Dihydro-NMN

Dihydronicotinamide mononucleotide (NMNH), also designated reduced nicotinamide mononucleotide or dihydro-NMN, is the 1,4-dihydropyridine analog of beta-nicotinamide mononucleotide (NMN). The compound differs from NMN by a single additional hydrogen at the C-4 position of the nicotinamide ring, converting the aromatic pyridinium to a non-aromatic 1,4-dihydropyridine and conferring distinct biochemical, pharmacokinetic, and pharmacological properties. NMNH was first characterized as a potent nicotinamide adenine dinucleotide (NAD+) precursor in mammalian systems in two independent 2021 reports: Zapata-Perez et al. in The FASEB Journal demonstrated that NMNH increases NAD+ levels to a substantially greater extent and faster than NMN or nicotinamide riboside (NR) across multiple tissues in mice, while Liu et al. in the Journal of Proteome Research showed that NMNH potently enhances NAD+ and NADH, suppresses glycolysis and the tricarboxylic acid cycle, induces reductive stress, and inhibits cell growth in hepatocellular carcinoma cells. The metabolic pathway of NMNH is mechanistically distinct from that of NMN: NMNH is converted directly to NADH by nicotinamide mononucleotide adenylyltransferase (NMNAT) without requiring nicotinamide phosphoribosyltransferase (NAMPT) or nicotinamide riboside kinase (NRK), the two rate-limiting enzymes of the canonical salvage and Preiss-Handler pathways. The resulting NADH is then oxidized to NAD+ by cellular oxidoreductases, producing a net elevation of both reduced and oxidized pyridine dinucleotide pools. In vivo, intraperitoneal administration of NMNH to mice elevates hepatic NAD+ approximately five-fold and renal NAD+ approximately two-fold, with significant increases also observed in brain, skeletal muscle, brown adipose tissue, and heart, tissues in which equivalent doses of NMN produce no statistically significant NAD+ elevation. The Zapata-Perez et al. study additionally demonstrated that NMNH protects conditionally immortalized proximal tubular epithelial cells against hypoxia and reoxygenation injury, reducing expression of the kidney injury biomarker Kim-1 and the mitochondrial dysfunction marker Tfam, establishing a preclinical basis for renal cytoprotection. The Liu et al. metabolomic analysis revealed that NMNH-treated cells exhibit marked suppression of glycolytic intermediates (glucose-6-phosphate, fructose-1,6-bisphosphate, phosphoenolpyruvate, pyruvate) and tricarboxylic acid cycle intermediates (citrate, alpha-ketoglutarate, succinate, fumarate, malate), accompanied by cell cycle arrest and growth inhibition. The compound induces cellular reductive stress through elevation of the NADH/NAD+ ratio, which paradoxically increases reactive oxygen species (ROS) production, linking the reductive stress phenotype to the anti-proliferative activity. NMNH is prepared by chemical reduction of NMN with thiourea dioxide in alkaline aqueous solution or by enzymatic cleavage of NADH with NADH pyrophosphatase (NudC). The compound is supplied as the disodium salt (CAS 108347-85-9) and is commercially available from multiple research chemical suppliers. A first-in-human clinical trial reported in January 2026 indicated that oral NMNH at 500 mg for 90 days approximately tripled circulating NAD+ levels in healthy adults, though these results remain unpublished and unverified by independent peer review. No regulatory approval exists for NMNH in any jurisdiction; the compound is sold as a dietary supplement or research reagent. This monograph reviews the chemistry, synthesis, and structural distinction from NMN; the NMNAT-dependent metabolic pathway; the preclinical pharmacology across NAD+ elevation, renal cytoprotection, metabolic reprogramming, and anti-proliferative activity; the limited pharmacokinetic data in mice and humans; the emerging clinical evidence; sourcing and quality verification; reconstitution and handling; stack interactions with other NAD+ precursors and metabolic modulators; the adverse-event and safety signal including reductive stress and reactive oxygen species concerns; and a comparative assessment of five NAD+ precursor candidates against NMNH on five competency standards.