Differences among Nicotinamide Riboside, Nicotinamide and Nicotinic Acid
As core members of the vitamin B3 family, nicotinamide riboside (NR), nicotinamide (NAM) and nicotinic acid (NA) are all key precursors for maintaining intracellular nicotinamide adenine dinucleotide (NAD⁺) homeostasis, yet they differ markedly in metabolic route, biological activity and safety profile.
Metabolic divergence
NA enters the NAD⁺ pathway via the Preiss–Handler route: it is first converted to nicotinic acid mononucleotide (NaMN) by nicotinic acid phosphoribosyl-transferase (NaPRTase) and then processed stepwise to NAD⁺. This sequence depends on specific enzymes and is easily perturbed by the cellular metabolic state.
NAM relies on the salvage pathway: nicotinamide phosphoribosyl-transferase (NAMPT) generates nicotinamide mononucleotide (NMN), and because NAMPT is the rate-limiting step its activity declines with age or disease, lowering NAD⁺ synthesis efficiency. NR possesses a dedicated route: it is directly phosphorylated to NMN by nicotinamide riboside kinases (NRK1/2) without requiring NaPRTase or NAMPT. Thus NR can sustain NAD⁺ synthesis even when these enzymes are limiting, and gut microbiota can further convert dietary NR into NAM, NA and other intermediates that indirectly feed NAD⁺ production.
Biological activity and safety
The three compounds diverge even more sharply in bioactivity and tolerability. NA's major drawback is its strong flush response—oral intake frequently provokes skin erythema and pruritus through activation of cutaneous G-protein-coupled receptors, restricting its use for chronic supplementation. NAM lacks this cutaneous irritation, but high doses may be hepatotoxic and, via feedback inhibition, suppress the activity of SIRT deacetylases that depend on NAD⁺, thereby blunting NAD⁺-mediated metabolic control.
Clinical studies show that NR has high oral bioavailability and carries neither the flushing of NA nor the hepatotoxic risk of NAM. Functionally, NR elevates NAD⁺ while more effectively activating SIRT1, SIRT3 and related proteins, promoting mitochondrial biogenesis and repair. In an Alzheimer's disease mouse model, for example, NR suppressed NLRP3 inflammasome activity and reduced pro-inflammatory cytokine release, whereas NAM, by inhibiting SIRT activity, produced only modest anti-inflammatory effects.
Therapeutic potential
NR's advantages become still clearer in disease intervention. In neurodegenerative disorders such as amyotrophic lateral sclerosis, NR can rapidly restore neuronal NAD⁺ through its proprietary pathway and delay motor-neuron death. In age-related decline of intestinal stem-cell function or skeletal-muscle performance, NR reinstates cellular vigor by activating the SIRT1/mTORC1 axis, whereas NAM's feedback inhibition limits its ability to improve aging-related biomarkers.
With its unique metabolic route, superior safety profile and stronger control of physiological functions, NR stands out among NAD⁺ precursors and offers a better option for health maintenance and disease modulation. Future work should focus on optimizing NR formulation and enhancing its metabolic stability to unlock its full clinical potential.
Reference
Sharma, C.; Donu, D.; Cen, Y. Emerging Role of Nicotinamide Riboside in Health and Diseases. Nutrients 2022, 14, 3889.
*Special note - This article is for informational purposes only and cannot replace a doctor's treatment diagnosis and advice. It should not be regarded as a recommendation or proof of efficacy of the medical products involved. If it involves disease diagnosis, treatment, and rehabilitation, please be sure to go to a professional medical institution to seek professional advice.
by GSHWORLD
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