Table of Contents
From a regulatory perspective, it has been a bumpy couple of years for N-acetylcysteine (NAC)—although the science of this well-researched amino acid was never in question. In this article, I’m going to review the science of NAC, as well as its erstwhile and current regulatory status. Let’s start with the science.
The Science of NAC
NAC is a derivative of the amino acid L-cysteine. It has several important functions, including its role as an antioxidant, and its roles in supporting immune function and expelling mucus from the body—in addition to its role in stimulating the synthesis of, and being a precursor to, glutathione. In fact, NAC effectively crosses the cell membrane, where it is converted to cysteine and then glutathione.1 At this point, it can play a role in the detoxification process. Detoxification
Fat soluble toxins cannot be excreted without undergoing transformation (detoxification) in the liver so that they can become water soluble. Essentially, toxic compounds are conjugated (attached) to molecules such as glutathione to render them more water soluble, and suitable for excretion via the intestinal tract.2 Since NAC promotes glutathione synthesis, it also promotes the glutathione conjugation pathway of detoxification. Research has demonstrated that NAC can effectively support liver detox mechanisms.3 This includes efficacy for excretion of a broad range of toxic compounds.4 Furthermore, animal research has also shown that NAC reduced the cytokine (inflammatory substance) secretion from some of the particulate pollution which in turn caused lung inflammation.5
Antioxidant & Immune Function
NAC is an effective antioxidant in its own right, as well as precursor to glutathione, which is also a powerful antioxidant scavenger of free radicals.6 While certain free radicals and reactive oxygen species (ROS) reduce intracellular and extracellular concentrations of glutathione, NAC is a very efficient way to replenish glutathione and reduce damage caused by free radicals/ROS.7 In addition, human clinical research in 262 subjects of both sexes demonstrated that supplementing with NAC was effective in promoting cell-mediated immunity when used for six months.8
Expelling Mucus From the Body
NAC has mucolytic properties—meaning that it can help to break down mucus. This makes it easier for the body to expel the mucus and reduce the frequency with which it needs to be expelled.9-10 This has been demonstrated by supplementing with NAC in human clinical research, including with COPD patients and those with bronchitis.11-13
The Regulatory Status of NAC
Given the science of NAC, it is no surprise that an FDA (U.S. Food and Drug Administration) warning letter about NAC caused such consternation. The warning letter was issued in August of 2020, and stated NAC was excluded from the definition of a dietary supplement. Their reason for this is that NAC was previously approved as a drug by FDA to treat liver side effects from an overdose of Tylenol (acetaminophen)—although NAC is given as an injection in this case, which is clearly not a dietary supplement delivery form—and more recently as a mucolytic agent in respiratory diseases.14 The FDA also indicated that, to their knowledge, NAC hadn’t been previously marketed as a food or supplement prior to FDA’s approval of it as a drug.
That being said, in the Old Dietary Ingredient List published by United Natural Products Alliance (UNPA), NAC is indeed identified as an old dietary ingredient marketed in the United States before Oct. 15, 1994. Nevertheless, even after the FDA warning letter, the dietary supplement industry continued to market NAC products to consumers without any apparent objection from the FDA, with the exception of those companies who were marketing it as a hangover remedy or making other egregious claims.
The Amazon Reaction
Subsequently, Amazon’s AI system recently identified some products containing NAC as disallowed for sale on their site. This action created further anxiety within the industry. This issue was discussed in a UNPA meeting that took place on April 22, 2021, causing the organization to look further into the issue and open a line of communication with Amazon.
FDA’s Guidance Document on NAC
Two years to the month after the FDA’s warning letter, the FDA issued “Policy Regarding N-acetyl-L-cysteine: Guidance for Industry.” In the guidance document, FDA stated: “…we are considering initiating rulemaking under section 201(ff)(3)(B) of the FD&C (Food, Drug & Cosmetic) Act to permit the use of NAC in or as a dietary supplement (i.e., to provide by regulation that NAC is not excluded from the definition of dietary supplement). If, among other considerations, FDA does not identify safety-related concerns as we continue our review of the available data and information, we are likely to propose a rule providing that NAC is not excluded from the definition of dietary supplement.”
The reason for the FDA’s apparent change of heart is that they received two citizen petitions: one from the Council for Responsible Nutrition (CRN) dated June 1, 2021, and one from the Natural Products Association (NPA) dated August 18, 2021, requesting that the FDA conclude that NAC not be excluded from the definition of dietary supplement. The short version of the guidance document is that the FDA intends to “exercise enforcement discretion with respect to the sale and distribution of certain products that contain NAC and are labeled as dietary supplements.” In other words, if the product is labeled appropriately and sticks to structure-function claims, the FDA won’t object.
Certificate of Free Sale … or Not
A Certificate of Free Sale is a document that indicates a particular product is marketed in the United States or is eligible for export, and that the particular manufacturer has no unresolved enforcement actions pending before or taken by the U.S. FDA. Clearly, NAC doesn’t exactly meet that definition. The FDA recently posted the following on its website:
Please note that products that contain NAC do not meet the definition of “dietary supplement” and, therefore, should not be included in an application for a “Certificate of Free Sale.” However, NAC-containing products that are labeled as dietary supplements may be eligible for a different certificate to facilitate exports. To request a specific export certificate for products labeled as dietary supplements that contain NAC, please submit a CAP application (with only NAC containing products) to initiate the process. Once the application is submitted, ODSP will reach out to your company for next steps. If you have additional questions, please contact [email protected]
So, even though you may be able to sell NAC domestically, it remains to be seen if the process to obtain “a different certificate to facilitate exports” will be forthcoming in a timely manner.
Conclusion
NAC is a solid, science-based nutraceutical with a broad range of applications. If you’re currently selling NAC, the good news is that you can continue doing so based upon the FDA’s guidance document. Of course, it would be nice if the FDA would go all the way and include NAC in the definition of a dietary ingredient. Meanwhile, make sure to stick to structure/function claims on your labels, and don’t make any claims with regard to the prevention, treatment or mitigation of any disease or medical condition. The process receiving a different certificate to facilitate exports, in place of a Certificate of Free Sale, is still ongoing. VR
References:
1 Anonymous. N-Acetyl-l-Cysteine monograph. Alternative Medicine Review 2000; 5(5); 467-471.
2 Roundtree R. The Use of Phytochemicals in the Biotransformation and Elimination of Environmental Toxins. IN Medicines from the Earth 2003: Official Proceedings. Brevard, North Carolina: Gaia Herbal Research Institute; 2003:115-128.
3 Anonymous. N-Acetyl-l-Cysteine monograph. Alternative Medicine Review 2000; 5(5); 467-471.
4 Zimet I. Acetylcysteine: A drug that is much more than a mucokinetic. Biomed & Pharmacother 1988;42:513-520.
5 Kennedy T, et al, Am J Respir Cell Mol Biol (1998) 19(3):366-78.
6 Anonymous. N-Acetyl-l-Cysteine monograph. Alternative Medicine Review 2000; 5(5); 467-471.
7 Kelly GS. Clinical applications of N-acetylcysteine. Altern Med Rev 1998;3:114-27.
8 De Flora S, Grassi C, Carati L. Attenuation of influenza-like symptomatology and improvement of cell-mediated immunity with long-term N-acetylcysteine treatment. Eur Respir J 1997;10:1535-41.
9 Anonymous. N-Acetyl-l-Cysteine monograph. Alternative Medicine Review 2000; 5(5); 467-471.
10 Roundtree R. The Use of Phytochemicals in the Biotransformation and Elimination of Environmental Toxins. IN Medicines from the Earth 2003: Official Proceedings. Brevard, North Carolina: Gaia Herbal Research Institute; 2003:115-128.
11 Pela R, Calcagni AM, Subiaco S, et al. N-acetylcysteine reduces the exacerbation rate in patients with moderate to severe COPD. Respiration 1999;66:495-500.
12 Grandjean EM, Berthet P, Ruffmann R, Leuenberger P. Efficacy of oral long-term N-acetylcysteine in chronic bronchopulmonary disease: a meta-analysis of published double-blind, placebo-controlled clinical trials. Clin Ther 2000;22:209-21.
13 Volkl KP, Schneider B, Fortschr Med (1992) 110(18):346-50.
14 Tardiolo G, Bramanti P, Mazzon E. Overview on the effects of n-acetylcysteine in neurodegenerative diseases. Molecules. 2018;23:3305.
15 Food Export Certificates. U.S. Food & Drug Administration. Content current as of 09/15/2022. Retrieved November 22, 2022 from www.fda.gov/food/exporting-food-products-united-states/food-export-certificates.
Gene Bruno, MS, MHS, the provost for Huntington University of Health Sciences, is a nutritionist, herbalist, writer and educator. For more than 40 years he has educated and trained natural product retailers and health care professionals, has researched and formulated natural products for dozens of dietary supplement companies, and has written articles on nutrition, herbal medicine, nutraceuticals and integrative health issues for trade, consumer magazines and peer-reviewed publications. He can be reached at [email protected].
From a regulatory perspective, it has been a bumpy couple of years for N-acetylcysteine (NAC)—although the science of this well-researched amino acid was never in question. In this article, I’m going to review the science of NAC, as well as its erstwhile and current regulatory status. Let’s start with the science.
The Science of NAC
NAC is a derivative of the amino acid L-cysteine. It has several important functions, including its role as an antioxidant, and its roles in supporting immune function and expelling mucus from the body—in addition to its role in stimulating the synthesis of, and being a precursor to, glutathione. In fact, NAC effectively crosses the cell membrane, where it is converted to cysteine and then glutathione.1 At this point, it can play a role in the detoxification process. Detoxification
Fat soluble toxins cannot be excreted without undergoing transformation (detoxification) in the liver so that they can become water soluble. Essentially, toxic compounds are conjugated (attached) to molecules such as glutathione to render them more water soluble, and suitable for excretion via the intestinal tract.2 Since NAC promotes glutathione synthesis, it also promotes the glutathione conjugation pathway of detoxification. Research has demonstrated that NAC can effectively support liver detox mechanisms.3 This includes efficacy for excretion of a broad range of toxic compounds.4 Furthermore, animal research has also shown that NAC reduced the cytokine (inflammatory substance) secretion from some of the particulate pollution which in turn caused lung inflammation.5
Antioxidant & Immune Function
NAC is an effective antioxidant in its own right, as well as precursor to glutathione, which is also a powerful antioxidant scavenger of free radicals.6 While certain free radicals and reactive oxygen species (ROS) reduce intracellular and extracellular concentrations of glutathione, NAC is a very efficient way to replenish glutathione and reduce damage caused by free radicals/ROS.7 In addition, human clinical research in 262 subjects of both sexes demonstrated that supplementing with NAC was effective in promoting cell-mediated immunity when used for six months.8
Expelling Mucus From the Body
NAC has mucolytic properties—meaning that it can help to break down mucus. This makes it easier for the body to expel the mucus and reduce the frequency with which it needs to be expelled.9-10 This has been demonstrated by supplementing with NAC in human clinical research, including with COPD patients and those with bronchitis.11-13
The Regulatory Status of NAC
Given the science of NAC, it is no surprise that an FDA (U.S. Food and Drug Administration) warning letter about NAC caused such consternation. The warning letter was issued in August of 2020, and stated NAC was excluded from the definition of a dietary supplement. Their reason for this is that NAC was previously approved as a drug by FDA to treat liver side effects from an overdose of Tylenol (acetaminophen)—although NAC is given as an injection in this case, which is clearly not a dietary supplement delivery form—and more recently as a mucolytic agent in respiratory diseases.14 The FDA also indicated that, to their knowledge, NAC hadn’t been previously marketed as a food or supplement prior to FDA’s approval of it as a drug.
That being said, in the Old Dietary Ingredient List published by United Natural Products Alliance (UNPA), NAC is indeed identified as an old dietary ingredient marketed in the United States before Oct. 15, 1994. Nevertheless, even after the FDA warning letter, the dietary supplement industry continued to market NAC products to consumers without any apparent objection from the FDA, with the exception of those companies who were marketing it as a hangover remedy or making other egregious claims.
The Amazon Reaction
Subsequently, Amazon’s AI system recently identified some products containing NAC as disallowed for sale on their site. This action created further anxiety within the industry. This issue was discussed in a UNPA meeting that took place on April 22, 2021, causing the organization to look further into the issue and open a line of communication with Amazon.
FDA’s Guidance Document on NAC
Two years to the month after the FDA’s warning letter, the FDA issued “Policy Regarding N-acetyl-L-cysteine: Guidance for Industry.” In the guidance document, FDA stated: “…we are considering initiating rulemaking under section 201(ff)(3)(B) of the FD&C (Food, Drug & Cosmetic) Act to permit the use of NAC in or as a dietary supplement (i.e., to provide by regulation that NAC is not excluded from the definition of dietary supplement). If, among other considerations, FDA does not identify safety-related concerns as we continue our review of the available data and information, we are likely to propose a rule providing that NAC is not excluded from the definition of dietary supplement.”
The reason for the FDA’s apparent change of heart is that they received two citizen petitions: one from the Council for Responsible Nutrition (CRN) dated June 1, 2021, and one from the Natural Products Association (NPA) dated August 18, 2021, requesting that the FDA conclude that NAC not be excluded from the definition of dietary supplement. The short version of the guidance document is that the FDA intends to “exercise enforcement discretion with respect to the sale and distribution of certain products that contain NAC and are labeled as dietary supplements.” In other words, if the product is labeled appropriately and sticks to structure-function claims, the FDA won’t object.
Certificate of Free Sale … or Not
A Certificate of Free Sale is a document that indicates a particular product is marketed in the United States or is eligible for export, and that the particular manufacturer has no unresolved enforcement actions pending before or taken by the U.S. FDA. Clearly, NAC doesn’t exactly meet that definition. The FDA recently posted the following on its website:
Please note that products that contain NAC do not meet the definition of “dietary supplement” and, therefore, should not be included in an application for a “Certificate of Free Sale.” However, NAC-containing products that are labeled as dietary supplements may be eligible for a different certificate to facilitate exports. To request a specific export certificate for products labeled as dietary supplements that contain NAC, please submit a CAP application (with only NAC containing products) to initiate the process. Once the application is submitted, ODSP will reach out to your company for next steps. If you have additional questions, please contact [email protected]
So, even though you may be able to sell NAC domestically, it remains to be seen if the process to obtain “a different certificate to facilitate exports” will be forthcoming in a timely manner.
Conclusion
NAC is a solid, science-based nutraceutical with a broad range of applications. If you’re currently selling NAC, the good news is that you can continue doing so based upon the FDA’s guidance document. Of course, it would be nice if the FDA would go all the way and include NAC in the definition of a dietary ingredient. Meanwhile, make sure to stick to structure/function claims on your labels, and don’t make any claims with regard to the prevention, treatment or mitigation of any disease or medical condition. The process receiving a different certificate to facilitate exports, in place of a Certificate of Free Sale, is still ongoing. VR
References:
1 Anonymous. N-Acetyl-l-Cysteine monograph. Alternative Medicine Review 2000; 5(5); 467-471.
2 Roundtree R. The Use of Phytochemicals in the Biotransformation and Elimination of Environmental Toxins. IN Medicines from the Earth 2003: Official Proceedings. Brevard, North Carolina: Gaia Herbal Research Institute; 2003:115-128.
3 Anonymous. N-Acetyl-l-Cysteine monograph. Alternative Medicine Review 2000; 5(5); 467-471.
4 Zimet I. Acetylcysteine: A drug that is much more than a mucokinetic. Biomed & Pharmacother 1988;42:513-520.
5 Kennedy T, et al, Am J Respir Cell Mol Biol (1998) 19(3):366-78.
6 Anonymous. N-Acetyl-l-Cysteine monograph. Alternative Medicine Review 2000; 5(5); 467-471.
7 Kelly GS. Clinical applications of N-acetylcysteine. Altern Med Rev 1998;3:114-27.
8 De Flora S, Grassi C, Carati L. Attenuation of influenza-like symptomatology and improvement of cell-mediated immunity with long-term N-acetylcysteine treatment. Eur Respir J 1997;10:1535-41.
9 Anonymous. N-Acetyl-l-Cysteine monograph. Alternative Medicine Review 2000; 5(5); 467-471.
10 Roundtree R. The Use of Phytochemicals in the Biotransformation and Elimination of Environmental Toxins. IN Medicines from the Earth 2003: Official Proceedings. Brevard, North Carolina: Gaia Herbal Research Institute; 2003:115-128.
11 Pela R, Calcagni AM, Subiaco S, et al. N-acetylcysteine reduces the exacerbation rate in patients with moderate to severe COPD. Respiration 1999;66:495-500.
12 Grandjean EM, Berthet P, Ruffmann R, Leuenberger P. Efficacy of oral long-term N-acetylcysteine in chronic bronchopulmonary disease: a meta-analysis of published double-blind, placebo-controlled clinical trials. Clin Ther 2000;22:209-21.
13 Volkl KP, Schneider B, Fortschr Med (1992) 110(18):346-50.
14 Tardiolo G, Bramanti P, Mazzon E. Overview on the effects of n-acetylcysteine in neurodegenerative diseases. Molecules. 2018;23:3305.
15 Food Export Certificates. U.S. Food & Drug Administration. Content current as of 09/15/2022. Retrieved November 22, 2022 from www.fda.gov/food/exporting-food-products-united-states/food-export-certificates.
