NAD+ and Its Precursors in Human Trials: What Was Administered and What Was Measured

Almost no human trial has administered NAD+ itself. The clinical literature is about precursors — nicotinamide riboside, nicotinamide mononucleotide and nicotinamide — and this article keeps them separate, trial by trial.

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The single most important thing to establish about this literature is what the trials actually gave people, because it is almost never NAD+ itself.

Four distinct molecules are routinely discussed as though they were one subject:

  • NAD+ — nicotinamide adenine dinucleotide, the dinucleotide itself.
  • Nicotinamide riboside (NR) — a precursor, and the one with the longest randomised record in humans.
  • Nicotinamide mononucleotide (NMN) — a precursor one step further along the same route.
  • Nicotinamide (Nam) — the simplest precursor, a form of vitamin B3.

These are chemically distinct compounds that enter NAD+ biosynthesis at different points, are absorbed differently, and — as a 2026 randomised comparison showed — do not produce the same result in people. A finding for one is not a finding for another, and a finding for a precursor is not a finding about administering NAD+.

This article separates them. It sets out what has been administered to humans, in what trials, with what endpoints and what results, and what the record does not contain. It describes published research and contains no guidance of any kind on handling any material.

The biochemistry, and why a decline was proposed

In vitro research

NAD+ is a co-substrate for enzymes including the sirtuins and the poly-ADP-ribose polymerases, and its metabolism and roles in cellular processes during ageing have been reviewed in detail [8]. The proposition that drives the entire field is that tissue NAD+ falls with age and that raising it would matter.

Two pieces of laboratory work define how that proposition should be read. First, the proposed mechanism of decline is consumption rather than failure of synthesis: CD38, an NAD+-consuming enzyme, has been described as dictating age-related NAD decline and mitochondrial dysfunction through an SIRT3-dependent mechanism [1]. If the problem is consumption, supplying more substrate is one strategy among several and not obviously the best one. Second, synthesis and breakdown fluxes have been quantified directly [6], which is what makes it possible to say anything quantitative about turnover rather than about concentrations alone.

The enzymology of precursor handling also differs between the precursors: NRK1 controls nicotinamide mononucleotide and nicotinamide riboside metabolism in mammalian cells [3], which is the cell-level reason the two are not interchangeable even though they sit on the same route.

The animal result that started the field

Animal research

Long-term administration of nicotinamide mononucleotide was reported to mitigate age-associated physiological decline in mice [4]. That study — a year-long administration in a rodent, measuring a broad panel of physiological parameters — is the origin of most of the interest in this area and is cited far more often than any human trial in it.

Two standard cautions apply and are worth stating precisely here. The endpoints were rodent physiological measures over a substantial fraction of a mouse lifespan; the equivalent human study would run for decades and has not been attempted. And rodents and humans differ in the precursor handling described above, so the same molecule does not necessarily follow the same route.

What has been administered to humans: NAD+ itself

Human clinical research

Results from pharmaceutical clinical trials describe the investigational material and populations used in those studies and should not be interpreted as establishing the effects of research-grade materials offered for laboratory use.

The direct question — what happens when NAD+ itself is administered to a person — has one published pilot study.

Design and endpoint. A pilot study documented changes in plasma and urine concentrations of NAD+ and its metabolites during and after a 6-hour intravenous infusion at 3 μmol/min in a human cohort. The study's own framing is explicit that, while precursors such as nicotinamide riboside had been shown to raise plasma NAD+, no data were available on the fate of directly infused NAD+ in humans [7].

Results as reported. No change in plasma NAD+ or in the measured metabolites — nicotinamide, methylnicotinamide, ADP-ribose and nicotinamide mononucleotide — was observed until after two hours. Increased urinary excretion of methylnicotinamide and of NAD+ was detected at six hours, with no significant rise in urinary nicotinamide. The authors state three conclusions: that at 3 μmol/min NAD+ is rapidly and completely removed from plasma for at least the first two hours; that the metabolite profile is consistent with NAD+ glycohydrolase and pyrophosphatase activity; and that urinary excretion products include NAD+ itself and methylnicotinamide but not nicotinamide [7].

What this establishes and does not. It is a pharmacokinetic observation in a small cohort, and it is the only human data on infused NAD+ in this record. It measured what happens to the molecule, not what the molecule does. Nothing in it is an efficacy finding, and the rapid clearance it documents is the reason the rest of this literature is about precursors.

Nicotinamide riboside

Human clinical research

Results from pharmaceutical clinical trials describe the investigational material and populations used in those studies and should not be interpreted as establishing the effects of research-grade materials offered for laboratory use.

Nicotinamide riboside has the longest randomised record of the precursors. It was shown to be uniquely and orally bioavailable in mice and humans [2], which established the premise that an oral precursor reaches the circulation intact.

The crossover trial. A 2 × 6-week randomised, double-blind, placebo-controlled crossover trial in healthy middle-aged and older adults reported that chronic supplementation with nicotinamide riboside is well tolerated and effectively stimulates NAD+ metabolism. The authors describe the physiological findings as initial insight, and specifically propose that future trials should further assess potential effects on blood pressure and arterial stiffness in this group [5].

Limitations. The primary demonstrated effect is biochemical — NAD+ metabolism is stimulated. The physiological observations are explicitly framed by the authors as preliminary and as a reason to run further trials, which is the correct reading and is routinely upgraded in secondary coverage into a demonstration. Six weeks per period in a healthy population cannot address any outcome that accrues over years.

Nicotinamide mononucleotide

Human clinical research

Results from pharmaceutical clinical trials describe the investigational material and populations used in those studies and should not be interpreted as establishing the effects of research-grade materials offered for laboratory use.

The prediabetes trial. Nicotinamide mononucleotide was reported to increase skeletal-tissue insulin sensitivity, insulin signalling and tissue remodelling in postmenopausal women with prediabetes who were overweight or obese, with expression of platelet-derived growth factor receptor β and other remodelling-related genes up-regulated after nicotinamide mononucleotide and unchanged after placebo [9, 10].

This is the most mechanistically detailed human result in the field and it is also narrow: one sex, one metabolic phenotype, a tissue-level insulin sensitivity measure obtained by clamp, and a small sample. It is a physiology finding in a specific population, not a demonstration that the compound improves a clinical condition.

The amount-ranging trial. A randomised, multicentre, double-blind, placebo-controlled, parallel-group trial in healthy middle-aged adults examined oral nicotinamide mononucleotide across amounts up to 900 mg daily over 60 days. Blood NAD concentrations increased; walking distance differed significantly from placebo at days 30 and 60 (all p<0.01), with the longest distances in the 600 mg and 900 mg groups; a blood biological-age estimate increased in the placebo group and was unchanged in all treated groups (all p<0.05); a general health questionnaire showed differences favouring treatment at most time points; and the insulin-resistance index showed no statistically significant difference from placebo in any group at day 60. The authors report the compound as safe and well tolerated to 900 mg daily, with the highest measured effect at 600 mg [12].

Limitations. A six-minute-walk-type distance measure and a questionnaire in a healthy population over 60 days are soft endpoints, and the "blood biological age" measure is a derived index rather than an established outcome. The insulin-resistance result is negative and sits alongside the positive ones. The trial's author list includes employees of the supplying companies, which is disclosed and is a reason to weight it alongside independent work rather than above it.

The comparison that separates the precursors

Human clinical research

Results from pharmaceutical clinical trials describe the investigational material and populations used in those studies and should not be interpreted as establishing the effects of research-grade materials offered for laboratory use.

Until recently no trial had compared the precursors head to head in people. A randomised, open-label, placebo-controlled study in 65 healthy participants did exactly that, giving nicotinamide riboside, nicotinamide mononucleotide or nicotinamide for 14 days [11].

Results as reported. Nicotinamide riboside and nicotinamide mononucleotide comparably increased circulating NAD+; nicotinamide did not. Only nicotinamide acutely and transiently affected the whole-blood NAD+ metabolome. Using ex vivo fermentation with human microbiota, the authors identified that nicotinamide riboside and nicotinamide mononucleotide give rise to nicotinic acid and enhance microbial growth and metabolism, and they showed ex vivo in whole blood that nicotinic acid is a potent NAD+ booster while nicotinamide mononucleotide, nicotinamide riboside and nicotinamide are not. They propose a gut-dependent model in which nicotinamide riboside and nicotinamide mononucleotide raise circulating NAD+ via the Preiss-Handler pathway through microbially produced nicotinic acid, while rapidly absorbed nicotinamide acts acutely through the salvage pathway [11].

Why this is the most consequential trial in the article. It establishes in humans that the three precursors are not equivalent, that two of them work and one does not on the chronic circulating endpoint, and — most disruptively — that the mechanism may be indirect, running through gut microbial conversion rather than through direct cellular uptake of the administered molecule. If that model holds, then the compound in the capsule is not the compound doing the work, and every earlier result has to be reread with that possibility in view. The trial is open-label, runs 14 days, enrols 65 people, and was conducted by researchers employed by a food-science company; it is a strong result that is not a final one.

What the evidence base does not establish

That administering NAD+ itself does anything. One pilot infusion study, measuring pharmacokinetics, found the molecule cleared from plasma within two hours [7]. There is no efficacy trial of NAD+ administration in this record.

That the precursors are interchangeable. A direct human comparison found nicotinamide ineffective on the chronic endpoint where nicotinamide riboside and nicotinamide mononucleotide were effective [11], and cell-level work shows their handling differs [3].

Any clinical outcome. Every human endpoint in this record is a blood concentration, a clamp-derived sensitivity measure, a walking distance, a blood-pressure or arterial-stiffness measure, or a questionnaire [5, 9, 12]. No trial has counted a disease event, a hospitalisation or a death.

That raising circulating NAD+ raises tissue NAD+ where it is proposed to matter. The human trials measure blood. The mechanistic case concerns intracellular NAD+ in specific tissues, and the two are not the same measurement.

That supplying substrate addresses the proposed problem. If age-related decline is driven by consumption through CD38 [1], then substrate supply is one hypothesis about what to do and not the only one, and no human trial has compared strategies.

Anything on the timescale the animal result concerns. The mouse study ran a substantial fraction of a lifespan [4]. The human trials run 14 days to 12 weeks.

Regulatory position. Nicotinamide riboside and nicotinamide mononucleotide are not approved as drugs for any indication in the United States, and NAD+ administration is not an approved therapy.

All of the research described in this article is research conducted under registered clinical or laboratory protocols, on material prepared for those studies. None of it is research into, or evidence about, research-grade material supplied for laboratory use.

Frequently Asked Questions

Have human trials administered NAD+ itself?
Almost none have. A pilot study documented plasma and urine changes during a 6-hour intravenous infusion of NAD+ at 3 μmol/min in a human cohort, and its own framing notes that no data were previously available on the fate of directly infused NAD+ in humans [7]. Essentially every other trial in this literature administered a precursor, not NAD+.
What is the difference between NAD+, NR, NMN and nicotinamide?
NAD+ is the dinucleotide itself. Nicotinamide riboside, nicotinamide mononucleotide and nicotinamide are three precursors that enter its biosynthesis at different points [8]. They are different molecules with different absorption and conversion routes, and a randomised comparison in 65 healthy participants found that 14 days of nicotinamide riboside and nicotinamide mononucleotide comparably raised circulating NAD+ while nicotinamide did not [11].
Does oral NAD+ precursor supplementation actually raise NAD+ in people?
Nicotinamide riboside was shown to be orally bioavailable in mice and humans [2], and a 2 × 6-week randomised, double-blind, placebo-controlled crossover trial found chronic supplementation well tolerated and effective at stimulating NAD+ metabolism in healthy middle-aged and older adults [5]. A randomised multicentre trial of nicotinamide mononucleotide reported increased blood NAD concentrations across amounts up to 900 mg daily [12].
What clinical endpoints have NAD+ precursor trials measured?
Mostly biochemical and physiological measures. Blood NAD concentration, blood pressure and arterial stiffness in the nicotinamide riboside crossover trial [5]; insulin sensitivity and signalling in prediabetic women receiving nicotinamide mononucleotide [9]; walking distance, a blood biological-age estimate and a general health questionnaire in a nicotinamide mononucleotide trial [12]. No trial in this record has reported a hard clinical outcome.
Why do NAD+ levels decline with age, according to this literature?
One proposed mechanism is increased consumption rather than reduced synthesis: CD38 has been described as dictating age-related NAD decline and mitochondrial dysfunction through an SIRT3-dependent mechanism [1]. NAD+ metabolism and its roles in cellular processes during ageing have been reviewed [8], and synthesis and breakdown fluxes have been quantified directly [6].
Are NAD+ precursors approved as medicines?
No. Nicotinamide riboside and nicotinamide mononucleotide are not approved as drugs for any indication in the United States, and the human studies described here are physiology trials and small randomised trials rather than a registrational programme [5, 9, 12].
What did the intravenous NAD+ infusion study find?
That infused NAD+ disappears from plasma quickly. No change in plasma NAD+ or its measured metabolites was observed until after two hours, increased urinary excretion of methylnicotinamide and NAD+ appeared at six hours, and no significant rise in urinary nicotinamide occurred. The authors concluded that at 3 μmol/min NAD+ is rapidly and completely removed from plasma for at least the first two hours [7].
Does animal evidence for NAD+ precursors transfer to humans?
It has not been shown to. Long-term nicotinamide mononucleotide administration mitigated age-associated physiological decline in mice [4], and that result is the origin of most interest in the field. The human trials that followed measured biochemical and physiological endpoints in small samples over weeks, not the outcomes the mouse study measured [5, 9, 12].

References

  1. CD38 Dictates Age-Related NAD Decline and Mitochondrial Dysfunction through an SIRT3-Dependent Mechanism Cell Metabolism; 2016. PMID 27304511 doi:10.1016/j.cmet.2016.05.006
  2. Nicotinamide riboside is uniquely and orally bioavailable in mice and humans Nature Communications; 2016. PMID 27721479 doi:10.1038/ncomms12948
  3. NRK1 controls nicotinamide mononucleotide and nicotinamide riboside metabolism in mammalian cells Nature Communications; 2016. PMID 27725675 doi:10.1038/ncomms13103
  4. Long-Term Administration of Nicotinamide Mononucleotide Mitigates Age-Associated Physiological Decline in Mice Cell Metabolism; 2016. PMID 28068222 doi:10.1016/j.cmet.2016.09.013
  5. Chronic nicotinamide riboside supplementation is well-tolerated and elevates NAD(+) in healthy middle-aged and older adults Nature Communications; 2018. PMID 29599478 doi:10.1038/s41467-018-03421-7
  6. Quantitative Analysis of NAD Synthesis-Breakdown Fluxes Cell Metabolism; 2018. PMID 29685734 doi:10.1016/j.cmet.2018.03.018
  7. 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 doi:10.3389/fnagi.2019.00257
  8. NAD(+) metabolism and its roles in cellular processes during ageing Nature Reviews Molecular Cell Biology; 2021. PMID 33353981 doi:10.1038/s41580-020-00313-x
  9. Nicotinamide mononucleotide increases muscle insulin sensitivity in prediabetic women Science; 2021. PMID 33888596 doi:10.1126/science.abe9985
  10. Effect of "Nicotinamide Mononucleotide" (NMN) on Cardiometabolic Function. NCT03151239
  11. The differential impact of three different NAD(+) boosters on circulatory NAD and microbial metabolism in humans Nature Metabolism; 2026. PMID 41540253 doi:10.1038/s42255-025-01421-8
  12. 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. PMID 36482258 doi:10.1007/s11357-022-00705-1

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