Evidence-Based Reviews

N-acetylcysteine: A potential treatment for substance use disorders

Current Psychiatry. 2018 June;17(6):30-36,41-42,55

References

1. Grella CE, Karno MP, Warda US, et al. Perceptions of need and help received for substance dependence in a national probability survey. Psychiatr Serv. 2009;60(8):1068-1074.
2. Everitt BJ, Robbins TW. Drug addiction: updating actions to habits to compulsions ten years on. Annu Rev Psychol. 2016;67:23-50.
3. McFarland K, Lapish CC, Kalivas PW. Prefrontal glutamate release into the core of the nucleus accumbens mediates cocaine-induced reinstatement of drug-seeking behavior. J Neurosci. 2003;23(8):3531-3537.
4. LaLumiere RT, Kalivas PW. Glutamate release in the nucleus accumbens core is necessary for heroin seeking. J Neurosci. 2008;28(12):3170-3177.
5. Kalivas PW, Volkow ND. New medications for drug addiction hiding in glutamatergic neuroplasticity. Mol Psychiatry. 2011;16(10):974-986.
6. Roberts-Wolfe D, Kalivas PW. Glutamate transporter GLT-1 as a therapeutic target for substance use disorders. CNS Neurol Disord Drug Targets. 2015;14(6):745-756.
7. Berk M, Malhi GS, Gray LJ, et al. The promise of N-acetylcysteine in neuropsychiatry. Trends Pharmacol Sci. 2013;34(3):167-177.
8. McClure EA, Gipson CD, Malcolm RJ, et al. Potential role of N-acetylcysteine in the management of substance use disorders. CNS drugs. 2014;28(2):95-106.
9. Deepmala, Slattery J, Kumar N, et al. Clinical trials of N-acetylcysteine in psychiatry and neurology: a systematic review. Neurosci Biobehav Rev. 2015;55:294-321.
10. Minarini A, Ferrari S, Galletti M, et al. N-acetylcysteine in the treatment of psychiatric disorders: current status and future prospects. Expert Opin Drug Metab Toxicol. 2017;13(3):279-292.
11. Grandjean EM, Berthet P, Ruffman R, et al. Efficacy of oral long-term N‑acetylcysteine in chronic bronchopulmonary disease: a meta-analysis of published double-blind, placebo-controlled clinical trials. Clin Ther. 2000;22(2):209‑221.
12. Rhodes K, Braakhuis A. Performance and side effects of supplementation with N-acetylcysteine: a systematic review and meta-analysis. Sports Med. 2017;47(8):1619-1636.
13. Olsson B, Johansson M, Gabrielsson J, et al. Pharmacokinetics and bioavailability of reduced and oxidized N-acetylcysteine. Eur J Clin Pharmacol. 1988;34(1):77-82.
14. United Nations Office on Drugs and Crime. World Drug Report 2016 (United Nations publication, Sales No. E.16.XI.7). https://www.unodc.org/doc/wdr2016/WORLD_DRUG_REPORT_2016_web.pdf. Published May 2016. Accessed April 26, 2018.
15. Amen SL, Piacentine LB, Ahmad ME, et al. Repeated N-acetyl cysteine reduces cocaine seeking in rodents and craving in cocaine-dependent humans. Neuropsychopharmacology. 2011;36(4):871-878.
16. Mardikian PN, LaRowe SD, Hedden S, et al. An open-label trial of N-acetylcysteine for the treatment of cocaine dependence: a pilot study. Prog Neuropsychopharmacol Biol Psychiatry. 2007;31(2):389-394.
17. LaRowe SD, Kalivas PW, Nicholas JS, et al. A double‐blind placebo‐controlled trial of N‐acetylcysteine in the treatment of cocaine dependence. Am J Addict. 2013;22(5):443-452.
18. Mousavi SG, Sharbafchi MR, Salehi M, et al. The efficacy of N-acetylcysteine in the treatment of methamphetamine dependence: a double-blind controlled, crossover study. Arch Iran Med. 2015;18(1):28-33.
19. Grant JE, Odlaug BL, Kim SW. A double-blind, placebo-controlled study of N-acetyl cysteine plus naltrexone for methamphetamine dependence. Eur Neuropsychopharmacol. 2010;20(11):823-828.
20. Lopez-Quintero C, Pérez de los Cobos J, Hasin DS, et al. Probability and predictors of transition from first use to dependence on nicotine, alcohol, cannabis, and cocaine: results of the National Epidemiologic Survey on Alcohol and Related Conditions (NESARC). Drug Alcohol Depend. 2011;115(1-2):120-130.
21. Chen CY, O’Brien MS, Anthony JC. Who becomes cannabis dependent soon after onset of use? Epidemiological evidence from the United States: 2000-2001. Drug Alcohol Depend. 2005;79(1):11-22.
22. Copersino ML, Boyd SJ, Tashkin DP, et al. Quitting among non-treatment-seeking marijuana users: reasons and changes in other substance use. Am J Addict. 2006;15(4):297-302.
23. Weiner MD, Sussman S, McCuller WJ, et al. Factors in marijuana cessation among high-risk youth. J Drug Educ. 1999;29(4):337-357.
24. Gray KM, Watson NL, Carpenter MJ, et al. N-acetylcysteine (NAC) in young marijuana users: an open-label pilot study. Am J Addict. 2010;19(2):187-189.
25. Gray KM, Carpenter MJ, Baker NL, et al. A double-blind randomized controlled trial of N-acetylcysteine in cannabis-dependent adolescents. Am J Psychiatry. 2012;169(8):805-812.
26. Roten AT, Baker NL, Gray KM. Marijuana craving trajectories in an adolescent marijuana cessation pharmacotherapy trial. Addict Behav. 2013;38(3):1788-1791.
27. Gray KM, Sonne SC, McClure EA, et al. A randomized placebo-controlled trial of N-acetylcysteine for cannabis use disorder in adults. Drug Alcohol Depend. 2017;177:249-257.
28. Rostron B. Mortality risks associated with environmental tobacco smoke exposure in the United States. Nicotine Tob Res. 2013;15(10):1722-1728.
29. Centers for Disease Control and Prevention. Quitting smoking among adults – United States, 2001–2010. MMWR. 2011;60(44):1513-1519.
30. McClure EA, Baker NL, Gipson CD, et al. An open-label pilot trial of N-acetylcysteine and varenicline in adult cigarette smokers. Am J Drug Alcohol Abuse. 2015;41(1):52-56.
31. Froeliger B, McConnell P, Stankeviciute N, et al. The effects of N-acetylcysteine on frontostriatal resting-state functional connectivity, withdrawal symptoms and smoking abstinence: a double-blind, placebo-controlled fMRI pilot study. Drug Alcohol Depend. 2015;156:234-242.
32. Prado E, Maes M, Piccoli LG, et al. N-acetylcysteine for therapy-resistant tobacco use disorder: a pilot study. Redox Rep. 2015;20(5):215-222.
33. Knackstedt LA, LaRowe S, Mardikian P, et al. The role of cystine-glutamate exchange in nicotine dependence in rats and humans. Biol Psychiatry. 2009;65(10):841-845.
34. Grant JE, Odlaug BL, Chamberlain SR, et al. A randomized, placebo-controlled trial of N-acetylcysteine plus imaginal desensitization for nicotine-dependent pathological gamblers. J Clin Psychiatry. 2014;75(1):39-45.
35. Schmaal L, Berk L, Hulstijn KP, et al. Efficacy of N-acetylcysteine in the treatment of nicotine dependence: a double-blind placebo-controlled pilot study. Eur Addiction Res. 2011;17(4):211-216.
36. Bernardo M, Dodd S, Gama CS, et al. Effects of N‐acetylcysteine on substance use in bipolar disorder: a randomised placebo‐controlled clinical trial. Acta Neuropsychiatr. 2009;21(5):239-245.
37. McClure EA, Baker NL, Gray KM. Cigarette smoking during an N-acetylcysteine-assisted cannabis cessation trial in adolescents. Am J Drug Alcohol Abuse. 2014;40(4):285-291.
38. Grant BF, Goldstein RB, Saha TD, et al. Epidemiology of DSM-5 alcohol use disorder: Results from the National Epidemiologic Survey on Alcohol and Related Conditions III. JAMA Psychiatry. 2015;72(8):757-766.
39. Back SE, McCauley JL, Korte KJ, et al. A double-blind randomized controlled pilot trial of N-acetylcysteine in veterans with PTSD and substance use disorders. J Clin Psychiatry. 2016;77(11):e1439-e1446.
40. Squeglia LM, Baker NL, McClure EA, et al. Alcohol use during a trial of N-acetylcysteine for adolescent marijuana cessation. Addict Behav. 2016;63:172-177.
41. Lebourgeois S, González-Marín MC, Jeanblanc J, et al. Effect of N-acetylcysteine on motivation, seeking and relapse to ethanol self-administration. Addict Biol. 2018;23(2):643-652.
42. Schneider R Jr, Santos CF, Clarimundo V, et al. N-acetylcysteine prevents behavioral and biochemical changes induced by alcohol cessation in rats. Alcohol. 2015;49(3):259-263.
43. Parnell SE, Sulik KK, Dehart DB, et al. Reduction of ethanol-induced ocular abnormalities in mice via dietary administration of N-acetylcysteine. Alcohol. 2010;44(7-8):699-705.
44. Ozkol H, Bulut G, Balahoroglu R, et al. Protective effects of Selenium, N-acetylcysteine and Vitamin E against acute ethanol intoxication in rats. Biol Trace Elem Res. 2017;175(1):177-185.
45. Seiva FR, Amauchi JF, Rocha KK, et al. Alcoholism and alcohol abstinence: N-acetylcysteine to improve energy expenditure, myocardial oxidative stress, and energy metabolism in alcoholic heart disease. Alcohol. 2009;43(8):649-656.
46. Setshedi M, Longato L, Petersen DR, et al. Limited therapeutic effect of N‐acetylcysteine on hepatic insulin resistance in an experimental model of alcohol‐induced steatohepatitis. Alcohol Clin Exp Res. 2011;35(12):2139-2151.
47. Miller AH, Maletic V, Raison CL. Inflammation and its discontents: the role of cytokines in the pathophysiology of major depression. Biol Psychiatry. 2009;65(9):732-741.

Clinical implications. Data on NAC’s efficacy for tobacco use disorder come from small, pilot trials. Although initial evidence is promising, it is premature to suggest NAC for smoking cessation until a fully powered, randomized clinical trial provides evidence of efficacy.

Alcohol use disorder

Alcohol use disorders are widely prevalent; 13.9% of U.S. adults met criteria in the past year, and 29.1% of U.S. adults meet criteria in their lifetime.³⁸ Alcohol use disorders can result in significant negative consequences, including relationship problems, violent behavior, medical problems, and death. Existing FDA-approved medications for alcohol use disorder include naltrexone, acamprosate, and disulfiram.

Due to the severe potential health consequences of alcohol, NAC has been examined as a possible aid in preventing relapse. However, most studies have been conducted using animals. Three studies have examined alcohol use in humans (Table 5^36,39,40). One was a pilot study,³⁹ and the other 2 were secondary data analyses.^36,40 None of them specifically focused on alcohol use disorders. A pilot study of 35 veterans with co-occurring posttraumautic stress disorder (PTSD) and SUDs (82% of whom had an alcohol use disorder) found that compared with placebo, NAC significantly decreased PTSD symptoms, craving, and depression.³⁹ In a study of 75 adults with bipolar disorder, secondary alcohol use was not significantly reduced.³⁶ However, one study suggested that NAC may decrease adolescent alcohol and marijuana co-use.⁴⁰ Future work is needed to examine the potential clinical utility of NAC in individuals with alcohol use disorders.

Findings from animal studies indicate that NAC may:

reduce alcohol-seeking⁴¹
reduce withdrawal symptoms⁴²
reduce the teratogenic effects of alcohol⁴³
prevent alcohol toxicity⁴⁴
reduce health-related consequences of alcohol (eg, myocardial oxidative stress⁴⁵ and alcohol-related steatohepatitis⁴⁶).

Continue to: Appropriate populations

N-acetylcysteine: A potential treatment for substance use disorders

References

Alcohol use disorder

Pages

Recommended Reading