N-acetyl cysteine (NAC): Uses, Benefits & Side Effects

Similar to L-glutamine, L-cysteine is a conditionally essential amino acid, meaning the body’s demand for it increases during times of stress. In this sense, active individuals, people with illnesses, and those who don’t consume a sufficient amount of quality protein are prone to cysteine deficiency.

In contrast to L-glutamine (which is abundant in most protein-rich foods), L-cysteine is generally scarce in the typical Western diet. Moreover, L-cysteine is a sulfur-containing amino acid due to its thiol side chain; it is also the biological precursor to glutathione, making it arguably the most important amino acid for controlling oxidative stress in the body.

In turn, lacking L-cysteine can significantly reduce antioxidant status in the body and increase the likelihood of chronic oxidative stress – the putative cause of many modern diseases.[1]

However, L-cysteine supplements present a bit of a conundrum as this amino acid isn’t well-absorbed in free-form. Thankfully, you can get more L-cysteine in your diet by using an acetylated version of this amino acid, called N-acetyl-L-cysteine (or “NAC,” for short).

Read on as this article provides a detailed understanding of what NAC is, its benefits, potential side effects, and where to buy it.

What is N-Acetyl-L-Cysteine (NAC)?

N-acetyl-L-cysteine, also known as NAC and acetylcysteine, is a modified form of L-cysteine with an acetyl group bonded to it’s amino (nitrogen-based) group. Under normal conditions, supplemental free-form L-cysteine is significantly degraded during the first-pass metabolism through the liver, yielding poor absorption into the bloodstream.

NAC, on the other hand, is deacetylated in the liver during the first-pass metabolism, producing a greater amount of hepatic L-cysteine (which may then go onto replenish liver glutathione levels or enter the bloodstream if necessary).

NAC and Glutathione

L-cysteine is kept within a tightly regulated range in the body under the regulation of the liver. When cysteine levels are elevated inside of cells, the liver reduces production of cysteine dioxygenase (CDO) – the enzyme that catabolizes/breaks down L-cysteine.[2] To remove excess cysteine from cells, more glutathione is produced via the glutamate-cysteine ligase (CGL) enzyme.

Contrarily, when cysteine is lacking inside cells, glutathione is degraded to resynthesize it. Glutathione is the primary endogenous antioxidant and a key tripeptide for neutralizing reactive oxygen species (e.g., superoxide, peroxide, etc.) and free radicals. In other words, glutathione helps detoxify the body of reactive compounds that can potentially disrupt all components of cells, including DNA, proteins, and lipids.

As such, having low amounts of glutathione can impair a myriad of physiological processes by allowing oxidative stress to become chronically elevated.[3] Make no mistake that some oxidative stress is necessary for biological processes as well as health and longevity, but when it becomes excessive and lasting, it can cause damage at the genetic and cellular levels.

For example, chronic oxidative stress is thought to play a role in the development of cancer, Alzheimer’s disease, Parkinson’s disease, ADHD, autism, depression, cardiovascular disease, and other debilitating, if not lethal, health conditions.[4]

You might think that simply supplementing with glutathione instead of NAC is the prudent thing to do, but glutathione is a tripeptide made up of L-cysteine, L-glutamic acid, and L-glycine and not orally bioactive.[5] Thus, if you see glutathione in a pill or powder supplement, it’s essentially worthless.

Sublingual glutathione preparations do, however, appear to be highly bioavailable.[6] Similarly, NAC is orally bioactive and efficacious for increasing intracellular cysteine levels and, consequently, glutathione levels.[7]

Theoretically speaking, since L-cysteine is one-third of a glutathione molecule, supplementing with 100 mg of NAC can lead to the de novo synthesis of 300 mg of reduced glutathione (GSH).

Interestingly, one study found that subjects supplementing with 200 mg of NAC per day experienced increases in GSH nearly as much as those taking 450 mg of sublingual GSH daily. This suggests that the aforementioned theoretical ratio of 100 mg of NAC producing 300 mg of GSH is not too far off.[8]

Benefits of NAC

NAC Increases Glutathione for Natural Immune Support

Biologically, glutathione is the quintessential “master antioxidant” of the body; it is a tripeptide (i., e. comprised of three amino acids) that serves as a reservoir of L-cysteine when the diet is lacking cysteine-rich food (i.e., protein). Conversely, L-cysteine serves as a reservoir for glutathione, but it is also necessary for protein synthesis.

Glutathione is involved in a multitude of metabolic reactions affecting all 12 body systems, especially the nervous system, immune system, and gastrointestinal system.[9]

Since glutathione is one of the major endogenous antioxidants of the body, its also involved in many metabolic reactions, low levels of this peptide are correlated with higher levels of oxidative stress and impairments in many bodily systems (especially immune function).[10]

A recent clinical study demonstrated that NAC enhances immune cell defense by restoring/increasing levels of key immune factors that protect against microbial agents and viruses, including TH1 cytokines, IL-1β, IL-12, IFN-γ, and TNF-α.[11] Thus, NAC is a beneficial supplement for fortifying your immune system, which can, in turn, can help defend against the symptoms of seasonal allergies (e.g., sneezing, runny nose, sore throat).

Moreover, NAC may be especially useful in older individuals as research shows glutathione levels are significantly lower in otherwise healthy elderly subjects.[12]


NAC is a Mucolytic Amino Acid

NAC appears to be a potent mucolytic agent and is commonly prescribed in various countries to treat cystic fibrosis and chronic obstructive pulmonary disease (COPD).[13] Mucolytic agents are nutrients that assist in breaking down and transporting mucus. Therefore, using mucolytics can help reduce symptoms of things like seasonal allergies and the common cold, such as congestion and clogged sinuses.

Research demonstrates the effectiveness of NAC as a mucolytic agent in the treatment of COPD – a progressive lung disease which is characterized by increased breathlessness, leading to labored breathing.[14] As part of COPD, genes that encode for mucins (glycoprotein components of mucus) tend to be overexpressed in the lungs. NAC works to divide the disulfide bond of a mucin protein backbone, making adhesive mucus water-soluble (and thus, can easily be removed out of the system).

NAC Protects the Liver

Glutathione is ostensibly the most essential endogenous molecule for protecting the liver from oxidative stress and toxic metabolites. Intuitively, supplementing with NAC is a prudent choice if you’re someone who consumes any substances that are stressful on the liver, especially alcohol, painkillers, and/or oral steroids.


NAC can Help the Reduce the Toxic Effects of Alcohol Consumption

Some murine data suggests that L-cysteine can mitigate the poisonous effects of alcohol consumption, particularly damage to the liver and possibly even hangovers. When you consume alcoholic beverages, the liver partially metabolizes the ethanol into acetaldehyde – an organic compound that is fairly toxic and classified as a Group 1 carcinogen by the International Agency for Research on Cancer (IARC).

L-cysteine helps metabolize acetaldehyde into acetic acid, thereby reducing the toxic buildup of the former. In fact, one study showed that rats who were given a lethal dose of acetaldehyde were 70% more likely to survive than the control group if they were also given cysteine.[15]

Unfortunately, there is no human research at this time that has investigated the association between low-to-moderate levels of alcohol consumption and potential hepatoprotective actions of NAC. Nevertheless, NAC seems to be beneficial if you’re a regular drinker.


NAC may Help Treat Painkiller (Acetaminophen) Overdose

The most common use of NAC in clinical applications if for treating paracetamol/acetaminophen overdose. Similar to alcoholic beverages, acetaminophen is toxic to the liver and is surprisingly the leading cause of acute liver failure and drug overdose in the United States (and many other first-world countries).[16]

As part of the metabolism of acetaminophen, glutathione is conjugated (bonded) to an intermediate metabolite known as N-acetyl-p-benzoquinone imine (NAPQI) – which is an otherwise toxic compound.[17] Hence, glutathione is essential for mitigating the toxicity of acetaminophen metabolism by irreversibly binding to NAPQI and changing its chemical structure.


NAC Side Effects

NAC is a highly safe supplement for most adults. Arguably its main drawback is that it doesn’t smell very pleasant (even when encapsulated).

Those at the highest risk of adverse reactions to NAC are asthmatics and pregnant women, though the chances are still relatively low in these individuals. NAC does readily cross the placenta, but no research suggests it’s harmful to an unborn baby.

If you have an upcoming surgery or a bleeding disorder, it’s best to consult with your physician before using NAC as it can slow blood clotting (and therefore, increase bleeding during/after surgery). This also applies to anyone planning on getting a large tattoo; it’s best to avoid anything that can slow the blood clotting process in the immediate days before and after these events.

In some cases, NAC use can result in fairly benign side effects, such as constipation, nausea, upset stomach, and diarrhea. In rare circumstances, using NAC can lead to hypotension, rash, and liver problems. However, side effects from using NAC, compared to most dietary supplements, are uncommon and easily remedied by dosage adjustments.

If you experience an allergic or severe adverse reaction to NAC, stop use immediately and contact your physician. The median lethal dose of NAC is estimated to be upwards of 300 mg/kg in humans (which is far beyond the recommended daily dose of NAC: 600-1,200 mg/day)

Where to Buy NAC

NAC is generally available over-the-counter at many pharmacies and health food stores. However, many NAC supplements are under-dosed and costly for what you get. Most research suggests that 600 mg/day of NAC is a good starting point, working up to a dose of 1,200 mg/day if necessary.[18] It also seems that NAC is most beneficial when taken for no less than 4 weeks at a time, if not indefinitely for supporting glutathione status.

Vaxxen Labs Descend

Descend is basically an evidence-based all-in-one liver and health fortifying supplement containing key nutrients that establish and maintain harmony in the body. You’ll find 600 mg of NAC in each dose of Descend, as well as vital organ-supporting nutrients, such as chrysin, milk thistle, saw palmetto, stinging nettle leaf and much more. This supplement is ideal for those who regularly use performance-enhancing drugs that may cause stress to the liver, as well as those who want a natural alternative for keeping their cardiovascular, endocrine, and immune systems in tip-top shape.


References

  1. Aruoma, O. I. (1998). Free radicals, oxidative stress, and antioxidants in human health and disease. Journal of the American oil chemists’ society, 75(2), 199-212.
  2. Yin, J., Ren, W., Yang, G., Duan, J., Huang, X., Fang, R., … & Kim, S. W. (2016). l‐Cysteine metabolism and its nutritional implications. Molecular nutrition & food research, 60(1), 134-146.
  3. Townsend, D. M., Tew, K. D., & Tapiero, H. (2003). The importance of glutathione in human disease. Biomedicine & Pharmacotherapy, 57(3-4), 145-155.
  4. Jomova, K., & Valko, M. (2011). Advances in metal-induced oxidative stress and human disease. Toxicology, 283(2-3), 65-87.
  5. Witschi A, Reddy S, Stofer B, Lauterburg BH: The systemic availability of oral glutathione. Eur J Clin Pharmacol. 1992;43(6):667-9.
  6. Chen, G., Bunt, C., & Wen, J. (2015). Mucoadhesive polymers‐based film as a carrier system for sublingual delivery of glutathione. Journal of Pharmacy and Pharmacology, 67(1), 26-34.
  7. Atkuri, K. R., Mantovani, J. J., Herzenberg, L. A., & Herzenberg, L. A. (2007). N-Acetylcysteine—a safe antidote for cysteine/glutathione deficiency. Current opinion in pharmacology, 7(4), 355-359.
  8. Bernard Schmitt, Morgane Vicenzi, Catherine Garrel, Frédéric M. Denis. Effects of N-acetylcysteine, oral glutathione (GSH) and a novel sublingual form of GSH on oxidative stress markers: A comparative crossover study. Redox Biology, Volume 6, 2015, pp. 198-205
  9. Foyer, C. H., & Noctor, G. (2001). The molecular biology and metabolism of glutathione. In Significance of glutathione to plant adaptation to the environment (pp. 27-56). Springer, Dordrecht.
  10. Dringen, R. (2000). Metabolism and functions of glutathione in brain. Progress in neurobiology, 62(6), 649-671.
  11. Geiler, J., Michaelis, M., Naczk, P., Leutz, A., Langer, K., Doerr, H. W., & Cinatl Jr, J. (2010). N-acetyl-L-cysteine (NAC) inhibits virus replication and expression of pro-inflammatory molecules in A549 cells infected with highly pathogenic H5N1 influenza A virus. Biochemical pharmacology, 79(3), 413-420.
  12. Lang, C. A., Naryshkin, S., Schneider, D. L., Mills, B. J., & Lindeman, R. D. (1992). Low blood glutathione levels in healthy aging adults. The Journal of laboratory and clinical medicine, 120(5), 720-725.
  13. Sadowska, A. M. (2012). N-Acetylcysteine mucolysis in the management of chronic obstructive pulmonary disease. Therapeutic advances in respiratory disease, 6(3), 127-135.
  14. Poole, P., Black, P. N., & Cates, C. J. (2012). Mucolytic agents for chronic bronchitis or chronic obstructive pulmonary disease. Cochrane Database of Systematic Reviews, (8).
  15. Sprince H, Parker CM, Smith GG, Gonzales LJ (April 1974). Protection against acetaldehyde toxicity in the rat by L-cysteine, thiamin and L-2-methylthiazolidine-4-carboxylic acid. Agents Actions. 4(2): 125–30.
  16. Larson AM; Polson J; Fontana RJ; et al. (2005). Acetaminophen-induced acute liver failure: results of a United States multicenter, prospective study. Hepatology. 42 (6): 1364–72
  17. Borne, Ronald F. (1995). Nonsteroidal anti-inflammatory drugs. In Foye, William O.; Lemke, Thomas L.; Williams, David A. Principles of Medicinal Chemistry (Fourth ed.). Williams & Wilkins. pp. 544–545.
  18. Briguori, C., Colombo, A., Violante, A., Balestrieri, P., Manganelli, F., Paolo Elia, P., … & Focaccio, A. (2004). Standard vs double dose of N-acetylcysteine to prevent contrast agent associated nephrotoxicity. European heart journal, 25(3), 206-211.
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