NAD+
low riskAlso: Nicotinamide Adenine Dinucleotide · NAD · β-NAD+ · Coenzyme I
NAD+ is a coenzyme present in all living cells and central to energy metabolism, DNA repair, and sirtuin activation. While technically not a peptide, it is widely administered in clinical and wellness contexts via IV infusion, intramuscular injection, and oral precursors (NMN, NR). Declining NAD+ levels with aging correlate with metabolic dysfunction, and supplementation shows measurable physiological effects in human trials. Evidence is strongest for metabolic and mitochondrial outcomes; longevity benefits remain unproven in humans.
Reported Benefits
Mitochondrial function and energy metabolism
Human trials show increased muscle NAD+ levels and improvements in mitochondrial markers with oral NMN/NR supplementation. IV NAD+ produces rapid but transient elevation.
DNA repair
NAD+ is an obligate substrate for PARP enzymes involved in single-strand break repair. Animal and in vitro data are strong; human RCT data is emerging.
Metabolic health (insulin sensitivity)
NMN supplementation improved insulin sensitivity in postmenopausal women with prediabetes in a double-blind RCT (Yoshino et al., 2021).
Neuroprotection / cognitive function
Animal models show neuroprotective effects. One small human trial suggests cognitive benefits in older adults; replication needed.
Longevity / lifespan extension
Lifespan extension is established in worms and mice; no human longevity data exists. This claim is speculative in humans.
Mechanism of Action
NAD+ is a hydride acceptor in glycolysis and the TCA cycle (NADH/NADPH redox). It is also a substrate for sirtuins (SIRT1–7), PARP enzymes (DNA repair), and CD38 (cADPR signaling). Sirtuin activation via NAD+ modulates gene expression, mitochondrial biogenesis, and inflammation. Depletion with age reduces these pathways.
Key Clinical Studies
Yoshino et al. (2021)
Randomized, double-blind, placebo-controlled · 25
NMN supplementation improved insulin sensitivity and muscle insulin signaling in postmenopausal women with prediabetes
Martens et al. (2023)
Randomized, double-blind, placebo-controlled · 30
NMN supplementation increased blood NAD+ levels and improved muscle strength and walking speed in older adults
Dollerup et al. (2018)
Randomized, double-blind, placebo-controlled · 40
NR supplementation increased NAD+ metabolome in obese men; no metabolic improvement detected
Overview
NAD+ (nicotinamide adenine dinucleotide) is not a peptide — it’s a coenzyme. It’s included here because it appears in the same clinical contexts as therapeutic peptides, is widely administered via IV infusion in longevity and functional medicine clinics, and generates substantial search traffic from practitioners evaluating its role alongside peptide protocols. NAD+ is central to cellular energy production, operating as a hydride acceptor in the electron transport chain, and serves as a substrate for key longevity-associated enzymes including sirtuins and PARP DNA repair proteins.
Evidence Summary
The evidence for NAD+ supplementation is more robust than most research peptides, but the claims often outrun the data. Oral precursors (NMN, NR) reliably increase blood and tissue NAD+ levels. The clinical trials showing metabolic and mitochondrial benefits are small but methodologically sound. The longevity narrative — that NAD+ restores youthful gene expression and extends healthspan — is compelling mechanistically but remains unproven in humans. IV NAD+ infusions produce rapid symptomatic effects (energy, mental clarity) that users report clearly, but controlled trial data for IV-specific protocols is limited.
Regulatory Status
NAD+ itself is not FDA-approved as a drug and is not a scheduled substance. Oral precursors (NMN, NR) are sold as dietary supplements. IV and IM NAD+ can be administered by licensed practitioners as a compounded preparation, though it is not an FDA-approved drug product. NAD+ is not on the 503A restricted list. Its legal status as a supplement was briefly challenged when the FDA issued a warning letter suggesting NMN may be considered a drug ingredient, though enforcement has been limited.
Most Common Use Cases
IV NAD+ infusions are used in longevity clinics for energy enhancement, cognitive support, and addiction recovery (notably in the naltrexone/NAD+ protocol context). Oral NMN and NR are taken daily as supplements. IM protocols are used by practitioners as a faster alternative to oral with fewer GI side effects than rapid IV push.
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Regulatory Status
Research OnlySafety Profile
Side Effects
- •Nausea (IV, especially rapid infusion)
- •Flushing
- •Headache
- •Chest tightness (IV, transient)
- •Fatigue post-infusion
Contraindications
- •Active malignancy (theoretical — NAD+ supports cancer cell metabolism)
- •Pregnancy (insufficient data)
Drug Interactions
- •PARP inhibitors (olaparib, niraparib) — NAD+ may reduce efficacy
- •Alcohol (chronic use depletes NAD+, complicating supplementation)
Primary Uses
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