Medicine or dietary supplement? N-acetylcysteine (NAC) is marketed as both and in 2021, the supplement abruptly became difficult to find, causing distress to people who had been using it for a variety of conditions. The story behind its disappearance is one of a cat-and-mouse chase between manufacturers, advocacy agencies, and the Food and Drug Administration.
NAC is a medication that was approved by the FDA in 1963. It has two FDA-approved uses: To prevent hepatotoxicity after overdose with acetaminophen, administered intravenously or by mouth, and as a mucolytic agent – previously available as Mucomyst, now available only as a generic – given by inhaler or nebulizer for pulmonary illnesses. Since the 1990s, NAC has been labeled by manufacturers as a dietary supplement. It is a derivative of the amino acid L-cysteine and a precursor to glutathione, an antioxidant.
Dr. Dinah Miller
Studies have had small sample sizes, and the supplement has not been considered an “off label” use of an already available medication. People have purchased NAC from retail drug and big box stores, Amazon, and online companies. So what’s the problem?
In July 2020, the FDA issued a warning letter to Purple Biosciences LLC, because of claims on the company’s website that the product “Purple Tree,” sold by Amazon, could cure hangovers that result from alcohol intoxication. The letter discussed justification for why a hangover is a disease, and goes on to note:
Based on the product label on your website, it appears that you intend to market your Purple Tree® product, which contains N-acetyl-L-cysteine (NAC), as a dietary supplement. However, even if your product labeling did not have therapeutic claims that make your product an unapproved new drug, your product could not be a dietary supplement, because it does not meet the definition of dietary supplement ... products containing that article are outside the definition of a dietary supplement, unless before such approval that article was marketed as a dietary supplement or as a food. NAC was approved as a new drug under section 505 of the Act [21 U.S.C. § 355] on September 14, 1963.
The issue here is that because NAC was first approved as a drug in 1963, it cannot be marketed as a supplement. If it had been marketed as a supplement before it was approved as a drug by the FDA, then it could remain on the market. The fact that it had been sold as a supplement since the 1990s and could be classified as an “old dietary ingredient” according to the Dietary Supplement Health and Education Act of 1994 did not seem to matter. Following the warning letter, NAC was pulled from shelves and websites.
Citizen petitions allow people and organizations to request that the FDA change their policy. During summer 2021, there were two citizen petitions – one from the Council for Responsible Nutrition (CRN) and another from the Natural Products Association (NPA) – asking that the FDA look at policy around NAC. In response, in November 2021, the FDA put out a request for more information about how long NAC had been used and if there were safety concerns, to determine if making it a lawful supplement would be appropriate. CRN promptly released a response that they were “extremely dissatisfied” and felt this was an unnecessary tactic to delay a decision. Two members of Congress wrote letters to the FDA in support of leaving NAC as an available supplement. Congressman Jeff Duncan noted that there were over 1,170 products containing NAC.
The FDA continued to issue responses. On March 31, 2022, the agency formally denied the requests of the two citizen petitions, and 3 weeks later the Guidance for Industry: Policy Regarding N-acetyl-L-cysteine was released, saying that the FDA would “... exercise enforcement discretion with respect to the sale and distribution of certain products that contain NAC.” While NAC was still not considered a supplement, no safety issues had been identified to date. Thus, while the FDA investigation continues, the agency will essentially look the other way.
The agency will consider rulemaking to include NAC as a supplement, a process that may take years. In a notice of final guidance released in August 2022, the FDA reiterated, “unless we identify safety-related concerns during our ongoing review, FDA intends to exercise enforcement discretion until either of the following occurs: we complete notice-and-comment rulemaking to allow the use of NAC in or as a dietary supplement (should we move forward with such proceedings) or we deny the NPA citizen petition’s request for rulemaking.”
It’s a win for the consumer who wants the supplement, and a half-win for the supplement manufacturers and their advocacy organizations who would like NAC to be an official dietary supplement. But just to be clear, the issue is one of a technicality: If NAC had been marketed as a supplement before it was a drug, it would just be a dietary supplement without all the controversy and scrutiny. It was not pulled because of a clinical concern.
For now, NAC is again readily available.
Dr. Miller is a coauthor of “Committed: The Battle Over Involuntary Psychiatric Care” (Johns Hopkins University Press, 2016). She has a private practice and is assistant professor of psychiatry and behavioral sciences at Johns Hopkins University, Baltimore. She has disclosed no relevant financial relationships.