What is the current clinical data supporting the use of Nicotinamide adenine dinucleotide (NAD+) supplementation?

Clinical Data Supporting NAD+ Supplementation

There is currently insufficient clinical evidence to support the use of NAD+ supplementation for improving health outcomes related to morbidity, mortality, or quality of life beyond treating niacin deficiency. 1, 2

NAD+ Basics and Physiological Role

NAD+ (nicotinamide adenine dinucleotide) is a critical coenzyme involved in numerous cellular processes:

• Functions as a cofactor for over 400 enzymes in the body 1, 2
• Essential for energy metabolism and ATP production 2
• Involved in DNA repair and creation 2
• Provides antioxidant effects 1, 2
• Supports mitochondrial function 2

Current Evidence Base

Established Clinical Applications

• Treatment of niacin deficiency (pellagra) with standard doses of niacin (15-20 mg/day nicotinic acid or 300 mg/day nicotinamide) 1
• Parenteral nutrition should provide at least 40 mg of niacin per day (Grade B recommendation) 1
• Enteral nutrition should provide 18-40 mg per day of niacin in 1500 kcal (Grade A recommendation) 1

Preclinical Research

While preclinical studies suggest potential benefits, clinical evidence remains limited:

• Animal studies show NAD+ levels decline with age, associated with:

  • Increased ROS production and DNA damage 1
  • Decreased SIRT1 activity 1
  • Increased PARP activity 1
  • Decreased ATP production and impaired mitochondrial function 1

• Preclinical models suggest potential benefits for:

  • Age-related cognitive decline 3
  • Non-alcoholic fatty liver disease 4
  • Neurodegenerative conditions 5, 6

Human Clinical Evidence

• Limited clinical trials with modest effects in people with obesity 4
• Some improvements in plasma and neuroimaging biomarkers in Alzheimer's disease trials with nicotinamide riboside 6
• Age-related decline in cellular NAD+ levels observed in humans 1

Safety and Risk Considerations

Potential Risks of NAD+ Supplementation

• Nicotinic acid (a form of niacin) can cause flushing at doses as low as 30 mg 1
• Serious hepatotoxicity can occur with niacin at doses around 3 g per day 1
• Theoretical concerns include:
  • Accumulation of putative toxic metabolites 7
  • Potential tumorigenesis 7
  • Promotion of cellular senescence 7

Safe Intake Levels

• Upper limit for nicotinic acid: 10 mg/day (due to flushing risk) 1, 2
• Upper limit for nicotinamide: approximately 900 mg/day for adults 1, 2

Recommendations for NAD+ Support

Dietary Approach (First-Line)

The most evidence-based approach to support NAD+ levels is through dietary consumption of niacin-rich foods:

• Meat and poultry (excellent sources of preformed niacin) 2
• Fish, especially tuna and salmon 2
• Nuts and legumes (good plant-based sources) 2
• Whole grains (moderate amounts of niacin) 2
• Fortified packaged foods 2

Daily Intake Recommendations

• Men over 14 years: 16 mg/day of niacin equivalents 1, 2
• Women over 14 years: 14 mg/day of niacin equivalents 1, 2
• Pregnant women: 18 mg/day of niacin equivalents 1, 2
• Lactating women: 16 mg/day of niacin equivalents 1, 2

Clinical Monitoring

• In cases of suspected deficiency with symptoms (diarrhea, dermatitis, dementia), blood or tissue NAD+ levels may be measured 1
• If measurement is difficult, a pragmatic approach is to store a blood sample and await effects of niacin supplements on symptoms 1

Key Takeaways

1. NAD+ is physiologically important, but supplementation beyond recommended dietary intake lacks robust clinical evidence
2. Dietary sources of niacin remain the best-supported approach for maintaining adequate NAD+ levels
3. Therapeutic supplementation should be reserved for documented deficiency states
4. More long-term human clinical trials are needed before recommending NAD+ supplementation for age-related conditions