NADH shows strongest cognitive improvement while NAD+ precursors fail to improve perceived fatigue or sleepNAD+ precursors show mixed results for fatigue and brain health

BackgroundFatigue is a multidimensional syndrome involving the cognitive and physical domains, and NAD+-dependent biological energy dysfunction is considered a key mechanism. This study aimed to compare the efficacy of niacinamide adenine dinucleotide (NAD+) precursors in cognitive, motor and perceived fatigue domains using a domain-based network meta-analysis (NMA).MethodsA systematic review and NMA were conducted on randomized controlled trials (RCTs) according to the PRISMA-NMA guidelines (PROSPERO: CRD420251237193). Including adults who receive NAD+ precursors [niacinamide nucleotide (NR), niacinamide mononucleotide (NMN), niacinamide adenine dinucleotide (NADH) and niacinamide (NAM)]. The outcomes were categorized within the domain-based fatigue framework, divided into perceived fatigue, cognitive performance and exercise performance (endurance and strength), with functional outcomes comprising quality of life (QoL) and sleep. The standardized mean difference (SMD) is summarized, and the surface under the cumulative ranking curve (SUCRA) was calculated.ResultsA total of 27 studies (n = 1,599) were synthesized, including 25 RCTs and 2 quasi-experimental tests. The influence of the NAD+ precursor is specific to the domain. No precursor can significantly improve perceived fatigue or sleep quality. In contrast, NMN showed dose-dependent enhancement in endurance (medium dose: SMD = 0.66, 95% CI 0.09–1.23; high dose: SMD = 1.02, 95% CI 0.43–1.60), while neuromuscular strength remained unchanged. For cognitive performance, NADH produced the strongest improvement (SMD = 1.50, 95% CI 0.82–2.19), especially in cognitive impairment cohorts, although this finding was sensitive to influential studies. Moderate improvement in the quality of life was observed, mainly NMN (high dose: SMD = 0.56, 95% CI 0.14–0.98; low dose: SMD = 0.45, 95% CI 0.11–0.78).ConclusionNAD+ precursor supplementation exerts a selective impact on fatigue-related outcomes. This study emphasizes the domain-based NMA framework to unravel heterogeneous fatigue outcomes, in which NAD+ precursor prioritizes improving endurance-related performance. But with limited translation to subjective fatigue and neuromuscular strength, it supports a precision-based approach of NAD+ supplements that considers outcome type, dosage, and population characteristics.Systematic review registrationPROSPERO. CRD420251237193. https://www.crd.york.ac.uk/PROSPERO/view/CRD420251237193