N-acetylcysteine in the treatment of substanceuse disorders

N-acetylcysteine (NAC) is an agent best known for its clinical efficacy in bronchopulmonary disorders due to its mucolytic properties, and in the treatment of acetaminophen overdose. Given the strong clinical evidence from animal studies of its critical role in regulating glutamatergic receptors, NAC has also been the subject of research related to several psychiatric disorders as a promising treatment approach. This editorial is a brief discussion of the characteristics of NAC and its place in substance use disorders and other psychiatric disorders.

___

1. Melendez RI, Vuthiganon J, Kalivas PW. Regulation of extracellular glutamate in the prefrontal cortex: focus on the cystine glutamate exchanger and group I metabotropic glutamate receptors. J Pharmacol Exp Ther 2005; 314:139-147.

2. LaRowe SD, Mardikian P, Malcolm R, Myrick H, Kalivas P, McFarland K, et al. Safety and tolerability of N-acetylcysteine in cocaine-dependent individuals. Am J Addict 2006; 15:105-110.

3. McClure EA, Gipson CD, Malcolm RJ, Kalivas PW, Gray KM. Potential role of N-acetylcysteine in the management of substance use disorders. CNS Drugs 2014; 28:95-106.

4. Baker DA, Xi ZX, Shen H, Swanson CJ, Kalivas PW. The origin and neuronal function of in vivo nonsynaptic glutamate. J Neurosci 2002; 22:9134-9141.

5. McBean GJ. Cerebral cystine uptake: a tale of two transporters. Trends Pharmacol Sci 2002; 23:299-302.

6. Olive MF, Cleva RM, Kalivas PW, Malcolm RJ. Glutamatergic medications for the treatment of drug and behavioral addictions. Pharmacol Biochem Behav 2012; 100:801-810.

7. Dean OM, van den Buuse M, Bush AI, Copolov DL, Ng F, Dodd S, et al. A role for glutathione in the pathophysiology of bipolar disorder and schizophrenia? Animal models and relevance to clinical practice. Curr Med Chem 2009; 16:2965-2976.

8. Berk M, Dean O, Cotton SM, Gama CS, Kapczinski F, Fernandes BS, et al. The efficacy of N-acetylcysteine as an adjunctive treatment in bipolar depression: an open label trial. J Affect Disord 2011; 135:389-394.

9. Cuzzocrea S, Mazzon E, Costantino G, Serraino I, Dugo L, Calabro G, et al. Beneficial effects of N-acetylcysteine on ischaemic brain injury. Br J Pharmacol 2000; 130:1219-1226.

10. Aldini G, Altomare A, Baron G, Vistoli G, Carini M, Borsani L, et al. N-acetylcysteine as an antioxidant and disulphide breaking agent: the reasons why. Free Radic Res 2018; 52:751-762.

11. Dean O, Giorlando F, Berk M. N-acetylcysteine in psychiatry: current therapeutic evidence and potential mechanisms of action. J Psychiatry Neurosci 2011; 36:78-86.

12. Tomko RL, Jones JL, Gilmore AK, Brady KT, Back SE, Gray KM. N-acetylcysteine: a potential treatment for substance use disorders. Curr Psychiatr 2018; 17:30-36, 41-42, 55.

13. Grant JE, Kim SW, Odlaug BL. N-acetyl cysteine, a glutamate-modulating agent, in the treatment of pathological gambling: a pilot study. Biol Psychiatry 2007; 62:652-657.

14. Paydary K, Akamaloo A, Ahmadipour A, Pishgar F, Emamzadehfard S, Akhondzadeh S. N-acetylcysteine augmentation therapy for moderate-to-severe obsessive-compulsive disorder: randomized, double-blind, placebo-controlled trial. J Clin Pharm Ther 2016; 41:214-219.

15. Grant JE, Odlaug BL, Kim SW. N-acetylcysteine, a glutamate modulator, in the treatment of trichotillomania: a double-blind, placebo-controlled study. Arch Gen Psychiatry 2009; 66:756-763.

16. Kilic F, Keles S. Repetitive behaviors treated with N-acetylcysteine: case series. Clin Neuropharmacol 2019; 42:139-141.

17. Grant JE, Chamberlain SR, Redden SA, Leppink EW, Odlaug BL, Kim SW. N-acetylcysteine in the treatment of excoriation disorder: a randomized clinical trial. JAMA Psychiatry 2016; 73:490-496.

18. Berk M, Dean OM, Cotton SM, Jeavons S, Tanious M, Kohlmann K, et al. The efficacy of adjunctive N-acetylcysteine in major depressive disorder: a double-blind, randomized, placebo-controlled trial. J Clin Psychiatry 2014; 75:628-636.

19. Berk M, Copolov D, Dean O, Lu K, Jeavons S, Schapkaitz I, et al. N-acetylcysteine as a glutathione precursor for schizophrenia-a double-blind, randomized, placebo-controlled trial. Biol Psychiatry 2008; 64:361-368.

20. Hardan AY, Fung LK, Libove RA, Obukhanych TV, Nair S, Herzenberg LA, et al. A randomized controlled pilot trial of oral N-acetylcysteine in children with autism. Biol Psychiatry 2012; 71:956-961.

21. Berk M, Malhi GS, Gray LJ, Dean OM. The promise of N-acetylcysteine in neuropsychiatry. Trends Pharmacol Sci 2013; 34:167-177.

22. Mardikian PN, LaRowe SD, Hedden S, Kalivas PW, Malcolm RJ. An open-label trial of N-acetylcysteine for the treatment of cocaine dependence: a pilot study. Prog Neuropsychopharmacol Biol Psychiatry 2007; 31:389-394.

23. Miller LF, Rumack BH. Clinical safety of high oral doses of acetylcysteine. Semin Oncol 1983; 10(1 Suppl.1):76-85.

24. Powell G, McClure EA, Olive MF, Gipson CD. Clinical treatment of addictive disorders with N-acetylcysteine; In Frye RE, Berk M (editors). The Therapeutic Use of N-Acetylcysteine (NAC) in Medicine. Singapore: Springer Nature, 2019, 219-233.

25. Schmaal L, Veltman DJ, Nederveen A, van den Brink W, Goudriaan AE. N-acetylcysteine normalizes glutamate levels in cocaine-dependent patients: a randomized crossover magnetic resonance spectroscopy study. Neuropsychopharmacology 2012; 37:2143-2152.

26. Ooi SL, Green R, Pak SC. N-Acetylcysteine for the treatment of psychiatric disorders: a review of current evidence. Biomed Res Int 2018; 2018:2469486.

27. Baker DA, Khroyan TV, O’Dell LE, Fuchs RA, Neisewander JL. Differential effects of intra-accumbens sulpiride on cocaine-induced locomotion and conditioned place preference. J Pharmacol Exp Ther 1996; 279:392-401.

28. Baker DA, McFarland K, Lake RW, Shen H, Toda S, Kalivas PW. N-acetylcysteine-induced blockade of cocaine-induced reinstatement. Ann N Y Acad Sci 2003; 1003:349-351.

29. Zhou W, Kalivas PW. N-acetylcysteine reduces extinction responding and induces enduring reductions in cue- and heroin-induced drug-seeking. Biol Psychiatry 2008; 63:338-340.

30. Bird MK, Lawrence AJ. Group I metabotropic glutamate receptors: involvement in drug-seeking and drug-induced plasticity. Curr Mol Pharmacol 2009; 2:83-94.

31. Bowers MS, Chen BT, Bonci A. AMPA receptor synaptic plasticity induced by psychostimulants: the past, present, and therapeutic future. Neuron 2010; 67:11-24.

32. Gass JT, Olive MF. Glutamatergic substrates of drug addiction and alcoholism. Biochem Pharmacol 2008; 75:218-265.

33. Kalivas PW, Lalumiere RT, Knackstedt L, Shen H. Glutamate transmission in addiction. Neuropharmacology 2009; 56:169-173.

34. Moussawi K, Kalivas PW. Group II metabotropic glutamate receptors (mGlu2/3) in drug addiction. Eur J Pharmacol 2010; 639:115-122.

35. Olive MF. Metabotropic glutamate receptor ligands as potential therapeutics for addiction. Curr Drug Abuse Rev 2009; 2:83-98.

36. Olive MF. Cognitive effects of Group I metabotropic glutamate receptor ligands in the context of drug addiction. Eur J Pharmacol 2010; 639:47-58.

37. Reissner KJ, Kalivas PW. Using glutamate homeostasis as a target for treating addictive disorders. Behav Pharmacol 2010; 21:514-522.

38. Tzschentke TM, Schmidt WJ. Glutamatergic mechanisms in addiction. Mol Psychiatry 2003; 8:373-382.

39. Uys JD, LaLumiere RT. Glutamate: the new frontier in pharmacotherapy for cocaine addiction. CNS Neurol Disord Drug Targets 2008; 7:482-491.

40. Kalivas PW, Volkow ND. New medications for drug addiction hiding in glutamatergic neuroplasticity. Mol Psychiatry 2011; 16:974-986.

41. LaRowe SD, Kalivas PW, Nicholas JS, Randall PK, Mardikian PN, Malcolm RJ. A double-blind placebo-controlled trial of N-acetylcysteine in the treatment of cocaine dependence. Am J Addict 2013; 22:443-452.

42. Nocito Echevarria MA, Andrade Reis T, Ruffo Capatti G, Siciliano Soares V, da Silveira DX, Fidalgo TM. N-acetylcysteine for treating cocaine addiction-a systematic review. Psychiatry Res 2017; 251:197-203.

43. LaRowe SD, Myrick H, Hedden S, Mardikian P, Saladin M, McRae A, et al. Is cocaine desire reduced by N-acetylcysteine? Am J Psychiatry 2007; 164:1115-1117.

44. Amen SL, Piacentine LB, Ahmad ME, Li SJ, Mantsch JR, Risinger RC, et al. Repeated N-acetyl cysteine reduces cocaine seeking in rodents and craving in cocaine-dependent humans. Neuropsychopharmacology 2011; 36:871-878.

45. Duailibi MS, Cordeiro Q, Brietzke E, Ribeiro M, LaRowe S, Berk M, et al. N-acetylcysteine in the treatment of craving in substance use disorders: systematic review and meta-analysis. Am J Addict 2017; 26:660-666.

46. Schechter JD. Effects of N-acetylcysteine on treatment outcomes for cocaine abusers. 2019. https://ubir.buffalo.edu/xmlui/handle/10477/81329.

47. Charntikov S, Pittenger ST, Pudiak CM, Bevins RA. The effect of N-acetylcysteine or bupropion on methamphetamine self-administration and methamphetamine-triggered reinstatement of female rats. Neuropharmacology 2018; 135:487-495.

48. Grant JE, Odlaug BL, Kim SW. A double-blind, placebo-controlled study of N-acetylcysteine plus naltrexone for methamphetamine dependence. Eur Neuropsychopharmacol 2010; 20:823-828.

49. Mousavi SG, Sharbafchi MR, Salehi M, Peykanpour M, Karimian Sichani N, Maracy M. The efficacy of N-acetylcysteine in the treatment of methamphetamine dependence: a double-blind controlled, crossover study. Arch Iran Med 2015; 18:28-33.

50. McKetin R, Dean OM, Turner A, Kelly PJ, Quinn B, Lubman DI, et al. A study protocol for the N-ICE trial: a randomised double-blind placebo-controlled study of the safety and efficacy of N-acetyl-cysteine (NAC) as a pharmacotherapy for methamphetamine (“ice”) dependence. Trials 2019; 20:325.

51. Gray KM, Watson NL, Carpenter MJ, LaRowe SD. N-acetylcysteine (NAC) in young marijuana users: an open-label pilot study. Am J Addict 2010; 19:187-189.

52. Gray KM, Carpenter MJ, Baker NL, DeSantis SM, Kryway E, Hartwell KJ, et al. A double-blind randomized controlled trial of N-acetylcysteine in cannabis-dependent adolescents. Am J Psychiatry 2012; 169:805-812

.53. Gray KM, Sonne SC, McClure EA, Ghitza UE, Matthews AG, McRae-Clark AL, et al. A randomized placebo-controlled trial of N-acetylcysteine for cannabis use disorder in adults. Drug Alcohol Depend 2017; 177:249-257.

54. Tomko RL, Baker NL, Hood CO, Gilmore AK, McClure EA, Squeglia LM, et al. Depressive symptoms and cannabis use in a placebo-controlled trial of N-acetylcysteine for adult cannabis use disorder. Psychopharmacology (Berl) 2020; 237:479-490.

55. Sheikh IA, Luksic M, Ferstenberg R, Culpepper-Morgan JA. Spice/K2 synthetic marijuana-induced toxic hepatitis treated with N-acetylcysteine. Am J Case Rep 2014; 15:584-588.

56. Mocelin R, Marcon M, da Rosa Araujo AS, Herrmann AP, Piato A. Withdrawal effects following repeated ethanol exposure are prevented by N-acetylcysteine in zebrafish. Prog Neuropsychopharmacol Biol Psychiatry 2019; 93:161-170.

57. Garcia-Keller C, Smiley C, Monforton C, Melton S, Kalivas PW, Gass J. N-acetylcysteine treatment during acute stress prevents stress-induced augmentation of addictive drug use and relapse. Addict Biol 2019:e12798.

58. Squeglia LM, Baker NL, McClure EA, Tomko RL, Adisetiyo V, Gray KM. Alcohol use during a trial of N-acetylcysteine for adolescent marijuana cessation. Addict Behav 2016; 63:172-177.

59. Squeglia LM, Tomko RL, Baker NL, McClure EA, Book GA, Gray KM. The effect of N-acetylcysteine on alcohol use during a cannabis cessation trial. Drug Alcohol Depend 2018; 185:17-22.

60. Quintanilla ME, Rivera-Meza M, Berrios-Carcamo P, Salinas-Luypaert C, Herrera-Marschitz M, Israel Y. Beyond the “first hit”: marked inhibition by N-acetyl cysteine of chronic ethanol intake but not of early ethanol intake: parallel effects on ethanol-induced saccharin motivation. Alcohol Clin Exp Res 2016; 40:1044-1051.

61. Morley KC, Baillie A, Van Den Brink W, Chitty KE, Brady K, Back SE, et al. N-acetylcysteine in the treatment of alcohol use disorder in patients with liver disease: rationale for further research. Expert Opin Investig Drugs 2018; 27:667-675.

62. Gipson CD, Spencer S, Stankeviciute N, Allen N, Garcia-Keller C, Kalivas PW. N-acetylcysteine inhibits nicotine relapse-associated synaptic plasticity and restores glial glutamate transport in nicotine-withdrawn animals. Drug Alcohol Depend 2015; 156:e80.

63. Ramirez-Nino AM, D’Souza MS, Markou A. N-acetylcysteine decreased nicotine self-administration and cue-induced reinstatement of nicotine seeking in rats: comparison with the effects of N-acetylcysteine on food responding and food seeking. Psychopharmacology (Berl) 2013; 225:473-482.

64. Schmaal L, Berk L, Hulstijn KP, Cousijn J, Wiers RW, van den Brink W. Efficacy of N-acetylcysteine in the treatment of nicotine dependence: a double-blind placebo-controlled pilot study. Eur Addict Res 2011; 17:211-216.

65. McClure EA, Baker NL, Gipson CD, Carpenter MJ, Roper AP, Froeliger BE, et al. An open-label pilot trial of N-acetylcysteine and varenicline in adult cigarette smokers. Am J Drug Alcohol Abuse 2015; 41:52-56.

66. Froeliger B, McConnell PA, Stankeviciute N, McClure EA, Kalivas PW, Gray KM. 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.

67. Ward P, Moss HG, Brown TR, Kalivas P, Jenkins DD. N-acetylcysteine mitigates acute opioid withdrawal behaviors and CNS oxidative stress in neonatal rats. Pediatr Res 2020, https://doi.org/10.1038/s41390-019-0728-6. [Epub ahead of print]

68. Minarini A, Ferrari S, Galletti M, Giambalvo N, Perrone D, Rioli G, et al. N-acetylcysteine in the treatment of psychiatric disorders: current status and future prospects. Expert Opin Drug Metab Toxicol 2017; 13:279-292.

69. Ng F, Berk M, Dean O, Bush AI. Oxidative stress in psychiatric disorders: evidence base and therapeutic implications. Int J Neuropsychopharmacol 2008; 11:851-876.

70. Atkuri KR, Mantovani JJ, Herzenberg LA, Herzenberg LA. N-Acetylcysteine – a safe antidote for cysteine/glutathione deficiency. Curr Opin Pharmacol 2007; 7:355-359.

71. Berk M, Ng F, Dean O, Dodd S, Bush AI. Glutathione: a novel treatment target in psychiatry. Trends Pharmacol Sci 2008; 29:346-351.
Düşünen Adam - Psikiyatri ve Nörolojik Bilimler Dergisi-Cover
  • ISSN: 1018-8681
  • Yayın Aralığı: Yılda 4 Sayı
  • Başlangıç: 1984
  • Yayıncı: Kare Yayıncılık
Sayıdaki Diğer Makaleler

A serious dermatological side effect due to vortioxetine: a case report

Burak OKUMUS, Kader Semra KARATAS, Asli Enzel KOC

What is the role of emotional regulation and psychological rigidity in the relationship between stress and pathological Internet use?

Elcin YORULMAZ, Orcun YORULMAZ, Umut CİVGİN

Health-related quality of life in multiple sclerosis: Links to mental health, self-esteem, and self-compassion

Zumrut GEDİK, Egemen IDİMAN

Typical Rett Syndrome in a young boy with hemizygous c.316C>T mutation in MECP2 gene

Murat COSKUN, Ilyas KAYA, Zeynep Nur GULLE, Seda ERBİLGİN, Ibrahim AKALİN, Afig BERDELİ

Cognitive functions in opioid-dependent males according to duration of abstinence

Buket KOPARAL, Ceyda Oktay YANİK, Ismail Volkan SAHİNER, Hatice Ayca KALOGLU, Muhammed Hakan AKSU, Cisem UTKU, Zehra ARİKAN

Psychometric validation of the Turkish Ten-Item Internet Gaming Disorder Test (IGDT-10)

Cuneyt EVREN, Bilge EVREN, Nilay KUTLU, Ercan DALBUDAK, Merve TOPCU

The gut microbiome integrates immune-inflammatory processes in depression

George ANDERSON

Relationship of Internet gaming disorder symptom severity with non-suicidal self-injury among young adults

Cuneyt EVREN, Bilge EVREN, Nilay KUTLU, Ercan DALBUDAK, Merve TOPCU

The validity and reliability of the Turkish brief version of the Zimbardo Time Perspective Inventory for adolescents

Ercan KOCAYORUK, Omer Faruk SİMSEK

Mediating effects of self-esteem in the relationship between attachment styles and social media addiction among university students

Zeynep Isil DEMİRCİOGLU, Asli Goncu KOSE