Highlights

  • In 2020, the FDA issued a series of warning letters to marketers of hangover cures for use of .
  • The Council for Responsible Nutrition (CRN) says that the US Food and Drug Administration (FDA) is dodging a central legal issue in its stance on NAC.
  • The CRN requests that the FDA commit to substantively respond to the concerns raised on the legality of NAC as a dietary supplement within 30 days of January 25, 2022. 

There is a battle between the US Food and Drug Administration (FDA) and two organizations that advocate for natural product manufacturers and retailers — the Natural Products Association (NPA) and the Council for Responsible Nutrition (CRN) — on the marketability of the antioxidant N-acetyl-L-cysteine (NAC) as a legal dietary supplement. And the heat just got turned up a notch in this dispute, which can set a precedent for the legality of similar natural products as dietary supplements.

On January 4th, 2022, the CRN, a Washington D.C.-based trade association and lobbying group representing ingredient suppliers and manufacturers in the dietary supplement industry, addressed a letter to the deputy director for regulatory affairs for the FDA regarding its position on disqualifying NAC as a dietary ingredient. The letter requests that all interested parties, including the FDA and the NPA, submit the requested information on NAC by January 25, 2022. At the heart of the request is a call for data to assess the safe use and identify potential safety concerns with NAC as or in a dietary supplement.

“We are very concerned that a safe, legal natural product that has been sold for over thirty years is under what appears to be a regulatory sneak attack by the FDA, and even more concerned if this illegal approach may be used for other ingredients,” said Daniel Frabricant, Ph.D., President and CEO of the NPA – the largest and oldest nonprofit organization representing the interests of manufacturers and retailers of the natural products industry, which includes organic and health foods, dietary supplements, natural ingredient cosmetics, and other similar products. “This is government regulation run amok. The FDA’s actions against NAC represent a reckless misuse of government resources and will do nothing to protect public health. We are hopeful that the agency will get back to its job of appropriately regulating the US. food and drug supply.”

What is NAC?

NAC is a safe and inexpensive compound that has been commercially accessible for many years. Studies have shown no maternal or fetal harmful effects of NAC treatment. The critical antioxidant power of NAC is due to its role as a precursor of glutathione, which is one of the most important naturally occurring antioxidants. The ingredient, which is a derivative of the amino acid L-cysteine and a precursor to the antioxidant glutathione, was first approved in the early 1960s as a mucolytic — a drug used to manage mucus hypersecretion in patients of COPD, cystic fibrosis, and bronchiectasis. 

The FDA’s argument against NAC as a dietary supplement

Back in July 2020, the FDA issued a series of warning letters to marketers of hangover cures. Several of these products included NAC. These warning letters stated that NAC was being marketed as a new drug — under section 201(g)(1)(B) of the Federal Food, Drug, and Cosmetic Act (the Act) [21 U.S.C. § 321(g)(1)(B)] — because of descriptions for its intended use in the cure, mitigation, treatment, or prevention of disease. According to the FDA, a hangover is a sign or symptom of alcohol intoxication, a disease. Like all poisonings, alcohol intoxication causes dose-related dysfunctioning and damage, ranging from mild impairments to death. Alcohol intoxication causes temporary damage to brain function, causing impairments of judgment, attention, reflexes, and coordination. Therefore, alcohol intoxication meets the definition of disease.

Also, the FDA stated that NAC is an illegal dietary ingredient because of its prior use as a drug. The definition of a “dietary supplement” specifically excludes articles that are approved as drugs, certified as antibiotics, or licensed as biologics, or authorized for investigation for therapeutic uses for which “substantial clinical investigations have been instituted and for which the existence of such investigations has been made public.” Dietary supplements are also required to not have been “marketed as a dietary supplement or as a food” before such approval, certification, or authorization.

The NPA takes the FDA to the courts

In December 2021, the NPA filed a lawsuit in the US District Court for the District of Maryland requesting the FDA cease its “unlawful retroactive application of the Food, Drug, and Cosmetic Act” against NAC. The NPA feels the FDA’s action is an overreach and asks the industry and industry trade groups to join their lawsuit and present a united front against the FDA to prevent a precedent.

“The FDA has gotten this wrong at every step of the way, and we’ve been left with no choice but to seek relief from the courts,” said Dr. Frabricant.

The NPA presented a timeline for the FDA’s shift about NAC. The complaint filed in US District Court for Maryland also attests that even earlier, in 1993, the FDA acknowledged NAC is lawful for use as a dietary ingredient. Hundreds of supplements containing NAC have been available to US consumers without objection by the FDA and apparently in compliance with the agency’s regulations under the Dietary Supplement Health and Education Act passed in 1994 before regulatory action surfaced from the agency against the ingredient’s use in supplements, according to the complaint submitted by attorneys for NPA.

A call for NAC safety data

On November 24, 2021, the FDA posted an update requesting information on the earliest date that NAC was marketed as a dietary supplement or as a food, the safe use of NAC in products marketed as a dietary supplement, and any safety concerns. The FDA’s public request follows letters issued by the FDA in tentative response to two citizens’ petitions — June 1, 2021 (CRN petition) and August 18, 2021 (NPA petition) — that ask the FDA to reconsider its position on the use of NAC as a dietary supplement.

Both petitions characterize FDA’s “drug exclusion” position on NAC as a sudden policy change. For example, the CRN petition notes that FDA has “considered over 100 structure-function claim notifications regarding NAC and at least one qualified health claim petition for a dietary supplement containing NAC, and has not objected to the presence of NAC in any of these products.” Both petitions ask FDA to distinguish NAC use as a dietary supplement from its use as a drug based on the form of administration — for example, ingestion in the case of a dietary supplement and intravenous injection or inhalation when used as a drug. The NPA petition additionally asks FDA, alternatively, to initiate discretionary rulemaking to permit NAC as a lawful dietary supplement under the FD&C Act.

When NAC was first marketed as a dietary supplement, CRN and other stakeholders already provided the agency with evidence that NAC was clearly grandfathered and was marketed before the Dietary Supplement Health and Education Act (DSHEA) was passed on October 25, 1994.  CRN is not aware of the FDA raising safety concerns about NAC in its decades-long history of use as a dietary supplement. The FDA has ready access to the requested information through the FDA Adverse Event Reporting System and manufacturing facility inspections. 

What’s next for NAC and related supplements?

Later this year, the FDA will respond to both petitioners directly once its review is completed. If the FDA is persuaded that the “drug exclusion” applies, it’s unclear whether future FDA warning letters will target NAC-based dietary supplements that do not make drug claims. The FDA may instead exercise enforcement discretion like it has for other products like cannabidiol (CBD) actively marketed as dietary supplements, despite the FDA’s position that the “drug exclusion” applies.

This dispute could set a precedent for the FDA for the legality of similar natural compounds marketed as dietary supplements. This could be the case for NAD+ and precursors to NAD+, such as nicotinamide mononucleotide (NMN) or nicotinamide riboside (NR), which have also been marketed as hangover cures.