Nicotinamide riboside and NAD+ injections show preliminary safety in healthy participants

Nicotinamide riboside (NR), an endogenous precursor to the essential coenzyme nicotinamide adenine dinucleotide (NAD+), is characterized as safe and effective at longitudinally elevating NAD+ in blood and tissues, when administered orally. Preclinical research on NR as an augmenter of NAD+ has demonstrated great promise in support of healthy aging, metabolic health, and several diseases, though clinical translation of these findings has been limited. 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. Two separate Phase 1 pilot clinical trials were conducted evaluating NR via bolus injections. While the designs of the two studies are different, the similarities warrant combined presentation to note the similarities, particularly with regards to safety-related outcomes. Trial 1 involved 45 participants that were randomized to a 3x3 design, accounting for three interventions, placebo, NR, and NAD+ and three routes of administration, intramuscular (IM), intravenous (IV), and subcutaneous (SC), resulting in a 9-arm study (placebo IM, n=5; placebo IV, n=5; placebo SC, n=5; NR IM, n=6; NR IV, n=5; NR SC, n=4; NAD+ IM, n=4; NAD+ IV, n=5; and NAD+ SC, n=6). Participants were administered NR once daily for three days, followed by a 7-day washout period. In Trial 2 (n=39), the 2x2 study design incorporated 4-arms for phase 1, where the participants were randomized to 50 or 100 mg of NR, administered either IM or SC in-clinic for 3 consecutive days, followed by a 7-day washout (50 mg IM, n=7; IM, 100 mg IM, n=11; 50 mg SC, n=11; and 100 mg SC, n=10). Phase 2 of Trial 2 involved participants self-administering either 50 or 100 mg of NR subcutaneously. Safety assessments for both trials included vitals, blood biomarkers, participant reported outcomes regarding the experience, and adverse event monitoring. Participant retention for both studies was 100%, and the injections did not result in any attributable unexpected adverse events or experiences. The experiences described by the participants regarding the actual injection varied. In Trial 2, pain more than two minutes after the injection and muscle soreness and tightness were reported by 45.9 and 43.2% of the participants, respectively, regardless of the route of administration or dose. Vitals remained generally consistent throughout both trials, and reductions in systolic blood pressure observed in both trials should be evaluated in larger, properly powered studies. Blood chemistry biomarkers for both trials did not elicit treatment-related patterns. Both trials presented within-group reductions in hsCRP in the NR SC arms, however, given baseline imbalance and small samples size, this finding should be considered hypothesis-generating, only. Overall, in both trials, the interventions, regardless of route of administration were associated with some discomfort but were well tolerated and did not produce any concerning safety signals. It is recommended that comprehensive metabolic and inflammatory panels should continue to be employed in future studies and clinical settings to assess whether consistent patterns emerge in larger populations.