NMN Safely Increases Circulating NAD+ Levels Without Adverse Effects in Overweight Adults
Updated on March 27, 2023 by Cambria Glosz, MS, RD
The “Geroscience Hypothesis” proposes that age-related conditions can be prevented or delayed by targeting common pathways of aging, including depleted stores of NAD+ (nicotinamide adenine dinucleotide). NAD+ is a coenzyme that helps other enzymes work properly, including those related to DNA repair, mitochondrial function and myriad other aspects of the aging process. Essentially, NAD+ plays a critical role in maintaining cellular and metabolic functions, which translates to better health and longevity of our cells, organs and bodies as a whole.
While there is mounting evidence that raising NAD+ levels slows aging in cell-based and animal models, the available research in humans is still in its infancy — especially with NMN (nicotinamide mononucleotide), the newer NAD+ precursor on the block. It’s been unknown if NMN effectively raises NAD+ levels in humans—and how much is needed—but research from scientists out of Harvard Medical School published in March 2022 proved it does.
The team of researchers from Harvard and Metro International Biotech analyzed the pharmacokinetics of NMN, or how different doses of the compound are safely absorbed, metabolized, and excreted in the human body. Although it may seem less exciting than disease-focused research, pharmacokinetics studies are vital to the research process, setting the stage for the appropriate dose and duration to use in future testing of NMN’s efficacy in human disease states. Plus, this research verifies that NMN does, in fact, raise NAD+ levels in humans without causing adverse effects.
Why We Need Pharmacokinetics Research
Animal studies have shown that raising NAD+ levels improves several aspects of aging, including metabolism, body weight, liver and heart health, aerobic capacity and mitochondrial function. But studies looking at NAD+ precursors in humans have yielded inconsistent results, likely due to small sample sizes, short durations or dosages insufficient to detect a meaningful change.
Plus, some formulations may use NAD+ precursors with too large of particle size, which can reduce its absorptive ability into cell membranes. Micronized or microcrystalline structure involves reducing the particle size until it is visible only through a microscope and can be measured in microns. Essentially, the smaller a compound is, the easier it is to be absorbed and used by cells. In this study, the Harvard-based research team used a microcrystalline and pharmaceutical-grade form of NMN called MIB-626 β NMN.
Although we have seen impressive results in animal and cell-based studies using NMN and other NAD+ precursors like nicotinamide riboside (NR), this research is still in its early stages. We hardly have any data about how NMN is absorbed, used, and excreted over time in the human body—a field known as pharmacokinetics.
Prior and subsequent research has produced several clinical trials showing that NMN is safe and tolerated for use in humans (Irie, 2020; Liao, 2021; Yoshino, 2021; Kim, 2022; Okabe, 2022; Huang, 2022). Particularly, Huang's 2022 study found that 300 mg of Uthever NMN per day raised NAD+ levels by 38% after 30 days.
NMN Effectively Raises Blood NAD+ Levels in Humans
In this study, Pencina and colleagues evaluated the effects of supplemental NMN in a group of 32 overweight or obese, medically stable adults between ages 55 and 80. They randomly split the participants into three groups—one taking 1,000 mg of NMN once per day, a second group taking 1,000 mg of NMN twice per day (2 grams total) and a placebo group. All groups were supplemented for 14 days, with blood measurements taken several times throughout the first day, as well as on Day 8 and Day 14 of treatment. The team chose higher doses than seen in other studies because their analyses found that 250-750 mg was inadequate to raise NAD+ levels consistently.
After this 2-week treatment, the participants in the twice-daily group (2 grams NMN per day) experienced significantly greater increases in blood NMN levels compared to the once-daily group and the placebo group. On Day 14, the twice-daily group showed a 4.5-times greater average Cmax (the highest concentration of a compound found in the blood after the dose is given) than the placebo, while the once-daily group had a 2.7-times greater Cmax than placebo. Essentially, double the quantity of NMN almost doubled the amount found in the blood.
They also looked at how the varying NMN doses impacted blood NAD+ levels—the primary goal of using NAD+ precursors. Both amounts of NMN significantly increased blood NAD+ in a dose-dependent manner (meaning, the higher doses increased NAD+ levels more). Specifically, circulating NAD+ levels increased by about double in the once-daily (1 g) group and triple in the twice-daily (2 g group) compared to the placebo.
NAD+ levels only modestly increased from baseline to 24 hours in both groups but were substantially higher on Day 8 and 14. Notably, Day 8 NAD+ levels were similar to Day 14 levels in both NMN dosage groups, suggesting that it takes up to a week for NMN to increase NAD+ in the blood, but doesn’t keep rising indefinitely. (Unfortunately, we don’t have data on Days 1-7 to see at precisely what point blood NAD+ reaches its peak after supplementing with NMN.)
Circulating metabolites of NAD+ were also measured, including nicotinamide (NAM), nicotinamide riboside (NR), N-methyl-2-pyridone-5-carboxamide (2-PY) and 1-methyl nicotinamide (1-methyl-NAM). All four metabolites were significantly raised by the end of Day 1, which further increased by Day 8 but did not markedly increase beyond that by Day 14. Higher levels of circulating metabolites following NMN supplementation indicate that the body is metabolizing and using NMN to make NAD+. Further, urinary NMN concentrations were similar among the treatment groups, meaning that very little NMN was eliminated unchanged in the urine and the body was able to utilize the compound.
NMN Proved to be Safe and Well-Tolerated
Both doses of NMN were found to be safe and relatively well-tolerated. There were no serious adverse events, but one participant in the twice-daily group experienced diarrhea and was discontinued from the study. One person in the once-daily NMN group had mildly elevated liver enzymes, but so did one participant in the placebo group. (Both returned to normal following the study period.) There were no differences in blood NMN or NAD+ levels based on sex, body mass index (BMI) or age.
There were no significant changes in any group to various metabolic and cardiovascular health markers, including fasting blood glucose, cholesterol panels or triglycerides (fats in the blood). However, 14 days of supplementation was likely insufficient to alter these markers in a meaningful way.
Next Steps in NMN Research
Overall, an oral administration of 1,000-2,000 mg of microcrystalline NMN for 14 days was safe, well-tolerated and dose-dependently effective at raising blood levels of NAD+ and its various metabolites in overweight middle-to-older aged adults. From this study, we now know that these doses gradually raised NAD+ on the first day of dosing and reached their peak by Day 8.
Pharmacokinetic studies like this one are necessary before moving on to efficacy trials because it’s crucial to show that the desired administered dose actually raises blood levels of the target — in this case, NAD+. Otherwise, money and time spent on clinical trials with untested and inadequate—or excessively high—doses would be a waste and potentially dangerous.
What we still don’t know, however, is if long-term 2-gram doses of NMN are similarly safe—future research is needed to test this.
As we wrote here in 2022, "From there, the next steps would be studying the effects of NMN on disease states and aging in humans, which could lead to NMN being sold only as a pharmaceutical drug, rather than a supplement, if clinical trials support its effectiveness in specific diseases."
In 2023, we have seen this come true, as the FDA has removed NMN from Amazon and other markets.
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Irie J, Inagaki E, Fujita M, et al. Effect of oral administration of nicotinamide mononucleotide on clinical parameters and nicotinamide metabolite levels in healthy Japanese men. Endocr J. 2020;67(2):153-160. doi:10.1507/endocrj.EJ19-0313
Liao B, Zhao Y, Wang D, Zhang X, Hao X, Hu M. Nicotinamide mononucleotide supplementation enhances aerobic capacity in amateur runners: a randomized, double-blind study. J Int Soc Sports Nutr. 2021;18(1):54.. doi:10.1186/s12970-021-00442-4
Pencina K, Lavu S, Dos Santos M, et al. 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. J Gerontol A Biol Sci Med Sci. 2022;glac049. doi:10.1093/gerona/glac049
Yoshino M, Yoshino J, Kayser BD, et al. Nicotinamide mononucleotide increases muscle insulin sensitivity in women. Science. 2021;eabe9985. doi:10.1126/science.abe9985