(143) Meta-Analysis of Ketamine’s Effects on Craving and Abstinence in Substance Use Disorders

Background & Introduction: Substance use disorders (SUDs) affect nearly 2% of the global population1 and are associated with important health, social, and economic consequences. Despite the availability of standard treatments, outcomes remain suboptimal. Two commonly studied indicators of treatment efficacy in SUDs are craving, defined as the intense urge to use a substance, and substance use (SU) outcomes, including reductions in use and abstinence. Craving is a core and transdiagnostic feature of SUDs and is associated with relapse risk, functional impairment, and distress, with potential persistence even during sustained remission.2,3 Ketamine, a noncompetitive N-methyl-D-aspartate receptor antagonist, is a promising intervention for the treatment of SUDs, with growing evidence suggesting beneficial effects on craving and SU-related outcomes. However, ketamine’s efficacy across SUDs and outcome domains remains unclear. The aim of this systematic review and meta-analysis is to evaluate ketamine’s effects on craving as well as abstinence in individuals with SUDs.

Methods: The study followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA)4 guidelines and was registered on the Prospective Register of Systematic Reviews (PROSPERO [ID: CRD42024570786]) in July 2024. Eight databases and trial registries (e.g., Medline, ClinicalTrials.gov) were searched (October 2024). Eligible studies were randomized controlled trials (RCTs) with a valid control arm that evaluated ketamine for SUDs or harmful/hazardous SU and reported post-intervention craving outcomes. For the primary outcome of post-intervention craving, standardized mean differences (Hedges’ g) with 95% confidence intervals (CIs) were pooled using a random-effects meta-analysis. Exploratory subgroup analyses examined substance type (alcohol, cocaine, opioids, tobacco), craving type (cue-induced vs. spontaneous), adjunctive psychotherapy, control condition (active vs. inactive placebo) and number of ketamine administrations. For the secondary outcome of abstinence, analyses were restricted to eligible trials that additionally reported short-term abstinence (no SU within 2-4 weeks post-intervention). Odds ratios (ORs) with 95% CIs were pooled using a random-effects meta-analysis. Additional outcomes, including SU patterns (e.g., quantity and frequency of use, relapse, and withdrawal), as well as psychiatric and clinical outcomes, safety and adverse events, and ketamine’s subjective effects, were extracted and synthesized narratively.

Results: From 3,275 records identified, 30 full texts were screened, and 11 RCTs were included (8 parallel, 3 crossover), resulting in a sample size of 489 participants. Six trials examined alcohol use disorder (AUD), three cocaine dependence, one tobacco use disorder, and one opioid use disorder. Participants were typically middle-aged (mean age 40.6 years, range 21.6-53.0), and 29.6% were female (range 0-52.5%). Most samples met Diagnostic and Statistical Manual of Mental Disorders, Four (DSM-IV) and Five (DSM-5) criteria for SUDs. Across nine trials contributing ten effect-size estimates (total N=389), ketamine was associated with a statistically significant reduction in post-intervention craving compared with control conditions under a random-effects model (Hedges’ g=0.34, 95% CI: 0.09-0.59, p=0.009). No significant baseline differences were observed between treatment groups (p=0.325) and between-study heterogeneity was moderate (I2=36%). Four RCTs (N=152) reported short-term abstinence outcomes. Ketamine was associated with significantly higher odds of abstinence compared with control (OR=3.35, 95% CI: 1.47-7.61, p=0.004), with low heterogeneity (I2=8.46%). For the craving outcome, there was minor funnel plot asymmetry, Begg’s and Egger’s tests were non-significant, and trim-and-fill analyses imputed one potentially missing study, yielding a similar pooled estimate (g=0.39). Subgroup analyses indicated statistically significant reductions in post-intervention craving among studies assessing cue-induced craving (p=0.001) and in cocaine dependence (p < 0.001), with a trend toward reduced craving in AUD (p=0.054). However, substance type was the only moderator for which the test for subgroup differences was statistically significant (p=0.021). The narrative synthesis indicated that ketamine was generally associated with reductions in SU consumption patterns and improvements in psychiatric symptom severity, alongside some transient subjective effects, although findings varied across studies.

Conclusion & Discussion: This systematic review and meta-analysis provide the first quantitative synthesis of RCTs examining ketamine’s effect on craving and abstinence in individuals with SUDs. Ketamine was associated with a statistically significant reduction in craving and higher odds of short-term abstinence compared with control conditions. These results suggest that ketamine may target important SUD-related outcomes, particularly craving, a central and transdiagnostic feature of SUDs. The observed effects align with mechanistic frameworks whereby ketamine’s impact on glutamatergic neuroplasticity, prefrontal regulatory control, large-scale brain network organization, and disruption of maladaptive reward memory reconsolidation may converge to reduce craving and SU.5 However, most included trials evaluated outcomes over short follow-up periods, which limits conclusions regarding ketamine’s long-term efficacy on outcomes. The observed clinical and methodological variability across studies further suggests that treatment effects may differ by therapeutic context, substance type, and patient characteristics. Larger, well-powered trials with longer follow-up durations are needed to clarify the durability of ketamine’s effects and to identify moderators of response. Overall, these findings support continued investigation of ketamine as a novel intervention in addiction psychiatry.

References: 1. Degenhardt L, Charlson F, Ferrari A, Santomauro D, Erskine H, Mantilla-Herrara A, et al. The global burden of disease attributable to alcohol and drug use in 195 countries and territories, 1990–2016: a systematic analysis for the Global Burden of Disease Study 2016. The Lancet Psychiatry. 2018 Dec 1;5(12):987–1012.
2. American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders, 5th ed. [Internet]. Arlington: American Psychiatric Association; 2013 [cited 2024 Dec 9]. Available from: https://doi/book/10.1176/appi.books.9780890425596
3. Vafaie N, Kober H. Association of Drug Cues and Craving With Drug Use and Relapse: A Systematic Review and Meta-analysis. JAMA Psychiatry. 2022 July 1;79(7):641–50.
4. Page MJ, McKenzie JE, Bossuyt PM, Boutron I, Hoffmann TC, Mulrow CD, et al. The PRISMA 2020 statement: an updated guideline for reporting systematic reviews. Systematic Reviews. 2021 Mar 29;10(1):89.
5. Ivan Ezquerra-Romano I, Lawn W, Krupitsky E, Morgan CJA. Ketamine for the treatment of addiction: Evidence and potential mechanisms. Neuropharmacology. 2018 Nov 1;142:72–82.