NAC (N-acetyl-L-cysteine) is a derivative of the amino acid L-cysteine and is a precursor of the cellular antioxidant glutathione. The ingredient was first approved as an inhaled mucolytic drug in 1963. At present it is used in emergency rooms as a treatment in cases of acetaminophen poisoning to prevent severe liver damage.
Despite its early use as a respiratory medication, the ingredient has been widely used for many years in finished dietary supplements, frequently as a standalone product. A search of the Dietary Supplement Label Database from the NIH’s Office of Dietary Supplements yields 1,468 products containing NAC (database accessed May 7, 2021), including some of the biggest brands in the industry.
Just last year, food and nutrition giant Nestlé launched its Celltrient range, with one of those products featuring NAC as a central ingredient.
According to data provided by SPINS to NutraIngredients-USA, sales of NAC-containing products grow year-on-year, with combined sales of supplements* in the Conventional Multi-Outlet Channel** and Natural Channel totaling $5.68 million in 2020, a 32% increase from $4.31 million in 2019.
FDA was surely aware of the ingredient being on the market in supplement form for decades, but took no action regarding its status until the summer of 2020 when the Agency sent seven warning letters to companies making hangover treatment claims, which FDA construed to be illegal disease treatment claims.
In the warning letter to Wilmington, NC-based Happy Hour Vitamins, the Agency stated: “FDA has concluded that NAC products are excluded from the dietary supplement definition under section 201(ff)(3)(B)(i) of the Act [21 U.S.C. § 321(ff)(3)(B)(i)]. Under this provision, if an article (such as NAC) has been approved as a new drug under section 505 of the Act [21 U.S.C. § 355], then 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. FDA is not aware of any evidence that NAC was marketed as a dietary supplement or as a food prior to that date.”
The letters marked a “sudden and drastic departure from past Agency practice”, said the Council for Responsible Nutrition (CRN) in a letter to Steven Tave, then Director of the Office of Dietary Supplement Programs (December 2020).
“For decades, manufacturers have safely marketed products containing NAC as dietary supplements in the United States,” stated the letter, which was signed by Steve Mister, CRN’s President and CEO, and Megan Olsen, Vice President and Associate General Counsel, CRN.
“… until recently, FDA has consistently and affirmatively permitted manufacturers to market these products. In fact, 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,” added the letter.
Speaking with NutraIngredients-USA, Olsen said: “There is strong legal evidence that NAC is a grandfathered ingredient co-existing as a dietary ingredient alongside the drug for decades.
“NAC has been available as a dietary ingredient in dietary supplements since before the passage of DSHEA [in 1994] and FDA has never raised any safety issues about the ingredient.”
The recent reported move by Amazon to remove NAC-containing dietary supplements from its website has caused concern in the dietary supplements industry, although no other retailers have confirmed they are exploring similar measures.
Cara Welch, PhD, the current Acting Director of ODSP, responded to CRN’s letter last week, noting that the Agency is “closely reviewing the information provided in your letter and will provide a more substantive response once our evaluation is complete”.
Olsen told us that the association has only been in contact with ODSP, and it is not clear if other offices or Centers within FDA are involved in the decision-making process.
“CRN is recommending to member to keep selling the NAC-containing dietary supplements,” she said. “FDA has not given the final word on NAC.”
Olsen noted that there is precedent for FDA reversing a stance, citing the KIND LLC issue from 2015 when the Agency sent a warning letter to the nutritional bar maker over label claims on its products and website that were deemed to step beyond the definition of 'healthy' because of the products' fat content. KIND pushed back and in 2016 the FDA conceded the point (with a couple of caveats).
“We’ve made clear with the Agency the seriousness of this [NAC] issue,” said Olsen. “This has real world repercussions for companies the longer this continues.
“CRN is pleased with the level of correspondence we’ve received from the Agency,” added Olsen. “We sent the letter in December 2020 and received a response in May, and that was a response from the Agency during an Administration change, I’d add.”
* This covers products in the following categories: Amino acid, digestive aids & enzymes, herbal formulas, miscellaneous supplements, performance nutrition, vitamins & minerals
** The Conventional Multi-Outlet Channel (powered by IRI) covers the Grocery Outlet (store with $2M+ annual ACV), the Drug Outlet (chains and independent stores, excluding Rx sales), and selected retailers across Mass Merchandisers, including Walmart, Club, Dollar, and Military representing over 105,000 retail locations.
SPINS’ Natural Enhanced Channel is composed of full-format stores with $2 million+ in annual sales and 40% or more of UPC coded sales from natural/organic/specialty products. It Includes co-ops, associations, independents, and large regional chains (excludes Whole Foods & Trader Joes).