Potential Role of N-Acetylcysteine in the Management of Substance Use Disorders

Abstract

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.

An open-label pilot trial ofN-acetylcysteine and varenicline in adult cigarette smokers

“…NAC appears to restore normal glutamate signaling and decrease reinstatement of heroin, cocaine, and nicotine seeking in animal models (16-22). Clinical data also support the efficacy of NAC as a pharmacotherapy to reduce compulsive behavior (23) and reverse addiction pathology (24, 25). Preliminary data with cigarette smokers has demonstrated that NAC reduces smoking and smoking-related reward (17, 26).…”

N-acetylcysteine decreased nicotine reward-like properties and withdrawal in mice

“…Markou's group did not test below 30 mg/kg. While precise cross-species and cross-paradigm comparisons are difficult, taking these data together is promising and potentially clinically relevant given that humans generally tolerate N-acetylcysteine well (Deepmala et al 2015; McClure et al 2014). N-acetylcysteine has also been shown to reduce cocaine- (Baker et al 2003), heroin-(Zhou and Kalivas 2008), and nicotine-seeking (Ramirez-Nino et al 2013) behavior in laboratory models and efficacy in some substance abuse clinical trials (Deepmala et al 2015; McClure et al 2014; Knackstedt et al 2009) including a reduction in the number of cigarettes smoked by daily smokers (Knackstedt et al 2009).…”

Psychostimulants

“…Recently, the potential utility of N-acetylcysteine to reduce cocaine seeking enhanced by coexisting depression was demonstrated (Frankowska et al, 2014). These findings suggest a potential treatment option for long-term application (Asevedo, Mendes, Berk, & Brietzke, 2014;McClure, Gipson, Malcolm, Kalivas, & Gray, 2014), although further studies will be needed to test this hypothesis.…”