N-Acetylcysteine

• How It Works

  N-acetylcysteine is an effective drug for acetaminophen overdose and to break up mucus. It has not been proven to be an effective treatment for cancer.

  N-acetylcysteine (NAC) is a compound that is found naturally in the body. It is converted to a chemical called glutathione, which plays a role in the detoxification of foreign substances in the body. It is used as an antidote for acetaminophen overdose. NAC itself is an antioxidant that is thought to neutralize free radicals that cause damage to DNA. Animals fed with NAC have less cellular damage and fewer lung, colon, and bladder tumors, compared with those fed a normal diet. In addition, NAC interferes with tumor invasion, metastasis, and blood vessel growth in lab experiments. However, few of these effects have been shown to occur in humans. An animal study shows NAC can speed up the growth of lung cancer cells due to its antioxidant activity.

  NAC can dissolve and loosen mucus in patients with respiratory disorders such as chronic bronchitis and chronic obstructive pulmonary disease (COPD), but study results are mixed. Animal studies also show that it might protect against tissue damage from drugs such as doxorubicin, ifosfamide, and cyclophosphamide. These effects are currently being studied in humans.

  NAC regulates glutamate levels in the brain. It has been studied for several psychiatric disorders in humans with limited success.

• Purported Uses
  • To treat lung conditions such as bronchitis and COPD
    Clinical trials evaluating NAC for chronic bronchitis due to its mucus-digesting effect are mixed.
  • To treat cystic fibrosis
    A meta-analysis found a small, but not very significant effect of inhaled N-acetylcysteine on lung function in patients with cystic fibrosis. A long-term study suggests it may help maintain lung function, but NAC had no effect on markers of inflammation. It was also not helpful for idiopathic pulmonary fibrosis.
  • To prevent and treat cancer
    Most clinical trials do not support the use of N-acetylcysteine for treating cancer. A few clinical trials suggest that this supplement can prevent certain pre-cancerous damage, but there is no proof that it can prevent cancer.
  • To treat drug-induced liver toxicity
    N-acetylcysteine is an effective treatment for acetaminophen poisoning, which can be life-threatening. If hepatic toxicity is suspected, seek immediate medical attention for proper treatment. One study also observed that NAC has a protective effect against liver toxicity from antituberculosis drugs.
  • To treat cirrhosis
    Although N-acetylcysteine is known to be a precursor for glutathione, an important detoxification enzyme in the liver, there is no proof from clinical trials that this supplement can treat cirrhosis.
  • To treat HIV and AIDS
    A few clinical trials suggest that N-acetylcysteine can raise cysteine and glutathione levels in HIV+ patients, but whether this supplement improves survival or immunity to disease is not known.
  • To treat Lou Gehrig’s Disease (amyotrophic lateral sclerosis)
    This use has only been tested in one clinical trial, in which it was found that NAC had no effect on progression of disease or survival in patients with Lou Gehrig’s disease.
  • To treat psychiatric disorders
    Several small scale studies suggest NAC may help to control substance abuse and gambling addictions. It may also help reduce symptoms of trichotillomania (hair pulling).
• Patient Warnings
  • NAC is used as an antidote for liver toxicity caused by acetaminophen poisoning, which can be life-threatening. If acetaminophen overdose is suspected, seek immediate medical attention for proper treatment.
• Do Not Take If
  • You are taking nitroglycerin:  N-acetylcysteine (NAC) can increase hypotension, headache, and worsen temporal artery dilation.
• Side Effects
  • Stomach upset
  • Diarrhea
  • Nausea
  • Vomiting
  • Fatigue
  • Irritation of the conjunctiva of the eyes
  • Skin rash
  • Less commonly reported side effects include low blood pressure, anaphylactic shock, asthma attacks, and headache.

  Case reports
  Light sensitivity: Occurred among pulmonary fibrosis patients taking acetylcysteine in combination with pirfenidone. The reaction could not be explained by causes such as location, season, or other medications taken at the same time.

• Special Point
  • It is controversial whether antioxidants like N-acetylcysteine can lessen or negate the effects of chemotherapy and radiation therapy. Because these therapies work by creating free radicals that kill cancer cells, high levels of antioxidants may neutralize these effects and protect cancer cells from these therapies. So what protects healthy cells may protect cancer cells as well. Patients who are interested in taking antioxidants during therapy should consult with their doctor.
• Scientific Name

  N-Acetylcysteine

• Clinical Summary

  N-acetylcysteine (NAC) is an antioxidant that is used as a prescription drug and as a dietary supplement. As a drug, it is given parenterally or orally to treat acetaminophen overdose. The inhalant and oral solution forms have a mucolytic effect to relieve obstructions in bronchial diseases and in tracheotomy procedures. The oral capsule is marketed as a dietary supplement for its liver protective function and is popular among patients with AIDS and cancer.

  Clinical studies show NAC can treat drug-induced hepatotoxicity ^(1) (2), prevent and treat conditions of oxidative stress and reduce GSH levels caused by diseases such as HIV/AIDS ⁽³⁾ and cancer ⁽⁴⁾, and alleviate toxicity from chemo- and radiotherapy ⁽⁴⁾.

  Results for treatment of chronic lung disease with NAC are mixed. NAC reduces the number of acute exacerbations in patients with chronic bronchopulmonary disease ⁽⁵⁾ and significantly improves lung function and endurance in COPD patients after exercise ⁽⁶⁾, but benefits were not observed in other trials ^(7) (8), including a study of high-dose NAC ⁽³⁷⁾. In cystic fibrosis patients, long-term oral NAC maintained lung function but had no effect on biomarkers of neutrophilic inflammation ⁽³⁸⁾. NAC was not helpful for idiopathic pulmonary fibrosis and did not alter the tolerability profile of pirfenidone ⁽³⁹⁾; nor was it helpful for Lou Gehrig’s disease ⁽¹⁰⁾.

  Oral NAC reduced oxidative stress and preserved renal function in hemodialysis patients ^(40) (41).

  NAC has glutamate modulating effects ⁽¹¹⁾ and has been tested as a treatment for psychiatric disorders ⁽¹²⁾ including addictions ⁽¹³⁾ and substance abuse ⁽¹¹⁾. It also reduced symptoms of trichotillomania ⁽¹⁴⁾ .

  Studies in smokers ⁽¹⁵⁾ and patients with a history of adenomatous colonic polyps ⁽¹⁶⁾ show NAC inhibits cancer biomarker development, although it did not inhibit the formation of secondary head and neck or lung tumors ⁽¹⁷⁾. In addition, NAC accelerated lung cancer growth in an animal model ⁽³⁶⁾.

  Preliminary studies suggest oral NAC may help reduce chemotherapy-induced neuropathy ⁽¹⁸⁾, but a single oral dose of NAC did not protect moles from UV-induced oxidative stress ⁽⁴²⁾. In leukemia patients undergoing allogeneic hematopoietic SCT preceded by high-dose chemotherapy, parenteral NAC reduced incidence and duration oral mucositis ⁽⁴³⁾.

  Gastrointestinal side effects from the consumption of NAC have been reported ⁽¹⁹⁾. Due to its antioxidant activity, it may interfere with the actions of some chemotherapy drugs.

• Food Sources

  Food is not a significant source of N-acetylcysteine.

• Purported Uses
  • Prevention of drug-induced hepatotoxicity
  • Cirrhosis
  • Bronchitis
  • Chronic obstructive pulmonary disorders
  • Cystic fibrosis
  • HIV and AIDS
  • Lou Gehrig’s disease
  • Cancer prevention
  • Prevention of chemo- and radiotherapy side effects
• Mechanism of Action

  NAC is a precursor to glutathione (GSH). It is used as both an antidote for acetaminophen-induced hepatotoxicity and as a mucolytic agent for respiratory diseases. NAC reduces disulphide bonds to sulfhydryl bonds to reduce mucus formation ⁽²⁰⁾. Its hepatoprotective action may occur by cytokine-mediated mechanisms as well as GSH replenishment ⁽²¹⁾. In animal studies, NAC exhibits chemopreventive effects against lung ⁽²²⁾, hepatocellular ⁽²³⁾, esophageal ⁽²⁴⁾, and immune system ⁽²⁵⁾ cancers.

  An in vitro study shows NAC may improve the benefit of ifosfamide by decreasing the risk of nephrotoxicity without interfering with the agent’s antitumor effect ⁽²⁶⁾. Another study finds that NAC alters doxorubicin-induced NF-κB activity via concentration-dependent anti- and pro-oxidant mechanisms ⁽²⁷⁾. This biphasic effect is also time-dependent ⁽²⁸⁾. In androgen-independent human prostate cancer PC-3 cells, NAC has an antiproliferative effect by upregulating Cyr61 protein expression ⁽²⁸⁾.

  NAC amide can increase bioavailability and reduce oxidative stress, but it does not decrease doxorubicin-induced cell death in H9c2 cardiomyocytes ⁽²⁹⁾. In an animal study, NAC increased lung cancer cell proliferation due to its antioxidant activity by reducing reactive oxygen species (ROS), DNA damage and p53 expression ⁽³⁶⁾.

  NAC crosses the blood-brain barrier and increases the brain GSH levels. NAC acts as a glutamine modulator ⁽¹¹⁾ and plays a role in treating psychiatry disorders ⁽¹²⁾.

• Adverse Reactions

  Common (Oral): Gastrointestinal disturbance, diarrhea, nausea, vomiting, fatigue, conjunctival irritation, skin rash ^(26) (28)
  Other: Hypotension, anaphylaxis, asthma attacks, headache ⁽²⁹⁾

  Case reports
  Photosensitivity not attributable to location, season, or concomitant medication: Occurred among pulmonary fibrosis patients more frequently with acetylcysteine than placebo in combination with pirfenidone ⁽³⁹⁾.

• Herb-Drug Interactions

  Nitroglycerin: Severe headache due to added vasodilation effect ⁽³⁴⁾.
  Antidepressants: May increase the effects of imipramine and escitalopram ⁽³⁵⁾.

• References

  1. Baniasadi S, Eftekhari P, Tabarsi P, et al. Protective effect of N-acetylcysteine on antituberculosis drug-induced hepatotoxicity. Eur J Gastroenterol Hepatol. Oct 2010;22(10):1235-1238.

  2. Yarema MC, Johnson DW, Berlin RJ, et al. Comparison of the 20-hour intravenous and 72-hour oral acetylcysteine protocols for the treatment of acute acetaminophen poisoning. Ann Emerg Med. Oct 2009;54(4):606-614.

  3. Borges-Santos MD, Moreto F, Pereira PC, et al. Plasma glutathione of HIV(+) patients responded positively and differently to dietary supplementation with cysteine or glutamine. Nutrition. Jan 18 2012.

  4. Al-Tonbary Y, Al-Haggar M, El-Ashry R, et al. Vitamin e and N-acetylcysteine as antioxidant adjuvant therapy in children with acute lymphoblastic leukemia. Advances in hematology. 2009;2009:689639.

  5. Grandjean EM, Berthet P, Ruffmann 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. Feb 2000;22(2):209-221.

  6. Stav D, Raz M. Effect of N-acetylcysteine on air trapping in COPD: a randomized placebo-controlled study. Chest. Aug 2009;136(2):381-386.

  7. Decramer M, Rutten-van Molken M, Dekhuijzen PN, et al. Effects of N-acetylcysteine on outcomes in chronic obstructive pulmonary disease (Bronchitis Randomized on NAC Cost-Utility Study, BRONCUS): a randomised placebo-controlled trial. Lancet. Apr 30-May 6 2005;365(9470):1552-1560.

  8. Schermer T, Chavannes N, Dekhuijzen R, et al. Fluticasone and N-acetylcysteine in primary care patients with COPD or chronic bronchitis. Respir Med. Apr 2009;103(4):542-551.

  9. Duijvestijn YC, Brand PL. Systematic review of N-acetylcysteine in cystic fibrosis. Acta Paediatr. Jan 1999;88(1):38-41.

  10. Louwerse ES, Weverling GJ, Bossuyt PM, et al. Randomized, double-blind, controlled trial of acetylcysteine in amyotrophic lateral sclerosis. Arch Neurol. Jun 1995;52(6):559-564.

  11. Schmaal L, Veltman DJ, Nederveen A, et al. N-acetylcysteine normalizes glutamate levels in cocaine-dependent patients: a randomized crossover magnetic resonance spectroscopy study. Neuropsychopharmacology. Aug 2012;37(9):2143-2152.

  12. Dean O, Giorlando F, Berk M. N-acetylcysteine in psychiatry: current therapeutic evidence and potential mechanisms of action. J Psychiatry Neurosci. Mar 2011;36(2):78-86.

  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. Sep 15 2007;62(6):652-657.

  14. 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. Jul 2009;66(7):756-763.

  15. Van Schooten FJ, Besaratinia A, De Flora S, et al. Effects of oral administration of N-acetyl-L-cysteine: a multi-biomarker study in smokers. Cancer Epidemiol Biomarkers Prev. Feb 2002;11(2):167-175.

  16. Estensen RD, Levy M, Klopp SJ, et al. N-acetylcysteine suppression of the proliferative index in the colon of patients with previous adenomatous colonic polyps. Cancer Lett. Dec 1 1999;147(1-2):109-114.

  17. van Zandwijk N, Dalesio O, Pastorino U, et al. EUROSCAN, a randomized trial of vitamin A and N-acetylcysteine in patients with head and neck cancer or lung cancer. For the EUropean Organization for Research and Treatment of Cancer Head and Neck and Lung Cancer Cooperative Groups. J Natl Cancer Inst. Jun 21 2000;92(12):977-986.

  18. Lin PC, Lee MY, Wang WS, et al. N-acetylcysteine has neuroprotective effects against oxaliplatin-based adjuvant chemotherapy in colon cancer patients: preliminary data. Support Care Cancer. May 2006;14(5):484-487.

  19. Mullins ME, Schmidt RU, Jr., Jang TB. What is the rate of adverse events with intravenous versus oral N-acetylcysteine in pediatric patients? Ann Emerg Med. Nov 2004;44(5):547-548; author reply 548-549.

  20. Sadowska AM, Verbraecken J, Darquennes K, et al. Role of N-acetylcysteine in the management of COPD. International journal of chronic obstructive pulmonary disease. 2006;1(4):425-434.

  21. Masubuchi Y, Nakayama J, Sadakata Y. Protective effects of exogenous glutathione and related thiol compounds against drug-induced liver injury. Biol Pharm Bull. Mar 2011;34(3):366-370.

  22. Balansky R, Ganchev G, Iltcheva M, et al. Prevention of cigarette smoke-induced lung tumors in mice by budesonide, phenethyl isothiocyanate, and N-acetylcysteine. Int J Cancer. Mar 1 2010;126(5):1047-1054.

  23. Shimamoto K, Hayashi H, Taniai E, et al. Antioxidant N-acetyl-L-cysteine (NAC) supplementation reduces reactive oxygen species (ROS)-mediated hepatocellular tumor promotion of indole-3-carbinol (I3C) in rats. J Toxicol Sci. 2011;36(6):775-786.

  24. Hao J, Zhang B, Liu B, et al. Effect of alpha-tocopherol, N-acetylcysteine and omeprazole on esophageal adenocarcinoma formation in a rat surgical model. Int J Cancer. Mar 15 2009;124(6):1270-1275.

  25. Reliene R, Schiestl RH. Antioxidant N-acetyl cysteine reduces incidence and multiplicity of lymphoma in Atm deficient mice. DNA repair. Jul 13 2006;5(7):852-859.

  26. Chen N, Hanly L, Rieder M, et al. The effect of N-acetylcysteine on the antitumor activity of ifosfamide. Can J Physiol Pharmacol. May 2011;89(5):335-343.

  27. Finn NA, Kemp ML. Pro-oxidant and antioxidant effects of N-acetylcysteine regulate doxorubicin-induced NF-kappa B activity in leukemic cells. Molecular bioSystems. Feb 2012;8(2):650-662.

  28. Lee YJ, Lee DM, Lee CH, et al. Suppression of human prostate cancer PC-3 cell growth by N-acetylcysteine involves over-expression of Cyr61. Toxicology in vitro : an international journal published in association with BIBRA. Feb 2011;25(1):199-205.

  29. Shi R, Huang CC, Aronstam RS, et al. N-acetylcysteine amide decreases oxidative stress but not cell death induced by doxorubicin in H9c2 cardiomyocytes. BMC pharmacology. 2009;9:7.

  30. Holdiness MR. Clinical pharmacokinetics of N-acetylcysteine. Clin Pharmacokinet. Feb 1991;20(2):123-134.

  31. 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.

  32. Pendyala L, Schwartz G, Bolanowska-Higdon W, et al. Phase I/pharmacodynamic study of N-acetylcysteine/oltipraz in smokers: early termination due to excessive toxicity. Cancer Epidemiol Biomarkers Prev. Mar 2001;10(3):269-272.

  33. Herr SM. Herb-Drug Interaction Handbook, 2nd ed. Nassau, NY: Church Street Books; 2002.

  34. Ardissino D, Merlini PA, Savonitto S, et al. Effect of transdermal nitroglycerin or N-acetylcysteine, or both, in the long-term treatment of unstable angina pectoris. J Am Coll Cardiol. Apr 1997;29(5):941-947.

  35. Costa-Campos L, Herrmann AP, Pilz LK, et al. Interactive effects of N-acetylcysteine and antidepressants. Prog Neuropsychopharmacol B ol Psychiatry. Feb 16 2013;44C:125-130.

  36. Sayin V, Ibrahim M, Larsson E, et al. Antioxidants Accelerate Lung Cancer Progression in Mice. Sci Transl Med. Jan 2014; 6:(221):ra15.

  37. Johnson K, McEvoy CE, Naqvi S, et al. High-dose oral N-acetylcysteine fails to improve respiratory health status in patients with chronic obstructive pulmonary disease and chronic bronchitis: a randomized, placebo-controlled trial. Int J Chron Obstruct Pulmon Dis. 2016;11:799-807.

  38. Conrad C, Lymp J, Thompson V, et al. Long-term treatment with oral N-acetylcysteine: affects lung function but not sputum inflammation in cystic fibrosis subjects. A phase II randomized placebo-controlled trial. J Cyst Fibros. Mar 2015;14(2):219-227.

  39. Behr J, Bendstrup E, Crestani B, et al. Safety and tolerability of acetylcysteine and pirfenidone combination therapy in idiopathic pulmonary fibrosis: a randomised, double-blind, placebo-controlled, phase 2 trial. Lancet Respir Med. Jun 2016;4(6):445-453.

  40. Shahbazian H, Shayanpour S, Ghorbani A. Evaluation of administration of oral N-acetylcysteine to reduce oxidative stress in chronic hemodialysis patients: A double-blind, randomized, controlled clinical trial. Saudi J Kidney Dis Transpl. Jan 2016;27(1):88-93.

  41. Ahmadi F, Abbaszadeh M, Razeghi E, et al. Effectiveness of N-acetylcysteine for preserving residual renal function in patients undergoing maintenance hemodialysis: multicenter randomized clinical trial. Clin Exp Nephrol. Apr 2017;21(2):342-349.

  42. Cassidy PB, Liu T, Florell SR, et al. A Phase II Randomized Placebo-Controlled Trial of Oral N-acetylcysteine for Protection of Melanocytic Nevi against UV-Induced Oxidative Stress In Vivo. Cancer Prev Res (Phila). Jan 2017;10(1):36-44.

  43. Moslehi A, Taghizadeh-Ghehi M, Gholami K, et al. N-acetyl cysteine for prevention of oral mucositis in hematopoietic SCT: a double-blind, randomized, placebo-controlled trial. Bone Marrow Transplant. Jun 2014;49(6):818-823.