Abstract
Nicotinamide (NAM) at doses far above those recommended for vitamins is suggested to be effective against a wide spectrum of diseases and conditions, including neurological dysfunctions, depression and other psychological disorders, and inflammatory diseases. Recent increases in public awareness on possible pro-longevity effects of nicotinamide adenine dinucleotide (NAD+) precursors have caused further growth of NAM consumption not only for clinical treatments, but also as a dietary supplement, raising concerns on the safety of its long-term use. However, possible adverse effects and their mechanisms are poorly understood. High-level NAM administration can exert negative effects through multiple routes. For example, NAM by itself inhibits poly(ADP-ribose) polymerases (PARPs), which protect genome integrity. Elevation of the NAD+ pool alters cellular energy metabolism. Meanwhile, high-level NAM alters cellular methyl metabolism and affects methylation of DNA and proteins, leading to changes in cellular transcriptome and proteome. Also, methyl metabolites of NAM, namely methylnicotinamide, are predicted to play roles in certain diseases and conditions. In this review, a collective literature search was performed to provide a comprehensive list of possible adverse effects of NAM and to provide understanding of their underlying mechanisms and assessment of the raised safety concerns. Our review assures safety in current usage level of NAM, but also finds potential risks for epigenetic alterations associated with chronic use of NAM at high doses. It also suggests directions of the future studies to ensure safer application of NAM.
Highlights
Since Elvehjem et al reported a cure for canine pellagra dogs using nicotinic acid amide in 1938 [1], nicotinamide (NAM) at doses far above those required as a vitamin (e.g., 500–3000 mg) has been applied to various diseases and conditions
Examples are the European Nicotinamide Diabetes Intervention Trial (ENDIT), where children were treated with 25–50 mg/kg a day for 5 years without reported adverse effects [20,97] and a recent clinical study which showed that intake of 1.5 g NAM twice daily for 6 months was safe in elderlies [NCT00580931]
In a study on human fibroblasts, NAM treatment lowered cellular ATP level by approximately 10% after 3-day treatment at 5 mM [65]. This is due to an increase of NAD+ level and the associated decrease in NADH/NAD+ in mitochondria, which leads to reduced electron supply for the electron transport chain and a decrease in oxidative phosphorylation [55]
Summary
Since Elvehjem et al reported a cure for canine pellagra dogs using nicotinic acid amide (known as nicotinamide) in 1938 [1], nicotinamide (NAM) at doses far above those required as a vitamin (e.g., 500–3000 mg) has been applied to various diseases and conditions. Some early studies showed improvement of psychological conditions such as depression and anxiety in humans upon NAM treatment [22,23]. NAM is currently used against skin diseases such as bullous pemphigoid [24], skin cancers [25], and acne lesions [26]. It is widely added as an effective ingredient in various cosmetic products [27]. Attenuated development of pulmonary fibrosis Decreased growth and progression of bladder tumors
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