NAC (N-acetyl-cysteine) is a supplement used by people with HIV, usually as part of an antioxidant regimen. NAC is usually taken two or three times daily and is available in capsule and tablet forms in some health food stores. NAC is also available by prescription in liquid form from pharmacies.
What is NAC?
NAC is a supplement used by some people living with HIV. NAC stands for N-acetyl-cysteine and is similar to the amino acid cysteine. Taking NAC helps to increase levels of the protective compound glutathione (GSH) in the body.
How does NAC work?
Before explaining how NAC works, we first need to give you some background information about GSH.
GSH is a compound that the body makes using various nutrients including the amino acid cysteine. GSH is the body's chief protector from the injury caused by harmful substances. Results from a number of studies suggest that in people with HIV the demand by the body for GSH exceeds the supply. Less-than-normal levels of GSH may result in impaired performance by cells of the immune system and perhaps increased sensitivity to the toxic effects of some drugs. When there is not enough cysteine available to make GSH, the body tears down muscles, which are rich in protein, to find the nutrients needed to make GSH. NAC works by acting as a source of cysteine and stimulating the production of GSH.
Why do some people with HIV use NAC?
1. As an antioxidant and to help reduce inflammation
In the late 1980s, researchers found that people with HIV were likely to have higher-than-normal levels of highly active compounds called "free radicals." These compounds damage cells in much the same way that rust damages a car. Some people with HIV take NAC as part of an antioxidant regimen to help counter the damaging effects of high levels of free radicals. NAC continues to be studied in clinical trials with HIV-positive participants such as the Maintain study in Canada. Excessive levels of free radicals can also lead to higher-than-normal levels of inflammation. Persistent and elevated levels of inflammation may degrade major organ-systems. A pilot study has found that a supplement of NAC and the amino acid glycine can significantly and quickly reduce excess inflammation in a small group of HIV-positive men. The study had only 10 participants, used very high doses of NAC and lasted for two weeks. Longer and larger studies are required to confirm these results.
2. To maintain GSH and muscle mass
HIV-positive people—whether or not they are taking potent combination anti-HIV therapy (commonly called ART)—can experience a loss of critical sulfur-containing amino acids, such as cysteine and methionine. Supplements of NAC may be able to replace lost cysteine, help maintain protein levels and possibly reduce muscle wasting. Together, all of these potential benefits may explain why one American study found that supplements of NAC—an average of 4 grams daily—prolonged survival for up to three years in the time before ART was widely available. That study was the impetus for the widespread use of NAC by HIV-positive people and so it may be useful to briefly review findings from that study.
In the early 1990s, researchers at Stanford University in California conducted an eight-week randomized, placebo-controlled study of NAC in HIV-positive people. The dose of NAC used was about 4,400 mg daily. After the initial eight weeks, all participants were offered NAC for six months. Researchers collected data on the survival of participants for several years after they stopped using NAC. They found that this supplement significantly increased GSH levels within CD4+ cells. However, NAC did not significantly raise CD4+ cell counts. The data also suggested that people who used NAC were twice as likely to survive over the next two years compared to people who did not ever use NAC. At the time of the study, ART was not available and most participants used AZT (zidovudine, Retrovir) with or without another nuke (nucleoside analogue). Due to the study design, firm conclusions about the effect of NAC on survival in HIV infection cannot be drawn and it is important to note that a large proportion of NAC users did eventually die. However, the trial did heighten interest in the use of antioxidants.
In the time before ART was available, researchers in Montreal also tested whey protein concentrates, which are rich in cysteine, in HIV-positive volunteers and found that they improved weight. In that era a sustained increase in weight was unusual in HIV-positive people.
A small study in the current era has found that NAC taken orally does replenish GSH levels inside cells and also reduces inflammation.
3. To protect the liver and kidneys from the toxicity of drugs
In some people, the pain reliever acetaminophen (Tylenol) can cause injury to the liver and kidneys even when used within normal doses. In hospitals in North America, in cases of overdose with paracetamol or acetaminophen, doctors can sometimes prevent the onset of severe liver injury (and death) by giving NAC intravenously. In theory, since the body uses GSH to protect cells from injury, it is possible that NAC may be protective in cases of poisoning from other drugs. However, NAC has not been tested for this purpose in well-designed clinical trials, so there is no firm data to support such a use in people.
4. Other potential uses
NAC is being studied for the treatment of addiction disorders.
At high doses, NAC may cause the following symptoms in some people:
- abdominal discomfort
In lab experiments with cells, high concentrations of NAC can weaken some activities of the immune system. There have been no studies of this in people.
If you are taking antibiotics, NAC should not be taken, as it may weaken their beneficial effects.
The best dose of NAC for people with HIV is not clear, but reviewing the data from clinical trials in people with HIV may be useful. In the previously mentioned American study, use of about 4 grams per day of NAC was associated with improved survival. However, anecdotal reports suggest that taking such large doses of NAC for prolonged periods can cause abdominal discomfort, nausea, vomiting and diarrhea.
According to results from two German studies, a dose of 3 grams every other day is effective at increasing GSH levels and does not appear to cause toxicity. Alternatively, some people with HIV take smaller doses of NAC, between 500 to 1,000 mg, once or twice daily.
Taking NAC with meals or acidic drinks (orange juice, cola beverages) may reduce nausea.
In drug stores, NAC is available in liquid form with a prescription. Some health food stores sell NAC in capsule form.
Sekhar RV, Liu CW, Rice S. Increasing glutathione concentrations with cysteine and glycine supplementation lowers inflammation in HIV patients. AIDS. 2015 Sep 10;29(14):1899-900.
Eck HP, Gmünder H, Hartmann M et al. Low concentrations of acid-soluble thiol (cysteine) in the blood plasma of HIV-1-infected patients. Biological Chemistry Hoppe-Seyler. 1989 Feb;370(2):101-8.
Buhl R, Jaffe HA, Holroyd KJ et al. Systemic glutathione deficiency in symptom-free HIV-seropositive individuals. Lancet. 1989 Dec 2;2(8675):1294-8.
Roederer M, Staal FJ, Osada H et al. CD4 and CD8 T cells with high intracellular glutathione levels are selectively lost as the HIV infection progresses. International Immunology. 1991 Sep;3(9):933-7.
Roederer M, Raju PA, Staal FJ et al. Cytokine-stimulated human immunodeficiency virus replication is inhibited by N-acetyl-L-cysteine. Proceedings of the National Academy of Sciences USA. 1990 Jun;87(12):4884-8.
Kalebic T, Kinter A, Poli G et al. Suppression of human immunodeficiency virus expression in chronically infected monocytic cells by glutathione, glutathione ester, and N-acetylcysteine. Proceedings of the National Academy of Sciences USA. 1991 Feb 1;88(3):986-90.
Bounous G, Baruchel S, Falutz J et al. Whey proteins as a food supplement in HIV-seropositive individuals. Clinical and Investigative Medicine. 1993 Jun;16(3):204-9.
Fuchs J, Schöfer H, Milbradt R et al. Studies on lipoate effects on blood redox state in human immunodeficiency virus infected patients. Arzneimittel-Forschung. 1993 Dec;43(12):1359-62.
Walmsley SL, Winn LM, Harrison ML et al. Oxidative stress and thiol depletion in plasma and peripheral blood lymphocytes from HIV-infected patients: toxicological and pathological implications. AIDS. 1997 Nov 15;11(14):1689-97.
Grant PR, Black A, Garcia N, et al. Combination therapy with interferon-alpha plus N-acetyl cysteine for chronic hepatitis C: a placebo controlled double-blind multicentre study. Journal of Medical Virology. 2000 Aug;61(4):439-42.
Borges-Santos MD, Moreto F, Pereira PC et al. Plasma glutathione of HIV(+) patients responded positively and differently to dietary supplementation with cysteine or glutamine. Nutrition. 2012; in press.
Milazzo L, Menzaghi B, Caramma I et al. Effect of antioxidants on mitochondrial function in HIV-1-related lipoatrophy: a pilot study. AIDS Research & Human Retroviruses. 2010 Nov;26(11):1207-14.
Antunes AM, Godinho AL, Martins IL et al. Amino acid adduct formation by the nevirapine metabolite, 12-hydroxynevirapine—a possible factor in nevirapine toxicity. Chemical Research in Toxicology. 2010 May 17;23(5):888-99.
Cemerski S, Cantagrel A, Van Meerwijk JP et al. Reactive oxygen species differentially affect T cell receptor signaling pathways. Journal of Biological Chemistry. 2002;277(22):19585-93.
Breitkruetz R, Holm S, Pittack N, et al. Massive loss of sulfur in HIV infection. AIDS Research and Human Retroviruses. 2000;16(3):203-09.
Lyons J, Rauh-Pfeiffer A, Yu YM, et al. Blood glutathione synthesis rates in healthy adults receiving a sulfur amino acid-free diet. Proceedings of the National Academy of Sciences USA. 2000;97(10):5071-6.
Nakamura H, De Rosa Sc, Yodoi J, et al. Chronic elevation of plasma thioredoxin: inhibition of chemotaxis and curtailment of life expectancy in AIDS. Proceedings of the National Academy of Sciences USA. 2001;98(5):2688-93.
Herzenberg LA, De Rosa SC, Dubs JG et al. Glutathione deficiency is associated with impaired survival in HIV disease. Proceedings of the National Academy of Sciences USA. 1997;94:1967-72.
Dröge W and Holm E. Role of cysteine and glutathione in HIV infection and other diseases associated with muscle wasting and immunological dysfunction. Federation of American Societies for Experimental Biology Journal. 1997;11:1077-89.
Fraternale A, Tonelli A, Casabianca A et al. Role of macrophage protection in the development of murine AIDS. Journal of Acquired Immune Deficiency Syndromes. 1999;21:81-9.
Martin JA, Sastre J, García de la Asunción J et al. Hepatic gamma-cystathionase deficiency in patients with AIDS. Journal of the American Medical Association. 2002;285(11):1444-5.
Dröge W and Breitkreutz R. Glutathione and immune function. Proceedings of the Nutrition Society. 2000;59:595-600.
WellSpring. Mucomyst (acetylcysteine); mucolytic; antidote for acetaminophen poisoning. Compendium of Pharmaceutical Specialities. 2012;1710-11.
Fored CM, Ejerblad E, Linblad P et al. Acetaminophen, aspirin, and chronic renal failure. New England Journal of Medicine. 2001;345:1801-1808.
Staal F. Antioxidant therapy for AIDS. European Journal of Clinical Investigation. 2000;30:841-2.
Müller F, Svardal AM, Nordøy I et al. Virological and immunological effects of antioxidant treatment in patients with HIV infection. European Journal of Clinical Investigation. 2000;30(10):905-14.
De Rosa SC, Zaretsky MD, Dubs JG et al. N-acetylcysteine replenishes glutathione in HIV infection. European Journal of Clinical Investigation. 2000;30(10):915-29.
Breitkreutz R, Pittack N, Nebe CT et al. Improvement of immune functions in HIV infection by sulfur supplementation: two randomized trials. Journal of Molecular Medicine. 2000;78:55-62.
Luft FC. The slime loosener strikes again! Journal of Molecular Medicine. 2000;78:1-2.
Verhasselt V, Vanden Berghe W, Vanderheyde N et al. N-acetyl-L-cysteine inhibits primary human T cells responses at the dendritic cell level: association with NF-kappaB inhibition. Journal of Immunology.1999;162(5):2569-74.
Ferrucci A, Nonnemacher MR, Cohen EA, et al. Extracellular human immunodeficiency virus type 1 viral protein R causes reductions in astrocytic ATP and glutathione levels compromising the antioxidant reservoir. Virus Research. 2012 Aug;167(2):358-69.
Borges-Santos MD, Moreto F, Pereira PC, et al. Plasma glutathione of HIV⁺ patients responded positively and differently to dietary supplementation with cysteine or glutamine. Nutrition. 2012 Jul;28(7-8):753-6
Blas-García A, Martí-Rodrigo A, Víctor VM, et al. The purine analogues abacavir and didanosine increase acetaminophen-induced hepatotoxicity by enhancing mitochondrial dysfunction. Journal of Antimicrobial Chemotherapy. 2016; in press.
Buckley NA, Dawson AH, Juurlink DN, et al. Who gets antidotes? Choosing the chosen few. British Journal of Clinical Pharmacology. 2016; in press.
Chughlay MF, Kramer N, Spearman CW, et al. N-acetylcysteine for non-paracetamol drug-induced liver injury: a systematic review. British Journal of Clinical Pharmacology. 2016; in press.
McClure EA, Baker NL, Gipson CD, et al. An open-label pilot trial of N-acetylcysteine and varenicline in adult cigarette smokers. American Journal of Drug and Alcohol abuse. 2015 Jan;41(1):52-6.
Brown RM, Kupchik YM, Kalivas PW. The story of glutamate in drug addiction and of N-acetylcysteine as a potential pharmacotherapy. JAMA Psychiatry. 2013 Sep;70(9):895-7.
McClure EA, Gipson CD, Malcolm RJ, et al. Potential role of N-acetylcysteine in the management of substance use disorders. CNS Drugs. 2014 Feb;28(2):95-106.
Author(s): Hosein SR