The acute effect of different NAD+ precursors included in the combined metabolic activators

Free Radic Biol Med. 2023 Aug 20:205:77-89. doi: 10.1016/j.freeradbiomed.2023.05.032. Epub 2023 Jun 2.


NAD+ and glutathione precursors are currently used as metabolic modulators for improving the metabolic conditions associated with various human diseases, including non-alcoholic fatty liver disease, neurodegenerative diseases, mitochondrial myopathy, and age-induced diabetes. Here, we performed a one-day double blinded, placebo-controlled human clinical study to assess the safety and acute effects of six different Combined Metabolic Activators (CMAs) with 1 g of different NAD+ precursors based on global metabolomics analysis. Our integrative analysis showed that the NAD+ salvage pathway is the main source for boosting the NAD+ levels with the administration of CMAs without NAD+ precursors. We observed that incorporation of nicotinamide (Nam) in the CMAs can boost the NAD+ products, followed by niacin (NA), nicotinamide riboside (NR) and nicotinamide mononucleotide (NMN), but not flush free niacin (FFN). In addition, the NA administration led to a flushing reaction, accompanied by decreased phospholipids and increased bilirubin and bilirubin derivatives, which could be potentially risky. In conclusion, this study provided a plasma metabolomic landscape of different CMA formulations, and proposed that CMAs with Nam, NMN as well as NR can be administered for boosting NAD+ levels to improve altered metabolic conditions.

Keywords: Carnitine; Cysteine; Metabolomics; NAD(+) precursors; Serine; Systems medicine.

Publication types

  • Controlled Clinical Trial
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Humans
  • Metabolic Diseases*
  • NAD / metabolism
  • Neurodegenerative Diseases*
  • Niacin*
  • Niacinamide
  • Nicotinamide Mononucleotide / metabolism
  • Nicotinamide Mononucleotide / pharmacology


  • NAD
  • Niacin
  • Niacinamide
  • Nicotinamide Mononucleotide