FDA is exploring rulemaking for NAC supplements

The U.S. Food and Drug Administration is planning to publish a proposed first-of-its-kind rule that would make an ingredient lawful in dietary supplements, despite it being first researched or approved as a drug.

The subject of the proposed rule is believed to be N-acetyl-L-cysteine (NAC), a popular ingredient sold in dietary supplements and the subject of previous litigation pitting an industry trade association against FDA.

A government document posted on July 5 revealed FDA’s plans to issue a notice of proposed rulemaking in December 2024. A notice-and-comment rulemaking — for an ingredient excluded from the definition of a dietary supplement due to its status as a researched or approved drug — would mark the first time FDA has exercised such authority in the nearly 30-year history of the Dietary Supplement Health and Education Act of 1994 (DSHEA).

The HHS/FDA document did not specifically identify the ingredient that is the subject of the proposed rule, though an FDA spokesperson confirmed the agency is exploring rulemaking for NAC.

In a final guidance published in August 2022, FDA announced its intent to exercise so-called enforcement discretion regarding the distribution and sale of certain products containing NAC and labeled as dietary supplements.

Four years ago, FDA set off alarm in the industry after sending warning letters to companies selling products that claimed to cure, treat, mitigate or prevent hangovers. The concerns focused on statements in several of the letters that NAC could not be lawfully marketed as a dietary supplement because it had been first approved as a new drug in September 1963.

Amazon in May 2021 confirmed it planned to remove NAC supplements from its e-commerce platform. Later that same year, the Natural Products Association (NPA) filed a lawsuit against FDA, seeking to set aside FDA’s determinations on NAC.

“NPA members who have been selling NAC for years, if not decades, have seen their sales dry up as a result of having to preemptively pull products from the shelves by virtue of FDA’s unlawful decisions,” NPA asserted in the complaint.

The merits of the case were never decided before the U.S. District Court in Maryland. NPA in November 2022 voluntarily dismissed the complaint against FDA following its issuance of the final enforcement discretion guidance.

Earlier that same year, FDA published a comprehensive response to two NAC citizen petitions filed by NPA and the Council for Responsible Nutrition (CRN). While FDA reiterated its view that NAC is excluded from the definition of a dietary supplement, it outlined plans to exercise enforcement discretion regarding NAC-containing products.

Those plans were implemented in draft and final guidance documents, and FDA during that process received hundreds of comments — many from consumers advocating that the agency keep NAC available as a supplement.

“NAC has demonstrated a multitude of beneficial effects based on oral administration,” George LeBaron wrote to FDA in 2022. “Most notable is its ability to help support glutathione levels and subsequently attenuate normal oxidative stress.”

The final guidance paved the way for NAC to be sold in the U.S. as a dietary supplement without fear of repercussions from FDA — so long as the products are otherwise compliant with FDA regulations and the Federal, Food, Drug & Cosmetic Act (FDCA).

The NAC controversy highlighted potential ambiguities over language in DSHEA that excludes an ingredient from a dietary supplement if it has been first approved or investigated as a drug. Industry stakeholders, for instance, provided FDA evidence that NAC has been marketed in nutritional products since the early 1990s, and they argued the drug preclusion provision was never intended to apply retroactively, or before DSHEA’s passage in 1994.

Reaction from industry trade groups

Dan Fabricant, Ph.D., president and CEO of NPA, said publication of a rule on NAC would mark “a big day for all those who believe in self-care as it represents that the law works and works well to resolve technical disputes.”

Steve Mister, president and CEO of CRN, said FDA's proposal "would be significant if finalized because not only would this landmark rulemaking potentially allow NAC to be lawfully marketed and sold in dietary supplements without enforcement discretion, it would also define standards for other ingredients facing drug preclusion — such as cannabidiol (CBD) and nicotinamide mononucleotide (NMN)."