Table 1.
Studies of NAD pharmacology and related interventions.
| Study | Intervention | N |
|---|---|---|
| Controlled evaluation of nicotinamide adenine dinucleotide in the treatment of chronic Schizophrenic patients, Kline et al., 1967 [18] Oral NAD 1 or 2 g daily. No systemic improvement in either treatment group. |
NAD | 14 |
| Diphosphopyridine nucleotide in the treatment of schizophrenia, Kline et al., 1967 [19] Oral NAD 1 g or 2 g daily. No positive results were seen. |
NAD | 20 |
| The behavioral effects of nicotinamide adenine dinucleotide in chronic schizophrenia, Meltzer et al., 1969 [20] Oral 2 g NAD daily for 21 days. NAD: After a single dose in volunteer blood samples, not in the study population. No gross clinical improvement was noted. |
NAD | 10 |
| Nicotinic acid in the treatment of schizophrenia, Ban, 1975 [21] Oral 3000 mg nicotinic acid daily. Inferior to placebo. |
Nicotinic acid | 86 |
| The coenzyme nicotinamide adenine dinucleotide (NADH) improves the disability of parkinsonian patients, Birkmayer et al., 1989 [22] Intravenous infusion of 25 mg NADH daily for 10–14 days. 21 patients (61.7%) showed a very good (better than 30%) improvement of disability; 13 patients (38.3%), a moderate (up to 30%) improvement. |
NADH | 34 |
| Nicotinamide adenine dinucleotide (NADH)--A new therapeutic approach to Parkinson’s disease. Comparison of oral and parenteral application, Birkmayer et al., 1993 [23] Intravenous infusion and oral NADH, 25–50 mg/day. 19.3% of the patients showed a very good (30–50%) improvement of disability; 58.8% a moderate (10–30%) improvement; 21.8% did not respond to NADH. |
NADH | 885 |
| Treatment of Parkinson’s disease with NADH, Dizdar et al., 1994 [24] Intramuscular 25 mg NADH on days 1–4, 14, 28. No statistically significant benefit. |
NADH | 9 |
| Coenzyme nicotinamide adenine dinucleotide: New therapeutic approach for improving dementia of the Alzheimer type, Birkmayer, 1996 [25] Oral 10 mg/day NADH for 8–12 weeks. Improvement in mini-mental state examination and global deterioration scale. This open-label trial represents a pilot study from which no definitive conclusion can be drawn. |
NADH | 17 |
| Nicotinic acid supplementation: Effects on niacin status, cytogenetic damage, and poly(ADP-ribosylation) in lymphocytes of smokers, Hageman et al., 1998 [26] Oral 0–100 mg/day nicotinic acid. NAD+: Small increase in PBMC. No evidence was found for a decrease in cigarette smoke-induced cytogenetic damage. |
Nicotinic acid | 21 |
| Therapeutic effects of oral NADH on the symptoms of patients with chronic fatigue syndrome, Forsyth et al, 1999 [27] Oral 10 mg NADH daily. A significant 31% favorable response to NADH versus 8% to placebo. |
NADH | 26 |
| No evidence for cognitive improvement from oral nicotinamide adenine dinucleotide (NADH) in dementia, Rainer et al., 2000 [28] Oral 10 mg NADH daily for 12 weeks. No evidence for any cognitive effect as defined by established psychometric tests. |
NADH | 25 |
| European Nicotinamide Diabetes Intervention Trial (ENDIT): A randomized controlled trial of intervention before the onset of type 1 diabetes, Gale et al., 2004 [29] Oral 1.2 g/m2 nicotinamide daily up to a maximum of 3 g/day for 5 years in two divided doses. No difference in the development of diabetes between the treatment groups. |
Nicotinamide | 552 |
| Nicotinamide effects oxidative burst activity of neutrophils in patients with poorly controlled type 2 diabetes mellitus, Osar et al., 2004 [30] Oral 50 mg/kg nicotinamide daily for 1 month. Oxidative burst activity was greater in patients receiving nicotinamide. |
Nicotinamide | 30 |
| Nicotinamide suppresses hyperphosphatemia in hemodialysis patients, Takahashi et al., 2004 [31] Oral 500 mg nicotinamide daily for 12 weeks increasing by 250 mg every 2 weeks. NAD: ~42% increase in blood levels. Increased serum HDL cholesterol, decreased LDL cholesterol and phosphate. |
Nicotinamide | 65 |
| In search for new antipsoriatic agents: NAD+ topical composition, Wozniacka et al., 2006 [32] Topical 1% or 0.3% NAD+ daily for 4 weeks. Topical NAD+ has an antipsoriatic potential, similar to that of anthralin. |
NAD+ | 37 |
| A topical lipophilic niacin derivative increases NAD, epidermal differentiation and barrier function in photodamaged skin, Jacobson et al., 2007 [33] Topical myristyl nicotinate 1–5% daily for 8–18 weeks. NAD: ~125% increase in the skin. MN treatment of photodamaged facial skin increased stratum corneum thickness by 70% and epidermal thickness by approximately 20%. |
Myristyl nicotinate | 16 and 60 |
| Skeletal muscle NAMPT is induced by exercise in humans, Costford et al., 2010 [34] Exercise: alternating day progressive 30–60-min interval protocol and 50-min aerobic protocol for 3 weeks. NAMPT protein increased in sedentary nonobese subjects. |
Aerobic exercise | 13 |
| The effect of antioxidant supplementation on fatigue during exercise: Potential role for NAD + (H), Mach et al., 2010 [35] Oral 0.36 mg pycnogenol 3 h prior to exercise. AD and NADH increased in muscle and serum. An increase of 17% in physical work capacity until fatigue. |
Pycnogenol | 13 |
| Epigenetic and neurological effects and safety of high-dose nicotinamide in patients with Friedreich’s ataxia: An exploratory, open-label, dose-escalation study, Libri et al., 2014 [36] Oral 2–8 g nicotinamide for 8 weeks. A sustained improvement in frataxin concentrations. Clinical measures showed no significant changes. |
Nicotinamide | 40 |
| Evidence for a direct effect of the NAD+ precursor Acipimox on muscle mitochondrial function in humans, van de Weijer et al., 2014 [37] Oral 250 mg Acipimox for 2 weeks. A rebound rise in plasma NEFA, negatively impacted insulin sensitivity. Skeletal muscle mitochondrial oxidative capacity and ATP production improved. |
Acipimox | 21 |
| Effect of coenzyme Q 10 plus nicotinamide adenine dinucleotide supplementation on maximum heart rate after exercise testing in chronic fatigue syndrome, A randomized, controlled, double-blind trial, Castro-Marrero et al., 2015 [38] Oral 50 mg of CoQ10 and 5 mg of NADH twice daily for 8 weeks. NADH: ~252% increase in PBMC. A significant reduction in max HR during a cycle ergometer test at week 8 versus baseline. |
CoQ10 / NADH | 80 |
| An open-label, non-randomized study of the pharmacokinetics of the nutritional supplement nicotinamide riboside (NR) and its effects on blood NAD+ levels in healthy volunteers, Airhart et al., 2017 [39] Oral 250–1000 mg NR twice daily for 8 days. NAD+: ~100% increase in whole blood. NR was safe and well-tolerated. |
NR | 8 |
| Prevention of non-melanoma skin cancers with nicotinamide in transplant recipients: a case-control study, Drago et al., 2017 [40] Oral 500 mg nicotinamide daily. Actinic keratoses (AKs) significantly decreased in size in 18/19 patients (88%). In controls, 91% showed an increase in size or number of AKs. |
Nicotinamide | 38 |
| Pharmacokinetics and tolerability of MB12066, a beta-lapachone derivative targeting NAD(P)H: quinone oxidoreductase 1: two independent, double-blind, placebo-controlled, combined single and multiple ascending doses first-in-human clinical trials, Kim et al., 2017 [41] Oral MB12066 up to a 400-mg single dose or 200 mg daily for 7 days. MB12066 was safe and well-tolerated. |
MB12066 | 56 and 20 |
| Pharmacokinetic and safety evaluation of MB12066, an NQO1 substrate, Lee et al., 2017 [42] Oral 100 mg MB12066 twice daily. MB12066 was safe and well-tolerated. |
MB12066 | 8 and 3 |
| Phase II clinical trial of nicotinamide for the treatment of mild to moderate Alzheimer’s disease, Phelan et al., 2017 [43] Oral 1500 mg nicotinamide twice daily for 24 weeks. There were no significant effects of nicotinamide on the primary or secondary endpoints. |
Nicotinamide | 31 |
| A randomized placebo-controlled clinical trial of nicotinamide riboside in obese men: safety, insulin-sensitivity, and lipid-mobilizing effects, Dollerup et al., 2018 [44] Oral 1000 mg NR twice daily for 12 weeks. No improvement in insulin sensitivity, endogenous glucose production, glucose disposal and oxidation, resting energy expenditure, lipolysis, oxidation of lipids, or body composition. |
NR | 40 |
| Chronic nicotinamide riboside supplementation is well-tolerated and elevates NAD + in healthy middle-aged and older adults, Martens et al., 2018 [45] Oral NR 500 mg twice daily. NAD+: ~60% increase in PBMC. NR is well tolerated and effectively stimulates NAD + metabolism. |
NR | 30 |
| De novo NAD+ biosynthetic impairment in acute kidney injury in humans, Mehr et al., 2018 [46] Oral 1 or 3 g nicotinamide daily for 3 days. Nicotinamide administration was not associated with increased adverse events compared to placebo. |
Nicotinamide | 55 |
| Effects of nicotinamide riboside on endocrine pancreatic function and incretin hormones in nondiabetic men with obesity, Dollerup et al., 2019 [47] Oral 1000 mg NR twice daily for 12 weeks. No effect on fasting or post-glucose challenge concentrations of glucose, insulin, C-peptide, glucagon, GLP-1, or GIP. β-cell function did not respond to the intervention. No change in circulating adipsin or bile acids after NR supplementation. |
NR | 40 |
| Acute nicotinamide riboside supplementation improves redox homeostasis and exercise performance in old individuals: a double-blind cross-over study, Dolopikou et al., 2019 [48] Oral 500 mg NR, one dose. NR supplementation significantly increased NADH and NADPH, improved isometric peak torque by 8%, and fatigue index by 15%. |
NR | 24 |
| Nicotinamide riboside augments the aged human skeletal muscle NAD+ metabolome and induces transcriptomic and anti-inflammatory signatures, Elhassan et al., 2019 [49] Oral 1 g NR daily for 21 days. NR elevated the muscle NAD+ metabolome; downregulated energy metabolism and mitochondria pathways without altering mitochondrial bioenergetics; depressed levels of circulating inflammatory cytokines. |
NR | 12 |
| Effect of oral administration of nicotinamide mononucleotide on clinical parameters and nicotinamide metabolite levels in healthy Japanese men, Irie et al., 2019 [50] Oral 100–500 mg NMN, single dose. Safe and effectively metabolized in healthy men without causing any significant deleterious effects. |
NMN | 10 |
| Efficacy and tolerability of EH301 for amyotrophic lateral sclerosis: A randomized, double-blind, placebo-controlled human pilot study, de la Rubia et al., 2019 [51] 600 mg EH301 twice daily for 4 months. EH301 was shown to significantly slow the progression of ALS relative to placebo. |
EH301 | 32 |
| Resistance training increases muscle NAD+ and NADH concentrations as well as NAMPT protein levels and global sirtuin activity in middle-aged, overweight, untrained individuals, Lamb et al., 2020 [9] 10 weeks of full-body resistance training. Muscle NAD+, NADH, and global SIRT activity are positively affected by resistance training in middle-aged, untrained individuals. |
Resistance training | 16 |
| Niacin cures systemic NAD + deficiency and improves muscle performance in adult-onset mitochondrial myopathy, Pirinen et al., 2020 [52] Oral niacin, 750–1000 mg daily, 4 months for controls, 10 months for patients. Blood NAD+ increased eightfold in controls and patients. Muscle NAD+ of patients reached that of controls. Muscle strength and biogenesis increased in controls and patients. Muscle metabolome of patients shifted towards controls. Liver fat decreased 50% in patients. |
Niacin | 15 |