NAD+ Supplement for Brain Function

Recruiting at 1 trial location

Overseen By Cindy E Tsotsoros, PhD

Age: 18+

Sex: Female

Trial Phase: Academic

Sponsor: University of Rhode Island

Must not be taking: Hormone medication

Disqualifiers: Pregnant, Breastfeeding, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Compensation: Varies

Number of Visits: 3

Duration: 4 weeks

50 Participants Needed

Trial Summary

What is the purpose of this trial?

The goal of this clinical trial is to learn if Nicotinamide adenine dinucleotide (NAD+) can influence cognition and biomarkers in healthy, cognitively intact women who identify as Latina and are between the ages of 40-80. The main questions it aims to answer are: Will executive function change in response to NAD+? Will inflammatory markers and serum indicators of neurodegeneration change in response to NAD+? Researchers will compare individuals receiving the NAD+ to see if the results differ from those receiving the placebo. Participants will: Complete an online questionnaire, Visit the lab for computerized cognitive testing and a blood draw, Take NAD+ or a placebo every day for 4 weeks, Visit the lab for computerized cognitive testing and a blood draw

Do I need to stop my current medications for the trial?

The trial does not specify if you need to stop taking your current medications, but you cannot participate if you are taking hormone medication.

What data supports the effectiveness of the treatment Nicotinamide adenine dinucleotide (NAD+) for brain function?

Research suggests that increasing NAD+ levels through supplements like nicotinamide riboside (NR) may help improve brain function, particularly in conditions like Alzheimer's disease and age-related cognitive decline. Studies in animals and some human trials have shown positive effects on memory and cognitive abilities, although more research is needed to confirm these benefits in humans. ^{1 2 3 4 5}

Is NAD+ supplementation safe for humans?

Research shows that NAD+ precursors like nicotinamide riboside (NR) and nicotinamide mononucleotide (NMN) are generally safe for human use. Studies in humans and animals have not reported significant adverse effects, even at higher doses, although more research is needed to confirm long-term safety. ^{1 6 7 8 9}

How is the NAD+ supplement treatment different from other treatments for brain function?

The NAD+ supplement treatment is unique because it aims to boost brain NAD+ levels, which may help improve cognitive function and protect against neurodegenerative diseases. Unlike other treatments, it uses nicotinamide riboside (NR), a form of vitamin B3, which has shown promise in increasing NAD+ levels and modifying biomarkers related to brain health. ^{1 2 5 10 11}

Eligibility Criteria

This trial is for Latina women aged 40-80 who are healthy and cognitively intact, have experienced three or more adverse childhood events, and have a BMI of at least 18.5. It's not open to those on hormone medication, or who are pregnant or breastfeeding.

Inclusion Criteria

Identify as Latina, have three or more adverse childhood experiences, and a BMI of 18.5 or above

Exclusion Criteria

Pregnant

Breastfeeding

I am currently taking hormone medication.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Pre-testing

Participants complete an online questionnaire and visit the lab for cognitive testing and a blood draw before receiving the supplement

1 week

1 visit (in-person)

Treatment

Participants take NAD+ or a placebo every day for 4 weeks

4 weeks

1 visit (in-person) at the end of treatment

Post-testing

Participants visit the lab for cognitive testing and a blood draw after receiving the supplement

1 week

1 visit (in-person)

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

Treatment Details

Interventions

• Nicotinamide adenine dinucleotide

Trial Overview Researchers are testing if NAD+ supplements can improve brain function (like planning and decision-making) and reduce markers of inflammation and neurodegeneration in the blood compared to a placebo over four weeks.

Participant Groups

Group I: Intervention Experimental Treatment 1 Intervention

For four weeks, the participant will consume an oral supplement, either Nicotinamide adenine dinucleotide or a placebo.

Group II: Pre-testing prior to intervention Active Control 1 Intervention

Prior to receiving the supplement, either Nicotinamide adenine dinucleotide or the placebo, participants will undergo cognitive testing and a blood draw.

Group III: Post-testing after intervention Active Control 1 Intervention

After receiving the supplement, either Nicotinamide adenine dinucleotide or the placebo, participants will undergo cognitive testing and a blood draw.

Who Is Running the Clinical Trial?

University of Rhode Island

Lead Sponsor

Trials

57

Recruited

22,400+

National Institute of General Medical Sciences (NIGMS)

Collaborator

Trials

315

Recruited

251,000+

Findings from Research

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 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]

A phase I trial involving 20 individuals with Parkinson's disease found that high-dose nicotinamide riboside (NR) therapy (1500 mg twice daily) was well tolerated, with no moderate or severe adverse events reported, indicating a good safety profile for this treatment.

NR therapy significantly increased blood NAD+ levels by up to 5-fold and was associated with clinical improvements in Parkinson's disease symptoms, although these improvements may be influenced by the timing of levodopa administration.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

NR-SAFE: a randomized, double-blind safety trial of high dose nicotinamide riboside in Parkinson's disease. Berven, H., Kverneng, S., Sheard, E., et al.[2023]

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]

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]

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 (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]

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]

The synthetic form of β-nicotinamide mononucleotide (NMN-C®) was found to be safe in a study involving acute and subchronic toxicity tests, with no mutagenic or genotoxic effects observed.

In a 90-day study with doses up to 1500 mg/kg/day, NMN-C® did not show any adverse effects, establishing a No-Observable Adverse Effect Level (NOAEL) of ≥1500 mg/kg/day, indicating its potential safety for short to intermediate-term use.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Safety evaluation after acute and sub-chronic oral administration of high purity nicotinamide mononucleotide (NMN-C®) in Sprague-Dawley rats. Cros, C., Cannelle, H., Laganier, L., et al.[2021]

Nicotinamide riboside (NR) is more effective than NAD+ in protecting against brain damage caused by excitotoxicity, as shown in experiments with cortical neurons and NMDA injections.

The protective effects of NR involve maintaining intracellular NAD+ levels, highlighting its potential as a neuroprotective agent in neurodegenerative conditions.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Nicotinamide riboside, a form of vitamin B3, protects against excitotoxicity-induced axonal degeneration. Vaur, P., Brugg, B., Mericskay, M., et al.[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]

References

1. Switzerland pubmed.ncbi.nlm.nih.gov

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

2. United States pubmed.ncbi.nlm.nih.gov

Nicotinamide ribose ameliorates cognitive impairment of aged and Alzheimer's disease model mice. [2022]

3. England pubmed.ncbi.nlm.nih.gov

NR-SAFE: a randomized, double-blind safety trial of high dose nicotinamide riboside in Parkinson's disease. [2023]

4. Switzerland pubmed.ncbi.nlm.nih.gov

A randomized placebo-controlled trial of nicotinamide riboside in older adults with mild cognitive impairment. [2023]

5. England pubmed.ncbi.nlm.nih.gov

Can nicotinamide riboside protect against cognitive impairment? [2021]

6. England 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. [2023]

7. Switzerland pubmed.ncbi.nlm.nih.gov

Possible Adverse Effects of High-Dose Nicotinamide: Mechanisms and Safety Assessment. [2021]

8. United States 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. [2021]

9. England pubmed.ncbi.nlm.nih.gov

Safety evaluation after acute and sub-chronic oral administration of high purity nicotinamide mononucleotide (NMN-C®) in Sprague-Dawley rats. [2021]

10. United States pubmed.ncbi.nlm.nih.gov

Nicotinamide riboside, a form of vitamin B3, protects against excitotoxicity-induced axonal degeneration. [2021]

11. England pubmed.ncbi.nlm.nih.gov

Oral nicotinamide riboside raises NAD+ and lowers biomarkers of neurodegenerative pathology in plasma extracellular vesicles enriched for neuronal origin. [2023]