The decline in NAD+ is a central driver of several key aging processes, from faltering DNA repair to declining energy production. This naturally leads to a critical question for anyone building a proactive healthspan strategy: what is the most effective and reliable way to restore it? As awareness has grown, two key precursor molecules have emerged as the leading options for supplementation: Nicotinamide Riboside (NR) and Nicotinamide Mononucleotide (NMN). Both have gained significant attention, but a crucial question remains for anyone serious about their cellular health: which one is the superior choice?
The Precursor Principle: Building the Ship in the Bottle
To understand the difference between NR and NMN, we must first understand why a "precursor" is necessary at all. The NAD+ molecule itself is too large and charged to easily pass through the cell membrane. Taking NAD+ directly is like trying to build a ship in a bottle by shoving the finished ship through the narrow neck. It simply doesn't work.
Instead, we must supply the cell with the smaller, more easily absorbed building blocks (the precursors) that can pass through the membrane and be assembled into NAD+ inside the cell where it's needed. NR and NMN are the two most advanced "pieces" for this assembly process.
“Taking NAD+ directly is like trying to build a ship in a bottle by shoving the finished ship through the narrow neck. It simply doesn't work.”
The Key Differentiator: The "Cellular Gateway"
The primary debate between NR and NMN comes down to a fundamental question of biochemistry: how does each molecule get inside the cell to be converted into NAD+?
The Direct Path of NR Nicotinamide Riboside (NR) is a smaller, more direct precursor. The scientific consensus is that NR enters cells through a well-established family of nucleoside transporters that are present on the cell membrane. Once inside the cell, it is efficiently converted into NMN and then, finally, into NAD+. This represents a direct and well-understood "front door" into the cell. This pathway is well-understood and documented in human biology.
The NMN Detour Nicotinamide Mononucleotide (NMN) is a larger molecule. For years, the predominant scientific view has been that NMN is too large to enter most cells directly. Instead, the evidence suggests that NMN must first be converted backwards into NR in the space outside the cell, enter the cell as NR through the nucleoside transporters, and then be converted back into NMN once inside. This represents an indirect, multi-step "detour."
However, in 2019, a study identified a potential NMN-specific transporter called Slc12a8 in mice. While a fascinating discovery, the significance and activity level of this transporter in human tissues are still subjects of scientific debate. The absorption pathway for NR remains the most clearly established and understood in humans.
“The absorption pathway for NR remains the most clearly established and understood in humans.”
Yoshino, J., Baur, J. A., & Imai, S. I. (2018). NAD+ intermediates: The biology and therapeutic potential of NMN and NR. Cell Metabolism, 27(3), 513–528. DOI: 10.1016/j.cmet.2017.11.002
The Gold Standard: What the Human Evidence Reveals
Animal studies are useful, but for supplements, the gold standard is human clinical data. When comparing NR and NMN, the body of human evidence is a major point of differentiation.
The Extensive Evidence for NR (nicotinamide riboside) is supported by a large and mature body of human clinical trials. A comprehensive 2023 meta-analysis, which pools the data from multiple studies, confirmed that NR supplementation is safe and consistently effective at raising NAD+ levels in healthy adults. Landmark trials, such as the head-to-head study by Brakedal et al. (2022), have not only confirmed NR's efficacy over NMN in raising NAD+ but have also shown it does so in a dose-dependent manner in crucial tissues like human skeletal muscle. This extensive data provides a high degree of confidence in its safety and bioavailability
The Emerging Evidence for NMN (Nicotinamide Mononucleotide) The human research on NMN is promising but is still in its earlier stages compared to NR. While studies have confirmed NMN's safety and ability to raise blood NAD+ levels, and have even shown specific benefits like improving muscle insulin sensitivity in prediabetic women, the overall volume of long-term and diverse human data is not yet as extensive.
“NR supplementation is safe and consistently effective at raising NAD+ levels in healthy adults.The human research on NMN is promising but is still in its earlier stages compared to NR. ”
The Deciding Factor: Regulatory Certainty
For consumers and responsible brands, scientific evidence is only part of the equation. Regulatory approval provides a critical guarantee of safety and legality.
In the European Union (EU):
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NR: Nicotinamide Riboside Chloride is fully authorized for sale as a "novel food," based on a comprehensive safety assessment by the European Food Safety Authority (EFSA). This is the highest stamp of approval in the EU.
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NMN: Nicotinamide Mononucleotide is not yet authorized and remains listed as an unapproved novel food in the EU Novel Food Catalogue. It cannot be legally sold as a food supplement within the EU.
In the United States (U.S.):
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NR: Has a long and stable regulatory history, having successfully achieved Generally Recognized as Safe (GRAS) status and been filed as a New Dietary Ingredient (NDI) with the FDA without issue.
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NMN: Has faced significant regulatory uncertainty. In November 2022, the FDA reversed its position, stating NMN could not be sold as a supplement due to the "drug preclusion clause". While this decision was recently reversed in September 2025, allowing NMN back on the market, the multi-year turmoil highlights a period of significant legal and commercial instability compared to NR.
The Scientific Verdict
When the goal is to address the age-related decline of NAD+ (a key factor in several Hallmarks of Aging) the evidence directs us toward the most reliable and well-proven tool.
While the science will continue to evolve, the current, comprehensive body of evidence - from the cellular level to human trials and global regulatory review - points to Nicotinamide Riboside (NR) as the most direct, well-researched, and scientifically validated choice for anyone looking to support their NAD+ levels as part of a proactive healthspan strategy.
References
Braidy, N., Berg, J., Clement, J., Khorshidi, F., Poljak, A., Jayasena, T., Grant, R., & Sachdev, P. (2019). Role of nicotinamide adenine dinucleotide and related precursors as therapeutic targets for age-related degenerative diseases: Rationale, biochemistry, pharmacokinetics, and outcomes. Antioxidants & Redox Signaling, 30(2), 251–294. https://doi.org/10.1089/ars.2017.7269
Braidy, N., & Grant, R. (2020). Pharmacokinetics and metabolism of intravenous NAD+ in humans. Current Opinion in Clinical Nutrition & Metabolic Care, 23(6), 405–409.
Brakedal, B., Dölle, C., Riemer, F., Ma, Y., Nido, G. S., Skeie, G. O., Craven, A. R., Schwarzlmüller, T., Brekke, N., Diab, J., Sverkeli, L., Skjeie, V., Varhaug, K., Tysnes, O.-B., Peng, S., Haugarvoll, K., Ziegler, M., Grüner, R., Eidelberg, D., & Tzoulis, C. (2022). The NADPARK study: A randomized phase I trial of nicotinamide riboside supplementation in Parkinson’s disease. Cell Metabolism, 34(3), 396–407.e6. https://doi.org/10.1016/j.cmet.2022.02.001
Camacho-Pereira, J., Tarragó, M. G., Chini, C. C. S., et al. (2016). CD38 dictates age-related NAD decline and mitochondrial dysfunction through a SIRT3-dependent mechanism. Cell Metabolism, 23(6), 1127–1139. DOI: 10.1016/j.cmet.2016.05.006
Cantó, C., Menzies, K. J., & Auwerx, J. (2015). NAD+ metabolism and the control of energy homeostasis: A balancing act between mitochondria and the nucleus. Cell Metabolism, 22(1), 31–53. https://doi.org/10.1016/j.cmet.2015.05.023
Chini, E. N., Tarragó, M. G., & Chini, C. C. S. (2021). NAD and the aging process: Role in life, death and everything in between. Cell Metabolism, 33(5), 837–857. https://doi.org/10.1016/j.mce.2016.11.003
Chu, X., & Raju, R. P. (2022). Regulation of NAD+ metabolism in aging and disease. Metabolism, 126, 154923. https://doi.org/10.1016/j.metabol.2021.154923
Commission Implementing Regulation (EU) 2020/16 of 10 January 2020 authorising the placing on the market of nicotinamide riboside chloride as a novel food under Regulation (EU) 2015/2283. (2020). Official Journal of the European Union. https://eur-lex.europa.eu/eli/reg_impl/2020/16/oj
Conze, D., Brenner, C., & Kruger, C. L. (2019). Safety and metabolism of long-term administration of NIAGEN (nicotinamide riboside chloride) in a randomized, double-blind, placebo-controlled clinical trial of healthy overweight adults. Scientific Reports, 9(1), 9772. https://doi.org/10.1038/s41598-019-46120-z
Covarrubias, A. J., Perrone, R., Grozio, A., & Verdin, E. (2021). NAD+ metabolism and its roles in cellular processes during ageing. Nature Reviews Molecular Cell Biology, 22(2), 119–141. https://doi.org/10.1038/s41580-020-00313-x
Dollerup, O. L., Christensen, B., Svart, M., Schmidt, M. S., Sulek, K., Ringgaard, S., Stødkilde-Jørgensen, H., Møller, N., Brenner, C., Treebak, J. T., & Jessen, N. (2018). A randomized placebo-controlled clinical trial of nicotinamide riboside in obese men: Safety, insulin-sensitivity, and lipid-mobilizing effects. Cell Metabolism, 29(4), 1003–1016.e4. https://doi.org/10.1093/ajcn/nqy132
EFSA Panel on Nutrition, Novel Foods and Food Allergens (NDA). (2019). Safety of nicotinamide riboside chloride as a novel food pursuant to Regulation (EU) 2015/2283. EFSA Journal, 17(8), e05775. https://doi.org/10.2903/j.efsa.2019.5775
Giner, M. P., Christen, S., Bartova, S., Makarov, M. V., Migaud, M. E., Cantó, C., & Moco, S. (2021). A method to monitor the NAD+ metabolome—from mechanistic to clinical applications. International Journal of Molecular Sciences, 22(19), 10598. https://doi.org/10.3390/ijms221910598
Grant, R., Berg, J., Mestayer, R., Braidy, N., Bennett, J., Broom, S., & Stowe, R. (2019). A pilot study investigating changes in the human plasma and urine NAD+ metabolome during a 6-hour intravenous infusion of NAD+. Frontiers in Aging Neuroscience, 11, 257. https://doi.org/10.3389/fnagi.2019.00257
Grozio, A., Mills, K. F., Yoshino, J., et al. (2019). Slc12a8 is a nicotinamide mononucleotide transporter. Nature Metabolism, 1(1), 47–57. https://doi.org/10.1038/s42255-018-0009-4
Imai, S., & Guarente, L. (2014). NAD+ and sirtuins in aging and disease. Trends in Cell Biology, 24(8), 464–471. https://www.cell.com/trends/cell-biology/abstract/S0962-8924(14)00063-4
Irie, J., Inagaki, E., Fujita, M., et al. (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
Martens, C. R., Denman, B. A., Mazzo, M. R., et al. (2018). Chronic nicotinamide riboside supplementation is well-tolerated and elevates NAD+ in healthy middle-aged and older adults. Nature Communications, 9(1), 1286. https://doi.org/10.1038/s41467-018-03421-7
Mills, K. F., Yoshida, S., Stein, L. R., Grozio, A., Kubota, S., Sasaki, Y., Redpath, P., Migaud, M. E., Apte, R. S., Uchida, K., Yoshino, J., & Imai, S. I. (2016). Long-term administration of nicotinamide mononucleotide mitigates age-associated physiological decline in mice. Cell Metabolism, 24(6), 795–806. https://doi.org/10.1016/j.cmet.2016.09.013
Poddar, S. K., Sifat, A. E., Hafeez, M. M., et al. (2019). Nicotinamide N-methyltransferase: A key regulator of metabolism, longevity, and disease. Current Developments in Nutrition, 3(8), nzz075.
Rajman, L., Chwalek, K., & Sinclair, D. A. (2018). Therapeutic potential of NAD-boosting molecules: The in vivo evidence. Cell Metabolism, 27(3), 529–547. https://doi.org/10.1016/j.cmet.2018.02.011
Ratajczak, J., Joffraud, M., Trammell, S. A. J., et al. (2016). NRK1 controls nicotinamide mononucleotide and nicotinamide riboside metabolism in mammalian cells. Nature Communications, 7, 13103. https://doi.org/10.1038/ncomms13103
U.S. Food and Drug Administration. (2016). GRAS Notice No. GRN 000635: Nicotinamide riboside chloride. https://www.cfsanappsexternal.fda.gov/scripts/fdcc/?set=GRASNotices&id=635
U.S. Food and Drug Administration. (2022, November). Re: New dietary ingredient notification for nicotinamide mononucleotide (NDI 1254). Letter to Inner Mongolia Kingdomway Pharmaceutical Limited. https://www.regulations.gov/document/FDA-2022-S-0023-0051
U.S. Food and Drug Administration. (2025, September). FDA statement on nicotinamide mononucleotide.
Xiao, W., Wang, R. S., Handy, D. E., & Loscalzo, J. (2018). NAD(H) and NADP(H) redox couples and cellular energy metabolism. Antioxidants & Redox Signaling, 28(3), 251–272. https://doi.org/10.1089/ars.2017.7216
Yoshino, J., Baur, J. A., & Imai, S. I. (2018). NAD+ intermediates: The biology and therapeutic potential of NMN and NR. Cell Metabolism, 27(3), 513–528. DOI: 10.1016/j.cmet.2017.11.002
