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Shelly Albaum

Editor, Science of NAD

Important Disclosures

1. This is my personal website

All opinions are my own. Nobody writes here but me.

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Health Supplements like nicotinamide riboside are not intended to cure or treat any disease, condition, or illness.

3. No Medical Advice

I am a lawyer and a journalist, not a doctor, and I offer no medical advice. But I do follow the science, and I can bring to your attention

some interesting studies. You can read more about me here. And check with your physician -- your physician can look at this research, too.

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  • Shelly Albaum

NMN versus NR?

Updated: Aug 17, 2023

Which is better, nicotinamide mononucleotide (NMN) or nicotinamide riboside (NR)?

NR and NMN can both boost NAD levels in most tissues. But how they do that, and the cost to get the effect, makes NR the easy choice: less is more.

All of the NAD precursors -- NA, NAM, NR, and NMN -- will have some effect in some tissues under some circumstances and at some cost. In order to determine the best one for your situation, it is helpful to understand the differences between the metabolic pathways used by each precursor.

But to evaluate NMN versus NR, the most important thing to understand is that the goal is to replenish intra-cellular NAD -- NAD inside the cell, not NAD outside the cell. That's because mitochondria, sirtuins, and other important consumers of NAD are located inside the cell.

The problem is that although most other NAD precursors are able to pass through the cell walls, NMN cannot. NR is the largest NAD precursor that can enter the cell. NMN is just NR plus a phosphate, and that phosphate is the thing that can't get through:

Here are how scientists describe this problem:

NMN dephosphorylation to NR constitutes a critical step in order to act as an exogenous NAD+ precursor ...These data...provide compelling evidence for the extracellular conversion of NMN to NR...

We also showed that extracellular cleavage of NAD+ and NMN to NR is a prerequisite for using these nucleotides to maintain intracellular NAD contents….The degradation of NAD+ and NMN to NR or Nam is essential for these nucleotides to act as extracellular precursors of intracellular NAD.

These observations strongly support the conclusion that both NAD+ and NMN need to be degraded to NR outside the cell to serve as precursors of intracellular NAD+

A study using stable isotope-labeled NR and NMN revealed that NMN is dephosphorylated into NR extracellularly. These results suggest that NMN is incorporated into cells after extracellular conversion to NR.

The administration of NMN was able to revert the endothelial dysfunction and inflammation by extracellular conversion to NR through CD73 (emphasis added)

But all hope is not loss for NMN. It still works, because there are enzymes circulating in your body that break NMN into smaller pieces so that it can enter cells. Those smaller pieces are nicotinamide riboside (NR) and nicotinamide (NAM).

So that's mostly why and how NMN works -- it is a reliable way of delivering NR and/or NAM to your cells.

The problems with NMN as an NAD precursor, then, are that (1) NMN typically costs more than NR or NAM, and (2) part of what you are paying for is a bunch of phosphate molecules that are going to be discarded. That means that a gram of NMN delivers less NR to your cells than a gram of NR does. Another way of thinking about that is that NMN contains filler. And the filler is about a third by weight, because the molecular weight of NMN (about 334 grams per mole) is about 30% higher than NR (about 255 grams per mole).

So does that mean you would be better off just supplementing with NR or NAM than using NMN? Probably, but there are still a couple wrinkles left to consider.

Is There an NMN Transporter?

First, some scientists believed that they had discovered a transporter that let NMN enter cells directly. The transporter had the unmemorable name, "Slc12a8."

Not everyone agreed that Slc12a8 transports NMN into cells. Dr. Carles Canto is one of the leading researchers in the field of NAD, and as recently as August 2022 Canto characterized the finding of an NMN transporter as "controversial":

This concept has been recently challenged by the identification of a potential NMN transporter, Slc12a8. This finding, however, has raised some controversy and future studies will have to define the physiological role of Slc12a8 as a path for NMN-induced NAD+ synthesis vs. its conversion to NR or NAM

Other scientists agreed that the matter was not settled:

Opposing views exist to Grozio et al.'s determination for Slc12a8 being an NMN transporter, Schmidt and Brenner point out that levels of NAD are 500 times higher than NMN in normal liver samples, and Grozio et al. (2019) had failed to examine background/control levels, which undermines any result Grozio et al. (2019) delivered. The debate remains open and no robust conclusion in this regard can be made.

Dr. Charles Brenner, perhaps the leading researcher in the field, said four years ago that slc12a8 was a salt transporter, not an NMN transporter:

It would be prudent to continue to consider that Slc12a8 encodes a salt transporter and not a transporter of NMN

More recently, on December 20, 2022, Dr. Brenner reiterated that NMN is not transported, that no compound with a phosphate is transported across the plasma membrane, and that this has been known for almost 40 years. Instead, the reaffirmed that the reported NMN transporter is actually sodium transporter.

Dr. Charles Brenner on Twitter: "NMN is not transported. No compound with phosphate is transported across the plasma membrane. This has been known for almost 40 years. The reported NMN transporter is a sodium transporter.

However, even if the alleged NMN transporter did exist, it was not expressed in all cells. Slc12a8 is highly expressed in the small intestine:

A newly reported NMN transporter, the Slc12a8, is highly expressed and regulated by NAD+, in the murine small intestine

But people who want to replenish their NAD levels are not particularly focused on the health of their small intestines. They are equally or more likely to be concerned about their heart, gut, liver, kidney, muscles, eyes, ears, and neurons, etc. So even if the NMN transporter turned out to be real, it would probably not turn out to be important, if NR can reach every cell in your body, and NMN reaches far fewer.

A new study in 2023, however, directly examining the metabolism of NMN using triple-marked isotopes, found no direct transport of NMN in the intestine, casting strong doubt on the possibility that slc12a8 was an NMN transporter. In fact, the study found no direct transport of NMN in most tissues, and just a very little in the kidney, spleen, and white fat tissue. Instead, nearly all NMN was converted to NR and NAM before being incorporated into cells and replenishing NAD. This study probably ends the speculation around direct NMN transport; if there is any at all, it is limited both in quantity and distribution.

NMN Toxicity

But there is another reason to at least hope that there is NOT an NMN transporter, and that maybe even explains why there is not an NMN transporter after all: flooding cells with NMN -- nerve cells at least -- can have toxic effects.

It is possible that local NMN accumulation, due to administration of high doses of NMN, has negative impacts in a brain region- or function-specific manner. Indeed, data obtained from in vitro experiments suggest that NMN promotes Wallerian degeneration

Intracellular accumulation of toxic to neurons

Nicotinamide mononucleotide (NMN), accumulates after nerve injury and promotes axon degeneration. Inhibitors of NMN-synthesising enzyme NAMPT confer robust morphological and functional protection of injured axons and synapses despite lowering NAD. Exogenous NMN abolishes this protection, suggesting that NMN accumulation within axons after NMNAT2 degradation could promote degeneration.

What the scientists are telling us here is that flooding nerve cells with NMN can kill them. "Wallerian degeneration" is what happens when your nerve is crushed, and Wallerian-like degeneration occurs in many neurodegenerative diseases, including Alzheimers and ALS.

As one study colorfully described it,

Axons are huge cellular structures. If a Volkswagen Beetle sprouted a tail proportional to the length of a human motor axon, it would be ~20 miles (or 30 km) long. Maintaining such an enormous cellular outgrowth is a major challenge for the nervous system, and it is accomplished through the combined support of neuronal cell bodies and axon-associated glial cells. Without the delivery of materials from cell bodies by axonal transport, axons undergo Wallerian degeneration...Remarkably, we still do not know the molecular pathway for Wallerian degeneration

That was in 2010. But the evidence is growing that NMN accumulation is what triggers it. This team notes that high NAD levels prevent axon degeneration,

In injured axons, NAD+ levels decrease, and preventing this axonal NAD+ decline by exogenous application of NAD+ protects axons from degeneration...These data suggest that NAD+ metabolism plays a crucial role in axon degeneration.

But another team concludes that the enzyme that is converting NMN to NAD in the cell is preventing axon degeneration not by increasing NAD levels, but by limiting the accumulation of NMN by turning it into NAD:

Our data strongly support an in vivo role for NMN accumulation in triggering axon degeneration both after injury and when NMNAT2 is constitutively depleted, with axon protection by WLDs /NMNATs and NMN deamidase in both situations at least partially relying on their ability to limit NMN accumulation.

Leading NAD researcher Carles Canto states the risk bluntly: Trying to create cell-permeable analogs to NMN, instead of just using NR, could trigger axonal death:

NMN, but not NR or NAMN, allosterically activated SARM1, with a half-maximal concentration in the low micromolar range. This generated a model in which a decrease in NMNAT2 expression after axonal damage would facilitate the accumulation of NMN, leading to SARM1 activation and a sharp increase in the consumption of NAD+ , which ultimately elicited axonal death. Hence, the direct binding of NMN to SARM1 constitutes a perfect example of how specific NAD+ -related metabolites can drive enzymatic functions irrespective of their role as NAD+ precursors. This is important when considering supplementation strategies based on cell-permeable NMN analogs, as they could accumulate enough to trigger SARM1 activity.

So too much NMN in cells activates SARM1, which kills the cell, but replenishing with NR could rescue the cell that almost died from too much NMN:

Together these data implicate NAD+ loss as a critical step in SARM1-mediated axon destruction...axon degeneration and cell death were blocked by supplementation with the cell-permeable NAD+ precursor Nicotinamide Riboside (NR)

Exactly what is going on here is still not resolved by science, but it probably doesn't impact our decision, either.

Nothing in this research suggests to me that taking NMN will flood your neurons with NMN and cause them to die. Your cells are smart enough to not flood themselves with NMN, and so NMN is probably safe to take.

But what this does mean is that there probably also is NOT an NMN transporter that would flood your cells with NMN -- at least not in neurons. And if there turns out to be no NMN transporter at all, or only in a few cells, then the argument for taking NMN instead of NR pretty much collapses.

Could NMN Have Greater Bioavailability Than NR?

The final argument we would consider for the potential superiority of NMN over other precursors would be if NMN had greater bioavailability. Much orally consumed NR gets degraded to NAM or NAR, although an effective dose seems to get through as NR.

If the same process that degraded NR to NAM only degraded NMN to NR, then you could imagine, paradoxically, that NMN could deliver more NR to cells than direct NR supplementation does.

The problem with this argument is that it really does require a lot of imagination. CD38 is quite common in the body, and effectively degrades NAD to NMN and to NR. Once that NMN helpfully gets degraded to NR, the same forces that degrade NR to NAM would be active for both NR sourced as NR and NR sourced as NMN. So we have no reason to believe that NMN is a better delivery vehicle for NR than NR is, and indeed some studies show otherwise. But we will watch for such studies, since it is theoretically possible.

But the data we have so far suggests otherwise. Although in theory NMN and NR should perform roughly equal, a number of head-to-head studies have found that NMN was less effective:

Ex vivo treatment...with NR or NAM promoted significant up-regulation of NAD+ levels, whereas treatment with NMN resulted in a nonsignificant upward trend...Although NMN also exhibited some antiinflammatory properties, its effects were less prominent compared with NR and NAM.

"NR is more effective than NMN in maintaining DNA integrity in cisplatin-treated cells."


Lots of studies show that NMN increases NAD levels, but most likely, in most or all cells, this is occurring as a result of extracellular degradation of NMN into smaller precursors like NR and NAM. It will typically be less expensive and more efficient to supplement with your preferred precursors rather than to take NMN and hope that it breaks down the right way and gets into the right cells.

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