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Home , Acetylcysteine, Amphetamine dependence, Cocaine dependence, Craving (withdrawal)

N-: A potential treatment for substance use disorders This OTC may benefit adults who use and adolescents who use marijuana

Rachel L. Tomko, PhD harmacologic treatment options for many substance use disor- Research Assistant Professor Department of and Behavioral Sciences ders (SUDs) are limited. This is especially true for cocaine use Jennifer L. Jones, MD disorder and use disorder, for which there are no FDA- Resident Physician approved . FDA-approved medications for other SUDs often Departments of Psychiatry and Behavioral Sciences take the form of replacement or agonist therapies (eg, 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 , or provide aversive counter-conditioning if the patient consumes and Behavioral Sciences the substance while on the (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 Abuse and (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 No reduction in subjective level of high or rush NAC for 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) 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, , , Numerous neural adaptations underlie and sleepiness are relatively infrequent and the transition from “liking” a substance to mild.11,12 The 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 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 (ie, cocaine and meth- www.facebook.com/ potential for treating substance use and psy- ), cannabis, , and alco- MDedgePsychiatry chiatric disorders. NAC is thought to upreg- hol use disorders. ulate the (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 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 (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 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 .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 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 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 . 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. venting relapse.17

Methamphetamine cessation and relapse prevention. One study (N = 32) that eval- There are no FDA-approved treatments for uated the use of NAC, 1,200 mg/d for cannabis use disorder. Individuals who use 4 weeks, vs placebo found reduced crav- marijuana or other forms of cannabis may be ings among methamphetamine users who less likely to report negative consequences were seeking treatment.18 In contrast, a or seek treatment compared with those who study of 31 methamphetamine users who use other substances. Approximately 9% Current Psychiatry were not seeking treatment evaluated the of individuals who use marijuana develop Vol. 17, No. 6 33 Table 3 NAC for the treatment of cannabis use disorder Study Sample Dosing Outcomes Gray N = 24 adolescents/ 1,200 mg twice daily Reduction in self-reported number of et al24 emerging adults (2,400 mg/d) for cannabis use days and number of “hits” (2010) (age 18 to 21) 4 weeks (open-label) per day with cannabis Reduction in self-reported craving dependence (75% NAC for substance Nonsignificant reduction in semi-quantitative male, 92% white) use disorders creatinine-normalized cannabinoid levels Gray N = 116 1,200 mg twice Double the odds of abstinence in NAC group et al25 adolescents daily (2,400 mg/d) relative to placebo (as confirmed via urine (2012); (age 15 to 21) vs placebo for 8 cannabinoid test) at end of treatment Roten with cannabis weeks (double-blind) No group differences in self-reported number 26 et al dependence (72% added to contingency of cannabis use days or craving (2013) male, 84% white) management Gray N = 302 adults 1,200 mg twice No group differences in odds of abstinence 27 et al with cannabis use daily (2,400 mg/d) No group differences in self-reported number Clinical Point (2017) disorder (77% vs placebo for 12 of cannabis use days male, 55% white, weeks (double-blind) Numerical, nonsignificant trend for double 29% black/African added to contingency Some evidence odds of abstinence among younger age American) management suggests NAC group receiving NAC vs placebo (age 18 to 21) may be useful for NAC: N-acetylcysteine reducing marijuana use among adolescents cannabis use disorder20; those who begin Appropriate populations. Evidence is using marijuana earlier in adolescence are stronger for use of NAC among adoles- at increased risk.21 Commonly reported cents (age 15 to 21) than for individuals reasons for wanting to stop using mari- older than age 21.25,27 Further research is juana include being concerned about health needed to explore potential reasons for consequences, regaining or demonstrat- age-specific effects. ing self-control, saving money, avoiding legal consequences, obtaining or keeping Safety and dosing. A safe and potentially employment, and reducing interpersonal efficacious dosage for the treatment of can- conflict.22,23 Table 324-27 summarizes initial nabis use disorder is 2,400 mg/d (1,200 mg evidence that suggests NAC may be par- twice daily).24,25,27 ticularly useful in reducing marijuana use among adolescents (age 15 to 21).24,25 Clinical implications. Combined with con- tingency management, NAC might be effi- Cessation. An open-label, pilot cacious for adolescents with cannabis use found significant reductions in self-reported disorder, with treatment gains evident by the marijuana use and craving—but not in bio- fourth week of treatment.24,25 To date, no clini- markers of use—among 24 adolescents after cal trials have examined the efficacy of NAC 4 weeks of NAC, 1,200 mg twice daily.24 In for treating cannabis use disorder without an 8-week, double-blind, randomized con- adjunctive , and trolled trial of 116 adolescents, NAC, 1,200 research is needed to isolate the clinical effect mg twice daily, plus contingency manage- of NAC among adolescents. ment doubled the odds of abstinence, but had no effect on self-reported craving or use.25,26 In a sample of 302 adults, a 12-week Tobacco use disorder trial of NAC, 1,200 mg twice daily, plus con- Cigarette smoking remains a leading cause tingency management was no more effective of preventable death in the United States,28 than contingency management alone in pro- and nearly 70% of people who start using Current Psychiatry 34 June 2018 moting abstinence.27 tobacco become dependent.20 Existing Table 4 NAC for the treatment of tobacco use disorder

Study Sample Dosing Outcomes MDedge.com/psychiatry McClure N = 116 1,200 mg twice daily No group differences in reported et al30 adolescents (2,400 mg/d) cigarettes smoked (2014) (age 15 to 21) vs placebo for with cannabis 8 weeks (double- dependence blind) added (72% male, to contingency 84% white; management 59% smokers) Froeliger N = 16 adult 1,200 mg twice daily NAC group more likely to maintain et al31 smokers (2,400 mg/d) vs abstinence during 3.5-day monetarily (2015) (69% male; placebo for 3.5 days incentivized abstinence period, as 56% black/African (double-blind) evidenced by lower carbon monoxide American, levels 44% white) NAC group reported decreased craving and higher positive affect relative to placebo group Clinical Point Prado N = 34 outpatients 1,500 mg twice daily NAC group reported fewer cigarettes et al32 with therapy- (3,000 mg/d) vs smoked and had lower carbon monoxide Although initial (2015) resistant tobacco placebo for 12 weeks levels at end of treatment, compared with use disorder (double-blind) placebo group evidence is (26.5% male) promising, it is Knackstedt N = 33 adults 1,200 mg twice daily When excluding 2 heavy drinkers from et al33 with nicotine (2,400 mg/d) vs analysis, the NAC group reported fewer premature to (2009) dependence placebo for 4 weeks cigarettes smoked per day than the suggest NAC for (58% male; (double-blind) control group 70% white, No group differences in carbon monoxide 21% black/African levels American) No group differences in self-reported craving or withdrawal Grant et al34 N = 28 adults 1,200 to 3,000 mg/d NAC group reported fewer symptoms (2014) with nicotine (titrated based on of in first half of dependence clinician’s judgment) treatment and pathological vs placebo for gambling (82% 12 weeks male; 82% white) (double-blind) Schmaal N = 22 1,800 mg twice daily No group differences in self-reported et al35 undergraduate for 3 days (3,600 craving (2011) smokers mg/d) and once on A trend for the NAC group to report (41% male) Day 4 (1,800 mg) vs reduced withdrawal symptoms placebo (double-blind) Post-treatment cigarette smoked in the laboratory was rated as less rewarding by the NAC group, compared with the placebo group Bernardo N = 75 adults with 1,000 mg twice daily No group differences in self-reported et al36 (2,000 mg/d) vs frequency of tobacco use (2009) (30% male; placebo for 6 months 45% smokers) (double-blind) NAC: N-acetylcysteine

FDA-approved treatments include nico- While these medications promote absti- tine replacement products, varenicline, and nence, NAC may be particularly beneficial . Even though efficacious treat- in preventing relapse after abstinence has ments exist, successful and sustained quit been achieved (Table 430-36). attempts are infrequent.29 NAC may exert a complementary effect to existing tobacco Several Cessation and relapse prevention. Current Psychiatry cessation interventions, such as varenicline.30 pilot studies found that adult smokers who Vol. 17, No. 6 35 Table 5 NAC for the treatment of alcohol use disorder Study Sample Dosing Outcomes Bernardo N = 75 adults 1,000 mg twice No group differences in alcohol use, tobacco use, et al36 with bipolar daily (2,000 mg/d) or use (except as described below) (2009) disorder vs placebo for NAC reduced caffeine use compared with (30% male; 24 weeks placebo at Week 2 of treatment NAC for substance 78.7% drank (double-blind) use disorders alcohol) Back N = 35 veterans 1,200 mg twice NAC combined with CBT reduced PTSD et al39 with SUD daily (2,400 mg/d) symptoms and craving compared with placebo (2016) (82% with AUD) vs placebo for NAC combined with CBT reduced and PTSD 8 weeks symptoms compared with placebo (double-blind) No group differences in substance use Squeglia N =116 1,200 mg twice Adolescents in NAC group with reductions in et al40 adolescents daily (2,400 mg/d) cannabis use also had reductions in number of (2016) (age 15 to 21) vs placebo for drinks per week Clinical Point with cannabis 8 weeks (86.5% No differences in alcohol use among adolescents dependence used alcohol in in the placebo group More research is (72% male; past 30 days) 84% white) needed to determine AUD: alcohol use disorder; CBT: cognitive-behavioral therapy; NAC: N-acetylcysteine; PTSD: posttraumatic stress disorder; if NAC is effective SUD: for treating patients with alcohol use received NAC (alone or in combination with 1,200 to 3,600 mg/d (600 to 1,800 mg twice disorders another treatment) had lower carbon mon- daily). oxide levels,31,32 smoked fewer cigarettes,32,33 and had fewer self-reported symptoms of Clinical implications. Data on NAC’s effi- nicotine dependence34 and/or less craving cacy for tobacco use disorder come from for cigarettes.31 However, one study of 33 small, pilot trials. Although initial evidence smokers did not find a reduction in craving is promising, it is premature to suggest or carbon monoxide for NAC compared NAC for smoking cessation until a fully with placebo.33 Another pilot study of 22 powered, randomized clinical trial pro- young adult smokers found that those who vides evidence of efficacy. received NAC rated their first cigarette after treatment (smoked in the laboratory) as less rewarding, relative to smokers who Alcohol use disorder received a placebo.35 Alcohol use disorders are widely prevalent; Secondary analyses of adults with bipo- 13.9% of U.S. adults met criteria in the past lar disorder36 and adolescents with can- year, and 29.1% of U.S. adults meet criteria nabis use disorder37 found no decreases in their lifetime.38 Alcohol use disorders can in tobacco use among those who received result in significant negative consequences, NAC compared with placebo. However, including relationship problems, violent the studies in these analyses did not specifi- behavior, medical problems, and death. cally recruit tobacco users, and participants Existing FDA-approved medications for who were tobacco users were not necessar- alcohol use disorder include naltrexone, ily interested in quitting. This may partially acamprosate, and disulfiram. explain discrepant findings. Due to the severe potential health con- sequences of alcohol, NAC has been exam- Appropriate populations. NAC has been ined as a possible aid in preventing relapse. studied mostly in adult cigarette smokers. However, most studies have been conducted using animals. Three studies have examined Suggested dosages for alcohol use in humans (Table 536,39,40). One Current Psychiatry Safety and dosing. 36 June 2018 treating tobacco use disorder range from was a pilot study,39 and the other 2 were continued on page 41 continued from page 36 secondary data analyses.36,40 None of them specifically focused on alcohol use disor- Related Resources ders. A pilot study of 35 veterans with co- • Deepmala, Slattery J, Kumar N, et al. Clinical trials of N-acetylcysteine in psychiatry and neurology: a systematic MDedge.com/psychiatry occurring posttraumautic stress disorder review. Neurosci Biobehav Rev. 2015;55:294-321. (PTSD) and SUDs (82% of whom had an • Roberts-Wolfe D, Kalivas P. Glutamate transporter GLT-1 as a alcohol use disorder) found that compared therapeutic target for substance use disorders. CNS Neurol Disord Drug Targets. 2015;14(6):745-756. with placebo, NAC significantly decreased • National Institute on Drug Abuse. Treatment approaches for 39 PTSD symptoms, craving, and depression. drug . https://www.drugabuse.gov/publications/ In a study of 75 adults with bipolar disorder, drugfacts/treatment-approaches-drug-addiction. secondary alcohol use was not significantly Drug Brand Names reduced.36 However, one study suggested Acamprosate • Campral Disulfiram • Antabuse Acetaminophen • Tylenol Naltrexone • Revia,Vivitrol that NAC may decrease adolescent alco- Baclofen • Lioresal Varenicline • Chantix hol and marijuana co-use.40 Future work is Bupropion • Zyban needed to examine the potential clinical util- ity of NAC in individuals with alcohol use disorders. Findings from animal studies indicate disorder. It is premature to recommend Clinical Point that NAC may: NAC for treatment of alcohol use disorders. NAC has anti- • reduce alcohol-seeking41 • reduce withdrawal symptoms42 inflammatory • reduce the teratogenic effects of Other psychiatric uses properties and may alcohol43 Although we have highlighted NAC’s reverse oxidative • prevent alcohol toxicity44 effect on glutamatergic transmission, evi- stress • reduce health-related consequences of dence suggests that NAC may have multi- alcohol (eg, myocardial oxidative stress45 ple mechanisms of action that could impact and alcohol-related steatohepatitis46). psychiatric functioning. For example, NAC may also reverse , which is Appropriate populations. Pilot studies frequently observed in psychiatric disor- have suggested that appropriate popula- ders such as and bipolar dis- tions may include veterans with SUD and order.10,12 NAC also has anti-inflammatory PTSD39 and adolescents with marijuana properties. When inflammatory pathways dependence who use alcohol.40 of the CNS are dysregulated, production of may be impaired, Safety and dosing. Suggested dosages for resulting in depression-like symptoms.10,12,47 the treatment of alcohol use disorder based Preliminary evidence suggests that NAC on these studies range from 1,000 to 2,400 may be effective in treating mood-related mg/d (500 to 1,200 mg twice daily). symptoms (eg, irritability, depression) in individuals with psychiatric disorders (eg, Clinical implications. Future work is bipolar and depressive disorders, PTSD, needed to determine if NAC is effective and SUDs) and general symptoms of for treating alcohol use disorders. Ongoing schizophrenia, obsessive-compulsive disor- randomized clinical trials are examining der, and , although mixed the efficacy of NAC in reducing alcohol findings in controlled studies suggest a use among individuals with alcohol use need for further research.12,39 continued Bottom Line N-acetylcysteine is likely to have modest effects for some patients who have a substance use disorder, particularly adults who use cocaine and adolescents who use marijuana. It may be useful in preventing relapse to substance use after an Current Psychiatry individual has achieved abstinence. Vol. 17, No. 6 41 NAC: A promising candidate 15. Amen SL, Piacentine LB, Ahmad ME, et al. Repeated N-acetyl reduces cocaine seeking in rodents and craving in Initial evidence suggests NAC may be help- cocaine-dependent humans. Neuropsychopharmacology. ful for treating patients with SUDs. A patient 2011;36(4):871-878. 16. Mardikian PN, LaRowe SD, Hedden S, et al. An open- seeking SUD treatment who is treated with label trial of N-acetylcysteine for the treatment of cocaine dependence: a pilot study. Prog Neuropsychopharmacol NAC may experience a decreased drive, Biol Psychiatry. 2007;31(2):389-394. craving, or compulsion to use. Notably, 17. LaRowe SD, Kalivas PW, Nicholas JS, et al. A double‐ blind placebo‐controlled trial of N‐acetylcysteine in the NAC may be particularly useful in prevent- treatment of cocaine dependence. Am J Addict. 2013; NAC for substance ing relapse after an individual has achieved 22(5):443-452. 18. Mousavi SG, Sharbafchi MR, Salehi M, et al. The efficacy use disorders abstinence. Evidence suggests that NAC of N-acetylcysteine in the treatment of methamphetamine may be useful in the treatment of adults with dependence: a double-blind controlled, crossover study. Arch Iran Med. 2015;18(1):28-33. cocaine use disorders who have achieved 19. Grant JE, Odlaug BL, Kim SW. 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