Invest in ME Conference 12: First Class in Every Way
OverTheHills wraps up our series of articles on this year's 12th Invest in ME International Conference (IIMEC12) in London with some reflections on her experience as a patient attending the conference for the first time.
Discuss the article on the Forums.

Methylfolate SIDE EFFECTS...

Discussion in 'Detox: Methylation; B12; Glutathione; Chelation' started by dannybex, May 30, 2013.

  1. Wayne

    Wayne Senior Member

    Ashland, Oregon

    Hi Caledonia, congratulations on your improvements. :thumbsup: I'm always impressed by the persistence displayed by some PR members, and am always delighted when a therapy begins to work, usually after trying a hundred or more that didn't work. --- Also, thanks much for your posts on this thread. I found them quite valuable, as I just recently started taking methyltetrahydrofolate, which was recommended by my ND (after I muscle tested positive for a certain gene mutation).

    Why he recommended this form, I don't know, but I have to be careful how much I take. I'm currently taking about 1/5 to 1/10 of a single 5 mg capsule every few days. It causes me to feel a bit unsettled for a day or so, but I then experience a little more mental clarity, and feel a certain strength in my system for the next few days. When that strength starts to dissipate, I then take another dose. We'll see how it goes.
    dannybex likes this.
  2. caledonia


    Cincinnati, OH, USA
    I haven't made a real study of Cutler's theory, but based on that link, he contradicts himself. Maybe there is not a direct metal detox from methylation, but methylation is required to make glutathione, which then in turn detoxes mercury. So you need methylation to detox mercury. To say otherwise is contradictory.
    dannybex likes this.
  3. dannybex

    dannybex Senior Member

    Yeah...I think his gripe is the 'direct connection' thing. But don't quote me! :)

    I'm sure he says elsewhere that methylation is important -- or else we'd be dead -- but I think -- emphasize 'think' -- that his issue is that methylation alone won't chelate mercury or other heavy metals. Seems to me even Rich was basically saying the same thing at one point (???) but I don't have a link right at the moment.
  4. Beatnik


    Glutathion is the key for metal detox, more methylation more metal detox. In my case deep acne grain in my nose for the cigar smoke, and another down my belly for the jeans button, thats empirical, but its true im not the only one. And of course a lot of metals in my pee. So chelation is methylation and metal load in your body is higher if your methylation fails. Cutler is a kind of tothem but not god.
  5. triffid113

    triffid113 Day of the Square Peg

    Dan, you have CBS issues like me. If I had the symptoms you list I would never have considered folate a problem, I would have treated each symptom separately...

    migraines & palpitations - need magnesium citrate
    palpitations - potentially need potassium
    anxiety - need P5P
    sore muscles & irritability - need potassium and potentially calcium citrate
    acne - need zinc
    achy joints = not enough SAMe (need for all methylation supplements - remember homocysteine provides feedback control - you will make less SAMe if your homocysteine is high - you need to clear it to get the cycle working again)

    All these things are necessary for the methyl cycle anyway. Well maybe not calcium but in general alkaline minerals are calming.

    Recall that I have a CBS +/+ and a CBS +/-. I believe that DHEA and P5P are what tames it for me. I have recently learned that the reason I could not dial down on DHEA was because the CBS needs and sucks up more P5P (CBS is not fully regulated by lower dose hormones and needs to be regulated by P5P) and this makes P5P unavailable to make neurotransmitters, which causes anxiety. I have been able to dial down DHEA to 50mg if I up my P5P to 100mg in two 50mg doses / day. So...for you, taking extra mfolate apparently is rasing your homocysteine thus requiring more P5P to atempt to clear it and leaving none for making neurotransmitters, causing anxiety. You either up your P5P, regulate CBS it with DHEA/testosterone, or take TMG with your mfolate to see if shunting off the homocysteine is enough. For me the TMG helped a lot but not enough and I needed the extra P5P if I wanted to dial down DHEA. I BELIEVE that if you do ot take DHEA/testosterone your required dose of P5P with CBS mutations might be VERY high. (Like maybe 600mg). I know they were giving very high P5P doses for some problems (autism?)

    Just some clues that may help you. I would stoke up on alkaline minerals now to feel better to start

    For reference, my protocol that works with CBS:
    50mg DHEA (if 50-100mg DHEA does not work for you, try bioidentical hormone replacement of testosterone) PLUS Life Extension cruciferous vegge caps and 50mg zinc picolinate (to regulate hormones)
    Thorne Basic B 2x/day
    50mg P5P 2x/day
    1g TMG 2x/day
    800mcg mfolate 1x/day (maybe you can leave this off and just rely on the mfolate in the Thorne...I am ambivalent about it...I will not take more as it makes me unstable and requires e to up all my methylation supplements)
    500mg potassium powder

    I take D3 to achieve a blood reading between 70-80 (I like to be at 70)
    I take high dose anti-oxidants (free radicals will provide bad feedback to the methyl cycle)

    Apparently the 1g olive leaf extract I take has the property of raising glutathione which apparently helps clear heavy metals

    I take 400-600mg magnesium citrate each and every day (in my calcium citrate supplement). I know how much I need because of my blood pressure, but everyone needs this for their heart. idk - someone said that you nede magnesium everytime you want to utilize an ATP.

    I take other stuff. But this MAY be the gist.
  6. triffid113

    triffid113 Day of the Square Peg

    I have a study that says that olive leaf extract raised glutathione if that's a help. I take it for blood pressure and can really feel the difference.

    I have CBS +/+ and +/- and my doctor is always trying to give me "stuff for clearing metals" due to my CBS but I don't feel I need it. The last thing he gave me, if of interest, is called metalloclear.
  7. triffid113

    triffid113 Day of the Square Peg

    Rich says/Yasko says CBS mutations lower homocysteine. I have CBS +/+ and +/- and w/o adequate supplementation I have HIGH homocysteine. So a reminder...there is NO EXPERT BUT YOURSELF and NO SUBSTITUTE for finding out what is going on with YOU.

    Furthermore, one of the causes of anxiety is insufficient P5P. Studies show that P5P is not only heavily needed by CBS but can correct CBS for a large percentage of those with the mutations. Thus it seems extremely likely (and proved true in my case) that if you take a supplement course that causes anxiety, that means you have stimulated your CBS enzyme to have to work more and it has used up all your P5P to do so leaving none for making neurotransmitters, causing anxiety. Supplying extra P5P does the trick.

    It does not work for all CBS'ers, but will do so for a significant percent. CBSer's are not the only ones affected for everyoe has to use that enzyme to lower P5P and it takes 2 P5P's to dispose of 1 Hcy. So simply not having enough P5P would do it for anyone. It's just that CBSers (those with CBS mutations) may be a super vacuum for P5P. (We are if we are in the percent for whom it works at all).
    topghetto likes this.
  8. triffid113

    triffid113 Day of the Square Peg

    OMG - here is perhaps the basis for the blood sugar issues caused by CBS mutations:

    Here is a study that supports that TMG in high enough doses will effectively treat CBS deficiency in those that are not pyridoxine responsive:

    idk what I read to show that a large pct of CBSers are responsive to B6 therapy, but this study shows testing CBSers in half a dozen cities ad the pct helped by pyridoxie was just under half.

    So..contray to Yasko,
    I find this study which says CBS C699T does not affact homocysteine levels. (BTW there are other CBS phenotypes not measured by Yasko that affect CBS responsiveness to SAMe, causing high Hcy).

    This study showed CBS 699 C>T also has no effect on homocysteine but does lower cholesterol:

    Ah---HERE is the AHA! (as in Eureka!) article on CBS upregulation...THIS article makes a case for it being only a factor IN CHILDREN (whose need for folic acid is high - remember folate is needed for cell division). What I find is true with me (supported by BLOOD TESTS) is supported by this article. I believe Yasko is WRONG regarding CBS and I do not believe she should be so highly quoted her in that regard as it sends people into depression and even panic as o one knows what to do about CBS overactivity (this article says even on the study Yasko refers to the difference is only 2.7% and her study has a lot more children in it).
    Valentijn likes this.
  9. triffid113

    triffid113 Day of the Square Peg

    Dan, sorry it was ME who brought up CBS. My advice still stands because it is based on symptoms and blood tests, not genes. I have too many mutations to decypher their effects and can only rely on the accumulated effect they have on my blood work. Based on the above CBS rebuttal I will print in entirety here, I no longer believe CBS has any relevant effect at all and your symptoms are due to your other genetic polymorphisms or nutrition.


    CBS Upregulation, Myth or Reality?
    By Mark London

    Upregulation of the CBS enzyme via two genetic polymorphisms has been
    theorized to be possibly detrimental for some conditions, based on the
    work by Dr. Amy Yasko in autism. These two polymorphisms were studied
    in 2000, and in that study, the Post Methionine Load (PML) test was
    used to determine the effects of different CBS polymorphism genotypes.
    That loading test can detect subtle defects in the transsulfuration
    pathway, which is the metabolic process that is affected by the CBS
    enzyme. The polymorphism with the greatest effect, as shown by the
    PML test, was found to be 699CàT (Y233Y). People with the TT (+/+)
    genotype of that polymorphism, and to a lesser degree CT (-/+),
    produce lower levels of homocysteine levels in response to the PML
    test, when compared with the CC (-/-) genotype. Lower homocysteine
    levels from that test infers greater CBS activity. By the way, none
    of these genotypes are rare. About 40% of the population has CC, 40%
    has CT, and 20% have TT. Thus, all the genotypes of this polymorphism
    are quite common. The study also looked at the CBS polymorphism
    1080CàT (A360A), but that was found to have less a significant effect.
    The TT genotype of that polymorphism only showed a significant
    decrease in homocysteine in the PML test, if 2 other polymorphisms
    were also excluded. Thus, 699TT seems to have the most significant
    affect on CBS activity.

    On the other hand, a similar study in 2003 on these polymoprhisms did
    not show a significant difference in homocysteine levels due to the
    different genotypes, in response to the PML test. One difference with
    this new study is that it was done on a different ethnic group, which
    is sometimes a factor in genetic studies. Also, while the mean age
    was the same in both studies, this new study had a much smaller range
    of ages, and did not include anyone younger than about 40 years old.
    This might be a factor, since CBS activity is known to decrease as a
    person gets older.

    Even more interestingly, is that a study on pregnant women in 2003
    surprisingly showed an increase in basal homocysteine levels from the
    TT genotype, the same genotype that had the lowest homocysteine level
    in the 2000 study. This study did not give any possible reason for
    this result.

    In any event, even in studies which showed increased CBS activity
    effects from the TT genotype, such as the one from 2000, and a more
    recent one from 2007, only small changes in homocysteine levels were
    observed. For example, in the latest study, which used a very large
    population of 10000, the basal homocysteine levels only differed by
    2.7%, between the TT genotype, which has the highest CBS activity,
    compared to the CC genotype, which has the lowest CBS activity.

    This minor decrease in homocysteine levels is in contrast to that
    which is seen in Down's syndrome, where CBS upregulation is definitely
    known to occur. In one study on Down's syndrome children, basal
    homocysteine levels were reduced by 25%, and plasma levels of
    cystathionine, which is produced by the transsulfuration pathway, was
    increased by 3.8 fold.

    On the other hand, a later study on Down's syndrome adults did not
    show decreased homocysteine levels. This surprising result was
    theorized to be due to the fact that adults have a much lower
    requirement for folic acid. When folic acid was given to the Down's
    syndrome children, their homocysteine levels rose significantly.

    Thus, age may become a factor when considering the effects from CBS
    upregulation. Dr. Yasko claims that these CBS polymorphisms can have
    significant effects for autistic children. Even if that claim is
    true, it is possible that it only has relevancy for children. Also,
    the claim may have no relevancy for other conditions, due to the fact
    that autism has many other metabolic disturbances that are not found
    in other conditions.

    It's also been claimed that increased urinary taurine and ammonia can
    help diagnose CBS upregulation. While it's true that CBS upregulation
    can cause increased taurine and ammonia production, there's no
    evidence that this increased production can be detected by measuring
    their urinary levels.

    Urinary taurine is an unreliable test for CBS upregulation, due to
    fact that urinary taurine is dependent on many factors, including age,
    genetics, gender, renal function, clinical conditions, and especially
    dietary intake. Thus, even though a study on Down's syndrome found a
    significant increase in plasma taurine, another study on Down's
    syndrome found that urinary taurine levels were normal. Urinary
    inorganic sulfur was also not significantly different, which doesn't
    confirm Dr. Yasko's prediction of excess sulfur byproducts from CBS
    upregulation .On the other hand, urinary thiosulfate was
    significantly increased. Thiosulfate is a metabolite of hydrogen
    sulfide, and CBS is one of only three enzymes known to be able to
    produce hydrogen sulfide. Thus, significant CBS upregulation was
    likely occurring, even though urinary taurine and sulfur levels were

    Urinary ammonia is an even less reliable method for testing for CBS
    upregulation. This is because most of the ammonia (NH4+) in urine is
    produced by the kidneys for ph regulation. The ammonia that is
    produced elsewhere in the body, is usually detoxified by being
    converted to urea, which is then excreted. This process mainly occurs
    in the liver, and the liver is quite capable of handling the large
    amount of ammonia that is produced in the body, which occurs due to
    the metabolization of amino acids. The liver has to be able to do
    this, because the nervous system can only tolerate very low levels of
    ammonia. Excess ammonia, i.e., hyperammonia, only usually occurs
    either when liver functioning has been greatly reduced, or where a
    genetic defect in the urea cycle exists. Only by testing serum
    ammonia, can such a condition be diagnosed.

    In conclusion, the medical literature states that these CBS
    polymorphisms have only very mild effects on CBS activity. And even
    if there is significant CBS upregulation, there is no evidence that it
    can significantly cause any negative effects, such as overproduction
    of ammonia. Furthermore, the medical literature doesn't support the
    claim that elevated levels of urinary ammonia or taurine is indicative
    of CBS upregulation.

    Dr. Yasko claims that CBS upregulation can lead to "a lack of
    glutathione." However, while glutathione is reduced in Down's
    syndrome, medical researchers do not believe that this is due to the
    CBS upregulation. Instead, they believe it is due to the
    overexpression of the superoxide dismutase (SOD) gene, which also
    occurs in Down's syndrome: "The reduced plasma glutathione observed in
    the children with DS most likely reflects an adaptive antioxidant
    response to chronic oxidative stress, resulting from SOD
    overexpression." This conclusion is possibly confirmed by a lab study
    on CBS overexpression in mice, where even though homocysteine levels
    were significantly reduced by the CBS upregulation, gluathione levels
    were unchanged.

    Thus, while some of the aspects of Dr. Yasko's treatment plan may have
    usefulness, there is no support that CBS upregulation can have any
    negative effects.
    topghetto and helen1 like this.
  10. triffid113

    triffid113 Day of the Square Peg

    Dan, what you have that I do not is: MTHFR C677T +/-. If the protocol I listed does not work for you then it might be of interest to you to concentrate on the effects of the MTHFR gene. I think that gene governs forward folate metabolism (?). (I have the MTHFR 1298A>C that governs backwards folate metabolism). You may find some things speed up/help this gene, but alternately you may find it can't be speeded up (which is ok as long as it works at least a little). If it cannot be speeded up, then idk what you would do with excess mfolate...and idk if excess mfolate floatig aroud in the blood is bad or not. At the least it would contribute to hypercoagulability IMHO because it is a particle therefore making blood thicker. I doubt if CBS can get rid of it as it is not homocysteine. I wonder if there is some mechanism to get rid of it? Maybe the kidneys filter it out at some rate? It is not possible to subsist on only SAMe generated by TMG. (Some cases of high dose TMG supplementation w/o other B's causing cerebral edema). However 2g TMG is a normal amount of TMG achievable by a very good diet and it can produce sufficient SAMe to help your joints and prevent homocysteine buildup. may NEVER want a lot of folate. idk how minimal you can get along with but you need some. As long as you are not growing or needing extensive skin repair (don't get burnt in a fire) you might be ok with low folate. But you will never be ok with low SAMe so if it were ME I would look at a good B complex and extra TMG, and depending on symptoms, possibly more P5P (for anxiety). I hear you need P5P to make GABA, serotonin, and dopamine. idk why taking folate would cause you to need more P5P uless it is indeed being turned into homocysteine and you don't have enough P5P to deal with the extra homocysteine (quite aside from CBS polymorphism).
  11. GenDylan


    Regarding the euphoria - I deal with the same thing. I attribute this ,no doubt, to low dopamine. I'm depressed with low dopamine, and when I get a kick of dopamine/happyness ,I get euphoric. This is because I'm so sensitive to dopamine, and that's because I'm low. I can't suggest how to fix this problem though..
    I'm not sure how methylation effects neurotransmitters, but I'm know it does..
    Wayne likes this.
  12. Beatnik


    D3 is needed to transport folate across choroid plexus, via PCFT, ph gradient in the gut is also important. Autism -folate conection in somalian people living in sweden, and in South korea 1/33 is because of that. Low sun exposure and Uv radiation- folate photolisis is the key. (Evolution of human skin. Nina jablonski). High methylation snp rates are the rest. Natural selection is modified by folic acid, and autism rates are growing w/o control. Amish population has zero rate. Why?
  13. Beatnik


    Bh4 and Same are needed to produce neurotransmisors, they play a key role. I can't explain everything but google it if u are interested ;)
  14. Beatnik


    And cbs upregulation myth comes from DS, they have 3 copies ;). Yasko is wrong.
  15. LynnD


    Am also trying to figure what to try first, Have been on methyl B12 for several years, just take about 250mcg/ day(will have to ck what a drop is). Also multiple vitamin (food based). some vitamin D3, but if take much get muscle cramps. A little more of the B1 and 2 helped, B5 didnt till tried vite A. Not sure why the liver didnt show up on vite D blood test week later. (my blood tests for folate and B12 for years show high or near top of in, heard should do a test for unmetabolized vitamins).
    So last week tried half capsule of Jarrow methylfolate (400mcg), and was SOoo tireder for 2 days then another of leg muscle that feel like energy pulled out and hip muscle gave out twice, trying to walk. wonder if blood sugar, ready to buy a tester.(2 yrs ago friend loaned me extra and at night would be 40-50,but in morning back to 81)
    Now afraid to try even really tiny bit, not sure what foods to shore up on.

    homozygous: MTHFR C677T, COMT V158M, COMT H62H, VDR Bsm, MAO-A R297R, CBS A360A
    heterozygous ACAT1-02, MTR A2756G, MTRR A664A, BHMT-08, SHMT1 C1420T
    Usually can at least walk to bus stop ~2-3xs/wk
    are there foods that have M B12?
  16. triffid113

    triffid113 Day of the Square Peg

    I think - and ths is only gut feel - that these supplements up your mineral requirements and poor mineral intake / levels could even be the reason for adverse effects from taking these methylation supplements (including D). I believe I read somewhere hat it is not good to take a lot of D (possibly K as well?) unless you take sufficient calcium. I believe the methyl supplements (which are used biochemically to turn o and off biochemical pathways) increase the need for various minerals...notably potassium, also magnesium, and possibly even zinc, if not others. I never was able to verify this but someone on the old B12 website said that a magnesium ion is used up for every use of ATP. You can also see that 2 magnesium ions are used up getting rid of homocysteine on the P5P path. I don't know where the potassium is used but Freddd and others have indeed found themselves with fangerously low potassium after aking these supplements. I personally thing that while methylation is necessary for life, yet one should probably take a good multi to make sure some basic level of all nutrients is available when turning on new biochemical pathways. I mean this suggestion for safety.
    Asklipia likes this.
  17. LynnD


    Thank yo TRiffid for the ideas. Have been trying to find a way to get more minerals. The bone tabs(Ca,Mg ) get problems with eating food for days. Do chew on ends of stewed organic chicken bones, and sometimes a pinch of epsom salts in water(sometimes lowers a low BP though) or bath. Keep hoping to do all this by food, just need to absorb better, (LOL, maybe take a bath in soup). Didnt feel good when tried p5p in past. WOnder what foods the different B12's are in.
    Just started a bit (pin head size) of Mb and noticed stomach feels like digesting better. Goal is to not need any of these supplements. Wake up feeling rested (front of face feels like wood in morning also) is also a goal. So I try to stay active enough wo overdoing.
  18. Dannylingo


  19. knackers323

    knackers323 Senior Member

    Anyonr get extreme fatigue and/tiredness from methylfolate or know what it indicates?

    Ivr read it can make inflammation worse.?
  20. dannybex

    dannybex Senior Member

    Folinic helps me sleep, sometimes too well. Also helps with sound sensitivity. I attribute it to helping slow down the 'wired but tired' excitation, so that I can finally get the much need sleep in order to restore and repair...

See more popular forum discussions.

Share This Page