NAD+ research: what the published studies show

Identity, and What the Evidence Is Actually About

NAD+ is a nucleotide coenzyme rather than a peptide, built from nicotinamide mononucleotide joined to adenosine monophosphate through a pyrophosphate bridge. The oxidized form carries the plus sign and the reduced form is written NADH, while NADP+ and NADPH are separate phosphorylated species. Two smaller molecules, nicotinamide riboside and nicotinamide mononucleotide, are precursors that cells convert into it. Six of the eight sources below concern a precursor rather than NAD+ itself, and every sentence names which molecule was used.

NAD+ and Age, Measured in Human Tissue

Pelvic skin samples were taken from 49 people, from newborns to age 77, and NAD+ fell as age rose in both sexes, more steeply in males than in females.^[1] Poly(ADP-ribose) polymerase activity rose with age in males and correlated inversely with tissue NAD+.^[1] Those associations were less evident in females, and SIRT1 activity fell with age in males but not in females.^[1]

That is a correlation.^[1] It is not a demonstration that adding NAD+ changes anything, it was measured in one tissue across people of different ages, and the paper does not claim otherwise.

The Only Human Study Here of NAD+ Itself

NAD+ was infused intravenously over six hours and plasma and urine were sampled throughout.^[2] Neither NAD+ nor its metabolites rose in plasma until after two hours.^[2] The authors describe that result as surprising.^[2] At the rate used, they conclude, NAD+ is rapidly and completely removed from the plasma for at least the first two hours.^[2]

The metabolite profile they measured was consistent with NAD+ glycohydrolase and NAD+ pyrophosphatase activity, which is to say the molecule was being broken apart.^[2] Methylnicotinamide and NAD+ appeared in urine at six hours, and nicotinamide did not rise there.^[2]

The direct route did not raise it.^[2] Infusing this molecule over six hours left the circulating amount unchanged for the first two hours. Everything else on this page is about giving the body something else and letting it build NAD+ instead.

Nicotinamide Riboside, the First Human Pharmacokinetics

The first clinical trial of NR pharmacokinetics gave three ascending single doses and found dose-dependent increases in the blood NAD+ metabolome.^[3] The paper also reports blood NAD+ rising as much as 2.7-fold after a single oral dose.^[3]Its own abstract states that this came from a pilot study of one individual.^[3] That figure is widely repeated without its denominator.

The same work identified NAAD as a sensitive marker of NAD+ repletion, which had not been thought to lie on the route from NR to NAD+.^[3]

Nicotinamide Riboside, the Outcome Trials

Forty sedentary obese men aged 40 to 70 were randomized to NR or placebo for twelve weeks, and insulin sensitivity, measured by hyperinsulinaemic euglycaemic clamp, did not improve.^[4] Neither did endogenous glucose production, glucose disposal or glucose oxidation.^[4] Resting energy expenditure, lipolysis, lipid oxidation and body composition were also unchanged.^[4] The authors conclude the regimen appears safe but does not improve insulin sensitivity or whole-body glucose metabolism in this group.^[4]

Twelve aged men took NR for 21 days in a placebo-controlled randomized double-blind crossover trial.^[5] Targeted metabolomics showed the muscle NAD+ metabolome elevated, evident as increased NAAD and nicotinamide clearance products.^[5] Muscle RNA sequencing showed energy metabolism and mitochondrial pathways downregulated, and mitochondrial bioenergetics were not altered.^[5] Circulating inflammatory cytokines fell.^[5]

Those two trials do not conflict.^[4][5] NR reaches human muscle and moves the metabolome, and across the endpoints anyone would care about it moved nothing in the larger and longer trial.^[4]

Nicotinamide Mononucleotide, and a Dispute in Print

A ten-week randomized placebo-controlled double-blind trial gave NMN to postmenopausal women with prediabetes who were overweight or obese.^[6] Insulin-stimulated glucose disposal rose after NMN and did not change after placebo, and skeletal muscle AKT and mTOR phosphorylation rose with it.^[6] The authors conclude NMN increases muscle insulin sensitivity, insulin signaling and remodelling in that group.^[6]

Charles Brenner published a formal Comment in the same journal.^[7] He reports baseline hepatic lipid content of 6.3 per cent in the 13 women given NMN against 14.8 per cent in the 12 on placebo, at P = 0.003.^[7] Given that liver fat clearance is a target of NMN, he argues this was not an effectively randomized trial.^[7]

Klein, Yoshino and colleagues replied.^[8] They state that muscle insulin sensitivity, the primary outcome, was identical in both groups at baseline and improved on NMN rather than placebo.^[8] Baseline differences in intrahepatic triglyceride, they argue, do not negate the muscle effect.^[8]

This page does not adjudicate between them.^[7][8] Both positions are stated above in their authors' own terms and a reader can follow either.

Brenner's was not the only published response.^[6] Three further commentaries on the same trial are indexed: Hepler and Bass in Science, Montllor-Albalate and colleagues in Cell Metabolism, and Abdellatif and Baur in Cardiovascular Research.^[9][10][11] They are commentary rather than primary work and none is a methodological objection; the Cell Metabolism piece describes the trial as providing clinical evidence for the approach.^[10] They are named here so that a reader who checks the record does not conclude the only published reaction was hostile.

State of the Evidence

Roughly 65,200 records are indexed for nicotinamide adenine dinucleotide, the largest literature of any product on this site. Eleven are cited here, of which eight are primary.

Three limits shape everything above, and the first is that six of the eight primary sources gave people a precursor rather than NAD+.^[3][4][5][6] NR and NMN are different molecules with different absorption, and a result for either is not a result for this one. Reference 2 is the only human study here that administered NAD+ itself.

The second limit is that reference 2 found what it found: given intravenously, NAD+ did not raise the circulating pool for two hours.^[2] Any page implying that supplying this molecule raises the amount in a person is contradicted by the one human study that tested exactly that. The third limit is disagreement.^[4][6] The largest and longest NR trial was null across every metabolic endpoint it measured, while a smaller NMN trial reported a positive result whose randomization is disputed in print.^[4][6][7] The disagreement is real, it is between named researchers, and it is unresolved.

Authorship overlaps twice. Ross Grant is an author of references 1 and 2, so the age correlation and the infusion study come from one group.^[1][2] Charles Brenner is an author of reference 3 and of the Comment at reference 7.^[3][7] The objection to the NMN trial came from a researcher whose own work is on the competing precursor.

Nothing here is extrapolated from a neighboring product. No result from any peptide sold on this site appears above, and no NAD+ result should travel to one.