NMN

Also known as: Nicotinamide Mononucleotide, β-NMN

Evidence: Clinical

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Overview

Nicotinamide mononucleotide, a direct oral precursor to NAD+; human trials report raised NAD+ metabolites and improved muscle insulin sensitivity in prediabetic women.

NMN is a nucleotide, not a peptide: a phosphorylated form of nicotinamide riboside and the immediate precursor of NAD+ in the salvage pathway (PubChem CID 14180). Human trials are small and short. A 10-week randomized placebo-controlled trial in 25 prediabetic postmenopausal women with overweight or obesity found higher insulin-stimulated glucose disposal by hyperinsulinemic-euglycemic clamp and raised muscle AKT and mTOR phosphorylation at 250 mg/day; body weight and liver fat did not change (Yoshino 2021). A 12-week trial at 250 mg/day in 36 middle-aged adults raised serum nicotinamide and showed a non-significant trend to lower pulse wave velocity (Katayoshi 2023). Daily doses to 1250 mg for 4 weeks were tolerated in 31 healthy adults (Fukamizu 2022). No trial has measured a clinical aging outcome.

Benefits

Raised blood NAD+ metabolites at 250 mg/day (human RCT), improved muscle insulin sensitivity in prediabetic postmenopausal women (human RCT, n=25), higher oxygen uptake during training at 600 to 1200 mg/day (human RCT, n=48), reversal of age-related metabolic decline (rodent only)

Dosing reference

Research dose: 250 to 500 mg daily, oral: the range used in the published placebo-controlled trials
Range: 250000 to 500000 mcg, 1x daily

Oral capsule. Published human doses: single doses of 100, 250 and 500 mg (Irie 2020); 250 mg/day for 10 weeks (Yoshino 2021) and 12 weeks (Katayoshi 2023); 250 mg/day for 8 weeks (Yamaguchi 2024); 300, 600 and 1200 mg/day for 6 weeks in trained runners, where only the 600 and 1200 mg arms separated from placebo on oxygen uptake (Liao 2021); 1250 mg/day for 4 weeks in a safety study (Fukamizu 2022).

Mechanism

NMN is converted to NAD+ by NMNAT enzymes in the salvage pathway, and NAD+ is the substrate for sirtuins, PARPs and CD38. In humans, oral NMN raises blood NAD+ and the downstream methylated metabolites, which is the only part of the chain measured directly (Irie 2020; Katayoshi 2023; Yamaguchi 2024). Two mechanistic claims that circulate as settled are not. Direct cellular uptake through the transporter Slc12a8 was proposed in mice (Grozio 2019) and contested in the same journal, on the grounds that the reported kinetics and NMN concentrations are not physiological (Schmidt 2019); Grozio replied and the original paper carries an author correction. Sirtuin activation and the rodent findings on mitochondrial function have not been shown to follow from NMN dosing in humans.

Evidence

Clinical: at least one published human trial or an approved drug

250 mg/day for 10 weeks raised insulin-stimulated glucose disposal and muscle AKT and mTOR phosphorylation in 25 prediabetic postmenopausal women; body weight, liver fat and blood pressure did not change (Yoshino et al., 2021)
Single oral doses of 100, 250 and 500 mg in 10 healthy men produced no clinical or laboratory signal, and plasma methylated nicotinamide metabolites rose dose-dependently over 5 h (Irie et al., 2020)
1250 mg/day for 4 weeks in 31 healthy adults, randomized and placebo-controlled, produced no changes beyond physiological variation and no serious adverse events (Fukamizu et al., 2022)
250 mg/day for 12 weeks in 36 healthy middle-aged adults raised serum nicotinamide; pulse wave velocity trended lower but did not separate from placebo (Katayoshi et al., 2023)
600 and 1200 mg/day for 6 weeks raised oxygen uptake and ventilatory threshold power in 48 amateur runners, while VO2max itself did not change in any arm (Liao et al., 2021)
Human-trial status: trials are consistent in raising NAD+ metabolites and are small, short and limited to surrogate endpoints. No trial has measured a clinical aging, mortality or disease-incidence outcome, and no regulator has approved NMN for any indication

References

Side effects

Short randomized trials report no adverse signal: 1250 mg/day for 4 weeks in 31 adults produced no changes beyond physiological variation and no serious adverse events (Fukamizu 2022), and single doses to 500 mg produced no symptoms or vital sign changes (Irie 2020). Reported events were mild and not more frequent than placebo; nausea, flushing and headache at higher doses come from user reports, not from the trials. Safety beyond 12 weeks has not been studied in humans, and the effect of sustained NAD+ elevation on existing tumors is unstudied.

Storage

Storage: Room temperature
Lyophilized: 24+ months

Pharmacology

Half-life: Not established. After single oral doses of 100 to 500 mg in healthy men, NMN itself was not the measured species; the methylated metabolites 2-PY and 4-PY rose dose-dependently and were still rising at 5 h (Irie 2020)
Bioavailability: Oral: absolute bioavailability has not been measured in humans. Oral dosing reliably raises blood NAD+ and nicotinamide metabolites (Irie 2020; Yamaguchi 2024). The Slc12a8 uptake route is a contested mouse finding, not a human one
Molecular weight: 334.22 Da

NMN