by Michael Stanclift, ND
Most clinicians know about N-acetylcysteine (NAC) as a treatment for acetaminophen overdose and psychiatric or neurological conditions.1,2 However, we don’t generally think about its role in the immune response and inflammation, but NAC is a promising nutrient for these areas. Clinicians treating infections may want to read on.
Mechanisms of action
N-acetylcysteine serves as a precursor in the production of our body’s strongest antioxidant, glutathione (GSH).3 Orally administered GSH is readily broken down before being absorbed, so supplementing with NAC is a good way to deliver this rate-limiting nutrient for GSH production in the body.4 Research shows supplementation with NAC increases tissue GSH levels in humans.3 Many of NAC’s health benefits are related to how glutathione protects tissues and cell components.
Inflammasome and cytokine regulation
Inflammasomes are protein complexes within cells that serve as sensors for danger that when detected amplify immune responses.5 The NOD-like receptor protein 3(NLRP3) inflammasome is important clinically because of its many activation triggers.6 In an experimental model of reactive oxygen species (ROS)-triggered NLRP3, treatment with NAC suppressed the activation of the inflammasome.7 NAC regulates mRNA expression of lipopolysaccharide (LPS)-triggered NLRP3 inflammasome, lowering inflammatory cytokines such as interleukin 1β(IL-1β).8
Figure: NLRP3 inflammasome activation
Protecting the delicate tissues of the lungs is important, as they are directly exposed to the outside world and a point of susceptibility. Researchers investigating the effects of e-cigarette vapor found adding NAC prevented the damaging effects to human alveolar macrophages, immune cells on the front lines of defense.9 Another research group looked at postinfection inflammation caused by Epstein-Barr Virus (EBV) and discovered NAC supplementation slowed disease progression in mice, providing evidence of a potential therapy for postviral disease.10 In a 12-month randomized controlled trial done in patients with a chronic lung condition (bronchiectasis), NAC at 600 mg twice a day reduced exacerbations of the disease by 59%, and more than twice as many patients were exacerbation-free at 12 months compared to control.11
NAC is one of the unique agents that can help with both viral and bacterial infections. Researchers using cell and animal models infected mice with a highly pathogenic flu virus (H5N1) and found NAC decreased production of proinflammatory cytokines and the secretion of mucin, a substance that thickens mucous.12 NAC given with oseltamivir (a drug used to treat flu) led to 100% survival in mice, compared to 60% with the drug by itself.12 Researchers looking at the effects of NAC on respiratory syncytial virus (RSV), a pathogen responsible for most lower respiratory infections seen in young children, found NAC provided a “drastic reduction in the number of damaged nuclei,” a significant marker of cell damage.13 The same study found NAC was present during viral adsorption (while they were experimentally infecting cells), “viral titers were very strongly reduced…indicating [NAC] might also have an effect on virus integrity, attachment, or entry into the cells.”13
NAC has also proven useful in treating bacterial infections, particularly in the respiratory tract and other areas where mucous and biofilms hinder treatment efficacy.14-16 In a small randomized controlled trial done in China with pneumonia patients, researchers compared usual care and usual care with 600 mg NAC twice daily for 10 days.14 They looked at measures of inflammation and oxidative stress and found the addition of NAC decreased inflammatory markers and increased measures of antioxidant capacity.14 Most bacterial infections form biofilms, protecting themselves with sticky mucous and cooperating with other organisms—making antibiotic drug penetration difficult.15,16 Preclinical research showed NAC has antibacterial activities and disrupts biofilm development.16 A systematic review found, “NAC, in combination with different antibiotics, significantly promoted their permeability to the deepest layers of the biofilm, overcoming the problem of the resistance to the classic antibacterial therapeutic approach.”16 NAC does this by breaking disulphide bonds in cross-linked glycoproteins of mucous, thus thinning the gel-like substance.17
N-acetylcysteine has been overlooked for many years but has recently gained more interest by researchers looking to take advantage of this versatile and well-tolerated nutrient. NAC’s ability to protect cells from oxidative damage and inflammatory signaling and its broad antimicrobial profile make it an important tool for clinicians treating infections. It may have additional benefits for patients with comorbid psychiatric or neurological conditions, as much of the recent research on NAC focuses on these mechanisms as well.
- Chiew AL et al. Interventions for paracetamol (acetaminophen) overdose. Cochrane Database Syst Rev. 2018;2(2):CD003328.
- Deepmala et al. Clinical trials of N-acetylcysteine in psychiatry and neurology: A systematic review. Neurosci Biobehav Rev. 2015;55:294-321.
- DiNicolantonio JJ et al. Supplemental N-acetylcysteine and other measures that boost intracellular glutathione can downregulate interleukin-1β signalling: a potential strategy for preventing cardiovascular events? Open Heart. 2017;4:e000599.
- Schmitt B et al. Effects of N-acetylcysteine, oral glutathione (GSH) and a novel sublingual form of GSH on oxidative stress markers: A comparative crossover study. Redox Biol. 2015;6:198–205.
- Schroder K et al. The inflammasomes. 2010;140:821-832.
- Yang et al. Recent advances in the mechanisms of NLRP3 inflammasome activation and its inhibitors. Cell Death and Disease. 2019;10:128.
- Wang R et al. Activation of NLRP3 inflammasomes contributes to hyperhomocysteinemia-aggravated inflammation and atherosclerosis in apoE-deficient mice. Lab Invest. 2017;97(8):922–934.
- Liu Y et al. The anti-inflammatory effects of acetaminophen and N-acetylcysteine through suppression of the NLRP3 inflammasome pathway in LPS-challenged piglet mononuclear phagocytes. Innate Immun. 2015;21(6):587-597.
- Scott A et al. Pro-inflammatory effects of e-cigarette vapour condensate on human alveolar macrophages. Thorax. 2018;73(12):1161–1169.
- Gao X et al. N-acetylcysteine (NAC) ameliorates Epstein-Barr virus latent membrane protein 1 induced chronic inflammation. PLoS One. 2017;12(12):e0189167.
- Qi Q et al. Effect of N-acetylcysteine on exacerbations of bronchiectasis (BENE): a randomized controlled trial. Respir Res. 2019;20(1):73.
- Hui DS et al. The role of adjuvant immunomodulatory agents for treatment of severe influenza. Antiviral Res. 2018;150:202–216.
- Martínez I et al. Induction of DNA double-strand breaks and cellular senescence by human respiratory syncytial virus. Virulence. 2016;7(4):427–442.
- Zhang Q et al. N-acetylcysteine improves oxidative stress and inflammatory response in patients with community acquired pneumonia: A randomized controlled trial. Medicine (Baltimore). 2018;97(45):e13087.
- Dinicola S et al. N-acetylcysteine as powerful molecule to destroy bacterial biofilms. A systematic review. Eur Rev Med Pharmacol Sci. 2014;18(19):2942-2948.
- Blasi F et al. The effect of N-acetylcysteine on biofilms: Implications for the treatment of respiratory tract infections. Respir Med. 2016;117:190-197.
- Aldini G et al. N-Acetylcysteine as an antioxidant and disulphide breaking agent: the reasons why. Free Radic Res. 2018;52(7):751-762.
Michael Stanclift, ND is a naturopathic doctor and senior medical writer at Metagenics. He graduated from Bastyr University’s school of naturopathic medicine and practiced in Edinburgh, Scotland, and Southern California. He enjoys educating other healthcare providers and impacting the lives of their many patients. When he’s not working, he spends his hours with his wife and two children.