Burned out folate receptors - why you need high dose methylfolate?

[PeterPositive]

In a person who cannot process Folic Acid efficiently unmetabolised Folic Acid builds up. If you avoid all supplementation and dietary folate (not that this is necessarily a good thing) some of the Folic Acid will be converted. A homozygous C677T operates at about 30% of normal in this conversion process.

If you supplement with methylfolate your body will use that preferentially and the unmetabolised Folic Acid will remain. If you don't avoid Folic Acid while supplementing methylfolate Folic Acid will build up.

I see what you mean. You're talking about the body using preferentially methylfolate when supplemented, instead of converting the existing folic acid which is a slow route. Makes sense.

And that's probably what's happened to me... my folic acid levels are the same of 10 months ago when I stopped it and started Metafolin.

 

[PeterPositive]

The issues Dr Lynch talks about occur with high doses of Folate, small amounts seem unlikely to do this.

The backlog the sentence refers to because of two things: 1 cells will only absorb so much folate or folic, 2 if there is loads of tetrahydro the enzymes that convert folic slow down. Hence lots of folate means folic builds up.

Ok, makes sense.
Although I haven't seen any declining in folic acid level when taking 400mcg of 5-MTHF vs 1600mcg.
And all the other forms of folate are below range according to my latest methylation panel, 5-MTHF included.

 

[PeterPositive]

I've done some more digging and have found one of the videos from Dr Lynch's seminar in October 2013 (it's a paid course provided from his website) where he talks about the possible issue with methylfolate.

He doesn't really talk about an issue with taking methylfolate but in essence the idea is that DHFR, the enzyme that converts DHF into THF, gets inhibited when enough THF is available in the folate cycle.

Now... how much THF is needed to slow down or even stop the activity of DHF is not said, but if this happens then DHF won't be converted anymore and create the backlog.

Lynch doesn't talk about DHF oxidizing and becoming unmetabolized folic acid though. I have yet to find an article or study that shows how this works. I've sent an email to Lynch's staff asking some questions. Let's see if they reply.

cheers

 

[adreno]

Well, according to his protocol here he recommends going as high as 4-6 caps per day, each containing 800 mcg methylfolate (if tolerated). So that would be a maximum of 3200-4800 mcg.

No where does he state that 800 mcg is the max dose, as has been suggested earlier in this thread.

Personally, I seem to do pretty well with 1600 mcg.

 

[PeterPositive]

Well, according to his protocol here he recommends going as high as 4-6 caps per day, each containing 800 mcg methylfolate (if tolerated). So that would be a maximum of 3200-4800 mcg.

No where does he state that 800 mcg is the max dose, as has been suggested earlier in this thread.

That's right, in fact in one of those videos he talks about a patient, a colleague's daughter if I recall correctly, where he started at 400mcg and gradually doubled the dose many times until overmethylation symptoms occurred. I think it was well over 5000mcg. Then he suggested to back off and settled for 3200 or so.

Personally, I seem to do pretty well with 1600 mcg.

Me too. 1600-2000 doesn't cause any side effects.
I have done a methylation panel when I was taking 800mcg and my levels of 5-MTHF was barely in range, while THF was not, suggesting more B12 was needed. So I don't see any risks of blocking DHFR at the moment

 

[Leopardtail]

Well, according to his protocol here he recommends going as high as 4-6 caps per day, each containing 800 mcg methylfolate (if tolerated). So that would be a maximum of 3200-4800 mcg.

No where does he state that 800 mcg is the max dose, as has been suggested earlier in this thread.

Personally, I seem to do pretty well with 1600 mcg.

He recommends those doses only under a doctor's supervision. He did fairly extensive presentation on normal requirements for MethylFolate and produced a tabulation of recommended maximums for 'home use' with various mutations.

 

[Leopardtail]

That's right, in fact in one of those videos he talks about a patient, a colleague's daughter if I recall correctly, where he started at 400mcg and gradually doubled the dose many times until overmethylation symptoms occurred. I think it was well over 5000mcg. Then he suggested to back off and settled for 3200 or so.


Me too. 1600-2000 doesn't cause any side effects.
I have done a methylation panel when I was taking 800mcg and my levels of 5-MTHF was barely in range, while THF was not, suggesting more B12 was needed. So I don't see any risks of blocking DHFR at the moment

Please clarify what you mean by "5-MTHF was barely in range, while THF was not" - what do you mean about each of them (high/low)?

 

[PeterPositive]

Please clarify what you mean by "5-MTHF was barely in range, while THF was not" - what do you mean about each of them (high/low)?

5-CH3-THF ==> 8.8 (range 8.4 - 72.6)
......THF ==> 0.49 (range 0.6 - 6.8)

All the details are here

 

[caledonia]

I got a reply back from MTHFRsupport. They say

"several doctors and PhDs have told [them] that excessive methylfolate can back up into folic when the liver cannot clear it out. Unmetabolized folic acid has been known to burn out folate receptors in the brain. If you overdo methylfolate it can also back up."

How much is too much? I don't think there is really any hard data for methylfolate at this time.*** (see below)

For folic acid, however, there is data. In general, the amount that causes unmetabolized folic acid is anything above 1000mcg. There is a wide variability in what can be tolerated for each person, dependent on the DHFR gene.
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2730961/

This blog post says

"The NMCD webstite cautions, ‘Clinical research shows that taking folic acid daily in doses of 800-1200 mcg for 3-10 years significantly increases the risk of developing cancer and adverse cardiovascular effects compared to placebo."

But other info is showing only 200mcg+ causing problems.
http://mthfr.net/l-methylfolate-not-needed-come-on/2011/09/26/

"Also, according to the NMCD, researchers have recommended that “Doses above 1000 mcg per day should be avoided if possible to prevent precipitation or exacerbation of neuropathy related to vitamin B12 deficiency. However, there is some evidence that doses of 5 mg per day orally for up to 4 months can be used safely if vitamin B12 levels are routinely measured."

Now this makes me think that all these folic acid tests were done independent of B12 supplementation...hmmm....that probably changes the game.

=-==-=-==-=-

MTHFRsupport also says there are other variables as to why some people might not absorb methylfolate as well as others:

"NAT2 G590A's have trouble with folate and alcohol metabolism in the liver
COMT's who are niacin deficient and the catalytic activity is 5MTHF and NAD.
DHFR's that have trouble converting folic into folate.
Someone with FOLR's already have compromised folate receptors."

These SNPs can probably be pulled via Sterling's App.

I also found info regarding milk causing cerebral folate antibodies, which would inhibit folate receptors.
http://forums.phoenixrising.me/index.php?threads/folate-receptor-antibodies.22653/

So if you were having trouble metabolizing methylfolate, you would want to avoid milk (dairy). Then if you had COMT, make sure you weren't niacin deficient, and supplement if you were. If you had NAT, avoid alcohol? If you had DHFR and FOLR, I don't think there's anything you could do except be aware that you genetically don't absorb as well as others.

-=-=-=-=-

***However, since methylfolate is better absorbed than folic acid, the amount that can be metabolized should be higher than the folic acid amount.

This blog post on MTHFR.net says that there are studies showing methylfolate absorbs either 2 to 7 times better than folic acid, or around 31-39% better. http://mthfr.net/l-methylfolate-not-needed-come-on/2011/09/26/

Extrapolating from this data - this amount of methylfolate would absorb the same as this amount of folic acid, and if you go any higher (without B12 supplementation?), you may end up with unmetabolized folate.

On a daily basis, for several years:
(200mcg x 31%) = 62 , so 200 +62mcg = 262mcg
(200mcg x 39%) = 78, so 200 +78 = 278mcg
800mcg x 31% = 248, 800 + 248 = 1048mcg
800mcg x 39% = 312, 800 + 312 = 1112mcg
1200mcg x 31% = 372, 1200 + 372 = 1572mcg
1200mcg x 39% = 468, 1200 + 468 = 1669mcg

200mcg x 2 = 400mcg
200mcg x 7 = 1400mcg
800mcg x 2 = 1600mcg
1200mcg x 2 = 2400mcg
800mcg x 7 = 5600mcg
1200mcg x 7 = 8400mcg

4 months only:
5000mcg x 31% = 1550, 5000 + 1550 = 6550mcg
5000mcg x 39% = 1950, 5000 + 1950 = 6950mcg
5000mcg x 2 = 10,000mcg
5000mcg x 7 = 35,000mcg

=-==-=-=-==-=-=

Ben Lynch says:

"In the meantime, for those wanting to evaluate their unmetabolized folic acid levels and methylfolate levels, I do recommend ordering the Unmetabolized Folic Acid Test by Metametrix...Stop guessing and identify if your methylfolate levels are where they should be."

http://www.seekinghealth.com/unmetabolized-folic-acid-serum.html

I think especially if I was taking high doses of methylfolate, I would be monitoring levels with this test, just to make sure...

 

[Leopardtail]

Peter with those figures 'over methylation' would be the last of my concerns. The very low amount of THF and your folic acid mentioned earlier concerns me, you are certainly unlikely to suffering the issues Lunch talks about. Bear in mind that if you are short of folinic acid, some scientists think your body will convert methyl-folate (I have no opinion how solid that evidence is)..

For that reason with those tests results I would take min 200mcg/day of folinic (at night would be good). You should normally aim for a 3:1 ratio of B12 to B9. So I would be thinking of starting at 800mcg minimum (or whatever dose you are on now if higher) and min 2-3mg of Methyl-B12 (again higher if needed to match your B-9 dose). You should take it in at least two bursts, neither late at night. Given the low amount of THF, I would try adding a strong NADH tablet (e.g. 10-20mg) once a day (mornings are best).

Assuming you are already taking Methyl-B9, my instinct would be to add NADH before increasing Methylfolate (less chance of bad reactions).

 

[PeterPositive]

Peter with those figures 'over methylation' would be the last of my concerns. The very low amount of THF and your folic acid mentioned earlier concerns me, you are certainly unlikely to suffering the issues Lunch talks about. Bear in mind that if you are short of folinic acid, some scientists think your body will convert methyl-folate (I have no opinion how solid that evidence is)..

For that reason with those tests results I would take min 200mcg/day of folinic (at night would be good). You should normally aim for a 3:1 ratio of B12 to B9. So I would be thinking of starting at 800mcg minimum (or whatever dose you are on now if higher) and min 2-3mg of Methyl-B12 (again higher if needed to match your B-9 dose). You should take it in at least two bursts, neither late at night. Given the low amount of THF, I would try adding a strong NADH tablet (e.g. 10-20mg) once a day (mornings are best).

Assuming you are already taking Methyl-B9, my instinct would be to add NADH before increasing Methylfolate (less chance of bad reactions).

Thanks. That's essentially what I am doing (B9 vs B12 ratio, some folinic acid and NADH)

 

[dannybex]

I just saw this info contained in an MTHFRsupport.com fact sheet. I put the relevant part in bold.
http://www.mthfrsupport.com/mthfr-facts/

"Many doctors are giving high doses of L-Methylfolate. When should they consider lower dosages?

When folate levels are not extremely low. Many people have done well on just 400mcg-800mcg of folate daily along with a folate (not folic) rich diet. Giving too much L-methylfolate to certain individuals can cause a back up in high folic acid levels for the folate that they are not utilizing. Unmetabolized folic acid is one of the risk factors in colorectal cancer. Excess folic acid (not folate) can then burn out folate receptors."
Thoughts?

@ahmo

I appreciate all your hard work @caledonia, and for writing to them to get some clarification. I didn't see any clarification (although maybe it was right in front of my eyes!) regarding their "fact" that "excess folic acid…can then burn out folate receptors."

Did I miss something or is there some reference or study to back that up?

 

[garyfritz]

You folks seem to have a very good handle on methyl folate issues... question:

I'm taking 1.2mg/day of methyl folate, along with 1.5-2.0mg mB12 + 4.5-6.0mg adB12 (effective absorbed dose from transdermal oil). I don't take any folic acid supplements and I try to avoid fortified flour products, but I do eat some.

The transdermal oil has been keeping my symptoms at bay very well for the last several months. But several times in the last few weeks I've had what I consider to be my "low B12" symptoms in the night -- agitation, twitching muscles, RLS, etc. In the past I could take some additional B12 and it would rapidly clear up the symptoms. In these recent cases, B12 didn't seem to have any effect. Then I took 400mcg methyl folate, and bam! Symptoms cleared up and I zonked out for the rest of the night.

I first tried this approach one night when I got stubborn symptoms after eating a lot of deep-dish pizza with a lot of (almost certainly fortified) crust. I suspected the folic acid in the crust might be causing a problem, so I took some extra methyl folate to counteract it. It seemed to work well. But now I wonder what my levels of folic acid are like (considering my SNPs) and whether I should be worried about a buildup.

Does the appearance of "B12 symptoms" that are relieved by methyl folate indicate I should increase my methyl folate levels? Should I titrate up like Dr. Lynch does? I've never experienced anything like the overmethylation symptoms. But on the other hand I've never noticed ANYthing from methyl folate, until these recent "B12 symptoms" events.

Also, I was recommended to take some B vitamins. I take the Douglas Labs B-complex because it has no folic acid -- but it includes 50mg of Niacin. Which could cause undermethylation? (And about 25 years ago I used a product that used extremely high levels of niacin. Could something like that cause long-term methylation issues?)

BTW I've been taking my methyl folate internally, in Solgar 400mcg and in the Douglas Labs B-complex. But here Dr. Lynch says that methyl folate is absorbed sublingually -- and I've taken my 400 mcg sublingually (with excellent results) during my night-time "B12 symptoms" events. Is Dr. Lynch just saying that because his particular patient is using a sublingual, or must methyl folate be taken sublingually?

 

[caledonia]

I appreciate all your hard work @caledonia, and for writing to them to get some clarification. I didn't see any clarification (although maybe it was right in front of my eyes!) regarding their "fact" that "excess folic acid…can then burn out folate receptors."

Did I miss something or is there some reference or study to back that up?

Unfortunately, Sterling sometimes has a cryptic writing style, and even the clarification is not that clear. I think this information is something that MTHFRsupport's docs have found out via experimentation in clinical practice. I don't think there is a study on this.

 

[Tunguska]

Huh, I gave up on genetics some time ago because it was going nowhere, but after reading these comments I looked up my FOLR and DHFR, and I have +/- DHFR (rs1643649), +/- FOLR1 (rs2071010) and +/+ FOLR2 (rs651933). According to opensnp that puts me in a minority if nothing else (39%, 11%, 18%). Methylfolate was certainly a factor.

 

[Gondwanaland]

DHFR

My husband is +/- for all the SNPs of this gene, except for one (for that one I am +/- and homozygous for all the others - just don't know if +/+ or -/- )

 

[liverock]

It seems that folic acid is self generated within the small intestine bacterial overgrowth(SIBO), according to Dr Rosenberg at Beyondmthfr.com
This could be why some people on this thread have tested for high folic acid and have never supplemented. Probably why Dr Lynch preaches healing the gut first before methylation.

More 'muddying of the water' on folic acid and methylation.

http://beyondmthfr.com/2014/09/09/mthfr-and-sibo/

 

[garyfritz]

There are darn few people (reading this, anyway) who haven't supplemented with folic acid, unless they live in the EU. 76 countries around the world currently require fortification of flour and other food products. Even in countries that don't mandate it (such as the UK), some flour is still fortified.
http://en.m.wikipedia.org/wiki/Folic_acid#Dietary_fortification

 

[liverock]

People in general may be taking in a lot of folic acid orally, but not absorbing a lot of it due to gut problems, including low stomach acid and hpyroli.
Some people who cannot absorb oral folate will do better on sublingual.

These studies show that the folic acid generated by gut overgrowth is absorbed by the host and can possibly compensate for poor oral absorption where this is a problem. With us trying to absorb metylfolate however, extra folic acid can cause problems which includes fortified foods.

http://www.ncbi.nlm.nih.gov/pubmed/3770372

http://www.ncbi.nlm.nih.gov/pubmed/8613033

 

[PennyIA]

Once a person has high Folic Acid levels I don't know whether they would be better off avoiding folate and Folic Acid altogether for a while (since they do have some capacity to convert). This would however leave them deficient in folate for a period of time. Perhaps an intermittent schedule of methylfolate supplementation would be best. The research doesn't have these answers yet.

I've been reading this post quite avidly. I DID have exceptionally high Folic Acid levels after years of supplementation with it before I found out I had MTHFR and understood the issues related to it.

I do better on high dose methylfolate - BUT to date, I either have not quite found the right balance of it to the other B vitamins - OR - like you have stated, maybe I need to do some intermittent schedule.

Right now I'm taking my supplements 5 days out of 7 for three weeks, off a week, etc. Then about every six months I stop for a full month. If I don't, It seems to be helping me manage my treatment and keep me at optimum while I work out any kinks I have around modifying the dosage of the other B vitamins to try to get the balance corrected.

I do avoid folic acid fortified foods for the most part, but have recently started added a few baked goods back in as I seem to tolerate small doses of gluten better now that I've been gluten free for over a year - but maybe I should avoid it after all - I was thinking of the gluten not the buried fortified flour.