65 replies to this topic

[M-K]

Sorry, I've only seen the abstract.  You might want to look for the Alzheimer's model studies mentioned.

[APBT]

Here’s the FULL TEXT: Nicotinamide riboside, a trace nutrient in foods, is a vitamin B3 with effects on energy metabolism and neuroprotection

[Phoenicis]

Thanks for that full text, thanks to you I managed to find:

 

Gong et al., Nicotinamide riboside restores cognition through an upregulation of proliferator-activated receptor-γ coactivator 1α regulated β-secretase 1 degradation and mitochondrial gene expression in Alzheimer's mouse models, Neurobiology of aging, 06/2013, Volume 34, Issue 6.

 

That study literally states that dose of: "250 mg/kg/day of NR (equivalent to 1300 mg/kg/day in the human)"  (!) improved cognitive performance in these Alzheimers model mice.

 

Just for giggles (don't go running off to try this ^v^): For a 70kg person that would be 91 grams / 91,000mg / day! That's about 607 Niagen capsules per day and at the current price of Niagen that would cost around $484.00/day!

 

How curious, could it be that NR's tolerable amount is extremely high? It almost seems like it should be getting sold in kg bags similar to protein powder lol!

 

They really should have put it up against NA, I'm wondering if the NR dose was that big for a reason...

 

The Alzheimers study used a mouse dose of 250mg/kg/day, the other study which showed NR had minimal effects in brain used a higher mouse dose of 400mg/kg/day for NR, NA, and NMN. Do these studies tell us anything about the toxicity of immediate release NA, NR and NMN? Those are pretty huge doses, does this confirm that elevated liver enzymes from NA are mostly limited to the sustained release formulations and lacking b6/b12/5-MTF/sAME for reducing homocysteine? The homocysteine is produced after NAD consuming enzymes produce the metabolite Nam, which is then methylated into MNA, so it should effect each of the NAD+ precursors and intermediaries correct?

 

 

Edited by Phoenicis, 03 August 2014 - 01:21 AM.

[Phoenicis]

This recent study used "40 [mcg]/g body weight per day" of nicotinamide on Alzheimers model mice with similar results - reduced cognitive decline and amyloid-beta, maintained mitochondrial integrity, autophagy function, NAD+ dependent SIRT1 etc.

 

That's 40mg/kg / day, which is about 6 times less than the lower 250mg/kg/day mouse dose for NR! Could this mean that Nam has similar or better efficacy to NR in the brain? The MS study states that in the brain, glial cells can efficiently perform salvage synthesis for Nam, as opposed to neurons. The MS study also stated that NA was found to have 200 fold increased efficacy over Nam in glial cells.

 

Ok nobody try this, this is hypothetical talk! This not intended to be medical advice, seek independent medical advice before administering any substances yourselves!

 

This is getting interesting! Would it be possible to therefore hypothesize that for NA the Nam mouse dose of 40mg/kg could be as low as:

 

40mg/200 = .2mg/kg/day (mouse dose)? Could one hypothetically then multiply this by 5.2 (1300/250) for a theoretical human dosage of 1.04mg/kg/day (72mg totoal)?

 

Taking the stated mouse dose of 40mg/kg for Nam, would that translate into roughly (40x5.2) x 70 = 14.5g Nam for a 70kg human?

 

 

What on earth is up with these doses? Is there even a safe/tolerable upper limit for Nam in humans?

 

Edited by Phoenicis, 03 August 2014 - 02:38 AM.

[Phoenicis]

I think we need new studies that take b6/b12/5-MTHF levels for homocysteine into account. This report for the European Commission even concedes that most toxicity studies are old and often small. Also the sustained release NA has been the cause of most issues.

 

Edited by Phoenicis, 03 August 2014 - 02:58 AM.

[Phoenicis]

This study in humans seems to confirm the benefits of Niacin for Alzheimer's (AD) prevention. They observed an inverse association between AD and niacin intake, both from foods and supplements. They also took into account "dietary intakes of folate and other B vitamins (vitamins B6, B12, B1, and B2)" and only "9 of the 815 participants were taking a prescribed form of niacin at baseline"

 

Multivitamins and food was used to increase Niacin, the highest quintile (5) of intake for food was 21mg (45 including supplements)  and produced a statistically significant increase in cognitive scores when compared to the lower quintile (12mg/day). There were five quintiles in total and the rate difference for quintiles 2-4 were not statistically significant. This means that only participants with higher intake levels showed "a statistically significant log linear inverse association" between AD and niacin.

 

The researchers did however note that it was "difficult to test for associations with supplemental niacin because it is obtained through multi- vitamins that contain many other nutrients that may confound observed effects." Too bad they did not test NA/NR/Nam individually and at higher doses.

 

Based on that, 72mg/day of NA doesn't sound too crazy for AD protection.

 

 

Edited by Phoenicis, 03 August 2014 - 02:19 PM.

[Kevnzworld]

Re: Homocysteine and NR supplementation

I've been taking 500-750 mg of NR daily for approx 6 months, and 100 mg of NA for a month. I just got my latest blood work back and my homocysteine dropped slightly from 7 to 6. Nothing else in my regimen changed significantly in the last 10 months since my previous lab work. There were no notable anomalies in the results other than a slight rise in my PSA and glucose. Neither I suspect are related to B3 supplementation
As I've previously posted, my homocysteine was 12~ Many years ago before I began taking 1000 mcg of 5 methyl folate per day.

[niner]

Gong et al., Nicotinamide riboside restores cognition through an upregulation of proliferator-activated receptor-γ coactivator 1α regulated β-secretase 1 degradation and mitochondrial gene expression in Alzheimer's mouse models, Neurobiology of aging, 06/2013, Volume 34, Issue 6.

 

That study literally states that dose of: "250 mg/kg/day of NR (equivalent to 1300 mg/kg/day in the human)"  (!) improved cognitive performance in these Alzheimers model mice.

 

Just for giggles (don't go running off to try this ^v^): For a 70kg person that would be 91 grams / 91,000mg / day! That's about 607 Niagen capsules per day and at the current price of Niagen that would cost around $484.00/day!

 

How in the world do they figure that 250 mg/kg in a mouse is equivalent to 1300 mg/kg in the human?  The usual scaling from mouse to human would be a factor of 1/12!  Thus:  250/12 = 21mg/kg.  70kg * 21mg/kg = 1470 mg.   This is a fairly large dose, but isn't crazy.  They didn't do a dose ranging study to find the lowest dose that would work in the Alzheimers mice, and people doing experiments like this usually use a large dose because they want to be sure they see an effect, so maybe they would have seen the same effect at half the dose.  Maybe they had some sort of reason for the 1300 number, but I didn't see it in the paper (which I didn't read all of). 

[StevesPetRat]

Taking the stated mouse dose of 40mg/kg for Nam, would that translate into roughly (40x5.2) x 70 = 14.5g Nam for a 70kg human?


What on earth is up with these doses? Is there even a safe/tolerable upper limit for Nam in humans?

15g Nam/day is well beyond the liver safety threshold, which I have seen as 1.5 - 5 g daily depending on which reference you read.

That paper has almost inspired me to buy a big bag o' niacin powder, but do you find the flushing reduces with continuous use? It's been a barrier to use before - some of us get a more "want to rip skin off" feeling rather than a "pleasant sauna" one.

Great thread!

[Kevnzworld]

Re: Homocysteine and NR supplementation

I've been taking 500-750 mg of NR daily for approx 6 months, and 100 mg of NA for a month. I just got my latest blood work back and my homocysteine dropped slightly from 7 to 6. Nothing else in my regimen changed significantly in the last 10 months since my previous lab work. There were no notable anomalies in the results other than a slight rise in my PSA and glucose. Neither I suspect are related to B3 supplementation
As I've previously posted, my homocysteine was 12~ Many years ago before I began taking 1000 mcg of 5 methyl folate per day.

I forgot to mention that my TSH is 1.7. It was 2.4 in the last test. Someone, I think SmithX mentioned having a concern about NR and thyroid function....
I will continue taking 750 mg of NR, and 100 mg NA ..

[Primal]

That study literally states that dose of: "250 mg/kg/day of NR (equivalent to 1300 mg/kg/day in the human)"  (!) improved cognitive performance in these Alzheimers model mice.

 

I suppose this is a typo, that they meant 1300mg/day for a 70kg human. Still, it's not sure if the conversion factor applies for NR.

 

 

Daily administration of 500 mg/kg (40g/170lb human equivalent) nicotinamide to EAE

mice from the day of MOG immunization or from day 10 pi., reduced all pathology parameters.

http://www.ncbi.nlm....les/PMC2651433/

 

 

The homocysteine is produced after NAD consuming enzymes produce the metabolite Nam, which is then methylated into MNA, so it should effect each of the NAD+ precursors and intermediaries correct?

 

NR can be cleaved to NAM (and riboside) without going through NAD, also niacin can be methylated without being converted to niacinamide and/or NAD. The upcoming NR PK data study should help answer your question

[M-K]

Nicotinamide Riboside Promotes Sir2 Silencing and Extends Lifespan via Nrk
and Urh1/Pnp1/Meu1 Pathways to NAD+

http://www.sciencedi...09286740700390X

"Although yeast cells can double intracellular NAD+ levels with
provision of either nicotinic acid or NR in the growth media, there are
important differences between the salvage pathways of the two vitamins.
As shown in Figure 2, nicotinic acid, which is almost universally used in
yeast synthetic media though not required for S. cerevisiae growth,
produces an intracellular NAD+ level that drops by more than 2-fold over
the course of growth in liquid culture. NR stably increases intracellular
NAD+ levels and extends lifespan via two distinct metabolic pathways."

Also of interest:

"The poor gene-silencing activities and rapid aging exhibited by strains
grown under conditions in which intracellular NAD+ levels are ¡­1 mM is
striking when one considers that the KM(NAD+) for yeast Sir2 is reported
to be 29 ¥ìM ( Borra et al., 2004), and virtually all KM(NAD+) values for
Sirtuin reactions are between 5 and 500 ¥ìM ( Sauve et al., 2006).
Regulation of Sirtuins in the cell by increase of NAD+ from ¡­1 mM toward
2 mM can be explained if most of the ¡°first mM¡± of NAD+ is protein
bound, such that there is a minimal amount of free NAD+. Our data suggest
that whereas the first mM of NAD+ fulfills essential functions through
NAD+-dependent oxidoreductases, the second mM fuels discretionary
functions of improved gene silencing, reduced rDNA recombination, and
increased lifespan."

[Thell]

I'm in awe of the intellectual power everyone has put into this across several topic forums. Especially Phoenicis, maxwatt, Primal, Darryl and many, many more.

 

I keep seeing references back to the 1983 study "Digestion and Absorption of NAD by the Small Intestine of the Rat" Within that study, on the first page they say; "The possibility exists that NR may be absorbed without further cleavage." Now I've spent a considerable number of hours/days researching this single point and the notion that NR is broken down into NAM before it's absorbed? I've also offered that comment taken from the 1983 study to stimulate some conversation given our immense global intellectual membership. I just cant predicate and pin my opinion on a 31-year old study which hasn't been challenged with a more recent one, especially when the researchers themselves admit; "The possibility exists that NR may be absorbed without further cleavage."

 

I also want the most bang for my buck and I will be closely following the current PK study: A Study of the Pharmacokinetics of Three Dosages of Niagen in Healthy Subjects (14NBHC)

 

Keep up the good work guys I will read every post and reference I can find the time for, thanks for your combined effort!

 

While trying to become more informed I noted that the PK study referred to is marked as complete (no result links on the page though) as of Sept 8 2014. Also, to note, two more studies registered on Nov 20, 2014: Pharmacokinetic Analysis of Nicotinamide Riboside[1] and The Effect of Vitamin B3 on Substrate Metabolism, Insulin Sensitivity, and Body Composition in Obese Men[2]. Of interest to me is that the original study study was 3 doses ( 100,300,1000 (mg) ) with a 7 day flush after each, and the two new studies are 500mg, 1000mg and 1000mg respectively with the first being an 8 hour time frame with blood sample every 15 minutes and the second being 3 month study.

 

 

 [1]:https://clinicaltria...m=Niagen&rank=3

 [2]:https://clinicaltria...how/NCT02303483

[Logic]

 

I'm in awe of the intellectual power everyone has put into this across several topic forums. Especially Phoenicis, maxwatt, Primal, Darryl and many, many more.

 

I keep seeing references back to the 1983 study "Digestion and Absorption of NAD by the Small Intestine of the Rat" Within that study, on the first page they say; "The possibility exists that NR may be absorbed without further cleavage." Now I've spent a considerable number of hours/days researching this single point and the notion that NR is broken down into NAM before it's absorbed? I've also offered that comment taken from the 1983 study to stimulate some conversation given our immense global intellectual membership. I just cant predicate and pin my opinion on a 31-year old study which hasn't been challenged with a more recent one, especially when the researchers themselves admit; "The possibility exists that NR may be absorbed without further cleavage."

 

I also want the most bang for my buck and I will be closely following the current PK study: A Study of the Pharmacokinetics of Three Dosages of Niagen in Healthy Subjects (14NBHC)

 

Keep up the good work guys I will read every post and reference I can find the time for, thanks for your combined effort!

 

While trying to become more informed I noted that the PK study referred to is marked as complete (no result links on the page though) as of Sept 8 2014. Also, to note, two more studies registered on Nov 20, 2014: Pharmacokinetic Analysis of Nicotinamide Riboside[1] and The Effect of Vitamin B3 on Substrate Metabolism, Insulin Sensitivity, and Body Composition in Obese Men[2]. Of interest to me is that the original study study was 3 doses ( 100,300,1000 (mg) ) with a 7 day flush after each, and the two new studies are 500mg, 1000mg and 1000mg respectively with the first being an 8 hour time frame with blood sample every 15 minutes and the second being 3 month study.

 

 

 [1]:https://clinicaltria...m=Niagen&rank=3

 [2]:https://clinicaltria...how/NCT02303483

 

 

See here and following arguments:

http://www.longecity...ndpost&p=694864

[Bryan_S]

The multifaceted mitochondrion: An attractive candidate for therapeutic strategies Available online 24 March 2015

http://www.sciencedi...043661815000468

 

Sorry I missed this one guys, I must be getting old.

[Logic]

The multifaceted mitochondrion: An attractive candidate for therapeutic strategies Available online 24 March 2015

http://www.sciencedi...043661815000468

 

Sorry I missed this one guys, I must be getting old.

 

 

You may wan to miss

30 Major Factors that Control SIRT1 Expression, SIRT1 Activity, and SIRT1-mediated Aging. Part 3 of the series NAD+ an emerging framework for health and life extension

too, as their conclusions mirror my theories and concerns as elucidated in our previous... debates.  

 

http://www.anti-agin...life-extension/

[Bryan_S]

 

You may wan to miss

30 Major Factors that Control SIRT1 Expression, SIRT1 Activity, and SIRT1-mediated Aging. Part 3 of the series NAD+ an emerging framework for health and life extension

too, as their conclusions mirror my theories and concerns as elucidated in our previous... debates.  

 

http://www.anti-agin...life-extension/

 

 

Yes what a deep read. They absolutely killed Nicotinamide.

[Logic]

 

 

You may wan to miss

30 Major Factors that Control SIRT1 Expression, SIRT1 Activity, and SIRT1-mediated Aging. Part 3 of the series NAD+ an emerging framework for health and life extension

too, as their conclusions mirror my theories and concerns as elucidated in our previous... debates.  

 

http://www.anti-agin...life-extension/

 

 

Yes what a deep read. They absolutely killed Nicotinamide.

 

 and NR

[Bryan_S]

 

 

 

You may wan to miss

30 Major Factors that Control SIRT1 Expression, SIRT1 Activity, and SIRT1-mediated Aging. Part 3 of the series NAD+ an emerging framework for health and life extension

too, as their conclusions mirror my theories and concerns as elucidated in our previous... debates.  

 

http://www.anti-agin...life-extension/

 

 

Yes what a deep read. They absolutely killed Nicotinamide.

 

 and NR

 

 

"However direct evidence  that NAD levels can be non-transiently enhanced in humans, either intracellular or extra-cellular, is thin to nonexistent."

 

He's also pointing out the obvious "animal is one thing human confirmation is another" more research is warranted. Hopefully he piss's off the right people and they fund the proper clinical trial to quiet the comments we are all thinking.

[Tom Andre F. (ex shinobi)]

Do we have access to the paper / clinical study done by chromadex now ?

 

They show conflicting information here, OR chromadex volontary didnt tested NAD level for more than one week.. thats the bad thing when we have financial interest

 

Would be great to have a discution with david sinclair about the critical points spoken in this blog

 

Also :

 

The blog explain that nicotinamide inhibit SIRT1, but I dont really see evidence for that, on this forum we even showed the opposite. They only speak about "excessive nicotinamide". Thus, if we consume MSM as methyl supplementation, we shouldnt have any problem.

 

What do you think guys ?

Edited by Tom Andre F. (ex shinobi), 21 April 2015 - 10:55 AM.

[YosefANaumovich]

Very good thread. I originally bought niacin (nicotinic acid) to treat my supposed schizophrenia-like symptoms (negative, not positive ones), including anxiety and more. I can say that it doesn't have much of a cognitive effect even in very high gram doses, with the exception of calming one down, sometimes causing euphoria and always reducing anxiety.

 

Silly me, I bought 5 bottles of 90+ capsules each with 500mg in them. Now I am trying to get elderly people in my family to take the capsules to remove fat in their arteries, thus to improve blood flow - and so far I am unsuccessful.

 

I've tried mixing niacin with choline before bed and upon waking up I've felt very good, almost as if I was on an SSRI, but I am not sure if niacin is even related to this effect.

 

One thing, besides calming me down that I find niacin to be useful in is endurance during training. Since niacin also increases growth hormone very significantly, it could technically be used before a thorough exercise to increase growth hormone and thus to increase muscle rehabilitation (which growth hormone contributes to) and so far it seems to work for me.

As for increasing workout endurance, it seems to be blood-sugar related primarily. Sometimes it unfortunately has a negative effect on my blood sugar (it increases it) by making me dizzy and thus unable to my workouts as good as I'd want, but this is rare and negligible and most of the times it has the opposite effect of actually making me able to perform a whole lot more, and feeling great after having performed, too.

 

I've been using this vitamin in high doses for a long while and I am in my 20s so if you have any questions then do ask me, and I wouldn't mind testing what niacin does in conjunction with other chemicals for research purposes (need to get rid of the bottles before they age and become useless).

[axonopathy]

Am I the only one that's concerned that exogenous nicotinic acid can lead to hyperglycemia and pre-diabetes? For this reason, physicians no longer recommend nicotinic acid to lower blood pressure. 

[burungnasar]

Am I the only one that's concerned that exogenous nicotinic acid can lead to hyperglycemia and pre-diabetes? For this reason, physicians no longer recommend nicotinic acid to lower blood pressure. 

 

No, you're not alone.

 

I took 500 mg to 1000 mg NA daily for a while (based on discussions here) and quickly developed prediabetic symptoms, such as numbness in extremities.

[YosefANaumovich]

 

Am I the only one that's concerned that exogenous nicotinic acid can lead to hyperglycemia and pre-diabetes? For this reason, physicians no longer recommend nicotinic acid to lower blood pressure. 

 

No, you're not alone.

 

I took 500 mg to 1000 mg NA daily for a while (based on discussions here) and quickly developed prediabetic symptoms, such as numbness in extremities.

 

Odd because I've been taking higher doses for a while and it was even prescribed in up to 10g doses for schizophrenics in the 60s and no such "diabetic symptoms" were reported besides the increase in blood sugar that niacin causes.

[axonopathy]

 

 

Am I the only one that's concerned that exogenous nicotinic acid can lead to hyperglycemia and pre-diabetes? For this reason, physicians no longer recommend nicotinic acid to lower blood pressure. 

 

No, you're not alone.

 

I took 500 mg to 1000 mg NA daily for a while (based on discussions here) and quickly developed prediabetic symptoms, such as numbness in extremities.

 

Odd because I've been taking higher doses for a while and it was even prescribed in up to 10g doses for schizophrenics in the 60s and no such "diabetic symptoms" were reported besides the increase in blood sugar that niacin causes.

 

 

I think it's a subtle creep up toward low-grade hyperglycemia - not frank diabetes. I wonder what the rational was for the treatment of schizophrenia. Hasn't the guy who promoted vitamin C for every malady been discounted? 

[YosefANaumovich]

 

 

 

Am I the only one that's concerned that exogenous nicotinic acid can lead to hyperglycemia and pre-diabetes? For this reason, physicians no longer recommend nicotinic acid to lower blood pressure. 

 

No, you're not alone.

 

I took 500 mg to 1000 mg NA daily for a while (based on discussions here) and quickly developed prediabetic symptoms, such as numbness in extremities.

 

Odd because I've been taking higher doses for a while and it was even prescribed in up to 10g doses for schizophrenics in the 60s and no such "diabetic symptoms" were reported besides the increase in blood sugar that niacin causes.

 

 

I think it's a subtle creep up toward low-grade hyperglycemia - not frank diabetes. I wonder what the rational was for the treatment of schizophrenia. Hasn't the guy who promoted vitamin C for every malady been discounted? 

 

The reasoning behind using nicotinic acid for schizophrenia was that chronic lack of it induced schizophrenia-like symptoms in people, which is a condition called pellagra.
This is the same reasoning behind the hypothesis that overactivity of the dopamine neurotransmitter causes psychosis and thus dopamine must be downregulated (hence antipsychotics like risperidone) - since people who take drugs that drastically increase dopamine (amphetamines, fx.) get psychotic-like symptoms (amphetamine psychosis).

 

However, now schizophrenia is centered around the NMDA receptor which is also the same with autism, though to my knowledge in schizophrenia the NMDA receptor is underactive while in autism it's overactive - or maybe it's vice versa; some sources claim that NMDA agonists are to be used for schizophrenia while others claim that antagonists are the ones.

 

Niacin is also a useful tranquilizer in psychotic patients since it induces a great calm and is anti-anxiolytic.

It is also necessary to note that Dr. Abraham Hoffer never used niacin alone but used various vitamins and minerals at the same time. He, for example, used zinc because he noticed that many of his patients (he was a psychiatrist) had white spots on their nails which indicated a zinc deficiency.

 

Lastly, for anyone who would criticize someone who used "alternative" (not to be confused with New Age garbage) medicines at that time: psychiatric drugs were highly damaging and dangerous to the patients and any attempt to improve the patients' symptoms without putting them on lethal "treatmens" was godsend. As Dr. Abraham Hoffer noted: with the use of megadoses of vitamins, the patients did not risk brain damage or death - it was the most reasonable way to treat at least the patients who were not murderous.

 

(Dr. Abraham Hoffer is one of the scientists who used niacin for schizophrenia in the 60s).

[YosefANaumovich]

I would be very, very glad if anyone here could tell me what niacin effects other than choline levels (which it supposedly very slightly effects).

Why does niacin only sometimes work for causing euphoria, clarity and so on? Often when a drug only sometimes works it's because it depends upon levels of some other chemicals and upon being administrated, those levels are reduced and thus further administration will not lead to any effect, or may lead to bad effects. 

[Skyguy2005]

I'm not sure I could take high dose Niacin, I get mega flushing even at 100mg. 

[Tom Andre F. (ex shinobi)]

I'm not sure I could take high dose Niacin, I get mega flushing even at 100mg. 

 

I think low dose and control NAD+/NADH ratio ?

[brosci]

Does Oxaloacetate have any NAD+/NADH ratio modifying benefits?  How does it compare with B3 / nicotinamide riboside?  Are the effects additive (Calorie restriction + NR / B3 + Oxaloacetate for the win?)

 

http://www.ncbi.nlm....les/PMC2988682/

"we hypothesized that alterations in the NAD+/NADH ratio, through dietary supplementation of metabolites of the citric acid cycle, might mimic the lifespan effect of caloric restriction. The conversion of oxaloacetate (3-carboxy-3-oxopropanoic acid) to malate is an energy favorable reaction in cells that promotes the conversion of NADH to NAD+. We report that the addition of oxaloacetate to agar plates supporting C. elegans increased lifespan in these worms in a FOXO/DAF-16 and AMPK-dependent manner."