The differential impact of three different NAD+ boosters on circulator

DesignRandomized, open-label, placebo-controlled four-arm trial lasting 14 days, supplemented by ex vivo gut-fermentation and whole-blood experiments.

PopulationHealthy adults aged 18–50 years with BMI 18.5–27 kg/m²; the modified intention-to-treat population had a mean age of 34.7 years and included 32 men and 33 women.

Sample67 randomized; 65 analyzed (NR n=16, NMN n=15, nicotinamide n=17, placebo n=17)

InterventionDaily oral NR 1 g, NMN 1 g, nicotinamide 0.5 g, or placebo for 14 days.

EndpointsPrimary: change from baseline in whole-blood NAD+ after 14 days; Acute four-hour and chronic NAD+ metabolome responses; Exploratory plasma and urine metabolomics; Adverse events and ex vivo microbiome and whole-blood metabolism

What the publication reported

Healthy adults were randomly assigned to NMN, nicotinamide riboside, nicotinamide, or placebo for 14 days. NMN and nicotinamide riboside approximately doubled whole-blood NAD+, while nicotinamide did not. The trial measured biomarkers rather than health outcomes. Laboratory experiments suggested that gut microbes may convert NMN and nicotinamide riboside into other forms, but that mechanism was not directly proven inside participants.

Key findings

After 14 days, NMN and nicotinamide riboside approximately doubled whole-blood NAD+ compared with placebo; nicotinamide did not. NMN and NR did not produce an acute four-hour circulating NAD-metabolome response, whereas nicotinamide caused a transient acute response. NADH, NADP+, and NADPH did not change significantly. Reported probable product-related events were abdominal pain in placebo, hypotension with NR, and headache with NMN. Ex vivo experiments showed microbial conversion of NMN and NR toward nicotinic acid and supported a possible gut-dependent pathway.

What it cannot establish

The intervention lasted only 14 days and each arm was small. Treatment was open-label, and the primary outcome was a biomarker rather than a clinical endpoint. Two randomized participants were excluded after receiving the wrong product. The microbiome mechanism relied heavily on ex vivo fermentation and whole-blood assays, which do not prove the same pathway operates in vivo. Long-term efficacy and safety were not tested.

HealthspanX claim boundary: The study supports short-term biomarker effects of 1 g/day NMN and NR in healthy adults. It does not establish clinical or anti-aging benefits, long-term safety, a proven in-vivo microbiome mechanism, or equivalence to HealthspanX Ultra Pure NMN.

Source identifiers

DOI: 10.1038/s42255-025-01421-8
PubMed: PMID 41540253
PubMed Central: PMC12855009
Trial registration: NCT05517122
Publication type: Randomized controlled trial
Publication: Nature Metabolism, 2026. 8(1):62–73

Transparency

Funding: Not stated in the publication.
Declared interests: Stefan Christen, Karine Redeuil, Laurence Goulet, Maria-Pilar Giner, Isabelle Breton, Riccardo Rota, Adrien Frézal, Atiye Nazari, Jean-Philippe Godin, and Sophie Nutten were employees of Nestlé Research. Bernard Cuenoud was an employee of Nestlé Health Science. Pieter Van den Abbeele was an employee of Cryptobiotix SA.

HealthspanX observation: The authors were employees of Nestlé Research, Nestlé Health Science, or Cryptobiotix SA; the proposed gut-microbiome mechanism was supported mainly by ex vivo experiments.

Interpretive status: ModerateRandomization, a placebo arm, and a prespecified NAD+ biomarker strengthen the result, but the trial was open-label, short, and not designed to show clinical outcomes.

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