Poor Results from an Initial Human Trial of Nicotinamide Mononucleotide

Mitochondria are the power plants of the cell, responsible for packaging energy store molecules that power cellular processes. NAD+ is an essential metabolite for mitochondrial function, but levels decline with age. The proximate causes of this decline are fairly well mapped, and involve insufficient resources in a variety of pathways for synthesis or recycling of NAD+. The deeper reasons are poorly understood, however, meaning how these pathway issues emerge from the underlying molecular damage to cells and tissues that causes aging. Ways to force an increase in NAD+ levels have been shown to improve mitochondrial function in old animals, reversing some of the losses that occur with age. Loss of mitochondrial function is implicated in age-related diseases, particularly those in energy-hungry tissues such as the brain and muscles.

There are a number of ways to raise NAD+ levels: delivery of sizable amounts of NAD+ directly via infusion, of which a tiny fraction makes it into cells where it is needed; delivery of various precursor molecules that are used to manufacture NAD+; or delivery of factors known to improve recycling of NAD+. Most present effort is focused on the second of those options, via supplements such as nicotinamide riboside or nicotinamide mononucleotide, though groups like Nuchido are trying to produce better means of raising NAD+ levels that target multiple mechanisms at once.

Nicotinamide riboside has been trialed in humans, in a small number of people, with data showing reductions in age-related increases in blood pressure through improvement in the function of vascular smooth muscle. A similarly small trial of nicotinamide mononucleotide took place in Japan, and in today's open access paper, the researchers involved report on the results. As you can see from their summary, this approach achieved none of the benefits noted in the trial of nicotinamide riboside. At least some of the patients were old enough to expect some positive outcome on blood pressure, but none was observed.

Recent studies have revealed that decline in cellular nicotinamide adenine dinucleotide (NAD+) levels causes aging-related disorders and therapeutic approaches increasing cellular NAD+ prevent these disorders in animal models. The administration of nicotinamide mononucleotide (NMN) has been shown to mitigate aging-related dysfunctions. However, the safety of NMN in humans have remained unclear. We, therefore, conducted a clinical trial to investigate the safety of single NMN administration in 10 healthy men of 40 to 60 years of age.

A single-arm non-randomized intervention was conducted by single oral administration of 100, 250, and 500 mg NMN. Clinical findings and parameters, and the pharmacokinetics of NMN metabolites were investigated for 5 hours after each intervention. Ophthalmic examination and sleep quality assessment were also conducted before and after the intervention.

The single oral administrations of NMN did not cause any significant clinical symptoms or changes in heart rate, blood pressure, oxygen saturation, and body temperature. Laboratory analysis results did not show significant changes, except for increases in serum bilirubin levels and decreases in serum creatinine, chloride, and blood glucose levels within the normal ranges, independent of the dose of NMN. Results of ophthalmic examination and sleep quality score showed no differences before and after the intervention. Plasma concentrations of N-methyl-2-pyridone-5-carboxamide and N-methyl-4-pyridone-5-carboxamide were significantly increased dose-dependently by NMN administration. The single oral administration of NMN was safe and effectively metabolized in healthy men without causing any significant deleterious effects. Thus, the oral administration of NMN was found to be feasible, implicating a potential therapeutic strategy to mitigate aging-related disorders in humans.

Link: https://doi.org/10.1507/endocrj.EJ19-0313

Comments

A single dose NMN safety study that concludes that NMN is safe... Poor results? How so?

...'a clinical trial to investigate the safety of single NMN administration in 10 healthy men of 40 to 60 years of age'
...
'The single oral administration of NMN was safe and effectively metabolized in healthy men without causing any significant deleterious effects. Thus, the oral administration of NMN was found to be feasible, implicating a potential therapeutic strategy to mitigate aging-related disorders in humans.'

Posted by: Jones at November 12th, 2019 1:15 AM

The purpose of the trial was to investigate the safety, not the effectiveness...of a single dose.

Posted by: Pierre at November 12th, 2019 5:59 AM

Given the study design and aim, which was to investigate safety not efficacy we cannot draw any conclusions whatsoever from this, aside from it is well tolerated at the dosage tested.

Posted by: Steve Hill at November 12th, 2019 6:38 AM

What are you doing man. How can you conclude that from that study, lol. Look NMN is probably not the precursor we're looking for, but shit, youre being really disingenuous

Posted by: richard at November 12th, 2019 12:34 PM

Maybe those guys are selling NR and want to talk down NMN? It is ridiculous to even expect any significant effect after just one dose and such a short time. Man, learn to read and understand studies.

Posted by: Matt at November 12th, 2019 12:46 PM

After reading the study posted here on May 6, "Boosting Levels of NAD+ May Make Senescent Cells More Aggressively Inflammatory" as well as the one posted here just last week on November 5, "An Investigation of Adverse Effects of Nicotinamide Riboside Supplementation" - I'm afraid to do anything to increase NAD!
The nuchido science is extremely interesting and may avoid those problems but I have no way to determine that. What is everyone else doing in light of these recent negative studies?

Posted by: August at November 12th, 2019 3:04 PM

David Sinclair as said that even in mice there's a dose threshold you need to surpass to get effects from NMN. I'm thinking that 500mg isn't enough in people.

Posted by: mike at November 12th, 2019 3:42 PM

Interesting if somewhat limited trial. Would be really good to hear Prof. David Sinclair's (and other professionals) comments on this article...

Posted by: Tom Lindsay at November 17th, 2019 7:41 PM

It is amazing that companies some companies are charging over ten thousand for intravenous treatments without having definitive proof that their treatments don't materially effect cellular NAD levels.

Posted by: Richard Plantan at November 19th, 2019 6:55 AM

From reading the paper abstract, I also do not understand why this news story leads with "Poor results". The paper looks like a report on a successful single dose safety study, where a therapeutic course would be expected, from animal studies, to be many doses.

Posted by: Karl Blasius at November 19th, 2019 1:25 PM

"Poor Results" What did you expect from a single dose? Real life administration indicates you need 2 to 12 weeks to see results depending on dosage. One dose is simply not enough to make a determination for anything else except it is safe to consume. Five hours is also not long enough for anything else. There are NAD spikes seen for 24 to 48 hours after initial dose in various organs. This is not a drug. It works with your body. The length of time and dose is very important when looking for any other type of result. This just looks like a way to get clicks with a sensational headline and no substance. This study was for safety only. Don't scare people who do not have the background to be able to tell the difference between science and sensationalized headlines.

Posted by: Deborah Smith at December 20th, 2019 1:15 PM

This site just discredited itself....

Posted by: Rob at January 16th, 2020 10:38 AM

People yelling at the author, claiming he doesn't understand the study should try to look if they know anything about science. So you guys think a study which finds what it is "searching for" and nothing else is a positive study? What you don't understand is that if it were effective, you would have seen change in blood pressure and other markers, which could have been in the acceptable range. But it saw nothing, at any level, which means it is not effective.
That said, the study is small, nonetheless, we should have seen improvements.

Posted by: bobleponge at May 17th, 2020 1:55 AM

Well bobleponge, serum levels of bilirub are inversely related to risk of certain heart diseases.

Novotný, L; Vítek, L (2003). "Inverse relationship between serum bilirubin and atherosclerosis in men: A meta-analysis of published studies". Experimental Biology and Medicine. 228 (5): 568-71. doi:10.1177/15353702-0322805-29. PMID 12709588.
^ Schwertner, Harvey A.; Vítek, Libor (2008). "Gilbert syndrome, UGT1A1*28 allele, and cardiovascular disease risk: Possible protective effects and therapeutic applications of bilirubin". Atherosclerosis. 198 (1): 1-11.

Posted by: Jack at May 26th, 2020 6:32 AM

I think people are desperate to to affirm their own beliefs and too many people got money, or heavily invested on a shelf full of NMN supplements to admit the reality. They've had decades to prove NMN's efficacy and never achieved clear results on anything. Keep wish and diverting resources into futile areas.

Posted by: Pippin the Truthspeaker at June 20th, 2020 11:44 AM

NAD+ has also attracted a wave of attention from cancer researchers. Recent studies suggest that cancer cells of many types depend on NAD+ to sustain their rapid growth and that cutting off the NAD+ supply could be an effective strategy for killing certain cancers. The data from these studies paint a more complicated picture of NAD+ and raise new questions about the diverse ways taking an NAD+-boosting supplement might influence health. "It might still slow down the aging part, but it might fuel the cancer part," says Versha Banerji, a clinician-scientist at the University of Manitoba. "We just need to figure out more about the biology of both of those processes, to figure out how we can make people age well and also not get cancer."

Posted by: matthew wright at July 25th, 2020 3:59 PM

Bottom line ...People will eventually live forever. It's just a matter of time. We used to live in caves, and now look at us. We can only keep improving. So for all you highly intelligent people, get involved in genetics, and speed up the inevitable fact of human and animal immortality. Man will never quit until we get there. And yes, there is an answer and solution for everything, and we will find it.

Posted by: greg at August 1st, 2020 9:57 AM

This is all a lot of nonsense. Not too many drugs have an impact after a single dose, and for those that do if the dosage is not high enough even they don't work. To the naysayers, what have you done to improve life expectancy and reversal of disease? Every time I see David he looks younger and younger decades have passed

Posted by: Robb at September 16th, 2020 11:35 AM

Does anyone know if NMN is marketed in the US legally? I have not been able to find a New Dietary Ingredient Notification has been filed with FDA

Posted by: Steve at September 26th, 2020 10:41 PM

I'm taking NMN from RevGenetics. It's expensive. I have no way of determining if there is any benefits yet.

Posted by: Joanne Grubbs at September 29th, 2020 2:26 PM

If I am not mistaken; this was simply a study to conclude NMN is safe for humans. It was not meant to conclude on effectiveness.

Posted by: andrew at October 10th, 2020 10:25 PM

The study should have looked at IV-administered NAD for a single dose.

I have had fantastic effects with *IV-administered* NAD, which is much more powerful than the pill form I also take. Two weeks of daily sessions of NAD enabled me to get off a devastating benzodiazepine dependency, and dramatically reduced my chronic back pain and inflammation. It increased my mental clarity and substantially increased my stamina and flexibility for weeks after a single dose, with further noticeable effects for months more.

Posted by: Luke at October 14th, 2020 7:23 PM

Conclusion based on 10 people trial and one dose ? :-) O.K.

This whole "test" is a joke anyways. Even tests on people with glaucoma showed promising results and is very good known the effects of this vitamin on our bodies.

Please delete this article so you don't confuse people, thanks.

Posted by: James at October 21st, 2020 7:27 AM

The positive effects are good enough to start taking NMN or NR regularly. I would ignore the cancer argument. Adjusting diets and environment is the solution. CRISPER is what we need to study eliminate cancer. Our entire body needs NAD just like other vitamins. Without them we deteriorate. Big farma isn't interested in our health. I am sure they will combat the over the counter solutions that drain there pockets. I believe Dr. Sinclair has made progress and the fact that he takes it like a vitamin is all the evidence I need to do the same.

Posted by: Patricia Hinman at November 6th, 2020 12:55 AM

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