Nicotinamide Riboside

• NAD+ enhancement
• Mitochondrial function
• Cellular energy production
• Sirtuin activation

• Cognitive function
• Cardiovascular health
• Metabolic health
• Exercise performance
• Neuroprotection
• Healthy aging
• DNA repair support

Nicotinamide riboside (NR) exerts its diverse biological effects primarily through its role as a precursor to nicotinamide adenine dinucleotide (NAD+), a critical coenzyme involved in hundreds of metabolic reactions. NAD+ levels naturally decline with age, stress, and metabolic dysfunction, making NAD+ replenishment a key target for promoting healthy aging and metabolic function. NR is converted to NAD+ through a unique and efficient salvage pathway that differs from other NAD+ precursors like niacin (nicotinic acid) and nicotinamide. After cellular uptake, NR is phosphorylated by the enzyme nicotinamide riboside kinase (NRK1 or NRK2) to form nicotinamide mononucleotide (NMN).

NMN is then converted to NAD+ by the enzyme nicotinamide mononucleotide adenylyltransferase (NMNAT). This NRK-dependent pathway is particularly significant because it bypasses the rate-limiting steps and negative feedback mechanisms that can limit NAD+ production from other precursors. The NRK pathway is also active in tissues with high energy demands, such as skeletal muscle, cardiac tissue, and neurons, potentially making NR especially beneficial for these tissues. By enhancing NAD+ levels, NR activates several critical cellular processes and enzymes.

One of the most significant is the activation of sirtuins, a family of NAD+-dependent deacylases (primarily SIRT1-7 in mammals) that regulate numerous cellular processes including gene expression, DNA repair, metabolic function, and stress responses. Sirtuins are often described as ‘longevity genes’ due to their role in promoting cellular health and potentially extending lifespan in various organisms. SIRT1, in particular, deacetylates and modulates the activity of key transcription factors like PGC-1α (peroxisome proliferator-activated receptor gamma coactivator 1-alpha), FOXO proteins, and p53, influencing mitochondrial biogenesis, stress resistance, and cellular senescence. NR also enhances mitochondrial function through multiple mechanisms.

By increasing NAD+ availability, NR supports the activity of mitochondrial sirtuins (SIRT3, SIRT4, and SIRT5), which regulate various aspects of mitochondrial metabolism. NR activates SIRT3, which deacetylates and activates numerous mitochondrial enzymes involved in energy production, antioxidant defense, and fatty acid oxidation. Additionally, NR-mediated NAD+ enhancement promotes mitochondrial biogenesis through the SIRT1-PGC-1α pathway, potentially increasing mitochondrial number and function. In the context of cellular energy production, NAD+ serves as a critical electron carrier in both glycolysis and oxidative phosphorylation.

By enhancing NAD+ levels, NR supports ATP production through these pathways, potentially improving cellular energy status, particularly in tissues with high energy demands. NR also influences cellular metabolism through effects on AMP-activated protein kinase (AMPK), a master regulator of cellular energy homeostasis. NAD+ enhancement can activate AMPK, which promotes glucose uptake, fatty acid oxidation, and mitochondrial biogenesis while inhibiting anabolic processes like lipogenesis and gluconeogenesis. Beyond energy metabolism, NR supports DNA repair mechanisms through NAD+-dependent enzymes like poly(ADP-ribose) polymerases (PARPs).

PARPs detect and initiate repair of DNA damage but consume significant amounts of NAD+ in the process. By replenishing NAD+ levels, NR may enhance the cell’s capacity for DNA repair, potentially reducing genomic instability associated with aging and various diseases. NR may also influence cellular inflammation and oxidative stress. NAD+ is required for the activity of CD38, an enzyme involved in calcium signaling and immune function.

However, CD38 can also deplete NAD+ levels. The complex interplay between NR supplementation, NAD+ levels, and CD38 activity may influence inflammatory processes and immune function. Additionally, by supporting mitochondrial function and sirtuin activity, NR may indirectly reduce oxidative stress and inflammation. In the brain, NR has shown neuroprotective effects in various models.

By enhancing NAD+ levels, NR may support neuronal energy metabolism, reduce excitotoxicity, and enhance brain-derived neurotrophic factor (BDNF) expression. NR may also influence neurotransmitter metabolism, as NAD+ is involved in the synthesis and breakdown of various neurotransmitters. In the cardiovascular system, NR has demonstrated potential benefits for heart function and vascular health. By enhancing mitochondrial function in cardiomyocytes and supporting SIRT1 activity in endothelial cells, NR may improve cardiac energy metabolism and vascular function.

NR has also shown promise for metabolic health, potentially improving insulin sensitivity, glucose metabolism, and lipid profiles through its effects on mitochondrial function, sirtuin activity, and AMPK activation. Through these diverse mechanisms, NR influences numerous physiological processes, explaining its wide range of potential health benefits from cognitive function to cardiovascular health to metabolic regulation.

No official Recommended Dietary Allowance (RDA) has been established specifically for nicotinamide riboside, as it is a relatively novel form of vitamin B3. While there are established RDAs for niacin (14-16 mg for adults), these do not directly apply to NR due to its unique metabolism and effects. Based on clinical research, effective doses of nicotinamide riboside typically range from 100-1,000 mg per day, with most studies using 250-500 mg daily. The optimal dose may vary depending on the specific health goal, age, and individual factors.

Most commercial NR supplements provide 250-300 mg per capsule or tablet, often recommending 1-2 capsules daily. Higher doses (750-1,000 mg daily) have been used in some clinical studies without significant adverse effects, but may not provide proportionally greater benefits than moderate doses for most individuals. Unlike some other supplements, NR appears to have good dose-dependent effects on NAD+ levels, with higher doses generally producing greater increases in blood NAD+ concentrations, though this relationship may plateau at very high doses.

Nicotinamide riboside (NR) demonstrates good oral bioavailability, though precise absorption rates in humans are not definitively established. Studies indicate that oral NR supplementation effectively increases blood and tissue NAD+ levels, confirming significant absorption and utilization. After ingestion, NR is absorbed in the small intestine, likely through nucleoside transporters, though the specific transporters involved in human NR absorption are still being characterized. Once absorbed, NR enters the bloodstream and is distributed to various tissues.

Unlike some NAD+ precursors, NR can be directly taken up by cells without requiring conversion to other forms first. Inside cells, NR is phosphorylated by nicotinamide riboside kinases (NRK1 and NRK2) to form nicotinamide mononucleotide (NMN), which is then converted to NAD+. This NRK-dependent pathway is unique to NR among NAD+ precursors and may contribute to its efficacy in certain tissues. Pharmacokinetic studies in humans show that blood NAD+ levels typically begin to increase within hours after NR ingestion, with peak levels often observed 4-8 hours post-supplementation.

The half-life of increased NAD+ levels following NR supplementation appears to be approximately 24 hours, suggesting that daily dosing is appropriate for maintaining elevated NAD+ levels. It’s worth noting that NR’s bioavailability may be influenced by various factors, including the specific salt form used (typically chloride in supplements), the presence of food, individual metabolic differences, and concurrent medications or supplements.

Taking with food may enhance absorption and reduce potential for mild gastrointestinal effects, Liposomal formulations may potentially improve cellular delivery and bioavailability, Enteric-coated formulations may protect NR from degradation in the stomach, Combining with quercetin or other CD38 inhibitors may help preserve NAD+ by reducing its breakdown, Taking earlier in the day may align with natural circadian rhythms of NAD+ metabolism, Consistent daily dosing maintains more stable NAD+ levels than intermittent use, Sublingual or buccal formulations may potentially bypass first-pass metabolism, Avoiding excessive alcohol consumption, which can deplete NAD+ levels, Maintaining adequate levels of complementary nutrients like zinc, magnesium, and riboflavin that support NAD+ metabolism

For general NAD+ enhancement, nicotinamide riboside can be taken once daily at any time, though morning dosing is often recommended to align with natural circadian patterns of NAD+ metabolism. Taking NR with food appears to be well-tolerated and may enhance absorption while reducing the potential for mild gastrointestinal effects that some users report with empty-stomach consumption. For those using NR to support energy levels and cognitive function, morning or early afternoon dosing may be preferable to avoid any potential impact on sleep, though NR is not typically stimulating in the way that caffeine or other energizing compounds might be. Some research suggests that NAD+ levels naturally fluctuate throughout the day as part of circadian rhythms, with higher levels typically occurring during active daylight hours.

Morning supplementation may therefore complement these natural patterns, though clinical studies specifically examining timing effects are limited. For those taking multiple supplements, NR can generally be taken alongside most other supplements without significant interaction concerns. However, separating NR from niacin (nicotinic acid) supplementation may be advisable to avoid competing for absorption pathways. When using NR for exercise performance or recovery, some evidence suggests taking it 1-2 hours before exercise may be beneficial, though research specifically examining timing relative to exercise is limited.

For those using NR to support sleep quality or circadian rhythm regulation, some preliminary research suggests that morning dosing may be more effective than evening dosing, though individual responses may vary. Consistency in daily supplementation is generally more important than specific timing for many of NR’s benefits, particularly for supporting healthy aging and mitochondrial function. NAD+ levels respond to consistent supplementation over time, with some studies suggesting cumulative benefits with regular use for several weeks or months.

• Generally well-tolerated with minimal reported side effects at recommended doses
• Mild gastrointestinal discomfort (nausea, stomach upset, indigestion)
• Flushing (much less common than with niacin, but occasionally reported)
• Fatigue (reported by some users, though clinical studies have not consistently found this effect)
• Headache (uncommon)
• Mild insomnia or sleep disturbances (rare, primarily with evening dosing in sensitive individuals)
• Changes in heart rate or blood pressure (rare, primarily in sensitive individuals)
• Potential for mild liver enzyme elevations at very high doses (based on limited data)
• Increased uric acid levels (observed in some studies, clinical significance unclear)

• Pregnancy and breastfeeding (insufficient safety data)
• Children and adolescents (insufficient safety data)
• Caution advised in patients with liver disease (theoretical concern based on metabolism)
• Caution in patients with gout or history of high uric acid levels (potential for increased uric acid)
• Caution in patients with significant kidney disease (limited data on safety in this population)
• Caution in patients with autoimmune conditions (theoretical concern based on immune effects)
• Caution in patients with hormone-sensitive cancers (theoretical concern, discussed further below)
• Known hypersensitivity to nicotinamide riboside or other vitamin B3 forms

• Potential interaction with medications metabolized by the liver (theoretical, based on limited evidence of mild liver enzyme effects)
• Possible interaction with blood pressure medications (monitor blood pressure if combining)
• Theoretical interaction with medications affecting NAD+ metabolism
• Potential interaction with other NAD+ precursors (niacin, nicotinamide, NMN) – not necessarily harmful but may not provide additive benefits
• Possible interaction with statins (both may affect cellular energy metabolism)
• Theoretical interaction with medications affecting sirtuin activity
• Caution with medications that may increase uric acid levels

No official Tolerable Upper Intake Level (UL) has been established specifically for nicotinamide riboside. Based on available research, doses up to 2,000 mg per day have been used in short-term clinical studies without serious adverse effects, though such high doses are not typically recommended for regular use. For comparison, the UL for nicotinamide (another form of vitamin B3) is 35 mg/kg/day, which would translate to approximately 2,450 mg for a 70 kg adult. However, this cannot be directly applied to NR due to its different metabolism and effects.

Most clinical studies have used doses of 250-1,000 mg daily with good safety profiles. For general supplementation, doses of 250-500 mg daily appear to be well-tolerated by most healthy adults for extended use. A note of caution regarding cancer: Some preclinical research has raised theoretical concerns that increasing NAD+ levels might potentially support the growth of existing cancer cells, particularly in certain hormone-sensitive cancers. However, other research suggests NR may have anti-cancer effects through improved cellular metabolism and DNA repair.

The current scientific consensus is that there is insufficient evidence to conclude that NR supplementation increases cancer risk in humans, but those with active cancer or high cancer risk should consult healthcare providers before supplementing. As with any supplement, it’s prudent to use the lowest effective dose for the intended purpose, particularly for long-term use. Those with pre-existing health conditions, on medications, or with specific sensitivities should consult healthcare providers before using NR.

Nicotinamide riboside chloride (NR-Cl) has been reviewed by the FDA through the Generally Recognized as Safe (GRAS) notification process. In 2016, the FDA issued a letter of no objection to ChromaDex’s GRAS notification for Niagen (their patented form of NR-Cl), effectively acknowledging its safety for use in food products at specified levels. As a dietary supplement ingredient, NR falls under the regulations of the Dietary Supplement Health and Education Act (DSHEA) of 1994. Under DSHEA, manufacturers are responsible for determining that their products are safe before marketing, but do not need FDA approval.

The FDA has not approved specific health claims for NR supplements. In 2018, the FDA issued a New Dietary Ingredient (NDI) notification response to ChromaDex for Niagen, acknowledging the company’s safety data for doses up to 300 mg per day. This does not constitute approval but indicates the FDA did not object to the safety information provided for this dosage. NR is not approved as a drug for treating any disease or condition in the United States.

Any marketing of NR supplements must avoid making disease treatment or prevention claims, which would classify the product as an unapproved drug under FDA regulations.

Eu: In the European Union, nicotinamide riboside chloride has been approved as a Novel Food ingredient following safety evaluation by the European Food Safety Authority (EFSA). In 2019, EFSA published a scientific opinion concluding that NR-Cl is safe for use in food supplements at doses up to 300 mg per day for the general adult population. This approval allows NR to be legally marketed in food supplements throughout the EU. The EU has stricter regulations than the US regarding health claims, and no specific health claims for NR have been approved under the EU Nutrition and Health Claims Regulation.

Canada: Health Canada has approved nicotinamide riboside chloride as a Natural Health Product (NHP) ingredient. NR products with approved Natural Product Numbers (NPNs) can be legally sold in Canada with specific authorized claims related to its role as a precursor to NAD+ and support for cellular energy metabolism. Health Canada has established specific quality requirements and maximum daily doses for NR products.

Australia: The Australian Therapeutic Goods Administration (TGA) regulates NR as a complementary medicine ingredient. NR products can be listed on the Australian Register of Therapeutic Goods (ARTG) after meeting safety, quality, and efficacy requirements. The TGA has specific guidelines regarding permitted indications for listed complementary medicines containing NR.

Japan: Information on NR’s regulatory status in Japan is limited in publicly available English-language sources. As a relatively new ingredient, it may be regulated under Japan’s system for Foods with Function Claims or as a food additive, but specific regulatory details are not widely documented.

China: Information on NR’s regulatory status in China is limited in publicly available English-language sources. As with many jurisdictions, novel supplement ingredients typically require specific approval processes, but details regarding NR’s status in China are not widely documented in English.

High

$1.00-$3.00 per day for branded forms (250-300 mg); $0.75-$2.00 per day for generic forms; $2.00-$5.00 per day for higher doses (500-1,000 mg)

Nicotinamide riboside is among the more expensive dietary supplements on the market, with costs significantly higher than many other NAD+ precursors and longevity-focused supplements. This premium pricing is primarily due to patent protection, complex manufacturing processes, and the relatively recent development of NR as a commercial ingredient. Branded forms of NR, particularly those using ChromaDex’s patented Niagen ingredient, typically command the highest prices, ranging from $1.00-$3.00 per day for standard doses (250-300 mg). These products often have the advantage of being used in clinical research, providing greater assurance of quality, potency, and efficacy.

Generic or less established brands may offer somewhat lower prices ($0.75-$2.00 per day), though caution is warranted as the quality, purity, and actual NR content may vary. Given the complexity of manufacturing NR and the patent landscape, extremely low-priced products should be approached with skepticism. For those seeking higher doses (500-1,000 mg daily) based on some clinical research, costs can reach $2.00-$5.00 per day, representing a significant ongoing investment. When evaluating the value proposition of NR, it’s important to consider that while it consistently raises NAD+ levels in clinical studies, the translation of this biochemical effect to meaningful health outcomes in humans remains an area of active research with mixed results thus far.

For general NAD+ enhancement, other precursors like niacin (vitamin B3) and nicotinamide are substantially less expensive, though they may have different side effect profiles and potentially less efficient conversion to NAD+ in certain tissues. Niacin typically costs $0.05-$0.20 per day, making it 10-50 times less expensive than NR. For specific applications where NR has shown promise in research, such as supporting mitochondrial function or cellular energy production, the premium price may be more justified, particularly for individuals with relevant health concerns or those at advanced ages where NAD+ decline is more pronounced. Subscription programs offered by some manufacturers can reduce costs by 10-30%, potentially improving the value proposition for those committed to long-term use.

When comparing products, calculate the cost per mg of NR rather than per capsule, as potency varies between brands. Some combination products pair NR with synergistic compounds like resveratrol or quercetin, potentially offering better overall value despite higher prices if these combinations provide enhanced benefits. For those interested in NR’s potential benefits but concerned about cost, starting with a lower dose (250 mg daily) may provide a reasonable compromise, as some research suggests significant NAD+ increases even at this entry-level dose.

Nicotinamide riboside is relatively unstable compared to many other supplements, with stability being a significant consideration for product formulation and storage. Properly formulated and packaged NR supplements typically have a manufacturer-assigned shelf life of 1-2 years under appropriate storage conditions. The stability is primarily limited by NR’s susceptibility to hydrolysis (breakdown in the presence of moisture) and oxidation. The specific salt form affects stability, with the chloride form (NR-Cl) being the most common and relatively more stable form used in supplements.

Some manufacturers use specialized stabilization technologies and packaging to extend shelf life, such as blister packs, desiccants, or specialized coatings. Quality manufacturers typically conduct stability testing throughout the product’s shelf life to ensure potency is maintained until the expiration date. Once opened, NR supplements should ideally be used within 3-6 months for optimal potency, though they may remain stable longer if properly stored.

Store in a cool, dry place away from direct light, heat, and moisture (below 25°C/77°F). Refrigeration is often recommended by manufacturers, particularly after opening, as it can significantly extend stability by reducing degradation rates. Keep containers tightly closed with the original desiccant packet (if included) to prevent moisture exposure, as NR is highly susceptible to hydrolysis in moist conditions. Avoid storing in bathrooms or other high-humidity areas.

Some manufacturers use blister packaging specifically to protect each dose from moisture until use – in these cases, only remove tablets/capsules from the blister pack immediately before consumption. For products in bottles, minimize the time the bottle is open during use to reduce exposure to air and moisture. Follow any specific storage instructions provided by the manufacturer, as different formulations may have unique stability requirements. If the supplement changes color, develops an unusual odor, or shows other signs of degradation, it should be discarded regardless of the expiration date.

Moisture (primary concern; causes hydrolysis of the glycosidic bond), Heat (accelerates degradation reactions; significant degradation occurs above 40°C/104°F), Light exposure (particularly UV light, can cause photodegradation), Oxygen exposure (leads to oxidation), pH extremes (NR is most stable at slightly acidic to neutral pH), Transition metals (can catalyze degradation reactions), Prolonged exposure to high humidity, Enzymatic degradation (if exposed to certain bacteria or enzymes), Freeze-thaw cycles (can accelerate degradation through physical stress and condensation)

Synthesis Methods

Natural Sources

Quality Considerations

Nicotinamide riboside has a relatively short history as a supplement, having only become commercially available in the past decade. However, its scientific discovery and the understanding of its role in metabolism have a longer history dating back to the mid-20th century. NR was first identified as a growth factor for Haemophilus influenzae bacteria in 1944 by scientists studying bacterial nutrition requirements. At that time, it was recognized as a form of vitamin B3 but was not extensively studied for human nutrition or supplementation purposes.

The scientific understanding of NR’s metabolic role began to expand significantly in the early 2000s. In 2004, Dr. Charles Brenner and colleagues at Dartmouth College published a landmark paper in the journal Cell identifying the specific pathway by which NR is converted to NAD+ in yeast. This research revealed that NR could be metabolized to NAD+ through a unique salvage pathway involving the enzyme nicotinamide riboside kinase (Nrk1), which was distinct from the known pathways for other forms of vitamin B3.

This discovery opened the door to understanding NR’s potential as an NAD+ precursor in humans. In 2007, the same research group demonstrated that the NR kinase pathway was conserved in humans, suggesting that NR could potentially serve as an effective NAD+ precursor in human metabolism. This finding was significant because it identified a new way to potentially boost NAD+ levels, which were already known to decline with age and in various disease states. The first major preclinical studies showing NR’s potential health benefits began to emerge around 2012.

Research by Dr. Johan Auwerx and colleagues at the École Polytechnique Fédérale de Lausanne (EPFL) in Switzerland demonstrated that NR supplementation could increase NAD+ levels in mice and improve various aspects of metabolic health, including mitochondrial function, exercise capacity, and protection against metabolic disorders. These findings generated significant interest in NR as a potential health-promoting compound. The commercial development of NR as a supplement began shortly thereafter.

ChromaDex, a California-based company, licensed patents related to NR from Dartmouth College and began developing a commercial form of NR called Niagen. In 2013, ChromaDex received Generally Recognized as Safe (GRAS) status for Niagen from the FDA, allowing it to be used in food and supplement products. The first human clinical trial of NR was published in 2016, demonstrating that single doses of NR were safe and effectively increased blood NAD+ levels in healthy volunteers. This was followed by additional clinical studies examining various doses, durations, and potential health effects of NR supplementation.

NR became commercially available to consumers around 2013-2014, initially through ChromaDex’s Niagen ingredient being included in various supplement products. In 2017, ChromaDex launched their own consumer NR supplement brand, Tru Niagen. Other companies have since developed their own NR products, though many use ChromaDex’s Niagen as the raw material due to patent protections. The scientific and commercial interest in NR has grown substantially in recent years, driven by research into NAD+ metabolism and its potential role in aging and various health conditions.

As of 2023, numerous clinical trials are ongoing to investigate NR’s effects on various aspects of health, including cardiovascular function, cognitive health, metabolic disorders, and mitochondrial diseases. Unlike many traditional supplements with centuries of historical use, NR’s history as a supplement is still unfolding, with much of the research and commercial development occurring within the past decade. This relatively short history means that long-term effects of supplementation are still being established, though safety data from clinical trials has generally been reassuring for short to medium-term use.

Nicotinamide riboside for Parkinson’s disease, NR supplementation for mild cognitive impairment and Alzheimer’s disease, Effects of NR on muscle function and metabolism in older adults, NR for heart failure with preserved ejection fraction, NR supplementation for non-alcoholic fatty liver disease, Effects of long-term NR supplementation on aging biomarkers, NR for mitochondrial myopathies and other rare mitochondrial disorders, Combination of NR with other NAD+ boosters or sirtuin activators, NR for post-COVID fatigue syndrome, Effects of NR on exercise adaptation and performance in various populations