-blind, proof-of-concept randomised controlled trial BJPsych Open July 1, 2023
- Serotonin 5-HT 2B receptor agonism and valvular heart disease: implications for the development of psilocybin and related agents Expert Opinion on Drug Safety August 15, 2023
- Psychedelics for the Treatment of Psychiatric Disorders: Interpreting and Translating Available Evidence and Guidance for Future Research. American Journal of Psychiatry 2025
- Efficacy and Safety of Four Psychedelic-Assisted Therapies for Adults with Symptoms of Depression, Anxiety, and Posttraumatic Stress Disorder: A Systematic Review and Meta-Analysis Journal of Psychoactive Drugs November 15, 2023
- Psilocybin and Eugenol Reduce Inflammation in Human 3D EpiIntestinal Tissue Life December 15, 2023
and 9 more in the library
Cites 33
- Psilocybin produces substantial and sustained decreases in depression and anxiety in patients with life-threatening cancer: A randomized double-blind trial Journal of Psychopharmacology November 30, 2016
- Rapid and sustained symptom reduction following psilocybin treatment for anxiety and depression in patients with life-threatening cancer: a randomized controlled trial Journal of Psychopharmacology November 30, 2016
- Psilocybin with psychological support for treatment-resistant depression: an open-label feasibility study. The Lancet Psychiatry May 17, 2016
- Trial of Psilocybin versus Escitalopram for Depression New England Journal of Medicine April 14, 2021
- Effects of Psilocybin-Assisted Therapy on Major Depressive Disorder JAMA Psychiatry November 4, 2020
and 28 more in the library