Bottom Line: N-acetylcysteine is not an effective treatment for cancer or Lou Gehrig's disease.
N-acetylcysteine (abbreviated here as NAC) is a compound that is found naturally in the body. It is a precursor to a chemical called glutathione, which plays a large role in detoxification of foreign substances in the body. NAC itself is a strong antioxidant; it can neutralize free radicals that damage DNA and cells. Several laboratory experiments have tried to see whether this strong antioxidant could prevent cancer in rats, which it appears to do, to some extent. Rats fed NAC have less cellular damage from mutagens and carcinogens (cancer-causing substances) and fewer carcinogen-induced lung, colon, and bladder tumors, compared to rats 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 (see Research Evidence for more information).
NAC also has mucolytic properties, meaning it can dissolve and loosen mucus in patients with respiratory disorders such as cystic fibrosis and COPD. 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.
To treat lung conditions such as bronchitis and chronic obstructive pulmonary disease (COPD) Most clinical trials show that N-acetylcysteine can prevent exacerbations of chronic bronchitis due to its mucus-digesting effect.
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.
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 fully prevent cancer.
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.
Cancer prevention: 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.
Cancer treatment: 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 of N-acetylcysteine (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 additions, almost 18% of the patients taking NAC alone reported stomach upset and/or skin rash.
Prevention of kidney damage from radiology contrast dyes: Radiology contrast dyes such as iopromide can cause a decrease in kidney function, especially in patients with chronic renal insufficiency. Before and after being given iopromide for a CT scan, 83 patients with chronic renal insufficiency were randomly given either N-acetylcysteine or a placebo. Immediately afterwards and for the next few days, patients taking NAC had better blood measures of kidney function than patients taking the placebo.
Chronic bronchitis: A meta-analysis was performed on the eight randomized controlled trials that have studied N-acetylcysteine (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 appears to be effective prevention for patients with chronic bronchitis.
Prevention of heart tissue damage from chemotherapy or radiation therapy: Heart damage can occur as a side effect of radiation therapy and some chemotherapy drugs. In a randomized controlled trial, 32 patients with no previous heart disease were given a mixture of 600 mg of vitamin E, 1 g of vitamin C, and 200 mg of N-acetylcysteine (NAC) or a placebo on the days of therapy. The patients taking the antioxidant mixture had less heart damage as measured by left ventricular ejection fraction. However, these results may not be valid, since the patients in the placebo group received on average higher doses of chemotherapy and radiation, which could explain the difference in tissue damage. Also, this study did not address whether antioxidants interfered with the effectiveness of the cancer treatment, which is a controversial issue.
HIV and AIDS: In order to test whether N-acetylcysteine (NAC) is effective in preventing progression of HIV, researchers gave 800 mg of NAC or a placebo pill to 45 HIV-positive, asymptomatic patients with CD4+ counts >200. After four months, patients taking NAC had higher blood cysteine levels and less of a decrease in CD4+ count than patients taking the placebo. At this point it is still unclear whether NAC has a beneficial effect upon asymptomatic HIV-positive patients.
This product is regulated by the FDA as a dietary supplement. Unlike approved drugs, supplements are not required to be manufactured under specific standardized conditions. This product may not contain the labeled amount or may be contaminated. In addition, it may not have been tested for safety or effectiveness.
N-acetylcysteine may be useful in reducing the liver toxicity associated with acetaminophen overdose, kidney damage from contrast agents (such as iopromide) in patients with chronic renal failure, and heart toxicity from doxorubicin.
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, some physicians have suggested that high levels of antioxidants can neutralize these free radicals and thereby protect cancer cells from these therapies. So what protects healthy cells may protect cancer cells as well. This question is still not fully understood and patients who are interested in taking antioxidants during therapy should consult with their doctor.
Endogenous antioxidant and precursor to intracellular glutathione. N-acetylcysteine (NAC) is used to prevent exacerbations of chronic bronchitis, treat drug-induced hepatotoxicity, and prevent and treat conditions of oxidative stress and reduced glutathione levels, such as HIV/AIDS, cancer, and toxicity from chemo- or radiotherapy. NAC increases plasma levels of cysteine and glutathione and has antioxidant, nucleophilic, mucolytic, and possibly chemopreventative properties. Animal models suggest anti-carcinogenic, antimetastatic, and antiangiogenic activities. Oral bioavailability is low (1). Studies in smokers (4) and patients with history of adenomatous colonic polyps (5) show an inhibition of cancer biomarker development, although NAC did not inhibit formation of secondary head and neck or lung tumors in a EUROSCAN trial (15). 400-1200 mg/day NAC reduces the number of acute exacerbations in patients with chronic bronchopulmonary disease (10), but little clinical effect on lung function is seen in patients with cystic fibrosis (11). NAC raises GSH and cysteine levels in HIV+ patients (12)(13), but shows no effect in Lou Gehrig's disease (14). Human studies evaluating the role of NAC in the prevention of chemo- or radiotherapy induced toxicities are inconclusive. Gastrointestinal side effects are most often reported.
NAC is a precursor to intracellular glutathione. It is a known nucleophile and free radical scavenger, either directly or as a source of cysteine and glutathione (1). In rodent models, NAC inhibits a variety of mutagen/carcinogen-induced cancer biomarkers, interferes with the promotion phase of multistage carcinogenesis, and produces a decrease in the incidence of carcinogen-induced tumors of the lung, colon, and bladder. This activity may be due to its ability to enhance glutathione S-transferases, glutathione peroxidase, glutathione reductase, and NADH- and NADPH-quinone reductase (4)(5). In vitro and in animal models, NAC exhibits anti-invasive, antimetastatic, and antiangiogenic properties. NAC can also be employed as a mucolytic agent in the treatment of respiratory diseases and as an antidote to acetaminophen poisoning (2). Animal studies report that NAC may also protect against doxorubicin toxicity and bladder cystitis induced by ifosfamide and cyclophosphamide (3).
Absorption 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 or total form. In plasma NAC may be found in intact, reduced, or various oxidized forms (1). Low bioavailability is most likely due to extensive first pass metabolism, and not to incomplete absorption (2). Distribution Studies show that volume distribution (Vd) for total NAC ranges from 0.33 to 0.47 L/kg. 2 hours after administration, tissue distribution is as follows in descending order: kidney, liver, adrenal gland, lung, spleen, blood, brain, and urine (1). Metabolism/Excretion 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 (2).
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 or placebo twice daily 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.
Tepel M, et al. Prevention of radiographic-contrast-agent-induced reductions in renal function by acetylcysteine. N Engl J Med 2000;343:180-4. A prospective, randomized, controlled trial of acetylcysteine in 83 patients with chronic renal insufficiency undergoing CT with iopromide. Patients were randomized to receive 600 mg BID oral acetylcysteine or placebo plus intraveous saline before and after administration of 75 ml iopromide. Serum creatinine and urea nitrogen were measured before, 48 hours after, and 6 days after administration of iopromide. An acute iopromide-induced reduction in renal function was defined as an increase in serum creatinine of at least 0.5 mg/dl, which occurred in one treatment patient and 9 controls. At the 48 hour reading, mean serum creatinine had increased slightly in the control group, but decreased significantly in the acetylcysteine group (p<0.001). Mean serum urea nitrogen also decreased significantly in the treatment arm, while increasing slightly in the control group (p<0.001). Patient diagnoses were heterogeneous, which may have influenced the efficacy of acetylcysteine treatment.
