Sublingual NMN administration increases early circulating terminal catabolites 2PY and 4PY compared with oral administration in healthy adult men

Sublingual administration of nicotinamide mononucleotide (NMN) is hypothesized to enhance systemic bioavailability by bypassing hepatic first-pass metabolism, a significant limitation of oral intake. However, direct comparative evidence in humans has been lacking. This study aimed to compare the acute pharmacokinetics of NMN following single-dose oral and sublingual administration in a randomized, two-period crossover trial involving 14 healthy adult males. Participants received NMN via both routes, separated by an 8-day washout period. Blood samples were collected for 60 min post-administration to measure NMN and its metabolites, including nicotinamide (NAM), nicotinamide adenine dinucleotide (NAD⁺), and the terminal catabolites N1-methyl-2-pyridone-5-carboxamide (2PY) and N1-methyl-4-pyridone-3-carboxamide (4PY). The incremental area under the curve (iAUC) was significantly higher for the terminal metabolites 2PY and 4PY following sublingual administration compared to the oral route. In contrast, no significant differences were found for the blood concentrations of NMN, NAM, or NAD⁺ between methods. Both administration routes were well-tolerated, with no adverse events reported. These findings provide the first direct evidence in humans that sublingual administration leads to a more rapid increase in the terminal metabolites (2PY and 4PY) over 0–60 min, although the metabolic origin of these increases could not be distinguished in the present study.