Examining the safety of nicotinamide for skin cancer prevention: Review of metabolism, adverse events, and toxic dosages

Summary: Abstract Body: Nicotinamide (niacinamide) supplementation for non-melanoma skin cancer (NMSC) prevention has sparked controversy over the past decade due to its inconsistent evidence of chemoprevention and recently challenged safety profile. In this scoping review, we summarize the metabolic mechanisms, adverse effects, and toxic thresholds of nicotinamide and its metabolites to better inform patient recommendations for nicotinamide supplementation. Nicotinamide undergoes hepatic metabolism via three pathways (methylation, oxidation, and hydroxylation) to yield renally excreted end-products: N-methylnicotinamide, 2PY, 4PY, 6PY, nicotinamide N-oxide, nicotinic acid, nicotinuric acid, and 6-hydroxynicotinamide. Reported adverse effects of these metabolites include diarrhea, rash, insulin insensitivity, hepatotoxicity, renal toxicity, thrombocytopenia, anemia, and lymphopenia. Elevated serum levels of nicotinamide metabolites have been correlated with metabolic syndrome, cirrhosis, chronic kidney disease, and bladder cancer. Long-term doses of up to 1g/day have been shown to be well-tolerated. However, patients with impaired nicotinamide elimination (renal failure, cirrhosis, concomitant CYP2E1-metabolized medication) are at higher risk of adverse events. Studies of toxic dosages have been limited to animal studies, and there remains limited research on the toxic threshold of chronic nicotinamide supplementation. Overall, the existing research regarding nicotinamide safety has been largely observational. Until future prospective studies confirm the toxic threshold, we advise that providers limit their recommendation of chronic nicotinamide supplementation for NMSC reduction given the conflicting evidence of its cancer-reducing effect and our incomplete understanding of its long-term toxicities. Katie Xu¹, Micah Belzberg², Allison Vidimos² 1. Case Western Reserve University School of Medicine, Cleveland, OH, United States. 2. Cleveland Clinic, Cleveland, OH, United States. Clinical Research: Epidemiology and Observational Research