NAD+ in humans: precursors, infusions and what the trials measure

Key points

• In human skin, NAD+ levels correlated negatively with age in both men and women [1].
• The precursors NR and NMN raise NAD+ and its metabolites in blood, muscle and even brain, and were well tolerated in randomized trials [3][4][6][13].
• Some trials show clinical signals: better muscle insulin sensitivity with NMN [5] and +17.6 m in 6-minute walk with NR in peripheral artery disease [7].
• During a 750 mg intravenous NAD+ infusion over 6 h, plasma NAD+ did not change for the first 2 h [8].
• A 2026 systematic review found no outcome trials of intravenous or intramuscular NAD+ for anti-aging or wellness [10].

US status (October 2026): NAD+ is not an approved drug. NAD is in FDA’s 503A Category 1, so a 503A pharmacy may compound it for a named patient under FDA’s interim policy. The outsourcing-facility position is unresolved. NAD+ status page.

NAD+ runs down with age in human tissue

NAD+ is the electron carrier of mitochondrial respiration and the substrate of sirtuins and PARPs, the DNA-repair enzymes. In a study of 49 human skin samples from people aged 0 to 77, the authors found a strong negative correlation between NAD+ and age in both men (r = -0.706) and women (r = -0.537). In men, PARP activity rose with age and correlated inversely with tissue NAD+ [1].

The second proposed mechanism is the enzyme CD38. In mice, its expression and activity increased with aging, and CD38 was required for the age-related NAD+ decline and mitochondrial dysfunction. The same work identified CD38 as the main enzyme degrading the precursor NMN in vivo [2]. That finding links to another strategy under study: inhibiting enzymes that consume nicotinamide, such as NNMT, the subject of our article on 5-amino-1MQ.

Oral precursors do raise NAD+

The best-studied route in humans is the precursors: nicotinamide riboside (NR) and nicotinamide mononucleotide (NMN). In a 2 x 6-week randomized, double-blind, crossover trial in healthy middle-aged and older adults, NR was well tolerated and effectively stimulated NAD+ metabolism. The authors suggested studying its possible effect on blood pressure and arterial stiffness [3]. In 12 older men, 1 g of NR daily for 21 days raised the skeletal-muscle NAD+ metabolome and lowered circulating inflammatory cytokines, without changing mitochondrial bioenergetics [4].

The NADPARK trial took the question to the brain. Thirty newly diagnosed, treatment-naive patients with Parkinson’s disease received 1,000 mg of NR or placebo for 30 days. NR was well tolerated and was associated with a significant but variable increase in cerebral NAD+ measured by phosphorus-31 magnetic resonance spectroscopy. In those whose brain NAD+ rose, cerebral metabolism changed, and this was associated with mild clinical improvement [6].

• r = -0.706: correlation between skin NAD+ and age in men [1]
• +17.6 m: 6-minute walk with NR vs placebo in peripheral artery disease [7]
• 0: outcome trials of intravenous or intramuscular NAD+ for anti-aging [10]

A few trials move from biomarkers to clinical signals

In a 10-week randomized, placebo-controlled, double-blind trial in postmenopausal women with prediabetes and overweight or obesity, NMN increased insulin-stimulated glucose disposal, measured by hyperinsulinemic-euglycemic clamp, and muscle insulin signaling. Placebo produced no change [5]. In the NICE trial of 90 people with peripheral artery disease, 6 months of NR improved 6-minute walk versus placebo (+7.0 m vs -10.6 m; difference +17.6 m, 90% CI +1.8 to +∞). Resveratrol added no benefit [7].

Meta-analyses put those signals in proportion. Across 10 trials with 349 participants with elevated blood pressure, NMN was associated with a modest reduction in diastolic pressure (-2.15 mmHg), with no significant change in systolic pressure except in the subgroup aged 60 and over (-3.94 mmHg) [12]. Across 15 trials (10 with safety data), oral NMN did not increase adverse events or transaminases. It also did not change weight, fasting glucose, HbA1c or lipids [13]. In trials of adults with a mean age over 60, the evidence did not support NMN or NR for preserving muscle mass or function [11].

IV NAD+ has a small, surprising pharmacokinetic literature

NAD+ given directly has far less literature. The reference study is a pilot in 11 healthy men aged 30 to 55: 8 received 750 mg of intravenous NAD+ over 6 hours and 3 received saline. According to the authors, the dose reflected a common clinic regimen. Plasma NAD+ and its metabolites did not change until after 2 hours: at that infusion rate, NAD+ was rapidly and completely removed from plasma. The metabolite profile was consistent with NAD+ glycohydrolase and pyrophosphatase activity, and at 6 hours urinary excretion of NAD+ and methylnicotinamide increased. No adverse events were observed during the infusion [8].

One of the few randomized trials of intravenous NAD+ is in cardiology, not longevity. In a single-center trial of 180 adults with heart failure due to ischemic cardiomyopathy (LVEF 45% or lower), 10 mg/day of intravenous NAD+ for 7 days, on top of standard therapy, was associated with higher LVEF at one month (45.44% vs 42.44%; p = 0.024). Major cardiovascular events at 6 months were less frequent (14.6% vs 24.7%), and the difference was not significant (p = 0.089) [9].

The intravenous and oral routes are not interchangeable. Extracellular NAD+ is rapidly broken down by enzymes such as CD38 [2][8], while the precursors hold most of the randomized data [3][5][6][7].

Where the evidence ends

Raising a biomarker is not the same as a clinical benefit. A 2026 systematic review examined 33 human intervention studies (28 randomized). Oral precursors showed consistent biochemical effect and good tolerability, and functional, metabolic and vascular effects were “heterogeneous and often null or endpoint-specific”. It found no outcome trial of intravenous or intramuscular NAD+ for anti-aging or wellness [10]. Our longevity article places NAD+ alongside epitalon, MOTS-c and SS-31.

On infusions, a 2026 narrative review describes sparse human evidence, mostly small uncontrolled studies and isolated case reports. Reported adverse effects include nausea, cramping, flushing and chest discomfort, and long-term safety data are lacking. The same review notes that recent large-scale human data indicate whole-blood NAD+ does not decline with healthy aging per se [14], a nuance next to the tissue findings [1].

What the evidence does support. NAD+ has a solid biological basis [1][2], its precursors raise NAD+ in blood, muscle and brain with good tolerability [3][4][6][13], and there are randomized trials with measurable clinical signals in insulin sensitivity [5], walking capacity [7] and cardiac function with intravenous NAD+ [9]. The open question is in whom NAD+ repletion helps, and for which outcome.

What this means for you. If you offer NAD+ infusions, the compounding pathway exists for a named patient through a 503A pharmacy, and the marketing claims do not get the same cover. Category 1 does not approve NAD+ for any use. Source it from a 503A pharmacy that documents the ingredient is suitable for sterile use (see 503A vs 503B sourcing), and keep your menu language inside what the trials above actually measured. Our peptide programs page describes how MDside structures these programs.

References

1. Massudi H, et al. Age-associated changes in oxidative stress and NAD+ metabolism in human tissue. PLoS One. 2012;7(7):e42357. PMID 22848760. Link
2. Camacho-Pereira J, et al. CD38 dictates age-related NAD decline and mitochondrial dysfunction through an SIRT3-dependent mechanism. Cell Metab. 2016;23(6):1127-1139. PMID 27304511. Link
3. Martens CR, et al. Chronic nicotinamide riboside supplementation is well-tolerated and elevates NAD+ in healthy middle-aged and older adults. Nat Commun. 2018;9(1):1286. PMID 29599478. Link
4. Elhassan YS, et al. Nicotinamide riboside augments the aged human skeletal muscle NAD+ metabolome and induces transcriptomic and anti-inflammatory signatures. Cell Rep. 2019;28(7):1717-1728.e6. PMID 31412242. Link
5. Yoshino M, et al. Nicotinamide mononucleotide increases muscle insulin sensitivity in prediabetic women. Science. 2021;372(6547):1224-1229. PMID 33888596. Link
6. Brakedal B, et al. The NADPARK study: a randomized phase I trial of nicotinamide riboside supplementation in Parkinson’s disease. Cell Metab. 2022;34(3):396-407.e6. PMID 35235774. Link
7. McDermott MM, et al. Nicotinamide riboside for peripheral artery disease: the NICE randomized clinical trial. Nat Commun. 2024;15(1):5046. PMID 38871717. Link
8. Grant R, et al. A pilot study investigating changes in the human plasma and urine NAD+ metabolome during a 6 hour intravenous infusion of NAD. Front Aging Neurosci. 2019;11:257. PMID 31572171. Link
9. Yu X, et al. Effect of nicotinamide adenine dinucleotide on heart failure caused by ischemic cardiomyopathy: a randomized, placebo-controlled trial. Am J Cardiovasc Drugs. 2026;26(1):97-106. PMID 40954388. Link
10. Gallagher C, Emmanuel OO. NAD+ supplementation for anti-aging and wellness: a PRISMA-guided systematic review of preclinical and clinical evidence. Ageing Res Rev. 2026;116:103057. PMID 41655607. Link
11. Prokopidis K, et al. The effect of nicotinamide mononucleotide and riboside on skeletal muscle mass and function: a systematic review and meta-analysis. J Cachexia Sarcopenia Muscle. 2025;16(3):e13799. PMID 40275690. Link
12. Zhang M, et al. Effects of nicotinamide mononucleotide supplementation on blood pressure: a systematic review and meta-analysis of randomized controlled trials. Nutrients. 2026;18(6):890. PMID 41901064. Link
13. Yang W, et al. Safety and metabolism-related outcomes of oral nicotinamide mononucleotide supplementation in adults: a systematic review and meta-analysis. Nutrients. 2026;18(14):2251. PMID 42514320. Link
14. Alangari A, et al. Narrative review of intravenous NAD+ and NAD+ precursors in wellness and translational medicine. Front Aging. 2026;7:1887175. PMID 42787547. Link

This is general information, not medical or legal advice. Rules vary by state and change. Confirm your own facts with counsel.