Potential role of N-acetylcysteine in the management of substance use disorders

Erin A. McClure, Cassandra D. Gipson, Robert J. Malcolm, Peter W. Kalivas, Kevin M. Gray

Research output: Contribution to journalArticlepeer-review

113 Scopus citations


There is a clear and pressing need to expand pharmacotherapy options for substance use disorders (SUDs) in order to improve sustained abstinence outcomes. Preclinical literature has demonstrated the role of glutamate in addiction, suggesting that new targets for pharmacotherapy should focus on the restoration of glutamatergic function. Glutamatergic agents for SUDs may span multiple addictive behaviors and help demonstrate potentially overlapping mechanisms in addiction. The current review will focus specifically on N-acetylcysteine (NAC), a safe and well-tolerated glutamatergic agent, as a promising potential pharmacotherapy for the treatment of SUDs across several substances of abuse. Building on recently published reviews of the clinical efficacy of NAC across a broad range of conditions, this review will more specifically discuss NAC as a pharmacotherapy for SUDs, devoting particular attention to the safety and tolerability profile of NAC, the wealth of preclinical evidence that has demonstrated the role of glutamate dysregulation in addiction, and the limited but growing clinical literature that has assessed the efficacy of NAC across multiple substances of abuse. Preliminary clinical studies show the promise of NAC in terms of safety, tolerability, and potential efficacy for promoting abstinence from cocaine, nicotine, and cannabis. Results from randomized clinical trials have been mixed, but several mechanistic and methodological factors are discussed to refine the use of NAC in promoting abstinence and relapse prevention across several substances of abuse. Further preclinical and clinical investigation into the use of NAC for SUDs will be vital in addressing current deficits in the treatment of SUDs.

Original languageEnglish
Pages (from-to)95-106
Number of pages12
JournalCNS Drugs
Issue number2
StatePublished - Feb 2014

Bibliographical note

Funding Information:
Many questions remain regarding the use of NAC for SUDs, both in preclinical and clinical investigation. Preclinically, it will be of interest to examine the ability of NAC to restore basal synaptic plasticity of glutamatergic NAcore synapses via a possible neuron-glial interaction, as well as the ability to inhibit the rapid, transient increase in synaptic plasticity found during cue-induced cocaine seeking. Additionally, it will be important to examine the mechanism contributing to the ability of NAC to restore GLT1, inhibit glutamate overflow, and inhibit activation of extrasynaptic NMDA receptors across different drugs of abuse. Among clinical investigators, more studies are needed to determine the conditions under which NAC is an efficacious pharmacotherapy for SUDs. NAC may be most effective when administered under conditions of abstinence, rather than during active use. NAC as a relapse prevention pharmacotherapy in abstinent cocaine-dependent adults is being explored in a recently funded study sponsored by the National Institute on Drug Abuse (R01DA034054, PI Malcolm). Conversely, studies with cannabis-dependent adolescents have demonstrated the efficacy of NAC during periods of active use [95]. This distinction could be based on differences in the substances of abuse being targeted by the study interventions, the behavioral support used in these clinical trials (e.g. abstinence-targeted contingency management in the cannabis trial), actual medication adherence rates, etc. RCTs assessing the efficacy of NAC that have yielded negative findings highlight the importance of careful consideration of conditions that may contribute to the efficacy of NAC. These and other possibilities are worthy of further inquiry.

Funding Information:
Acknowledgments The authors wish to acknowledge the funding sources for this study. Funding was provided by the National Institute on Drug Abuse grants DA031779 (Kevin M. Gray, Erin A. McClure), DA013727 (Kevin M. Gray, Erin A. McClure), DA033690 (Cassandra D. Gipson), and DA003906, DA012513, and DA015369 (Peter W. Kalivas). The funding source had no role other than financial support.

ASJC Scopus subject areas

  • Clinical Neurology
  • Psychiatry and Mental health
  • Pharmacology (medical)


Dive into the research topics of 'Potential role of N-acetylcysteine in the management of substance use disorders'. Together they form a unique fingerprint.

Cite this