NAD+

01 · What it is

NAD+ is not a peptide. It is nicotinamide adenine dinucleotide — a dinucleotide coenzyme, present in every living cell, and one of the most-studied molecules in biochemistry. It appears in this project because it is sold alongside research peptides and discussed in the same terms, not because it belongs to the same chemical class.

It has the largest randomised human literature of any compound in this family. Almost none of that literature is about NAD+.

The molecule carries electrons in redox reactions and is consumed as a substrate by three families of enzymes — the sirtuins, the PARPs, and CD38 — which cleave it to do their work. Because those enzymes consume it rather than catalyse it back, cells must continuously resynthesise NAD+, and the rate at which they can do so is proposed to fall with age. That proposition is the entire commercial and scientific rationale for supplementing it.

The problem is delivery, and it shapes everything that follows. NAD+ is a large, charged molecule that does not readily cross cell membranes. The practical response has been to give precursors instead — nicotinamide riboside (NR) and nicotinamide mononucleotide (NMN), both taken orally, both converted to NAD+ inside cells. A PubMed search for randomised or placebo-controlled human studies of these two precursors returns 92 records. A search for intravenous NAD+ pharmacokinetics in humans returns 24, most of which are about something else.

So the evidence base has a shape worth stating plainly, and it is the thesis of this guide:

The biomarker moves almost every time. The clinical outcome moves only sometimes.

Oral NR raised NAD+ in healthy middle-aged and older adults in a randomised placebo-controlled trial ², in aged human skeletal muscle with accompanying transcriptomic and anti-inflammatory signatures ⁴, and in Parkinson’s disease, where it augmented cerebral NAD levels and altered cerebral metabolism ⁹. Oral NMN raised blood NAD+ in healthy subjects ¹⁰, in healthy older men ¹¹, and in older adults ¹⁹. That part of the literature is consistent.

The outcomes are not. NMN increased muscle insulin sensitivity in prediabetic women, published in Science ⁶. It enhanced aerobic capacity in amateur runners ⁷. It maintained walking speed and improved sleep quality in older adults ¹⁹. Against that: NR for peripheral artery disease ¹⁸, NR for airway inflammation in COPD ²⁰, NR in older adults with mild cognitive impairment ¹⁷, and NR with coenzyme Q10 in chronic kidney disease ¹⁵ were each conducted as randomised controlled trials in real disease populations, and the 2026 systematic review of the whole field concludes that clinical benefits remain variable and context-dependent ²⁵.

NAD+ itself has now been tested. A randomised, placebo-controlled trial examined nicotinamide adenine dinucleotide in heart failure caused by ischaemic cardiomyopathy, and its own authors note that research investigating this effect in human patients is limited ²¹. That is the compound this guide is named for, and it has one indexed randomised trial to the precursors’ dozens.

02 · Evidence at a glance

Evidence grade

Mixed Evidence — extensive human randomised data, consistent on the biomarker, inconsistent on outcomes ²⁵

Chemical class

A dinucleotide coenzyme, not a peptide

Consumed by

Sirtuins, PARPs and CD38, which cleave it rather than recycle it

Delivery problem

Large and charged; poor membrane permeability

What most human trials actually test

Nicotinamide riboside (NR) and nicotinamide mononucleotide (NMN), taken orally

Randomised or placebo-controlled human records for the precursors

92

Randomised trials of NAD+ itself

One indexed, in ischaemic cardiomyopathy ²¹

Effect on the biomarker

Consistent — blood and tissue NAD+ rise ^2,4,10,11,19

Clearest positive outcome

Muscle insulin sensitivity in prediabetic women, Science ⁶

Trials in disease populations

PAD ¹⁸, COPD ²⁰, mild cognitive impairment ¹⁷, CKD ¹⁵, Parkinson’s ⁹

Systematic review verdict

Benefits variable and context-dependent ²⁵

Long-term human safety data

Yes, for NR specifically ³

Regulatory status

Sold as a dietary supplement in the US; not an approved drug for any age-related indication

03 · Mechanism of action

What NAD+ does, and why it runs down

NAD+ has two distinct roles, and confusing them is the commonest error in discussion of this compound.

The first is catalytic. In redox reactions NAD+ accepts a hydride to become NADH and gives it back again; the molecule is not consumed. Glycolysis, the citric acid cycle and oxidative phosphorylation all depend on this cycling, and a cell’s NAD+/NADH ratio is a core metabolic variable.

The second is consumptive, and it is the one that matters here. Sirtuins remove acetyl groups from proteins using NAD+ as a co-substrate and destroying a molecule of it each time. PARP enzymes, activated by DNA damage, consume NAD+ to build poly-ADP-ribose chains. CD38, an ectoenzyme whose expression rises with age and inflammation, degrades NAD+ directly. Each of these leaves nicotinamide behind, which must be salvaged back into NAD+ at metabolic cost.

The ageing hypothesis follows: accumulated DNA damage activates PARPs, inflammation raises CD38, salvage capacity does not keep up, and NAD+ falls. Supplementation aims to restore the pool.

The hypothesis is coherent and the decline has been measured in tissue. Whether restoring the pool restores function is the question the trials in Section 4 were built to answer, and their answers disagree.

Why precursors rather than the molecule

NAD+ is a dinucleotide — two nucleotides joined through their phosphates — carrying multiple negative charges at physiological pH. Molecules of that description do not diffuse across membranes.

Nicotinamide riboside and nicotinamide mononucleotide are smaller pieces of the same pathway. Both raise intracellular NAD+ after oral administration, which is established by the trials that measured it ^2,4,10,11,19. Whether NMN enters cells intact or is first dephosphorylated to NR at the cell surface has been argued in the field and is not settled by anything in the human literature.

Intravenous administration of NAD+ itself bypasses the gut but not the membrane. A 2026 systematic review of the field notes the existence of an intravenous NAD+ pharmacokinetic pilot study among the human evidence it assembled ²², and a 2026 review states that oral precursors raise circulating NAD+ while treating intravenous administration as a separate and less established question ²⁵.

A compound given intravenously reaches the bloodstream. Reaching the inside of a cell, where every proposed mechanism operates, is a different problem, and the human data addressing it is thin.

New chemistry aimed at the same problem

The delivery problem is being worked on. A 2026 paper describes preclinical pharmacological profiling of an intravenous agent designated MP-04, reporting rapid dose-dependent increases in intracellular NAD+ across human cell types, markedly greater potency than NR, and sustained elevation of NAD+ and NADH in rat blood, liver and other tissues after intravenous administration ²³.

Preclinical, and a different molecule again — but it is the clearest acknowledgement in the literature that neither oral precursors nor intravenous NAD+ has solved intracellular delivery well.

04 · Key research findings

The biomarker results, which agree. Six weeks of NR was well tolerated and elevated NAD+ in healthy middle-aged and older adults in a randomised double-blind placebo-controlled crossover design ². NR augmented the aged human skeletal muscle NAD+ metabolome and induced transcriptomic and anti-inflammatory signatures ⁴. Oral NMN was safe and efficiently increased blood NAD+ in healthy subjects ¹⁰; chronic NMN elevated blood NAD+ and altered muscle function in healthy older men ¹¹; NMN increased blood NAD levels in older adults ¹⁹. In Parkinson’s disease, NR augmented cerebral NAD levels and affected cerebral metabolism in a double-blinded phase 1 trial ⁹.

Across two precursors, multiple countries, healthy and diseased populations, the pharmacodynamic result is reproducible: oral precursors raise NAD+. That is a real and unusual level of consistency for anything in this project.

The positive outcome results. A ten-week trial found NMN increased muscle insulin sensitivity in prediabetic women, published in Science ⁶. A six-week randomised double-blind placebo-controlled four-arm trial in 48 recreationally trained runners found NMN enhanced aerobic capacity ⁷. Twelve weeks of NMN in older adults increased blood NAD levels, maintained walking speed and improved sleep quality ¹⁹. A twelve-week randomised double-blind placebo-controlled study in 108 older Japanese adults examined sleep quality, fatigue and physical performance with time-of-day-dependent intake ⁸. NMN was studied in older patients with diabetes and impaired physical performance ¹², and a randomised multicentre double-blind placebo-controlled dose-dependent trial assessed NMN in healthy middle-aged adults ¹³.

The insulin sensitivity result is the single strongest positive finding in this file: a functional endpoint, in a defined population, in a top-tier journal. It is also one trial, in one population, of one precursor.

The disease trials, which are less encouraging. The NICE trial randomised 90 people with peripheral artery disease to NR ¹⁸. A randomised double-blind placebo-controlled trial tested NR for airway inflammation in COPD ²⁰. A randomised placebo-controlled trial examined NR in older adults with mild cognitive impairment, described by its authors as a pilot ¹⁷. A randomised placebo-controlled double-blind crossover trial tested coenzyme Q10 and NR for exercise tolerance and metabolic profile in chronic kidney disease ¹⁵. A physiologic study administered a β-nicotinamide mononucleotide preparation to thirty overweight or obese middle-aged and older adults ¹⁶. Twelve weeks of NMN was assessed for NAD metabolism and arterial stiffness ¹⁴.

Five randomised trials in five disease populations. The 2026 systematic review’s summary of the field — benefits variable and context-dependent ²⁵ — is the accurate reading of this set, and it is the reading this guide adopts.

NAD+ itself. A randomised placebo-controlled trial assessed nicotinamide adenine dinucleotide in heart failure caused by ischaemic cardiomyopathy, with the authors observing that human research on this question is limited despite extensive animal work suggesting improved cardiac bioenergetics ²¹.

One randomised trial of the actual molecule, published in 2026, nearly a decade after the precursor trials began. That gap is the central fact about this compound’s evidence base.

Animal work on parenteral NAD+. In swine, intravenous NAD+ was given after cardiac arrest and cardiopulmonary resuscitation, with the protocol used in that study delivering 20 mg/kg over one hour beginning five minutes after resuscitation, and reported reversal of ferroptosis-related changes in lung injury ²⁴. In a 2026 study of calcific aortic valve disease, NMN supplementation was tested early versus late alongside UK Biobank proteomics and Mendelian randomisation analysis of circulating NAMPT and aortic stenosis ²⁶.

Historical parenteral work. An open prospective study of parenteral NADH — the reduced form, a different molecule again — in 15 patients with Parkinson’s disease reported clinical improvement attributed partly to stimulation of endogenous levodopa biosynthesis ¹.

Cited here because it is often invoked as evidence for parenteral NAD, and it concerns NADH, was open-label, and enrolled fifteen people in 1996.

Long-term safety. A randomised double-blind placebo-controlled trial of long-term nicotinamide riboside chloride administration in healthy overweight adults supported the derivation of a tolerable upper intake limit based on human data ³. Six weeks of NR in healthy obese humans altered body composition and skeletal muscle acetylcarnitine concentrations ⁵.

05 · Evidence overview

06 · Safety profile

Animal data. Extensive, and largely reassuring at the doses studied. The swine cardiac arrest work delivered intravenous NAD+ without reported acute toxicity ²⁴.

Human data. This is the best human safety dataset in Family E after SS-31, and it is better in one respect: it comes from healthy volunteers as well as patients. A randomised double-blind placebo-controlled trial of long-term NR supported deriving a tolerable upper intake limit from human data ³. Multiple trials describe oral NR and NMN as well tolerated across six to twelve weeks ^2,10,13. Trials have been conducted in populations with peripheral artery disease ¹⁸, COPD ²⁰, chronic kidney disease ¹⁵, Parkinson’s disease ⁹, diabetes ¹² and mild cognitive impairment ¹⁷ without reports of serious harm attributable to the intervention in the abstracts reviewed here.

What is genuinely unknown. Duration: the longest randomised exposures are measured in weeks to months, and the proposition being sold is lifelong use. Whether raising NAD+ has consequences for cells that should not be helped — sirtuins, PARPs and CD38 all operate in tumour biology, and PARP inhibition is an established anticancer strategy, so increasing the substrate of the enzyme that inhibitors target is a question the trial literature has not addressed. The pharmacology of intravenous NAD+ specifically, where a pilot exists ²² and a randomised trial has only just appeared ²¹. Whether the intracellular concentrations achieved by any route are those at which the proposed mechanisms operate, given that the delivery problem remains unsolved enough to justify new chemistry ²³. Purity and identity of supplement-channel material, which is regulated as a food rather than a drug in the United States and for which no independent published analysis was located for this guide. And the composition of intravenous preparations administered outside clinical trials, about which nothing is published.

07 · US regulatory status

Current as of 6 September 2026. NAD+ is not approved as a drug in the United States for any age-related indication and is not a controlled substance.

Nicotinamide riboside is marketed in the United States as a dietary supplement ingredient — a regulatory category that requires safety but not demonstrated efficacy, and which does not involve approval of any claim about treating or preventing disease. Long-term human safety work on a specific NR product supported the derivation of a tolerable upper intake limit ³, which is a nutritional rather than a pharmaceutical standard.

Nicotinamide mononucleotide’s status as a supplement ingredient in the United States has been contested, and this guide does not characterise its current position, because doing so accurately would require current agency records that have not been consulted for this piece. That question is logged.

Intravenous NAD+ administered in clinics is a different matter again: an injectable preparation of a substance with no approved injectable form. No indexed publication describes the composition or quality standards of the preparations used in that setting.

Under the World Anti-Doping Code, NAD+ and its precursors do not appear as named prohibited substances in the classes reviewed for this guide. Competitors should consult the current Prohibited List directly rather than rely on secondary summaries, including this one.

08 · Limitations of the evidence

1. Most of the evidence is for a different molecule than the one named on the product. Twenty randomised human trials of oral NR and NMN ^2–20; one of NAD+ itself ²¹. Anyone citing “the NAD+ trials” in support of intravenous or oral NAD+ is citing precursor trials, and the two are not interchangeable — the whole reason precursors exist is that NAD+ does not get into cells.
2. The biomarker and the outcome come apart, and this is the central finding. Blood and tissue NAD+ rise reliably ^2,4,10,11,19. Clinical benefit is variable and context-dependent by the assessment of the field’s own systematic review ²⁵. A compound that reliably moves a surrogate and unreliably moves an outcome is the classic profile of a surrogate that does not predict.
3. The positive results cluster in healthy or pre-disease populations; the disease trials are less favourable. Insulin sensitivity in prediabetic women ⁶, aerobic capacity in trained runners ⁷, sleep and walking speed in older adults ¹⁹ — against randomised trials in PAD ¹⁸, COPD ²⁰, MCI ¹⁷ and CKD ¹⁵.
4. Trial durations are short relative to the proposition. Six to twelve weeks is typical ^2,5,7,8,14. Nothing establishes what years of supplementation do.
5. The oncology question is unaddressed. NAD+ is the substrate of PARP enzymes, and PARP inhibitors are approved anticancer drugs. No trial in this literature was designed to detect an effect on tumour biology in either direction, and the reviews do not resolve it.
6. Intravenous administration has almost no human evidence and is the route most heavily commercialised. One pharmacokinetic pilot noted in a systematic review ²² and one randomised trial in ischaemic cardiomyopathy ²¹. The gap between what is sold by infusion and what has been studied by infusion is the largest such gap in this family.
7. NADH is not NAD+, and the 1996 Parkinson’s study is frequently cited as though it were. That study used the reduced form, was open-label, and enrolled fifteen patients ¹.
8. Supplement-channel material is not pharmaceutical material. US dietary supplement regulation does not require pre-market demonstration of identity or potency to a drug standard, and no independent published analysis of commercial NAD+, NR or NMN products was located for this guide.
9. Publication and sponsorship patterns were not assessed here. Several trials in this literature involve commercial products by name ^3,16, which is normal and disclosed, and this guide has not attempted to weight results by funding source.
10. The delivery problem is unsolved, and the field says so. New intravenous chemistry is being developed specifically because existing options achieve intracellular NAD+ elevation poorly ²³.

09 · References

1. Kuhn W, Müller T, Winkel R, Danielczik S, Gerstner A, Häcker R, Mattern C, Przuntek H. Parenteral application of NADH in Parkinson’s disease: clinical improvement partially due to stimulation of endogenous levodopa biosynthesis. J Neural Transm (Vienna). 1996;103(10):1187–1193.

   PMID 9013405 ↗

2. Martens CR, Denman BA, Mazzo MR, et al. Chronic nicotinamide riboside supplementation is well-tolerated and elevates NAD+ in healthy middle-aged and older adults. Nat Commun. 2018 Mar 29;9(1):1286.

   PMID 29599478 ↗

3. Conze D, Brenner C, Kruger CL. 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. Sci Rep. 2019 Jul 5;9(1):9772.

   PMID 31278280 ↗

4. 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 Rep. 2019 Aug 13;28(7):1717–1728.e6.

   PMID 31412242 ↗

5. Remie CME, Roumans KHM, Moonen MPB, et al. Nicotinamide riboside supplementation alters body composition and skeletal muscle acetylcarnitine concentrations in healthy obese humans. Am J Clin Nutr. 2020 Aug 1;112(2):413–426.

   PMID 32320006 ↗

6. Yoshino M, Yoshino J, Kayser BD, et al. Nicotinamide mononucleotide increases muscle insulin sensitivity in prediabetic women. Science. 2021 Jun 11;372(6547):1224–1229.

   PMID 33888596 ↗

7. Liao B, Zhao Y, Wang D, Zhang X, Hao X, Hu M. Nicotinamide mononucleotide supplementation enhances aerobic capacity in amateur runners: a randomized, double-blind study. J Int Soc Sports Nutr. 2021 Jul 8;18(1):54.

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8. Kim M, Seol J, Sato T, Fukamizu Y, Sakurai T, Okura T. Effect of 12-week intake of nicotinamide mononucleotide on sleep quality, fatigue, and physical performance in older Japanese adults. Nutrients. 2022 Feb 11;14(4):755.

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9. Brakedal B, Dölle C, Riemer F, et al. The NADPARK study: a randomized phase I trial of nicotinamide riboside supplementation in Parkinson’s disease. Cell Metab. 2022 Mar 1;34(3):396–407.e6.

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10. Okabe K, Yaku K, Uchida Y, Fukamizu Y, Sato T, Sakurai T, Tobe K, Nakagawa T. Oral administration of nicotinamide mononucleotide is safe and efficiently increases blood nicotinamide adenine dinucleotide levels in healthy subjects. Front Nutr. 2022 Apr 11;9:868640.

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11. Igarashi M, Nakagawa-Nagahama Y, Miura M, et al. Chronic nicotinamide mononucleotide supplementation elevates blood nicotinamide adenine dinucleotide levels and alters muscle function in healthy older men. NPJ Aging. 2022 May 1;8(1):5.

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12. Akasaka H, Nakagami H, Sugimoto K, et al. Effects of nicotinamide mononucleotide on older patients with diabetes and impaired physical performance: a prospective, placebo-controlled, double-blind study. Geriatr Gerontol Int. 2023 Jan;23(1):38–43.

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13. 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 Feb;45(1):29–43.

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14. Katayoshi T, Uehata S, Nakashima N, et al. Nicotinamide adenine dinucleotide metabolism and arterial stiffness after long-term nicotinamide mononucleotide supplementation: a randomized, double-blind, placebo-controlled trial. Sci Rep. 2023 Feb 16;13(1):2786.

    PMID 36797393 ↗

15. Ahmadi A, Begue G, Valencia AP, et al. Randomized crossover clinical trial of coenzyme Q10 and nicotinamide riboside in chronic kidney disease. JCI Insight. 2023 Jun 8;8(11):e167274.

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16. Pencina KM, Valderrabano R, Wipper B, et al. Nicotinamide adenine dinucleotide augmentation in overweight or obese middle-aged and older adults: a physiologic study. J Clin Endocrinol Metab. 2023 Jul 14;108(8):1968–1980.

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17. Orr ME, Kotkowski E, Ramirez P, et al. A randomized placebo-controlled trial of nicotinamide riboside in older adults with mild cognitive impairment. Geroscience. 2024 Feb;46(1):665–682.

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18. McDermott MM, Martens CR, Domanchuk KJ, et al. Nicotinamide riboside for peripheral artery disease: the NICE randomized clinical trial. Nat Commun. 2024 Jun 13;15(1):5046.

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19. Morifuji M, Higashi S, Ebihara S, Nagata M. 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 Oct;46(5):4671–4688.

    PMID 38789831 ↗

20. Norheim KL, Ben Ezra M, Heckenbach I, et al. Effect of nicotinamide riboside on airway inflammation in COPD: a randomized, placebo-controlled trial. Nat Aging. 2024 Dec;4(12):1772–1781.

    PMID 39548320 ↗

21. Yu X, Xu J, Cao J, et al. Effect of nicotinamide adenine dinucleotide on heart failure caused by ischemic cardiomyopathy: a randomized, placebo-controlled trial. Am J Cardiovasc Drugs. 2026 Jan;26(1):97–106.

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22. Gallagher C, Emmanuel OO. NAD+ supplementation for anti-aging and wellness: a PRISMA-guided systematic review of preclinical and clinical evidence. Ageing Res Rev. 2026 Apr;116:103057.

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23. Ghosh A, Pranesh G, Zachariah N, et al. Pharmacological profiling of intravenous MP-04: sustained NAD+ augmentation, immune modulation, and renal protection in preclinical models. Front Pharmacol. 2026 Jun 10;17:1832979.

    PMID 42358367 ↗

24. Chen M, Hu Y, Yang X, Lai L, Liu M, Liu Y, Xu J, Lan P. Effects and mechanisms of NAD+ on lung injury after cardiac arrest and cardiopulmonary resuscitation in swine. Shock. 2026 Jul 1;66(1):183–191.

    PMID 42053361 ↗

25. Pandolfi S, Ghezzi C, Björklund G, Metalla M, Paone FM, Chirumbolo S. NAD+ biology and supplementation: from mechanisms to clinical perspectives. Mol Biol Rep. 2026 Jul 23;53(1):1249.

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26. Qian X, Xu L, Zheng Y, et al. Senescence-associated metabolic alterations aggravate calcific aortic valve disease. Eur Heart J. 2026 Aug 7;47(30):4133–4153.

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