The FDA recently announced that Nicotinamide Mononucleotide cannot legally be sold as a health supplement in the United States
The ruling will no doubt be subject to legal challenge, but it seems likely to stick
The law governing the sale of health supplements in the United States is called the Dietary Supplement Health and Education Act of 1994 (DSHEA).
DSHEA tries to balance the competing interests of the pharmaceutical and health supplement industries in a number of ways, most prominently by requiring health supplement sellers to acknowledge that the health supplement cannot "diagnose, treat, cure, or prevent any disease."
But there is a lot more to DSHEA than just the label warnings, and one of those parts determines what can be sold as a health supplement, and what can only be sold as a pharmaceutical.
If something has for a long time been a part of the food supply, then generally it can be sold as a health supplement. But if it has not been a part of the food supply, then you would have to notify the FDA of your desire to sell it as a New Dietary Ingredient, and the NDI Notification would include information about why you think it's safe to sell as a supplement.
Here is the catch. There is ANOTHER provision of DSHEA (21 USC 321(ff)(3)(B)(ii)) that says if an ingredient is being investigated as a pharmaceutical, then it cannot be subsequently introduced as a new dietary ingredient for sale as a health supplement:
The term "dietary supplement" does not include an article authorized for investigation as a new drug, antibiotic, or biological for which substantial clinical investigations have been instituted and for which the existence of such investigations has been made public
The purpose of this provision, presumably, is to protect pharmaceutical companies from investing a lot of money to determine whether a substance has pharmaceutical uses, and then, when the ingredient works, to have their new drug undersold without a prescription because it later becomes available as an inexpensive health supplement. This could hamper the pharmaceutical company's ability to recover their investment.
MetroBiotech's Letter
On December 1, 2021, a pharmaceutical company called "Metro International Biotech" wrote a letter to the FDA. Harvard professor and NMN evangelist David Sinclair co-founded Metro Biotech and chairs its scientific advisory board. MetroBiotech's letter asked the FDA invoke this very provision to block the sale of NMN in the United States. The letter says that because Metro Biotech "has instituted publicly available clinical trials on [NMN], we request that FDA take the preclusion provision" seriously.
Here is Metro Biotech's letter to the FDA:
Metro Biotech essentially said that the purpose of this law is to protect people like us, and we have satisfied the law's requirements, so you should do what you are legally required to do and protect our pharmaceutical from the risk of having to compete with subsequently available, less expensive health supplements.
Even after MetroBiotech's letter, health supplement companies continued to file New Dietary Ingredient Notifications (NDIN) alerting the FDA to their intention to sell NMN as a food supplement in the United States.
But by then it was too late.
The FDA's Decision to Block NMN
In October and November 2022, about ten months after MetroBiotech's request, the FDA responded to one of the NDI requests with an announcement that the NDIs were too late, and that publicly announced clinical trials had already begun, and so NMN was no longer eligible to be sold as a food supplement.
You can read the seller's NDIN, the FDA's initial response, and the FDA's supplemental response. (Most of the analysis is in the supplemental response.)
The NMN seller hired a top-notch (i.e., expensive) law firm to assert two primary arguments in favor of NMN. First, that NMN was already in the food supply before the clinical investigations had begun, because it was sold as a food supplement in the US, even though without an NDIN. Second, NMN was sold as a food supplement in Japan in 2016, so NMN was in the food supply before the clinical investigations had begun that way, too.
The FDA said none of that counts. Being sold as a food supplement doesn't count as being in the food supply. Moreover, being sold without an NDI is not legally present in the food supply, so that also does not count. Finally, what happens in Japan does not count.
The FDA's arguments here are pretty strong and well-supported, and seem to me likely to withstand any legal challenge.
And there may well be a legal challenge. There is apparently a lot of money at stake. And if someone could pay a big law firm to take the argument this far, they might well be willing to keep it going, especially if that delayed imposition of the FDA ban. We'll see.
So What Happens Next?
I don't know. The FDA no doubt has already alerted the NMN sellers of their decision. Presumably most NMN retail sales are occurring through Amazon's website, which currently lists many brands of NMN. Maybe Amazon will voluntarily stop NMN sales.
That seems to be what happened when the FDA determined last year that NAC could not be sold as a food supplement for similar reasons. At first, Amazon cleared all the NAC out of its catalog. But about a year later, after the FDA announced that it was going to exercise enforcement discretion to basically ignore the legal problem with NAC, Amazon invited the NAC back.
I don't think that's as likely to happen in the case of NMN.
The FDA made clear with NAC that its policy of non-enforcement resulted from the fact that NAC had been sold as a health supplement for a long time and the FDA's own safety review showed no concerns.
That by itself may be a different situation from NAC, since there have been some suggestions that NMN can be contaminated with an endotoxin (Lipopolysaccharide or LPS), an irritant from bacteria. David Sinclair most prominently suggested this in a Facebook post:
In theory, it might be that if NMN was particularly prone to contamination then the FDA might think that more stringent pharmaceutical manufacturing processes were warranted to ensure safety. But I'm not sure how seriously take this safety concern. Dr. Sinclair said this after Metro Biotech petitioned to have NMN removed, and before the FDA agreed to do so. So it is conceivable that he might have a motive to accentuate the safety concern. And I can't find anything else published that suggests the threat here is significant or peculiar to NMN.
But even if safety turns out not to be an issue with NMN, there seems to be an actual "race to market" situation here that was not a factor in the NAC decision. DSHEA sets up a "race to market" dilemma when health supplement and pharmaceutical companies both want to sell an ingredient, and DSHEA offers pharmaceutical companies statutory exclusivity if they publicly commence clinical testing before the ingredient enters the food supply. Here, the pharmaceutical company (MetroBiotech), has specifically requested exclusivity under the statute, and that request appears to be consistent with the purpose of the law. Moreover, the FDA agrees that Metro Biotech won the race and that the law requires it.
NMN sellers may wish to challenge the FDAs decision in court, but Metro Biotech could just as easily challenge the FDA's contrary decision in court, and it seems as if the law would be on their side. Supplement providers don't care for DSHEA's race-to-market provision, but it is currently the law, and the presence of the race seems to distinguish the NMN controversy from the NAC controversy.
Is This a Bad Thing?
For MetroBiotech this appears to be a good thing -- it's what they asked for, anyway. For NMN sellers it's a bad thing, at least to the extent that they were making money selling NMN. But for ordinary consumers of health supplements trying to get the benefits of NMN, this ban probably doesn't matter much.
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Consumers who switch to NR
could actually be better off.
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The reason it doesn't matter much is because, as we have shown elsewhere, NMN's primary use is for replenishing NAD. NMN does that either mostly or entirely by delivering nicotinamide (NAM) or nicotinamide riboside (NR) to cells.
The reason we know that NMN actually delivers NR is because NMN cannot enter most or all cells directly, and instead must be degraded to NR or NAM to enter cells and replenish intracellular NAD, and there are circulating enzymes that do exactly that.
So although NMN seems to work okay, you could also just take NR or NAM directly. Nobody using NMN to replenish NAD needs NMN to do it.
Some people believe that there is an NMN transporter that can allow NMN to enter some cells directly -- slc12a8. But even if that were true, the slc12a8 transporter is not expressed in most cells.
You can read more about all that here: NMN v. NR.
Is Nicotinamide Riboside Next to Go?
NR is and should remain readily available, because NR seems to have been approved for sale as a dietary ingredient before any pharmaceutical companies began any publicly announced clinical trials.
To the extent that nicotinamide riboside is actually more efficient, more effective, less expensive, and/or safer than NMN, NMN consumers who switch to NR could actually be better off.