NR vs. NMN Supplement: A Comparison of Science (2023)

Nicotinamide riboside (NR) and nicotinamide mononucleotide (NMN) are both precursors to nicotinamide adenine dinucleotide (NAD+), a coenzyme that plays important roles in energy production, DNA repair, and other cellular processes.

The primary difference is that NR is a form of Vitamin B3 (Niacin), while NMN is a type of nucleotide. 

NMN vs. NR

NMN is converted into NAD+ directly by enzymes in the body, while NR needs to go through an additional step in the body in order to be converted into NAD+. 

NR is converted into NAD+ in the body and is used to support the production of NAD+ . It is used in therapies for aging, weight loss, and cognitive decline.

NMN is also a precursor to NAD+ and is used to support the production of NAD+ . NMN is a type of nucleotide, which are the building blocks of DNA and RNA, NMN is found in small amounts in some foods, such as edamame.

Both NR and NMN supplements are used to boost NAD+ levels in the body, and are used to support the anti-aging and overall wellness, However, NMN is directly converted into NAD+ by cells, while NR needs to go through an additional step in the body in order to be converted into NAD+.

NR used to be considered superior because no NMN transporter — required to get it into cells — had been detected. 

We now know there is such a transporter (published in Nature in 2019: R, R), which gives NMN the advantage as it’s also a more direct NAD+ precursor. However, this is disputed by Chromadex in a 2019 publication.

Chromadex claimed that NMN must first be converted into NR in the blood before it can be used by the cells.

Pitting NR and NMN against each other is, for now, somewhat of a moot point because the two molecules have never been studied side by side in humans. The biggest, and most obvious, difference between NMN and NR is size. NMN is simply larger than NR, meaning it often needs to be broken down to fit into the cell. NR (Nicotinamide Riboside), when compared to other NAD+ precursors (like nicotinic acid or nicotinamide) reigns supreme in efficiency.

But give NMN a new door, one it can fit through, and it’s a whole new game. This is where cellular transporters come into play. Transporters are proteins that are doors on the cell; they allow molecules to enter the cell without needing to chemically transform.

As research grows, it is likely to become clearer that NMN and NR may have differing benefits depending on the part of the body and their use. Where NMN transporters are found, they could make one more preferable over the other. NMN has also been found to improve insulin activity and production which could help to accelerate metabolisms and make the body more glucose tolerant.

That said, according to David Sinclair in this podcast:

NAD is a big molecule relative to vitamin B3. It's got those phosphates on there. It's got a sugar. It's got the vitamin B attached. So you've got all these components that come together to make this very complicated molecule called NAD. And when you give NMN, it contains all three components that the body needs to make NAD. If you give NR or just vitamin B3, which is an even smaller molecule, the body has to find these other components from somewhere else. So where do you get phosphate? Well, body needs it for DNA, needs it for bones. So high doses of something that requires additional phosphate makes me a little concerned, and we have compared NMN and NR head-to-head in mouse studies. We've shown that NMN makes mice run further, old mice can run 50% further because they better blood flow, better energy. NR the same dose did not do that. In fact, it had no effect.

Related:

• NMN vs NR: TruNiagen version
• NMN vs NR: NovosLabs version

NMN vs. NR Supplements: 7 Key Distinctions

1. Human Studies

Another huge difference between NR and NMN is its applicability to humans.

NMN Studies

One of the most comprehensive NMN clinical trial to date on human subjects, with 80 participants ranging between the ages of 40 and 65, and an eye to determining dosing efficacy. The study is now peer-reviewed. The study confirmed that NMN effectively raises NAD levels in the blood, and health scores for participants taking NMN improved significantly over the course of the trial. In addition to substantiating the role of NMN in human health, the study also highlights the importance of dosing for efficacy.

Another 2022 study on human subjects concluded that Oral Administration of Nicotinamide Mononucleotide (NMN) Is Safe and Efficiently Increases Blood Nicotinamide Adenine Dinucleotide (NAD) Levels.

In another 2022 peer reviewed, double blind placebo controlled clinical study NAD+ decline was reversed by an average of 12 years. That's 38% more NAD+ in 60 days. Higher NAD+ levels are associated with more energy, feeling younger, less genetic damage, heart health, and SIRTUIN activation- longevity genes that are key for living better longer. Also, study participants’ quality-of-life test scores improved by 6.5%.

NR Studies

Although NMN clinical studies may be promising, NR studies are more advanced.

There have been several NR supplementation studies in humans. These studies have examined NR’s impact on cardiovascular health, exercise performance, systemic metabolic functions, and skeletal muscle metabolism.

Niagen®, a patented form of nicotinamide riboside (or NR) is one of the most prominent NAD+ precursors on the market today. 

According to Clinicaltrials.gov, a government-sponsored database of human clinical studies, as well as the World Health Organization (WHO) International Clinical Trials Registry, there are more than 40 ongoing or completed studies involving Niagen versus more than 20 for NMN.  

These numbers show double the growing amount of research behind Niagen over NMN to investigate the various health benefits of raising NAD+ levels in humans. 

2. Cell Entry

Transformation in NAD+ happens within the cell. So both molecules need to find their way through the cell barrier first.

One of the main differences of NMN and NR is size. NMN is larger than NR.

It’s large enough that it needs to be broken down into another form before it can pass through the cell barrier. NR’s smaller size allows it to penetrate the cell barrier without transforming into another molecule.

A collection of published studies conducted by some of the field’s leading researchers demonstrates that NMN cannot enter cells directly; rather, it must be converted to NR first. 

One such study (published in Nature Communications in 2016) on NMN’s metabolism in mammalian cells concluded NMN cannot directly enter the cell. Simply put, NR enters cells directly; NMN does not. 

NR and NMN are chemically identical, with the exception of one phosphate group present on NMN. The study demonstrates that this additional phosphate group must be removed from NMN, converting it into nicotinamide riboside before it can enter the cell.  

However, a study published in Nature Metabolism in 2019 claimed to have identified a transport protein for NMN in the small intestine of mice. But researchers Mark S. Schmidt and Charles Brenner questioned the validity of this claim, stating there is an absence of evidence for this NMN transporter. 

3. Steps to Make NAD

The cellular pathway it takes to transform NMN to NAD requires three steps, but the pathway from NR to NAD+ only requires two steps.

NMN has to turn into NR before it can enter the cell. Once it’s inside the cell, it needs to transform back into NMN before it becomes NAD+.

NR, on the other hand, can make its way into the cell on its own. Once it’s inside the cell, it transforms into NMN and then to NAD+. So NR seems to have a more efficient path to NAD+ generation.

4. Vitamin Status

Only one of the molecules has vitamin status—NR. NR is a form of vitamin B3.

You can actually find small traces of NR in milk, fruits, meat, and vegetables. Just like other forms of vitamin B, B3 helps turn food into energy.

It also acts as an antioxidant. Your body needs this vitamin to function well. In fact, a vitamin B3 deficiency may lead to the following symptoms:

• Diarrhea

• Dermatitis

• Mental confusion

• Memory issues

• Fatigue

Even though NMN is a precursor to NAD+, it isn’t considered a vitamin. This larger molecule is actually made up of other B vitamins, and it contains phosphate.

5. Administration Routes

Various companies sell NMN and NR supplements in pill form. If you examine how they are used in scientific experiments, their routes of administration are quite different.

In most animal studies, NMN is administered to rats via injections. NR, on the other hand, is given as a supplement mixed with food or water.

The same route of NR administration is used in human studies as well. NR usually is given to participants like regular vitamins in capsule form.

6. Safety Notifications

Running studies with human participants are essential because it helps researchers establish the safety of the treatment. Researchers haven’t gotten that far with NMN.

When it comes to NR supplements, though, researchers ran clinical trials to test its safety. The results show that NR is a safe supplement.

There were no significantly different adverse events between the NR group and placebo groups in the clinical studies. There were also other side effects, such as an increase in low-density lipoprotein (LDL) cholesterol.

So, researchers believe that it’s a safe and tolerable supplement. On top of that, NR supplements have records with the US Food and Drug Administration (FDA).

In March 2016, a pharmaceutical company sent a Generally Recognized as Safe (GRAS) notice for NR supplements to the FDA. A few months later, the FDA sent in a favorable response to the GRAS notice. They did not raise any issues with the safety of NR supplements.

7. Evidence of Utility

There are several promising findings when it comes to the effects of NMN in animal studies. But NR is ahead of the game because it has evidence of utility in human studies.

In one study, older adults were given two doses of NR pills (500 mg/dose). After six weeks, there were no adverse effects among the older adults who took the NR supplements. On top of that, the oral NR supplementation stimulated NAD+ metabolism by up to 60%.

It’s clear which molecule is ahead of the game when it comes to NMN vs. NR. NAD+ plays a vital role in one’s healthspan, so researchers are naturally interested in responding to its age-related decline.

The research continues, and scientists are learning more about NAD+ and its precursors.

Sources and References: 

https://blog.trudiagnostic.com/nmn-vs-nr/

https://www.truniagen.com/blog/nr-vs-others/nicotinamide-riboside-vs-nmn-debunking-the-nmn-science/