N-acetyl-cysteine (NAC) Research

NAC — scientific infographic poster

N-Acetylcysteine (NAC) is the acetylated form of the amino acid L-cysteine. It has been used clinically since the early 1960s — first as an inhaled mucolytic (approved in the United States in 1963) and then as the antidote for acetaminophen (paracetamol) overdose. In a series of 100 severe poisonings, intravenous NAC given within eight hours of ingestion gave virtually complete protection against liver damage, and efficacy fell progressively after that (Prescott 1979); in a US multicentre study of 2,540 patients treated with oral NAC, no deaths were clearly caused by acetaminophen among those whose treatment began within 16 hours (Smilkstein 1988). Beyond these two classic uses, research over the past three decades has examined NAC in kidney health, liver health, respiratory disease, psychiatric disorders, fertility, and cardiovascular medicine, with positive and negative trials in most of these areas.

The usual explanation for this breadth is that NAC supplies cysteine for glutathione, a major intracellular antioxidant. Cysteine is generally considered the rate-limiting substrate for glutathione synthesis. Lower glutathione has been measured in older adults, where two weeks of the precursors cysteine and glycine restored it to the levels of younger controls in an eight-person study (Sekhar 2011), and in CD4 T cells of people with HIV, where low levels predicted poorer survival (Herzenberg 1997). Other proposed actions of NAC are direct scavenging of reactive oxygen species, cleavage of disulfide bonds in mucus, modulation of the cystine-glutamate antiporter in the brain, and supply of sulfhydryl groups that potentiate the effect of nitroglycerin.

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Research Topics

NAC & Kidney Health

Covers the kidney research: contrast-induced nephropathy, from Tepel 2000 (in 83 patients with chronic renal insufficiency, a creatinine rise after CT contrast in 1 of 41 on NAC versus 9 of 42 on placebo) to the large ACT trial (2,308 patients) and PRESERVE trial (4,993 analysed), both of which found no benefit of NAC over placebo; chronic kidney disease and hemodialysis oxidative stress, cystinuria, diabetic nephropathy, sepsis and cardiac-surgery acute kidney injury, and rhabdomyolysis. Includes Tepel's 2003 trial in 134 hemodialysis patients, in which NAC 600 mg twice daily lowered a composite of cardiovascular events (28% versus 47%) with no significant difference in total mortality.

NAC & Glutathione (the Master Antioxidant)

Why cysteine is considered the rate-limiting step, how NAC delivers it, and the evidence on whether oral NAC raises blood and tissue glutathione. Covers Sekhar's GlyNAC work on age-related glutathione deficits, Herzenberg's HIV studies, liposomal glutathione comparisons, and the roles of glycine (a glutathione building block) and selenium (a glutathione peroxidase cofactor). Also discusses the low oral bioavailability of intact NAC.

NAC & Liver Health

Covers acetaminophen overdose and beyond: the Lee 2009 Gastroenterology trial in non-acetaminophen acute liver failure (overall 3-week survival, the primary outcome, did not differ, 70% versus 66%; transplant-free survival was better with NAC, 40% versus 27%, a benefit confined to patients in early coma grades I–II), the Nguyen-Khac 2011 NEJM trial in severe alcoholic hepatitis (NAC added to prednisolone lowered 1-month mortality, 8% versus 24%, but not 6-month mortality, the primary outcome, 27% versus 38%, P=0.07), and evidence in NAFLD/NASH, drug-induced liver injury, and hepatic ischemia-reperfusion during transplantation.

NAC & Respiratory Health

From mucus thinning to COPD exacerbations. Covers the PANTHEON trial in 1,006 Chinese patients with moderate-to-severe COPD (600 mg twice daily for a year; exacerbation rate 1.16 versus 1.49 per patient-year, risk ratio 0.78), the 2019 Cochrane review of mucolytics (a small reduction in exacerbations, with smaller effects in more recent and longer trials), the BENE trial in 161 people with bronchiectasis, the IPF story (IFIGENIA, where NAC added to prednisone and azathioprine slowed the decline in lung function, versus PANTHER-IPF, where NAC alone did not differ from placebo), and De Flora's 1997 trial in 262 mostly elderly people, where NAC reduced influenza-like episodes and symptoms but not infection rates.

NAC & Mental Health

Covers the psychiatric trials: Berk's 2008 trials in schizophrenia (140 patients, improvement in total and negative symptom scores) and bipolar disorder (75 patients, improvement in depressive symptoms but no effect on time to a mood episode), the Grant 2009 trichotillomania trial (50 adults; 56% much or very much improved with NAC versus 16% with placebo), OCD augmentation studies, Gray's 2012 adolescent cannabis trial (positive) and the 2017 adult trial (no difference from placebo), cocaine and nicotine addiction work, Hardan's pilot trial on irritability in 33 children with autism, and Back's pilot trial in 35 veterans with PTSD and substance use disorders. Explains the glutamate-homeostasis hypothesis via the cystine-glutamate antiporter.

NAC, Fertility & PCOS

Reproductive medicine is one of the most studied areas for NAC — and one where several trials have since been retracted. Covers the male-factor trials (Safarinejad 2009, which carries a 2023 Expression of Concern, and the placebo-controlled Ciftci 2009, in which semen volume and motility improved but sperm count and morphology did not differ), the clomiphene-adjunct trials in PCOS (Rizk, Badawy, Salehpour) and the 2015 Thakker meta-analysis, whose clomiphene-resistant ovulation odds ratio of 8.40 pools two trials, one of them retracted in 2025; NAC-versus-metformin data (in the meta-analysis, metformin gave higher odds of ovulation and pregnancy); the Amin 2008 recurrent pregnancy loss study (take-home baby rate RR 1.98 with NAC plus folic acid versus folic acid alone); and Porpora's observational endometriosis cohort reporting smaller ovarian endometriomas.

NAC & Cardiovascular Health

Early cardiovascular studies paired NAC with nitroglycerin: in heart failure, oral NAC partially reversed nitrate tolerance in eight patients (Packer 1987), and in 46 patients with unstable angina, NAC plus nitroglycerin was followed by fewer heart attacks than nitroglycerin alone (3 versus 10) but more symptomatic hypotension (7 versus 0) (Horowitz 1988). In the NACIAM trial in STEMI patients undergoing primary PCI, high-dose intravenous NAC given with low-dose nitroglycerin was associated with an absolute 5.5% reduction in MRI-measured infarct size (median 11.0% versus 16.5% of the left ventricle); its authors called for a larger trial of clinical outcomes. Homocysteine (lowered by 45% in an 11-person crossover study, Wiklund 1996, but not significantly in a 4-week trial in hemodialysis patients, Friedman 2003) and endothelial function are also covered, along with the interaction with nitroglycerin.

Common Themes Across All Indications

  1. Glutathione replenishment — NAC → deacetylation → cysteine → the rate-limiting step of glutathione synthesis.
  2. Direct thiol antioxidant action — the free -SH group scavenges hydroxyl radicals, hypochlorous acid, and reactive nitrogen species independently of glutathione.
  3. Disulfide exchange — NAC cleaves S–S bonds in mucus glycoproteins (mucolytic effect), in plasma protein-homocysteine disulfides (proposed for homocysteine lowering), and in cystine (proposed for cystine stones).
  4. Nitric oxide donation — interaction with nitroglycerin may form S-nitroso-NAC, which inhibits platelet aggregation, and sulfhydryl groups are proposed to potentiate nitroglycerin's vasodilator effect (Horowitz 1988).
  5. Glutamate homeostasis — in the brain, cystine exchanges for glutamate via system xc-, which is proposed to normalize extrasynaptic glutamate tone and is the main hypothesis behind the psychiatric trials.
  6. NF-kB suppression — cellular redox state is coupled to inflammatory transcription, so glutathione restoration is proposed to lower cytokine output.

Doses Used in Studies

The doses below are those reported by the studies cited on this page, not dosing guidance.

In a study of six healthy volunteers, the oral bioavailability of NAC was 4.0% for reduced NAC and 9.1% for total NAC (Olsson 1988). Much of an oral dose is deacetylated on first pass to cysteine, the substrate for glutathione synthesis, so a low plasma level of intact NAC does not by itself show how much cysteine reaches tissues. The sulfurous odor of NAC is associated with nausea.

Safety Profile

NAC was approved in the US as a drug in 1963. The FDA says it has held for more than 20 years that a substance first approved as a drug is excluded from the dietary-supplement definition, and its July 2020 warning letters restated that position; in 2022 the agency issued guidance saying it would exercise enforcement discretion over NAC sold as a supplement (see the NAC History page for the FDA documents).

Related Pages

Key Research Papers

  1. Prescott LF, Illingworth RN, Critchley JA, Stewart MJ, Adam RD, Proudfoot AT. Intravenous N-acetylcystine: the treatment of choice for paracetamol poisoning. Br Med J 1979;2(6198):1097–100. PubMed PMID: 519312
  2. Smilkstein MJ, Knapp GL, Kulig KW, Rumack BH. Efficacy of oral N-acetylcysteine in the treatment of acetaminophen overdose. Analysis of the national multicenter study (1976 to 1985). N Engl J Med 1988;319(24):1557–62. PubMed PMID: 3059186
  3. Bateman DN, Dear JW, Thanacoody HK, Thomas SH, Eddleston M, Sandilands EA, et al. Reduction of adverse effects from intravenous acetylcysteine treatment for paracetamol poisoning: a randomised controlled trial. Lancet 2014;383(9918):697–704. PubMed PMID: 24290406
  4. Lee WM, Hynan LS, Rossaro L, Fontana RJ, Stravitz RT, Larson AM, et al. Intravenous N-acetylcysteine improves transplant-free survival in early stage non-acetaminophen acute liver failure. Gastroenterology 2009;137(3):856–64, 864.e1. PubMed PMID: 19524577
  5. Nguyen-Khac E, Thevenot T, Piquet MA, Benferhat S, Goria O, Chatelain D, et al. Glucocorticoids plus N-acetylcysteine in severe alcoholic hepatitis. N Engl J Med 2011;365(19):1781–9. PubMed PMID: 22070475
  6. Tepel M, van der Giet M, Schwarzfeld C, Laufer U, Liermann D, Zidek W. Prevention of radiographic-contrast-agent-induced reductions in renal function by acetylcysteine. N Engl J Med 2000;343(3):180–4. PubMed PMID: 10900277
  7. ACT Investigators. Acetylcysteine for prevention of renal outcomes in patients undergoing coronary and peripheral vascular angiography: main results from the randomized Acetylcysteine for Contrast-induced nephropathy Trial (ACT). Circulation 2011;124(11):1250–9. PubMed PMID: 21859972
  8. Weisbord SD, Gallagher M, Jneid H, Garcia S, Cass A, Thwin SS, et al. Outcomes after Angiography with Sodium Bicarbonate and Acetylcysteine. N Engl J Med 2018;378(7):603–614. PubMed PMID: 29130810
  9. Briguori C, Airoldi F, D'Andrea D, Bonizzoni E, Morici N, Focaccio A, et al. Renal Insufficiency Following Contrast Media Administration Trial (REMEDIAL): a randomized comparison of 3 preventive strategies. Circulation 2007;115(10):1211–7. PubMed PMID: 17309916
  10. Tepel M, van der Giet M, Statz M, Jankowski J, Zidek W. The antioxidant acetylcysteine reduces cardiovascular events in patients with end-stage renal failure: a randomized, controlled trial. Circulation 2003;107(7):992–5. PubMed PMID: 12600912
  11. Sekhar RV, Patel SG, Guthikonda AP, Reid M, Balasubramanyam A, Taffet GE, et al. Deficient synthesis of glutathione underlies oxidative stress in aging and can be corrected by dietary cysteine and glycine supplementation. Am J Clin Nutr 2011;94(3):847–53. PubMed PMID: 21795440
  12. Herzenberg LA, De Rosa SC, Dubs JG, Roederer M, Anderson MT, Ela SW, et al. Glutathione deficiency is associated with impaired survival in HIV disease. Proc Natl Acad Sci U S A 1997;94(5):1967–72. PubMed PMID: 9050888
  13. Olsson B, Johansson M, Gabrielsson J, Bolme P. Pharmacokinetics and bioavailability of reduced and oxidized N-acetylcysteine. Eur J Clin Pharmacol 1988;34(1):77–82. PubMed PMID: 3360052
  14. Zheng JP, Wen FQ, Bai CX, Wan HY, Kang J, Chen P, et al. Twice daily N-acetylcysteine 600 mg for exacerbations of chronic obstructive pulmonary disease (PANTHEON): a randomised, double-blind placebo-controlled trial. Lancet Respir Med 2014;2(3):187–94. PubMed PMID: 24621680
  15. Poole P, Sathananthan K, Fortescue R. Mucolytic agents versus placebo for chronic bronchitis or chronic obstructive pulmonary disease. Cochrane Database Syst Rev 2019;5(5):CD001287. PubMed PMID: 31107966
  16. Qi Q, Ailiyaer Y, Liu R, Zhang Y, Li C, Liu M, et al. Effect of N-acetylcysteine on exacerbations of bronchiectasis (BENE): a randomized controlled trial. Respir Res 2019;20(1):73. PubMed PMID: 30975143
  17. Demedts M, Behr J, Buhl R, Costabel U, Dekhuijzen R, Jansen HM, et al. High-dose acetylcysteine in idiopathic pulmonary fibrosis. N Engl J Med 2005;353(21):2229–42. PubMed PMID: 16306520
  18. Martinez FJ, de Andrade JA, Anstrom KJ, King TE Jr, Raghu G. Randomized trial of acetylcysteine in idiopathic pulmonary fibrosis. N Engl J Med 2014;370(22):2093–101. PubMed PMID: 24836309
  19. De Flora S, Grassi C, Carati L. Attenuation of influenza-like symptomatology and improvement of cell-mediated immunity with long-term N-acetylcysteine treatment. Eur Respir J 1997;10(7):1535–41. PubMed PMID: 9230243
  20. Berk M, Copolov D, Dean O, Lu K, Jeavons S, Schapkaitz I, et al. N-acetyl cysteine as a glutathione precursor for schizophrenia--a double-blind, randomized, placebo-controlled trial. Biol Psychiatry 2008;64(5):361–8. PubMed PMID: 18436195
  21. Berk M, Copolov DL, Dean O, Lu K, Jeavons S, Schapkaitz I, et al. N-acetyl cysteine for depressive symptoms in bipolar disorder--a double-blind randomized placebo-controlled trial. Biol Psychiatry 2008;64(6):468–75. PubMed PMID: 18534556
  22. 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(7):756–63. PubMed PMID: 19581567
  23. 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(5):490–6. PubMed PMID: 27007062
  24. 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(8):805–12. PubMed PMID: 22706327
  25. 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. PubMed PMID: 28623823
  26. 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(11):956–61. PubMed PMID: 22342106
  27. Back SE, McCauley JL, Korte KJ, Gros DF, Leavitt V, Gray KM, et al. A Double-Blind, Randomized, Controlled Pilot Trial of N-Acetylcysteine in Veterans With Posttraumatic Stress Disorder and Substance Use Disorders. J Clin Psychiatry 2016;77(11):e1439–e1446. PubMed PMID: 27736051
  28. Safarinejad MR, Safarinejad S. Efficacy of selenium and/or N-acetyl-cysteine for improving semen parameters in infertile men: a double-blind, placebo controlled, randomized study. J Urol 2009;181(2):741–51. PubMed PMID: 19091331 — Expression of concern (notice: PubMed PMID: 36626340)
  29. Ciftci H, Verit A, Savas M, Yeni E, Erel O. Effects of N-acetylcysteine on semen parameters and oxidative/antioxidant status. Urology 2009;74(1):73–6. PubMed PMID: 19428083
  30. Rizk AY, Bedaiwy MA, Al-Inany HG. N-acetyl-cysteine is a novel adjuvant to clomiphene citrate in clomiphene citrate-resistant patients with polycystic ovary syndrome. Fertil Steril 2005;83(2):367–70. PubMed PMID: 15705376
  31. Thakker D, Raval A, Patel I, Walia R. N-acetylcysteine for polycystic ovary syndrome: a systematic review and meta-analysis of randomized controlled clinical trials. Obstet Gynecol Int 2015;2015:817849. PubMed PMID: 25653680
  32. Amin AF, Shaaban OM, Bediawy MA. N-acetyl cysteine for treatment of recurrent unexplained pregnancy loss. Reprod Biomed Online 2008;17(5):722–6. PubMed PMID: 18983759
  33. Porpora MG, Brunelli R, Costa G, Imperiale L, Krasnowska EK, Lundeberg T, et al. A promise in the treatment of endometriosis: an observational cohort study on ovarian endometrioma reduction by N-acetylcysteine. Evid Based Complement Alternat Med 2013;2013:240702. PubMed PMID: 23737821
  34. Packer M, Lee WH, Kessler PD, Gottlieb SS, Medina N, Yushak M. Prevention and reversal of nitrate tolerance in patients with congestive heart failure. N Engl J Med 1987;317(13):799–804. PubMed PMID: 3114637
  35. Horowitz JD, Henry CA, Syrjanen ML, Louis WJ, Fish RD, Smith TW, et al. Combined use of nitroglycerin and N-acetylcysteine in the management of unstable angina pectoris. Circulation 1988;77(4):787–94. PubMed PMID: 3127076
  36. Pasupathy S, Tavella R, Grover S, Raman B, Procter NEK, Du YT, et al. Early Use of N-acetylcysteine With Nitrate Therapy in Patients Undergoing Primary Percutaneous Coronary Intervention for ST-Segment-Elevation Myocardial Infarction Reduces Myocardial Infarct Size (the NACIAM Trial [N-acetylcysteine in Acute Myocardial Infarction]). Circulation 2017;136(10):894–903. PubMed PMID: 28634219
  37. Wiklund O, Fager G, Andersson A, Lundstam U, Masson P, Hultberg B. N-acetylcysteine treatment lowers plasma homocysteine but not serum lipoprotein(a) levels. Atherosclerosis 1996;119(1):99–106. PubMed PMID: 8929261
  38. Friedman AN, Bostom AG, Laliberty P, Selhub J, Shemin D. The effect of N-acetylcysteine on plasma total homocysteine levels in hemodialysis: a randomized, controlled study. Am J Kidney Dis 2003;41(2):442–6. PubMed PMID: 12552508
  39. Riggs BS, Bronstein AC, Kulig K, Archer PG, Rumack BH. Acute acetaminophen overdose during pregnancy. Obstet Gynecol 1989;74(2):247–53. PubMed PMID: 2748061

PubMed Topic Searches

  1. PubMed: NAC and glutathione synthesis
  2. PubMed: NAC and acetaminophen hepatotoxicity
  3. PubMed: NAC and COPD/chronic bronchitis
  4. PubMed: NAC in PCOS and ovulation
  5. PubMed: NAC in OCD and trichotillomania
  6. PubMed: NAC and contrast-induced nephropathy
  7. PubMed: NAC and nitrate tolerance
  8. PubMed: NAC in bipolar depression
  9. PubMed: NAC in pulmonary fibrosis
  10. PubMed: NAC and homocysteine
  11. PubMed: NAC and sperm quality/fertility
  12. PubMed: NAC in autism-associated irritability

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