# The drug-exclusion rule

Rating: Proven — Replicated results in human randomized trials
Type: Regulatory
Updated: 2026-11-01
Canonical: https://heretic.bio/articles/drug-exclusion-rule-pyridoxamine-nmn-nac.html

> US law bars a substance from being a dietary supplement if it was approved as a drug, or authorised for investigation as one with substantial public trials, before anyone marketed it as a supplement or food. Pyridoxamine, a natural form of vitamin B6, was excluded in 2009 at a drug developer's request, and the drug was never approved. NMN was excluded in 2022 and reinstated in 2025 after the FDA accepted evidence of earlier supplement sales. NAC remains formally excluded but on sale under FDA enforcement discretion.

> US law has a race-to-market rule: if a substance is approved as a drug, or authorised for investigation as one with substantial public clinical trials, before anyone sold it as a supplement or food, it cannot be a dietary supplement unless the FDA writes a rule allowing it. The rule is meant to protect drug developers' investment. In practice it has let a drug company get a form of vitamin B6 pulled from supplement shelves for a drug that was never approved, kept NMN out of the supplement market for almost three years until the FDA reversed itself, and left NAC, sold for decades, officially "not a supplement" but on shelves only because the FDA chooses not to enforce. Each status below says how it came about.

## The rule

Section 201(ff)(3)(B) of the Food, Drug, and Cosmetic Act excludes from the definition of a dietary supplement (i) an article approved as a new drug, and (ii) an article authorised for investigation as a new drug for which substantial clinical investigations have been instituted and made public, unless the article was marketed as a dietary supplement or food first, or the FDA issues a regulation, after notice and comment, finding it lawful ([FDA guidance on NAC, 2022](https://www.fda.gov/media/157784/download), quoting the statute). Courts have accepted the FDA's reading that the "article" can be a single active ingredient rather than a finished product: in 2000 the Tenth Circuit upheld the FDA's position that Cholestin, a red yeast rice product standardised for lovastatin, the active ingredient of Merck's Mevacor, could be excluded ([Pharmanex v. Shalala, 221 F.3d 1151](https://law.resource.org/pub/us/case/reporter/F3/221/221.F3d.1151.99-4087.html)).

The rule turns on dates, not on safety. A molecule with a long safe record can be excluded because a company filed an investigational drug application before anyone can prove a supplement was on sale.

## Pyridoxamine: a vitamin removed at a drug developer's request

  * **What it is.** Pyridoxamine is one of the natural forms of vitamin B6, studied as an inhibitor of advanced glycation end products. It was sold in US supplements before 2005.
  * **The petition.** On 29 July 2005 BioStratum, developer of the pyridoxamine drug Pyridorin, petitioned the FDA to state that pyridoxamine supplements were adulterated and to remove them from interstate commerce. Its investigational drug application had become effective in 1999. In November 2005 the FDA tentatively agreed and asked for evidence of earlier supplement or food marketing ([Federal Register, 18 November 2005](https://www.federalregister.gov/documents/2005/11/18/05-22884/request-for-comment-on-the-status-of-pyridoxamine)).
  * **The ruling.** In January 2009 the FDA concluded that pyridoxamine is excluded from the supplement definition and may not be marketed as or in a dietary supplement, finding no independent, verifiable evidence that it had been sold as a food or supplement before the drug application took effect ([FDA Law Blog summary of the response, docket FDA-2005-P-0259](https://www.thefdalawblog.com/2009/01/fda-determines-that-pyridoxamine-is-excluded-from-the-definition-of-dietary-supplement-under-fdc-act/)).
  * **The drug.** In a 317-patient trial in diabetic kidney disease, Pyridorin missed its primary endpoint, with a possible benefit only in patients with the least kidney damage (Lewis 2012, [PMID 22034637](https://pubmed.ncbi.nlm.nih.gov/22034637/)). In February 2016 its developer paused the phase 3 programme, citing the remaining trial costs, its cash balance and the state of the capital markets ([NephroGenex corporate update, 24 February 2016](https://www.sec.gov/Archives/edgar/data/1338095/000133809516000099/exhibit991companyupdate02-.htm)), and the developer filed for bankruptcy that April ([US Bankruptcy Court, District of Delaware](https://www.deb.uscourts.gov/sites/deb/files/opinions/nephrogenex-opinion-and-order-re-fees_0.pdf)). Pyridorin was never approved. Pyridoxamine stayed off US supplement shelves anyway.



The science is on [advanced glycation and crosslink breakers](advanced-glycation-and-crosslink-breakers.html).

## NMN: excluded in 2022, reinstated in 2025

  * **The exclusion.** In November 2022 the FDA told a supplier that beta-NMN was excluded from the supplement definition because it had been authorised for investigation as a new drug, Metro International Biotech's MIB-626, with substantial public clinical investigations, and the FDA did not accept that earlier supplement sales counted ([FDA letter, 4 November 2022](https://www.crnusa.org/sites/default/files/Daily/2022-11/FDA-Response-NDI-1247.pdf)).
  * **The reversal.** After citizen petitions from the Natural Products Association, the Alliance for Natural Health and the Council for Responsible Nutrition, the FDA concluded on 29 September 2025 that NMN is not excluded. It said it was aware of evidence that NMN was marketed as a supplement in the US before it was authorised for investigation as a drug, and it agreed that this earlier marketing need not have been "lawful" to count ([FDA response to the Natural Products Association and Alliance for Natural Health petition, docket FDA-2023-P-0872](https://www.npanational.org/wp-content/uploads/2026/10/FDA-Response.pdf); [Nutritional Outlook](https://www.nutritionaloutlook.com/view/fda-responds-to-citizen-petitions-on-nmn-amending-its-position-on-the-ingredient-s-status-as-a-dietary-ingredient)). In December 2025 it reinstated acknowledgement letters for NMN ingredient notifications ([NutraIngredients, 9 December 2025](https://www.nutraingredients.com/Article/2025/12/09/fda-reinstates-ndi-status-of-nmn-with-new-letters-to-ingredient-players/)).



The NMN evidence, including vendor-funded trials, is on [NAD+ and sirtuin activators](nad-and-sirtuin-activators.html).

## NAC: "not a supplement", sold by permission

  * **The history.** The FDA says N-acetyl-L-cysteine was approved as a new drug in 1963, before any supplement or food marketing, so it is excluded under clause (i), even though NAC had been sold as a supplement for decades. On 31 March 2022 it denied the industry petitions asking it to reverse that view ([FDA guidance, August 2022](https://www.fda.gov/media/157784/download)).
  * **The workaround.** In August 2022 the FDA issued final guidance saying it would exercise enforcement discretion for NAC products labelled as supplements that otherwise comply with the law, while it considers a rule to allow NAC. It noted that NAC supplements had been sold in the US for more than 30 years and that its initial review had not found safety concerns ([Federal Register, 2 August 2022](https://www.federalregister.gov/documents/2022/08/02/2022-16499/policy-regarding-n-acetyl-l-cysteine-guidance-for-industry-availability); [FDA constituent update](https://www.fda.gov/food/hfp-constituent-updates/fda-releases-final-guidance-enforcement-discretion-certain-nac-products)).
  * **Where it stands.** The federal regulatory agenda lists a proposed rule to declare an ingredient, which industry identifies as NAC, not excluded from the supplement definition, with a July 2026 target ([RIN 0910-AI91](https://www.reginfo.gov/public/do/eAgendaViewRule?RIN=0910-AI91&pubId=202510)). As of 1 November 2026 we found no such proposal in the Federal Register. NAC remains legally excluded and available only because the FDA is not enforcing.



## What this means

  * A supplement's legal status can depend on a filing date at a drug company, not on new safety or efficacy data.
  * The rule can be triggered by a drug that is never approved, as with pyridoxamine.
  * The FDA can change its reading. The NMN reversal came after industry petitions, and the NAC position rests on discretion that can be withdrawn by revising the guidance.
  * None of this says whether these compounds work. That depends on the trials, which are covered on each compound's page. Who pays for those trials is covered on [industry funding and trial results](industry-funding-and-trial-results.html).



This page explains regulation; it is not legal or medical advice.

## Who paid, and how it got here

### How it got here

- FDA says NAC is excluded from the supplement definition but will not act against properly labelled NAC supplements while it considers a rule. ([FDA guidance, August 2022](https://www.fda.gov/media/157784/download))
- FDA reversed its NMN exclusion on 29 September 2025. ([FDA petition response, docket FDA-2023-P-0872](https://www.npanational.org/wp-content/uploads/2026/10/FDA-Response.pdf))

Checked 2026-11-01.

## Sources

1. Lewis EJ, Greene T, Spitalewiz S et al. Pyridorin in type 2 diabetic nephropathy. J Am Soc Nephrol. 2012;23(1):131-6. PMID 22034637 (PubMed 22034637)