Nicotinamide (NAM)

Nicotinamide (NAM, also called niacinamide) is the amide form of vitamin B3 and a direct precursor in NAD+ biosynthesis via the salvage pathway enzyme NAMPT. It is biochemically distinct from the NAD+ precursors nicotinamide mononucleotide (NMN) and nicotinamide riboside (NR): whereas NR and NMN feed into the salvage pathway before NAM's NAMPT entry point, NAM is the common end-product of NAD+ consumption by sirtuins, PARPs, and CD38, making intracellular NAM accumulation a feedback inhibitor of SIRT1 and other sirtuins at high concentrations. This dual role — both precursor and sirtuin inhibitor — complicates interpretation of supplementation studies and distinguishes it mechanistically from NR/NMN. NAM has established medical uses: topical niacinamide is widely used for acne and skin barrier function, and oral high-dose nicotinamide (500 mg twice daily) reduced actinic keratoses and non-melanoma skin cancer rates in a randomized trial in immunocompetent high-risk adults (Chen et al., 2015, NEJM); however, a subsequent phase 3 trial in solid-organ transplant recipients (ONTRANS; Allen et al., NEJM 2023) found no reduction in keratinocyte cancers or actinic keratoses, limiting confidence that the ONTRAC result generalises to the higher-risk transplant population. Its use as a systemic longevity supplement is investigational and the net effect on sirtuin-dependent processes at supplemented doses in humans is not established.