Nicotinamide Riboside (NR)

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2023, Nicotinamide Riboside, a Promising Vitamin B₃ Derivative for Healthy Aging and Longevity: Current Research and Perspectives ^[1]
2023, NAD+ Precursors Nicotinamide Mononucleotide (NMN) and Nicotinamide Riboside (NR): Potential Dietary Contribution to Health ^[2]
2022, Balancing NAD⁺ deficits with nicotinamide riboside: therapeutic possibilities and limitations ^[3]
2019, Safety and Metabolism of Long-term Administration of NIAGEN (Nicotinamide Riboside Chloride) in a Randomized, Double-Blind, Placebo-controlled Clinical Trial of Healthy Overweight Adults ^[4]
https://www.thorne.com/take-5-daily/article/three-reasons-to-pair-a-methyl-donor-with-nicotinamide-riboside
2017, An open-label, non-randomized study of the pharmacokinetics of the nutritional supplement nicotinamide riboside (NR) and its effects on blood NAD+ levels in healthy volunteers ^[5]
2016, Nicotinamide riboside is uniquely and orally bioavailable in mice and humans ^[6]

References

↑ Biţă A et al.: Nicotinamide Riboside, a Promising Vitamin B₃ Derivative for Healthy Aging and Longevity: Current Research and Perspectives. Molecules 2023. (PMID 37630330) [PubMed] [DOI] [Full text] Many studies have suggested that the oxidized form of nicotinamide adenine dinucleotide (NAD+) is involved in an extensive spectrum of human pathologies, including neurodegenerative disorders, cardiomyopathy, obesity, and diabetes. Further, healthy aging and longevity appear to be closely related to NAD+ and its related metabolites, including nicotinamide riboside (NR) and nicotinamide mononucleotide (NMN). As a dietary supplement, NR appears to be well tolerated, having better pharmacodynamics and greater potency. Unfortunately, NR is a reactive molecule, often unstable during its manufacturing, transport, and storage. Recently, work related to prebiotic chemistry discovered that NR borate is considerably more stable than NR itself. However, immediately upon consumption, the borate dissociates from the NR borate and is lost in the body through dilution and binding to other species, notably carbohydrates such as fructose and glucose. The NR left behind is expected to behave pharmacologically in ways identical to NR itself. This review provides a comprehensive summary (through Q1 of 2023) of the literature that makes the case for the consumption of NR as a dietary supplement. It then summarizes the challenges of delivering quality NR to consumers using standard synthesis, manufacture, shipping, and storage approaches. It concludes by outlining the advantages of NR borate in these processes.
↑ Alegre GFS & Pastore GM: NAD+ Precursors Nicotinamide Mononucleotide (NMN) and Nicotinamide Riboside (NR): Potential Dietary Contribution to Health. Curr Nutr Rep 2023. (PMID 37273100) [PubMed] [DOI] [Full text] PURPOSE OF REVIEW: NAD+ is a vital molecule that takes part as a redox cofactor in several metabolic reactions besides being used as a substrate in important cellular signaling in regulation pathways for energetic, genotoxic, and infectious stress. In stress conditions, NAD+ biosynthesis and levels decrease as well as the activity of consuming enzymes rises. Dietary precursors can promote NAD+ biosynthesis and increase intracellular levels, being a potential strategy for reversing physiological decline and preventing diseases. In this review, we will show the biochemistry and metabolism of NAD+ precursors NR (nicotinamide riboside) and NMN (nicotinamide mononucleotide), the latest findings on their beneficial physiological effects, their interplay with gut microbiota, and the future perspectives for research in nutrition and food science fields. RECENT FINDINGS: NMN and NR demonstrated protect against diabetes, Alzheimer disease, endothelial dysfunction, and inflammation. They also reverse gut dysbiosis and promote beneficial effects at intestinal and extraintestinal levels. NR and NMN have been found in vegetables, meat, and milk, and microorganisms in fermented beverages can also produce them. NMN and NR can be obtained through the diet either in their free form or as metabolites derivate from the digestion of NAD+. The prospection of NR and NMN to find potential food sources and their dietary contribution in increasing NAD+ levels are still an unexplored field of research. Moreover, it could enable the development of new functional foods and processing strategies to maintain and enhance their physiological benefits, besides the studies of new raw materials for extraction and biotechnological development.
↑ Cercillieux A et al.: Balancing NAD⁺ deficits with nicotinamide riboside: therapeutic possibilities and limitations. Cell Mol Life Sci 2022. (PMID 35918544) [PubMed] [DOI] [Full text] Alterations in cellular nicotinamide adenine dinucleotide (NAD+) levels have been observed in multiple lifestyle and age-related medical conditions. This has led to the hypothesis that dietary supplementation with NAD+ precursors, or vitamin B3s, could exert health benefits. Among the different molecules that can act as NAD+ precursors, Nicotinamide Riboside (NR) has gained most attention due to its success in alleviating and treating disease conditions at the pre-clinical level. However, the clinical outcomes for NR supplementation strategies have not yet met the expectations generated in mouse models. In this review we aim to provide a comprehensive view on NAD+ biology, what causes NAD+ deficits and the journey of NR from its discovery to its clinical development. We also discuss what are the current limitations in NR-based therapies and potential ways to overcome them. Overall, this review will not only provide tools to understand NAD+ biology and assess its changes in disease situations, but also to decide which NAD+ precursor could have the best therapeutic potential.
↑ Conze D et al.: Safety and Metabolism of Long-term Administration of NIAGEN (Nicotinamide Riboside Chloride) in a Randomized, Double-Blind, Placebo-controlled Clinical Trial of Healthy Overweight Adults. Sci Rep 2019. (PMID 31278280) [PubMed] [DOI] [Full text] Nicotinamide riboside (NR) is a newly discovered nicotinamide adenine dinucleotide (NAD+) precursor vitamin. A crystal form of NR chloride termed NIAGEN is generally recognized as safe (GRAS) for use in foods and the subject of two New Dietary Ingredient Notifications for use in dietary supplements. To evaluate the kinetics and dose-dependency of NR oral availability and safety in overweight, but otherwise healthy men and women, an 8-week randomized, double-blind, placebo-controlled clinical trial was conducted. Consumption of 100, 300 and 1000 mg NR dose-dependently and significantly increased whole blood NAD+ (i.e., 22%, 51% and 142%) and other NAD+ metabolites within 2 weeks. The increases were maintained throughout the remainder of the study. There were no reports of flushing and no significant differences in adverse events between the NR and placebo-treated groups or between groups at different NR doses. NR also did not elevate low density lipoprotein cholesterol or dysregulate 1-carbon metabolism. Together these data support the development of a tolerable upper intake limit for NR based on human data.
↑ Airhart SE et al.: An open-label, non-randomized study of the pharmacokinetics of the nutritional supplement nicotinamide riboside (NR) and its effects on blood NAD+ levels in healthy volunteers. PLoS One 2017. (PMID 29211728) [PubMed] [DOI] [Full text] OBJECTIVES: The co-primary objectives of this study were to determine the human pharmacokinetics (PK) of oral NR and the effect of NR on whole blood nicotinamide adenine dinucleotide (NAD+) levels. BACKGROUND: Though mitochondrial dysfunction plays a critical role in the development and progression of heart failure, no mitochondria-targeted therapies have been translated into clinical practice. Recent murine studies have reported associations between imbalances in the NADH/NAD+ ratio with mitochondrial dysfunction in multiple tissues, including myocardium. Moreover, an NAD+ precursor, nicotinamide mononucleotide, improved cardiac function, while another NAD+ precursor, nicotinamide riboside (NR), improved mitochondrial function in muscle, liver and brown adipose. Thus, PK studies of NR in humans is critical for future clinical trials. METHODS: In this non-randomized, open-label PK study of 8 healthy volunteers, 250 mg NR was orally administered on Days 1 and 2, then uptitrated to peak dose of 1000 mg twice daily on Days 7 and 8. On the morning of Day 9, subjects completed a 24-hour PK study after receiving 1000 mg NR at t = 0. Whole-blood levels of NR, clinical blood chemistry, and NAD+ levels were analyzed. RESULTS: Oral NR was well tolerated with no adverse events. Significant increases comparing baseline to mean concentrations at steady state (Cave,ss) were observed for both NR (p = 0.03) and NAD+ (p = 0.001); the latter increased by 100%. Absolute changes from baseline to Day 9 in NR and NAD+ levels correlated highly (R2 = 0.72, p = 0.008). CONCLUSIONS: Because NR increases circulating NAD+ in humans, NR may have potential as a therapy in patients with mitochondrial dysfunction due to genetic and/or acquired diseases.
↑ Trammell SA et al.: Nicotinamide riboside is uniquely and orally bioavailable in mice and humans. Nat Commun 2016. (PMID 27721479) [PubMed] [DOI] [Full text] Nicotinamide riboside (NR) is in wide use as an NAD+ precursor vitamin. Here we determine the time and dose-dependent effects of NR on blood NAD+ metabolism in humans. We report that human blood NAD+ can rise as much as 2.7-fold with a single oral dose of NR in a pilot study of one individual, and that oral NR elevates mouse hepatic NAD+ with distinct and superior pharmacokinetics to those of nicotinic acid and nicotinamide. We further show that single doses of 100, 300 and 1,000 mg of NR produce dose-dependent increases in the blood NAD+ metabolome in the first clinical trial of NR pharmacokinetics in humans. We also report that nicotinic acid adenine dinucleotide (NAAD), which was not thought to be en route for the conversion of NR to NAD+, is formed from NR and discover that the rise in NAAD is a highly sensitive biomarker of effective NAD+ repletion.

[pmid37630330-1] Biţă A et al.: Nicotinamide Riboside, a Promising Vitamin B₃ Derivative for Healthy Aging and Longevity: Current Research and Perspectives. Molecules 2023. (PMID 37630330) [PubMed] [DOI] [Full text] Many studies have suggested that the oxidized form of nicotinamide adenine dinucleotide (NAD+) is involved in an extensive spectrum of human pathologies, including neurodegenerative disorders, cardiomyopathy, obesity, and diabetes. Further, healthy aging and longevity appear to be closely related to NAD+ and its related metabolites, including nicotinamide riboside (NR) and nicotinamide mononucleotide (NMN). As a dietary supplement, NR appears to be well tolerated, having better pharmacodynamics and greater potency. Unfortunately, NR is a reactive molecule, often unstable during its manufacturing, transport, and storage. Recently, work related to prebiotic chemistry discovered that NR borate is considerably more stable than NR itself. However, immediately upon consumption, the borate dissociates from the NR borate and is lost in the body through dilution and binding to other species, notably carbohydrates such as fructose and glucose. The NR left behind is expected to behave pharmacologically in ways identical to NR itself. This review provides a comprehensive summary (through Q1 of 2023) of the literature that makes the case for the consumption of NR as a dietary supplement. It then summarizes the challenges of delivering quality NR to consumers using standard synthesis, manufacture, shipping, and storage approaches. It concludes by outlining the advantages of NR borate in these processes.

[pmid37273100-2] Alegre GFS & Pastore GM: NAD+ Precursors Nicotinamide Mononucleotide (NMN) and Nicotinamide Riboside (NR): Potential Dietary Contribution to Health. Curr Nutr Rep 2023. (PMID 37273100) [PubMed] [DOI] [Full text] PURPOSE OF REVIEW: NAD+ is a vital molecule that takes part as a redox cofactor in several metabolic reactions besides being used as a substrate in important cellular signaling in regulation pathways for energetic, genotoxic, and infectious stress. In stress conditions, NAD+ biosynthesis and levels decrease as well as the activity of consuming enzymes rises. Dietary precursors can promote NAD+ biosynthesis and increase intracellular levels, being a potential strategy for reversing physiological decline and preventing diseases. In this review, we will show the biochemistry and metabolism of NAD+ precursors NR (nicotinamide riboside) and NMN (nicotinamide mononucleotide), the latest findings on their beneficial physiological effects, their interplay with gut microbiota, and the future perspectives for research in nutrition and food science fields. RECENT FINDINGS: NMN and NR demonstrated protect against diabetes, Alzheimer disease, endothelial dysfunction, and inflammation. They also reverse gut dysbiosis and promote beneficial effects at intestinal and extraintestinal levels. NR and NMN have been found in vegetables, meat, and milk, and microorganisms in fermented beverages can also produce them. NMN and NR can be obtained through the diet either in their free form or as metabolites derivate from the digestion of NAD+. The prospection of NR and NMN to find potential food sources and their dietary contribution in increasing NAD+ levels are still an unexplored field of research. Moreover, it could enable the development of new functional foods and processing strategies to maintain and enhance their physiological benefits, besides the studies of new raw materials for extraction and biotechnological development.

[pmid35918544-3] Cercillieux A et al.: Balancing NAD⁺ deficits with nicotinamide riboside: therapeutic possibilities and limitations. Cell Mol Life Sci 2022. (PMID 35918544) [PubMed] [DOI] [Full text] Alterations in cellular nicotinamide adenine dinucleotide (NAD+) levels have been observed in multiple lifestyle and age-related medical conditions. This has led to the hypothesis that dietary supplementation with NAD+ precursors, or vitamin B3s, could exert health benefits. Among the different molecules that can act as NAD+ precursors, Nicotinamide Riboside (NR) has gained most attention due to its success in alleviating and treating disease conditions at the pre-clinical level. However, the clinical outcomes for NR supplementation strategies have not yet met the expectations generated in mouse models. In this review we aim to provide a comprehensive view on NAD+ biology, what causes NAD+ deficits and the journey of NR from its discovery to its clinical development. We also discuss what are the current limitations in NR-based therapies and potential ways to overcome them. Overall, this review will not only provide tools to understand NAD+ biology and assess its changes in disease situations, but also to decide which NAD+ precursor could have the best therapeutic potential.

[pmid31278280-4] Conze D et al.: Safety and Metabolism of Long-term Administration of NIAGEN (Nicotinamide Riboside Chloride) in a Randomized, Double-Blind, Placebo-controlled Clinical Trial of Healthy Overweight Adults. Sci Rep 2019. (PMID 31278280) [PubMed] [DOI] [Full text] Nicotinamide riboside (NR) is a newly discovered nicotinamide adenine dinucleotide (NAD+) precursor vitamin. A crystal form of NR chloride termed NIAGEN is generally recognized as safe (GRAS) for use in foods and the subject of two New Dietary Ingredient Notifications for use in dietary supplements. To evaluate the kinetics and dose-dependency of NR oral availability and safety in overweight, but otherwise healthy men and women, an 8-week randomized, double-blind, placebo-controlled clinical trial was conducted. Consumption of 100, 300 and 1000 mg NR dose-dependently and significantly increased whole blood NAD+ (i.e., 22%, 51% and 142%) and other NAD+ metabolites within 2 weeks. The increases were maintained throughout the remainder of the study. There were no reports of flushing and no significant differences in adverse events between the NR and placebo-treated groups or between groups at different NR doses. NR also did not elevate low density lipoprotein cholesterol or dysregulate 1-carbon metabolism. Together these data support the development of a tolerable upper intake limit for NR based on human data.

[pmid29211728-5] Airhart SE et al.: An open-label, non-randomized study of the pharmacokinetics of the nutritional supplement nicotinamide riboside (NR) and its effects on blood NAD+ levels in healthy volunteers. PLoS One 2017. (PMID 29211728) [PubMed] [DOI] [Full text] OBJECTIVES: The co-primary objectives of this study were to determine the human pharmacokinetics (PK) of oral NR and the effect of NR on whole blood nicotinamide adenine dinucleotide (NAD+) levels. BACKGROUND: Though mitochondrial dysfunction plays a critical role in the development and progression of heart failure, no mitochondria-targeted therapies have been translated into clinical practice. Recent murine studies have reported associations between imbalances in the NADH/NAD+ ratio with mitochondrial dysfunction in multiple tissues, including myocardium. Moreover, an NAD+ precursor, nicotinamide mononucleotide, improved cardiac function, while another NAD+ precursor, nicotinamide riboside (NR), improved mitochondrial function in muscle, liver and brown adipose. Thus, PK studies of NR in humans is critical for future clinical trials. METHODS: In this non-randomized, open-label PK study of 8 healthy volunteers, 250 mg NR was orally administered on Days 1 and 2, then uptitrated to peak dose of 1000 mg twice daily on Days 7 and 8. On the morning of Day 9, subjects completed a 24-hour PK study after receiving 1000 mg NR at t = 0. Whole-blood levels of NR, clinical blood chemistry, and NAD+ levels were analyzed. RESULTS: Oral NR was well tolerated with no adverse events. Significant increases comparing baseline to mean concentrations at steady state (Cave,ss) were observed for both NR (p = 0.03) and NAD+ (p = 0.001); the latter increased by 100%. Absolute changes from baseline to Day 9 in NR and NAD+ levels correlated highly (R2 = 0.72, p = 0.008). CONCLUSIONS: Because NR increases circulating NAD+ in humans, NR may have potential as a therapy in patients with mitochondrial dysfunction due to genetic and/or acquired diseases.

[pmid27721479-6] Trammell SA et al.: Nicotinamide riboside is uniquely and orally bioavailable in mice and humans. Nat Commun 2016. (PMID 27721479) [PubMed] [DOI] [Full text] Nicotinamide riboside (NR) is in wide use as an NAD+ precursor vitamin. Here we determine the time and dose-dependent effects of NR on blood NAD+ metabolism in humans. We report that human blood NAD+ can rise as much as 2.7-fold with a single oral dose of NR in a pilot study of one individual, and that oral NR elevates mouse hepatic NAD+ with distinct and superior pharmacokinetics to those of nicotinic acid and nicotinamide. We further show that single doses of 100, 300 and 1,000 mg of NR produce dose-dependent increases in the blood NAD+ metabolome in the first clinical trial of NR pharmacokinetics in humans. We also report that nicotinic acid adenine dinucleotide (NAAD), which was not thought to be en route for the conversion of NR to NAD+, is formed from NR and discover that the rise in NAAD is a highly sensitive biomarker of effective NAD+ repletion.

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References