Safety and Metabolism of Long-term Administration of NIAGEN (Nicotinamide Riboside Chloride) in a Randomized, Double-Blind, Placebo-controlled Clinical Trial of Healthy Overweight Adults

Abstract

Nicotinamide riboside (NR) is a newly discovered nicotinamide adenine dinucleotide (NAD⁺) precursor vitamin. A crystal form of NR chloride termed NIAGEN is generally recognized as safe (GRAS) for use in foods and the subject of two New Dietary Ingredient Notifications for use in dietary supplements. To evaluate the kinetics and dose-dependency of NR oral availability and safety in overweight, but otherwise healthy men and women, an 8-week randomized, double-blind, placebo-controlled clinical trial was conducted. Consumption of 100, 300 and 1000 mg NR dose-dependently and significantly increased whole blood NAD⁺ (i.e., 22%, 51% and 142%) and other NAD⁺ metabolites within 2 weeks. The increases were maintained throughout the remainder of the study. There were no reports of flushing and no significant differences in adverse events between the NR and placebo-treated groups or between groups at different NR doses. NR also did not elevate low density lipoprotein cholesterol or dysregulate 1-carbon metabolism. Together these data support the development of a tolerable upper intake limit for NR based on human data.

Figure 1

Study design. Subjects were screened over a 4-week period. Eligible subjects were enrolled and instructed to avoid foods containing high amounts of tryptophan and forms of niacin for the duration of the study. Following a 2-week run-in period, the subjects visited the clinic on Day 0 for baseline safety assessments, blood and urine collection, and randomization to one of four supplementation groups (placebo, 100 mg, 300 mg, 1000 mg NIAGEN per day). The subjects then consumed either placebo or the NIAGEN treatments for 56 days and visited the clinic on Day 7, 14, 28, and 56 for safety assessments, and blood and urine collection. Dietary counseling and food records were dispensed and collected throughout the run-in and supplementation periods to ensure that the subjects adhered to the dietary restrictions.

Figure 2

Disposition of the study participants. Two hundred and eighty-six men and women were screened for eligibility. One hundred and forty subjects met the eligibility criteria and were enrolled in the study. After the 2-week run-in (Day 0), the subjects were randomized to one of four treatment groups (Placebo, 100 mg, 300 mg, or 1000 mg NIAGEN per day; n = 35/group). Over the course of the 56-day supplementation period, one subject withdrew from the placebo-treated group due to an adverse event, two subjects withdrew consent in the 100 mg NIAGEN treated group, one subject was withdrawn from the 300 mg NIAGEN-treated group and two subjects withdrew consent and one was lost to follow-up in the 1000 mg NIAGEN-treated group.

Figure 3

NIAGEN supplementation significantly increases NAD⁺ and other NAD⁺ metabolites. (A) Whole blood levels of NAD⁺ in the intent-to-treat (ITT) population over the course of 56 days of placebo, 100, 300, or 1000 mg of NIAGEN per day supplementation. (B) Plasma nicotinamide (NAM); (C) Plasma 1-methylnicotinamide MeNAM; (D) urinary (MeNAM); and (E) urinary N-methyl-2-pyridone-3/5-carboximide (Me2PY) levels in the ITT population before and after 56 days of supplementation with placebo, 100, 300, or 1000 mg of NIAGEN per day. Urinary MeNAM and Me2PY levels were normalized to urinary creatinine concentrations. Asterisks denote significant (p < 0.05) between group differences versus placebo. Number signs denote significant (p < 0.05) within group differences relative to Day 0. Error bars represent standard error of the mean. Only data from participants who completed the study and had metabolite levels above the limit of quantitation were included in the analysis. Data for within group differences in panels A, B, C and E were transformed logarithmically to achieve normality.

Figure 4

NIAGEN supplementation does not disturb plasma homocysteine. Plasma HCY levels in the intent-to-treat population before and after 56 days of supplementation with placebo, 100, 300, or 1000 mg of NIAGEN per day. Error bars represent standard error of the mean. Only data from participants who completed the study and had metabolite levels above the limit of quantitation were included in the analysis.