NMN versus NR: what the 2025 evidence actually says

A new review in Food Frontiers lines up the two NAD+ precursors that drive the longevity-supplement aisle. NMN and NR. Xinpeng Yang and colleagues weigh them on mechanism, on animal data, and on the human trial record. Both raise blood NAD+. Neither has earned the longevity-extension claims printed on the box.

NAD+ is the cofactor sirtuins, PARPs, and CD38 rely on. Its concentration in tissue falls with age. The pitch for NMN and NR has always been intuitive: swallow a precursor, refill the pool, restore the dependent enzymes, slow some part of the aging program. Mouse work has been encouraging. Human pharmacokinetic data are clear that oral NMN and oral NR raise circulating NAD+ in a dose-dependent way. The question Yang’s team presses on is what happens after the levels move.

How the two molecules differ

NMN sits one phosphate group closer to NAD+ than NR does. The cellular routing is what splits them. NR is taken up via equilibrative nucleoside transporters and is converted to NMN inside the cell by nicotinamide riboside kinases. NMN, despite once being thought to require dephosphorylation to NR before crossing the membrane, may have its own dedicated transporter, Slc12a8, identified in mouse small intestine in 2019 and still actively disputed in humans.

What this means in practice is that the two precursors converge on the same intracellular pool by different routes. The supplement-marketing claim that NMN is “more efficient because it is closer to NAD+” overstates a difference that, on current evidence, may not hold once the molecules clear the gut. Yang and colleagues argue that head-to-head pharmacokinetic comparisons in humans are too sparse to settle the matter.

What human trials have actually measured

The clinical record splits roughly in two: trials asking whether NAD+ goes up, and trials asking whether anything else changes. The first set has been a quiet success. The second has been more sobering.

Earlier short-duration studies showed modest 40 to 59 percent NAD+ elevations on 300 mg of either precursor. A randomized placebo-controlled trial of NR in older adults with mild cognitive impairment, led by Miranda Orr at Wake Forest in 2023, used a four-week dose escalation to 1 g/day over 10 weeks and saw blood NAD+ rise 139 percent in the active arm (p<0.001). Cognition, measured by the Montreal Cognitive Assessment, did not move in either direction. The placebo arm declined 0.89 points; the NR arm declined 0.3 points. Orr’s team concluded that “NR significantly increased blood NAD+ concentrations in older adults with MCI” and that the supplement “was well tolerated and did not alter cognition.”

A larger 2025 trial out of Massachusetts General Hospital, led by Chao-Yi Wu and published in eClinicalMedicine, pushed the NR dose to 2,000 mg/day in adults with long-COVID. NAD+ rose 2.6 to 3.1-fold within five to 10 weeks. The headline endpoint, between-group differences in fatigue, sleep, anxiety, depression, and cognition, did not separate from placebo. Within-group analyses after 10 weeks did show signals in executive function and depressive symptoms, but the authors are explicit that those are exploratory. “NAD+ augmentation did not produce statistically significant between-group differences,” they wrote.

NMN’s record is similar in pattern but smaller in volume. Morifuji and colleagues published a 12-week, double-blind, placebo-controlled trial of 250 mg/day NMN in older Japanese adults in GeroScience in 2024. NAD+ rose, the placebo group’s 4-meter walking speed declined while the NMN group’s held steady, and Pittsburgh Sleep Quality Index scores improved relative to placebo. It is the most encouraging functional readout in the recent NMN literature, and it comes from a single 36-person trial.

Where the meta-analysis lands

The most decisive recent paper is not a primary trial but a synthesis. A 2025 systematic review and meta-analysis in the Journal of Cachexia, Sarcopenia and Muscle, led by Konstantinos Prokopidis at the University of Liverpool, pooled 10 randomized controlled trials of NMN and NR in older adults, six on NMN and four on NR, with mean ages between 60.9 and 83 years. On the muscle endpoints that motivate much of the longevity supplement pitch, the pooled effect was null. Skeletal muscle index showed a mean difference of negative 0.42 with a 95 percent confidence interval crossing zero (p=0.14). Handgrip strength, gait speed, and the 5-time chair stand test all returned similar non-effects. The authors compared NMN and NR head-to-head and found neither precursor outperformed the other or placebo.

“Current evidence does not support the use of NMN and NR as effective interventions for improving muscle function and mass in adults above 60 years old,” Prokopidis and colleagues concluded.

That sentence, with its caveats and qualifiers, is roughly where the field sits as Yang’s review surveys it. NAD+ goes up. The downstream physiology that mouse studies suggested would follow has, so far, refused to follow on schedule.

Why the preclinical-to-clinical gap

Several explanations are plausible and not mutually exclusive. Mouse models of aging are highly inbred, fed a fixed diet, and live in temperature-controlled cages. Humans accumulate NAD+ deficits more heterogeneously, and intramuscular NAD+, the pool that a sarcopenia trial would care about, is not always reflected by blood concentrations. Yang and colleagues note that tissue distribution of orally administered NMN and NR varies considerably across organs in animal data, with liver and kidney saturating quickly while skeletal muscle and brain take up the precursors more slowly.

There is also the question of whether the right people are being studied. Most clinical trials enroll healthy older adults or patients with one specific condition. The NAD+ deficit hypothesis predicts that the people most likely to benefit are those whose tissue NAD+ has dropped the furthest. That subgroup has not been cleanly defined, and trial inclusion criteria have not been built around it.

The regulatory wrinkle

The FDA’s 2022 determination that NMN cannot be marketed as a dietary supplement, because it is being investigated as a drug, sits awkwardly over the field. NR remains available as a supplement under the Niagen brand. NMN has continued to be sold in a regulatory gray zone, often by sellers who use the FDA’s silence on enforcement as a tacit license. Yang’s review does not weigh in on the regulatory question directly, but it does note that the pharmacological grade of NMN used in clinical trials is not always what consumers buy at retail.

What an honest read of 2025 says

The Yang review is best read as a status check rather than a verdict. NMN and NR both raise blood NAD+. Neither has a clinical trial portfolio robust enough to support the longevity-extension claims in the supplement-marketing layer. The best human evidence is for short-term safety and confirmed pharmacokinetic effect. The functional endpoints that most consumers care about, including muscle, sleep, cognition, fatigue, and energy, remain a mix of small positive trials and well-powered nulls.

For someone trying to decide between the two molecules, the comparative literature does not yet offer a basis for preference. Larger, longer, mechanism-stratified trials are the bottleneck, not the chemistry of which precursor is one phosphate closer to NAD+. Consult your doctor before starting any supplement.

References

1. Yang X, Lu A, Guan X, et al. An updated review on the mechanisms, pre-clinical and clinical comparisons of nicotinamide mononucleotide (NMN) and nicotinamide riboside (NR). Food Frontiers. 2025. https://doi.org/10.1002/fft2.511
2. Orr ME, Kotkowski E, Ramirez P, et al. A randomized placebo-controlled trial of nicotinamide riboside in older adults with mild cognitive impairment. GeroScience. 2023. https://doi.org/10.1007/s11357-023-00999-9
3. Wu CY, Reynolds WC, Abril I, et al. Effects of nicotinamide riboside on NAD+ levels, cognition, and symptom recovery in long-COVID: a randomized controlled trial. eClinicalMedicine. 2025. https://doi.org/10.1016/j.eclinm.2025.103633
4. Prokopidis K, Moriarty F, Bahat G, et al. The effect of nicotinamide mononucleotide and riboside on skeletal muscle mass and function: a systematic review and meta-analysis. Journal of Cachexia, Sarcopenia and Muscle. 2025. https://doi.org/10.1002/jcsm.13799
5. Morifuji M, Higashi S, Ebihara S, et al. Ingestion of β-nicotinamide mononucleotide increased blood NAD levels, maintained walking speed, and improved sleep quality in older adults in a double-blind randomized, placebo-controlled study. GeroScience. 2024. https://pmc.ncbi.nlm.nih.gov/articles/PMC11336149/