For Patients & Caregivers
Bottom Line: 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 (spread), and blood vessel growth (angiogenesis) 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. Studies in animals 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.
- To treat lung conditions such as bronchitis and COPD
Clinical trials evaluating NAC for prevention of exacerbations of 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 (9)
- 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(2), 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 N-acetylcysteine 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 substances and gambling addictions. It may also help to reduce symptoms of trichotillomania (hair pulling) .
A small clinical trial examined the effect of N-acetylcysteine (NAC) supplements on DNA damage caused by smoking. For six months, 21 healthy smokers took 600 mg of NAC twice a day, while 20 took a placebo pill. Researchers measured the level of DNA damage in these smokers by looking at DNA adducts, which are alterations in DNA that can lead to mutations and may eventually lead to cancer. The people taking NAC had a lower level of certain types of DNA adducts than people taking the placebo, but similar levels of other types of adducts. However, these results do not really tell us whether NAC would be effective in preventing cancer, and more studies are needed that look at cancer development as an endpoint, not DNA adducts.
Adenomatous colonic polyps are growths in the colon that can be pre-cancerous. A clinical trial looked at the ability of NAC to slow the growth of these polyps. Sixty-four patients with previous adenomatous colonic polyps were randomly assigned to taking 800 mg of NAC daily or a placebo pill. The average number of polyp cells showing growth (measured via biopsy) decreased slightly in the group taking NAC, but increased a tiny bit in the placebo group. Like the previous study, this does not tell us whether NAC would prevent colon cancer, and more clinical trials are needed.
In a clinical trial, 2573 patients with non-small-cell lung cancer (NSCLC), cancer of the larynx (voicebox), or cancer of the mouth were split into four groups, taking: (1) vitamin A only, (2) 600 mg NAC only, (3) both, or (4) two placebo pills. After two years, average survival rates and development of secondary tumors were not significantly different between the four groups. This indicates that neither vitamin A nor NAC are effective in treating these cancers. In addition, almost 18% of the patients taking NAC alone reported stomach upset and/or skin rash.
A meta-analysis was performed on eight randomized controlled trials that have studied NAC for preventing exacerbations of chronic bronchitis. Overall, doses from 400 to 1200 mg/day were very effective in reducing the risk of bronchitis exacerbations. When taken for 2-6 months, NAC appeared to be an effective prevention for patients with chronic bronchitis. However, the small number of trials that could be compared were dated and more recent randomized controlled trials have had mixed results.
- 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 the 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.
For Healthcare Professionals
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 reduced 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 these effects were not observed in other trials (7)(8). NAC has no significant benefits in patients with cystic fibrosis (9) or with Lou Gehrig’s disease (10).
NAC has glutamate modulating effect (11) and has been tested as a treatment for psychiatric disorders (12) including addictions (13) and substance abuses (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). And preliminary results suggests oral NAC may help reduce chemotherapy-induced neuropathy (18). However, NAC accelerated lung cancer growth in an animal model (36).
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.
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).
Orally administered NAC reaches peak plasma concentrations (Cmax) in 1-2 hours. Bioavailability is estimated to be between 4 and 10% depending on whether the drug is in its reduced form. In plasma, NAC may be found intact, or appear in reduced or oxidized forms (26). Low bioavailability is most likely due to extensive first-pass metabolism, and not to incomplete absorption (27). Absorption of NAC can be increased using an amide formulation (25).
Studies show that volume distribution (Vd) for total NAC ranges from 0.33 to 0.47 L/kg. Tissue distribution 2 hours post-administration follows this descending order: kidney, liver, adrenal gland, lung, spleen, blood, and brain (26).
Animal and human studies show the major metabolites of NAC to be cysteine and cystine. Inorganic sulphate is the primary urinary excretion product together with small amounts of taurine and unchanged NAC (27).
Al-Tonbary Y, et al. Vitamin E and N-acetylcysteine as antioxidant adjuvant therapy in children with acute lymphoblastic leukemia. Adv Hematol. 2009:689639.
This study evaluated vitamin E and NAC as adjuvant antioxidant therapy for treatment-induced toxicity in a cohort of children aged 2 to 15 years with acute lymphoblastic leukemia. Patients receiving chemo- and radiotherapy were assigned to either adjuvant supplementation with vitamin E and NAC (Group I) or no supplementation (Group II; n=20 each group). Measures included the occurrence of complications, serum glutathione peroxidase (Glu.PX), malondialdehyde (MDA), and tumor necrosis factor-alpha (TNF-alpha) levels, liver enzymes, and bone marrow status. Group I experienced reduced toxicity as demonstrated by significantly increased Glu.Px, and decreased occurrence of toxic hepatitis, hematological complications, and need for blood/platelet transfusions compared with Group II. However, the decreases seen in MDA and TNF-alpha levels were not significant. The authors conclude these results merit further study to assess long-term benefits while incorporating additional parameters to evaluate the relative benefits and risks.
Lin PC, et al. N-acetylcysteine has neuroprotective effects against oxaliplatin-based adjuvant chemotherapy in colon cancer patients: preliminary data. Support Care Cancer. 2006;14:484-7.
This pilot study evaluated the effect of oral NAC on oxaliplatin-induced neuropathy. Fourteen patients with stage III colon cancer and regional lymph node metastases receiving adjuvant biweekly oxaliplatin 85 mg/m2 plus weekly fluorouracil boluses and low-dose leucovorin were randomized to 1200 mg NAC (Arm A, n=5) or placebo (Arm B, n=9). Neurological and electrophysiological evaluations were performed at baseline and after 4, 8, and 12 treatment cycles and treatment-related toxicity was evaluated based on National Cancer Institute criteria. After 4 cycles of chemotherapy, 7 patients in Arm B vs 2 patients Arm A experienced grade 1 neuropathy. After 8 cycles, 5 patients in Arm B experienced grade 2-4 neuropathy vs no patients in Arm A (p=0.038). After 12 cycles, grade 2-4 neuropathy was observed in 8 and 1 patients in Arm B vs Arm A, respectively (p=0.01). No significant electrophysiological changes in Arm A after 4, 8, or 12 cycles of chemotherapy were found. The authors concluded that oral NAC reduces the incidence of oxaliplatin-induced neuropathy in colon cancer patients receiving oxaliplatin-based adjuvant chemotherapy. Larger confirmatory studies are needed.
Baniasadi S, et al. Protective effect of N-acetylcysteine on antituberculosis drug-induced hepatotoxicity. Eur J Gastroenterol Hepatol. 2010 Oct;22(10):1235-8.
This randomized trial investigated the effect of NAC on antituberculosis drug-induced hepatotoxicity in 60 patients with tuberculosis aged 60 years or more. Patients randomized to Group 1 (n=32) received daily doses of isoniazid, rifampicin, pyrazinamide, and ethambutol. Patients assigned to Group II (n=28) were treated with the same regimen, plus 600 mg NAC, orally twice daily. At both the one- and two-week follow-up, mean alanine aminotransferase and aspartate aminotransferase values were significantly higher (p<0.05) in Group I than in Group II. The authors reported that hepatotoxicity was observed in 12 patients (37.5%) in Group I, and in none of the patients in Group II.
Stav D and Raz M. Effect of N-acetylcysteine on air trapping in COPD: a randomized placebo-controlled study. Chest. 2009 Aug;136(2):381-6.
This randomized, double-blind, cross-over study enrolled patients (n=24) with a diagnosis of COPD aged 40 and older. Enrollment criteria required that patients have a forced expiratory volume in 1 second (FEV1) < 70% of predicted, FEV1/FVC ratio < 0.70, and a functional residual capacity > 120% of predicted normal. Patients were randomized to receive either 1200 mg/day (600 mg twice daily) NAC or placebo treatment for six weeks. This phase was followed by a 2-week washout period and then 6 weeks therapy with the alternate treatment. This study found that the COPD patients had better endurance (p<0.001), inspiratory capacity (p<0.0033), and forced vital capacity (p<0.0029), particularly after exercise, after NAC treatment compared with placebo. The authors concluded that NAC treatment of patients with moderate-to-severe COPD has a beneficial effect on physical performance, probably due to a reduction in air trapping.
Decramer M, 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. 2005;365(9470):1552-60.
This 50-center randomized double-blind placebo-controlled trial assigned 523 patients with COPD to NAC 600 mg daily or placebo. Patients were followed for 3 years to measure the primary endpoints of yearly reduction in FEV1 and the number of exacerbations annually; secondary endpoints included quality of life measures. Annual FEV1 decline did not differ between NAC and placebo groups and no difference was seen in subgroup analyses. The number of yearly exacerbations also did not differ between groups, although a subgroup analysis suggested that the exacerbation rate might be reduced with NAC in patients not treated with inhaled corticosteroids and a secondary analysis suggested an effect on hyperinflation. The investigators concluded that NAC was ineffective at preventing lung function deterioration or exacerbations in patients with COPD.
Van Schooten FJ, et al. Effects of oral administration of N-acetyl-L-cysteine: a multi-biomarker study in smokers. Cancer Epidemiol Biomarkers Prev. 2002;11:167-75.
A double-blind, controlled evaluation of NAC supplementation (n=21) versus placebo (n=20) in healthy smokers. Internal dose markers (plasma and BAL fluid cotinine, and urine mutagenicity), biologically effective dose markers (smoking-related DNA adducts, oxidative DNA damage and Hb adducts), and biological response markers (frequency of micronuclei and antioxidants scavenging capacity) were assessed pre- and post-intervention. Patients were randomized to receive 600 mg NAC twice daily or placebo for 6 months. NAC administration significantly inhibited formation of lipophilic-DNA adducts and 8-OH-dG adducts in BAL cells, but had no effect on MFC/BMC PAH-DNA adducts, PBL lipophilic-DNA adducts, and 4-ABP-Hb adducts. Further studies, possibly with development of lung cancer as an outcome, should be conducted.
Van Zandwijk N, et al. EUROSCAN, a randomized trial of vitamin A and N-acetylcysteine in patients with head and neck cancer or lung cancer. J Nat Can Inst. 2000;92:977-86.
A prospective, open-label, randomized evaluation of vitamin A (300,000 IU daily for 1 year followed by 150,000 IU daily for 1 year), N-acetylcysteine (NAC, 600 mg once daily for 2 years), both agents, or placebo in patients with non-small-cell lung cancer (NSCLC), laryngeal cancer, or cancer of the oral cavity. A total of 2,573 patients were randomized to vitamin A (n=647), NAC (n=642), both agents (n=643), or placebo (n=641). Demographics appear similar between treatment arms, but no statistical tests were reported. Five-year survival, event-free survival, and development of secondary tumors were not significantly different between treatment arms. Nearly 18% of patients receiving NAC alone reported adverse occurrences related to gastric events and skin rash. The authors conclude that vitamin A alone, in combination with NAC, or NAC alone is no better than placebo in improving survival or decreasing second tumors for patients with primary NSCLC or head and neck cancers.