Part 1 of a 2-part, open-label clinical trial evaluating repeated nicotinamide riboside parenteral administration: 3 consecutive days of intramuscular and subcutaneous injections

Nicotinamide riboside (NR), an endogenous precursor to the essential coenzyme nicotinamide adenine dinucleotide (NAD+), is characterized as safe and effective for longitudinally elevating NAD+ in blood and tissues, when administered orally. Interest in alternative routes of administration of NR has increased in recent years and led to the development of pharmaceutical-grade NR for intravenous and injectable administration. To evaluate the safety and efficacy of repeat daily injections of NR, an open-label, pilot, trial was initiated. Utilizing a 2x2 parallel study design, 39 study participants were randomized to intramuscular (IM) or subcutaneous (SC) injection administration, and 50 or 100 mg of NR, for 3 consecutive days, followed by a 7-day washout (50 mg IM, n=7; 100 mg IM, n=11; 50 mg SC, n=11; and 100 mg SC, n=10). To assess the primary outcome of safety, vitals, blood biomarkers, and adverse event monitoring were employed. Additional assessments included NAD+ pharmacokinetics and subjective participant-reported outcomes. Daily injections of NR were well tolerated and did not result in any unexpected adverse events or experiences. Pain and muscle soreness/tightness more than two minutes after the injection were reported by 44% and 41% of the participants, respectively, regardless of the route of administration or dose. Significant heterogeneity of pharmacokinetic parameters for NAD+ augmentation of whole blood was observed, however an average of the daily percentage increases in NAD+ was consistent across treatment groups, resulting in 9.51, 9.97, 7.83, and 9.05% for 50 mg IM, 100 mg IM, 50 mg SC, and 100 mg SC, respectively. Exploratory participant-reported outcomes suggest potential benefits on fatigue and sleep, with mixed effects on global physical health. Repeat daily injections of NR were well tolerated, and findings warrant investigation in larger, powered, placebo-controlled trials.