What is NR, and how was it discovered?
Nicotinamide riboside (NR) is a naturally occurring form of vitamin B3, first identified in yeast in 1944 but only biochemically characterized as an independent NAD+ precursor in humans by Charles Brenner from the University of Iowa in 2004. Brenner's discovery, published in the journal Cell, showed that NR has an independent, niacin-independent pathway into NAD+ biosynthesis via specific nicotinamide riboside kinases (NRK1 and NRK2).
NR naturally occurs in small amounts in cow's milk, as Trammell and Brenner showed in 2016 in the Journal of Nutrition. The form used in dietary supplements is nicotinamide riboside chloride, a stable salt known on the market as TruNiagen (ChromaDex). Chemically, NR is the precursor molecule to NMN: NR is first phosphorylated to NMN in the body before being further synthesized to NAD+.
How NR becomes NAD+ in the body
The classic synthesis pathway for NR runs via the salvage pathway: NR is phosphorylated to NMN in the cell by NRK1/2. NMN is then converted to NAD+ by NMNAT enzymes. This pathway was long assumed to be the primary mechanism by which NR supplementation increases NAD+.
Christen et al. showed in 2026 in Nature Metabolism in a first controlled human study that this direct cellular pathway actually plays a subordinate role. According to this, NR is mainly converted to nicotinamide in the intestine and increases NAD+ primarily via the Preiss-Handler pathway, the same route as NMN. This explains why NMN and NR produced comparable NAD+ increases in this study, although they are structurally different precursor molecules. [5]
A unique feature of NR metabolism: Nicotinic acid adenine dinucleotide (NAAD) is considered a sensitive biomarker for NAD+ increase through NR. Trammell et al. discovered in 2016 that NAAD rises particularly strongly with NR supplementation and can be used as a reliable signal for effective NAD+ replenishment.
What clinical studies in humans show
Bioavailability: First controlled study
Trammell et al. published in 2016 in Nature Communications the first controlled clinical study on the pharmacokinetics of NR in humans. Twelve healthy adults (six men, six women) received single doses of 100, 300, and 1,000 mg NR. All three doses produced dose-dependent increases in the NAD+ metabolome in blood. The study was funded by ChromaDex, the manufacturer of TruNiagen, which should be considered when evaluating; however, the results have been widely replicated in subsequent literature. [1]
Skeletal muscle tissue: Direct tissue measurements
Elhassan et al. published in 2019 in Cell Reports a crossover study considered unique in NAD+ precursor research: Twelve older men received 1 g NR daily for 21 days, and NAD+ content was measured directly via muscle biopsies, not just in blood. NR measurably increased the NAD+ metabolome in skeletal muscle. Additionally, anti-inflammatory transcription signatures were observed in muscle tissue. Mitochondrial bioenergetics, substrate utilization, and blood flow remained unchanged. Thus, muscles did not function differently due to NR but contained more NAD+ metabolites. [2]
This direct tissue work distinguishes NR from NMN in the published human literature: While blood NAD+ data for NMN are well documented, comparable muscle biopsy RCTs for NMN are currently lacking.
Long-term effect: Mitochondrial biogenesis in a twin study
Lapatto et al. published in 2023 in Science Advances the longest NR intervention study in humans to date. Forty monozygotic twin pairs with different BMIs received NR in escalating doses from 250 to 1,000 mg daily over 5 months. NR increased NAD+ metabolism in blood and tissue, improved the number of mitochondria in muscle tissue and myoblast differentiation (the maturation of muscle stem cells), and positively altered the gut microbiota. Obesity and metabolic health were not improved by NR. [3]
An important methodological note: Some results of this study were calculated using the Wilcoxon test with very small sample sizes, which was listed as a statistical issue in a critical analysis in Science Advances 2023. Nevertheless, the general direction of the results regarding NAD+ metabolism is considered a robust finding that aligns well with other studies.
Safety and Tolerability
Dollerup et al. investigated in 2018 in a randomized, placebo-controlled study (American Journal of Clinical Nutrition) 40 obese men over 12 weeks with 1,000 mg NR daily. NR was well tolerated without safety-relevant events. Insulin sensitivity and body composition were not improved by NR in this study. The tolerability data from this and other studies support the safety profile of NR at doses up to 2,000 mg daily in studies lasting up to 24 weeks. [4]
Berven et al. expanded the tested safety limit upwards in 2023 in Nature Communications: In the randomized, placebo-controlled phase I study NR-SAFE, 20 Parkinson's patients received 3,000 mg NR daily for 4 weeks. No moderate or severe side effects occurred. All reported events were mild and their frequency was comparable between the NR and placebo groups. The authors conclude that a direct initial dose up to 3,000 mg daily without gradual titration appears safe but call for longer safety data for future studies. [8]
Physical performance: First evidence of effect in peripheral vascular disease
McDermott et al. published in 2024 in Nature Communications the most convincing evidence so far of NR's effect on a functional endpoint in humans. In the randomized, double-blind NICE Trial, 90 patients with peripheral arterial disease (pAVK) received either NR alone, NR combined with resveratrol, or placebo for 6 months. The primary endpoint was the 6-minute walk distance. NR improved walking distance by 17.6 meters compared to placebo (90% CI: +1.8 to +∞). Among participants with at least 75% adherence, the improvement was 31 meters. Resveratrol provided no additional benefit. [7]
pAVK is a condition where atherosclerotic narrowings reduce blood flow in the leg arteries, thereby limiting walking ability and muscle function. The hypothesis was that NR, by increasing NAD+, could improve mitochondrial energy metabolism in ischemic muscles. The results of the NICE Trial are the first to show a functional benefit from NR supplementation in a controlled design with 90 people over 6 months. The study was not powered for a two-sided statistical test; a replication study is planned according to the authors.
Long-COVID: Fatigue and cognition as exploratory endpoints
Wu et al. published in 2025 in eClinicalMedicine (Lancet group) the first RCT on NR in Long-COVID. 58 patients with persistent symptoms after SARS-CoV-2 infection received either 2,000 mg NR daily or placebo for up to 20 weeks. The primary endpoint, an objectively measured improvement in cognitive performance, was not significantly reached. In exploratory analyses of participants who took part for at least 10 weeks, NR recipients reported improvements in fatigue, sleep, mood, and some executive function tests. NAD+ levels in the blood increased significantly due to NR. [9]
The study was funded by Niagen Bioscience and other institutions; co-author Rudolph Tanzi holds equity in Niagen Bioscience but was not involved in the conduct. The high dosage of 2,000 mg daily and the Long-COVID context limit the transferability to healthy adults. The results justify an upgrade of the evidence status for cognitive and fatigue endpoints without proving an effect.
What the study situation has not yet proven
The NAD+ increase in the blood is one of the most robust findings for NR in supplement research and is consistently replicated. It is less clear whether this increase leads to clinically measurable improvements in healthy adults.
Insulin sensitivity and body composition were not improved in several high-quality RCTs, including Dollerup et al. 2018 and the Lapatto twin study. Improved mitochondrial function in resting bioenergetics tests was not observed in Elhassan et al. 2019. Cognitive endpoints and cardiovascular risk reduction have been investigated in exploratory studies. The NICE Trial 2024 provides the first functional evidence of effect for vascular patients; for healthy adults, the evidence for clinically measurable benefits remains limited. In Long-COVID patients, Wu et al. 2025 suggests exploratory potential for fatigue reduction, without reaching the primary endpoint. A critical review in Science Advances (2023) concludes that clinically relevant effects of NR in healthy adults are so far limited. This does not diminish the value of the substance but calls for caution regarding strong individual claims.
NR in direct comparison with NMN
The first controlled direct comparison of NMN and NR in humans was published in 2026 by Christen et al. in Nature Metabolism. In a four-arm RCT (n=65), participants received NMN, NR, a combination, or placebo for 14 days. Both substances increased circulating NAD+ levels comparably. The mechanistic finding was surprising: both NMN and NR increase NAD+ mainly through gut flora conversion to nicotinic acid and then via the Preiss-Handler pathway, not as long assumed via the direct intracellular salvage pathway. The study was funded by Nestlé Research; only surrogate markers (NAD+ levels) were measured, no functional endpoints. [5]
The practical consequence for choosing between NMN and NR is small. Both substances reliably increase NAD+. The main difference lies not in the mechanism of action but in regulatory status: NR has Novel Food approval in the EU, NMN currently does not.
Novel Food Approval in the EU: What It Means
NR (as nicotinamide riboside chloride) received Novel Food approval from the European Commission in 2019 through Implementing Regulation (EU) 2019/696. The basis was a risk assessment by EFSA (European Food Safety Authority), which rated NR’s safety profile at approved usage levels as acceptable. [6]
What this approval means: NR may be marketed and sold in the EU as a dietary supplement with legal certainty. The approval says nothing about proof of efficacy; it confirms the safety assessment. What this approval does not mean: that NR is more effective than NMN, or that NMN is unsafe. NMN is currently under EFSA evaluation at the time of this article’s creation. For people who value legal certainty in the EU, NR is currently the clearer choice.
State of Evidence
| Endpoint | Evidence Status | Comment |
|---|---|---|
| NAD+ Increase in Blood | 🟢 Human Studies | Consistently replicated across all doses 300–2,000 mg. Most robust finding in the NR literature. |
| Skeletal Muscle NAD+ | 🟢 Human Studies (Biopsy) | Elhassan et al. 2019: direct tissue evidence. Unique in NAD+ precursor research. |
| Mitochondrial Biogenesis | 🟡 Human Studies | Lapatto et al. 2023: increased mitochondrial number after 5 months. Note methodological limitations. |
| Anti-inflammatory Effects | 🟡 Human Studies | Elhassan et al. showed transcription signatures; circulating inflammatory markers in further studies. |
| Insulin Sensitivity | 🔴 Human Studies | Not improved in RCTs (Dollerup 2018, Lapatto 2023). No confirmed effect in healthy adults. |
| Body Composition | 🔴 Human Studies | Lapatto 2023: Obesity not reduced by NR. |
| Cognitive Function / Fatigue | 🟡 Exploratory RCTs | Wu et al. 2025 (n=58, Long COVID): fatigue, sleep, mood improved in exploratory analysis; primary cognition endpoint not significant. Orr et al. 2024 (MCI): NAD+ increased, cognition not improved. |
| Physical performance | 🟡 RCT (peripheral artery disease) | McDermott et al. 2024 (NICE Trial, n=90): 6-minute walk distance +17.6 m vs. placebo. First functional endpoint. Replication pending. |
| Cardiovascular markers | 🟡 Pilot studies | Martens et al. 2018: reduced blood pressure and arterial stiffness. Lin et al. 2025 (hypertension): pilot RCT, blood pressure results confounded by antihypertensives. |
🟢 Well-documented human studies · 🟡 Exploratory evidence · 🔵 Pilot studies / animal models · 🔴 Not proven
Who is NR suitable for?
NR is especially relevant for two groups. First, for people in the EU who explicitly value the regulatory status as an approved novel food. As the only NAD+ precursor with novel food approval, NR offers the clearest legal basis here. Second, for people specifically interested in the evidence related to skeletal muscle and mitochondrial biogenesis: the direct tissue data from Elhassan et al. and the mitochondrial data from the Lapatto twin study are published data for NR, whereas comparable muscle biopsy RCTs are not yet available for NMN.
The choice between NMN and NR as NAD+ precursors is, based on current knowledge, primarily a matter of regulatory context and personal preference, not the mechanism of action. Those already taking NMN and tolerating it well have no proven reason to switch. Those starting new and living in the EU have the legally safer option with NR.
Dosage and practical notes
In clinical studies, dosages of 250 to 2,000 mg daily were used. The best-studied range is 1,000 mg daily, where robust NAD+ increases and a good safety profile have been documented. In the Lapatto twin study, dosing started at 250 mg and escalated weekly to 1,000 mg; this gradual approach may improve tolerability. Substance-specific dosing recommendations for different age groups and indications are not conclusively established.
NR was taken in the morning in studies. Since NR is converted by the gut flora before it increases NAD+, the exact time of intake is less critical than with substances that have a direct absorptive effect. NR is approved as a dietary supplement in the EU and is available as such.
