Human Studies on NMN Supplements: Are There Any Benefits?

Aging is one of the greatest challenges we face as a species, and uncountable amounts of time and money have been spent and will continue to be spent, in seeking ways to combat the aging process. Many different avenues have presented themselves as potential ways to smooth out and slow the aging process, including the subject of today's post: NMN supplements.

NMN supplements are promising enough to have been the subject of over a dozen human studies and more in mice. I read through all of these studies to extract the lessons we can learn from them and determine whether or not NMN supplements are a valuable addition to our health routines or if they aren't all they're cracked up to be.

I have four key takeaways from these studies, so let's discuss them. If you would like to watch this overview in video form, check it out on my YouTube channel here.

What are NMN Supplements and Why Are People Excited?

NMN supplements are specifically formulated doses of the molecule nicotinamide mononucleotide. Your body naturally produces this molecule, but it can also be taken as a supplement. Excitement about NMN began around five years ago when Harvard professor David Sinclair talked about them on the Joe Rogan Experience. Normally, this isn't the kind of authoritative program you would want to cite, however, which is why I've gone beyond the interview and looked at human studies directly.

NMN is essentially a molecule your body uses to power various energy production processes and metabolic functions. NMN is the raw material, sort of like crude oil; your body refines it into nicotinamide adenine dinucleotide, or NAD, which is more like the refined gasoline used to fuel your body. Your body can only make NAD if NMN is present.

NAD, and therefore NMN, is used in a variety of different ways, including for energy metabolism, the repair of your DNA, to manage cellular stress responses, and to handle gene expression. As you grow older, the amount of NMN your body produces declines. This is key because – as the theory goes – taking NMN supplements could conceivably help support your body for longer, delaying the impact of aging on the processes that use it.

At the time when David Sinclair was promoting NMN, virtually no research had been performed on it. A single study in mice found that NMN supplements reduced the age-related decline in muscle performance. It didn't extend life, but it did seem to reduce the detrimental impact of aging on metabolism and muscle performance.

We can, however, credit David Sinclair with driving interest in NMN, which has led to the slate of human studies now available.

The Results of 18 Studies of NMN in Human Research

After a handful of mice studies, human studies have been performed into the effects of NMN. The hope is to find that this supplement can improve muscle performance, make us more resilient to illness and infection, boost our energy levels, and improve metabolic health. What do the studies actually say?

The confounding variable of the placebo effect

First, we have to take a moment to understand why human studies are necessary. If you look up NMN, you'll see tons of content from health influencers, personal bloggers, and customers leaving reviews on NMN supplement websites, all singing the praises of the supplement. There are widespread anecdotal reports of higher energy levels and a variety of beneficial effects.

The issue here is the placebo effect. The placebo effect is a known effect of, essentially, mind over matter. Thousands of studies have examined the impact of a potential supplement or medicine in comparison to a placebo. A placebo is a neutral, dummy medication, something known to have no effect on the body at all, either positive or negative.

What happens is that people who take a medication can see effects, but so can people taking a placebo, as long as they think they're taking the medication. A famous study on knee osteoarthritis pain looked at the combination of glucosamine and chondroitin and found that 60% of the people taking the medication had a significant reduction in knee pain. But, they also found that 60% of the people taking a placebo – which would have zero biological effect on pain at all – also experienced a reduction in pain. Effectively, simply believing that they were taking something that would have a beneficial effect was enough to trick their bodies into experiencing that beneficial effect.

The placebo effect is one of the greatest mysteries in medical science, and it's a confounding factor in every single medicinal and supplement test we perform. That's why "placebo-controlled" is such an important aspect of a well-formed study. Without testing the molecule against a placebo, you can't know whether it's actually effective or if it's a placebo effect.

Examining the eighteen human NMN studies

In addition to the placebo effect, there are several factors that we need to consider when looking at a human study for a supplement.

The first is safety. All eighteen of the human studies of NMN were short-term studies, and none of them showed harmful side effects. This means that, at least within the dosages that were studied and within a limited timeframe, there are no notable adverse effects to NMN supplements. That's a good sign! But that's not the end of the story. I'll come back to this later, so keep it in mind.

Next up is the formatting for the trial. The gold standard for a clinical trial is the RCT, or Randomized Controlled Trial. An RCT divides the sample group of patients into two; one receives the medication and one receives the placebo. The choice is random, so there's no bias in who gets which, and no one – not even the researchers – knows which patients are which, to prevent outside influences from skewing the results.

Of the eighteen human trials, four of them were not randomly controlled. So, I've omitted these from my analysis, as they can't be said to be reliable.

The next factor to consider is whether or not taking NMN increases your levels of NAD. NAD is the molecule that has the actual effect on the body; NMN is just the building block to make it. If you were to take NMN and not see an increase in NAD, it would be safe to say that taking NMN doesn't work; it simply would not enter the body the right way to have the right kind of impact. So, what do the remaining fourteen studies show?

Good news on this front; every one of the studies that checked for blood NAD levels showed an increase after taking NMN supplements. Unfortunately, blood NAD isn't necessarily the factor we want to see; if we're looking at muscle performance, we want to see an increase in muscle NAD as well. Only one of the fourteen studies took muscle biopsies and checked for muscle NAD, and this one study did not show an increase.

This is unfortunate but not necessarily enough to kill the idea of NMN having benefits. In fact, another report from 2022 showed that older adults who exercise had similar muscle NAD levels as younger adults. It is another small strike against NMN, though; if you can achieve the same effects just through a healthy diet and exercise, what use is the supplement?

The controversial muscle factor

Another consideration is that it's possible NMN works in a different way than simply putting more NAD into muscles to support their function. Several of our fourteen studies looked at this alternative. These studies looked at 16 different measures of physical performance. Of those, only four showed any change from a placebo, and one of those four was very controversial. We'll set the twelve that showed nothing aside and discuss these remaining four.

The tenth human study of NMN took place in India and is the source of the greatest controversy. The factor in question was the distance spent walking in a given period and suggested that NMN could improve walking stamina and speed. However, the source of the data was odd; the people examined had such a slow default walking speed that, despite being middle-aged, they acted like they were 80-year-olds. Because of this, and because of some other oddities in the data, the results of this study have been struck down.

Examining metabolic health

The next path of interest regarding NMN from mouse studies is the impact on metabolic health. So, many of the NMN studies looked at overall metabolic health markers, like LDL cholesterol levels, glucose and insulin levels, and HbA1c levels.

Just like muscle performance, most of the factors monitored in these studies showed no effect. There were a total of 28 factors being monitored, and 23 of them had zero change attributable to NMN supplements. One showed that insulin levels were hindered. Only four showed a benefit, and one of them was quite odd.

This odd factor was from a placebo group, which showed a significant worsening of insulin sensitivity. If looked at purely in comparison, you might think that NMN improved insulin sensitivity; in reality, NMN had no effect, and something strange was going on with the control group.

Rounding things out, a handful of other factors were examined.

• Overall fatigue and energy levels: While NMN groups showed improvement on these fronts, so did control groups at the same rate, showing no real effect from NMN.
• Arterial stiffness: Two studies looked at this; one showed no change, and one showed a statistically insignificant improvement.
• Hearing and cognition: No changes were observed.

All of this puts a damper on the idea that NMN has tangible benefits to performance and health as we age.

Revisiting Safety

I mentioned that NMN seems safe, but all of the studies that examined it were short-term studies. If we're planning to take a supplement over the long term, it's important to look at long-term impacts and cumulative effects.

One area of concern comes from studies of Niacin. NMN and Niacin are both forms of Vitamin B3. Studies of high doses of vitamin B3 showed that it increased all-cause mortality by 10%. Now, these studies took megadoses of 1-3 grams of niacin per day. In a reasonable dose – like the 50 mg of niacin I put in Microvitamin – this isn't a concern. But, most NMN supplements recommend a daily dose of 1,000 mg, or 1 gram, a whopping 6,250% of your recommended daily intake.

A new study in 2024 backs this up. It examined vitamin B3, and found that the metabolites 2PY and 4PY went up with vitamin B3 consumption. These metabolites appear to worsen blood vessel inflammation and increase risk of cardiovascular death.

Four Key Takeaways

To sum up everything above, there are four key takeaways regarding NMN supplements.

#1: It appears that NMN is safe, at least in the short term. You aren't going to be doing any harm to yourself as long as you're taking it in reasonable doses and for a short period.

#2: There may be some slight promise of muscle function improvement, but by and large, there was very little tangible evidence to support this impact.

#3: It seems unlikely that NMN provides serious benefits to metabolic function. There may be some possible benefits, but they're unlikely.

#4: There are ongoing concerns for long-term safety with NMN, especially in large ongoing doses like those recommended by supplement companies.

Until we have better long-term research, I don't recommend taking NMN supplements or any form of Vitamin B3 at any higher amount than around 50 mg per day. Instead, the best option to balance bodily NMN and NAD levels is simply maintaining a healthy diet and exercise routine.

Sources:

1. Effect of oral administration of nicotinamide mononucleotide on clinical parameters and nicotinamide metabolite levels in healthy Japanese men: https://pubmed.ncbi.nlm.nih.gov/31685720/
2. Nicotinamide mononucleotide increases muscle insulin sensitivity in prediabetic women: https://pmc.ncbi.nlm.nih.gov/articles/PMC8550608/
3. Nicotinamide mononucleotide supplementation enhances aerobic capacity in amateur runners: a randomized, double-blind study: https://pmc.ncbi.nlm.nih.gov/articles/PMC8265078/
4. Effect of 12-Week Intake of Nicotinamide Mononucleotide on Sleep Quality, Fatigue, and Physical Performance in Older Japanese Adults: A Randomized, Double-Blind Placebo-Controlled Study: https://pmc.ncbi.nlm.nih.gov/articles/PMC8877443/
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6. A 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: https://pmc.ncbi.nlm.nih.gov/articles/PMC9261366/
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11. Chronic nicotinamide mononucleotide supplementation elevates blood nicotinamide adenine dinucleotide levels and alters muscle function in healthy older men: https://pmc.ncbi.nlm.nih.gov/articles/PMC9158788/
12. MIB-626, an Oral Formulation of a Microcrystalline Unique Polymorph of β-Nicotinamide Mononucleotide, Increases Circulating Nicotinamide Adenine Dinucleotide and its Metabolome in Middle-Aged and Older Adults: https://pubmed.ncbi.nlm.nih.gov/35182418/
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17. Fingerstick blood assay maps real-world NAD+ disparity across gender and age: https://onlinelibrary.wiley.com/doi/10.1111/acel.13965
18. NAD+ exhaustion by CD38 upregulation contributes to blood pressure elevation and vascular damage in hypertension: https://www.nature.com/articles/s41392-023-01577-3
19. Long-term administration of nicotinamide mononucleotide mitigates age-associated physiological decline in mice: https://pmc.ncbi.nlm.nih.gov/articles/PMC5668137/
20. 17-a-estradiol late in life extends lifespan in aging UM-HET3 male mice; nicotinamide riboside and three other drugs do not affect lifespan in either sex: https://onlinelibrary.wiley.com/doi/10.1111/acel.13328
21. LONG-TERM NMN TREATMENT INCREASES LIFESPAN AND HEALTHSPAN IN MICE IN A SEX DEPENDENT MANNER: https://academic.oup.com/innovateage/article/7/Supplement_1/1077/7490297?login=false
22. β-Nicotinamide mononucleotide supplementation prolongs the lifespan of prematurely aged mice and protects colon function in aging mice: https://pubs.rsc.org/en/content/articlehtml/2024/fo/d3fo05221d
23. Glucosamine, chondroitin sulfate, and the two in combination for painful knee osteoarthritis: https://pubmed.ncbi.nlm.nih.gov/16495392/
24. Nicotinamide riboside does not alter mitochondrial respiration, content, or morphology in skeletal muscle from obese and insulin-resistant men: https://pubmed.ncbi.nlm.nih.gov/31710095/
25. Healthy aging and muscle function are positively associated with NAD+ abundance in humans: https://www.nature.com/articles/s43587-022-00174-3
26. Supplemental Vitamins and Minerals for CVD Prevention and Treatment: https://www.sciencedirect.com/science/article/pii/S0735109718345601?via%3Dihub
27. Balancing NAD+ deficits with nicotinamide riboside: therapeutic possibilities and limitations: https://pmc.ncbi.nlm.nih.gov/articles/PMC9345839/
28. A terminal metabolite of niacin promotes vascular inflammation and contributes to cardiovascular disease risk: https://pubmed.ncbi.nlm.nih.gov/38374343/