NMN Safely Increases Circulating NAD+ Levels Without Adverse Effects in Overweight Adults

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NMN Safely Increases Circulating NAD+ Levels Without Adverse Effects in Overweight Adults

The “Geroscience Hypothesis” posits that age-related diseases can be prevented or delayed by targeting common pathways of aging, including depleted stores of NAD+ (nicotinamide adenine dinucleotide). NAD+ functions as 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 how much NMN and how long of a duration is needed to effectively and consistently raise NAD+ levels in humans — until now, with recent research from scientists out of Harvard Medical School. For the first time, the team of researchers from Harvard and Metro International Biotech — a company founded by aging and longevity research posterchild Dr. David Sinclair – analyzes 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. 

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 form called MIB-626 β-NMN. (FYI, MIB-626 is the name of the biotech company’s specific formulation, and β-NMN is the active and traditionally used form of the compound; we’ll just use “NMN” from here on out.) 

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. Recent research has produced three clinical trials showing that NMN is safe and tolerated for use in humans (Irie, 2020; Liao, 2021; Yoshino, 2021). However, research hasn’t yet demonstrated if NMN reliably and consistently raises NAD+ levels in the blood — and how much NMN, or how long of a duration, is needed to do so. 

NMN Effectively Raises Blood NAD+ Levels in Humans

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. 

NMN Proved to be Safe and Well-Tolerated

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. 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. As the authors conclude in their paper, “These pharmacokinetic data obtained using a pharmaceutical-grade formulation of microcrystalline βNMN…should facilitate the design of randomized trials to determine the efficacy of NAD augmentation in disease conditions.”

Show references
  

​​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

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