NAD+: what the published research shows

Nicotinamide adenine dinucleotide (NAD+), also known as diphosphopyridine nucleotide (DPN) and coenzyme I, is a dinucleotide coenzyme found in all living cells. Its chemical formula is C21H27N7O14P2, and its molecular weight is approximately 663.43 g/mol. As a research compound, nicotinamide adenine dinucleotide is supplied for laboratory use only. The published clinical work on NAD+ centres on its role as an essential cofactor in redox reactions and as a substrate for enzymes in the sirtuin and PARP families, with most interventional studies using precursors such as nicotinamide, nicotinamide riboside (NR), or nicotinamide mononucleotide (NMN) rather than NAD+ itself.

No human study in the evidence reviewed here establishes a clinical indication for NAD+ or its precursors; all cited trials are either ongoing, recently completed, or observational, and several are early-phase safety studies. The sections below summarise what each registered study was designed to measure.

Research Studies

NAD+ and whole-blood NAD+ levels in healthy adults

A clinical trial is assessing the absorption, safety, and efficacy of an oral NAD+ supplement in healthy adults [1]. The primary question is the change in NAD+ levels in whole blood from baseline to day 56 between the NAD+ supplement and placebo. Participants are asked to complete questionnaires, provide blood samples, consume either the supplement or a placebo for 55 days, and undergo evaluation of endothelial function. The study compares the supplement to placebo to evaluate absorption, safety, and efficacy [1]. No results are reported in the registry entry.

Nicotinamide and retinal nerve cell protection in primary open-angle glaucoma

The NADIR trial is investigating whether high-dose nicotinamide (a form of vitamin B3) can protect retinal nerve cells in adults with primary open-angle glaucoma (POAG) who are already receiving standard glaucoma eye drops or laser treatment [2]. The main question is whether adding nicotinamide to standard therapy slows the rate of thinning of the inner retinal nerve cell layer, measured by a non-invasive eye scan, compared to standard therapy alone over 12 months. Participants are randomly assigned to one of two groups; the treatment group takes nicotinamide tablets by mouth, starting at a lower dose of 1.5 grams per day [2]. The registry entry does not report outcomes.

Nicotinamide riboside and walking distance in peripheral artery disease

The NICE-PAD II trial is testing the hypothesis that among people with peripheral artery disease (PAD) age 50 and older, participants randomised to nicotinamide riboside (NR) will have greater improvement or less decline in six-minute walk distance at six-month follow-up compared to those randomised to placebo [3]. The study will randomise 250 participants with PAD age 50 and older to one of two groups for six months: NR versus placebo. The primary outcome is change in six-minute walk distance at six-month follow-up. Secondary outcomes include Walking Impairment Questionnaire (WIQ) distance score, PROMIS Mobility score, and calf muscle perfusion measured by magnetic resonance arterial spin labelling [3]. No results are available in the registry entry.

Nicotinamide and post-COVID syndrome

An observational study is examining the use of CICR-NAM, a special nicotinamide formulation, as a food for special medicinal purposes in patients with post-COVID syndrome (PCS) [4]. The background notes that in patients with post-COVID syndrome, changes in tryptophan metabolism, energy metabolism, and the gut microbiome may occur. In an earlier nutritional study, patients with COVID-19 recovered their physical performance more quickly when taking nicotinamide (vitamin B3), and patients who responded to nicotinamide also developed post-COVID syndrome less frequently. At the University Hospital Schleswig-Holstein in Kiel, special nicotinamide tablets (CICR-NAM) were developed that release the active substance selectively in the lower intestine and have been shown to be very well tolerated in several studies. Patients with post-COVID syndrome and documented tryptophan deficiency may therefore take one [4]. The registry entry does not report outcomes.

NMN and safety in adults with Down syndrome

A study is determining the safety and tolerability of different increasing doses of MIB-626, a microcrystalline form of beta-nicotinamide mononucleotide (NMN), given daily for 28 consecutive days to adults with Down syndrome (DS) [6]. The study will also explore how the drug moves through the body over time (pharmacokinetics or PK) and how the drug affects the body in different ways (pharmacodynamics or PD). Participants will be monitored for adverse events, and measurements to detect safety events will take place, including laboratory tests of blood counts, chemistries, and coagulation profile, and electrocardiogram (ECG). The trial will enrol a total of 24 adults with DS [6]. No results are reported in the registry entry.

Topical nicotinamide riboside and facial skin aging

A clinical trial is evaluating the efficacy of topical niacinamide riboside (topical NR, also known as nicotinamide riboside) on the signs of facial skin aging [7]. The background states that niacinamide riboside is an endogenous compound and a precursor to the essential cellular co-enzyme nicotinamide adenine dinucleotide (NAD+). Research published by Maussudi et al. 2012 demonstrated that skin NAD+ levels were negatively correlated with age in both males and females, and aged skin was also correlated to an increase in DNA damage. Therefore, it is proposed that supporting skin NAD+ with precursors such as NR may be a strategy to combat DNA damage that leads to undesirable signs of skin aging, thus supporting skin cell resilience. The use of NR as a dietary supplement has produced effective, efficient, and reproducible results [7]. The registry entry does not report outcomes.

Nicotinamide riboside and brain blood vessel health, memory, and physical function in Parkinson's disease

A clinical trial is investigating whether nicotinamide riboside (NR), a form of vitamin B3, can improve blood vessel health in the brain, memory, and physical function in eligible study participants with Parkinson's disease [8]. NR is considered investigational for this study because it is not yet established for this specific use. The main questions are whether NR can improve non-invasive measures of blood vessel health in the brain and whether it can improve memory testing results and physical function. Researchers will compare participants who receive NR with participants who receive a placebo, an inactive substance that looks like the study drug, to see if NR has beneficial effects [8]. No results are reported in the registry entry.

Nicotinamide and retinal protection: comparison of trial designs

Two registered trials in this evidence block examine nicotinamide in different populations and with different outcome measures. The table below summarises their key design features as stated in the registry entries [2][4].

NAD+ precursors and clinical outcomes: ongoing evidence

The trials summarised above are registered but do not yet report results. They cover a range of populations and outcomes, from whole-blood NAD+ levels in healthy adults [1] to retinal structure in glaucoma [2], walking distance in peripheral artery disease [3], symptom burden in post-COVID syndrome [4], safety in Down syndrome [6], skin aging [7], and brain blood vessel health and cognition in Parkinson's disease [8]. No efficacy conclusions can be drawn from these registry entries alone.

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Sources

• [1] A Clinical Trial to Assess the Absorption, Safety, and Efficacy of an Oral Nicotinamide Adenine Dinucleotide (NAD+) Supplement in Healthy Adults
• [2] Nicotinamide for Retinal Protection in Primary Open-Angle Glaucoma (NADIR Trial)
• [3] The NICE-PAD II Trial
• [4] Observational Study With CICR-NAM as a Food for Special Medicinal Purposes in Post-COVID Syndrome (PCS)
• [6] NAD Augmentation to Prevent or Reverse Alzheimer's Disease in People With Down Syndrome
• [7] Efficacy of Topical Niacinamide Riboside on the Signs of Facial Skin Aging
• [8] NAD Supplementation in Parkinson's Disease