N-Acetyl-L-Cysteine

NAC is N-acetyl-L-cysteine, also written N-acetylcysteine or N-acetyl cysteine. Its drug name is acetylcysteine. It is the N-acetyl derivative of the amino acid L-cysteine, studied as an antioxidant and as a disulfide-breaking agent (Aldini et al., 2018). Its free thiol group reduces disulfide bonds in proteins, and the molecule is a source of cysteine for glutathione synthesis (Samuni et al., 2013).

An intravenous form followed on January 23, 2004 (NDA 021539).

Labels list the solution as a mucolytic and acetaminophen antidote, and the 2004 form as an antidote to prevent or lessen liver injury after a potentially hepatotoxic acetaminophen ingestion. The research liquid sold here is not one of those drug products.

PubChem CID 12035 lists the same formula and 163.20 g/mol, and is the source of the CAS number, structure and synonyms.

N-acetylcysteine research falls into five areas, each summarized below with its model. Mechanism work is mostly cell and animal data; human studies appear as research history.

Glutathione supply and thiol chemistry

A 2018 review attributes NAC's antioxidant effect mainly to glutathione supply, plus direct reactions with oxidants such as nitrogen dioxide and hypohalous acids when cysteine and glutathione are depleted (Aldini et al., 2018). A 2013 review notes fast reactions with hydroxyl, nitrogen dioxide, carbonate and thiyl radicals, but slow ones with superoxide, hydrogen peroxide and peroxynitrite, which casts doubt on their importance under physiological conditions (Samuni et al., 2013).

In human lung adenocarcinoma H838 cells, NAC-derived cysteine was converted to hydrogen sulfide and then to sulfane sulfur species, mainly in mitochondria. The authors proposed these species as the actual mediators of NAC's fast antioxidant effects (Ezeriņa et al., 2018). Models: reviews and a human cancer cell line.

Oxidative-stress cell models

Three studies show why NAC's effects in these models need careful reading. In serum-deprived PC12 cells and in neonatal sympathetic neurons deprived of nerve growth factor, NAC prevented apoptotic DNA fragmentation and kept cells alive. The D-stereoisomer did too, while other antioxidants did not, and both forms slowed PC12 proliferation, pointing the authors toward a cell cycle mechanism (Ferrari et al., 1995).

In human cancer cell lines, NAC, unlike catalase or Trolox, bound proteasome inhibitors directly and blocked their effects, so the authors cautioned that a rescue by NAC alone may not show that reactive oxygen species were involved (Halasi et al., 2013). In mouse models of B-RAF- and K-RAS-driven lung cancer, NAC or vitamin E in the diet increased tumor progression and reduced survival; in lung tumor cells, both lowered ROS, DNA damage and p53 expression (Sayin et al., 2014). Models: cell lines, primary neurons and mice.

Acetaminophen poisoning: mechanism and antidote history

In rats given a hepatotoxic amount of acetaminophen, radiolabeled NAC formed almost no adduct with the drug's toxic metabolite. Instead it reversed glutathione depletion, raising glutathione synthesis from 0.54 to 2.69 µmol/g per hour (Lauterburg et al., 1983). In a 1979 series of 100 cases of severe paracetamol (acetaminophen) poisoning, intravenous NAC started within eight hours gave virtually complete protection against liver damage; efficacy fell with later starts and was absent after 15 hours (Prescott et al., 1979).

A 50-year review records that the UK developed the intravenous form while the US trialed an oral regimen. It notes nausea, vomiting and anaphylactoid reactions with early intravenous regimens, and that no placebo-controlled trials were done (Bateman et al., 2023). Models: rats, a human case series and a review.

Cystine-glutamate exchange and addiction models

The cystine-glutamate exchanger, system xc-, trades extracellular cystine for intracellular glutamate. In rats withdrawn from repeated cocaine, reduced exchange lowered extracellular glutamate in the nucleus accumbens; systemic NAC restored it and prevented cocaine-primed reinstatement of drug seeking (Baker et al., 2003). In a later rat study, suppressing the exchanger subunit xCT in the nucleus accumbens did not change NAC's effect on cue-induced reinstatement, but suppressing the glutamate transporter GLT-1 abolished it (Reissner et al., 2015).

Human trials, as published: in 116 cannabis-dependent adolescents who all received contingency management, NAC gave more than twice the odds of negative urine cannabinoid tests versus placebo (Gray et al., 2012). A 302-person adult trial on the same platform found no difference (Gray et al., 2017). A 192-person youth trial without contingency management found none either and reported more gastrointestinal adverse events with NAC (Gray et al., 2025). Models: rats and randomized human trials.

Mucolytic action and a lung trial

The same disulfide-breaking activity explains NAC's mucolytic action: it reduces heavily cross-linked mucus glycoproteins (Aldini et al., 2018). In a 3-year placebo-controlled trial of 523 people with chronic obstructive pulmonary disease at 50 centers, NAC did not change the yearly decline in FEV1 or the number of exacerbations. A subgroup analysis suggested fewer exacerbations in those not using inhaled corticosteroids (Decramer et al., 2005). Models: a chemistry review and a human trial.