An Investigation of Adverse Effects of Nicotinamide Riboside Supplementation

Nicotinamide riboside is so far the only approach to NAD+ upregulation for which there is published human trial data, though other trials for other approaches are underway at the present time. NAD+ declines with age, for reasons that remain comparatively poorly understood, and this has a negative impact on mitochondrial function. Thus there is considerable enthusiasm at the moment for intervening in this known manifestation of aging by tackling the proximate causes, raising NAD+ levels, but without addressing underlying causes.

Researchers here find the potential for adverse effects on glucose metabolism and white adipose tissue function to result from nicotinamide riboside supplementation, but there are a great many details involved: dietary differences and genetic differences in mice appear important as to whether problems arise, and the final sections of the discussion in the paper are worth reading closely. It is hard to say whether or not the discoveries made in mice that are reported in this open access paper will apply to humans, but the specific details suggest that investigation is warranted.

Nicotinamide riboside (NR) is a nicotinamide adenine dinucleotide (NAD+) precursor vitamin. The scarce reports on the adverse effects on metabolic health of supplementation with high-dose NR warrant substantiation. Here, we aimed to examine the physiological responses to high-dose NR supplementation in the context of a mildly obesogenic diet and to substantiate this with molecular data. An 18-week dietary intervention was conducted in male C57BL/6JRccHsd mice, in which a diet with 9000 mg NR per kg diet (high NR) was compared to a diet with NR at the recommended vitamin B3 level (control NR). Both diets were mildly obesogenic (40 en% fat). Metabolic flexibility and glucose tolerance were analyzed and immunoblotting, qRT-PCR, and histology of epididymal white adipose tissue (eWAT) were performed.

Mice fed with high NR showed a reduced metabolic flexibility, a lower glucose clearance rate and aggravated systemic insulin resistance. This was consistent with molecular and morphological changes in eWAT, including sirtuin 1 (SIRT1)-mediated PPAR╬│ (proliferator-activated receptor ╬│) repression, downregulated AKT/glucose transporter type 4 (GLUT4) signaling, an increased number of crown-like structures and macrophages, and an upregulation of pro-inflammatory gene markers. In conclusion, high-dose NR induces the onset of WAT dysfunction, which may in part explain the deterioration of metabolic health.



9000 mg NR per kg is insanely high compared to current supplementation strategies.
From that I know daily recommended doses range between 100mg-1000mg total (not per kg)

Posted by: Yaniv at November 5th, 2019 6:01 AM

you have difficulties understanding English language (like a lot):

"High Dose of Dietary Nicotinamide Riboside Induces Glucose Intolerance and White Adipose Tissue Dysfunction in Mice Fed a Mildly Obesogenic Diet"

if you do NOT understand what the study says, ask somebody who understands it, and it will translate it for you.

Posted by: z at November 5th, 2019 11:07 AM

I can give you some anecdotal, personal experience with the Sirtuins (NR and AMPK). I starting using these around 2015-2016. I developed a persistent cough over the next three years. I read somewhere on the longecity forums that one of the side effects of excessive NAD+ boosting is increased histamine production, which produced the return of my allergies and, hence, my cough. I stopped taking NR and AMPK activator about 3 months ago. My cough has largely disappeared. I also read that excessive NAD+ boosting my also interfere with proper clearance of senescent cells, necessitating the greater use of senolytics. The interesting thing about the first symptom is that it would not have occurred if NAD+ boosting did not work at all. In my particular experience, I did not need much of it at all.

In short, I think NR and the other Sirtuins are useful. But they must be used judiciously while keeping in mind the idiosyncrasies of one's own molecular biology.

Posted by: Abelard Lindsey at November 5th, 2019 11:08 AM

The study states reason for using high dose NR here: "Since we did not observe beneficial effects of an NR dose of 900 mg per kg of diet (900NR in [19]), which is at the low end of the dose range that displayed NAD+ boosting or beneficial effects on metabolic function in other studies [3,4,5,13,14], we here imposed a dose of 9000 mg NR per kg diet (high NR), which is one order of magnitude higher and just at the high end of this dose range."

Posted by: August at November 5th, 2019 11:19 AM

So..Did I make a big mistake by getting a 4 hour intravenous infusion of NAD+ ??

Posted by: August at November 5th, 2019 11:20 AM

Possibly of interest is this recent paper --

"Adipose tissue NAD+ biosynthesis is required for regulating adaptive thermogenesis and whole-body energy homeostasis in mice"

Posted by: L Pagnucco at November 6th, 2019 2:28 PM

Every time I have tried NAD+ I have felt terrible. Niacin interferes with b vitamin methylation and I have a genetic variant that already reduces my methylation considerably. I do take methylated B-12 and folate, and I find that I need B1 and B2 daily to feel my best. I also avoid B complex vitamins like the plague. They really pile on the niacin in those things which for me makes them worse than useless.

Personally I think that NAD+ messes up methylation.

Posted by: John Whitling at November 11th, 2019 6:52 AM

I've been considering taking supplements for NAD or Nicotinamide Riboside, but according to some of the comments here, it does seem to interfere with Niacin- or Niacinamide- vitamin B3...can anyone with experience/knowledge on this elaborate and share what your experience is on this regard? Great subject btw

Posted by: Eduardo Torres-Betancourt at September 4th, 2020 3:08 AM

I am a believer in these advanced nutritional s. I started taking NAD3 plus a resveratrol approximately 14 months ago after surgery. I was not working for 5 months.
I am a shift worker so energy levels can be an issue.
I have been very tired for more than 12 months. Cannot remember when the fatigue started. When I ran out of the NAD3 for 2 weeks earlier this year I noticed that my energy picked up. But I dismissed the connection. I continued on the NAD3 till a week ago when I stopped again because my energy, tiredness, aching, not sleeping well was so bad. Within a week I am feeling so much better.
I am going to resume in the new year 2021 to see that I am on the right track and maybe have some blood tests.
I did have blood test a while ago in response to my tiredness . Everything was fantastic except for white blood cell slightly low. I am 61 years of age.

Posted by: Vicki Richardson at December 13th, 2020 5:58 PM

The recommended dose of Nicotinamide in the highly touted Heliocare Advanced is 500mg/day (two capsules) together with Fernblock (Polypodium leucotomos) which claims to support skin health and is recommended by Dermatologists. Anyone have experience with this combination available on Amazon?

Posted by: Robert Pedersen, MD at March 31st, 2021 5:05 PM

Do you think taking NAD+ booster (nicotinamide riboside) while you are sick / during a virus (for instance EBV/mononucleosis for sake of example) would help fight the virus faster or on the opposite end it would help the virus reproduce and get stronger ?

Posted by: christophe parroco at July 3rd, 2021 12:48 AM

I took my first NAD IV therapy drip and felt like crap for 2 days afterwards- lethargic. I took it for the promise of cell regeneration and to ward off the nasty Covid. I'm active, no health issues, great health. I took the drip in April- contracted the Delta Variant 4 days afterwards. Symptoms were equivalent to having a nasty case of the flu- without body aches.
I suspected my immune system was off from the NAD but dismissed it.
I revisited the NAD drip because I like to live on the wild side, apparently. Again, 4 days later- like right now, Covid again!!! I practice social distancing, wear a mask, stay sanitized yet Covid - again? I escaped Covid and all nasty bugs before the NAD supplement only to seem more susceptible after taking it. I did notice that I feel completely drained after having the NAD- in an unhealthy way.
So tread lightly here folks- especially if one doesn't know how one's genetic markers will react to such a supplement. I'm convinced that the nasty Covid bug was manufactured with whatever is in NAD. I may sound like extremely dense and dumb to you medical scholars, but I felt that my experience was worth sharing. Now I have to overdose on Vitamin C, D, zinc and others to not feel like this bug is consuming me. Oh and I must keep my house tempered like I live in Sub Sahara Africa just to ward off the mucus production in my lungs- with lots of high proof gin. Gin, sun, heat and vitamins are my life savers for this nasty crap. Don't chance NAD right now with this virus out.

Posted by: Veronica Laoye at September 7th, 2021 6:53 PM

The top of my leg hurt when i take it.

Posted by: Nancy at March 21st, 2022 7:54 AM

@Veronica Laoye
to be fair, it seems you got infected while taking the NAD .

Posted by: Cuberat at March 21st, 2022 10:32 AM

i got an e mail regarding Nicotinamid Riboside the B-3 variance Niasid or NAD can cause brian cancer along with other side effects????? please verify any Scientific facts, tests, or any new investigations? thank you very much r. poursaid

Posted by: ray poursaid at November 17th, 2022 12:55 PM!po=39.2857

It's true that NAD+ has contradictory results, and could either decrease or increase cancer growth. It's written above link and under the last 2nd paragraph of the NIH study on NAD+.

NAD+ is still complex to understand so I would be always cautious on taking them. Being always alert and careful are good everyone. Even vitamins, if you take too much of them, can poison you. So always moderation is the key.

Posted by: Dan at March 21st, 2023 11:28 PM

I tried 100 mg of NR. I had brain fog the whole day, was drowsy and sleepy. Then I tried taking the same suppliment at night...I had broken sleep , would wake up at 3AM. Next I tried the suppliment over long weekend.( 3 days continously) Along with 1st 2 symptoms I had itchy face.
I think NR is not for me

Posted by: Aru at May 14th, 2023 11:48 AM
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