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N-Acetylcysteine: a Potential Treatment for Substance Use Disorders This OTC Antioxidant May Benefit Adults Who Use Cocaine and Adolescents Who Use Marijuana

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N-Acetylcysteine: a Potential Treatment for Substance Use Disorders This OTC Antioxidant May Benefit Adults Who Use Cocaine and Adolescents Who Use Marijuana N-acetylcysteine: A potential treatment for substance use disorders This OTC antioxidant may benefit adults who use cocaine and adolescents who use marijuana Rachel L. Tomko, PhD harmacologic treatment options for many substance use disor- Research Assistant Professor Department of Psychiatry and Behavioral Sciences ders (SUDs) are limited. This is especially true for cocaine use Jennifer L. Jones, MD disorder and cannabis use disorder, for which there are no FDA- Resident Physician approved medications. FDA-approved medications for other SUDs often Departments of Psychiatry and Behavioral Sciences take the form of replacement or agonist therapies (eg, nicotine replace- and Internal Medicine ment therapy) that substitute the effects of the substance to aid in ces- Amanda K. Gilmore, PhD sation. Other pharmacotherapies treat symptoms of withdrawal, reduce Research Assistant Professor College of Nursing and Department of Psychiatry craving, or provide aversive counter-conditioning if the patient consumes and Behavioral Sciences the substance while on the medication (eg, disulfiram). Kathleen T. Brady, MD, PhD The over-the-counter (OTC) antioxidant N-acetylcysteine (NAC) may Distinguished University Professor be a potential treatment for SUDs. Although NAC is not approved by the Department of Psychiatry and Behavioral Sciences FDA for treating SUDs, its proposed mechanism of action differs from Sudie E. Back, PhD that of current FDA-approved medications for SUDs. NAC’s potential for Professor Department of Psychiatry and Behavioral Sciences broad applicability, favorable adverse-effect profile, accessibility, and low Kevin M. Gray, MD cost make it an intriguing option for patients with multiple comorbidi- Professor ties, and potentially for individuals with polysubstance use. This article Department of Psychiatry and Behavioral Sciences reviews the current evidence supporting NAC for treating SUDs, to • • • • provide insight about which patients may benefit from NAC and under Medical University of South Carolina which circumstances they are most likely to benefit. Charleston, South Carolina Disclosures NAC may correct glutamate dysregulation The authors report no financial relationships with any company whose products are mentioned in this article Approximately 85% of individuals with an SUD do not seek treatment for or with manufacturers of competing products. This it, and those who do are older, have a longer history of use, have more article was supported by National Institutes of Health 1 grants from the National Institute of Drug Abuse (R25 severe dependence, and have sought treatment numerous times before. By DA020537, R01 DA042114, R01 DA038700, R01 DA026777, the time most people seek treatment, years of chronic substance use have K23 DA042935, K02 DA039229, UG1 DA013727) and the likely led to significant brain-related adaptations. Individuals with SUDs National Institute on Alcohol Abuse and Alcoholism (T32 AA007474, R01 AA025086) and the Department of Defense often indicate that their substance use began as a pleasurable activity—the (W81XWH-13-2-0075 9261sc). effects of the drug were enjoyable and they were motivated to use it again. With repeated substance use, they may begin to develop a stronger urge Current Psychiatry ANDREW JUDD/MASTERFILE Vol. 17, No. 6 31 Table 1 NAC for the treatment of cocaine use disorder Study Sample Dosing Outcomes Amen et N = 6 inpatients, 400 to 800 mg Reduction in self-reported cocaine cravings al15 (2011) treatment- 3 times a day (using visual analog scale) during a cue- seeking adults (1,200 to 2,400 induction, visual stimuli task with cocaine mg/d) vs baclofen No reduction in subjective level of high or rush NAC for substance dependence 20 mg 3 times a during cocaine challenges day (60 mg/d) for use disorders 4 days (single-blind) Mardikian N = 23 treatment- 1,200 mg/d Reduction in self-reported amount of cocaine et al16 seeking adults vs 2,400 mg/d cravings (using visual analog scale), frequency (2007) with cocaine vs 3,600 mg/d of cravings, amount spent on cocaine, and dependence for 4 weeks self-reported use (96% male, (open-label) Increased study retention rates with higher 52% white) doses (88% at 2,400 mg/d, 83% at 3,600 mg/d, and 37.5% at 1,200 mg/d) LaRowe N = 111 non- 1,200 mg/d No reduction in self-reported amount of Clinical Point et al17 abstinent adults vs 2,400 mg/d vs cocaine cravings or cocaine use when NAC is thought to (2013) with cocaine placebo for participants were not previously abstinent dependence 8 weeks (double- Those in the NAC group who were abstinent upregulate GLT-1, (43% white, 55% blind) at the beginning of treatment were more likely African American, to remain abstinent longer and report lower which removes excess 2% Hispanic) craving levels (relative to those abstinent in the glutamate from the placebo group at treatment onset) nucleus accumbens NAC: N-acetylcysteine to use the drug, driven not necessarily by a The adverse-effect profile of NAC is rela- desire for pleasure, but by compulsion.2 tively benign. Nausea, vomiting, diarrhea, Numerous neural adaptations underlie and sleepiness are relatively infrequent and the transition from “liking” a substance to mild.11,12 The bioavailability of NAC is about engaging in the compulsive use that is char- 4% to 9%, with an approximate half-life acteristic of an SUD.2 For example, repeated of 6.25 hours when orally administered.13 use of an addictive substance may result in Because NAC is classified as an OTC supple- excess glutamate in the nucleus accumbens,3,4 ment, the potency and preparation may vary an area of the brain that plays a critical role by supplier. To maximize consistency, NAC in motivation and learning. As a result, it has should be obtained from a supplier that been proposed that pharmacotherapies that meets United States Pharmacopeia (USP) help correct glutamate dysregulation may standards. be effective in promoting abstinence or pre- venting relapse to a substance.5,6 NAC may reverse the neural dysfunc- NAC for SUDs: Emerging evidence tion seen in SUDs. As an OTC antioxidant Several recent reviews have described the that impacts glutamatergic functioning in efficacy of NAC for SUDs and other psy- the brain, NAC has long been used to treat chiatric disorders. Here we summarize the acetaminophen overdose; however, in recent current research examining the efficacy of Discuss this article at years, researchers have begun to tap its NAC for stimulant (ie, cocaine and meth- www.facebook.com/ potential for treating substance use and psy- amphetamine), cannabis, tobacco, and alco- MDedgePsychiatry chiatric disorders. NAC is thought to upreg- hol use disorders. ulate the glutamate transporter (GLT-1) that removes excess glutamate from the nucleus Stimulant use disorders. The United accumbens.6 Several published reviews pro- Nations Office for Drugs and Crime esti- vide more in-depth information about the mates that worldwide, more than 18 million Current Psychiatry 32 June 2018 neurobiology of NAC.6-10 people use cocaine and more than 35 million Table 2 NAC for the treatment of methamphetamine use disorder Study Sample Dosing Outcomes MDedge.com/psychiatry Mousavi N = 32 treatment- 1,200 mg/d vs placebo Reduction in methamphetamine et al18 seeking adults with (crossover design) for cravings during treatment (but not (2015) methamphetamine 4 weeks each after crossover) using the Cocaine dependence (83% male, Craving Questionnaire brief 100% recruited from Iran) (CCQ-brief) Grant N = 31 non-treatment- 2,400 mg/d NAC plus No reduction in craving as et al19 seeking adults with 200 mg/d naltrexone measured by the Penn Craving (2010) methamphetamine vs placebo for Scale or frequency of use (urine dependence (71% male) 8 weeks drug screen) NAC: N-acetylcysteine use amphetamines.14 There are currently no use of NAC, 2,400 mg/d, plus naltrexone, FDA-approved treatments for stimulant use 200 mg/d, vs placebo for 8 weeks.19 It found Clinical Point disorders, and clinicians treating patients no significant differences in craving or use NAC will likely be with cocaine or amphetamine dependence patterns. Further research is needed to opti- often are at a loss for how best to promote mize the use of NAC for stimulant use dis- most helpful for abstinence. Recent studies suggest that NAC orders, and to better understand the role patients who are may decrease drug-seeking behavior and that abstinence plays. abstinent from cravings in adults who seek treatment. The stimulants when results of studies examining NAC for treat- Appropriate populations. The most sup- they start taking NAC ing cocaine use and methamphetamine use port for use of NAC has been as an anti- are summarized in Table 115-17 (page 32) and relapse agent in treatment-seeking adults. Table 2,18,19 respectively. Safety and dosing. Suggested dosages for Cocaine cessation and relapse prevention. the treatment of cocaine use disorder range Several small pilot projects15,16 found that from 1,200 to 3,600 mg/d (typically 600 to compared with placebo, various doses of 1,800 mg twice daily, due to NAC’s short NAC reduced craving (as measured with a half-life), with higher retention rates noted visual analog scale). However, in a double- in individuals who received 2,400 mg/d and blind, placebo-controlled study, NAC did 3,600 mg/d.16 not decrease cravings or use after 8 weeks of treatment in individuals with cocaine Clinical implications. NAC is thought to act use disorder who were still using cocaine as an anti-relapse agent, rather than an agent (ie, they had not yet become abstinent). that can help someone who is actively using Interestingly, those who were abstinent stimulants to stop. Consequently, NAC will when treatment began reported lower likely be most helpful for patients who are craving and remained abstinent longer if motivated to quit and are abstinent when they received NAC (vs placebo), which they start taking NAC; however, this hypoth- suggests that NAC may be useful for pre- esis needs further testing.
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