Niacin vs. niacinamide - SAMe/SAH ratio

Kimsie

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It seems to me that as far as under-over methylation or the SAMe/SAH ratio is concerned, niacin and niacinamide are opposites, at least in larger doses. In a low dose of about 50 mg, most of the niacin gets changed to niacinamide before being excreted.

GNMT, glycine N methyltransferase, keeps the SAMe level from getting too high. GNMT-deficient individuals have elevated serum methionine and SAMe. According to Dr. Walsh, undermethylated people have a low SAMe/SAH ratio, where the enzymes that use SAMe are inhibited due to higher SAH (the product of all enzymes using SAMe.) The opposite it true of overmethylated people.

A dose of regular niacin will mainly be metabolized by combining (conjugating) with glycine, using up glycine. Niacinamide is metabolized by NNMT, which uses SAMe as a methyl donor, and uses up SAMe.
Here is a little graphic I made to illustrate:
Over and under.jpg
Dr. Walsh says that niacin and niacinamide act as dopamine reuptake promoters, but I can't find any support for this idea. Does anyone have any information about this? I realize that niacin and niacinamide have various effects in the body and it is hard to assess what the outcome would be.

He also only espouses niacin or niacinamide for overmethylation, as if they had the exact same effect. I don't know if this is because he has tried using niacin for undermethylated people and it hasn't helped, or what.

Anyone have any thoughts about this?

By the way, from our experience, if a person has enough folate, they will produce sufficient glycine through SHMT to negate the effects of niacin. We are having to cut out high folate foods.
 

PeterPositive

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Interesting post.
My SAM/SAH balance is out of range with elevated SAH and insufficient SAM, thus making me an undermethylator... Indeed I do well with high dose of methyl-B12 and methyl-folate but at times, depending on other factors, I can get excessive anxiety and irritability.

I use between 100 and 300mg of niacinamide to fix the issue and it usually works very fast. If I keep going for too many days I eventually start getting low mood, mild depression, and other symptoms of insufficient B12 such as various pains and heavy brain fog.

So, yeah, intuitively it kind of make sense the connection with niacinamide and dopamine reuptake.
 

Kimsie

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Interesting post.
My SAM/SAH balance is out of range with elevated SAH and insufficient SAM, thus making me an undermethylator... Indeed I do well with high dose of methyl-B12 and methyl-folate but at times, depending on other factors, I can get excessive anxiety and irritability.

I use between 100 and 300mg of niacinamide to fix the issue and it usually works very fast. If I keep going for too many days I eventually start getting low mood, mild depression, and other symptoms of insufficient B12 such as various pains and heavy brain fog.

So, yeah, intuitively it kind of make sense the connection with niacinamide and dopamine reuptake.
Have you ever tried using niacin instead of niacinamide? It causes a bothersome flush, but it would not drain your SAMe so much.
 

PeterPositive

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Have you ever tried using niacin instead of niacinamide? It causes a bothersome flush, but it would not drain your SAMe so much.
Yep, I have histamine issues and the niacin flush is pretty bad, especially if I need more than 50mg.
Now that I am a little more familiar with the effects of methyl donors and B3 in my system, I can use the latter without causing side effects.

cheers
 

ebethc

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Yep, I have histamine issues and the niacin flush is pretty bad, especially if I need more than 50mg.
Now that I am a little more familiar with the effects of methyl donors and B3 in my system, I can use the latter without causing side effects.

cheers
@PeterPositive - what's the link between histamine & niacin flush & methyl donors?
 

ebethc

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Periodically, I take SAMe and, at first, it seems like a miracle... My joint pain, chronic sinus issues, inflammation & brain fog and general vitality are vastly improved... then it poops out.. Presumably, a co-factor is depleted after some time, which leads to the "pooping out"

Periodically, I take Niacinamide, which has a similar effect as SAMe, but also poops out.. I don't take Niacin due to the flushing...

I tested low in glycine, so I supplement w that sometimes too.

I have histamine problems (high tryptase), and quercetin is helpful.

I've never taken these supplements all at once, so maybe I'll try that for a couple of weeks
 

PeterPositive

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@PeterPositive - what's the link between histamine & niacin flush & methyl donors?
All I was saying is that I already struggle with histamine related problems and taking niacin makes it worse, so I usually stay away from it. Niacinamide works fine for me without causing histamine release.

The link between histamine and methyl donors is not a direct one, but at the end of the methylation cycle we should produce SAMe, which in turn helps breaking down histamine.

I have experimented taking supplemental SAMe (200 or 400mg/day) but I didn't have any success in terms of dealing with the histamine issues.

cheers
 

Kimsie

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Periodically, I take SAMe and, at first, it seems like a miracle... My joint pain, chronic sinus issues, inflammation & brain fog and general vitality are vastly improved... then it poops out.. Presumably, a co-factor is depleted after some time, which leads to the "pooping out"

Periodically, I take Niacinamide, which has a similar effect as SAMe, but also poops out.. I don't take Niacin due to the flushing...

I tested low in glycine, so I supplement w that sometimes too.

I have histamine problems (high tryptase), and quercetin is helpful.

I've never taken these supplements all at once, so maybe I'll try that for a couple of weeks
How long did it take for SAMe and niacinamide to "poop out"? Was the amount of time the same for both of them?

In our family we have observed this often, and I believe that it is a result of the body adjusting the levels of the enzyme. Since SAMe and niacinamide have opposite effects on methylation, I think the improvement from the niacinamide may have come from a temporary improvement in the TCA cycle or in antioxidant capacity.
 

Kimsie

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All I was saying is that I already struggle with histamine related problems and taking niacin makes it worse, so I usually stay away from it. Niacinamide works fine for me without causing histamine release.

The link between histamine and methyl donors is not a direct one, but at the end of the methylation cycle we should produce SAMe, which in turn helps breaking down histamine.

I have experimented taking supplemental SAMe (200 or 400mg/day) but I didn't have any success in terms of dealing with the histamine issues.
I see from reading your past posts that you drain zinc and not so much B6, so it probably isn't B6.

By the way, regarding other posts you have made, we have found that with pyrrole disorder taking folate makes zinc and B6 get drained more quickly, if one or both of them are being drained. Some people have high pyrroles in their urine don't drain zinc or B6, some drain both and some drain one or the other. One of my sons drain only B6 and the other B6 and zinc. And we also stop supplements (5 days) before testing zinc.

Have you ever tried a limited folate diet with no folate supplementation plus taking some methionine (for undermethlyation)? I would say that you would have to do it for about 3 weeks to know if it was helping or not, and it might seem to be better or worse at first and then either stop working or get better respectively. The methionine helps bypass the need for recycling of methionine by folate, but you need to make sure that your B6 is OK so that you don't get a buildup of homocysteine. It doesn't hurt to take a little molybdenum, too, to make sure you can get rid of the extra cysteine.
 
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PeterPositive

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I see from reading your past posts that you drain zinc and not so much B6, so it probably isn't B6.

By the way, regarding other posts you have made, we have found that with pyrrole disorder taking folate makes zinc and B6 get drained more quickly, if one or both of them are being drained. Some people have high pyrroles in their urine don't drain zinc or B6, some drain both and some drain one or the other. One of my sons drain only B6 and the other B6 and zinc. And we also stop supplements (5 days) before testing zinc.
Yep, I seem to be draining zinc only.

Have you ever tried a limited folate diet with no folate supplementation plus taking some methionine (for undermethlyation)? I would say that you would have to do it for about 3 weeks to know if it was helping or not, and it might seem to be better or worse at first and then either stop working or get better respectively. The methionine helps bypass the need for recycling of methionine by folate, but you need to make sure that your B6 is OK so that you don't get a buildup of homocysteine. It doesn't hurt to take a little molybdenum, too, to make sure you can get rid of the extra cysteine.
Unfortunately my homocysteine stays under control (around 11) only with fairly high doses of folate and B12. Additionally the combo (B9 + B12) helps me keep up decent levels of energy and mental clarity which slowly fades away as I stop them. Typically all my symptoms get worse within 14-20 days after I suspend those two supplements.

cheers
 

Kimsie

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Yep, I seem to be draining zinc only.

Unfortunately my homocysteine stays under control (around 11) only with fairly high doses of folate and B12. Additionally the combo (B9 + B12) helps me keep up decent levels of energy and mental clarity which slowly fades away as I stop them. Typically all my symptoms get worse within 14-20 days after I suspend those two supplements.

cheers
So you have not tried methionine when you suspend B9 and B12? This should alleviate all of the symptoms you mention because it relieves the need to recycle methionine and raises the SAMe levels to activate CBS and take care of homocysteine through the transsulferation pathway and take care of other things that you need SAMe for. Met in.jpg
 
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Kimsie

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Yep, I seem to be draining zinc only.
How is your zinc now? If it is still low, that could explain the fatigue and brain fog due to insufficient purine salvage. In that case as long as you are not getting symptoms from undermethylation of histones (such as depression, etc. ) then taking higher folate is probably OK, but the thing you have to watch out for is that the higher the folate the more zinc you will probably drain because you will have more glycine to allow more pyrrole production.

In our family the combination of undermethylation and pyroluria causes a condition where the more folate the more of a drain on zinc and P5P. (or just a drain on P5P with one of them)
 

aquariusgirl

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How is your zinc now? If it is still low, that could explain the fatigue and brain fog due to insufficient purine salvage. In that case as long as you are not getting symptoms from undermethylation of histones (such as depression, etc. ) then taking higher folate is probably OK, but the thing you have to watch out for is that the higher the folate the more zinc you will probably drain because you will have more glycine to allow more pyrrole production.

In our family the combination of undermethylation and pyroluria causes a condition where the more folate the more of a drain on zinc and P5P. (or just a drain on P5P with one of them)
KKimsie ...who is helping you w/this . It is so complicated.
 

Kimsie

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KKimsie ...who is helping you w/this . It is so complicated.
I have been studying these pathways from sources on the internet for 3 years, ever since I learned that my very fatigued son, who was 16 at that time, had the MTHFR 677 mutation and he started taking 5 mg of methylfolate a day, which cured his fatigue, but then he became depressed instead after a couple of months.

I feel I have just now finally been coming to an understanding of what is really going on. At least I hope so. I can create the old fatigue symptoms in him by lowering folate levels through dietary restrictions, and make the fatigue come and go all day long by giving him things to drain or elevate glycine, which is needed for the purine de novo pathway to make ATP. Methionine and niacin drain glycine, niacinamide lets glycine levels rise.

I know from past experience that if his folate is low enough to cause fatigue that his depression will go away in less than a month, but not if he eats a low methionine diet so both low folate and sufficient SAMe are required to make his depression go away. I have realized for quite some time that his depression symptoms must be caused by epigenetic changes (changes in methylation of histones, which changes the expression of genes), and that folate makes his depression worse, but I didn't realize that glycine was such a critical element.
THF.jpg

The thing is that if folate is restricted and glycine levels are low, then LSD1, which takes methyl groups off of histones, has to compete with SHMT (which makes glycine from serine) for THF, slowing down the demethylation of histones and changing epigenetic expression of the genes. Probably in the case of my son the gene affected is for SERT, the serotonin transporter. Undermethylation of this gene is probably causing too many transporters to be made, taking too much serotonin out of the synapses. At least that is what William Walsh, PhD says and it makes sense to me.
 

PeterPositive

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So you have not tried methionine when you suspend B9 and B12? This should alleviate all of the symptoms you mention because it relieves the need to recycle methionine and raises the SAMe levels to activate CBS and take care of homocysteine through the transsulferation pathway and take care of other things that you need SAMe for. View attachment 14472
Thanks for the diagram.
Is this a theory of yours or can you point to research done on this topic?

I have only a basic understanding of the methylation cycle from following some of the seminars by Dr Lynch. The subject matter can get terribly technical if one goes into the biochemical details.

My (very simplified) understanding is that anyone with a tendency to high homocysteine levels already has enough methionine, although he might not be converting the Hcy back to methionine correctly.

Also I am not familiar with LSD1 but I am not sure it does what you say it does...
http://www.ncbi.nlm.nih.gov/pubmed/24715612

It seems that it participates in the formation of 5,10-methylene-THF starting from THF...

cheers
 

PeterPositive

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Oh... one more thought. I am not sure that the benefits of B12 (in my case as well as for other people) are purely due to helping methylation. My methylation status pretty much sucks whether I take B12 or not :lol: and my labs have always showed poor SAMe and GSH pretty much regardless of how much methyl groups I throw at it.

At the same time B12 and folate participate in dozens of other functions besides methylation and I suspect most of the benefit I get from the combo fall outside the scope of the methylation cycle. Such as direct effects on cognition, nerves, inflammation, oxidation...etc...

my 2c
 

Kimsie

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Thanks for the diagram.
Is this a theory of yours or can you point to research done on this topic?
Moreover, SAMe activates CBS and inhibits MTHFR. I am not sure if this is what you are referring to.
My (very simplified) understanding is that anyone with a tendency to high homocysteine levels already has enough methionine, although he might not be converting the Hcy back to methionine correctly.
Low B6 levels can also inhibit CBS, maybe low serine could, too, because CBS requires B6 and serine. We already concluded that your B6 levels are not too low, but I don't know what they were at the time you were tested for homocysteine. Low SAMe also inhibits CBS, or rather CBS needs to be activated by both high SAMe and high homocysteine, if you think about it you will see that if that wasn't so we would not have enough homocyseine to recycle back to methionine when methionine was low. So if there is a block in the folate recycling of methionine at methionine synthase (MTR), which it seems that you probably do have, assuming that other factors such as low B6 are not blocking CBS, then taking methionine will raise your SAMe and activate CBS. If you want more references I can get them for you.
Also I am not familiar with LSD1 but I am not sure it does what you say it does...
http://www.ncbi.nlm.nih.gov/pubmed/24715612

It seems that it participates in the formation of 5,10-methylene-THF starting from THF...
The abstract you linked says LSD1, a flavin containing enzyme which carries out the demethylation of di- and monomethyllysine 4 in histone H3...We showed earlier that LSD1 binds THF with high affinity which suggests its possible participation in the histone demethylation reaction...This position of the folate suggests that the bound THF accepts the formaldehyde generated in the course of histone demethylation to form 5,10-methylene-THF

So the article says that LSD1 demethylates histones, or takes methyl groups off histones. It isn't proven that high folate can cause undermethylation of histones, but it seems logical that it could happen in certain people given the above information. Does this make sense to you?
 

Kimsie

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Oh... one more thought. I am not sure that the benefits of B12 (in my case as well as for other people) are purely due to helping methylation. My methylation status pretty much sucks whether I take B12 or not :lol: and my labs have always showed poor SAMe and GSH pretty much regardless of how much methyl groups I throw at it.

At the same time B12 and folate participate in dozens of other functions besides methylation and I suspect most of the benefit I get from the combo fall outside the scope of the methylation cycle. Such as direct effects on cognition, nerves, inflammation, oxidation...etc...

my 2c
B12 only does 2 things, as far as has been discovered. The other thing besides recycling folate and methionine is that it allows the branched chain amino acids to enter the TCA cycle at succinyl-CoA. Succinyl-CoA is also used to make heme, which is needed for the ETC in the TCA cycle and to make catalase for reducing oxidative stress, among other things. So these are other ways B12 can help a person feel better.

I am wondering if some of the people who have low SAMe when they take lots of folate and B12 do not have an upregulation in GNMT, which is the enzyme that regulates SAMe levels by using up SAMe. This is why glycine availability and also the fact that high folate levels gives a person a much greater ability to produce glycine is so important. If this is correct, then the way to get higher SAMe would be to limit glycine to slow down GNMT.
 

Tunguska

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I am wondering if some of the people who have low SAMe when they take lots of folate and B12 do not have an upregulation in GNMT, which is the enzyme that regulates SAMe levels by using up SAMe. This is why glycine availability and also the fact that high folate levels gives a person a much greater ability to produce glycine is so important. If this is correct, then the way to get higher SAMe would be to limit glycine to slow down GNMT.
This was of interest to me some time ago. Retinoids upregulate GNMT: http://forums.phoenixrising.me/inde...ed-depression-isotretinoin.12117/#post-206042 (though I don't believe GNMT explains the accutane problems)

(then T3 prevents the increased GNMT activity: http://www.ncbi.nlm.nih.gov/pubmed/15514252)