138 replies to this topic

[Debaser]

TL;DR: I have the MTHFR 677T mutation (amongst others) and I don't know how to interpret all the information that's out there or how best to treat my condition.

 

Through 23andMe I discovered that I have this mutation (homozygous). I've done a lot of reading over the last few weeks. I've been wondering whether it could explain a lot of the inexplicable symptoms I've been having over the past few years, including brain fog, fatigue, sleep difficulties, heart pain and palpitations, unexplained weight loss, joint/muscle/nerve pains, slow healing injuries and skin issues, amongst others, always without the doctor being able to explain it.

 

My basic understanding:

• My body cannot process folic acid very well (about 30% as efficient). I do not know if this applies only to the artificial folic acid that is found in supplements and fortified foods, or if I also can't process folate that you get from leafy vegetables. But I think I've probably suffered from folate deficiency quite often in my life.
• I believe my body also doesn't process vitamin B12 very well.
• This can lead to elevated homocysteine levels in the blood, which is bad.
• Supplementation with folic acid or B12 is ineffective because my body cannot process it very well. In fact, supplementation with folic acid can make it worse, because the folic acid will just build up in the blood and inhibit the active forms from being taken up. This means you can have elevated folic acid levels in the blood but still be deficient in folate. This means I should avoid fortified foods like cereals.
• Folate (or folic acid?) supplementation can mask vitamin B12 deficiency, which can lead to "pernicious anaemia". Vitamins B9 and B12 need to be in balance.
• I should supplement with bioavailable forms of the vitamins, e.g. 5-methyltetrahydrofolate and methylcobalamin.
• However, even if you do this, if you take them in the wrong proportions you can get a "methyl trap". I don't fully understand this, but I think the solution is to take more B12.

I started taking Metafolin and methylcobalamin nearly a week ago, and I felt incredible. I didn't realise how chronically fatigued I was until suddenly I felt wide awake during the day, and a great sense of wellness. A lot of my pains reduced and I was able to think clearly, and I was sleeping better. It was like a switch had been flicked in me and my body was suddenly working.

 

Since then, I've been reading up on it more and particularly about how other people taking these two supplements have experienced bad side effects and had to stop taking them or take them in different amounts, or how they've had to stop eating vegetables, or how they've had a methyl trap occur. Obviously there is more than a single nucleotide polymorphism involved in methylation, so not everybody is the same. I've even read that some people with this mutation are fine and don't need supplements.

 

Another issue is that I have other mutations which affect the methyl cycle, but they are less well-documented. Some of them might make me an over-methylator rather than an under-methylator, and by taking these supplements I may be doing harm. I don't know though. I can't find enough information about it.

 

A lot of the websites out there are triggering my quackery alarms. Most of the forums seem to be filled with hypochondriacs, many of whom also think they have Lyme disease, or are treating their child who has ADHD or autism (probably due to Dr. Amy Yasko). Many of the doctors seem to have qualifications from suspicious nutrition schools rather than real medical qualifications and want you to take brand name supplements that they no doubt make money from.

 

I'm really struggling to distinguish the valuable scientific information from the hype and the quackery. I'm really looking for any advice about this mutation and how to best treat it.

[niner]

A lot of the websites out there are triggering my quackery alarms. Most of the forums seem to be filled with hypochondriacs, many of whom also think they have Lyme disease, or are treating their child who has ADHD or autism (probably due to Dr. Amy Yasko). Many of the doctors seem to have qualifications from suspicious nutrition schools rather than real medical qualifications and want you to take brand name supplements that they no doubt make money from.

 

This is clueful; it sounds like you have a good BS detector. It also sounds like you've basically found the answer- take 5-MTHF (aka metafolin) and make sure you aren't B12-deficient. I suspect that a lot of these methylation SNPs are not that important, particularly if you are a heterozygote. If you're feeling good now, you are probably very much on the right track.

Edited by niner, 21 April 2014 - 04:47 AM.

[Debaser]

Yeah I guess you are right. I am feeling good actually.

 

I'm not totally sure that I need the 5-MTHF though, because I eat plenty of broccoli and green leafy vegetables, which contain folate rather than folic acid. It's my understanding that my body can't methylate the folic acid in the liver, but I can absorb folate in the lower intestine just fine? So I need to avoid fortified foods and folic acid supplements. But I think there are other issues than just the metabolism of folic acid. I think I'll carry on taking the supplements for the next month and see what happens.

[niner]

I don't think that the source, whether natural folate or synthetic folic acid, is going to make a difference here.  You have a reduced ability to metabolize either of these, although the level isn't zero.  I would try to avoid fortified foods and folic acid supplements, but I wouldn't avoid natural sources of folate because they are also sources of other important micronutrients.  I would continue to take 5-MTHF in order to avoid deficiency there, since you aren't making as much as a wild-type or heterozygote would make.

[Debaser]

A small update for posterity.

 

I found that after about 2 weeks I began to get scalp issues, which I've never had before. My scalp was itchy, sore, with scabs/spots, possibly seborrhoeic dermatitis. I was also occasionally getting sores on my tongue, and the edges of my mouth were getting a bit red and dry, and sometimes I got dry, scaly patches on my scrotum (which I've had before and suspect to be caused by riboflavin deficiency).

 

Anyway, I did a bit of research, and it seems that these problems, particularly the sore scalp, could be caused by deficiencies of riboflavin (B2), B6 or biotin (B7). I found some other reports that if your body suddenly has a supply of folate and B12 that it had previously been lacking, it can put an increased demand on other vitamins because it is doing a lot of healing and repair. Anyway, I dropped down to taking the methylated folate and B12 every other day, and supplemented riboflavin and B6 at the same time. The scalp issue went away pretty much overnight and hasn't come back, and so did all the other issues.

 

Overall I think my body seems to be healthier than ever now. My hair and nails and skin look really healthy and exuberant. My eyes are very bright with thick limbal rings and white sclera. People have even remarked that I look very well.

Edited by Debaser, 18 May 2014 - 07:22 PM.

[SearchingForAnswers]

Debased, how is this going? I suspect I may have similar issues, as sometime back Sam-e did wonders for me, but then did just the opposite. I didn't understand methylation and hadn't discovered longecity back then; I've ordered the supplements, but since I'm now in Afghanistan it will take a couple of weeks. Do you think the Sam-e could have unbalanced my b-vitamins?

[world33]

I had my 23andme.com DNA results analysed by Promethease, Genetic Genie and nutrahacker.com and found to have the same C677T mutation (Homozygous). I suffer from anxiety and fatigue and the mutation could explain the lower level of neurotransmitters in my brain. I watched Dr. Neil Rawlins' interesting lecture on MTHFR mutations (4 parts) at



and he recommends to try:

• methyl folate
• methyl b12
• Tetrahydrobiopterin BH4
• N-acetyl-L-cysteine (NAC)
• Full spectrum minerals
• Vitamin B6 (Pyridoxal-5-Phosphate)
• Trimethylglycine (TMG)

Jarrow Formulas B-Right is cheap and contains all the active forms of B vitamins including the ones mentioned above. No need to buy separate supplements in my opinion.
Tetrahydrobiopterin BH4 is sold by nutrimedical.com but bloody expensive. If it works for me I will try to source it from an Alibaba supplier in bulk. N-acetyl-L-cysteine (NAC) and Trimethylglycine (TMG) are not difficult to find. I will try all these supplements and report back.

Edited by world33, 27 August 2014 - 02:21 PM.

[Debaser]

I dunno. I still haven't got it right. I'm still getting problems with my scalp/acne and the only thing that seems to help is reducing dosages. I think it might be the B12 but I really don't know for sure. I'm wondering if it is hormonal... maybe now that my body has access to large quantities of these B vitamins it is able to produce testosterone in higher quantities?

 

I'm messing with dosages now, but the problem is I just don't know what dosages are right for my body. If you get the vitamins in the normal way then your body will use them in the quantities it needs and discard the rest, but obviously that doesn't happen for me. So I'm taking the biologically active forms directly but probably in the wrong quantities/proportions and it's throwing things out of balance. I'm definitely better with them than without, but the side effects are annoying.

 

 

Debased, how is this going? I suspect I may have similar issues, as sometime back Sam-e did wonders for me, but then did just the opposite. I didn't understand methylation and hadn't discovered longecity back then; I've ordered the supplements, but since I'm now in Afghanistan it will take a couple of weeks. Do you think the Sam-e could have unbalanced my b-vitamins?

That is very possible. Sam-e can increase your body's usage of B12 and folate, leading to deficiencies and homocysteine build up.

[SearchingForAnswers]

Since I started taking these, I feel completely different. Way way better... a host of "mystery symptoms" have dissappeard to dissipated to almost nothing.

I'm taking the following:

Thorne Research Basic B complex

Separte 400mcg methylfolate and subling methylcobalmin, about 5,000mcg every other day

TMG

Zinc + copper

Sometimes albion potassium

 

I also just added adenesocobalamin and I believe that too is helping.

 

My symptoms were:

Depression

Anxiety

Something close to dysautonomia, even went positive on a tilt table test!

Dizziness

A kind of feeling like I was going to faint, or pass out, for no reason. Felt "Fragile" if that makes sense.

 

I had also finished a course of nsi-189, and though it helped with my depression, it seems to have also sent me for a loop after some time. I believe it may have drastically increased my need for active b vitamins, or methylation since it stimulates neurogenesis and that would require dna transcription.

 

However, the bad symptoms have all disappeared; though I am getting other, milder symptoms that make me uncomforatable. I find that Potassium seems to help, and if I really need it a little bit of niacin (the theory being that I'm producing too much sam-e and niacin will soak it up).

 

This is absolutly life-changing for me. I believe I've also read that hydroxocobalamin can reduce some of the side effects from the methylfolate, so I believe I will order some of that.

 

What an experience... so many doctor's have just thrown up their hands and had no idea. I'm currently waiting for my 23andme vial so I can get tested. Fairly certainly I'll show MTHFR and possibly others. The difference is just so drastic... like I've had a cup of coffe after waking up before I've had any.

 

Not it's just about balancing out the dosages and finding what works with the fewest side effects.

[world33]

Same here searchingforanswers. I take Jarrow Formulas B-Right and I feel almost like in my twenties. I always wondered why I always felt so tired now I have the answer. It was so simple and still hard to find out. Once you get your DNA results you can connect your data to the following services:

promethease.com (fee-based but worth it)
nutrahacker.com (free for a limited version and fee based for the extended version, it tells you what supplements to take and what to avoid)
geneticgenie.org (free)
livewello.com (fee based, lots of info but you need to interpret your mutations yourself)

[Mayardur]

Tetrahydrobiopterin BH4 is sold by nutrimedical.com but bloody expensive. If it works for me I will try to source it from an Alibaba supplier in bulk. N-acetyl-L-cysteine (NAC) and Trimethylglycine (TMG) are not difficult to find. I will try all these supplements and report back.

 

 

Like the OP, I too have the MTHFR 677T mutation, along with others that would indicate BH4 deficiency.

 

Just curious if you ended up sourcing BH4, and if it has any effect for you? Seems to be out of stock all over, except Alibaba.

[world33]

 

Tetrahydrobiopterin BH4 is sold by nutrimedical.com but bloody expensive. If it works for me I will try to source it from an Alibaba supplier in bulk. N-acetyl-L-cysteine (NAC) and Trimethylglycine (TMG) are not difficult to find. I will try all these supplements and report back.

 

 

Like the OP, I too have the MTHFR 677T mutation, along with others that would indicate BH4 deficiency.

 

Just curious if you ended up sourcing BH4, and if it has any effect for you? Seems to be out of stock all over, except Alibaba.

 

 

I bought from nutrimedical.com and it was the most stupid thing I have ever done in my life. Each capsule contains only 2.5 mg (homeopathic level ...) where the normal dosage is much higher. It costed bloody 90 dollars plus shipping and it arrived 7 days after shipping when it is supposed to be always refrigerated. The owner from nutrimedical.com also does not have a good reputation if you google his name. I tried the capsules and it did nothing probably for the low dosage. Basically a scam like the entire homeopathy discipline is in my opinion. BH4 is very expensive unfortunately and the alibaba supplier quoted me 193 $ per gram which is ridiculous. Unfortunately I think I will give BH4 a miss. Vitamin C apparently increases BH4 levels indirectly so I guess I would focus on supplements that indirectly have an effect on BH4.
 

[Mayardur]

 

I bought from nutrimedical.com and it was the most stupid thing I have ever done in my life. Each capsule contains only 2.5 mg (homeopathic level ...) where the normal dosage is much higher. It costed bloody 90 dollars plus shipping and it arrived 7 days after shipping when it is supposed to be always refrigerated. The owner from nutrimedical.com also does not have a good reputation if you google his name. I tried the capsules and it did nothing probably for the low dosage. Basically a scam like the entire homeopathy discipline is in my opinion. BH4 is very expensive unfortunately and the alibaba supplier quoted me 193 $ per gram which is ridiculous. Unfortunately I think I will give BH4 a miss. Vitamin C apparently increases BH4 levels indirectly so I guess I would focus on supplements that indirectly have an effect on BH4.
 

 

 

Sorry to hear that. Was the brand Ecological Formulas, by chance? I purchased from Spectrum Supplements ($75) but they claim that Ecological Formulas won't have stock until the end of October. Spectrum and Nutrimedical seem to be the only two suppliers. It is also 2.5mg, but if BH4 is going to help you, I've read that a 2.5mg dose once or twice daily is appropriate. Spectrum claims that this supplement is their #1 seller globally. Hey, I was quoted $670/g shipped from an Alibaba vendor, so your quote is actually appealing. 

[world33]

For the PKU treatment they have been using from 10mg/Kg to 20mg/Kg (Source: http://www.pkunews.o...rch/matalon.htm ) so I am not sure 2.5 mg per day make any difference despite we do not suffer from PKU. For a 70 kg PKU sufferer it would be from 700mg to 1400mg per day. I might be wrong thought. Where did you read about the 2.5mg dosage? The brand was nutrimedical itself.

Edited by world33, 17 September 2014 - 08:22 PM.

[Debaser]

I now think that acne issues are caused by high doses of B12. This is backed up by a useful book I found called Herb, Nutrient and Drug Interactions, which says:

 

Megadoses of vitamin B12 may cause or exacerbate acne symptoms.

 

Another issue I've been having is peripheral neuropathy (tingling and pins and needles sensations of the hands and feet). This is something I've never had before, which strongly suggests my vitamin regime (as the only big change I've made) is causing it.

 

It can be caused by deficiencies of B12 or B6, as well as overdose of B6. Initially I had it very bad (constant, never going away, including loss of sensation). This was when I was taking P-5-P, so I stopped taking it. I've decided that B6 is something that you should very rarely need to take a supplement of. It is abundant in most people's diets, and too much of it causes serious nerve damage. I eat a healthy diet, so by supplementing the bioactive form my body was probably flooded by far too much of it. I stopped taking it and also reduced the amount of 5-MTHF from 800 μg to 400 μg and the symptoms gradually went away over about 2 weeks (with occasional relapses after eating certain things). That was months ago.

 

Now they've come back, but not as bad, and more intermittent. The following quote is again from Herb, Nutrient and Drug Interactions:

 

Inappropriate use of folic acid in large doses could precipitate neuropathy in individuals with undiagnosed B12 deficiency (usually from pernicious anemia). ... Folic acid at doses greater than 800 μg/day is contraindicated when vitamin B12 status is uncertain. Doses greater than 1mg/day may obscure pernicious anemia, with irreversible progression of neuropathy, unless the B12 deficiency is corrected with high-dose (1-2 mg/day) oral or parenteral B12.

 

Additionally, I'm now more sure that the form of folate that is found in foods could be the methylated form, which suggests I probably didn't need to be supplementing it as much as I was. I was taking 800 μg/day for a long time (now down to 400 μg). From the same book again:

 

Folate is the preferred term for the mixture of related compounds occurring naturally in foods, whereas folic acid is the more stable form and is used in supplements and added to fortified foods, but rarely occurs in foods or the human body. ... Naturally occurring folates include 5-methyltetrahydrofolate (5-MTHF), 5-formyltetrahydrofolate (5-formyl-THF), 10-formyltetrahydrofolate (10-formyl-THF), 5,10-methylenetetrahydrofolate (5,10-methylene-THF), 5,10-methenyltetrahydrofolate (5,10-methenyl-THF) ...

 

It lists a few more and then goes into great detail about how it's absorbed and how it moves around the body, as well as the C677T mutation and lower MTHFR enzyme activity. What interests me is that this form of the vitamin I've been taking all this time (5-MTHF) occurs naturally in foods.

 

According to http://www.whfoods.c...trient&dbid=63:

 

We also know that a methylated form of folate (5-methyl-tetrahydrofolate) is the major form of folate in most plant cells

 

I eat a lot of broccoli nearly every day. I can't find which form of folate is in broccoli, but it wouldn't surprise me if it was 5-MTHF. The other day I ate a big bowl of lentils and my hands were tingling a lot more than usual. Turns out lentils are the richest source of folate there is. Again, I don't know which form, but it wouldn't surprise me if combined with the 400 μg 5-MTHF pill I took, plus whatever I got from broccoli and other vegetables I'd eaten that day, I was well over 1mg. Later on I took another sublingual methylcobalamin (B12) and the tingling went away. The next day I skipped my 400 μg 5-MTHF and got no tingling.

 

This is all anecdotal, but my conjecture is that I am getting too much folate and this is putting a high demand on B12 which I am not meeting. I think the bioavailability of the sublingual methylcobalamin is quite low. That's why it's such a high dose, because hardly any of it gets absorbed. From Herb, Nutrient and Drug Interactions:

 

Absorption of large doses of B12 in the form of oral supplements is relatively poor. Sublingual forms are available but may not offer significant absorption advantages.

 

I think I could have given myself pernicious anemia or megaloblastic anemia. But I can't be sure. Apart from the neurological symptoms I've had tingling/weird feeling of my tongue, some redness around my mouth, and shortness of breath, which is strange because I'm physically fit and go to the gym regularly. The gym is actually where it happens most. I get a really strong sensation of not having enough oxygen after relatively small amounts of exertion (e.g. after lifting a dumbell 8 times I am doubled over breathing as if I've run a marathon).

 

As I'm writing this my hands are tingling, and I think I am gonna stop taking the 5-MTHF, or drop it to every other day, but continue with the B12, if not increase it further. Part of me thinks the possibility of hyperhomocysteinemia has got to be better than permanent nerve damage. Maybe I should just stop trying to self-medicate my C677T mutation altogether.

[SearchingForAnswers]

Well,

I just thought I'd check in and give my own progress update.

 

Though I'm homzygous a1298c, and a few others labled MTHFR, and homozygous for serveral MTRR mutations, taking sublingual methylcobalamin and adeonosocobalamin along with metafolin has been life changing. I've tried many things, NSI-189 which helped for awhile, various antidepressants throughout my life, racetams, noopept, tianeptine etc....

 

Nothing has had the sustained effect of these products.

 

Metafolin: about 3mg daily

Adenosylcobalamin: about 5 mg daily (sublingual)

Methlycobalamin: about 5 mg daily (sublingual)

 

There was a period where things got bad, I had to tailor way back and take regular old niacin to soak up what I believe were too many methyl donors (obviously I can't prove that).

 

I also have some of the mutations which could make me an "overmetylator", and would create incredible anxiety over and above my previously normal levels. It took some time to balance things out.

 

I'd reccommend "B12: The hidden story". Yes, there are Yasko followers and other quacks, but you know because some info is bad doesn't mean it all is. Unfortunately, mainstream medicine hasn't jumped on this bandwagon yet, and probably never will. There's no money in it.

 

So in my opinion, I've been treated for what amounts to a vitamin deficiency with antidepressants, clonopin, xynax [sic], vyvanse, and other things by clueless doctors. It angers me, as I'm now 53 and feel I could have accomplished much more without this monkey on my back.

 

So I'm only about 4 months into it, but nothing has ever held up this long. I just mostly feel pretty damned good, and when I don't fee that way I mostly just feel normal. If things go south I'll update here, but hopefully they won't.

Edited by SearchingForAnswers, 13 January 2015 - 09:27 AM.

[world33]

Good to hear SearchingForAnswers, I am having good results as well with active B12 (oral Adenosylcobalamin or even better with hydroxocobalamin injections) and Metafolin (Solgar brand). I tought I could give up my Lexapro for GAD but I just could reduce it. I also found removing wheat and grains from my diet very helpful. It is like if they cause inflammation in my body and cause morning anxiety. In that case I take lots of curcumin to reduce inflammation and feel better.
Have you tried tyrosine (precursor of dopamine and noradrenaline) and tryptophan (precursor of serotonin) as an additional boost to your regime? Tyrosine (up to 3 grams per day) works particularly well for me for energy and concentration. I take it with an empty stomach 30 mins before breakfast.
If I did not do my own research (23andme DNA test + resources mentioned above) I would still be searching for an answer :-) or relying on pharmaceutical driven doctors advices.

[frenchmoxie]

For what its worth, lithium is needed to properly utilize B12.

[Kingsley]

I thought I'd resurrect this thread and see if some of you original posters can give an update on your progress.  I think this is such a vital topic, and I am seeing more and more accounts of people benefitting from active b-vitamins and other vitamins and minerals more dramatically and with more consistency than from all the exotic nootropics out there.  I am one of them.

 

To briefly summarize my situation, I am homozygous for the c677t mutation, with long-standing problems with focus, brain-fog, fatigue, etc.  Recently I have had a lot of success with methylfolate, b-vitamins, and some other key nutrients, and I am becoming more and more convinced that a significant subset of mental problems are made much worse or are even caused by vitamin and mineral deficiencies and/or genetic mutations affecting their metabolism. 

 

Some of the experiences described by Debaser and SearchingForAnswers very closely mirror my own, both positive and negative.  Like Debaser, I initially had great gains from methylfolate/methyl-b12 but eventually began experiencing side-effects and lost many of the benefits.  Exactly like Debaser, I ended up with significant neuropathy in my hands and feet, which manifested as a tingling or buzzing, electric feeling.  I also got to a point where all methyl donors would make me feel sick, stupid, and generally worse. 

 

However, with some key additions to my regimen, I have kicked these side effects and am in a better spot than I have ever been in terms of my cognitive complaints and fatigue. 

 

The first side-effect to manifest for me was fatigue and the feeling of being in a sick stupor, which I'll call Symptom #1.  Once I realized that it was the methyl donors causing it, I cut way back on all methyl donors and b-vitamins and gradually felt better, relatively.  At a certain point after cutting way back, I began experiencing the tingling and buzzing in my hands and feet, which I'll call Symptom #2.  I read online that this is a classic symptom of B12 deficiency and began taking high dose cyanocobalamin (not methyl) and the relief was almost instant.  The tingling receded and I felt much better in general.  Gradually, I began adding back in some folic acid and methylfolate to good effect, but after a while Symptom #1 began to creep back in whenever I would take too much. 

 

Through a lot of forum-surfing, I came across a lot of anecdotal reports and speculation that increased methylation could increase the body's need for potassium by triggering the body to produce more cells and heal itself of the subtle damage caused by years of stunted methylation.  I also read that many of us fall far short of the recommended daily potassium intake of 3.5 grams.  So, I dramatically increased my potassium intake, mainly in the form of V-8 Low Sodium (900 mg per serving), bananas, and potassium tablets.  Almost overnight, Symptom #1 was history.  I no longer experience anything resembling the sick, brain-fogged, tired feeling I was getting from methyl donors before, regardless of how much I take.  Further, the potassium itself had dramatic benefits, which I would describe as a general feeling of well-being, relaxation, and a "smoothing-out" of my cognition.  Also, I've read that acne can be a side effect of low potassium, which may shed some light on Debaser's experiences.  

 

As to Symptom #2, the neuropathy, it has not returned.  I still take high dose cyanocobalamin (probably 5 mg per day) on top of moderate methylfolate and methyl-b12.  I have the impression that no matter how much methyl-b12 I take, I still benefit from cyanocobalamin, and I suspect that the body needs a steady supply of non-methyl-b12 to make full use of the methylfolate, whose primary purpose is to donate its methyl group to b12.  I also suspect that methylfolate supplements can easily out-pace and use up b12 supplies, since it is my understanding that methylfolate is much better absorbed than b12.  Then again, I'm too much of a layman to know if it even makes sense to speak of "using up" vitamins, as I understand that some degree of recycling goes on.   

 

My final breakthrough as to my cognitive symptoms has come from adding calcium supplements, of all things.  I won't take up space speculating why that might be, but suffice to say that I am in a better spot in terms of managing my symptoms that I have ever been.  My current regimen consists primarily of 800-1600 mcg methylfolate, 4-5mg cyanocobalamin, 2mg methyl-b12, 600+ mg elemental calcium, 400 mg magnesium glycinate, lots of potassium from V-8 Low Sodium and moderate use of potassium tablets, and a mixture of other b-vitamins and other vitamins and minerals. 

 

In sum, sufficient potassium and b12 intake appear to be key to benefitting from methylfolate and staving off side-effects, at least for some of us.  I'd love to hear how any of you original posters are currently doing, or from anyone else experimenting with methyl donors.

 

 

[YOLF]

Do you have one of the COMT mutations? I've been thinking one of the available enzymes or enzyme complexes might help with that. As I understand it, if you have the MTHFR gene and get a toxic feeling, it means you have a COMT mutation or some other health issue contributing to the problem. Otherwise, fixing your diet should get you pretty amped. Too much in the way of methyl donors can also help you produce too much in the way of catecholamines and reduce or disable your supersensitivity. At first they're great, but when you lose the supersensitivity you stop getting the euphoria response to passionate thinking and can lose some motivation and maybe even experience withdrawal symptoms depending on how addicted you are to your brain chemistry. 

 

I've been taking the MFolate periodically now rather than daily, mostly to ward off joint pain, but I think smaller doses could be better with this stuff for retaining supersensitivity.

 

Oh, and I like creatine monohydrate too... Your body uses half of it's SAMe to produce the stuff and it's cheap, but taken in larger quantities and it promotes positive mood. 3g of ginger, and 1.5g ea of onion and garlic (all powdered or granulated) are great for keeping a positive mood too. 

 

Any other conditions? I've found that other seemly unrelated problems can get me moody. Maintaining a strong immune system is also important as getting sick can cause pretty bad depression in some as can auto immune diseases (and sometime the drugs used to treat them). MTHFR has it's own aging disease component unfortunately, but there's lots of stuff that can reverse aging and I'm sure more to come and that stuff helps alot to prevent developing depression IMO.

 

I used to love drinking V8 too, it felt great, but something in it made me sick... maybe the celery, it's top of the list for containing the proaging sugar galactose if you happen to be lactose intolerant it could bother you or it might have been something else.

 

The calcium is a good thought, but where does one draw the line? Less prevents mineralization of the vascular system and more might promote it... I certainly get some extra amperage from calcium containing foods though. Elemental Ca is supposed to be bad though... what's your thoughts on that?

[Kingsley]

Hi there:

 

Thanks for your response.  In fact I do have the homozygous met/met COMT mutation.  I have read many times on the internet that those with COMT mutations are prone to side effects from methyl donors, but the symptoms that are always described, i.e. overstimulation, agitation, anxiety, racing heart, etc., do not match up with mine.  If anything, my symptoms are the opposite.  I have wondered if this idea that the val/met COMT mutation affects response to methyl donors is a myth, but who knows.  Since the focus on methylation in treating health issues is relatively new, I think that a lot of the ideas floating around out there do not have much of a foundation but become established as fact simply because they are so often repeated, and we tend to latch onto any information that we can get.  Or maybe it's completely valid; I'm open to the possibility.

 

In any event, potassium has 100% solved any and all issues I was having with methyl donors.  I can now take as much methylfolate and methyl-b12 as I want with no apparent side effects, though I still think moderation is a good idea.

 

I think you make a good point about losing supersensity to methyl donors so that they don't give you the little burst of motivation and euphoria that they did in the beginning.  However, I believe that if you have major mutations affecting methylation like I do, they are consistently beneficial even if the initial strong reaction is attenuated.  Luckily I'm not really looking for motivation/mood/euphoria; I just want to keep my cognition and health at base line or better.   

 

Thanks for your supplement suggestions.  I continually hear good things about creatine and would like to research it more.  Sounds like you're recommending some anti-inflammatory stuff too for mood (ginger, garlic, etc.) which I think has a pretty solid basis.  I think it is becoming more and more accepted that inflammation can cause depression or at least can be a major contributing factor. 

 

I also think that you make a good point about the calcium.  Too much calcium has certainly been tied to some health issues including mineralization of organs, prostate cancer, cognitive decline, etc.  It is hard to know where to draw the line.  I think what I will ultimately do away with the calcium supplements and up my dietary calcium in the form of kefir, healthy yogurts, and plant-based sources of calcium.  The health benefits of these could balance out or outweigh any health risks from increased calcium intake.

 

Interesting update on my strong response to calcium.  As noted in my previous post, I experienced a period of significant peripheral neuropathy that mostly resolved when I added high dose B12, indicating a transitory B12 deficiency.  However, I still experience minor but frequent tingling in hands and feet, which I interpreted as perhaps some residual nerve damage from the period of B12 deficiency that hadn't resolved yet.  I also experience frequent muscle twitches in the hands and sometimes the calves.  Lo and behold, these are common symptoms of calcium deficiency, and I am finding that my increased calcium intake is significantly helping.  My diet has been pretty deficient in calcium in the last few months as I have been off dairy, so I suppose a calcium deficiency would make sense.  In any even, the calcium, combined with methyl donors and potassium, have been a miracle for me.  I'm a new man at work, sharp, on the ball, more social, I could go on.  I'm hoping these gains hold.  

 

Finally, you asked if I have any other health complaints that could contribute to the mental issues I have complained about.  I do have some digestive complaints and I wonder if I don't have some inflammation of the colon/intestines or sub-clinical colitis.  This could impact my nutrient absorption and could help to explain why I appear to be prone to vitamin deficiencies.  Maybe adding kefir, pro-biotics, and some anti-inflammatory foods and supplements could help.

 

Anyway, thanks for your response, and sorry for the long reply! 

[YOLF]

Well B12 is made by bacteria in the gut, we can manipulate it as far as the methyl groups go, but if you're gut isn't stable, neither will your head be  

 

I know I'm lactose intolerant and even elevated prolactin levels might be causing me some problems from time to time, but I stay away from food coloring and basically just simplified my diet down to a few safe things and take supplements for everything else I need as that seems to be the easiest way to get the right nutrition. 

 

Digestive enzymes are also pretty good. Swanson has an nzymes product with lactase and alot of other stuff that's needed for the various types of lactose intolerance that exist and so far it works wonders for me (I've only used it twice so far, the real test is using it daily for a week or so), otherwise kefir may be of some benefit for the probiotics and nutrition it provides, but it will cause regular digestive upset depending on your intake and other factors.

oh and lactose is made in you as part of digestion, so taking lactose enzymes regularly regardless of dairy intake will help, especially if you're eating food high in galactose (also a pro aging sugar).

[YOLF]

What else is there for potassium? I'm on an intermittent fasting diet, so I mostly need things as supplements and can't cram in the calories without gaining weight. I do eat the occasional banana and raisins, but that still doesn't get near to the 100% RDI... that would take like 3k calories... lol. Supplements aren't allowed to go over 3% or 100mg or something like that, but I'm thinking there must be a chelated form that won't kill us if taken in reasonable doses... I'm seeing alot of chelated potassiums like gluconate, aspartate,   Oh and weight is another big factor for me. Being fat is being proportionally depressed and being thin is being continuously high as kite on my own neurochemistry (with or without supplements) as long as everything else is in order.

 

The MTHFR supersensitivity is catecholamine related, things like dopamine, adrenaline, serotonin, etc. Oh and maintaining a good level of physical activity is important too. That helps you maintain the supersensitivity as does Mg Threonate. 

 

Here's a list a Calciums and Potassiums that are available for reference:

Calcium -

Gluconate

Lactate (probably not for me?)

Pyruvate

 

Potassium -

Aspartate

Gluconate

 

Any others you see available? I know there are citrate forms that are good for periodic use to remove possible mineralization in the kidneys etc, but IIRC, elementals are to be avoided at reasonable doses?

[Darryl]

The current evidence is that MTHFR C677T¹ and other genetic loci² associated with elevated homocysteine do not predispose to higher risk of cardiovascular disease, and do not predispose to higher risk of dementia in Caucasians and Indians^3,4. This implies that elevated homocysteine is a coincident, but not causal, biomarker in these diseases, and is in accord with the failure of homocysteine lowering vitamin interventions to reduce cardivascular events or mortality⁵. I believe elevated homocysteine, while not causal, is a marker of high methionine^6,7 and low folate^8,9,10,11 intake, which may increase atherosclerosis independent of their effects on homocysteine, and these are the real reasons for the association. Too much animal protein, too few greens and beans.

 

1. Clarke R et al. 2012. Homocysteine and coronary heart disease: meta-analysis of MTHFR case-control studies, avoiding publication bias. PLoS medicine, 9(2), 205.

2. van Meurs JB et al. 2013. Common genetic loci influencing plasma homocysteine concentrations and their effect on risk of coronary artery disease. The American journal of clinical nutrition, 98(3), 668-676.

3. Zhang MY et al. 2010. Meta-analysis of the methylenetetrahydrofolate reductase C677T polymorphism and susceptibility to Alzheimer's disease. Neuroscience research, 68(2), 142-150.

4. Zhub XC et al. 2015. Genetics of vascular dementia: systematic review and meta-analysis. Journal of Alzheimer's disease: JAD.

5. Debreceni B & Debreceni L. 2012. Why do homocysteine-lowering B vitamin and antioxidant E vitamin supplementations appear to be ineffective in the prevention of cardiovascular diseases?. Cardiovascular therapeutics, 30(4), 227

6. Troen AM et al. 2003. The atherogenic effect of excess methionine intake. Proceedings of the National Academy of Sciences, 100(25), 15089-15094.

7. Virtanen JK et al 2006. High dietary methionine intake increases the risk of acute coronary events in middle-aged men. Nutrition, metabolism and cardiovascular diseases, 16(2), 113-120.

8. Antoniades C. et al. 2009. MTHFR 677 C>T polymorphism reveals functional importance for 5-methyltetrahydrofolate, not homocysteine, in regulation of vascular redox state and endothelial function in human atherosclerosis. Circulation, 119(18), 2507-2515.

9. Morrison HI et al. 1996. Serum folate and risk of fatal coronary heart disease. Jama, 275(24), 1893-1896.

10. Rimm EB et al. 1998. Folate and vitamin B6 from diet and supplements in relation to risk of coronary heart disease among women. Jama,279(5), 359-364.

11. Robinson K et al. 1998. Low circulating folate and vitamin B6 concentrations risk factors for stroke, peripheral vascular disease, and coronary artery disease. Circulation, 97(5), 437-443.

Edited by Darryl, 03 August 2015 - 05:54 PM.

[Darryl]

What else is there for potassium?

 

Tubers, greens, beans & nuts make it easy. Some typical serving sizes in my diet:

 

1 large (300 g) baked potato 1626 mg

1 large (300 g) baked sweet potato 1425 mg

1 cup (177 g) cooked kidney beans 717 mg

1.5 oz (42 g) pistachio nuts 428 mg

1 oz (28 g) wheat bran 335 mg

1.5 oz (42 g) almonds 302 mg

3 tbsp (30 g) flaxseed 251 mg

3 tbsp (21 g) wheat germ, toasted 227 mg

1 cup (30 g) spinach 167 mg

1 cup (16 g) kale 78 mg

[Kingsley]

The current evidence is that MTHFR C677T¹ and other genetic loci² associated with elevated homocysteine do not predispose to higher risk of cardiovascular disease, and do not predispose to higher risk of dementia in Caucasians and Indians^3,4. This implies that elevated homocysteine is a coincident, but not causal, biomarker in these diseases, and is in accord with the failure of homocysteine lowering vitamin interventions to reduce cardivascular events or mortality⁵. I believe elevated homocysteine, while not causal, is a marker of high methionine^6,7 and low folate^8,9,10,11 intake, which may increase atherosclerosis independent of their effects on homocysteine, and these are the real reasons for the association. Too much animal protein, too few greens and beans.

 

 

Interesting.  I have come across this idea before, that homocysteine itself may not be the culprit even though it is associated with various health risks.  If I understand you, you seem to be stating that low folate itself would also not be a causative factor, since the reduced activity of the C677T mutation essentially mimics low folate.  Rather, low folate would be associated with low intake of high-folate foods which reduce the risk of cardiovascular disease and dementia for reasons unrelated to their folate content?

 

So, what is it about folate-containing foods, i.e. greens, that is beneficial for cardiovascular disease and dementia prevention?  Antioxidant content / anti-inflammation?

 

Also, is methionine itself harmful or is it the other attributes of animal protein/fat that it comes along with?  Seemingly if methionine itself were harmful then the MTHFR C677T mutation could actually be protective since it results in less methionine generation from homocysteine.

 

Cardiovascular disease and dementia risks aside, would it still be sound to speculate that the C677T mutation could predispose one to issues with mood/general cognition due to reduced production of SAM-E?  I seem to remember reading studies linking the C677T mutation to increased risk of certain mental disorders.  Plus, I believe that it is pretty well accepted that low B-vitamin status or deficiency can cause issues with mood and cognition, which I would think the C677T would compound.  Sorry, I don't have time to look up the studies at the moment.

[Darryl]

What is it about folate-containing foods, i.e. greens, that is beneficial for cardiovascular disease and dementia prevention?

 

Also, is methionine itself harmful or is it the other attributes of animal protein/fat that it comes along with? 

 

would it still be sound to speculate that the C677T mutation could predispose one to issues with mood/general cognition due to reduced production of SAM-E?  I seem to remember reading studies linking the C677T mutation to increased risk of certain mental disorders.  Plus, I believe that it is pretty well accepted that low B-vitamin status or deficiency can cause issues with mood and cognition, which I would think the C677T would compound.  Sorry, I don't have time to look up the studies at the moment.

 

 

Folate inhibits NADPH oxidase (a major source of extracellular oxidative stress), quenches its most harmful by product, peroxinitrate quencher, and supports endothelial nitric oxide synthase for vascular dilation.

 

Stroes ESG et al. 2000. Folic acid reverts dysfunction of endothelial nitric oxide synthase. Circulation research, 86(11), 1129-1134.

Rezk BM et al. 2003. Tetrahydrofolate and 5-methyltetrahydrofolate are folates with high antioxidant activity. Identification of the antioxidant pharmacophore. FEBS letters, 555(3), 601-605.

Tawakol A et al. 2005. High-dose folic acid acutely improves coronary vasodilator function in patients with coronary artery disease. Journal of the American College of Cardiology, 45(10), 1580-1584.

Moens AL et al. 2008. High-dose folic acid pretreatment blunts cardiac dysfunction during ischemia coupled to maintenance of high-energy phosphates and reduces postreperfusion injury. Circulation, 117(14), 1810-1819.

Tian R & Ingwall JS. 2008. How does folic acid cure heart attacks?.Circulation, 117(14), 1772-1774.

McCarty MF et al. 2009. High-dose folate and dietary purines promote scavenging of peroxynitrite-derived radicals–clinical potential in inflammatory disorders. Medical hypotheses, 73(5), 824-834.

Cagnacci A. et al. 2009. High-dose short-term folate administration modifies ambulatory blood pressure in postmenopausal women. A placebo-controlled study. European journal of clinical nutrition, 63(10), 1266-1268.

Hwang SY et al. 2011. Folic acid supplementation inhibits NADPH oxidase-mediated superoxide anion production in the kidney. American Journal of Physiology-Renal Physiology,300(1), F189-F198.

Gao L et al. 2012. Role of uncoupled endothelial nitric oxide synthase in abdominal aortic aneurysm formation: treatment with folic acid.Hypertension, 59(1), 158-166.

Huo Y et al. 2015. Efficacy of folic acid therapy in primary prevention of stroke among adults with hypertension in China: the CSPPT randomized clinical trial. JAMA,313(13), 1325-1335.

 

The last study was stratified by MTHFR C677T genotype: folic acid benefited everyone and no significant difference by genotype was found. Overall, I think the results are impressive enough that I'd consider asking a doctor for a leukovorin Rx for an autoinjector, if I was at high risk for heart attack or stroke.

 

 

In Troen AM et al. 2003 (cited above), high methionine intake was sufficient to induce vascular pathology in mice, even when when the diet was replete with B-vitamins and homocysteine was low. There's a body of evidence from methionine restriction and supplementation experiments that excess methionine intake may suppress UCP1, decrease uncoupled respiration and endogenous H₂S production, and increase ROS production at mitochondrial complex I. My comment here looks at methionine restriction studies, but it coheres with the supplementation studies:

 

 

Yalçınkaya S et al. 2007. Methionine-supplemented diet augments hepatotoxicity and prooxidant status in chronically ethanol-treated rats. Experimental and Toxicologic Pathology, 58(6), 455-459.

Park CM et al. 2008. Methionine supplementation accelerates oxidative stress and NF-κB activation in livers of C57BL/6 mice. Journal of medicinal food, 11(4), 667-674.

Gomez J et al. 2009. Effect of methionine dietary supplementation on mitochondrial oxygen radical generation and oxidative DNA damage in rat liver and heart.Journal of bioenergetics and biomembranes, 41(3), 309-321.

Yalçınkaya, S et al. 2009. Oxidative and nitrosative stress and apoptosis in the liver of rats fed on high methionine diet: protective effect of taurine. Nutrition, 25(4), 436-444.

Yalçinkaya S et al. 2009. Effects of high methionine diet on oxidative stress in serum, apo-B containing lipoproteins, heart, and aorta in rabbits. Annals of Clinical & Laboratory Science, 39(4), 386-391.

Zulli A & Hare DL. 2009. High dietary methionine plus cholesterol stimulates early atherosclerosis and late fibrous cap development which is associated with a decrease in GRP78 positive plaque cells. International journal of experimental pathology, 90(3), 311-320.

Aissa AF et al. 2013. Methionine concentration in the diet has a tissue-specific effect on chromosomal stability in female mice. Food and Chemical Toxicology, 62, 456-462.

 

Some studies found an association of C677T with mood disorders, and others none. I'd love to see a meta-analysis along the lines of Zhang MY et al. 2010 which included results from unpublished studies, as publication bias had a huge influence on early Mendelian randomization studies, but to date, there's nothing comparable.

 

Dempster EL et al. 2007. No evidence of association between a functional polymorphism in the MTHFR gene and childhood-onset mood disorders.Molecular psychiatry, 12(12), 1063-1064.

Schiepers OJ. et al. 2011. Genetic variation in folate metabolism is not associated with cognitive functioning or mood in healthy adults. Progress in Neuro-Psychopharmacology and Biological Psychiatry, 35(7), 1682-1688.

[Kingsley]

Thank you.  Very educational.

 

 

 

The last study was stratified by MTHFR C677T genotype: folic acid benefited everyone and no significant difference by genotype was found. Overall, I think the results are impressive enough that I'd consider asking a doctor for a leukovorin Rx for an autoinjector, if I was at high risk for heart attack or stroke.

 

 

 

It looks like the studies you cite are based on the benefits of high dose folic acid supplementation, and I'll take your word that no significant difference by genotype was found.  This makes sense; a person with the C677T genotype would still benefit from folic acid supplementation.  I would wonder, though, if the C677T genotype could take on significance in lower-folate populations outside of supplementation.  To the extent that the folate benefits in the studies you cite require conversion to methylfolate (which I understand they do for the most part), it would seem to follow that someone homozygous for C677T who is already low in folate would be exposed to additional risks due to their significantly lower production of methylfolate, or would require higher supplementation to get the full benefit.  I'd be curious if there has been a study of the mutation in low-folate populations specifically. 

 

In any event, I've always suspected that this idea that you hear about from some of the more quackish methylation "authorities" out there that C677T mutants must avoid folic acid at all costs and don't benefit from it is, well, quackery, and at least the one study you reference seems to support this.  What about the argument that folic acid can build up in the blood of C677T mutants due to the bottle-neck and cause problems, i.e. increased cancer risk?  You don't have to answer, it's another argument I've heard that I suspect is overblown.     

 

Anyway, I have found b-vitamins, including methylfolate, to be an important piece of the puzzle, along with other supplements, in addressing some long-standing health complaints and clearing up brain fog, regardless of the role that my C677T mutation may play.  Perhaps my diet was deficient, perhaps I have absorption problems, who knows, but I have experienced marked benefits.  Placebo is always a possibility but I'm skeptical of that in my case.    

[Kingsley]

Well B12 is made by bacteria in the gut, we can manipulate it as far as the methyl groups go, but if you're gut isn't stable, neither will your head be

 

I know I'm lactose intolerant and even elevated prolactin levels might be causing me some problems from time to time, but I stay away from food coloring and basically just simplified my diet down to a few safe things and take supplements for everything else I need as that seems to be the easiest way to get the right nutrition. 

 

Digestive enzymes are also pretty good. Swanson has an nzymes product with lactase and alot of other stuff that's needed for the various types of lactose intolerance that exist and so far it works wonders for me (I've only used it twice so far, the real test is using it daily for a week or so), otherwise kefir may be of some benefit for the probiotics and nutrition it provides, but it will cause regular digestive upset depending on your intake and other factors.

oh and lactose is made in you as part of digestion, so taking lactose enzymes regularly regardless of dairy intake will help, especially if you're eating food high in galactose (also a pro aging sugar).

 

Yes, I suspect that I have some gut issues which I need to address.

 

As for kefir, one study I saw concluded that it actually helps lactose intolerance and improves digestive upset.  I can't post the link for some reason; the study is from 2003 and is entitled "Kefir improves lactose digestion and tolerance in adults with lactose maldigestion."  Plus, you can buy lactose-free kefir. 

 

As for the calcium and potassium supplements, I don't have much to add based on my brief research.  As I said, I find V-8 Low Sodium to be a quick and easy way to supplement potassium, though I know you had some concerns about it.  Darryl suggested some good food-sources of potassium, though I find it uniquely difficult to get enough potassium through diet alone because I have so little time to prepare really healthy, whole meals.

[Kingsley]

 

 

Schiepers OJ. et al. 2011. Genetic variation in folate metabolism is not associated with cognitive functioning or mood in healthy adults. Progress in Neuro-Psychopharmacology and Biological Psychiatry, 35(7), 1682-1688.

 

 

I dug into this study a little bit.  The authors note that the homozygous C677T mutation has actually been associated with some benefits, including reduced risk of colorectal cancer.  They also note that one of their studies actually showed a cognitive benefit in aging subjects, though this would have to be counterbalanced against other studies showing no effect or a detrimental effect.  Still, the reduced colorectal cancer risk seems to be genuine (showed up in another 2010 study that I can't link).  Apparently non-methylated folates play a role in DNA synthesis and repair.  I had no idea!  So much to learn. 

 

More reason to disregard all the BS out there recommending that C677T people totally replace folic acid with methylfolate. 

Edited by Kingsley, 04 August 2015 - 03:41 PM.