N-acetylcysteine

NAC is the acetylated form of cysteine. It is used in three quite different ways: as a hospital antidote, as a lung medicine and as a supplement.

Paracetamol poisoning. NAC is first-line treatment for paracetamol (acetaminophen) overdose, now usually given intravenously [10]. A Cochrane review found it better than placebo and better tolerated than older antidotes, and one small trial suggested it lowers mortality in fulminant liver failure. Most of the evidence is observational, because the antidote became standard before large trials were run [2]. US and Canadian poison centres published consensus guidance on its use in 2023 [1].

COPD and chronic bronchitis. In PANTHEON, 1,006 Chinese patients with moderate-to-severe COPD took 600 mg twice daily or placebo for a year. Exacerbations fell from 1.49 to 1.16 per patient-year (risk ratio 0.78) [11]. A 2024 meta-analysis found about 24% fewer exacerbations in COPD and 19% fewer in chronic bronchitis [3]. A Cochrane review of all mucolytics reported a small benefit, and it noted that newer trials show smaller effects than older ones [4].

Psychiatry and addiction. In 116 cannabis-dependent adolescents, NAC 1,200 mg twice daily more than doubled the odds of a negative urine test [5]. A larger trial in 302 adults using the same dose found no difference at all: 22.3% of tests were negative on NAC and 22.4% on placebo [6]. In adults with trichotillomania (hair-pulling), 56% were much or very much improved on NAC versus 16% on placebo [12]; a Cochrane review rated this as moderate-certainty evidence from one trial, and a trial in children found no clear benefit [13]. A meta-analysis of six trials found a benefit as add-on treatment in schizophrenia, none in bipolar disorder, and only a small effect in major depression [14]. A later 80-patient trial in bipolar depression was negative [15].

Negative trials. In idiopathic pulmonary fibrosis, NAC 600 mg three times daily did not slow the loss of lung function over 60 weeks [7]. In PRESERVE, 5,177 high-risk patients having angiography received oral NAC or placebo. It did not reduce death, dialysis or lasting kidney decline, and it did not prevent contrast-associated kidney injury [8].

Ageing. A 16-week trial in 24 older adults combined NAC with glycine ("GlyNAC") and reported corrections in glutathione, oxidative stress, mitochondrial function and physical function against an alanine placebo [16]. It was small, and it tested the combination, not NAC alone.

NAC supplies cysteine, which the liver uses to make glutathione [17]. In paracetamol overdose it works as an antidote to NAPQI, the toxic metabolite that damages the liver [2]. In the airways it is used as a mucolytic with antioxidant properties [3].

The psychiatric trials rest on a different idea: preclinical work suggests NAC restores extracellular glutamate in the nucleus accumbens, a brain region involved in reward and habit [5][12]. Whether oral doses do much in the human brain is unclear. In a small study, 6 g a day for four weeks raised some blood antioxidant measures but did not raise brain glutathione, which the authors linked to poor oral bioavailability [18].

Oral NAC is heavily broken down in the gut wall, so only about 6–10% of a dose reaches the blood [9][17]. In a crossover study of a single 600 mg dose, the fast-dissolving forms had the highest bioavailability and a slow-release tablet the lowest [9]. Peak levels of about 14–17 µmol/L arrive 40–70 minutes after standard tablets [17].

Intravenous NAC is fully bioavailable [17]. The traditional three-bag infusion front-loads 150 mg/kg in the first hour, while simplified two-bag regimens spread that dose over several hours [10].

Oral NAC was well tolerated in trials. In PANTHEON, 29% of patients on NAC and 26% on placebo reported adverse events over a year [11]. In both cannabis trials, adverse events were no more common than on placebo [5][6], and the adult trichotillomania trial reported none in the NAC group [12]. At 6 g a day, indigestion was common, and three of five people with Parkinson's disease had symptoms, including worse tremor, which resolved after stopping [18].

In the pulmonary fibrosis trial, serious cardiac events were more frequent on NAC than placebo (6.8% vs 1.5%), while serious gastrointestinal events were less frequent (0% vs 4.6%) [7].

Intravenous NAC often causes non-allergic anaphylactoid reactions such as flushing and itching and, less often, bronchospasm, low blood pressure or swelling [10]. In one emergency department series, 31 of 64 patients (48%) reacted, 71% of them within the first 15 minutes [19]. Two-bag regimens that slow the loading dose cause fewer of these reactions [10].

In mouse models of lung cancer, NAC in the diet sped up tumour growth and shortened survival by lowering oxidative stress, DNA damage and p53 in tumour cells. The authors raised the concern for smokers and people with COPD who take NAC [20]. This has not been shown in humans.

Clearance of NAC falls sharply in advanced kidney disease, so levels stay high for much longer [17]. No interactions with other compounds on this site have been documented.