Effects of Trigonelline Monohydrate on NAD+ Metabolism, Pharmacokinetics, Safety, and Tolerability in Healthy Adults

Nicotinamide adenine dinucleotide (NAD+) is a vitamin B3-derived coenzyme that plays a central role in energy production, cellular metabolism, mitochondrial function, and other physiological processes. NAD+ levels decline with advancing age and this decline has been associated with metabolic dysfunction and age-related physiological changes. Trigonelline is a naturally occurring alkaloid and methylated derivative of nicotinic acid that has been identified as a potential NAD+ precursor. Preclinical and translational research suggests that trigonelline may increase NAD+ levels through the Preiss-Handler pathway. It has also been reported that trigonelline may influence mitochondrial function, muscle health, inflammation, and other metabolic processes. Human clinical data on trigonelline supplementation, however, remain limited.

This Phase 1 study will evaluate the pharmacodynamic effects, pharmacokinetics, bioavailability, safety, and tolerability of trigonelline monohydrate supplementation in generally healthy adults aged 40 to 70 years. The study will use a randomized, double-blind, parallel-arm, placebo-controlled design with an active comparator arm. A total of 60 participants will be randomized in a 1:1:1:1:1:1 ratio to receive one of four daily doses of trigonelline monohydrate (equivalent to 150 mg, 300 mg, 450 mg, or 600 mg of trigonelline daily), 600 mg nicotinamide mononucleotide (NMN; active comparator), or placebo for approximately 4 weeks.

The primary objective is to assess the effect of daily trigonelline monohydrate supplementation on NAD metabolism by evaluating the change from baseline to Week 4 in circulating whole blood NAD+ concentrations measured by liquid chromatography-mass spectrometry (LC-MS).

Secondary objectives include characterizing the bioavailability and pharmacokinetic profile of trigonelline after a single dose, assessing plasma accumulation following repeated dosing, evaluating changes in whole blood NAD-related metabolites over time, and quantifying 24-hour urinary excretion of trigonelline and NAD-related metabolites after acute and repeated dosing. Pharmacokinetic parameters include area under the plasma concentration-time curve (AUC0-24 and AUCinf), maximum plasma concentration (Cmax), time to maximum concentration (Tmax), elimination half-life (T½), and the AUC0-24:AUCinf ratio.

Exploratory objectives include assessment of plasma and peripheral blood mononuclear cell (PBMC) NAD-related metabolites, circulating inflammatory biomarkers (high-sensitivity C-reactive protein [hs-CRP], interleukin-6 [IL-6], tumor necrosis factor alpha [TNF-α], and interleukin-1 beta [IL-1β]), and dose-response relationships of trigonelline supplementation on NAD metabolism. Additional samples may be analyzed for gut microbiome composition, metabolomic profiles, short-chain fatty acids, microbial functional pathways, and methylation, oxidative stress, and redox-related metabolites.

Participants will attend a screening visit, a baseline/randomization visit (Day 1), a 24-hour pharmacokinetic and safety visit (Day 2), a Week 1 safety visit, and an end-of-study visit at Week 4. Safety and tolerability will be evaluated through monitoring of adverse events, vital signs, anthropometric measurements, and clinical laboratory assessments throughout the study.