NMN is a compound that cells can use to make NAD, a molecule that is vital for many aspects of a cell’s function. NAD is needed for cells to produce energy using the nutrients from our food, is used to repair damaged DNA and much more. With increasing age, NAD levels decline, and it is suggested that this decline is involved in multiple aspects of the ageing process. NMN is quite possibly the most promising potential ‘anti-ageing’ compound that is classified as a dietary supplement as opposed to a pharmaceutical drug. This means that anyone can buy and take NMN, but that might not be the case for much longer – at least in the US. That’s because the US Food and Drug Administration (FDA) recently sent out a letter to sellers stating that, after reviewing the situation, NMN can no longer be marketed as a dietary supplement.
FDA rules state that a compound can’t be categorised as a dietary supplement if it is authorized for investigation as a new drug, and if ”substantial clinical investigations have been instituted”. There is an exception for compounds that were marketed as dietary supplements before such investigations were authorised. However, the FDA states that according to its review of the available information, NMN was ”not marketed as a dietary supplement, except unlawfully without an NDI” (New Dietary Ingredient) notification, ”or as a food before FDA authorized it for investigation as a new drug”. An NDI notification is a notification that companies must submit before marketing a dietary supplement that hasn’t previously been sold as such in the US. In other words, NMN was being investigated as a new drug before it was being legally sold as a supplement under the current laws, and so the FDA deems that it can’t be classified as such.
The FDA says that the decision was made ”based on new information that came to light when we were reviewing another notification”, which led them to review previous notifications anew. So, it appears that the FDA approved NDI notifications for NMN. They were then made aware of recent studies investigating NMN as a drug or as part of one. They realised that clinical study of NMN predated the NDI notifications, so they reversed their approval.
When discussing dietary supplements, it’s important to stress that the line between supplements and drugs is entirely artificial. There is nothing inherent about the chemical structure of rapamycin that defines it as a drug as opposed to NMN – both are naturally occurring compounds and both have physiological effects within the body when ingested. The fact that only rapamycin is classified as a drug is based only on its clinical applications.
Given the above, one could argue that reclassifying NMN isn’t unreasonable considering the increasing clinical evidence that it can be used to treat or delay age-related disability. However, this argument starts to look tenuous when you begin to compare NMN to similar compounds. Nicotinamide riboside (NR), which is a type of vitamin B3, works in the same way as NMN (acting as a precursor for NAD) but with more side effects, and is not likely to be classified as a drug any time soon. Regulations for dietary supplements should exist to protect consumers from mis-marketed, unproven and potentially harmful substances, and recently they haven’t doing particularly good job of it.
This decision has raised some eyebrows, in part due to a lack of transparency over exactly how and why it was made. This has led some to accuse the FDA of favouritism towards pharmaceutical companies. If a compound is first marketed as a dietary supplement, it can still be incorporated into a pharmaceutical product at a later date, coexisting as part of both a supplement and a drug. This doesn’t work the other way around: if a pharmaceutical company can get in on a compound before a new ingredient notification can be filed, then they guarantee greater control of the future market.
The above has always been the case, but some people are upset with the FDA’s interpretation of the law here, as it suggests that new research can void NDIs if they were investigated as a drug first. They worry that this will allow a pharmaceutical company to apply for an investigational new drug, then sit on that application for years, only beginning research in earnest when new evidence emerges. Companies in the supplement industry, meanwhile, are discouraged from filing NDIs by the knowledge that they may one day be reversed.
Others have directed blame towards a company called Metro International Biotech and it’s co-founder and advisor David Sinclair. They have been developing an NMN-based compound called MIB-626, and have been working to market this as an FDA-approved drug. It was upon learning of the relationship between NMN and MIB-626 that the FDA made the decision to review its classification of NMN. Furthermore, Metro International previously lobbied the FDA to uphold a ban on another supplement called NAC, which the FDA wanted to exclude from the definition of a dietary supplement in 2020 for essentially the same reasons as the current exclusion of NMN.
Though some companies have decided to halt the sale of NMN supplements following this announcement, others have said they intend to continue sales while fighting the FDA. If we look back to the aforementioned situation with NAC supplements, the FDA ended up implementing an ‘enforcement discretion policy’ that essentially allowed sales of NAC labelled as dietary supplements to continue. It might therefore be a while before we know how this story ends.
NDI 1259 - B-Nicotinamide Mononucleotide (NMN) from Inner Mongolia Kingdomway Pharmaceutical Limited: https://www.regulations.gov/document/FDA-2022-S-0023-0051
Title image: Alexander Grey, Upslash