Table Info

Table 2.

Effects of NAD⁺ precursor-based clinical interventions on the liver and isolated PBMCs

NAD⁺ precursor	Doses and study design	Liver effects	PBMC effects	Other effects	Clinical trial identifier	Reference
NR	Non-randomized, open-label pharmacokinetic study of 8 healthy volunteers; 250 mg NR were orally (capsules) administered on days 1 and 2, then up-titrated to peak dose of 1,000 mg twice daily on days 7 and 8. On the morning of day 9, subjects completed a 24-hour study after receiving 1,000 mg NR.	Not reported.	nd	No adverse side effects.	NCT02689882 (a)	Airhart SE, 2017 [91]
NR	One hundred and forty healthy male and female participants were enrolled in a randomized, double-blind, placebo-controlled parallel study; oral NR (100 mg/day, 300 mg/day, and 1,000 mg/day) were administered over 8 weeks.	Not reported.	nd	No adverse side effects; elevated values of NAD⁺ derived metabolites in blood and urine.	NCT0271593 (a)	Conze D, 2019 [92]
NR	A multicenter, three-arm, randomized, double-blinded, placebo-controlled study in a population of 120 healthy adults between the ages of 60 and 80 years; oral (capsules) combined NR (250 mg and 500 mg/day) and pterostilbene (50 and 100 mg/day) were administered (being NRPT 1× the recommended dose and NRPT 2×, the double of recommended dose, respectively); the intervention phase was 8 weeks with a 30-day follow-up period.	Not reported.	nd	No adverse side effects; elevated values of NAD⁺ in blood.	NCT02678611 (a)	Dellinger RW, 2017 [93]
NR	A randomized, placebo-controlled, double-blinded, and parallel-group designed clinical trial, forty healthy, sedentary men with a BMI > 30 kg/m², age-range 40–70 years were randomly assigned to 12 weeks of NR (2,000 mg/day) or placebo.	Borderline decrease in hepatic triglycerides.	Not assessed.	No effects on glucose and insulin tolerance; increased urinary NR-derived metabolites.	NCT02303483 (a)	Dollerup OL, 2018 [94]
NR	A multicenter, randomized, double blind, placebo-controlled trial; the intervention phase was 26 weeks, with a 14-day follow-up period; participants were randomized into three arms (1:1:1): placebo, recommended dietary supplement dose (NRPT 1×), or double the recommended dose (NRPT 2×).	At the end of the study, no significant change was seen in the primary endpoint of hepatic fat fraction with respect to placebo; a time-dependent decrease in the circulating levels of the liver enzymes ALT and GGT was observed in the NRPT 1× group, and this decrease was significant with respect to placebo.	Not assessed.	A significant decrease in the circulating levels of the toxic lipid ceramide 14:0 was also observed in the NRPT 1× group versus placebo.	NCT03513523 (a)	Dellinger RW, 2023 [95]
NR	A randomized, double-blinded, placebo-controlled, crossover intervention study was conducted in 13 healthy overweight or obese men and women. Participants received NR for 6 weeks (1,000 mg/day) and placebo supplementation.	No effects on hepatic lipid accumulation.	nd	Increased skeletal muscle NAD⁺ metabolites, especially NAAD and MeNAM; supplementation with NR did not result in any change in mitochondrial respiration compared with the placebo state; affected skeletal muscle acetylcarnitine metabolism and induced minor changes in body composition and sleeping metabolic rate.	NCT02835664 (a)	Remie CME, 2020 [96]
NR	A 2 × 6-week randomized, double-blind, placebo-controlled crossover clinical trial. Subjects (middle-aged and older men and postmenopausal women aged 55−79 years) ingested NR chloride (NIAGEN^®; 500 mg, twice per day; ChromaDex, Inc.) and placebo capsules for 6 weeks each in a randomly determined order.	Not shown.	Elevated content of NAD⁺ in PBMCs by ~60% compared with placebo, especially NAAD and NAD⁺.	Increased blood cellular NAD⁺ concentrations.	NCT02921659 (a)	Martens CR, 2018 [97]
NR	Escalating doses of NR (250 mg twice a day for day 1, 500 mg twice a day for day 2, and 1,000 mg twice a day from day 3 on) for 5 to 9 days, 19 hospitalized patients with (stage D HFrEF) heart failure were compared with that of 19 healthy participants.	Not shown.	Improved mitochondrial respiration using standard Seahorse Mito Stress Test; attenuated proinflammatory activation.	nd	NCT03727646 (a)	Zhou B, 2020 [38]
NR	A 12-week, randomized, placebo-controlled trial, 30 participants with Stage C HFrEF were randomized to either NR or matching placebo (2:1 allocation ratio).	nd	Improved mitochondrial respiration using a Seahorse Extracellular Flux Analyzer; attenuated proinflammatory activation.	nd	NCT04528004 (a)	Wang DD, 2022 [98]
NR	A group of 8 healthy volunteers enrolled in a blood collection protocol to enable the collection of blood cells to test the effects of NR. This group consisted of 6 women and 2 men, with an age range of 23 to 48 years. These subjects had no history of acute or chronic disease.	nd	Increased maximal respiratory capacity assessed by using a Seahorse Extracellular Flux Analyzer; reduced inflammasome induction-mediated IL-1β secretion.	nd	NCT02122575 and NCT00442195 (a)	Traba J, 2015 [99]
NR	A 7-day NR supplementation on whole-body metabolism and exercise-induced mitochondrial biogenic signaling in skeletal muscle. Eight male participants received NR (1 g/day) or cellulose placebo supplementation for one week.	Not assessed or reported.	Not analyzed.	No effect of NR supplementation on skeletal muscle NAD⁺ concentration, but it did increase the concentration of deaminated NAD⁺ precursors NAR and NAMN and methylated nicotinamide break-down products (Me2PY and Me4PY); global acetylation, auto-PARylation of PARP1, acetylation of p53 Lys382, and MnSOD Lys122 were not affected.	Not reported, but the study was pre-approved by the National Health Service Research Ethics Committee Black Country, West Midlands, UK (17/WM/0321).	Stocks B, 2021 [100]
NMN	A 10-week, randomized, placebo-controlled, double-blind trial to evaluate the effect of NMN supplementation on metabolic function in postmenopausal women with prediabetes who were overweight or obese.	nd	Increased basal NAD⁺ content in PBMCs after treatment.	nd	NCT03151239 (a)	Yoshino M, 2021 [101]
NR	A randomized, double-blind, three-arm crossover pharmacokinetic study of oral NR chloride to 12 healthy, non-pregnant subjects (6 males and 6 females) (between the ages of 30 and 55 with body mass indices of 18.5–29.9 kg/m²) was performed at 100, 300 and 1,000 mg doses after overnight fasting were given on 3 test days separated by 7-day periods.	nd	Increased PBMC NAD⁺ metabolome, especially NAD⁺, Me2PY, and NAAD was elevated.	Increased NAD⁺ metabolome in human plasma and urine samples, especially MeNAM, Me2PY, and Me4PY.	NCT02191462 (a)	Trammell SAJ, 2016 [76]
NR	Oral administration in 12 aged men with 1 g NR per day for 21 days in a placebo-controlled, randomized, double-blind, crossover trial.	Not assessed; but hepatic ALT was not changed by NR administration.	Not assessed.	Elevations in NAD⁺ metabolites, and induction of transcriptomic and anti-inflammatory signatures in treated elder skeletal muscle biopsies.	NCT02950441 (a)	Elhassan, 2019 [102]
NMN	An open-label, single-arm exploratory study on 10 healthy individuals, including five males and five females (age, 20–70 years), recruited from the Tokyo Tsukishima Clinic; after a 12-hour fast NMN was intravenously administered until the end of the clinical trial; intravenous drip infusion was performed at 5 mL/min by dissolving 300 mg of NMN in 100 mL of saline and inserting an extension tube through a vein in the middle of the arm.	Clinical variables of liver function were within the normal range.	nd	Increased blood NAD⁺; reduced blood triglycerides.	Not reported but the study was approved by the Japanese Organization for Safety Assessment of Clinical Research (#20210623-02; 23/06/2021) and registered with the University Hospital Medical Information Network (UMIN; Japan) (UMIN-ID: UMIN000047134; 09/03/2022)	Kimura S, 2022 [103]
NMN	A single-center, single-arm, open-label trial; twenty-eight healthy adult Japanese (40–60 years) male volunteers; a dose of 250 mg/day was administered for 8 weeks.	Not observed; no changes in hepatic transaminases were seen.	NAD⁺ levels in PBMCs increased over the course of NMN administration.	No adverse effects were observed.	Japanese 031180242 (b)	Yamaguchi S, 2024 [104]
NAM	Seventy diabetic MASLD patients were randomly assigned either to the nicotinamide group (n = 35) who received nicotinamide 1,000 mg once daily for 12 weeks in addition to their antidiabetic therapy or the control group (n = 35) who received their antidiabetic therapy only.	Decreased serum ALT, but no effect on liver fibrosis or steatosis.	nd	nd	NCT03850886 (a)	El-Kady RR, 2022 [105]

ALT: alanine aminotransferase; BMI: body mass index; GGT: gamma-glutamyl transferase; HFrEF: heart failure with reduced ejection fraction; MeNAM: 1-methylnicotinamide; Me2PY: N-methyl-2-pyridone-5-carboxamide; MnSOD: manganese superoxide dismutase; NAAD: nicotinic acid adenine dinucleotide; NAD⁺: nicotinamide adenine dinucleotide; NAMN: nicotinic acid mononucleotide; NAR: nicotinic acid riboside; nd: not described; NMN: nicotinamide mononucleotide; NR: nicotinamide riboside; NRPT: nicotinamide riboside and pterostilbene; PARP1: poly-adenosine diphosphate-ribose polymerase 1; PBMCs: peripheral blood mononuclear cells; p53: tumor protein 53. (a) registered at ClinicalTrials.gov (https://clinicaltrials.gov/). (b) registered at jRCT

Declarations

Author contributions

JNN, JR, MIRL, E Moreira, E Mateus, and EMR: Writing—original draft, Writing—review & editing. AJRA, BRM, and LOM: Writing—original draft, Writing—review & editing, Funding acquisition. MG: Conceptualization, Writing—original draft, Writing—review & editing. JJ: Conceptualization, Writing—original draft, Writing—review & editing, Funding acquisition. All authors read and approved the manuscript.

Conflicts of interest

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Ethical approval

Not applicable.

Consent to participate

Not applicable.

Consent to publication

Not applicable.

Availability of data and materials

Not applicable.

Funding

This research was supported by Consorcio Centro de Investigación Biomédica en Red – CIBER- de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM) (group [CB15/00071], leading group) and CIBER de Enfermedades Cardiovasculares (CIVERCV) [CB16/11/00257], Ministerio de Ciencia e Innovación Instituto de Salud Carlos III (ISCIII), Spain. MIRL holds a predoctoral grant from Pla Estratègic de Recerca i Innovació en Salut (PERIS) 2021-2024 of Generalitat de Catalunya [SLT017/20/000107]. JJ has received financial support from Agencia Estatal de Investigación (MCIN/AEI/10.13039/501100011033 and European Union “NextGeneration EU”/PRTR) within the action “Consolidación Investigadora 2022” [CNS2022-135559], and from Ministerio de Sanidad y Consumo, ISCIII [PI21/00770, PI24/00156], and Fondo Europeo de Desarrollo Regional (FEDER) “Una manera de hacer Europa”. BRM is supported by the “Miguel Servet” program, ISCIII, Spain; co-funded by the FEDER [CP19/00098]. AJRA was funded by Biomedical Research Institute of Murcia [IMIB/CI/09]. LOM has received funding from the IHU HealthAge [ANR-23-IAHU-0011]. Institut de Recerca de l’Hospital de la Santa Creu i Sant Pau (Institut de Recerca SANT PAU) is accredited by the Generalitat de Catalunya as Centre de Recerca de Catalunya (CERCA). JJ also belongs to the XARTEC Salut network, and is part of the coordinated consolidated group AGAUR [2021 SGR 00857, and 2021 SGR 01211]. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

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