Placebo Effects in Alcohol, Cocaine, and Methamphetamine Use Disorder: A Systematic Review and Meta-Analysis

Clinical Snapshot

Key Findings

• P Value: Statistically significant only for alcohol use disorder

• Effect Size: Alcohol: SMD=0.93; Cocaine: SMD=0.61; Methamphetamine: SMD=0.44

• Primary Outcome: Standardized mean difference in craving scores pre-post placebo treatment

• Nnt Or Sensitivity: Large effect size for alcohol (SMD=0.93), moderate for cocaine and methamphetamine but with substantial uncertainty

• Confidence Interval: Alcohol: 95% CI 0.33-1.54; Cocaine: 95% CI -1.41-2.62; Methamphetamine: 95% CI -3.43-4.32

Clinical Application

Limited by small evidence base and uncertainty in effect estimates for most substance types Relevant to Australian addiction medicine practice but limited by lack of quality assessment and small study numbers; may inform PBS-funded treatment expectations Adults with alcohol use disorder in clinical trial settings; limited evidence for cocaine and methamphetamine use disorders

Abstract

Objective: The placebo effect is established in psychiatry, yet its role in substance use disorders (SUDs) treatment remains unclear. The aim of this study was to evaluate changes in craving scores in placebo groups in randomized controlled trials (RCTs) across different SUDs in adults. Data sources: Eight different databases (PubMed, Embase, Web of Science, Cochrane Library, Emcare, MEDLINE, PsycINFO, and Academic Search) were systematically searched up to October 28, 2024, by 2 independent researchers. Study selection: Placebo-controlled, double-blind RCTs assessing craving in patients with SUDs were included based on predefined eligibility criteria, published in English, Dutch, Spanish, or German language. Search terms were a combination and synonyms of "craving," "addiction," and "placebo." From a total of 1945 unique records identified, 9 articles met our eligibility criteria. Data extraction: Data on demographic characteristics, study design, and outcome results were extracted. Standardized mean differences (SMDs) with 95% confidence intervals (CIs) were calculated for pre-post craving scores within each placebo group; a positive difference point towards improvement in the postplacebo period. Results: A total of n=495 placebo-treated participants were included from nine RCTs in three different SUDs (n=300 in alcohol, n=88 in cocaine, and n=107 in methamphetamine use disorder). Craving scores significantly decreased over time (meaning symptom improvement) in the placebo treatment group in alcohol use disorder (5 studies, SMD=0.93 [95% CI=0.33 to 1.54]) but did not reach statistical significance in cocaine use disorder (2 studies, SMD=0.61 [95% CI=-1.41 to 2.62]) or in (meth)amphetamine use disorder (2 studies, SMD=0.44 [95% CI=-3.43 to 4.32]). Conclusions: Placebo treatment led to reductions in craving scores across all three SUDs, although statistical significance was achieved only in alcohol use disorder. Given the low number of studies for cocaine and (meth)amphetamine use disorder, these estimates were captured with much uncertainty. These findings may inform the design of future RCTs and support the development of more individualized treatment approaches in clinical settings.

References

1. 1.van der Meer, P. B., Schoones, J. W., Luykx, J., Dekkers, O. M., Fiocco, M., Kramers, C. K., Schellekens, A., & Batalla, A. (2026). Placebo Effects in Alcohol, Cocaine, and Methamphetamine Use Disorder: A Systematic Review and Meta-Analysis. *The Journal of Clinical Psychiatry*. https://doi.org/10.4088/JCP.25r16118