What is nicotinamide adenine dinucleotide (NAD⁺) therapy?

What is Nicotinamide Adenine Dinucleotide (NAD⁺) Therapy?

NAD⁺ therapy refers to supplementation strategies aimed at increasing cellular levels of nicotinamide adenine dinucleotide, a critical coenzyme involved in energy metabolism, DNA repair, and cellular aging processes, primarily through oral administration of NAD⁺ precursors like nicotinamide, nicotinamide riboside (NR), or nicotinamide mononucleotide (NMN). 1, 2

Core Biochemistry and Function

NAD⁺ is a pyridine nucleotide coenzyme that exists in two forms:

• NAD⁺ (oxidized form) and NADH (reduced form) function as electron carriers in cellular redox reactions, particularly in mitochondrial energy production through oxidative phosphorylation 3
• NAD⁺ serves as a substrate for over 400 enzymatic reactions including DNA repair enzymes (PARPs), sirtuins (longevity proteins), and CD38 (immune regulator) 1, 4, 5
• The molecule consists of two nucleotides joined by phosphate groups—one containing adenine and one containing nicotinamide 1

NAD⁺ plays essential roles in:

• Energy metabolism and ATP production in mitochondria 3
• DNA base excision repair through PARP activation 3
• Gene expression regulation through sirtuin activity 3, 5
• Calcium homeostasis and cellular signaling 3
• Immune function and inflammatory responses 6, 5

Age-Related Decline and Rationale for Therapy

Cellular NAD⁺ levels decline progressively with aging, creating the therapeutic rationale for supplementation:

• Age-related NAD⁺ depletion occurs in both men (P = 0.001) and women (P = 0.01), associated with increased PARP activation and decreased SIRT1 activity 2
• NAD⁺ depletion contributes to mitochondrial dysfunction, cellular energy crisis, and apoptosis-inducing pathways 3
• Low NAD⁺ levels result in impaired DNA repair, oxidative stress accumulation, and cellular senescence 6, 5
• Chronic inflammation and immune activation accelerate NAD⁺ consumption through CD38 activity 5

Guideline-Recommended Supplementation Approaches

Oral Precursor Supplementation (First-Line)

The American Society for Parenteral and Enteral Nutrition recommends the oral/enteral route for niacin supplementation whenever the gastrointestinal tract is functional, as it has established safety data and effectively increases blood NAD⁺ levels. 2

Recommended daily intake of niacin (NAD⁺ precursor):

• Adult males (>14 years): 16 mg/day 1, 2
• Adult females (>14 years): 14 mg/day 1, 2
• Pregnant women: 18 mg/day 1
• Lactating women: 16 mg/day 1

Dietary sources include:

• Fortified packaged foods, meat and poultry 1, 2
• Red fish (tuna, salmon) 1, 2
• Nuts, legumes, and seeds 1, 2
• Whole-grain cereals, dark-green leafy vegetables 3

Forms of NAD⁺ Precursors

Different precursors have distinct properties:

Nicotinamide (NAM):

• Does not cause flushing (unlike nicotinic acid) 1
• Upper safety limit: approximately 900 mg/day for adults (12.5 mg/kg body weight/day) 1, 2
• Used therapeutically at 300 mg/day for pellagra treatment 2
• No adverse effects observed at doses up to 25 mg/kg body weight/day in diabetic subjects 1

Nicotinic Acid (NA):

• Commonly causes facial, arm, and chest flushing within 30 minutes at doses as low as 30 mg 1, 2
• Upper safety limit: only 10 mg/day for free nicotinic acid 1, 2
• Clinical doses for hypercholesterolemia can reach 3 g/day but require monitoring 1

Nicotinamide Riboside (NR) and Nicotinamide Mononucleotide (NMN):

• Do not typically cause flushing 1
• Most common side effects are gastrointestinal (nausea, vomiting, diarrhea) 1, 2
• Studied in research settings but lack extensive long-term safety data 6, 5

Parenteral Administration (Only When Oral Route Unavailable)

For patients requiring parenteral nutrition due to non-functional GI tract, guidelines recommend standard niacin at 40 mg/day, not injectable NAD⁺, to maintain adequate NAD⁺ levels. 1, 2

Injectable NAD⁺: Critical Safety Concerns

Injectable NAD⁺ is NOT recommended in clinical practice guidelines and lacks FDA approval for therapeutic use:

• No published randomized controlled trials exist for NAD⁺ infusions in humans 2
• FDA labeling for intravenous NAD⁺ lists only cosmetic applications, not therapeutic medical indications 2
• NAD⁺ is a large, charged molecule with poor bioavailability and stability when injected 2
• A 2026 retrospective study found NAD⁺ IV caused moderate to severe gastrointestinal symptoms, increased heart rate, and chest pressure during infusions, with average infusion times of 97 minutes versus 37 minutes for NR IV 7

Risks of injectable administration include:

• Infection risk from improper sterile technique 8
• Hypersensitivity reactions 8
• Unknown pharmacokinetics when administered parenterally 8
• No standardized dosing protocols 8

Monitoring and Safety Parameters

When using therapeutic doses of niacin compounds (approaching or exceeding 1000 mg daily):

• The American College of Cardiology recommends monitoring hepatic transaminases (ALT, AST) before initiation and every 6 months 1
• Monitor baseline fasting glucose or hemoglobin A1c for metabolic effects 1
• Discontinue immediately if hepatic transaminases exceed 2-3 times the upper limit of normal 1

Assessment of niacin status:

• Urinary metabolites (N-methyl-nicotinamide and N-methyl-2-pyridone-carboxamide) can assess niacin status 1
• Blood NAD⁺ levels can be measured if pellagra symptoms are present (diarrhea, dermatitis, dementia) 2

Clinical Algorithm for Patient Requests

When patients inquire about NAD⁺ therapy:

1. First, optimize dietary intake of niacin-rich foods: fortified foods, meat, poultry, red fish, nuts, and legumes 2

2. Assess for deficiency risk factors: corn-based diet, malnutrition, chronic alcoholism, malabsorption states 2

3. If deficiency suspected, measure blood or tissue NAD⁺ levels 2

4. For confirmed deficiency (pellagra), use oral nicotinic acid (15-20 mg/day) or nicotinamide (300 mg/day) 2

5. For age-related supplementation in healthy adults, consider oral nicotinamide at doses up to 900 mg/day with appropriate monitoring 1, 2

6. Do NOT use NAD⁺ infusions for therapeutic purposes outside of research protocols due to lack of guideline support, poor pharmacokinetics, and absent proven clinical benefit 2

Critical Pitfalls to Avoid

• Do not assume injectable NAD⁺ is superior to oral precursors—no evidence supports this claim and guidelines explicitly recommend oral routes 2
• Do not confuse niacin precursors with direct NAD⁺ administration—they have different safety profiles and evidence bases 2
• Do not use nicotinic acid forms without warning patients about flushing at doses as low as 30 mg 1, 2
• Do not recommend NAD⁺ injections based on marketing claims—they lack regulatory approval for therapeutic use 2
• Do not overlook hepatotoxicity monitoring when using doses approaching 1000 mg daily 1

Potential Long-Term Risks

While NAD⁺ precursors show promise in preclinical studies for age-related conditions 4, 6, 5, potential risks require consideration:

• Accumulation of putative toxic metabolites 6
• Theoretical tumorigenesis concerns 6
• Promotion of cellular senescence 6
• NAD(P)H oxidase activity implicated in anthracycline-induced cardiotoxicity 8

Evidence for long-term human clinical trials remains limited, and most benefits demonstrated are in preclinical models 6, 5.