NAD+
NAD+ is a dinucleotide in which nicotinamide mononucleotide and adenosine monophosphate are joined through a pyrophosphate bridge (C21H27N7O14P2, molecular weight 663.4, PubChem CID 5892). It is not a peptide and not a drug candidate in the usual sense: it is a central metabolic cofactor present in every cell, cycling between oxidised NAD+ and reduced NADH as a hydride carrier, and simultaneously serving as a consumed substrate for enzymes that cleave its nicotinamide-ribose bond. NAD+ itself has no approved therapeutic indication in any jurisdiction, and the human literature attached to it is overwhelmingly about its oral precursors rather than the dinucleotide: nicotinamide riboside chloride, for instance, holds GRAS status and two New Dietary Ingredient notifications as a supplement ingredient, while the fate of NAD+ given directly to humans has been characterised in a single small intravenous pilot in 11 men. Tissue NAD+ declines with age in multiple model organisms, chiefly rodents, with far more limited human data; that observation drives most current research interest.
Information on this page is provided for laboratory research reference. The compound is not a drug, supplement, or medical product, and is not for human or veterinary use, ingestion, or consumption.
No reviewed report has been published for this product family yet. The molecular values opposite are public reference data, not results measured on a CRX sample.
Browse published reports →Two roles are firmly established. As a redox cofactor NAD+ accepts and donates hydride in glycolysis, the TCA cycle and oxidative phosphorylation, where it is recycled rather than consumed. As a signalling substrate it is destroyed: sirtuins, poly(ADP-ribose) polymerases, CD38 and SARM1 all cleave NAD+ and release nicotinamide, which ties the activity of those enzymes to cellular NAD+ availability. Isotope-tracer flux work in mice shows NAD+ turnover is fast and highly tissue-specific; cultured cells make NAD+ mainly from nicotinamide through the salvage pathway, while in mice de novo synthesis from tryptophan is confined largely to liver, which then exports nicotinamide to the rest of the body. What remains unsettled is the therapeutic premise. There is no human evidence that infused NAD+ reaches tissues intact — during a 6-hour infusion it is cleared from plasma completely for at least the first 2 hours, with a urinary metabolite profile the authors read as glycohydrolase and pyrophosphatase cleavage — and in mice orally administered precursors are largely degraded to nicotinamide in the liver before reaching peripheral tissues, so raising a blood NAD+ measurement and restoring NAD+ inside a target tissue are not the same claim, and the second has been demonstrated far less often than the first.1,2,3,5,6,7
NAD+-dependent protein deacylases; yeast and mouse Sir2 were shown to be NAD-dependent histone deacetylases, with NAD+ a consumed co-substrate rather than a modulator, which is the mechanistic basis for coupling sirtuin activity to metabolic state. In mice a fall in nuclear NAD+ impairs SIRT1 signalling and disrupts nuclear-mitochondrial communication.8,9
DNA-damage-activated NAD+ consumers. Isotope-tracer flux work identifies PARPs together with sirtuins as the dominant route of NAD+ consumption in cultured cell lines.2,6
Ecto-NAD glycohydrolase whose expression and activity rise with age in mice. In mice CD38 is required for the age-related decline in NAD+ and the mitochondrial dysfunction that follows it, and is the main enzyme degrading nicotinamide mononucleotide in vivo.10
TIR-domain NADase implicated in axon self-destruction. In cultured mouse neurons, dimerisation of the SARM1 TIR domain triggers rapid axonal NAD+ breakdown and local axon degeneration, and boosting NAD+ synthesis counteracts it; the authors propose that this NAD+ depletion explains the axon protection seen in Wallerian degeneration slow (Wld-s) mice.11
Metabolic & weight
In a pilot in 11 healthy men aged 30-55 (8 given 750 mg NAD+ intravenously over 6 hours, 3 given saline), plasma NAD+ and its metabolites did not change for the first 2 hours, indicating essentially complete removal from plasma; NAD+ was then about 398% above baseline at 6 hours and still raised at 8 hours versus saline. NAD+ and methylnicotinamide, but not nicotinamide, appeared in urine by 6 hours.5
In a 10-week randomised, double-blind, placebo-controlled trial in 25 postmenopausal women with prediabetes who were overweight or obese, insulin-stimulated muscle glucose disposal on hyperinsulinaemic-euglycaemic clamp rose 25 ± 7% from baseline with the NAD+ precursor nicotinamide mononucleotide (250 mg/day, n = 13, p < 0.01) and did not change with placebo (n = 12). Hepatic and adipose insulin sensitivity, body composition, muscle mitochondrial respiration and physical function were unchanged, as was muscle NAD+ content.13
In a 12-week randomised, double-blind, parallel-group trial in 40 obese, insulin-resistant men aged 40-70, nicotinamide riboside 2,000 mg per day produced no improvement over placebo in clamp-measured insulin sensitivity, endogenous glucose production, glucose disposal or oxidation, resting energy expenditure, lipolysis, lipid oxidation or body composition.14
In an 8-week randomised, double-blind, placebo-controlled trial in 140 healthy overweight adults aged 40-60 (35 per group), whole-blood NAD+ rose dose-dependently by 22%, 51% and 142% in the 100 mg, 300 mg and 1,000 mg daily nicotinamide riboside groups within 2 weeks and stayed elevated, with no LDL cholesterol elevation and no dysregulation of one-carbon metabolism relative to placebo.4
In wild-type C57BL/6N mice given nicotinamide mononucleotide orally for 12 months during normal ageing, treatment suppressed age-associated body weight gain, enhanced energy metabolism and physical activity, improved insulin sensitivity and plasma lipid profile, ameliorated eye function and enhanced skeletal muscle mitochondrial oxidative metabolism, without obvious toxicity.15
Longevity & cellular ageing
In a 2 x 6-week randomised, double-blind, placebo-controlled crossover trial in 30 healthy adults aged 55-79 (24 completed), nicotinamide riboside 500 mg twice daily raised peripheral blood mononuclear cell NAD+ about 60% over placebo. A mean 3.9 mmHg fall in systolic blood pressure was not significant after multiple-comparison correction; a 9 mmHg systolic difference in participants with elevated or stage 1 hypertension was an exploratory post-hoc finding.16
In a 2025 systematic review and meta-analysis of randomised placebo-controlled trials in adults with mean ages from 60.9 to 83 years, nicotinamide mononucleotide had no effect on skeletal muscle index (3 trials; mean difference -0.42, 95% CI -0.99 to 0.14), handgrip strength, gait speed (4 trials; mean difference -0.01, 95% CI -0.08 to 0.06) or five-time chair stand time; nicotinamide riboside was covered only by narrative synthesis, where it was associated with longer 6-minute walking distance in peripheral artery disease but with lower short physical performance battery scores and slower chair stands in mild cognitive impairment. The authors concluded that current evidence does not support nicotinamide mononucleotide or nicotinamide riboside for preserving muscle mass and function in adults with mean age over 60.17
In aged mice, the NAD+ precursor nicotinamide riboside induced the mitochondrial unfolded protein response and prohibitin synthesis, rejuvenated muscle stem cells, delayed senescence of neural and melanocyte stem cells and increased lifespan; it also prevented muscle stem cell senescence in mdx mice, a model of muscular dystrophy.18
Cognition & neuroprotection
In the NADPARK phase 1 trial, 30 newly diagnosed, treatment-naive patients with Parkinson's disease received 1,000 mg nicotinamide riboside or placebo for 30 days; cerebral NAD measured by 31-phosphorus magnetic resonance spectroscopy rose significantly but variably, and only recipients whose brain NAD actually rose showed altered cerebral metabolism on FDG-PET, associated with mild clinical improvement.19
In the DNA-repair-deficient 3xTgAD/Polbeta+/- mouse model of Alzheimer's disease, which has a reduced cerebral NAD+/NADH ratio, nicotinamide riboside normalised that ratio, reduced phosphorylated tau, DNA damage, neuroinflammation and hippocampal neuronal apoptosis, improved cognition on multiple behavioural tests and restored hippocampal synaptic plasticity, while leaving amyloid beta accumulation unchanged.20
Inflammation & immune
In a randomised, double-blind, placebo-controlled crossover trial in 12 aged men (median age 75) given 1 g nicotinamide riboside daily for 21 days, skeletal muscle NAD+ metabolites rose and serum IL-6, IL-5, IL-2 and TNF-alpha fell relative to baseline, though for IL-2 and TNF-alpha the comparison against the placebo phase was complicated by carry-over. Muscle mitochondrial bioenergetics were unchanged, and the transcriptome showed downregulation of energy metabolism and mitochondrial pathways.21
In 19 hospitalised patients with stage D heart failure compared against 19 healthy participants, patient peripheral blood mononuclear cells showed reduced respiratory capacity and elevated proinflammatory cytokine gene expression; in a separate uncontrolled, open-label before-and-after group of only 4 patients, 5 to 9 days of oral nicotinamide riboside increased PBMC respiration and reduced proinflammatory cytokine gene expression.22
What investigators recorded alongside the results above, at the rates their papers state.
No adverse events observed with intravenous NAD+ itself. At 8 hours the liver enzyme activities GGT, LD and AST had fallen modestly and total bilirubin had risen by 2.75 micromol/L; the authors judged none of these changes clinically significant. This is the entire published human safety record for infused NAD+ — 8 exposed men over a single 6-hour session against 3 saline controls — and it supports no conclusion about repeated or longer exposure.5
0 of 8 men receiving NAD+ and 0 of 3 receiving saline
No moderate or severe adverse events at the highest nicotinamide riboside dose yet tested in a controlled trial (3,000 mg per day, above the 2,000 mg per day previously studied); mild adverse events did not differ from placebo. Nicotinamide riboside recipients showed a slight initial rise in serum homocysteine, though methyl donor pool integrity was preserved.23
0 moderate or severe events among 10 participants on nicotinamide riboside and 10 on placebo over 4 weeks
Mild treatment-emergent adverse events including nausea, flushing, leg cramps and increased bruising during the nicotinamide riboside phase, and headache, skin rash, flushing, fainting and drowsiness during the placebo phase; no serious adverse events, and clinical laboratory values stayed within normal reference ranges in both phases. Both study withdrawals for side effects occurred during placebo, not nicotinamide riboside.16
14 events reported by 7 of 30 randomised participants, all mild; 2 of 30 withdrew for side effects, both while on placebo
No reports of flushing and no significant difference in adverse events between nicotinamide riboside and placebo, or between dose groups; LDL cholesterol was not elevated and one-carbon metabolism was not dysregulated. Flushing — the characteristic limitation of nicotinic acid — did not occur at any dose.4
no significant between-group difference across 140 participants over 8 weeks; 1 withdrawal for an adverse event (nausea), in the placebo group
No adverse events and no abnormalities in standard blood tests in either group during 10 weeks of nicotinamide mononucleotide or placebo.13
0 reported events across 13 participants on nicotinamide mononucleotide and 12 on placebo over 10 weeks
Absence of long-term human safety data for NAD+ itself. A 2024 systematic review of randomised trials of NAD+ and NADH formulations across chronic fatigue syndrome, Parkinson's disease, Alzheimer's disease, prediabetes, overweight and older adults identified only 10 studies totalling 489 participants; it reported supplementation as safe and well tolerated with a low incidence of side effects, while noting that every included study reported some side effects — most commonly muscle pain, nervous disorders, fatigue, sleep disturbance and headache — none of which posed a serious risk. Beyond a single 6-hour infusion pilot, the tolerability record above is a record of oral precursors and NADH formulations rather than of infused NAD+.5,24
10 randomised trials, 489 participants total, across mixed clinical conditions
- 1.NAD⁺ in aging, metabolism, and neurodegeneration. · Science · 2015 · PMID 26785480
- 2.NAD+ metabolism and its roles in cellular processes during ageing. · Nature Reviews Molecular Cell Biology · 2021 · PMID 33353981
- 3.NAD+ homeostasis in health and disease. · Nature Metabolism · 2020 · PMID 32694684
- 4.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 · 2019 · PMID 31278280
- 5.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 · 2019 · PMID 31572171
- 6.Quantitative Analysis of NAD Synthesis-Breakdown Fluxes. · Cell Metabolism · 2018 · PMID 29685734
- 7.Nicotinamide riboside is uniquely and orally bioavailable in mice and humans. · Nature Communications · 2016 · PMID 27721479
- 8.Transcriptional silencing and longevity protein Sir2 is an NAD-dependent histone deacetylase. · Nature · 2000 · PMID 10693811
- 9.Declining NAD(+) induces a pseudohypoxic state disrupting nuclear-mitochondrial communication during aging. · Cell · 2013 · PMID 24360282
- 10.CD38 Dictates Age-Related NAD Decline and Mitochondrial Dysfunction through an SIRT3-Dependent Mechanism. · Cell Metabolism · 2016 · PMID 27304511
- 11.SARM1 activation triggers axon degeneration locally via NAD⁺ destruction. · Science · 2015 · PMID 25908823
- 12.Circadian clock feedback cycle through NAMPT-mediated NAD+ biosynthesis. · Science · 2009 · PMID 19299583
- 13.Nicotinamide mononucleotide increases muscle insulin sensitivity in prediabetic women. · Science · 2021 · PMID 33888596
- 14.A randomized placebo-controlled clinical trial of nicotinamide riboside in obese men: safety, insulin-sensitivity, and lipid-mobilizing effects. · The American Journal of Clinical Nutrition · 2018 · PMID 29992272
- 15.Long-Term Administration of Nicotinamide Mononucleotide Mitigates Age-Associated Physiological Decline in Mice. · Cell Metabolism · 2016 · PMID 28068222
- 16.Chronic nicotinamide riboside supplementation is well-tolerated and elevates NAD+ in healthy middle-aged and older adults. · Nature Communications · 2018 · PMID 29599478
- 17.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 · PMID 40275690
- 18.NAD⁺ repletion improves mitochondrial and stem cell function and enhances life span in mice. · Science · 2016 · PMID 27127236
- 19.The NADPARK study: A randomized phase I trial of nicotinamide riboside supplementation in Parkinson's disease. · Cell Metabolism · 2022 · PMID 35235774
- 20.NAD+ supplementation normalizes key Alzheimer's features and DNA damage responses in a new AD mouse model with introduced DNA repair deficiency. · Proceedings of the National Academy of Sciences of the United States of America · 2018 · PMID 29432159
- 21.Nicotinamide Riboside Augments the Aged Human Skeletal Muscle NAD+ Metabolome and Induces Transcriptomic and Anti-inflammatory Signatures. · Cell Reports · 2019 · PMID 31412242
- 22.Boosting NAD level suppresses inflammatory activation of PBMCs in heart failure. · The Journal of Clinical Investigation · 2020 · PMID 32790648
- 23.NR-SAFE: a randomized, double-blind safety trial of high dose nicotinamide riboside in Parkinson's disease. · Nature Communications · 2023 · PMID 38016950
- 24.Evaluation of safety and effectiveness of NAD in different clinical conditions: a systematic review. · American Journal of Physiology. Endocrinology and Metabolism · 2024 · PMID 37971292
- 25.An open-label, non-randomized study of the pharmacokinetics of the nutritional supplement nicotinamide riboside (NR) and its effects on blood NAD+ levels in healthy volunteers. · PLoS One · 2017 · PMID 29211728
- 26.Effect of oral administration of nicotinamide mononucleotide on clinical parameters and nicotinamide metabolite levels in healthy Japanese men. · Endocrine Journal · 2020 · PMID 31685720