haidut

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This is a human study, so the findings are that much more relevant even though they probably do not come as a surprise to users of this forum. The duration of the study was just 6 weeks and the dose was 500mg nicotinamide riboside (NR) twice a day (for a total of 1,000mg). There were no side effects, except two people dropping out due to allergic reactions and rash but those occurred while in the placebo phase, so we can say that in fact NR did not have side effects at this dose. The most striking effect was a 10-point reduction in blood pressure, which led the authors conclude that vitamin B3 may reduce risk of heart attacks by more than 25%.
Now, an earlier study by the same company (ChromaDex) testign various doses of NR for raising NAD found that a dose of 300mg raised NAD levels by the same amount as a 1,000mg dose within a 24-h period. So, there seems to be a saturation effect for NAD precursors like NR and niacinamide, which suggests that a lower dose of about 300mg may achieve the same effects as the ones seen in this study. As most people here know, the 300mg daily dose also happens what Ray recommends for most people, and he also said that up to 1g is probably safe for long term use.

Chronic nicotinamide riboside supplementation is well-tolerated and elevates NAD<sup>+</sup> in healthy middle-aged and older adults
Supplement that mimics fasting reduces heart attack risk up to 25% | Daily Mail Online

"...A new pill mimics the effects of a crash diet and slashes the risk of a heart attack by up to 25 per cent, a study claims. The tablet contains nicotinomide riboside, a form of vitamin B3, that is advertised as promoting endurance, energy and healthy ageing. And a new study, involving 24 lean and healthy volunteers, found taking it twice a day can reverse cardiovascular ageing. It works in the same way as a calorie restricted diet, which boosts the health of blood vessels and reduces blood pressure in middle aged patients."

"...Results showed in 13 participants with elevated blood pressure or stage 1 hypertension (120-139/80-89 mmHg), systolic blood pressure was about 10 points lower after supplementation. A drop of that magnitude could translate to a 25 per cent reduction in heart attack risk. He added: 'If this magnitude of systolic blood pressure reduction with NR supplementation is confirmed in a larger clinical trial, such an effect could have broad biomedical implications.' Such caloric restriction mimicking compounds could provide an additional option, alongside the dietary changes and exercise currently recommended, for people whose blood pressure is not yet high enough to warrant medication but who are still at risk for a heart attack."
 

Wagner83

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B3 mimics fasting??
In such studies why don't they test for vitamins imbalances that could be created from using a high dose of one?
There were no side effects, except two people dropping out due to allergic reactions and rash but those occurred while in the placebo phase, so we can say that in fact NR did not have side effects at this dose.
That's funny, could the fillers be allergenic? :ss2
 
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haidut

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B3 mimics fasting??
In such studies why don't they test for vitamins imbalances that could be created from using a high dose of one?

That's funny, could the fillers be allergenic? :ss2

Well, that is their guess - that it mimics fasting. In reality, what they mean is that it has been shown that both fasting and NR raise NAD and AMPK levels. So, since NR raised NAD they compare it to fasting. CR is a very popular topic right now and if you are company with a product that showed benefit it would probably help sales if you tie it to CR as the official version is that CR is the only approach so far shown to retard aging in humans.
And yes, the excipients in the placebo group probably caused the allergic reactions. I think they should have called it the "nocebo" group, which btw is a valid medical term.
 

aguilaroja

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This is a human study, so the findings are that much more relevant even though they probably do not come as a surprise to users of this forum. The duration of the study was just 6 weeks and the dose was 500mg nicotinamide riboside (NR) twice a day (for a total of 1,000mg). There were no side effects, except two people dropping out due to allergic reactions and rash but those occurred while in the placebo phase, so we can say that in fact NR did not have side effects at this dose. The most striking effect was a 10-point reduction in blood pressure, which led the authors conclude that vitamin B3 may reduce risk of heart attacks by more than 25%.
Chronic nicotinamide riboside supplementation is well-tolerated and elevates NAD<sup>+</sup> in healthy middle-aged and older adults
Supplement that mimics fasting reduces heart attack risk up to 25% | Daily Mail Online

Thanks @haidut. Abram Hoffer and William Kaufman are resting easier today. :^)

The study did report one subject each with skin rash and with flushing among the niacinamide riboside user group, though these two did not drop out.
Table 2 Treatment-emergent adverse events (AEs)
It is rare but not unheard of for persons using niacinamide to get histamine-type skin flushing, similar to what happens very commonly taking regular niacin. It is possible that excipients or impurities may factor in, but Hoffer worked in days when vitamin quality might have been higher. I would expect the same occasional flushing possibility exists for people using niacinamide riboside, but there is probably not enough of a track record to hear regular reports.

I of course am in agreement with Dr. Peat’s & @haidut’s view that niacinamide is the preferable B3 for support.

Niacin, Coronary Disease and Longevity by Abram Hoffer, M.D., Ph.D.
Niacinamide And Histamine
 

Wagner83

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Well, that is their guess - that it mimics fasting. In reality, what they mean is that it has been shown that both fasting and NR raise NAD and AMPK levels. So, since NR raised NAD they compare it to fasting. CR is a very popular topic right now and if you are company with a product that showed benefit it would probably help sales if you tie it to CR as the official version is that CR is the only approach so far shown to retard aging in humans.
And yes, the excipients in the placebo group probably caused the allergic reactions. I think they should have called it the "nocebo" group, which btw is a valid medical term.
Given all the talk there has been about fasting and CR, an increase NAD levels is intriguing.
I just checked and "nocebo" is still caused by the expectations and psychological state of the patients. I wonder if they think the fillers ar responsible for the reactions or if they just discard the evidence as "placebo effect". I mean given the excipients of some of the drugs on the market (I think about the german metergoline with titanum dioxide), the latter sounds possible.

@aguilaroja What do you think a safe dose of b3 is?
I of course am in agreement with Dr. Peat’s & @haidut’s view that niacinamide is the preferable B3 for support.

Niacin, Coronary Disease and Longevity by Abram Hoffer, M.D., Ph.D.
Niacinamide And Histamine
 

griesburner

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Would be nice if there was a study in humans showing this with pure niacinamide instead of the nicotinamide-ribose. I am always a bit sceptical if we can conclude that niacinamide have the exact same effect, only cause it raises NAD+ like the NR. Dont get me wrong i would be happy if niacinamide could do it cause its very cheap. But what if its something special about the nicotinamide-ribose that led to the observed effects?
 

aguilaroja

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Given all the talk there has been about fasting and CR, an increase NAD levels is intriguing.
...@aguilaroja What do you think a safe dose of b3 is?
I am guessing the question is about the niacinamide form. Even so, I lack a precise answer. Dr. Peat, @haidut and others have rationale for more exact determinations. As with pharmaceuticals, a parallel question is: What is the minimum effective dose?

Generally (given quality supplement), the maximum range seems something in the low hundreds to low thousand of milligrams. @Travis gave a thoughtful calculation last year about vitamin D safety, which gives ideas about how estimates might be constructed for niacinamide.
Vitamin D Really Toxic?

When experimenting with high amounts of niacinamide, before and after studying Dr. Peat’s work, I found anything near a few grams (3000 mg) total per day gave headache, nausea, digestive irregularity or all three. However, I have met people who took larger doses (several grams per day total) in the William-Kaufman-described manner and got great benefit with no side effects.

IIRC Kaufman emphasized for therapeutic effects in severe osteoarthritis, frequent use of niacinamide was very important good results. Most people, even with will power, have difficulty taking a supplement say, six times per day. I am not aware of successful formulations of extended-release niacinamide. In searching for niacinamide effective minimum doses, it is possible that tens of milligrams throughout the day would work best.
Niacinamide: Safe Upper Limit?
 
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aguilaroja

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Would be nice if there was a study in humans showing this with pure niacinamide instead of the nicotinamide-ribose. I am always a bit sceptical if we can conclude that niacinamide have the exact same effect, only cause it raises NAD+ like the NR. Dont get me wrong i would be happy if niacinamide could do it cause its very cheap. But what if its something special about the nicotinamide-ribose that led to the observed effects?

Side by side studies would be great. Proprietary claims relate to propriety interests, and may sway full investigation. There is one major player in nicotinamide riboside distribution. Even among major pharmaceutical products, few thorough product comparisons exist, especially for multiple product choices. Hundreds of billions of euros/dollars could be saved with better choice information, but it doesn’t happen. I was reading data recently about sucrosomial minerals, trying to gauge the extent of bioavailability assertions and cost/benefit.

Niacinamide sale has no major profit, and so no research sponsors. Current Niacinamide Riboside and Nicotinamide Mononucleotide OTC prices are many times similar quantities of plain niacinamide. Years ago, a physician who saw Kaufman’s clear niacinamide results exclaimed, “It costs pennies a day!”

Props to @haidut for continued intriguing NAD+/nicotinamide posts.
NAD/NADH Ratio - The One Metabolic Cause To Rule Them All
 

Wagner83

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I am guessing the question is about the niacinamide form. Even so, I lack a precise answer. Dr. Peat, @haidut and others have rationale for more exact determinations. As with pharmaceuticals, a parallel question is: What is the minimum effective dose?

Generally (given quality supplement), the maximum range seems something in the low hundreds to low thousand of milligrams. @Travis gave a thoughtful calculation last year about vitamin D safety, which gives ideas about how estimates might be constructed for niacinamide.
Vitamin D Really Toxic?

When experimenting with high amounts of niacinamide, before and after studying Dr. Peat’s work, I found anything near a few milligrams total per day gave headache, nausea, digestive irregularity or all three. However, I have met people who took larger doses (several grams per day total) in the William-Kaufman-described manner and got great benefit with no side effects.

IIRC Kaufman emphasized for therapeutic effects in severe osteoarthritis, frequent use of niacinamide was very important good results. Most people, even with will power, have difficulty taking a supplement say, six times per day. I am not aware of successful formulations of extended-release niacinamide. In searching for niacinamide effective minimum doses, it is possible that tens of milligrams throughout the day would work best.
Niacinamide: Safe Upper Limit?
Thanks for the pointers , I'm surprised you had such issues with few mg but then after using 30mg twice a day for some time I started getting stress reactions (particularly cold feet), perhaps the effects build up as well.
 

haidut

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Would be nice if there was a study in humans showing this with pure niacinamide instead of the nicotinamide-ribose. I am always a bit sceptical if we can conclude that niacinamide have the exact same effect, only cause it raises NAD+ like the NR. Dont get me wrong i would be happy if niacinamide could do it cause its very cheap. But what if its something special about the nicotinamide-ribose that led to the observed effects?

There have been, by the same company that did this trial. It showed that NR, niacinamide, and NMN were all equivalent in effectiveness with NR showing a small statistically insignificant advantage over niacinamide. Search the forum, the study is posted somewhere here.
More importantly, in human clinical practice it is the niacinamide that is approved as an NAD precursor, not NR. The vast majority of animal and human clinical trials on raising NAD have been done with niacinamide (or in small number of cases niacin). In addition, niacinamide is unique among the NAD precursors that it is also an SIRT inhibitor (which has its own benefirts). Niacin, NR, and NMN are all SIRT activators.
 

aguilaroja

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Thanks for the pointers , I'm surprised you had such issues with few mg but then after using 30mg twice a day for some time I started getting stress reactions (particularly cold feet), perhaps the effects build up as well.

It is my error in keyboarding. I did not notice problems until the two to three gram (2000 to 3000 mg) range. I have edited my comment and have not managed to find the strike through font for formatting. Apologies.
 

ejalrp

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Thanks @haidut. Abram Hoffer and William Kaufman are resting easier today. :^)

I of course am in agreement with Dr. Peat’s & @haidut’s view that niacinamide is the preferable B3 for support.

Niacin, Coronary Disease and Longevity by Abram Hoffer, M.D., Ph.D.
Niacinamide And Histamine

But this confuses NR (an expensive supplement) with niacin (a cheap supplement). Niacin is well known for its ability to lower cholesterol (and cause a flush). I assume NAD is working differently. I was also under the impression that niacinamide doesn't lower cholesterol (if it does, certainly not as dramatically as niacin does).
 

aguilaroja

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But this confuses NR (an expensive supplement) with niacin (a cheap supplement). Niacin is well known for its ability to lower cholesterol (and cause a flush). I assume NAD is working differently. I was also under the impression that niacinamide doesn't lower cholesterol (if it does, certainly not as dramatically as niacin does).

Please see post #10 in this thread by @haidut, which describes effects of niacin, NR, niacinamide, and NMN.

The links just re-cited were given in the context of noting the rare flushing response to the niacinamide form.

It is in large part due to Hoffer’s work that the effect of niacin on serum cholesterol became known and applied. Some specifics are mentioned in the linked article. Dr. Peat over many years has emphasized the benefits of the niacinamide form. There are many niacinamide posts on the forum, by @haidut and others. Further, many mentions of the cholesterol issue can be found at Dr. Peat’s site and in the forum.

Though I, and perhaps others, have a differing view of the context for supplementation of niacin, Hoffer did very admirable work. He helped many people, made inquiries in nutrition, worked late into a very long life, and patiently shared his findings.
 

bdawg

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There have been, by the same company that did this trial. It showed that NR, niacinamide, and NMN were all equivalent in effectiveness with NR showing a small statistically insignificant advantage over niacinamide. Search the forum, the study is posted somewhere here.
More importantly, in human clinical practice it is the niacinamide that is approved as an NAD precursor, not NR. The vast majority of animal and human clinical trials on raising NAD have been done with niacinamide (or in small number of cases niacin). In addition, niacinamide is unique among the NAD precursors that it is also an SIRT inhibitor (which has its own benefirts). Niacin, NR, and NMN are all SIRT activators.

Niacinamide can be a Sirt1 enhancer in vivo

Nicotinamide is an inhibitor of SIRT1 in vitro, but can be a stimulator in cells. - PubMed - NCBI

However, once administered to cells, NAM is rapidly converted to NAD+ and, therefore, the cellular concentration of NAM decreases rapidly while that of NAD+ increases. The result would be an inhibition of SIRT1 for a limited duration, followed by an increase in the activity. This possibility raises a concern on the validity of the interpretation of the results in the studies that use NAM as a SIRT1 inhibitor. To understand better the effects of cellular administration of NAM, we reviewed published literature in which treatment with NAM was used to inhibit SIRT1 and found that the expected inhibitory effect of NAM was either unreliable or muted in many cases. In addition, studies demonstrated NAM administration stimulates SIRT1 activity and improves the functions of cells and organs. To determine if NAM administration can generate conditions in cells and tissues that are stimulatory to SIRT1, the changes in the cellular levels of NAM and NAD+reported in the literature were examined and the factors that are involved in the availability of NAD+ to SIRT1 were evaluated. We conclude that NAM treatment can hypothetically be stimulatory to SIRT1.
 

haidut

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Niacinamide can be a Sirt1 enhancer in vivo

Nicotinamide is an inhibitor of SIRT1 in vitro, but can be a stimulator in cells. - PubMed - NCBI

However, once administered to cells, NAM is rapidly converted to NAD+ and, therefore, the cellular concentration of NAM decreases rapidly while that of NAD+ increases. The result would be an inhibition of SIRT1 for a limited duration, followed by an increase in the activity. This possibility raises a concern on the validity of the interpretation of the results in the studies that use NAM as a SIRT1 inhibitor. To understand better the effects of cellular administration of NAM, we reviewed published literature in which treatment with NAM was used to inhibit SIRT1 and found that the expected inhibitory effect of NAM was either unreliable or muted in many cases. In addition, studies demonstrated NAM administration stimulates SIRT1 activity and improves the functions of cells and organs. To determine if NAM administration can generate conditions in cells and tissues that are stimulatory to SIRT1, the changes in the cellular levels of NAM and NAD+reported in the literature were examined and the factors that are involved in the availability of NAD+ to SIRT1 were evaluated. We conclude that NAM treatment can hypothetically be stimulatory to SIRT1.

As the study says - it depends on the dose. In lower doses niacinamide mostly raises NAD and that activates SIRT1. But in higher doses in the range of 1g+ daily niacinamide metabolizes into 6-methylnicotinamide and both niacinamide and the 6-methyl metabolite are SIRT inhibitors.
 
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