Risk of bias in randomized clinical trials on psychedelic medicine: A systematic review

Abstract

Background: The classical psychedelics, psilocybin, peyote, ayahuasca/ N,N-dimethyltryptamine, and lysergic acid diethylamide are considered promising new treatments for psychiatric illnesses, such as depression, anxiety, addiction, and obsessive-compulsive disorders. However, their profound and characteristic subjective effects raise concern for distinctive biases in randomized clinical trials. Methods: We performed a systematic literature search to identify all clinical trials on classical psychedelics with patient populations to examine descriptive data and determine the risk of bias. Two independent reviewers searched three databases (PubMed, Embase, and APA PsycNet) and extracted information on study design, study population, use of active or inactive placebo, dropouts, evaluation of blinding of intervention, and reporting of expectancy and therapeutic alliance. Results: We included 10 papers reporting on 10 unique trials. The trials generally included populations that were predominantly white and highly educated. The trials had small samples and considerable dropout. Blinding was either unsuccessful or not reported regardless of type of placebo. Few trials published protocols, statistical analysis plans (SAPs), and outcomes relating to psychotherapy fidelity. All trials but one were rated as high risk of bias. Conclusion: Successful blinding of intervention is a significant challenge in this field. To better accommodate this, we suggest that future trials use a parallel-group design and utilize an active placebo on a psychedelic-naïve population. Future trials should publish trial protocol and SAPs, use clinician-rated outcomes accessed by a blinded rater, evaluate blinding of intervention, and consider measuring expectancy and therapeutic fidelity.

Longitudinal experiences of Canadians receiving compassionate access to psilocybin-assisted psychotherapy

“…most were expecting minor to major improvements), reflective perhaps of the promising findings from clinical trials and related media reports. Indeed, the risk of biases and the possible confounding effects of expectations are prominent concerns in this research field 39 . All participants expected the psilocybin session to yield major or minor improvements in depression, fear of death, spiritual well-being, relationships, and past trauma.…”

Science, safety and education: Informing the psychedelic treatment of psychiatric disorders

“…In an important article for all in the field to consider, Hovmand et al (2023), report the risk of bias in randomized clinical trials of psychedelic medicine in an important systematic review. The authors performed a systematic literature search to identify all the clinical trials on classical psychedelics with patient populations and examined the descriptive data to determine the risk of bias.…”

“…Successful blinding of the relevant intervention is a significant challenge in this field. To better accomplish this, Hovmand et al (2023), suggest that future trials use a parallel-group design and utilise an active placebo with a psychedelic naïve population. The authors also recommend that future trials should: publish trial protocol and statistical analysis plans; use clinician-rated outcomes accessed by a blinded rater; evaluate blinding of interventions and consider measuring expectancy and therapeutic fidelity.…”

From Taboo to Treatment: The Emergence of Psychedelics in the Management of Pain and Opioid Use Disorder

“…137 Systematic reviews of the RCTs of psychedelics have illustrated that many trials have used various forms of placebo groups including placebo control groups, inert placebo control, or active placebo control, or both, but there is room to improve on quality and blinding assessment and blinding failure in these trials. 138 Blinding integrity tools in the context of psychedelic micro-dosing studies have also been recently developed, as well as recommendations to improve blinding issues in psychedelic trials. 139 The impact of preparatory sessions on expectancy, as well as the set and setting and other controllable factors in psychedelics sessions, should be also thoughtfully considered as possible factors influencing outcomes.…”