NAD Supplementation for Brain Health in Aging

Overseen By Andriy Yabluchanskiy, MD, PhD

Age: 18+

Sex: Any

Trial Phase: Phase 4

Sponsor: University of Oklahoma

Must not be taking: NAD enhancers

Disqualifiers: CNS disease, Major psychiatric, others

Prior Safety Data This treatment has passed at least one previous human trial

Compensation: Varies

Number of Visits: 2

Duration: 8 weeks

214 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests whether Nicotinamide Riboside (NR), a form of Vitamin B3, can improve brain health and memory in older adults. Participants will take either NR or a placebo (a pill with no active ingredient) daily for eight weeks. The trial aims to determine if NR can maintain brain health as people age. Individuals aged 60 to 85 with good hearing and vision, who can read and write in English, may be suitable for this trial. As a Phase 4 trial, this research seeks to understand how this already FDA-approved and effective treatment benefits more patients.

Will I have to stop taking my current medications?

The trial does not specify if you need to stop taking your current medications, but you cannot take other NAD enhancers like Nicotinamide riboside or nicotinamide mononucleotide within 4 weeks before starting the trial.

What is the safety track record for Nicotinamide riboside?

Research has shown that nicotinamide riboside (NR), a type of Vitamin B3, is generally safe for people. Studies have found that NR can safely increase levels of NAD+, a molecule important for cell health. In one study, participants took NR for a long time without any serious side effects, suggesting it is safe for daily use at the tested doses.

The FDA has classified NR as Generally Recognized As Safe (GRAS) for use in foods, meaning experts consider it safe based on its history and research.

While NR is mostly safe, some people might experience mild side effects, such as stomach issues like nausea or diarrhea. However, these effects are uncommon and usually mild.

Overall, current evidence supports the safe use of NR in humans, especially at the doses typically tested in studies. ^{1 2 3 4 5}

Why are researchers enthusiastic about this study treatment?

Researchers are excited about nicotinamide riboside (NR) for brain health in aging because it offers a novel approach by boosting NAD+ levels, which play a crucial role in cellular energy production and repair. Unlike standard treatments that may focus on symptomatic relief, NR targets the underlying cellular processes associated with aging. This unique mechanism of action has the potential to support brain health and cognitive function more directly and effectively than current options.

What evidence suggests that Nicotinamide riboside might be an effective treatment for brain health in aging?

Research shows that nicotinamide riboside (NR), a type of Vitamin B3, can increase levels of NAD+, a molecule that provides energy to cells. One study found that NR improved brain function by enhancing thinking skills in some people. Another study demonstrated that NR reduced brain inflammation and improved cognition in diabetic mice. Evidence also suggests that NR might help with conditions like Parkinson's disease by restoring NAD levels. This trial will test NR supplementation, which participants may receive, to evaluate its potential to support brain health and memory with aging. ^{6 7 8 9 10}

Who Is on the Research Team?

Andriy Yabluchanskiy, MD, PhD

Principal Investigator

University of Oklahoma

Are You a Good Fit for This Trial?

This trial is for people aged 60 to 85 who can read and write in English, have good enough vision and hearing to participate, and can give informed consent. It's not for those with recent severe strokes, major uncontrolled psychiatric conditions, substance abuse issues, active brain diseases or poor kidney function.

Inclusion Criteria

I am between 60 and 85 years old.

I can see and hear well enough to undergo tests.

I understand and can agree to the study's procedures and risks.

Exclusion Criteria

I haven't taken NAD enhancers like nicotinamide riboside or mononucleotide in the last 4 weeks.

You have a serious mental illness, such as severe depression that is not well controlled with medication, or you have a problem with alcohol or drug abuse.

I have not had a stroke, excluding TIA, in the last 60 days.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive either Nicotinamide Riboside (NR) or placebo daily for 8 weeks to assess effects on neurovascular coupling and endothelial function

8 weeks

Weekly visits for monitoring and assessments

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

2 visits (in-person)

What Are the Treatments Tested in This Trial?

Interventions

• Nicotinamide riboside
• Placebo

Trial Overview The study tests if Nicotinamide Riboside (NR), a form of Vitamin B3, improves brain health and memory in older adults. Participants will take NR daily or a placebo without knowing which one they're getting to compare the effects fairly.

How Is the Trial Designed?

Group I: NR Experimental Treatment 1 Intervention

Treatment with oral NR (1g/day per os for 8 weeks)

Group II: Control Placebo Group 1 Intervention

Visually identical placebo (daily, per os, for 8 weeks)

Nicotinamide riboside is already approved in United States, European Union for the following indications:

Approved in United States as Niagen for:

• Dietary supplement for general health and wellness

Approved in European Union as Tru Niagen for:

• Dietary supplement for general health and wellness

Who Is Running the Clinical Trial?

University of Oklahoma

Lead Sponsor

Trials

484

Recruited

95,900+

University of Pennsylvania

Collaborator

Trials

2,118

Recruited

45,270,000+

Elysium Health

Industry Sponsor

Trials

18

Recruited

37,000+

Oklahoma Medical Research Foundation

Collaborator

Trials

24

Recruited

8,400+

Published Research Related to This Trial

Nicotinamide riboside (NR) is a form of vitamin B3 that effectively increases NAD+ levels, which may help counteract age-related declines in this important metabolite.

In a 90-day safety study on Sprague Dawley rats, NR-E showed no significant adverse effects at doses up to 1,200 mg/kg/d, establishing a no-observed-adverse-effect-level (NOAEL) of 500 mg/kg/d for males and 1,200 mg/kg/d for females.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Safety Assessment of High-Purity, Synthetic Nicotinamide Riboside (NR-E) in a 90-Day Repeated Dose Oral Toxicity Study, With a 28-Day Recovery Arm. Marinescu, AG., Chen, J., Holmes, HE., et al.[2021]

Oral supplementation with nicotinamide riboside has shown potential in improving learning and memory while reducing Alzheimer's disease-related pathology in mouse models, indicating its efficacy in combating age-related cognitive decline.

Nicotinamide riboside is well tolerated in humans with minimal side effects, suggesting it could be a safe therapeutic option for enhancing cognitive function and maintaining brain health as we age.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Can nicotinamide riboside protect against cognitive impairment? Braidy, N., Liu, Y.[2021]

Nicotinamide (NAM) has potential benefits for various health conditions, but high doses can lead to adverse effects, including inhibition of protective enzymes and alterations in cellular metabolism.

While current usage levels of NAM are considered safe, chronic high-dose use may pose risks for epigenetic changes, highlighting the need for further research on its long-term safety.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Possible Adverse Effects of High-Dose Nicotinamide: Mechanisms and Safety Assessment. Hwang, ES., Song, SB.[2021]

A study involving 22 healthy older adults showed that oral supplementation with nicotinamide riboside (NR) significantly increases NAD+ levels in neuronal extracellular vesicles, which are indicators of brain health.

The NR supplementation also reduced levels of biomarkers associated with neurodegenerative diseases, such as Aβ42 and certain kinases, suggesting a potential therapeutic effect on neuroinflammatory pathways and insulin resistance.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Oral nicotinamide riboside raises NAD+ and lowers biomarkers of neurodegenerative pathology in plasma extracellular vesicles enriched for neuronal origin. Vreones, M., Mustapic, M., Moaddel, R., et al.[2023]

Supplementing with NAD+ precursors shows promise in preserving cognitive ability and may help with age-related cognitive decline and other conditions like diabetes and traumatic brain injury, based on mostly positive findings from animal studies.

Despite the potential benefits, there are some reports of null or adverse effects, highlighting the need for more controlled clinical research to determine the true impact of NAD+ precursor supplementation on human cognitive health.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Supplementation with NAD+ and Its Precursors to Prevent Cognitive Decline across Disease Contexts. Campbell, JM.[2022]

Nicotinamide riboside (NR) was safely administered to 20 older adults with mild cognitive impairment (MCI) over a 10-week period, resulting in a significant 2.6-fold increase in blood NAD+ levels without any adverse effects reported between the NR and placebo groups.

While NR treatment did not improve cognitive function as measured by the Montreal Cognitive Assessment (MoCA), it did lead to a reduction in cerebral blood flow in specific brain regions, indicating that further research is needed to explore its potential effects on cognition and brain health.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A randomized placebo-controlled trial of nicotinamide riboside in older adults with mild cognitive impairment. Orr, ME., Kotkowski, E., Ramirez, P., et al.[2023]

In an 8-week clinical trial with overweight but healthy participants, nicotinamide riboside (NR) significantly increased whole blood NAD+ levels in a dose-dependent manner, with increases of 22%, 51%, and 142% for doses of 100, 300, and 1000 mg, respectively.

The study found NR to be safe, with no significant adverse effects reported compared to placebo, and it did not negatively impact cholesterol levels or 1-carbon metabolism, supporting its potential as a dietary supplement.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

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. Conze, D., Brenner, C., Kruger, CL.[2023]

Nicotinamide ribose (NR) supplementation for 3 months improved cognitive functions, such as short-term spatial memory in aged mice and contextual fear memory in Alzheimer's disease (AD) model mice, indicating its potential efficacy in combating cognitive decline.

NR supplementation also reduced harmful effects associated with AD, such as the accumulation of amyloid-beta (Aβ) and the activation of astrocytes, suggesting a mechanism of action that may help prevent the progression of dementia.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Nicotinamide ribose ameliorates cognitive impairment of aged and Alzheimer's disease model mice. Xie, X., Gao, Y., Zeng, M., et al.[2022]

Citations

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Nicotinamide Riboside, a Promising Vitamin B3 Derivative for ... Lee H.J., Yang S.J. Supplementation with nicotinamide riboside reduces brain inflammation and improves cognitive function in diabetic mice. Int. J. Mol. Sci ...

2. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC10828186/

A randomized placebo-controlled trial of nicotinamide riboside ... Nicotinamide riboside (NR) increases blood levels of NAD+, a cofactor central to energy metabolism, and improves brain function in some ...

3. nature.com nature.com/articles/s41467-023-43514-6

NR-SAFE: a randomized, double-blind safety trial of high ... Nicotinamide adenine dinucleotide (NAD) replenishment therapy using nicotinamide riboside (NR) shows promise for Parkinson's disease (PD) ...

4. sciencedirect.com sciencedirect.com/science/article/pii/S1043276025000700

NAD augmentation as a disease-modifying strategy for ... Our N-DOSE_AD trial is exploring the optimal dose of NR in AD and monitors brain metabolism and cognitive function over a course of 3 months ( ...

5. clinicaltrials.gov clinicaltrials.gov/study/NCT02942888?intr=nicotinamide%20riboside&rank=59&page=1&limit=100

The Effects of Nicotinamide Adenine Dinucleotide (NAD) ... The purpose of this study is to determine the effects of Niagen (nicotinamide riboside, vitamin B3), on NAD levels, brain function including cognition and blood ...

6. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC7352172/

Nicotinamide Riboside—The Current State of Research and ... Nicotinamide riboside (NR) has recently become one of the most studied nicotinamide adenine dinucleotide (NAD+) precursors, due to its numerous potential health ...

7. webmd.com webmd.com/vitamins/ai/ingredientmono-1560/nicotinamide-riboside

NICOTINAMIDE RIBOSIDE – Uses, Side Effects, and More The body needs NAD+ for many processes to work normally. Low levels can cause health problems. Taking nicotinamide riboside can help raise low NAD+ levels.

8. nature.com nature.com/articles/s41598-019-46120-z

Safety and Metabolism of Long-term Administration ... Safety and Metabolism of Long-term Administration of NIAGEN (Nicotinamide Riboside Chloride) in a Randomized, Double-Blind, Placebo-controlled ...

9. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC7277745/

Possible Adverse Effects of High-Dose Nicotinamide Nicotinamide (NAM) at doses far above those recommended for vitamins is suggested to be effective against a wide spectrum of diseases and conditions.

10. fda.gov fda.gov/files/food/published/GRAS-Notice-000635--Nicotinamide-riboside-chloride.pdf

GRAS Notice 635: Nicotinamide riboside chloride The substance ofthis Generally Recognized As Safe (GRAS) determination is. Nicotinamide Riboside Chloride (NR), a form ofvitamin B3. NR is a ...