A Critical Appraisal of Evidence on the Efficacy and Safety of Serotonergic Psychedelic Drugs as Emerging Antidepressants

Abstract

Purpose/BackgroundThere 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/ProceduresA 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/ResultsPsilocybin, 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/ConclusionsGiven 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.

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“…Concerns regarding the safety and tolerability of psychedelics have been the subject of recent reviews [93,94]. Despite common opinion, psilocybin has not been shown to be neurotoxic with either enteral or parenteral administration [95].…”

Psilocybin for treatment-resistant depression without psychedelic effects: study protocol for a 4-week, double-blind, proof-of-concept randomised controlled trial

“…However, most published trials to date are limited by small sample sizes, inadequate control groups, lack of blinding or highly selected participants. 15,16 Despite these methodological limitations, the results of these trials have led to growing enthusiasm for the use of psilocybin for the treatment of MDD and related disorders. Currently, it is assumed that psilocybin's therapeutic effects in MDD require altered consciousness (i.e.…”

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“…One of the psilocybin studies 3 included in the mentioned review 2 received a lot of attention, as it was published in the New England Journal of Medicine . It presented results of a phase 2, double-blind, randomized 6-week study comparing (in a complicated design) psilocybin 25 mg in 2 separate doses 3 weeks apart, to escitalopram 10 mg daily (increased to 20 mg after 3 weeks) in patients with long-standing, moderate-to-severe major depressive disorder.…”

“…Nevertheless, the accompanying editorial 4 labeled this as an “evidentiary milestone in the development of psychedelic drugs.” However, this editorial 4 also raised several important issues, such as “whether the putative therapeutic effects of psychedelic drugs would require a patient to have a mystical experience or would occur in its absence through the pharmacologic effects on the serotonergic system or remodeling of neural circuitry.” How do we explain mystical experience to patients and what is the psychedelic drugs' potential for addiction? 4 The question whether the mystical experience is needed is especially important. As noted by Ledwos and colleagues, 2 it would be interesting and helpful if the mystical psychedelic experience could be attenuated or blocked, and psilocybin's putative antidepressant effect could be evaluated without this experience.…”

“…On the other hand, a review article in this issue of the Journal of Clinical Psychopharmacology 2 presents an analysis of clinical trials of psilocybin, LSD, and ayahuasca in depression. The authors convey a more reserved and cautionary view of the efficacy of psilocybin, LSD, and ayahuasca in the treatment of depression.…”