NAD+ (nicotinamide adenine dinucleotide) is not a peptide but a coenzyme — a small molecule without which neither energy production in mitochondria, nor the enzymes that repair DNA, nor the sirtuins regarded as “guardians” of ageing can work. Its level in tissues falls with age, and the idea of topping it up has become a pillar of longevity protocols. Supplements use precursors that the body converts into NAD+: NMN (nicotinamide mononucleotide) and NR (nicotinamide riboside), while wellness clinics offer intravenous infusions of NAD+ itself. In this review we separate what has been shown in humans (blood NAD+ really does rise) from what was promised (strength, performance, metabolism), because two meta-analyses from 2024–2025 return a null result there.
What NAD+ is, and what NMN and NR are
NAD+ is present in every living cell. It cycles between an oxidised form (NAD+) and a reduced form (NADH), carrying electrons in cellular respiration, but it is also consumed as a substrate by enzymes: the sirtuins (which regulate genes and metabolism), PARPs (DNA repair) and CD38 (calcium signalling and immunity). The body makes NAD+ afresh from tryptophan (the kynurenine pathway) or recycles it from vitamin B3 in its various forms: nicotinic acid, nicotinamide and nicotinamide riboside (Braidy and Liu, 2020). NR is thus a form of vitamin B3, and NMN the next step of the same pathway, just before NAD+. Trammell et al. (2016) showed that NR is well absorbed orally: in the first human pharmacokinetic study, single doses of 100, 300 and 1,000 mg raised NAD+ metabolites in blood in a dose-dependent way, and in one person (a pilot study) blood NAD+ rose as much as 2.7-fold.
How it works — the logic of “adding substrate”
The logic of supplementation is one of supply: we provide substrate rather than activating an enzyme. If an ageing tissue lacks NAD+, replenishing it should let the sirtuins and repair enzymes work more efficiently. This chain of reasoning has two weak links, though. First, the decline of NAD+ with age is well documented in animals, but — as Elhassan et al. (2019) note — human data are sparse. Second, a rise in blood NAD+ need not mean a rise in muscle or brain, let alone a change in function. So the key question is not “does NAD+ rise” (it does) but “does anything improve as a result”.
The biomarker — what has definitely been shown in humans
That precursors raise NAD+ is known from several sound studies. Martens et al. (2018), in a placebo-controlled crossover trial in healthy middle-aged and older adults (24 completed the study), gave NR at 1,000 mg for 6 weeks: NAD+ in blood cells rose by about 60% relative to placebo, the supplement was well tolerated, and in an exploratory analysis systolic blood pressure in people with elevated baseline pressure was 9 mmHg lower than after placebo — the authors treated that as a hypothesis to test, not a result. Yi et al. (2023), in 80 healthy middle-aged adults, compared placebo with NMN at 300, 600 and 900 mg for 60 days: blood NAD+ rose in all groups, most at 600 and 900 mg, and the six-minute walking distance improved more than after placebo; it should be known, however, that the trial was co-run by employees of supplement-industry companies (the first author works for Abinopharm). Elhassan et al. (2019), in 12 older men (NR 1 g daily for 21 days), showed that oral NR reaches muscle — NAD+ metabolites rose there — and lowered circulating inflammatory cytokines, though it did not change mitochondrial bioenergetics. That is the source of the “anti-inflammatory signature”: a result from 12 people and 3 weeks.
Function — what the meta-analyses say
When the randomised trials are added up, the picture differs from the advertisements. Prokopidis et al. (2025), in a systematic review with meta-analysis, gathered 10 RCTs (6 with NMN, 4 with NR) in people with a mean age of 60.9 to 83 years. NMN did not change the skeletal muscle index, handgrip strength, gait speed or the five-times chair-stand test; nor did it improve knee-extension strength or thigh muscle mass. NR lengthened walking distance only in patients with peripheral artery disease, and in people with mild cognitive impairment the performance scores were actually worse. The authors' conclusion: current evidence does not support NMN and NR for preserving muscle mass and function in adults over 60. Chen et al. (2024) gathered 8 RCTs of NMN (250–2,000 mg, from 14 days to 12 weeks, 342 middle-aged and older adults, mainly non-diabetic): no significant effect on fasting glucose, insulin, glycated haemoglobin, the HOMA-IR index or the lipid profile. So: biomarker yes, function no.
Conflicting trials — insulin sensitivity
A null result in meta-analyses does not mean nothing ever worked — the trials conflict, and both poles are worth showing. Yoshino et al. (2021), in the journal Science, gave NMN for 10 weeks to postmenopausal women with prediabetes who were overweight or obese: muscle insulin sensitivity measured by the most accurate method (the hyperinsulinaemic clamp) increased after NMN but not after placebo, and insulin signalling in muscle improved too. But Dollerup et al. (2018), in 40 obese, insulin-resistant men, gave NR (2,000 mg for 12 weeks) and with the same method found no improvement in insulin sensitivity, glucose production, energy expenditure or body composition — with good safety. The differences: a different precursor, a different sex, a different population. We do not average these results; they show that the effect — if it exists — is narrow and context-dependent.
Intravenous infusions — what happens during administration
A separate topic is the intravenous NAD+ infusions offered by wellness clinics. Reyna et al. (2026) reviewed the records of a commercial clinic: 6 people received 500 mg of NAD+ intravenously on four consecutive days, and 8 people 500 mg of NR intravenously. Everyone in the NAD+ group reported moderate to severe symptoms during the infusion: abdominal cramping, diarrhoea, nausea, vomiting, a faster heart rate, throat pain and a feeling of pressure in the chest. The symptoms ceased immediately once the infusion ended, and patients slowed the infusion themselves, so that an NAD+ infusion took on average 97 minutes versus 37 minutes for NR. The NR group felt only tingling of the tongue, jaw and arms and mild cramping. Liver and kidney markers did not change over 30 days. It is a retrospective study of 14 people — it does not say whether infusions do any good, but it documents that a reaction to intravenous NAD+ is the rule, not the exception; the authors note that formal studies of how the infusion rate affects symptoms do not exist.
Safety and the limits of the evidence
Oral NMN and NR were well tolerated in trials lasting up to 12 weeks: Martens et al. and Dollerup et al. recorded no serious adverse events, and Yi et al. no problems at doses up to 900 mg. There are no data from multi-year studies. The review by Braidy and Liu (2020), covering 147 papers (113 preclinical and 34 clinical), lists the potential risks of raising NAD+: accumulation of putatively toxic metabolites, promotion of tumour formation and of cellular senescence — and stresses that long-term human trials are still nascent. The cancer question is therefore unresolved, and in active cancer the very absence of safety data is an argument. Intravenous infusions without medical supervision are a bad idea for the reasons described above. There is also a conflict of interest in some of the trials: industry employees took part in the Yi et al. trial, and authors of the Trammell and Elhassan papers held shares in or advisory roles with ChromaDex, the supplier of NR. We deliberately give no methods of use and no doses.
The wider context — mitochondria and ageing
NAD+ precursors are the “substrate” approach to mitochondria and ageing. Other strategies described in this encyclopaedia are SS-31 (elamipretide), which stabilises the mitochondrial membrane and is the only compound in this group to have completed phase 3 trials, and MOTS-c, a peptide encoded in mitochondrial DNA for which there are as yet no data from administration to humans. By comparison, NAD+ today has the most human RCTs in the whole group — which is exactly why we know how modest the effect is.
Summary
NAD+ is a coenzyme consumed by the sirtuins, DNA-repair enzymes and CD38; NMN and NR are its precursors, which after oral intake reproducibly raise blood NAD+ — by tens of per cent to more than two-fold, depending on the dose. That is where the hard evidence ends. A meta-analysis of 10 RCTs in older adults showed no effect on muscle mass, grip strength, gait speed or chair-stand performance, and a meta-analysis of 8 NMN trials none on glucose, insulin, HbA1c or lipids. Individual trials give signals (insulin sensitivity in women with prediabetes, inflammatory cytokines in 12 older men, blood pressure in an exploratory analysis), but other, equally sound trials do not confirm them. Intravenous NAD+ causes unpleasant symptoms during infusion in almost everyone. State of the evidence: biomarker yes, function no — at least in trials lasting up to 12 weeks.
Sources
- Prokopidis K, Moriarty F, Bahat G, McLean J, Church DD, Patel HP. 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;16(3):e13799. PMID: 40275690. DOI: 10.1002/jcsm.13799. pubmed.ncbi.nlm.nih.gov/40275690
- Chen F, Zhou D, Kong AP, et al. Effects of Nicotinamide Mononucleotide on Glucose and Lipid Metabolism in Adults: A Systematic Review and Meta-analysis of Randomised Controlled Trials. Current Diabetes Reports. 2024;25(1):4. PMID: 39531138. DOI: 10.1007/s11892-024-01557-z. pubmed.ncbi.nlm.nih.gov/39531138
- Yoshino M, Yoshino J, Kayser BD, et al. Nicotinamide mononucleotide increases muscle insulin sensitivity in prediabetic women. Science. 2021;372(6547):1224–1229. PMID: 33888596. DOI: 10.1126/science.abe9985. pubmed.ncbi.nlm.nih.gov/33888596
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- Elhassan YS, Kluckova K, Fletcher RS, et al. Nicotinamide Riboside Augments the Aged Human Skeletal Muscle NAD+ Metabolome and Induces Transcriptomic and Anti-inflammatory Signatures. Cell Reports. 2019;28(7):1717–1728.e6. PMID: 31412242. DOI: 10.1016/j.celrep.2019.07.043. pubmed.ncbi.nlm.nih.gov/31412242
- Yi L, Maier AB, Tao R, et al. The efficacy and safety of β-nicotinamide mononucleotide (NMN) supplementation in healthy middle-aged adults: a randomized, multicenter, double-blind, placebo-controlled, parallel-group, dose-dependent clinical trial. GeroScience. 2023;45(1):29–43. PMID: 36482258. DOI: 10.1007/s11357-022-00705-1. pubmed.ncbi.nlm.nih.gov/36482258
- Trammell SA, Schmidt MS, Weidemann BJ, et al. Nicotinamide riboside is uniquely and orally bioavailable in mice and humans. Nature Communications. 2016;7:12948. PMID: 27721479. DOI: 10.1038/ncomms12948. pubmed.ncbi.nlm.nih.gov/27721479
- Reyna K, Heinzen G, Patel N, et al. Intravenous infusion of nicotinamide adenine dinucleotide (NAD+) versus nicotinamide riboside (NR): a retrospective tolerability pilot study in a real-world setting. Frontiers in Aging. 2026;7:1652582. PMID: 41704678. DOI: 10.3389/fragi.2026.1652582. pubmed.ncbi.nlm.nih.gov/41704678
- Braidy N, Liu Y. NAD+ therapy in age-related degenerative disorders: A benefit/risk analysis. Experimental Gerontology. 2020;132:110831. PMID: 31917996. DOI: 10.1016/j.exger.2020.110831. pubmed.ncbi.nlm.nih.gov/31917996
For in-vitro laboratory research only. It is not a human medicine and is not for treatment.