N-Acetylcysteine (NAC): History and Discovery

N-acetylcysteine (NAC, also called acetylcysteine) is a laboratory-made drug, so its history can be traced through documents: a patent, approval records, and the clinical papers that changed how it was used. A US patent application for its use as a mucus-thinner was filed in 1960 and granted in 1963, and the US Food and Drug Administration (FDA) approved acetylcysteine solution for inhalation or oral use on 14 September 1963. In the 1970s it became an antidote for paracetamol (acetaminophen) overdose, through work by Prescott and colleagues in Edinburgh published in 1977 and 1979. This article covers what NAC is and how it relates to the amino acid cysteine, who patented it, how it became a mucus-thinner and then a poisoning antidote, how its link to the antioxidant glutathione came to be understood, how the oral and intravenous treatment schedules developed, how its research record grew, and why its status as a dietary supplement in the United States was disputed. Where a date or a name comes from a source, the source is named; where the sources do not settle a detail, the article says so.

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Table of Contents

  1. What NAC Is: A Small Tweak to Cysteine
  2. Invention and Patent: Sheffner, 1960–1963
  3. The Inhaled Mucus-Thinning Drug
  4. The Paracetamol Antidote: Prescott, 1977
  5. Understanding Why It Works: The Glutathione Story
  6. From Drip to Drink: Intravenous and Oral Protocols
  7. An Old Drug With New Tricks
  8. Drug or Supplement? A Recent Tangle
  9. Key Research Papers
  10. Connections
  11. Featured Videos

What NAC Is: A Small Tweak to Cysteine

To understand NAC's history it helps to know what the molecule is. The US label for acetylcysteine solution describes it as the N-acetyl derivative of the naturally occurring amino acid L-cysteine; chemically, it is N-acetyl-L-cysteine. FDA's 2022 guidance lists the names under which the same ingredient appears, including acetylcysteine, N-acetyl cysteine, N-acetyl-L-cysteine and NAC. "N-acetyl" means that an acetyl group is attached to the nitrogen of cysteine. Like cysteine, NAC carries a sulfur-containing sulfhydryl (thiol) group, and the label credits that group for its mucus-thinning action. The label also states that acetylcysteine undergoes rapid deacetylation in the body to yield cysteine, or oxidation to yield diacetylcystine.

This relationship matters because of glutathione, an antioxidant made inside cells. Reviews describe NAC as a cysteine prodrug that replenishes intracellular glutathione (Atkuri 2007) and as a precursor of reduced glutathione (Aldini 2018). None of that was the original goal. NAC was first developed to thin thick mucus, and its glutathione-related uses were explored only afterwards, which is why the history reads the way it does.

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Invention and Patent: Sheffner, 1960–1963

NAC's use as a medicine has a documented patent. US Patent 3,091,569, "Mucolytic-N-acylated sulfhydryl compositions and process for treating animal mucus," names Sheffner, of Evansville, Indiana, as inventor; it was assigned to an American pharmaceutical company. The application was filed on 26 August 1960 and the patent was granted on 28 May 1963. It describes a process for treating mucus with N-acylated sulfhydryl compounds so that the mucus's viscosity is "quickly and markedly reduced," and it lists N-acetylcysteine alongside related compounds such as N-propionylcysteine and N-acetylpenicillamine. Sheffner's laboratory results were published in 1963 in the Annals of the New York Academy of Sciences as "The reduction in vitro in viscosity of mucoprotein solutions by a new mucolytic agent, N-acetyl-L-cysteine," and a 1964 paper by Sheffner and colleagues reported the same kind of test on human tracheobronchial secretions.

The patent records a use and a family of compounds, not the discovery of a new molecule: it states that the compounds "may be prepared by conventional procedures" and gives preparation methods for several of them. What it documents is the development of NAC and its relatives as agents for thinning mucus, the starting point of NAC's career as a drug.

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The Inhaled Mucus-Thinning Drug

Drugs@FDA records the approval of acetylcysteine solution (10% and 20%, for inhalation or oral use) under New Drug Application 013601 on 14 September 1963, classed as a new molecular entity. That product was later discontinued; Drugs@FDA notes a Federal Register determination that it was not withdrawn for safety or effectiveness reasons, and generic acetylcysteine solutions remain approved. FDA's 2022 guidance gives the same approval date and cites the December 1963 Federal Register notice that announced it. The current US label for acetylcysteine inhalation solution lists it as a mucolytic (mucus-dissolving) adjuvant therapy for abnormal, viscid or inspissated mucus in conditions including chronic and acute bronchopulmonary disease and the pulmonary complications of cystic fibrosis. On mechanism, the label states that the mucolytic action is related to the sulfhydryl group, which probably opens disulfide linkages in mucus and so lowers its viscosity; a 2018 review likewise attributes the mucolytic activity to NAC's reduction of heavily cross-linked mucus glycoproteins (Aldini 2018).

The label also records two features of the inhaled drug. Patients may at first notice a slight disagreeable odor. And occasionally, people inhaling an acetylcysteine aerosol develop increased airway obstruction of varying and unpredictable severity; the label states that clinically overt bronchospasm occurs infrequently and unpredictably, even in people with asthmatic bronchitis, and its warnings call for careful observation of people with asthma during treatment. The use that changed NAC's reputation, as a poisoning antidote, came in the 1970s.

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The Paracetamol Antidote: Prescott, 1977

The turning point came from a different problem: poisoning by paracetamol (called acetaminophen in the United States). In overdose, paracetamol can severely damage the liver; in Prescott's 1979 report, 33 of 57 patients (58%) studied retrospectively who had received supportive treatment alone developed severe liver damage. The search for an antidote followed from new understanding of why the drug is toxic, the subject of the next section. A 2023 review co-written by Prescott and Rumack describes how a range of sulfhydryl donors was then tested in animals and in "at risk" patients, and how acetylcysteine was developed as the lead intravenous antidote in the United Kingdom (Bateman 2023). Earlier candidates included cysteamine and methionine: Prescott's group reported in 1977 that, in contrast to cysteamine, NAC was very well tolerated, and in 1979 that intravenous acetylcysteine was more effective than cysteamine and methionine and "noticeably free of adverse effects."

In 1977, Prescott and colleagues published "Treatment of paracetamol (acetaminophen) poisoning with N-acetylcysteine" in The Lancet. Fifteen poisoned patients received intravenous NAC (300 mg/kg given over 20 hours). Liver-function tests stayed normal or were only slightly disturbed in 11 of the 12 patients treated within 10 hours of ingestion; severe liver damage developed in the twelfth patient and in the three whose treatment began more than 10 hours after ingestion. The authors noted that NAC had the advantage of already being available as a pharmaceutical preparation in a 20% sterile solution. Their 1979 report in the British Medical Journal extended this to 100 cases of severe poisoning: protection against liver damage was virtually complete in the 40 patients treated within eight hours, only 1 of 62 patients treated within 10 hours developed severe liver damage, efficacy fell progressively after eight hours, and treatment after 15 hours was completely ineffective. The authors called intravenous acetylcysteine "the treatment of choice for paracetamol poisoning." Today the World Health Organization's Model List of Essential Medicines lists acetylcysteine injection among the specific antidotes used in poisoning.

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Understanding Why It Works: The Glutathione Story

The antidote grew from laboratory work on how paracetamol injures the liver. In 1973, Mitchell, Jollow, Potter, Gillette, Brodie and colleagues published a series of papers in the Journal of Pharmacology and Experimental Therapeutics under the title "Acetaminophen-induced hepatic necrosis"; part I dealt with the role of drug metabolism, and part IV carried the subtitle "protective role of glutathione." PubMed holds no abstracts for these papers. The 2023 review by Bateman and colleagues summarises the series as showing that paracetamol liver toxicity was caused by a "toxic intermediate epoxide metabolite," normally detoxified by glutathione, which in excess bound covalently to liver enzymes and proteins.

That finding pointed to restoring the liver's glutathione as the way to treat the poisoning, and NAC, described in a 2007 review as a cysteine prodrug that replenishes intracellular glutathione (Atkuri 2007), fitted that role. The same glutathione link is the explanation usually offered for the other uses of NAC that have been explored since. The fuller biochemistry, and the modern research into raising glutathione, is covered on the main N-Acetylcysteine (NAC) page and in the Glutathione Precursor article.

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From Drip to Drink: Intravenous and Oral Protocols

Prescott's protocol gave NAC by intravenous drip. The United States took a different route: according to the 2023 review by Bateman and colleagues, the US licence holder refused to make an intravenous formulation, so oral acetylcysteine became the antidote tested in the US National Multicenter Study. Both countries came to rely on the Rumack–Matthew nomogram to decide whom to treat; the same review states that the nomogram was developed from data collected in Edinburgh, and that the US study used a treatment line starting at 150 mg/L at 4 hours after the overdose, while the UK line was initially 200 mg/L at 4 hours and was lowered to 100 mg/L in 2012. Rumack and Bateman (2012) explain that such nomograms predict possible liver damage from the blood paracetamol level and the time since ingestion, using what they call a relatively arbitrary definition of toxicity (an AST or ALT above 1,000 IU/L). Rumack and Matthew's 1975 review in Pediatrics, "Acetaminophen poisoning and toxicity," opens by describing how little American experience existed: in spring 1973 one of the authors contacted nine US university poison services and found that none had clinical experience or analytical methods in operation, while Denver had since recorded 156 ingestions with four deaths in a year.

The oral regimen was reported in 1988 in the New England Journal of Medicine by Smilkstein, Knapp, Kulig and Rumack. Of 11,195 suspected overdoses reported during the investigational use of oral NAC, the analysis described 2,540 treated patients who received 140 mg/kg by mouth followed by 70 mg/kg every four hours for 17 further doses. Liver toxicity developed in 6.1% of patients at probable risk when NAC began within 10 hours of ingestion and in 26.4% when it began 10 to 24 hours after ingestion, and no deaths were clearly caused by acetaminophen among patients whose treatment began within 16 hours. The authors concluded that the 72-hour oral regimen was as effective as the 20-hour intravenous regimen and might be superior when treatment was delayed.

In the United States an intravenous product followed in 2004: Drugs@FDA records the approval of an acetylcysteine injection (NDA 021539) on 23 January 2004, classed as a new dosage form, and its label indicates it to prevent or lessen liver injury after ingestion of a potentially hepatotoxic quantity of acetaminophen. The standard intravenous regimens (150 mg/kg, then 50 mg/kg over four hours, then 100 mg/kg over 16 hours) were associated with nausea, vomiting and anaphylactoid reactions that interrupted treatment, and newer regimens give the loading dose more slowly, including a 12-hour regimen widely adopted in the United Kingdom (Bateman 2023). The same review notes that no dose-ranging or placebo-controlled studies of acetylcysteine were done, so the best dose, particularly after very large overdoses, remains uncertain. Across the Edinburgh and US studies, protection was greatest when treatment began early.

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An Old Drug With New Tricks

Once NAC was understood to supply cysteine for glutathione, researchers began asking whether it could help in other conditions linked to low glutathione. On 14 October 2026, PubMed indexed 15,589 records under the medical subject heading "acetylcysteine." A 2007 review in Current Opinion in Pharmacology by Atkuri, Mantovani, Herzenberg and Herzenberg, from Stanford University's Department of Genetics, called NAC "a safe antidote for cysteine/glutathione deficiency," described its use to treat glutathione deficiency in a wide range of infections, genetic defects and metabolic disorders, including HIV infection and COPD, and reported that over two-thirds of 46 placebo-controlled trials of oral NAC had indicated beneficial effects, measured either as trial endpoints or as general measures of quality of life and well-being.

NAC has since been studied in respiratory disease (notably chronic obstructive pulmonary disease), liver disease beyond paracetamol poisoning, fertility and polycystic ovary syndrome, psychiatric disorders and cardiovascular medicine, with positive and negative trials in most of these areas. One recent line of work comes from Sekhar and colleagues at Baylor College of Medicine on GlyNAC, glycine combined with NAC. In their 2023 randomised trial, 24 older adults received GlyNAC or an alanine placebo for 16 weeks (12 per group) and 12 young adults received GlyNAC for two weeks; the authors reported that GlyNAC, and not placebo, improved or corrected the older group's glutathione deficiency, oxidative stress, mitochondrial dysfunction, inflammation, insulin resistance, physical function and several hallmarks of ageing. A large and growing research record shows sustained scientific interest; it does not show that NAC works for every use being tested. The evidence for each use, what is strong and what is preliminary, is set out in the NAC Benefits articles; this history marks how a 1960s mucus-thinner came to be studied across so much of medicine.

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Drug or Supplement? A Recent Tangle

A modern chapter concerns NAC's legal status in the United States rather than its biology. Federal law excludes from the definition of a dietary supplement an article approved as a new drug, unless it was marketed as a dietary supplement or food before that approval or FDA issues a regulation finding it lawful. FDA has determined that NAC falls under this exclusion because it was approved as a new drug on 14 September 1963, and it states that it is not aware of any evidence that NAC was marketed as a supplement or food before that date. FDA describes this as its position for over 20 years, citing a 2001 response to a health-claim petition, a 2010 letter and a 2017 search-warrant affidavit. In July 2020 it repeated the position in four warning letters to companies selling NAC products with hangover claims. Two dietary-supplement trade associations then filed citizen petitions, in June and August 2021, calling the position recently adopted and a sudden policy change; FDA disagreed that it was a change and, on 31 March 2022, denied the request to conclude that NAC is not excluded from the supplement definition.

FDA then said it would exercise "enforcement discretion." In a draft guidance (April 2022) and a final guidance (August 2022), it stated that its initial safety review had not revealed safety concerns with NAC as a supplement ingredient, that NAC products sold as dietary supplements had been on the US market for more than 30 years, and that it intended not to object to the sale of certain NAC products labelled as dietary supplements while it considers rulemaking to permit NAC in supplements. The policy does not cover products intended to diagnose, cure, mitigate, treat or prevent disease, and FDA said it would last until it completes such a rulemaking or denies the petition's request for one. NAC's dual identity, an approved drug since 1963 and a supplement ingredient sold for decades, follows directly from where its story began.

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Key Research Papers

The list below gathers the key primary sources behind the history above, followed by curated PubMed topic searches and the agency records used. Author names, titles, and journals are given as plain text; only the stable DOI, PMID, or archive link is hyperlinked, and each opens in a new tab.

  1. Prescott LF, Park J, Ballantyne A, Adriaenssens P, Proudfoot AT. Treatment of paracetamol (acetaminophen) poisoning with N-acetylcysteine. Lancet. 1977;2(8035):432-434. — doi:10.1016/s0140-6736(77)90612-2 · PubMed PMID: 70646
  2. Mitchell JR, Jollow DJ, Potter WZ, Davis DC, Gillette JR, Brodie BB. Acetaminophen-induced hepatic necrosis. I. Role of drug metabolism. Journal of Pharmacology and Experimental Therapeutics. 1973;187(1):185-194. — PubMed PMID: 4746326
  3. Mitchell JR, Jollow DJ, Potter WZ, Gillette JR, Brodie BB. Acetaminophen-induced hepatic necrosis. IV. Protective role of glutathione. Journal of Pharmacology and Experimental Therapeutics. 1973;187(1):211-217. — PubMed PMID: 4746329
  4. 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). New England Journal of Medicine. 1988;319(24):1557-1562. — doi:10.1056/NEJM198812153192401 · PubMed PMID: 3059186
  5. Atkuri KR, Mantovani JJ, Herzenberg LA, Herzenberg LA. N-Acetylcysteine — a safe antidote for cysteine/glutathione deficiency. Current Opinion in Pharmacology. 2007;7(4):355-359. — doi:10.1016/j.coph.2007.04.005 · PubMed PMID: 17602868
  6. Kumar P, Liu C, Suliburk J, Hsu JW, Muthupillai R, Jahoor F, Minard CG, Taffet GE, Sekhar RV. Supplementing Glycine and N-Acetylcysteine (GlyNAC) in older adults improves glutathione deficiency, oxidative stress, mitochondrial dysfunction, inflammation, physical function, and aging hallmarks: a randomized clinical trial. The Journals of Gerontology: Series A. 2023;78(1):75-89. — doi:10.1093/gerona/glac135 · PubMed PMID: 35975308
  7. Prescott LF, Illingworth RN, Critchley JA, Stewart MJ, Adam RD, Proudfoot AT. Intravenous N-acetylcystine: the treatment of choice for paracetamol poisoning. British Medical Journal. 1979;2(6198):1097-1100. — doi:10.1136/bmj.2.6198.1097 · PubMed PMID: 519312
  8. Sheffner AL. The reduction in vitro in viscosity of mucoprotein solutions by a new mucolytic agent, N-acetyl-L-cysteine. Annals of the New York Academy of Sciences. 1963;106:298-310. — doi:10.1111/j.1749-6632.1963.tb16647.x · PubMed PMID: 13977050
  9. Sheffner AL, Medler EM, Jacobs LW, Sarett HP. The in vitro reduction in viscosity of human tracheobronchial secretions by acetylcysteine. American Review of Respiratory Disease. 1964;90:721-729. — PubMed PMID: 14211458
  10. Rumack BH, Matthew H. Acetaminophen poisoning and toxicity. Pediatrics. 1975;55(6):871-876. — doi:10.1542/peds.55.6.871 · PubMed PMID: 1134886
  11. Rumack BH, Bateman DN. Acetaminophen and acetylcysteine dose and duration: past, present and future. Clinical Toxicology. 2012;50(2):91-98. — doi:10.3109/15563650.2012.659252 · PubMed PMID: 22320209 — two corrections published 2021 (PubMed PMID: 33576263, PubMed PMID: 33988061)
  12. Bateman DN, Dart RC, Dear JW, Prescott LF, Rumack BH. Fifty years of paracetamol (acetaminophen) poisoning: the development of risk assessment and treatment 1973-2023 with particular focus on contributions published from Edinburgh and Denver. Clinical Toxicology. 2023;61(12):1020-1031. — doi:10.1080/15563650.2023.2293452 · PubMed PMID: 38197864
  13. Aldini G, Altomare A, Baron G, Vistoli G, Carini M, Borsani L, Sergio F. N-Acetylcysteine as an antioxidant and disulphide breaking agent: the reasons why. Free Radical Research. 2018;52(7):751-762. — doi:10.1080/10715762.2018.1468564 · PubMed PMID: 29742938

PubMed Topic Searches

  1. N-acetylcysteine history and mucolytic origins PubMed: NAC history and mucolytic use
  2. N-acetylcysteine and glutathione — mechanism PubMed: NAC as a glutathione/cysteine precursor

Patent and Agency Records

  1. US Patent 3,091,569. Mucolytic-N-acylated sulfhydryl compositions and process for treating animal mucus. Filed 26 August 1960; granted 28 May 1963. — Google Patents: US3091569A
  2. US Food and Drug Administration. Drugs@FDA: New Drug Application 013601, acetylcysteine solution for inhalation or oral use (original approval 14 September 1963). — Drugs@FDA: NDA 013601
  3. US Food and Drug Administration. Drugs@FDA: New Drug Application 021539, acetylcysteine injection (original approval 23 January 2004). — Drugs@FDA: NDA 021539
  4. US National Library of Medicine. DailyMed: acetylcysteine solution for inhalation or oral use, prescribing information. — DailyMed: acetylcysteine solution
  5. US Food and Drug Administration. Final response to two citizen petitions on NAC (31 March 2022), Docket FDA-2021-P-0523. — Regulations.gov: FDA-2021-P-0523-0022
  6. US Food and Drug Administration. Policy Regarding N-acetyl-L-cysteine: Draft Guidance for Industry; Availability. Federal Register. 22 April 2022;87:24170. — Federal Register 2022-08560
  7. US Food and Drug Administration. Policy Regarding N-acetyl-L-cysteine; Guidance for Industry; Availability. Federal Register. 2 August 2022;87:47220-47221. — Federal Register 2022-16499
  8. US Food and Drug Administration. Policy Regarding N-acetyl-L-cysteine: Guidance for Industry (August 2022), Docket FDA-2022-D-0490. — Regulations.gov: FDA-2022-D-0490-0374
  9. World Health Organization. Electronic Model List of Essential Medicines: acetylcysteine. — WHO eEML: acetylcysteine

External Authoritative Resources

  1. NCCIH — Antioxidants: In Depth
  2. MedlinePlus — Acetylcysteine
  3. PubMed — All research on acetylcysteine

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Connections

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