Cellular NAD+ depletion, altered tryptophan metabolism and gut microbiome dysbiosis are associated with disease progression and unfavourable clinical outcomes in COVID-19. Here, we show that supplementing tryptophan metabolism with nicotinamide alleviates COVID-19 symptoms. We evaluate a 4-week intervention with a novel nicotinamide formulation (1,000 mg) in a prospective, double-blind, randomized, placebo-controlled trial in 900 symptomatic outpatients with PCR-proven COVID-19. In the primary analysis population of participants at risk for severe COVID-19, 57.6% of those receiving nicotinamide and 42.6% receiving placebo recover from their performance drop at week 2 (P = 0.004). Nicotinamide is also beneficial for returning to normal activities (P = 0.009). Effects on gut metagenomic signatures parallel clinical efficacy, suggesting that nicotinamide influences COVID-19-associated faecal microbiome changes. After 6 months, responders to nicotinamide in acute COVID-19 show fewer post-COVID symptoms than placebo responders (P = 0.010). No relevant safety signals are observed. Overall, our results show that nicotinamide leads to faster recovery of physical performance and modulates COVID-19-associated faecal microbiome changes.
© 2025. The Author(s).