Oral LNAD+ Rapidly Elevates Intracellular NAD and Metabolic Flux Without Elevating Circulating NAD: Evidence from a Randomized Controlled Trial

ABSTRACT Declines in nicotinamide adenine dinucleotide (NAD+) are linked to metabolic stress accompanying aging and disease. While precursor-based approaches elevate systemic NAD, their clinical translation can be constrained by biosynthetic bottlenecks and first-pass metabolism. RENEWAL-NAD+ (ClinicalTrials.gov NCT07336836; retrospectively registered 01/04/2026) was a double-blind, randomized, placebo-controlled Phase 0/1b trial in healthy adults aged 45–75 years (60 randomized; primary analysis n=50) evaluating 5 days of oral LathMized® NAD+ (LNAD+), a physicochemically modulated formulation that alters the supramolecular organization and solution behavior of NAD+ while preserving its native molecular structure. The primary endpoints were change in intracellular NAD (icNAD), measured in whole blood, and circulating NAD (cirNAD), measured in separated plasma, relative to baseline. LNAD+ produced a rapid and pronounced increase in icNAD, with a 53% elevation versus placebo at Day 6 (p=5.48e−14; Hedges’ g=3.66), while cirNAD was unchanged (p=0.60), demonstrating compartment-selective augmentation. Plasma NAD catabolites increased substantially (1-methyl-nicotinamide, MeNAM p=5.39e−13; N1-methyl-2-pyridone-5-carboxamide, 2PY p=2.95e−16), consistent with downstream engagement of NAD metabolic flux. Exploratory analyses identified non-overlapping correlates for the two compartments (cirNAD tracking inflammatory and metabolic markers, icNAD tracking red blood cell indices and NAM). Treatment was very well tolerated: symptom incidence was comparable between groups (p=0.68), only one mild adverse event (nausea, Grade 1) occurred in the LNAD+ arm, and no secondary clinical, vital-sign, wellbeing, or wearable-derived endpoint survived multiplicity correction. These data demonstrate rapid intracellular NAD augmentation after oral LNAD+ dosing with pharmacodynamic evidence of downstream metabolism, compartment-specific physiological signatures, and a favorable short-term safety profile, with exploratory multi-omic analyses ongoing. Competing Interest Statement At the time of the study, SK was an employee of Institute for Systems Biology. SK and WJH hold stock options in BioNADRx and are paid consultants who received consultancy fees during the preparation of this manuscript. WK is the CEO of BioNADRx and holds stock options and shares. LFM holds stock options in BioNADRx and is a Company Advisor. SMC and ATM are founders of ISB BioAnalytica Inc. SMC is an investor in BioNADRx and holds shares. ML is an investor in BioNADRx and holds stock options and shares. Footnotes The title was changed to accommodate feedback.