Nicotinamide Mononucleotide (NMN), a Clinician’s Perspective

What Is NMN

Nicotinamide mononucleotide, or NMN, is a molecule that is naturally present in the human body. Scientists and health professionals are interested in NMN because of its relation to another molecule in your body called NAD+, which plays a role in several essential processes, including helping your body produce energy and keep your DNA healthy. NMN is a 'precursor' to NAD+ and is involved in the process of making some of your body's NAD+.

Why Is NMN Being Studied?

NAD+ levels seem to decline as we age, so scientists are interested in determining if increasing NAD+ levels can improve and preserve people's health. NMN is found in small amounts in some foods, but scientists are investigating whether consuming additional NMN can help improve people's health.

What Have Lab and Animal Testing Found?

First, a warning! We should never assume a medication or supplement is safe or effective based on lab or animal testing. Mice are very different from humans—not just because they have tails. Read about a hepatitis B drug that worked in mice but then caused seven people's death during human testing here. Often, interventions that seem promising during animal studies don't cause the same benefits in humans and even cause unexpected significant harm.

Benefits in Animal Testing

In animal models, increasing NAD+ has been shown to help with age-related skin problems, cardiovascular disease, age-related muscle weakness, osteoarthritis, vision and hearing loss, metabolic disorders including diabetes and cholesterol, neurodegenerative diseases, reproductive disorders, immune function, and kidney function. Braidy & Liu (2020) give an in-depth review of the preclinical research in this article.

Risks In Animal Testing

Animal studies and other lab research have identified possible risks of increasing NAD+ levels, including developing new cancers, causing existing tumors to grow, accumulating various toxins in the blood, decreasing exercise performance, and increasing inflammation. Braidy & Liu (2020) review the preclinical research in the same article linked above.

What Have Human Trials Found?

This author found six human studies of NMN.

• Two of the five were only safety evaluations. A study published in 2020 tested the safety of a single dose of 100, 200, or 500 mg of NMN (Irie et al., 2020). A study published in 2022 evaluated a daily intake of 1250 mg of NMN for four weeks (Fukamizu, 2022). Neither study reported any observed adverse effects. Importantly, authors in both of these studies had conflicts of interest (in one study, an author holds a patent related to NMN; a manufacturer of NMN supplements sponsored the other study, and employees participated in the research). These studies also only considered short-term safety, whereas consumers would potentially take NMN supplements for years.
• A study published in 2021 found that healthy younger and middle-aged (primarily male) amateur runners had increased aerobic capacity when taking NMN supplements ranging from 300-1200 mg per person per day over a 6-week trial period. This increase was dosage dependent, with increased effect noted at a higher dosage. The authors did not report any conflicts of interest and did not observe any adverse events (Liao et al., 2021).
• A study published in 2022 found that when older adults took 250 mg of NMN daily, they had improved lower limb function and reduced drowsiness over a 12-week trial period. The authors did not report any conflicts of interest. No adverse events were observed (Sakuri & Okura, 2022).
• A study published in 2022 found that overweight and obese postmenopausal women who were prediabetic had increased insulin sensitivity during a 10-week study taking 250 mg of NMN daily. The authors considered it clinically relevant and similar to the improvement that would be seen with 10% weight loss. No adverse events were noted. Several authors had competing interests (Patti et al., 2021).
• A study published in 2022 found that when 22 healthy men 65 years and over took 250 mg of NMN daily, their left-side grip strength was somewhat improved (which they hypothesized was because most of the Japanese population is right-handed). Skeletal muscle mass was not affected. The study reported no adverse events, and the researchers did not report any competing interests (Igarashi et al., 2022).
• According to ClinicalTrials.gov, nine additional clinical trials are currently in progress or recruiting for NMN.

Are NMN Supplements Safe for People?

This author only found six human trials of NMN. None of these trials observed any significant adverse events. However, they have all been small trials in restricted populations with results that may not be generalizable to broader populations. The longest trial only evaluated safety for twelve weeks, whereas proponents of these supplements recommend taking them for many years. There is also significant concern for bias in the limited results documented, as three of the six clinical trials described above involved parties with competing interests.

Researchers in this field recommend further study before general use. Here is a sample of statements:

• "NMN side effects on long-term supplementation in humans should also be well-studied before drawing any conclusions about the safety" (Soma & Lalam, 2022, p. 9745)
• "Recently, NMN supplements for anti-aging have been launched on the market; however, the authors of this study still hold the opinion that the effectiveness and safety of NMN should be clarified through further human clinical studies" (Kim et al., 2022, p. 12)
• "…published reports about NMN's long-term safety and clinical efficacy of anti-aging effects in humans are scarce…the first priority should be to establish toxicology, pharmacology and safety profiles of NMN in humans, including healthy and diseased" (Nadeeshani et al., 2021, p. 278)

Major proponents of NMN supplementation may have competing interests when recommending this use. For example, Dr. David Sinclair, a Harvard University expert on aging, promotes supplements to increase NAD+ levels but also has significant stakes in companies that sell these products.

Are NMN Supplements Beneficial for People?

Four small, short human trials showed evidence of benefit for the specific populations evaluated. One trial showed increased aerobic capacity in younger and middle-aged, mostly male, amateur runners over six weeks. A second trial showed improved lower limb function and decreased drowsiness when taken by older adults over 12 weeks. The third study showed increased insulin sensitivity for overweight and obese postmenopausal women during a 10-week study. (This study involved a researcher with competing interests.) The final study showed a nominally significant increase in left-handed grip strength for healthy males 65 and older after 12 weeks.

Most beneficial effects noted in animal studies have yet to be evaluated in humans and thus cannot be considered as part of the evidence for human benefit at this point (see above for more info on this). Compared with other interventions for healthy aging, such as the Mediterranean diet, evidence of human benefit is still extremely sparse.

Alternatives to NMN Supplements

What alternatives are available for those looking to protect their health while aging? The Mediterranean diet is a dietary pattern inspired by the traditional cuisines of countries in the Mediterranean region, such as Italy, Greece, and Spain. It is characterized by an emphasis on plant-based foods, such as fruits, vegetables, whole grains, legumes, and nuts, as well as healthy fats, such as olive oil. It also includes moderate amounts of fish, poultry, and dairy, and small amounts of red meat.

The Mediterranean diet also may include a moderate intake of wine, typically with meals. The diet focuses on whole, minimally processed foods and a healthy balance of macronutrients. The Mediterranean diet has been associated with numerous health benefits, including reducing the risk of heart disease, diabetes, and certain cancers. It has also been shown to have anti-inflammatory effects and improve cognitive function. The Mediterranean diet may also help to improve mood, sleep, and energy levels and may even have anti-aging effects on the brain. Overall, the Mediterranean diet is a nutritious, delicious, and evidence-based way to support healthy aging (Dominguez et al., 2021; Mazza et al., 2021).

If You Decide to Use NMN Supplements

1. Discuss your plans with your health providers before using NMN, so they are aware of your supplement use and can offer personalized advice based on your medical conditions.
2. Make sure that you purchase supplements from a reputable source. There have been many fake supplements sold by large and well-known stores. (See here and here.)

References:

Armstrong, D. & Waldman, A. (2019, December 9). Health researchers disclose $188 million in conflicts of interest, NIH data suggests. PBS News Hour. https://www.pbs.org/newshour/health/health-researchers-disclose-188-million-in-conflicts-of-interest-nih-data-suggests

Braidy, N., & Liu, Y. (2020). NAD+ therapy in age-related degenerative disorders: A benefit/risk analysis. Experimental gerontology, 132, 110831. https://doi.org/10.1016/j.exger.2020.110831

ClinicalTrials.gov. (N.D.). Nicotinamide mononucleotide. https://clinicaltrials.gov/ct2/results?cond=Nicotinamide+mononucleotide&term=&cntry=&state=&city=&dist=

Dominguez, L. J., Di Bella, G., Veronese, N., & Barbagallo, M. (2021). Impact of Mediterranean Diet on Chronic Non-Communicable Diseases and Longevity. Nutrients, 13(6), 2028. https://doi.org/10.3390/nu13062028

Fukamizu Y, Uchida Y, Shigekawa A, Sato T, Kosaka H, Sakurai T. Safety evaluation of β-nicotinamide mononucleotide oral administration in healthy adult men and women. Sci Rep. 2022 Aug 24;12(1):14442. doi: 10.1038/s41598-022-18272-y. PMID: 36002548; PMCID: PMC9400576.

Igarashi, M., Nakagawa-Nagahama, Y., Miura, M. et al. Chronic nicotinamide mononucleotide supplementation elevates blood nicotinamide adenine dinucleotide levels and alters muscle function in healthy older men. npj Aging 8, 5 (2022). https://doi.org/10.1038/s41514-022-00084-z

Irie, J., Inagaki, E., Fujita, M., Nakaya, H., Mitsuishi, M., Yamaguchi, S., Yamashita, K., Shigaki, S., Ono, T., Yukioka, H., Okano, H., Nabeshima, Y. I., Imai, S. I., Yasui, M., Tsubota, K., & Itoh, H. (2020). Effect of oral administration of nicotinamide mononucleotide on clinical parameters and nicotinamide metabolite levels in healthy Japanese men. Endocrine journal, 67(2), 153–160. https://doi.org/10.1507/endocrj.EJ19-0313

Kaplan, S. (2015, February 3). GNC, Target, Wal-Mart, Walgreens accused of selling adulterated ‘herbals’. The Washington Post. https://www.washingtonpost.com/news/morning-mix/wp/2015/02/03/gnc-target-wal-mart-walgreens-accused-of-selling-fake-herbals/

Kim, M., Seol, J., Sato, T., Fukamizu, Y., Sakurai, T., & Okura, T. (2022). 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. Nutrients, 14(4), 755. https://doi.org/10.3390/nu14040755

Liao, B., Zhao, Y., Wang, D., Zhang, X., Hao, X., & Hu, M. (2021). Nicotinamide mononucleotide supplementation enhances aerobic capacity in amateur runners: a randomized, double-blind study. Journal of the International Society of Sports Nutrition, 18(1), 54. https://doi.org/10.1186/s12970-021-00442-4

Matsakis, L. (2019, July 19). Amazon Warns Customers: Those Supplements Might Be Fake. Wired. https://www.wired.com/story/amazon-fake-supplements/

Mazza, E., Ferro, Y., Pujia, R., Mare, R., Maurotti, S., Montalcini, T., & Pujia, A. (2021). Mediterranean Diet In Healthy Aging. The journal of nutrition, health & aging, 25(9), 1076–1083. https://doi.org/10.1007/s12603-021-1675-6

Nadeeshani, H., Li, J., Ying, T., Zhang, B., & Lu, J. (2021). Nicotinamide mononucleotide (NMN) as an anti-aging health product - Promises and safety concerns. Journal of advanced research, 37, 267–278. https://doi.org/10.1016/j.jare.2021.08.003

Soma, M., & Lalam, S. (2022). The role of nicotinamide mononucleotide (NMN) in anti-aging, longevity, and its potential for treating chronic conditions. Molecular Biology Reports, 49(10), 9737-9748. https://pubmed.ncbi.nlm.nih.gov/35441939/

Yoshino, M., Yoshino, J., Kayser, B. D., Patti, G. J., Franczyk, M. P., Mills, K. F., Sindelar, M., Pietka, T., Patterson, B. W., Imai, S. I., & Klein, S. (2021). Nicotinamide mononucleotide increases muscle insulin sensitivity in prediabetic women. Science (New York, N.Y.), 372(6547), 1224–1229. https://doi.org/10.1126/science.abe9985

Zimmerman, S. (2020, February 11). Why Drugs Tested in Mice Fail in Human Clinical Trials. Harvard University, The Graduate School of Arts and Sciences. https://sitn.hms.harvard.edu/flash/2020/why-drugs-tested-in-mice-fail-in-human-clinical-trials/