Relationship and Absorption of NMN, NR, NM, NA and NAD+

In a clinical study comparing IV and oral administered NMN and NR, it was shown that IV administration delivered intact molecules to multiple tissues however when given orally, the same agents were metabolized into Nicotinamide in the liver. Nicotinamide was responsible for the increased NAD+ levels within the body. (1)  Based on this report, there doesn’t seem to be any benefit or reason to take NMN over an alternative precursor to increase the body’s NAD+ levels.  While there are clinical studies demonstrating the benefits of oral administered NMN, these clinical trials do not explain the absorption pathway used. As demonstrated in this clinical trial, the pathway used by NMN is to convert into either NM or NR via the liver and it is these precursors that are responsible for the increased activity rates.

To date, there is no Human study showing the benefits nor absorption pathway for NMN.  There is no evidence of sublingual absorption being of benefit as there is only one study that shows any evidence of absorption possibilities being via the small intestine.

In a more recent clinical study, it was demonstrated when sodium ion is present, NMN is absorbed through the small intestine and transported via Slc12a8 however this is only present in the older mice not the younger ones. (2)

Initially it appears at that the second study contradicts the first by stating that NMN can be absorbed and transported via the Slc12a8 however the analytical methods, transport data, and interpretation underlying this assignment is not sound and do not support transport of NMN by Slc12a8. (3) An absence of evidence regarding the transporter raised genuine concerns regarding the claim of NMN transport molecule, the absence of evidence, and the disregard of key parameters.  The clinical study ignored the point that there were 500 times more NAD+ than NMN in the liver samples and the dependence of NMN on NR and its intra and extracellular presence – extracellular conversion of NMN to NR before the intracellular NMN can be formed.  It would be fair to consider that Slc12a8 is a salt transportation not an NMN transportation protein. 

In conclusion, NMN appears to be beneficial after its absorption and conversion into NM. NR remains 8% more effective than NM in absorption and cellular uptake in increasing the levels of NAD+.  NMN still remains an unknown element, with all indications that NMN has no direct action on increasing the NAD+ levels, instead of increasing the NM or NR extracellular levels.  NMN intracellular and orally administered NMN is not the same with clear transportation concerns of orally administered NMN into the cell.  It is safe to say that based on available clinical evidence, NR, NM, and NA remain the best sources of NAD+ precursors with NMN being an overpriced source with no direct improvement link established.

• 2018May1;27(5):1067-1080.e5.doi:10.1016/j.cmet.2018.03.018. “Quantitative Analysis of NAD Synthesis-Breakdown Fluxes”
• Nat Metab. 2019 Jan;1(1):47-57.doi: 10.1038/s42255-018-0009-4. Epub 2019 Jan 7. “Slc12a8 is a nicotinamide mononucleotide transporter”
• https://doi.org/10.1038/s42255-018-0009-4 (2019) “Absence of evidence that Slc12a8 encodes a nicotinamide mononucleotide transporter”