What is NMN?
NMN is a naturally occurring form of Vitamin B3 that is studied for slowing aging and for preventing diseases of aging. Dietary NMN is converted to nicotinamide adenine dinucleotide (NAD+), a coenzyme in all living cells which is required for numerous biological processes. NAD+ levels naturally decline with age, reaching less than 50% of youthful levels by middle age.[3] Decreased NAD+ levels have been attributed to increased inflammation and oxidative stress as well as to the development of age-related conditions such as hypertension, cognitive decline, and type 2 diabetes. While the anti-aging effects of NMN in rodents are well-established, studies are ongoing to determine whether equally impressive anti-aging effects are possible in humans.
What are NMN’s main benefits?
NMN is taken as a supplement to increase levels of the coenzyme NAD+. It is unknown whether NMN will have the same therapeutic effects in humans as seen in rodent models, but emerging evidence is promising.[4][5]
So far, most randomized controlled trials in humans have focused on proving the safety of NMN supplements and their ability to increase blood NAD+ levels in different populations. Some clinical research has shown that NMN increases physical ability in aging populations,[1] improves cardiovascular disease biomarkers such as arterial stiffness,[6] and increases cellular NAD+/NADH levels.[4] Although these results have been promising, additional large-scale trials are needed to better understand the benefits in humans.
What are NMN’s main drawbacks?
The main drawback to NMN is a lack of long-term studies in humans. NMN has been shown to be safe in doses up to 1200 mg daily for 6 weeks and 900 mg daily for 8 weeks. Doses of 2000 mg daily have been taken for up to 14 days with no adverse effects.[1] Long-term safety of chronic and/or higher doses of NMN hasn’t been tested.
It is also important to note that more research is needed to better-understand the effects of boosting NAD+ in certain contexts. For example, by elevating cellular NAD+ levels, NMN could potentially exacerbate chronic inflammation by increasing the release of pro-inflammatory cytokines from senescent cells.[7] It is important to note, however, that NMN-induced inflammation has not been observed in human trials to date.
How does NMN work?
As a precursor to NAD+, NMN supplementation has the potential to restore NAD+ to youthful levels, thereby restoring the function of NAD+-dependent enzymes in the body. After NMN is taken, it is absorbed into the bloodstream and rapidly converted to NAD+,[8] which is an important cofactor for many biological processes, including immune response, DNA repair, cell division, mitochondrial function, epigenetics, and redox reactions.[9] As NAD+ levels naturally decrease with age, the activity of enzymes dependent on NAD+ for their function also decreases.[10] Since reduced activity of NAD+-consuming enzymes (e.g. sirtuin 1) has been linked to the aging process, restoring NAD+ levels to more youthful levels is theorized to slow down the aging process.[11] [12]
What is the legal status of NMN in the U.S.?
NMN is currently in legal limbo in the U.S., and most retailers have pulled NMN products from their shelves.
The path from NMN being legal for sale as a dietary supplement to effectively banned for supplement sales has several twists and turns. In 2018, NMN was granted GRAS (Generally Regarded As Safe) status by an FDA panel in 2018, which made it legal for use as a food additive. GRAS designation doesn’t apply to supplements, however—only food or food additives. For a product to be marketed and sold as a supplement, manufacturers need to submit a notification of a “New Dietary Ingredient” (NDI) to the FDA, before bringing the product to the market. NDI's contain information providing the basis for concluding that the supplement is reasonably safe and, if approved by the FDA, pave the way for sales and marketing as a supplement.
One company did successfully get an NDI approved by the FDA for NMN supplements in 2022, which gave NMN the appropriate legal status for supplement sales. However, later the same year, the FDA changed their stance on NMN’s status as a dietary supplement. Several companies that were testing NMN in clinical trials successfully lobbied the FDA to have NMN classified as an investigational drug. This effectively made NMN supplement sales illegal according to 21 U.S.C. § 321(ff) (section 201(ff) of the Federal Food, Drug, and Cosmetic Act, which prevents the sales or marketing of agents classified as investigational drugs.
This prompted the FDA to revoke the NDI, which effectively banned the sales and marketing of NMN supplements in the US. Technically, selling NMN as a food additive is still legal, since NMN’s GRAS status was not affected by the withdrawal of the NDI. Nonetheless, most retailers stopped selling NMN products considering its uncertain legal status.
What are other names for Nicotinamide Mononucleotide
- Beta-nicotinamide mononucleotidee
- Nicotinamide mononucleotide
- Nicotinamide ribotide
- NMN zwitterion
- Beta-NMN
- Nicotinamide nucleotide
- Beta-nicotinamide D-ribonucleotide
- Nicotinamide ribonucleotide
- Vitamin B3
- Niacinamide
- Nicotinamide riboside
Dosage information
NMN has been taken by mouth in doses of 250–1200 milligrams daily for 4–12 weeks. Higher doses of 2000 milligrams daily have been taken by mouth for 2 weeks.[1]
Examine Database: Nicotinamide Mononucleotide
Research FeedRead all studies
Frequently asked questions
NMN is a naturally occurring form of Vitamin B3 that is studied for slowing aging and for preventing diseases of aging. Dietary NMN is converted to nicotinamide adenine dinucleotide (NAD+), a coenzyme in all living cells which is required for numerous biological processes. NAD+ levels naturally decline with age, reaching less than 50% of youthful levels by middle age.[3] Decreased NAD+ levels have been attributed to increased inflammation and oxidative stress as well as to the development of age-related conditions such as hypertension, cognitive decline, and type 2 diabetes. While the anti-aging effects of NMN in rodents are well-established, studies are ongoing to determine whether equally impressive anti-aging effects are possible in humans.
Like many other supplements, such as creatine, NMN is naturally present in small amounts in dietary sources, but these amounts are much lower than those found in the supplements used in clinical studies for improving longevity. Trace amounts of NMN (concentrations no more than 0.002% by weight) are found in fruits and vegetables including avocados, broccoli, tomatoes, cucumbers, cabbage, and edamame.[13]
Not likely. Although NAD+ and NADH differ by only the respective absence or presence of an electron and NADH is a commercially available supplement, no effects of oral NADH supplements on plasma and/or cellular NAD+ levels have been reported in humans.
NADH can be converted to NAD+ via the enzyme NADH reductase, an enzyme present in mitochondria. However, NADH bioavailability is likely low when taken orally, as suggested by a rodent study, which failed to detect absorption of orally administered NADH. The investigators also found that the NADH molecule was unstable under the acidic conditions of the stomach.[19]
Although NADH supplements do seem to be safe, and have shown some potential efficacy in helping to improve energy levels and quality of life levels in people with chronic fatigue syndrome,[20][21][22] the mechanism(s) at work are not clear, and may occur independently of NAD+.
NMN is taken as a supplement to increase levels of the coenzyme NAD+. It is unknown whether NMN will have the same therapeutic effects in humans as seen in rodent models, but emerging evidence is promising.[4][5]
So far, most randomized controlled trials in humans have focused on proving the safety of NMN supplements and their ability to increase blood NAD+ levels in different populations. Some clinical research has shown that NMN increases physical ability in aging populations,[1] improves cardiovascular disease biomarkers such as arterial stiffness,[6] and increases cellular NAD+/NADH levels.[4] Although these results have been promising, additional large-scale trials are needed to better understand the benefits in humans.
NMN has been shown to slow aging-associated decline in rodents, bringing about the following effects:[14]
- improved insulin sensitivity
- reduced inflammation
- improved mitochondrial function
- improved cognition and brain health
Aside from potential differences between human and rodent physiology that may cause different responses to NMN supplementation, early human clinical trials always err on the side of caution when testing safety. Initial NMN trials in humans tested doses of up to 500 mg NMN daily, with no adverse effects; more recent human trials have tested doses approaching 1000 mg/day. However, in mice NMN is typically administered in doses of up to 500 mg/kg daily, which, taking into account the more rapid turnover of NMN in mice than in humans, may be roughly equivalent to a 75 kg human taking 3,000 mg NMN per day.[10]
The main drawback to NMN is a lack of long-term studies in humans. NMN has been shown to be safe in doses up to 1200 mg daily for 6 weeks and 900 mg daily for 8 weeks. Doses of 2000 mg daily have been taken for up to 14 days with no adverse effects.[1] Long-term safety of chronic and/or higher doses of NMN hasn’t been tested.
It is also important to note that more research is needed to better-understand the effects of boosting NAD+ in certain contexts. For example, by elevating cellular NAD+ levels, NMN could potentially exacerbate chronic inflammation by increasing the release of pro-inflammatory cytokines from senescent cells.[7] It is important to note, however, that NMN-induced inflammation has not been observed in human trials to date.
Although NMN has shown postive effects in clinical trials to date, there may be potential drawbacks in particular contexts. NMN’s interactions in neurological health warrant further investigation. NAD+ is also a cofactor for the enzyme sterile alpha and Toll/interleukin-1 receptor motif-containing 1 (SARM1), an enzyme that instigates neuronal degeneration after injury.[16] In people with neurological disorders and reduced activity of a specifc enzyme that converts NMN to NAD+ (nicotinamide mononucleotide adenylyltransferase 2, or NMNAT2), NMN supplementation could theoretically enhance neuron degeneration by increasing SARM1 activity.[17] However, in the context of healthy NMNAT2 enzyme activity, NMN supplementation could potentially be neuroprotective[18] Although more research is needed, it is safe to assume that NMN supplementation could have potential drawbacks in certain contexts, which warrants further study.
Under certain conditions NMN can enhance the pro-inflammatory characteristics of senescent cells, promoting chronic inflammation. However there's currently no evidence that this occurs in humans in the range of NMN supplement doses tested to date.
Most research has suggested that NMN supplements reduce inflammation. Numerous animal models[23] and one study using cultured primary human cells[24] have indicated that boosting cellular NAD+ levels with NMN has is anti-inflammatory effects, and evidence is mounting that increased inflammation associated with aging is linked to low NMN levels.
However, the terms “always” and “never” rarely apply in the life sciences. Additional research models have suggested that NMN can potentially promote inflammation in older, senescent cells which accumulate during aging by enhancing their pro-inflammatory characteristics. In this type of cells, the concern is that NMN could have the unintended consequence of increasing the production of pro-inflammatory cytokines, leading to chronic inflammation. This could theoretically impair tissue repair regeneration, promote further accumulation of senescent cells, and create conditions permissive for the development cancer.[7][25]
Outside of cancer biology, normal, well-behaved cells undergo a finite number of cell divisions. This is thought to be a general anti-cancer mechanism, since tired, older cells with metabolic dysfunction and increased exposure to environmental toxins- if they were to divide- are more likely to accumulate, and pass on mutations that cold promote the development of cancer. Because senescent cells have permanently exited the cell cycle, they are no longer at risk for passing along potentially harmful DNA mutations to daughter cells, potentially reducing cancer risk.[26]
However, cellular senescence can be a double-edged sword. Senescent cells tend to develop pro-inflammatory characteristics, constantly secreting low-levels of pro-inflammatory molecules. This phenomenon has been called SASP (Senescence-associated secretory phenotype). Although senescent cells with SASP are at a lower risk for developing into tumors themselves, their tendency create a pro-inflammatory tissue microenvironment in/around their non-senescent neighbors has been implicated in NAD+ depletion [27] and potentially the development of cancer in neighboring cells.[25]
On one hand, increasing cellular NAD+ levels in non-senescent cells can suppress the transition to senescence by reducing DNA damage and mitochondrial dysfunction. On the other hand, increased NAD+ levels could actually enhance SASP by encouraging sensecent cells to develop the SASP, as well as increasing pro-inflammatory cytokine production in cells that already have the SASP.[28]
Research has shown that the resulting increased level of pro-inflammatory cytokines produced by senescent cells with SASP lead to increased levels of the NAD+ consuming enzyme CD38 in neighboring cells. This has the effect of reducing NAD+ levels in normal cells nearby senescent cells with the SASP.[27][29][30] When NAD+ levels are reduced in the normal, non-sensescent cells, mitochondrial dysfunction and the accumulation of DNA-damage can in-turn promote the development of senescence.[28]
Thus, the theoretical concern is that increasing NAD+ levels, in spite of all of the healthy / anti-inflammatory effects in normal cells, could also increase inflammation while promoting neighboring cells to transtion to sensescence and SASP in a potential viscious cycle. More research is needed to determine whether the potential for NMN supplements to promote SASP is only a theoretical one, or if caution may be warranted for NMN supplementation in certain individuals or populations. Nonetheless, it is important to emphasize the no evidence has been found so far in human clincal trials to date that NMN may promote SASP.
As a precursor to NAD+, NMN supplementation has the potential to restore NAD+ to youthful levels, thereby restoring the function of NAD+-dependent enzymes in the body. After NMN is taken, it is absorbed into the bloodstream and rapidly converted to NAD+,[8] which is an important cofactor for many biological processes, including immune response, DNA repair, cell division, mitochondrial function, epigenetics, and redox reactions.[9] As NAD+ levels naturally decrease with age, the activity of enzymes dependent on NAD+ for their function also decreases.[10] Since reduced activity of NAD+-consuming enzymes (e.g. sirtuin 1) has been linked to the aging process, restoring NAD+ levels to more youthful levels is theorized to slow down the aging process.[11] [12]
Enzymes are simply proteins that are folded into a configuration that allows them to bind other molecules and compounds, catalyzing chemical reactions. Often they can’t accomplish this catalysis alone—many enzymes also require cofactors (aka coenzymes) to function.
The way that NAD+ functions as an enzyme cofactor depends on the enzyme. First, NAD+ helps to catalyze ‘redox’ (reduction-oxidation) reactions by accepting electrons from other compounds and molecules, becoming reduced (gaining electrons) in the process and forming the compound NADH. The reduction of NAD+ to NADH is critical for a number of enzymes and pathways associated with metabolic regulation and energy homeostasis.
Second, some enzymes consume NAD+ in the course of carrying out their catalytic function, converting NAD+ into other forms. In many cases, NAD+-consuming enzymes convert NMN to nicotinamide, which can later be recycled back to NMN. Some examples are the class of enzymes known as sirtuins, which have anti-aging activity,[11] and poly (ADP-ribose) polymerases (PARPs), which help to repair DNA damage.
NAD+ levels decrease during aging through two main mechanisms. The first one is reduced biosynthesis—the older we get, the less NAD+ is produced by the body, possibly due to oxidative stress and chronic inflammation.[15] The second mechanism is thought to be increased NAD+ consumption. Increased activity of NAD+-dependent enzymes, coupled with a decreased total pool of available NAD+, creates a situation where there’s not enough NAD+ to support maximal function of the dependent enzymes. For example, DNA damage tends to increase during aging, causing PARP enzymes to consume more NAD+, leaving less of this cofactor available to support the function of other enzymes, such as the sirtuins.
NMN is currently in legal limbo in the U.S., and most retailers have pulled NMN products from their shelves.
The path from NMN being legal for sale as a dietary supplement to effectively banned for supplement sales has several twists and turns. In 2018, NMN was granted GRAS (Generally Regarded As Safe) status by an FDA panel in 2018, which made it legal for use as a food additive. GRAS designation doesn’t apply to supplements, however—only food or food additives. For a product to be marketed and sold as a supplement, manufacturers need to submit a notification of a “New Dietary Ingredient” (NDI) to the FDA, before bringing the product to the market. NDI's contain information providing the basis for concluding that the supplement is reasonably safe and, if approved by the FDA, pave the way for sales and marketing as a supplement.
One company did successfully get an NDI approved by the FDA for NMN supplements in 2022, which gave NMN the appropriate legal status for supplement sales. However, later the same year, the FDA changed their stance on NMN’s status as a dietary supplement. Several companies that were testing NMN in clinical trials successfully lobbied the FDA to have NMN classified as an investigational drug. This effectively made NMN supplement sales illegal according to 21 U.S.C. § 321(ff) (section 201(ff) of the Federal Food, Drug, and Cosmetic Act, which prevents the sales or marketing of agents classified as investigational drugs.
This prompted the FDA to revoke the NDI, which effectively banned the sales and marketing of NMN supplements in the US. Technically, selling NMN as a food additive is still legal, since NMN’s GRAS status was not affected by the withdrawal of the NDI. Nonetheless, most retailers stopped selling NMN products considering its uncertain legal status.
Update History
FAQ on the current legal status of NMN added, where we break down the convoluted path from legal dietary supplement to being pulled from the shelves of most retailers in the U.S.
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FAQs on the potential for NMN interactions with chronic inflammation and SASP (senescence-associated secretory phenotype) added
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Edited by
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Error in "potential mechanisms of drawbacks" FAQ
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FAQ and database update
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References
Examine Database References
- Walking Ability - Yi L, Maier AB, Tao R, Lin Z, Vaidya A, Pendse S, Thasma S, Andhalkar N, Avhad G, Kumbhar VThe efficacy and safety of β-nicotinamide mononucleotide (NMN) supplementation in healthy middle-aged adults: a randomized, multicenter, double-blind, placebo-controlled, parallel-group, dose-dependent clinical trial.Geroscience.(2023-Feb)
- Insulin Resistance - Huang HA Multicentre, Randomised, Double Blind, Parallel Design, Placebo Controlled Study to Evaluate the Efficacy and Safety of Uthever (NMN Supplement), an Orally Administered Supplementation in Middle Aged and Older Adults.Front Aging.(2022)
- Pulse Wave Velocity - Katayoshi T, Uehata S, Nakashima N, Nakajo T, Kitajima N, Kageyama M, Tsuji-Naito KNicotinamide adenine dinucleotide metabolism and arterial stiffness after long-term nicotinamide mononucleotide supplementation: a randomized, double-blind, placebo-controlled trial.Sci Rep.(2023-Feb-16)
- Anaerobic Capacity - Bagen Liao, Yunlong Zhao, Dan Wang, Xiaowen Zhang, Xuanming Hao, Min HuNicotinamide mononucleotide supplementation enhances aerobic capacity in amateur runners: a randomized, double-blind studyJ Int Soc Sports Nutr.(2021 Jul 8)
- Insulin Resistance - Mihoko Yoshino, Jun Yoshino, Brandon D Kayser, Gary J Patti, Michael P Franczyk, Kathryn F Mills, Miriam Sindelar, Terri Pietka, Bruce W Patterson, Shin-Ichiro Imai, Samuel KleinNicotinamide mononucleotide increases muscle insulin sensitivity in prediabetic womenScience.(2021 Jun 11)
- Serum NAD+ Levels - Zhang J, Poon ET, Wong SHEfficacy of oral nicotinamide mononucleotide supplementation on glucose and lipid metabolism for adults: a systematic review with meta-analysis on randomized controlled trials.Crit Rev Food Sci Nutr.(2024 Aug 8)