Evaluation of Nicotinamide Riboside in Prevention of Small Nerve Fiber Axon Degeneration and Promotion of Nerve Regeneration

BACKGROUND AND AIMS: Recent preclinical studies have shown that nicotinamide adenine dinucleotide (NAD⁺) plays a critical role in molecular mechanisms of axon degeneration, and reductions in NAD⁺ levels are associated with axonal degeneration. Nicotinamide riboside (NR) is a safe and widely available pyridine-nucleoside form of vitamin B3 and is an NAD⁺ precursor. METHODS: To investigate if oral supplementation of synthetic NR can act as a therapeutic agent to prevent degeneration of small somatic sensory axons innervating the skin or promote regeneration of these same fibers in humans, we utilized a validated experimental model of cutaneous nerve degeneration and regeneration and conducted a placebo-controlled, double-blinded Phase 2 study. RESULTS: NR supplementation did not result in elevation of plasma NAD⁺ levels but resulted in a small increase in NAD⁺ in the skin samples. NR supplementation did not prevent capsaicin-induced degeneration of the epidermal sensory nerve fibers, and there was no difference in the amount of epidermal reinnervation at the 90-day visit. Although there was a small but statistically significant increase in the number of epidermal sensory nerve fibers at the 60-day visit, these results are preliminary and will need to be validated in larger studies. INTERPRETATION: At present oral NR supplementation, at the doses used in this study, cannot be recommended to prevent neuropathy or to improve nerve regeneration.