NMN, FDA, and the Supplement Industry’s Fight for Its Life

For well over a century, scientists sought to understand and embrace a universal energy-carrying compound known as NAD, short for nicotinamide adenine dinucleotide.

The many benefits of NAD+, ranging from metabolism to cell survival and DNA repair to liver detox and far more. When we’re low on NAD+, bad things happen.

Researchers originally thought it was just an important fermentation factor,^[84-86] but we now know that NAD’s “raw” form, NAD+, is fundamental to energy metabolism, facilitating countless biochemical reactions in the body.^{[65-68,87-91]} It participates in cell survival, inflammation, DNA repair, liver detoxification, and several processes that combat aging.^[88,92-94]

We now also understand that poor NAD metabolism can lead to severe health consequences, many of which deal with cellular energy insufficiency and are age-related.^{[65,67,87,90,95]} Let’s explore how we historically came to understand this, and how it coincides with some critical vitamin discoveries.

1948: ATP + NMN ⇌ NAD

Scientists first learned about the underpinnings of NAD in the early 1900s. Four key Nobel Prize laureates from 1904 through 1948^{[84-86,96,97]} contributed to the understanding that NAD is synthesized by linking two separate molecules, ATP and NMN.^[97]

Known as nicotinamide mononucleotide, in the 1950s NMN was identified in human red blood cells.^[98-101] Now we know how critically important this molecule is: In the body, it’s a key biological precursor of NAD+.^[86] NMN studies led to groundbreaking discoveries in the 1960s that greatly contributed to our understanding of RNA/DNA,^[102,103] metabolism, and cellular health at large.

Soon, NAD+ would reveal its importance. This was discovered through its deficiency:

In parallel: A devastating skin disease and finding the P-P Factor

A crucial medical journey played out for centuries, long before our quest to understand the NAD system.^[104] Humans have long battled pellagra, a nutritional deficiency disease that manifests as a skin condition (pelle is Latin for skin; and agra means rough).^[104,105]

This condition is highly-intertwined with our quest for better NAD production. Pellagra is characterized by the “four D’s”:^[104]

1. Dermatitis
2. Dementia (or depression)
3. Diarrhea, and eventually
4. Death

The NAD+ molecule, which comes from a combination of NMN and ATP

Tracking back to medieval times, pellagra was always more likely to occur in humans who live in poverty and/or have diets heavily-reliant on processed corn and are low in meat, eggs, and dairy.^[104,106]

After decades of experimentation — much of it insanely unethical from the modern lens — a renowned scientist named Joseph Goldberger finally cracked the pellagra code. After discovering that the disease could be eradicated with proper nutrition (mainly a diet rich in animal-based foods), he came up with the “P-P Factor”, short for pellagra-preventive factor, which was temporarily renamed to “vitamin P-P” until it was fully understood.

Goldberger died before he could figure out the exact identity of vitamin P-P, but he knew there was something about consuming healthy, animal-based products that was key to keeping the disease at bay. It turns out that P-P Factor is an important NAD+ precursor! We’ll return to this storyline shortly…

The search for NAD Boosting Supplements

As a co-enzyme that mediates various reactions, NAD has many protective effects. But insufficiency can lead to many health problems.^[65]

As research into the NAD signaling system expanded with crucial discoveries from 1976 through 2000,^[107-110] NMN itself remained elusive.

However, it became quite clear in the past few decades that maintaining healthy NAD levels is critically necessary.^{[65,66,68,87]} Emphasizing its importance, the body has four* known pathways to create NAD+^[65-68] — it provides redundancy for life-critical molecules.

Upon learning this, the search began in earnest for ways to increase NAD+ and keep it high. Since supplemental NAD+ is unstable and degrades too easily^[111] — and isn’t orally bioavailable anyway^[112,113] — we need to ingest NAD’s precursors through food and, if necessary, supplementation.

Three dietary supplements have been used since mid-1900s,^[107] and as you’ll see, the pellagra solution would be one of them:

• Popular Forms of Niacin / Vitamin B3: Nicotinic Acid and Niacinamide

  Many are familiar with niacin, sometimes known as vitamin B3. This class of vitamins is prominent in healthy diets. It’s primarily supplemented in a couple of forms, namely nicotinic acid (NA) and nicotinamide / niacinamide (NAM). These are two major dietary sources of NAD+ precursors – and they’re historically significant.

  NA can be converted to NAD+ through two pathways:

  1. The Preiss-Handler pathway, also known as the nicotinic acid salvage pathway
  2. The nucleoside salvage pathway^[68]

  NAM can be converted via the nicotinamide salvage pathway.^[65-68]

  Below, centered in the red box, is an illustration of how the body works toward NAD+:

  

  The NAD Pathways, in blue.^[66] * In the description above, we mention that there are four known pathways. This is counting the two different salvage pathways on the bottom separately.

  The elusive P-P Factor is discovered!

  Remember the P-P Factor discussed in the hunt to solve the growing pellagra problem in poverty-stricken populations? It turned out it’s none other than nicotinic acid!^[114] Thus, as early as 1937, nicotinic acid was rightfully deemed essential because it alone was found to cure the skin disease.^{[104,115-117]}

  Animal-based foods are incredible dietary sources of nicotinic acid and niacinamide, but as more people turn to vegetarian and vegan diets, it increases the need for supplementation. Unfortunately, there are a few major problems when using these two as dietary supplements:

  1. The niacin flush!

     You’ve likely heard of the “niacin flush”. It’s a side effect that people either love or hate. Many find it downright uncomfortable, while a select few actually enjoy it. The sensation is the result of therapeutically-dosed nicotinic acid supplementation.^[120-124] The flush, caused when NA binds to the GPR109A receptor,^[125] is an effect that ultimately leads to poor compliance in niacin users.

  2. Flush-Free Niacin (niacinamide / nicotinamide / NAM) is less effective

     There are many supplements marketed as “flush-free niacin”. They contain niacinamide (originally called nicotinic acid amide but now known as nicotinamide / NAM in research). However, there is only one pathway this form can take, and that pathway can be limited and degraded by poor health.^[68,126,127]

     

     Niacinamide (NAM) can raise NAD+ levels, but as its concentration goes up, it strongly inhibits aging regulators known as sirtuins.^[128] Long story short, it’s not a good NAD+ booster.

     Further, even with heroic doses of niacinamide, which indeed raise NAD+ levels, certain anti-aging markers known as sirtuins are still not activated (and may even be inhibited).^[128,129] Early research made it clear – there are simply fewer use-cases for this particular NAD+ precursor,^[122] even though it can still be labeled as niacin on a dietary supplement.

     Speaking from the perspective of a dietary supplement formulator, nicotinic acid is side effect ridden, and niacinamide is practically useless. We need something better.

  Niacin’s murky definition

  A quick point that we need to make here is that the word “niacin” is often used as a class of vitamins (niacinamide can be claimed as niacin on labels), but it originally just meant nicotinic acid.

  This is an important legal issue that has become a point of confusion in labeling. It’s unclear what exactly “niacin” means, and to whom one meaning applies versus another. We dive further into this later on. The next ingredient is involved in this labeling situation as well:

• Tryptophan

  NAD+ can also be made from the essential amino acid L-tryptophan, but it’s an eight-step process through two pathways (first the de novo / kynurenine pathway and then the Preiss-Handler / nicotinic acid salvage pathway).^[130-133] This can provide support in niacin-deficient diets,^[68] but not all tissues express the enzymes needed to make the conversion to NAD+ (mainly just the liver can do this).^[130,134]

  A 60:1 Niacin Equivalent

  

  In the red box, the pathway to generate NAD+ from tryptophan.^[130] Obviously this is quite a long pathway, so it’s not highly effective – but is worth knowing about.

  It’s legal to label tryptophan a niacin equivalent” due to the above biochemistry, and you may see “Niacin NE” on the supplement facts label of a tryptophan-containing supplement. Every 60 milligrams of tryptophan must be labeled as 1 milligram of niacin.^[135,136] Those numbers are based on human research published in 1961 showing a range of 34 to 86 milligrams of tryptophan being the equivalent of 1 milligram of niacin^[137] – the actual number depends on on the consumer’s physiology.

  While we always suggest eating a meat-based diet high in essential amino acids, tryptophan is simply not the NAD booster we’re looking for — there are too many potential breaks in the chain and it doesn’t touch our predominant pathway.

  So the quest continued for a better means of NAD+ supplementation. In the mid 2000s, it was realized:

• NR (Nicotinamide Riboside)

  

  Highlighted in the larger box, the pathway from nicotinamide riboside (NR) to NAD+… which goes through NMN.^[66] Which begs the question… why not just supplement NMN directly?!

  In 2004, researchers discovered the mechanism of another NAD+ intermediate called nicotinamide riboside, abbreviated to NR.^[138] Once NR enters the cell, it’s metabolized into NMN through the nucleoside salvage pathway,^[68,138] and then into NAD+ as the final step.^[68,139-141]

  NR is often considered a source of vitamin B3, like NA and NAM.^[142] Since it’s found in milk,^[70,71,138] and is already a part of the human diet, it was eligible for consideration as a dietary supplement.

  So in 2015 and then in 2018, ChromaDex Inc filed two New Dietary Ingredient Notifications for Niagen (nicotinamide riboside hydrochloride): NDIN 882^[143,144] and NDIN 1062.^[145,146] Additionally, in 2016, nicotinamide riboside was affirmed GRAS, having received a “LONO” (letter of no objections) from the FDA.^[147]

  Per DSHEA 1994 guidelines, NR is a legal dietary supplement ingredient.^[3,14]

  This event led to a tremendous amount of hype and sales for Niagen. Niagen search trends weren’t again matched until the recent news of the FDA’s reversal on NMN:

  

  Nicotinamide Riboside had some serious trends after the new dietary ingredient Niagen came out^[148]

  The trouble with NR

  Despite its approval, there were some issues with NR. It turns out that its oral bioavailability is highly variable among individuals^[149] — some people respond incredibly well to the ingredient, others, less so.

  It’s possible that suboptimal gut health may limit its uptake.^[149] Unfortunately, this is a major concern because metabolically-dysfunctional individuals — those who may need NAD+ support the most — generally have poor gut health!^[150]

  Additionally, much of NR’s momentum was crushed when a catastrophic study was published showing that in swimming tests, NR-supplemented rats had a whopping 35% reduced performance compared to the control group.^[151]

  As this was playing out, in the background there was another NAD+ precursor gaining momentum.

• NMN – Nicotinamide Mononucleotide

  Recall how we said that NR gets converted to NMN and then to NAD+.^[68,138] Flush-free niacinamide is also converted into NMN in its earliest stage.^[65-68] So why not spare yourself an ATP molecule and go straight to the source by simply supplementing with NMN — the direct precursor to NAD+?

  

  NMN is the direct precursor to NAD+, and using it instead of NR or nicotinic acid spares precious ATP molecules.

  That’s exactly what researchers from Washington University in St. Louis postulated in 2007^[152] when they published results from their successful research in mice.^[153] But it wasn’t until 2011 when scientific interest in NMN supplementation really exploded. Reason being, that same team demonstrated that NMN had a positive effect on diet and age-induced type 2 diabetes.^[154]

  

  Earlier, we covered a research study on overweight, insulin-resistant women has shown that NMN supplements improve muscle insulin sensitivity.^[155] This just scratches the surface of the ingredient’s benefits.

  The researchers concluded that “NMN supplementation might also be effective in human T2D patients”,^[154] and with that, it was off to the races for scientists around the world.

  A difficult ingredient to produce…

  At that moment in time, supplementation was easier said than done. NMN is difficult to manufacture and stabilize in a bioavailable format. After an exciting article titled “Scientists Find Way to Make Aging Clock Stop Ticking” was published in late 2013,^[156] users of a popular longevity discussion forum joked that you could get NMN for only $1,700 a gram.^[157]

  Thankfully due to industry pioneers like Nutraland, SyncoZymes, CellMark, and NNB Nutrition, we no longer need to worry about those prices. And just as prices came down, more data was published regarding NMN’s prevalence in nature.

  …but a natural part of our common food supply

  

  NMN is found in numerous foods, as discovered in a study published in 2016.^[72]

  When investigating potential dietary supplement ingredients, many ask, “Are there natural sources of NMN?” It turns out there are plenty.

  NMN was first identified in food in 1969 where, in barley, “significant amounts of NMN were detected.”^[69] This alone makes a frequently-cited 2012 paper that states “NMN has not yet been found in dietary constituents”,^[158] to be factually and historically erroneous. But much more evidence would come soon.

  In 2013, researchers claimed to have found NMN in our daily food sources (according to their “unpublished finding”),^[159] but officially, it was discovered in milk alongside NR in early 2016.^[70] Later that year, another team of scientists discovered that NMN is actually quite abundant in many foods, including edamame, broccoli, cucumbers, cabbage, avocado, tomato, mushrooms, beef, and shrimp.^[72] Different researchers confirmed its existence in milk in 2017.^[71]

  More recently, in late 2022, another group of scientists found NMN in numerous types of cinnamon,^[73] a spice notably used for its antidiabetic effects.^[161]

  NMN is more prevalent in food than we realize

  Combining this data with the knowledge that two different NMN precursors (NR and niacinamide) are also abundant in our food supply, we’re led to believe that NMN is not just “found” in healthy foods — it’s actually quite ubiquitous in many foods that contain vitamin B3. This is illustrated by the aforementioned cinnamon study, where hundreds of tested samples were shown to contain small amounts of the molecule:

  

  NMN is found in small amounts in hundreds of foods, and is pervasive throughout our food supply,^[73] with a cumulative intake that’s likely higher than most researchers estimated earlier on.

  With that data in mind, there’s a great chance that researchers and dietary supplement companies have been underestimating the amount of NMN we cumulatively get from a healthy diet high in protein and other whole foods.

  Going further: NMN’s superiority and the discovery of an NMN transporter

  In fact, a team of scientists recently found a transporter named Slc12a8 that they believe is an NMN transporter,^[162] bringing even greater significance to the powerful NAD+ precursor.

  

  Back to our NAD+ synthesis map.^[66] Circled in green are all of the areas where an ATP molecule is required. NMN combines with a single ATP molecule to directdly generate NAD+. However, using NR or NAM or NA all require a second ATP molecule every time, which is costly. The human body would greatly prefer to save that ATP, and absorbing as much NMN as possible enables that.

  This discovery has led other research teams to state that “Slc12a8 is found to be extremely upregulated in the small intestines of mice, which may demonstrate an organism’s requirement to pull as much NMN from food as possible“^[163] — a statement that reinforces its dietary significance if/when the transporter is found in humans as well.

  Understand this: The human body is “lazy”. If it can generate critical NAD+ from a molecule that requires fewer highly-prized ATP molecules to do so, then it will do proverbial evolutionary backflips to make that happen. This efficiency is indeed the case for NMN compared to NR or nicotinic acid. It’s also another reason why an NMN transporter likely exists: Energetically speaking, it’s a “less expensive” nutrient to work with.

  There’s no longer a debate about whether or not NMN is found in food. Instead, the real question is how critical it is to a healthy diet, and should it be included as an essential dietary vitamin?

  That may seem like a bold statement now, but the data is beginning to back it up, and we’ll explore this line of thinking later in this article.

  What about safety?

  Incredible human data and safety research coming at an accelerating clip

  Since the landmark study in 2011,^[154] more peer-reviewed studies have been published demonstrating NMN’s oral safety and efficacy in various health metrics in both animals^[72,164-166] and humans,^{[27-30,155,167-170]} with more certainly on the way.

  In fact, one of these completed human trials^[155] was enrolled in ClinicalTrials.gov on May 12, 2017, describing the intervention as a “Dietary Supplement: NMN supplement”.^[171] ClinicalTrials.gov is run by the National Institutes of Health (NIH), a part of the U.S. Department of Health and Human Services (HHS), an agency under the executive branch of the federal government — the same branch in which the FDA and USPTO reside.^[81]

  Recall from the intro of this article: The law only states that the FDA can recall an NDIN if there is a demonstrated safety concern — and the burden of proof rests on the FDA.^[3,5] NMN has zero safety issues – none of these studies showed any side effects.

  Also notice that many of these highly-successful human trials (as well as one very noteworthy animal experiment^[172]) were published in 2022. NMN seems to be achieving “escape velocity”, which makes the FDA’s recent decisions even more concerning. Here we are, arguing that NMN is the naturally-found “niacin” vitamin we’ve been looking for all along, and the federal government has attempted to capture it and make it a pharmaceutical drug.

So let’s dig more deeply into this “NMN is a vitamin” line of thinking, because it provides everyone with a long-term solution that will protect public health.

Now that we’ve been through the regulatory torture chamber and have explained NMN’s basic history and biochemistry, we have a simple and profound statement to make.

Knowing what we now know, there’s a very simple realization that supersedes most of this legal hand-wringing:

NMN is in the vitamin B3 class and should be counted as niacin.

We’ll go even further to say that it’s not just a form of vitamin B3 or a niacin derivative, but it is the vitamin B3 that the body most prefers.

Let’s first look at it from a few angles — legal/historical and biochemical — and then draw a few conclusions.

Historical basis for niacin requirements

“Niacin” was supposed to mean nicotinic acid. But as you’ll see – things are about to get confusing.

The word niacin was originally conceived as a new name for nicotinic acid, coined in 1942 using letters from nicotinic acid vitamin, and to avoid the molecule’s association with nicotine.^[118,119] It was deemed essential because it could cure the pellagra, a skin disease found in animals and humans with deficient diets.^[104,115]

It was also discovered that enough tryptophan could often cure the disease^[173] — and we now know why given the pathways in our biochemistry lesson above. This is the reason why we have Niacin Equivalent (NE) guidelines for our food and supplement labels.^[135-137] And that’s where things start to get murky.

Confusion in the definition of “niacin”

Unfortunately, over the past several decades, our language has evolved in a way that has become quite confusing. We now have at least three different ingredients that can contribute to the “niacin” listed on your label, each with multiple names of their own:

Had NMN been readily available in the 1940s through 1960s, it would be in your multivitamin right now, listed as an essential vitamin.

• Nicotinic acid / “niacin” / NA / pyridine-3-carboxylic acid
• Nicotinic acid amide / nicotinamide / niacinamide / NAM / pyridine-3-carboxamide
• Tryptophan / L-Tryptophan

So the word “niacin” now potentially means two different things – a class of vitamins (vitamin B3), and/or a single molecule that was haphazardly renamed (nicotinic acid).

As an example, when referencing suggested dietary intakes, the NIH links to the National Academies Press (NAP).^[174] What does NAP say about this class of vitamins?

Take a look at Chapter 6 of their “1998 Dietary Reference Intakes for Thiamin, Riboflavin, Niacin, Vitamin B6, Folate, Vitamin B12, Pantothenic Acid, Biotin, and Choline”, which is what NIH’s website currently links to:^[174,175]

The term niacin refers to nicotinamide (nicotinic acid amide), nicotinic acid (pyridine-3-carboxylic acid), and derivatives that exhibit the biological activity of nicotinamide.^[175]

Here, we have the government citing niacin in the broad context — one that mentions derivatives that most definitely include NMN.

There are more examples of this usage below, but the point is that the definition of “niacin” has become very unclear. So let’s try to capture the intent:

“Niacin” is deemed essential because it’s an NAD+ precursor

Is the nicotinic acid itself important, or the resultant end product important?

Remember, this vitamin class was deemed essential — and rightfully so — to prevent nutritional deficiencies leading to horrifying disease. Even back in 1965, researchers understood the greater significance:

Functions of Niacin.—The functions of niacin have been widely studied in recent years. Niacin or one of its derivatives is required by all living cells. It is an essential component of two coenzymes, diphosphopyridine nucleotide or coenzyme I (niacine adenine dinucleotide [NAD]) and triphosphopyridine nucleotide or coenzyme II (niacine adenine dinucleotide phosphate [NADP]).^[176]

Thus, the point isn’t that it’s essential to get “nicotinic acid” or “nicotinic acid amide” in. The real goal is to have enough of something — anything — to generate NAD! This is exactly what NMN does — and extraordinarily well at that.

Further, if you look up the definition of “niacin” in medical texts, you’ll see statements such as the following:^[104]

The general term “niacin” now includes nicotinic acid and its amide, i.e., nicotinamide, and any derivatives convertible in vivo to biologically active compounds.^[104]

In fact, the federal government’s own website — the NIH’s niacin fact sheet — says this itself:^[142]

Niacin (also known as vitamin B3) is one of the water-soluble B vitamins. Niacin is the generic name for nicotinic acid (pyridine-3-carboxylic acid), nicotinamide (niacinamide or pyridine-3-carboxamide), and related derivatives, such as nicotinamide riboside.^[142]

NMN is very clearly a “related derivative” — hell, it’s THE derivative. And it’s obviously bioavailable and active, given the tremendous amount of orally-supplemented research discussed above.^{[27-30,155,167-170]}

NMN fits perfectly into the broadly-used definition of the term “niacin”. Image taken from NIH website.^[142]

Meanwhile, did you see what they did there? They even added nicotinamide riboside (NR) to that definition!^[142]

Hilariously, ChromaDex’s own GRAS notice for NR states that “…NMN is the only metabolite that can be converted to NAD+ in mitochondria…”^[177] – even they allude to the incredible power of NMN!

It’s the NAD precursors we’re after

Getting back to pellagra, which is the main reason for niacin’s prominence, we have to ask a question: Is this disease a nicotinic acid deficiency, or NAD+ precursor deficiency?

We now know the answer to that, thanks to modern research: “Pellagra is a curable dietary illness that unchecked leads to dementia, diarrhoea, dermatitis and death due to lack of the precursors for NAD(H).”^[95]

So it’s not specifically the nicotinic acid the body is after. It’s the NAD+ production, full stop. Nicotinic acid was merely the easiest such vitamin to find last century.

Had NMN been readily available in the 1940s through 1960s, it would be in your multivitamin right now, listed as an essential vitamin.

What is the definition of Vitamin B3?

There’s a way out of this, though – with Vitamin B3.

All too frequently, vitamin B3 is used interchangeably with “niacin”. However, we don’t see an official definition for “vitamin B3” in any of the federal government’s regulations – whether it’s law signed by Congress or federal code applied by the FDA.

Using niacin and vitamin B3 interchangeably makes sense when we broadly consider niacin to be the class of vitamins and vitamers that serve as bioavailable precursors to NAD+. But this does not make sense if we stick with the FDA’s codified definition of niacin, which is nicotinic acid,^[61] again derived from nicotinic acid vitamin. And since we’re in a legal quagmire, the distinction does matter.

Yet the FDA itself isn’t even consistent with its language:

The FDA uses Vitamin B3 as a class of vitamins in response letter

In ChromaDex’s two NDIs for nicotinamide riboside,^[143,145] they write:

“Vitamin B3 is defined as the dietary precursor to nicotinamide adenine dinucleotide (NAD+) other than the amino acid tryptophan. (Erdman et al. 2012)“^[143,145]

In those NDIs, ChromaDex cites Erdman, et al. 2012, copying the above definition from Chapter 19 of the esteemed textbook, “Present Knowledge in Nutrition, Tenth Edition”.^[178] This chapter was written by W. Todd Penberthy and James B. Kirkland of the University of Central Florida and edited by Professor Emeritus John Erdman, Jr. of the University of Illinois, all three of which are esteemed PhDs.

And in the FDA’s response letter of non-objection to Chromadex’s GRAS notification for NR, the agency wrote the following:

“NR is a precursor of the coenzyme nicotinamide adenine dinucleotide and is a source of vitamin B3”.^[147]

— Dennis M. Keefe, Ph.D., 2016 Director for the FDA’s Office of Food Additive Safety at the Center for Food Safety and Applied Nutrition

The above usage of “vitamin B3” makes sense, and other researchers seem to agree. A book written by prominent biochemists Martha Stipanuk and Marie Caudill from Cornell University states:^[179]

“Vitamin B3 is defined as the precursor to NAD and potentially includes three different molecular forms: nicotinic acid, niacinamide, and nicotinamide riboside.”^[179]

Back to the biochemistry: a better NAD+ precursor

We argue that NMN is a better NAD+ precursor than nicotinic acid (NA), nicotinamide (NAM), nicotinamide riboside (NR), and certainly tryptophan.

Get your NAD+ requirements with the fewest green circles and you save ATP.

After all, it requires less work for the body to create NAD+ from NMN: It takes one less ATP molecule to get to NAD+ compared to that of NR, and the same goes for NA (along with much less enzymatic activity). This is significant — ATP is finite and extremely valuable.

Additionally, there’s a good chance we have a dedicated transporter for it,^[162] because it’s that useful to the body. Anytime the body can spare precious ATP molecules for performing other operations, it’ll gladly take that opportunity.

Worthy of a “Niacin equivalent”

So if tryptophan gets a “niacin equivalent”, so should NMN (and NR for that matter). What equivalent? That’s for scientists to discover — but it’d possibly be less than a 1:1 ratio if/when it’s shown to elevate NAD+ levels greater than nicotinic acid on a gram-for-gram basis!

Long story short: this class of vitamins is essential because its components all lead to NAD+ production. Nicotinic acid was merely the first one discovered in the fight against pellagra. NMN is squarely in this class — and is likely best in class — and should be added to the list of B3 vitamins that can be labeled as “niacin” as well.

This is the FDA’s long-term way out

FDA can get out of their bind here by making NMN an officially GRAS substance like niacin, allowing it to be sold supplementally or as a drug.

Our suggestion for the FDA is to clarify and re-define this class of vitamins in a sensical fashion. If they’re serious about public health, they’ll investigate this line of thinking and come up with a guideline that benefits everyone. That potentially means ditching niacin requirements and instead using vitamin B3, which would include nicotinic acid, nicotinic acid amide, NR, and NMN.

More easily, the FDA could propose a rule for NMN, giving it de-facto GRAS status alongside nicotinic acid and nicotinamide, and open a docket for comments while the research phase is ongoing. Given their refusal to open a docket for the NPA,^[24] however, this all seems unlikely.

Just like Niacor can be a prescription drug for specific medical claims while nicotinic acid is a dietary supplement for vitamin optimization and overall energy, a similar compromise can be made for NMN between the pharmaceutical and dietary supplement industries.

Until then, the simple solution is already here: NMN is GRAS, and NMN is a B3 vitamin that fits the broadly-used definition of the word “niacin”. NDIN 1247 should remain legitimate with no objections, but we see no reason why MIB-626 shouldn’t proceed with specific drug claims.

It would be remiss to publish this article without discussion of two episodes of Joe Rogan’s podcast featuring David Sinclair. This is especially the case since Sinclair is in partnership with Metro International Biotech, the company attempting to make the “NMN supplement” (their words) into a drug.

However, before proceeding, let us make two things very clear:

1. This section adds very little weight in the legal and scientific arguments in the NMN case. It’s here for purposes of historical context and thoroughness.
2. David Sinclair is not the face of NMN, nor did he discover it. Like the rest of us, he stands on the shoulders of true giants, such as the four Nobel laureates from the early 1900s. He simply mentioned it first on one of the world’s most popular podcasts.

The Joe Rogan Experience #1234 and #1349

In January 2019, Joe Rogan, host of the widely-popular podcast The Joe Rogan Experience (JRE), hosted anti-aging researcher David Sinclair on episode #1234.^[180]

While discussing his anti-aging exercise, caloric restriction, and fasting protocol, Sinclair mentioned, “I also take supplements, and in fact, most of my colleagues are — in the field of aging or ‘anti-aging’ as people call it. So I take NMN every morning.”

He goes on to state that he takes a gram every morning in his yogurt. You can watch it in this clip:

If you’re unaware of the power of the Joe Rogan Experience, take a look at this Google Trend to show how much search volume on ‘NMN’ amplified:

While Sinclair’s episodes on JRE definitely boosted NMN’s search traffic, the recent FDA letters caused an even greater surge thanks to the “Streisand Effect”.^[181]

Sinclair returned to JRE later that year for #1349,^[182] and they get into NMN supplementation a bit more:

This led to a dramatic increase in both NMN’s popularity and Sinclair’s following.

More on Sinclair’s use of NMN Supplements

Digging deeper into Sinclair, he gives a 2017 interview to Harper’s Bazaar. The article, titled “The Future of Anti-Aging”, states that “Sinclair, 48, has been taking his own custom NMN supplement (500 milligrams) for almost two years. Tests have revealed that his cells now behave like that of a 31-year-old.”^[183]

A similar interview in Kaiser Health News appeared in February 2019, discussing some of Sinclair’s financial interests and legal ramifications of the claims made on an NR-containing supplement he and his partners were selling.^[184] (That supplement, Elysium Basis, does not contain NMN).

Coinciding with his second JRE appearance later in 2019, Sinclair published Lifespan: Why We Age—and Why We Don’t Have To.^[185] In that book, he mentions nicotinamide mononucleotide or NMN 22 times,^[186] and also discusses his and his father’s use of NMN multiple times,^[187] notably calling NMN a supplement.^[188]

Thanks to Joe Rogan’s platform, this exposure brought NMN supplements — a molecule mostly known to anti-aging enthusiasts — to the mainstream. The number of supplements on the market steadily increased ever since.

David Sinclair at Metro International Biotech

As it turns out, the company with two clinical drug trials, Metro International Biotech, was actually co-founded by Sinclair!^[189] Oddly enough, this is the man who has been calling it a supplement for years, and now the FDA is trying to retroactively change that. In fact…

Metro International Biotech’s own studies call NMN a supplement!

Here’s where things get really dicey. If you take a look at the History of Changes of the three studies the FDA cites as evidence that a clinical drug trial predates the NDIN,^[17] you’ll notice that the trial was submitted as a dietary supplement and changed three weeks later!^[18]

See for yourself:^[18]

Look at the edit history of this clinical trial: it was changed to remove the words “supplement” and “βNMN”!^[18] This situation cannot possibly be more preposterous.

They simply changed the words supplement and βNMN to say “MIB-626”!^[18]

So this ingredient — which is really a vitamin that’s found extensively in the food supply — becomes an “investigational new drug” because someone hit the “edit” button? Is that where we are in this cycle?

Yet other studies posted on ClinicalTrials.org that have been completed call it a supplement!^[155,171]

So at this point:

Hundreds of researchers, including the pharma company itself, have called it a supplement!^[18]

• It’s scientifically classified as a vitamin
• It’s found in hundreds of natural compounds and numerous foods
• It’s generally recognized as safe in foods, per the FDA’s own guidelines
• It’s patented for applications in foods and supplements
• It’s called a dietary supplement by 100+ researchers from all around the world
• It’s called a supplement for years by the co-founder of the pharmaceutical outlet in question
• It’s historically called a supplement in the pharmaceutical outfit’s own clinical trial

… but now it’s a drug because someone had editing permissions?

This situation is beyond the point of preposterous.

But again, none of this should be legally relevant. NDIN 1247 was acknowledged and has not been deemed adulterated for safety reasons. Thus, it can be argued that NMN is still a legal dietary supplement, yet it seems that will have to be for a judge to decide. And that requires the supplement industry to pull it together.

It’s no secret that we’re living through a grave health crisis – with the obesity epidemic raging at near-immeasurable speeds,^[190] we’ve found ourselves in a situation where Americans are simultaneously overfat, yet malnourished.^[191] A 2019 publication showed that 88% of Americans were not metabolically healthy according to data from 2009–2016^[192] — and it’s likely even worse today.

While there’s no single solution to this problem — it’s caused by a multitude of factors — one of the core contributors to our ongoing health crisis is the pervasive consumption of ultra-processed foods,^[193] which have low nutrient density.^[194] This is especially the case for children.^[195]

“NAD+ Deficiency Disease is a Common Central Pathological Factor of a Number of Diseases”^[196]

Just as the pellagra epidemic devastated poor communities with low access to animal foods in the early 1900s,^[104,106] we’re seeing a similar epidemic of malnutrition unfold here. History rhymes: only this time, there’s plenty of access to caloric energy, just low access to nutrition — hence obesity.

One of the many concerns is the resurgence of poor access to foods with quality NAD+ precursors, leading to severe health consequences.^[196-198]

You’ve likely seen a television ad or two for drugs treating psoriasis recently. Is this trending disease really a resurgence of pellagra itself?! That was the case in at least one situation,^[199] and potentially many others.^[200,201]

NAD+ Precursors for Human Health

The point is, NAD+ precursors are incredibly valuable to human health, but they’re mostly found in foods that are increasingly more expensive – meat, eggs, and dairy. The existing NAD+ precursors in supplements have drawbacks: nicotinic acid has unbearable side effects, and niacinamide is far less effective – and even has negative effects.

NMN is a better solution than both of these, and deserves its place in the niacin supplement category. It may be more expensive now, but we will get the price down (this is PricePlow, after all).

Allowing companies to fortify foods and multivitamins with this superior B3 vitamin won’t solve all of our problems, but it will certainly help with some of them.

The FDA should do the right thing for the health of this nation, especially in impoverished areas where their earnest leadership can make a serious difference. But it’s the supplement industry who is going to need to make it happen.

To date, several organizations and interested parties have weighed in:

Dan Fabricant, Natural Products Association (NPA)

Dan Fabricant, CEO of the Natural Products Association (NPA) and former Director of the Division of Dietary Supplement Programs at the FDA, emailed us the following comment:

What public health are the FDA’s actions on NMN, NAC and CBD protecting? When it comes to dietary supplements and foods FDA is dug in on an adversarial strategy, whereas with pharmaceuticals the agency clearly sees them as a customer and behaves with trusting and cooperative postures. A land of two extremes, and an agency focused on using their self-described limited resources to make matters difficult for white hat companies, following rules that submitted an NDI or performed a self-GRAS, versus applying those resources to those who are deliberately adulterating or misbranding products.

On the latest correspondence on NMN, the agency, despite it not being in statute, believes that if an ingredient supplier performed a self-GRAS consistent with scientific procedure, marketed/press released that notice, and then a pharma firm filed an IND on that ingredient after seeing that GRAS press release, prior to the first order of that ingredient being shipped/fulfilled, then it’s the agency’s interpretation that said ingredient would be excluded/precluded from the market. That coupled with their (FDA’s) reversal on an NDI AKL letter, which isn’t authorized in either the statute or the regulations, without a rendering of a product being adulterated or misbranded, should get everyone’s attention, if they can pull an AKL once without foundation, what’s to stop it from happening again and again.

It would seem the agency has returned to their pre-DSHEA view that their job is to limit the entry of novel ingredients to the food and dietary supplement marketplace. As we did on NAC, we will leave no stone unturned in finding a solution to ensure a safe and vibrant marketplace. Americans who want access to and want to develop innovative health and wellness products shouldn’t be treated like a second-class citizen by the FDA.

— Dan Fabricant, Natural Products Association

Recall that the NPA had formally asked the FDA to open a docket on NMN, which would allow stakeholders and consumers to submit comments to the agency, but that was rejected.^[24]

Steven Mister, Council for Responsible Nutrition

Steven Mister, President and CEO of the Council for Responsible Nutrition (CRN), responded to our email request for comment with the following:

“This episode with NMN is FDA’s latest, over-expansive application of the drug preclusion provision. That provision was intended to provide protection to pharmaceutical manufacturers against dietary supplements being marketed directly to consumers using the same ingredients for similar indications as the drug and thereby undercutting years and millions of dollars of drug research. As we have seen with CBD, NAC and now NMN, it is being weaponized to award drug companies with monopolies over ingredients that are rightfully within the realm of dietary supplements.

“It’s being invoked to prevent innovation in the supplement market even when the dosage forms and intended uses drastically differ. What makes the NMN and NAC circumstances so especially concerning is that FDA previously appeared to permit the introduction of these ingredients as supplements and then changed its mind. That undercuts the ability of supplement manufacturers to invest in research and product development with any expectation that they will be allowed to market the ingredients as supplements and recoup their investments.”

— Steven Mister, Council for Responsible Nutrition

You can also learn more about Steven’s position in a video and article published byin Natural Products Insider in late 2022.^[202]

David Sinclair (via Twitter):

David Sinclair stated the following via a thread on Twitter:^[203]

On November 4th, 2022, the US Food and Drug Administration (FDA) published a letter regarding the marketing and sales of nicotinamide mononucleotide (NMN) as a supplement to boost NAD levels

I am deeply grateful for your patience while I’ve gathered information to share with you about the impact of this decision. I know many of you are worried about what this means about the safety of NMN, and the possible limitations to the availability of NMN supplements

While NAD boosters such as NMN have become popular as supplements, in part because of my research, I am not, and have not, been involved as an owner, cofounder, investor, shareholder, marketer, spokesperson or sponsor of any company that sells NAD boosters as supplements

The FDA’s decision was preceded by a letter from MetroBiotech, a company I co-founded but do not manage or control, pointing out that the company had begun clinical trials with a special, crystalline form of NMN that is stable and made under FDA drug standards

The FDA’s letter is based on the Food, Drug & Cosmetic Act, which states “…the term ‘dietary supplement’ does not include an article authorized for investigation as a new drug…”

In other words, if a clinical trial of a substance has been initiated, it cannot be classified as a dietary supplement

In its action, the FDA is in line with its own regulations, which do not allow for the authorization of a substance to be classified as a dietary supplement if it has already been cleared by the FDA for clinical trials

I remain enthusiastic about the science of NAD boosters and their promise of improving human health. Furthering that science, and the prospect of cellular age reversal, continues to be my life’s work, which includes helping other researchers perform clinical trials to address medical conditions like glaucoma, kidney failure, frailty, and rare diseases such as Freidreich’s ataxia

Human clinical trials conducted by MetroBiotech on NMN have produced promising results, some of which are published (Pencina et al., 2022) and some are under peer review

The important work of bringing NMN to market as an FDA-approved medication is in the best interest of the tens of millions of people who suffer from and will succumb to aging-related diseases

The FDA standards for testing, quality control, and efficacy are among the most responsible consumer protection regulations in the world. All consumers deserve the trust, safety and reliability that comes with appropriate regulation and oversight

Whether NMN will remain on the supplement market is not yet known but another molecule, N-acetylcysteine (NAC), which is sold both as a supplement and prescribed as a medicine for acetaminophen overdosing and as a mucolytic agent in respiratory diseases, fell under the same law and remains on the US supplement market

Thank you for your patience and please rest assured that advancing the health and well-being of everyone who could potentially benefit from scientific curiosity and discovery will continue to be my highest priority

— David Sinclair, via Twitter^[203]

It’s noteworthy that even Sinclair suggests the “compromise” of both drug and supplement status, as we have with NAC.

If you want the FDA’s overall opinion, you can best get it from Cara Welch’s January 20th letter to Dan Fabricant.^[24]