N-acetylcysteine (NAC) may serve as a novel pharmacotherapy for substance use and substance craving in individuals with substance use disorders (SUDs), possibly through its potential to regulate glutamate. Though prior meta-analyses generally support NACs efficacy in reducing symptoms of craving, individual trials have found mixed results. The aims of the this updated meta-analysis were to (1) examine the efficacy of NAC in treating symptoms of craving in individuals with a SUD and (2) explore subgroup differences, risk of bias, and publication bias across trials. Database searches of PubMed, Cochrane Library, and ClinicalTrials.gov were conducted to identify relevant randomized control trials (RCTs). The meta-analysis consisted of 9 trials which analyzed data from a total of 623 participants. The most targeted substance in the clinical trials was alcohol (3/9; 33.3%), followed by tobacco (2/9; 22.2%) and multiple substances (2/9; 22.2%). Meta-analysis, subgroup analyses, and leave-one-out analyses were conducted to examine treatment effect on craving symptoms and adverse events. Risk of bias assessments, Eggers tests, and funnel plot tests were conducted to examine risk of bias and publication bias. NAC did not significantly outperform placebo in reducing symptoms of craving in the meta-analysis (SMD = 0.189, 95% CI = -0.015 - 0.393). Heterogeneity was very high in the meta-analysis (99.26%), indicating that findings may have been influenced by clinical or methodological differences in the study protocols. Additionally, results indicate that there may be publication bias present. There were no between-group differences in risk of AEs. Overall, our findings are contrary to those of prior meta-analyses, suggesting limited impact of NAC on substance craving. However, the high heterogeneity and presence of publication bias identified warrants cautious interpretation of the meta-analytic outcomes.

The authors have declared no competing interest.

This work was supported by funding from the National Institute on Alcohol Abuse and Alcoholism (R01-AA030041) and the Department of Defense (HU0001-22-2-0066).

I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained.

Yes

The details of the IRB/oversight body that provided approval or exemption for the research described are given below:

The meta-analysis used only openly available data that were originally presented by trial authors of each trial included in the meta-analysis. One study (Roten et al., 2013) did not include follow-up data in their publication but provided it upon request. DOIs/ClinicalTrial ID of included trials: Schmaal et al., 2011: https://doi.org/10.1159/000327682 Yoon, 2013: NCT00568087 Roten et al., 2013: https://doi.org/10.1016/j.addbeh.2012.11.003 Back et al., 2016: https://doi.org/10.4088/JCP.15m10239 Schulte et al., 2017: https://doi.org/10.1177/0269881117730660 Back, 2021: NCT02911285 McKetin et al., 2021: https://doi.org/10.1016/j.eclinm.2021.101005 Back, 2023: NCT02966873 Morley et al., 2023: https://doi.org/10.1093/alcalc/agad044

I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals.

Yes

I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance).

Yes

I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable.

Yes