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Maximum Methylation and Healing Occurs at 1000mcg Folate

adreno

PR activist
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4,841
According to research by the NIH, maximal DNA methylation, and axonal regeneration occurred at 80mcg/kg in rats:

"Interestingly, the more folate we gave, the more regrowth we saw, eventually achieving almost a tenfold increase in axonal regeneration," Dr. Iskandar said. Beyond the peak dose of 80 micrograms per kilogram of body weight, the effect decreased but without causing toxicity or nerve damage.

http://www.nih.gov/news/health/jun2010/nichd-24.htm


This dose translates to about 1000mcg, for a 80kg human.


The full research article is here:

http://www.jci.org/articles/view/40000


From the article:

For reasons yet to be elucidated, the beneficial effects of folate supplementation after CNS injury also exhibit a biphasic dose response curve with optimal regeneration occurring at a dose of 80 ?g/kg. A strikingly parallel biphasic response is also observed in both the methylation status of the CNS genome and the protein levels of the Folr as well as in the de novo methyltransferases in response to folate after injury. Specifically, 80 ?g/kg of parenteral FA optimizes Folr1 expression, Dnmt3a and Dnmt3b protein levels, the methylation status of the adult CNS, and its ability to regenerate after injury.

Doses of FA higher than 80 ?g/kg induce relative hypomethylation associated with reduced de novo methyltransferase levels and decreased axonal regeneration. The effect, which reaches levels comparable to those seen in untreated groups only at very high doses, suggests a loss of benefit from higher folate doses rather than toxicity.
 

maddietod

Senior Member
Messages
2,859
Nice find, Adreno! I imagine that the rats' diet included no other sources of folates, unlike mine.
 

adreno

PR activist
Messages
4,841
I should add that the folate was administered through injection. As we are using oral route, it would be interesting to know how much folate is absorbed orally.
 

Dreambirdie

work in progress
Messages
5,569
Location
N. California
Interesting, but I would take it with a big grain of salt.

As we have witnessed here so often, finding the ideal dose of each of the methylation supplements, and the necessary co-factors, that work best for each person is an art, not a science. There are so many other factors involved, especially when you are dealing with a community of seriously ill PWME.

Also, rats are a LOT tougher and more resilient than most of us. And I bet they have FAR FEWER food sensitivities. :)
 

adreno

PR activist
Messages
4,841
Interesting, but I would take it with a big grain of salt.

As we have witnessed here so often, finding the ideal dose of each of the methylation supplements, and the necessary co-factors, that work best for each person is an art, not a science. There are so many other factors involved, especially when you are dealing with a community of seriously ill PWME.

Also, rats are a LOT tougher and more resilient than most of us. And I bet they have FAR FEWER food sensitivities. :)

True, and nobody said anything about tolerance. Just because methylation peaks at a certain dose, it is by no means implied that everyone can tolerate that dose.
 

drex13

Senior Member
Messages
186
Location
Columbus, Ohio
According to research by the NIH, maximal DNA methylation, and axonal regeneration occurred at 80mcg/kg in rats:



http://www.nih.gov/news/health/jun2010/nichd-24.htm


This dose translates to about 1000mcg, for a 80kg human.


The full research article is here:

http://www.jci.org/articles/view/40000


From the article:

Hi Adreno,

Wouldn't that translate into about 6400 micrograms for a person what weighs 80 kgs, and not 1000 mcgs ? (80 mcgs * 80 kgs = 6400). Or for me, I weigh about 205 lbs. which comes out to just under 93 kilograms would translate to a dose of 7440 mcgs, or 7.4 milligrams, or the dose of a deplin tablet.
 

adreno

PR activist
Messages
4,841
Hi Adreno,

Wouldn't that translate into about 6400 micrograms for a person what weighs 80 kgs, and not 1000 mcgs ? (80 mcgs * 80 kgs = 6400). Or for me, I weigh about 205 lbs. which comes out to just under 93 kilograms would translate to a dose of 7440 mcgs, or 7.4 milligrams, or the dose of a deplin tablet.

I'm afraid you can't calculate it like that. It's explained here:

www.fasebj.org/content/22/3/659.full.pdf
 

snowathlete

Senior Member
Messages
5,374
Location
UK
I think the oral route must make quite alot of difference, compared to injection.

I have no idea how much we absorb...a quarter tops i would guess at, but i bet its alot less than that.
Maybe someone knows?
 

Adster

Senior Member
Messages
600
Location
Australia
I think this variable is often overlooked. Surely gut condition/function makes a big difference to absorption of drugs and supplements. I think the difference in actual dose between people could be significant.


I think the oral route must make quite alot of difference, compared to injection.

I have no idea how much we absorb...a quarter tops i would guess at, but i bet its alot less than that.
Maybe someone knows?
 

adreno

PR activist
Messages
4,841
Also, I'm wondering about half life. For methylfolate, it's about 3 hours. So, in that case, would it then make sense to dose something like 3 x 1000mcg daily, to keep methylation running at maximum?
 

Rand56

Senior Member
Messages
675
Location
Myrtle Beach, SC
I take my methylfolate sublingually. Since it is my most expensive supplement being that I take Deplin size dosages <15mg>, I want more bang for my buck so to speak as far as increasing the absorption. Prior to me upping my daily dose I took the Solgar Metafolin and they actually taste good under the tongue and they disolve pretty quickly. Now I take the Thorne 5-MTHF 5mg caps 3 times per day. Even though it's not as tasty under the tongue as the Solgar Metafolin, it's not bad at all because actually there is no taste to it.
 

adreno

PR activist
Messages
4,841
I take my methylfolate sublingually. Since it is my most expensive supplement being that I take Deplin size dosages <15mg>, I want more bang for my buck so to speak as far as increasing the absorption. Prior to me upping my daily dose I took the Solgar Metafolin and they actually taste good under the tongue and they disolve pretty quickly. Now I take the Thorne 5-MTHF 5mg caps 3 times per day. Even though it's not as tasty under the tongue as the Solgar Metafolin, it's not bad at all because actually there is no taste to it.

I know I will have a lot of people disagreeing with this, but there simply is no evidence that sublingual absorption is better than oral.
 

snowathlete

Senior Member
Messages
5,374
Location
UK
I know I will have a lot of people disagreeing with this, but there simply is no evidence that sublingual absorption is better than oral.

Are you talking about just metafolin, or in general.

I take my B12 under the tongue, and i can feel it working in a few minutes.
I havent tries non sublingual though, i suppose it could be as good.
 

adreno

PR activist
Messages
4,841
Are you talking about just metafolin, or in general.

I take my B12 under the tongue, and i can feel it working in a few minutes.
I havent tries non sublingual though, i suppose it could be as good.

Even with B12, studies show the same absorption rate. Maybe sublingual is faster. I'm aware that many people feel that sublingual works better. I use sublingual B12 also. But I'm not sure if we are simply deluding ourselves. Maybe if someone has gastrointestinal issues, sublingual works better. But in healthy people there seem to be no difference, according to the evidence I've seen.
 

Lou

Senior Member
Messages
582
Location
southeast US
Even with B12, studies show the same absorption rate. Maybe sublingual is faster. I'm aware that many people feel that sublingual works better. I use sublingual B12 also. But I'm not sure if we are simply deluding ourselves. Maybe if someone has gastrointestinal issues, sublingual works better. But in healthy people there seem to be no difference, according to the evidence I've seen.

Hi adreno,

"But in healthy people there seems to be no difference......." If you have ME/cfs chances are you're not THAT healthy, and gut malabsorption is a big problem for many of us, maybe a vast majority from what I've read here. Think I'm going to stick with Fred's advice on this one.

Just another viewpoint, adreno. Thanks.
 

rydra_wong

Guest
Messages
514
True, and nobody said anything about tolerance. Just because methylation peaks at a certain dose, it is by no means implied that everyone can tolerate that dose.

Well the thing that bugs me is that there is no checking what genes these rats have...so what the experiment says is that that dose is potentially optimal for a normal person with no broken genes. But what about those of us with genetic defects regarding folate? I dont think it sheds light on that.

But it sure is interesting...it implies that there IS a max limit and that going beyond it is not optimal. Which makes this all harder of course.

Rydra

PS. Someone on another board said they took 400units folic acid (i know, i know) and it made his high blood pressure normal,
but then he tried 800units and his high blood pressure came back.

I always thought he ran out of methyls after the 400 but now I wonder if he had normal folate genes and had just gone past his optimal dose.
 

richvank

Senior Member
Messages
2,732
Even with B12, studies show the same absorption rate. Maybe sublingual is faster. I'm aware that many people feel that sublingual works better. I use sublingual B12 also. But I'm not sure if we are simply deluding ourselves. Maybe if someone has gastrointestinal issues, sublingual works better. But in healthy people there seem to be no difference, according to the evidence I've seen.

Hi, adreno.

It's true that in otherwise healthy people who have an absolute B12 deficiency, it is possible to treat either orally or sublingually, so long as a high enough dosage is used. However, if a person has ME/CFS, with glutathione depletion and a functional B12 deficiency, I don't believe that oral dosing will work unless a very large dosage is used. Here's why:

When B12 is taken orally, if a person has normal intrinsic factor production, the limit of absorption by the intrinsic factor mechanism for a single dose is about 2 micrograms. However, if larger dosages are taken orally, about 1% will be absorbed by diffusion, without intrinsic factor involvement. So, for example, if 500 micrograms are taken orally, about 5 micrograms will be absorbed apart from the intrinsic factor mechanism. This is enough to treat an otherwise healthy person who has an absolute B12 deficiency, even if it is due to pernicious anemia, which knocks out the intrinsic factor mechanism.

However, if a person has ME/CFS, the amount of B12 that must be put into the blood is of the order of 1,000 micrograms or more per day. So if oral absorption is to be relied upon, the person would have to take about 100,000 micrograms, or 100 milligrams of B12. This is a very big dosage. However, if it is taken sublingually, the fraction absorbed will be much higher, so that something like 2,000 micrograms will do the job.

As I posted on another thread, I think the reason why such a high dosage is needed to treat ME/CFS is that glutathione is depleted. Normally, glutathione increases the affinity for the CblC complementation group, part of the intracellular B12 metabolic pathway, by a factor of over 100. When glutathione is depleted, the affinity drops, and it is necessary to raise the concentration of B12 significantly in order to achieve a high enough rate in the B12 metabolic pathway. This is based on research done in Korea, published only a few months ago.

Best regards,

Rich
 

adreno

PR activist
Messages
4,841
Well the thing that bugs me is that there is no checking what genes these rats have...so what the experiment says is that that dose is potentially optimal for a normal person with no broken genes. But what about those of us with genetic defects regarding folate? I dont think it sheds light on that.

But it sure is interesting...it implies that there IS a max limit and that going beyond it is not optimal. Which makes this all harder of course.

Rydra

PS. Someone on another board said they took 400units folic acid (i know, i know) and it made his high blood pressure normal,
but then he tried 800units and his high blood pressure came back.

I always thought he ran out of methyls after the 400 but now I wonder if he had normal folate genes and had just gone past his optimal dose.

I agree with you on both counts. We don't know the genetics of those rats. But aren't we bypassing this issue, by going straight to ingesting methylfolate?

And yes, if nothing else, the study tells us that there is a bell shaped curve of methylation and neuronal healing when taking folate; that these have a peak, and do not continually increase with dose. I don't know if the same can be said with B12; studies seem to indicate the more the better.

It is also interesting how the drug companies arrived at the dosages for metanx, deplin and cerefolin (6-15mg methylfolate daily). Were these doses just arbitrarily picked? Based on what?