Safety, Efficacy, and Blinding Integrity of Psilocybin-Assisted Therapy for Substance Use Disorders: A Systematic Review of Randomized Controlled Trials

Abstract

Substance use disorders (SUDs) represent a persistent global public health burden for which existing pharmacological and behavioral interventions show limited long-term efficacy across various patient populations (Sinha, 2011). Psilocybin-assisted therapy (PAT) has reemerged as a promising therapeutic treatment approach and has had renewed clinical interest with a growing amount of research examining its potential for treating addiction across several SUDs; these include alcohol, tobacco, and opioids among others (Hogea et al., 2025). However, the literature to date has still been dominated by qualitative, observational, and non-randomized study designs with existing systematic reviews largely reflecting this by including non-RCT evidence. As the volume of randomized controlled trial (RCT) data has rapidly grown over the past few years, a review restricted exclusively to these highest-quality study designs is warranted. This project is a single-reviewer systematic review examining the safety, efficacy, and blinding integrity of PAT for the treatment of SUDs, limited exclusively to RCTs. The primary research question asks: in adults with SUDs, what is the efficacy of PAT compared to control conditions in RCTs, as measured by changes in substance use behavior. Two secondary questions address (1) the safety profile of PAT across trials as assessed by adverse event reporting, and (2) the extent to which functional unblinding occurs in double-blinded RCTs and how trials formally assess and report blinding integrity. A particular methodological focus of this review is functional unblinding, the case where participants correctly identify whether they received psilocybin or placebo due to its pronounced psychoactive effects. This is a well-documented challenge in psychedelic trial design and may bias efficacy estimates if left unaddressed (Muthukumaraswamy et al., 2021, Expert Review of Clinical Pharmacology). This review will characterize which double-blinded trials formally assessed blinding, the control agents used, and the reported functional unblinding rates. For this review, a comprehensive search will be conducted across five data bases: MedLine, Cochrane CENTRAL, Embase, PsychINFO, and ClinicalTrials.gov. It will use pre-specified Boolean search strings with a preliminary scoping search returning 189 results via PubMed, 44 of which appear to be RCTs; using this preliminary information, 5-10 studies are anticipated to meet full eligibility after screening. Reference management will be handled via Zotero and screening using Rayyan software. Included studies will undergo a standardized data extraction and risk of bias assessment using the Revised Cochrane Risk of Bias tool (RoB 2). Due to the anticipated clinical and methodological heterogeneity across trials, a formal meta-analysis is not planed. Findings will be synthesized narratively following the SWiM reporting guideline (Campbell et al., 2020, BMJ) and will be organized by SUD type, safety outcomes, and blinding integrity. Lastly, expected outputs include a structured evidence table of all included RCTs, a RoB 2 summary, and a narrative synthesis across the three outcome domains. References Campbell, M., McKenzie, J. E., Sowden, A., Katikireddi, S. V., Brennan, S. E., Ellis, S., Hartmann-Boyce, J., Ryan, R., Shepperd, S., Thomas, J., Welch, V., & Thomson, H. (2020). Synthesis without meta-analysis (SWiM) in systematic reviews: reporting guideline. British Medical Journal, 368(1). https://doi.org/10.1136/bmj.l6890 Hogea, L., Tabugan, D. C., Costea, I., Albai, O., Nussbaum, L., Cojocaru, A., Corsaro, L., & Anghel, T. (2025). The Therapeutic Potential of Psychedelics in Treating Substance Use Disorders: A Review of Clinical Trials. Medicina, 61(2), 278. https://doi.org/10.3390/medicina61020278 Muthukumaraswamy, S. D., Forsyth, A., & Lumley, T. (2021). Blinding and expectancy confounds in psychedelic randomized controlled trials. Expert Review of Clinical Pharmacology, 14(9), 1133–1152. https://doi.org/10.1080/17512433.2021.1933434 Sinha, R. (2011). New Findings on Biological Factors Predicting Addiction Relapse Vulnerability. Current Psychiatry Reports, 13(5), 398–405. https://doi.org/10.1007/s11920-011-0224-0

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