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The importance of MTHFR, methylation, & B vitamins: Eat leafy green veggies!

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Altostrata

ADMIN NOTE Also see

 

Genetic testing: "Personalized medicine," liver enzymes, genotypes, GeneSightRx, Genomind, etc.

 

Vitamin B3 (niacin, niacinamide)

 

Folic acid, folate, L-methylfolate, and Deplin (vitamin B9)

 

Vitamin B12 -- essential for mood, nervous system

 

Skip to information post:

 


 

There is a test that checks for the MTHFR gene mutation causing poor absorption of ordinary folate.

 

The MTHFR mutation (there are several variations) is associated with a number of health conditions other than psychiatric, see http://ghr.nlm.nih.gov/gene/MTHFR and may also cause vitamin B12 deficiency http://ajpheart.physiology.org/content/293/1/H860.full

 

Taking a folate supplement in the form of L-Methylfolate and sublingual B12 or shots alleviates the risk caused by an MTHFR mutation.

 

There are many manufacturers offering L-Methylfolate supplements. An early one was called Metafolin. They are somewhat more expensive than ordinary folate supplements, which are very cheap.

 

Recently, psychiatry jumped on the L-Methylfolate bandwagon with a study paid for by the manufacturer of Deplin, another L-Methylfolate supplement (topic here). The authors trumpeted improvement in their patients as a huge success, when they should have been deeply ashamed of misdiagnosing and treating them with antidepressants rather than L-Methylfolate for years.

 

This paper caused a fad among doctors of prescribing exorbitantly overpriced brand-name Deplin L-Methylfolate for depression.

 

However, in my opinion, this is another reprehensible example of psychiatry mistaking a medical condition for a psychiatric condition. Depression may be a symptom of low folate or vitamin B12; this condition does not deserve a psychiatric diagnosis. Everyone with "depression" should first be tested for deficiencies of this sort and recommended the appropriate supplements rather than psychiatric drugs.

 

Edited by ChessieCat
Added admin note/cc fixed link to info post

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Christiana

Just thinking out loud here and offering up some food for thought...

 

Does anyone here have or ever been tested for:

 

Pyroluria/HPU/KPU (they kind of go together to form a hemoglobin synthesis defect for some)

MTHFR (a methylation cycle defect for some)

 

From my understanding, if someone has one or more of these conditions, then it can affect the way your body reacts to what you ingest or are exposed to.  I'm just now beginning to learn more about these things and the tests involved.

 

Rich Van Koneynenberg Ph.d, Dr. Amy Yasko, and Dr. Dietrich Klinghardt have websites that talk about these things.  A quick Google search will bring up lots of links to a lot more info.

 

One test, which can be done, is through 23andme at http://www.23andme.com.  From my understanding, it can indicate whether or not someone is inclined to have problems taking SSRI medications, ingesting sulphur, etc., etc.

 

As I said, I'm just learning about all of these things and finding it quite interesting.  So, if you have any thoughts about any of them, please let me know.  There is plenty of info on the internet to learn about them.  There are even plenty of YouTube videos to watch, so that they can be understood better.

Edited by Altostrata
removed admin note

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Barbarannamated

Christiana,

 

I am positive for the MTHFR genetic mutation though I don't know which one.

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Altostrata

I have two MTHFR mutations. This affects how one processes folate. The fix is to take a special kind of folate. It's no big deal.

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Francis

I am homozygous for the A1298C MTHFR mutation.  Ive read that that is somehow different from the other type of mutation (C677T) and possibly more linked to ammonia detox... and not as much to do with folate.  I havent been able to make any sense of that.  

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Christiana

Thank you all for replying.  Sorry for my absence, as I've been feeling really rotten.

 

I'm trying to learn more about this.  I think it is more of a problem for some, whereas not such a big deal for others, depending on where the mutations are.

 

I plan to get tested soon, if I can.  I'll post, if I find out more.

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Altostrata

About 40% of the general population carries a genetic variation that might affect methylation. Dr. Kelly Brogan explains the importance of methylation in the article below. (I don't know why this is directed towards women. Men also have MTHFR mutations and may benefit from methylfolate supplementation.)

 

Methylation is necessary for B vitamin metabolism, and B vitamin metabolism is necessary for neurological health and maintenance.

 

Aside from genetic variations, if you're taking any of these, they can interfere with methylation and important B vitamin absorption:

  • metformin
  • oral contraceptives,
  • lamotrigine
  • Antacids and stomach acid blockers (PPI)
  • Folic acid supplements (found in multivitamins and enriched foods)

Low thyroid hormone (hypothyroidism) may also interfere with methylation.

 

These can improve methylation:

  • FOLATE NOT FOLIC ACID, specifically L-methylfolate supplements (Quatrefolic or Metafolin)*
  • B12 in the form of methylcobalamin*
  • vitamins B2, B3, B6*
  • trimethylglycine
  • vitamin C

*CAUTION For people with sensitized nervous systems, the B vitamins, including L-methylfolate, may be activating. this article suggests "if you do have an adverse reaction to methylfolate (agitation, increased anxiety, headache), you can take nicotinic acid or niacinamide in 50mg dosages every 30 minutes until you experience relief." I have no idea if this works. I would start with a very small amount of L-methylfolate in the morning, gradually increasing the dosage, and perhaps take niacinamide in the evening in case any activation is underway.

 

http://www.greenmedinfo.com/blog/methylwho-why-you-should-know-about-methylation
 
Methylwho? Why You Should Know About Methylation

Wednesday, December 25th 2013 at 11:00 am
Dr. Kelly Brogan, M.D.

I was giving a lecture to a group of psychiatric fellows recently, and I got to my slide on folate.  I get excited about this topic, and so I rambled on about the one-carbon cycle, and SAMe, methylcobalamin, and the MTHFR mutation.  As I looked away from my slides, I could see the vacant stares from the near-audience and knew I had lost them.  If highly educated and trained physicians don't know about this, it may be safe to assume that the average woman with mental illness may not either.  This article will serve as a boarding call for anyone not on the methylation-train.

Here's the deal:  there are a number of processes in the body that, when compromised, broken, or otherwise dysfunctional can manifest as fatigue, worry, insomnia, low mood, poor concentration and attention, agitation, a trip to your psychiatrist, and a stop off at the pharmacy.

What if you could manage this particular problem without a psychiatrist?  When I consider symptoms of psychiatric illness, I think gut, hormones, mitochondria, and methylation.  These arenas are so intimately inter-connected, that it rarely makes sense to look at one without the other, and it never makes sense (to me, anymore) to think about invented neurochemical imbalances before addressing these bedrock issues.

When you eat folate, or B9, in foods like spinach, or you take a multivitamin or eat flour "enriched" with the much-lauded folic acid, your body has to convert that into a usable form.  This process requires an enzyme called MTHFR (5,10-methylenetetrahydrofolate reductase) to convert folic acid and food folate into 5-methylenetetrahydrofolate.  Here's what this form of folate does:

  • Donates a methyl group to homocysteine to ultimately make SAMe – the brain's major methyl donor which is responsible for the formation of phospholipids, glutathione, myelin, coenzyme q10, carnitine, and creatine.  Vital stuff.
  • Synthesizes BH4 or biopterin, a major cofactor for neurotransmitter synthesis.
  • Synthesizes DNA and tRNA.
  • Recycles the inflammatory amino acid, homocysteine.
  • Builds red and white blood cells, and platelets.

Methyl-folate is pretty busy. It doesn't work alone; however. Vitamins B2, B6, and B12 as well as cofactors like magnesium all help support the functioning of this pivotal cycle in the body.

Maybe She's Born With It
MTHFR is just one example of a gene for which we can test for decently studied variants at a local lab. There are two common variants to this gene wherein replacements of single nucleotides results in lesser functioning.  These variants are inherited.

C677T – one bad copy means your enzyme is functioning at 70% and two means you're down to 30%.  This mutation has been associated with cardiovascular and psychiatric pathology and its impact is often assessed through screening of homocysteine.

And...
A1298C – this variant has been less well studied but is estimated to confer 70% functioning when both copies are mutated.  This mutation has been implicated in the production of neurotransmitters (because of its involvement in making biopterin, and important cofactor), and breakdown of ammonia.

Predicated on associations of low folate to depression incidence and treatment resistance, this review discusses the evidence-based association between MTHFR C677T and depression, schizophrenia, and bipolar, but only included one study on 1298.

Estimates of prevalence for these variants range by ethnicity from 2-20%, but in my practice, over 5 years of testing for this gene, only 3 patients have been mutation-free.

Given the prevalence of thyroid dysfunction in women, it is worth noting that active thyroid hormone is needed to support MTHFR function, so women with hypothyroidism may bring an additional handicap to this process.  Thyroxine regulates conversion of riboflavin, a necessary co-factor for the FAD, an MTHFR-stabilizing enzyme.

Alcohol and yeast overgrowth also produce acetylaldehyde which functionally interferes with a related enzyme MTR, which allows activated folate to enter this one-carbon cycle.

Brain access to activated folate may be dramatically improved by non-synthetic forms as demonstrated in this case report of reversal of paraplegia with folinic acid. Even cow dairy can cause increase in folate receptor antibodies which functionally interfere with cerebral access to folate.

There are also a number of medications that interfere with folate metabolism including metformin, oral contraceptives, and lamotrigineAntacids can alter the stomach conditions needed for B12, a vital cofactor for the one-carbon cycle.
....

The Good News
....Methyl-folate (or 5MTHF) is a form of this critical B vitamin that can be taken, over the counter, in an effort to bypass any gene mutations. Different forms of activated B12 (hydroxy, methyl, and adenosylcobalamin) are typically essential players in treatment with methylfolate, as well.
 
There have been at least 5 studies (3 randomized, controlled trials) looking at using methylfolate as a treatment for depression, either by itself or in addition to medication.  Most of these trials employed high doses (up to 50mg) of methylfolate and had partial to notable response rates. 

Need to Know For Pregnancy
When I first started testing for this variant (now available at commercial labs like Quest and typically covered by insurance), I noted that obstetricians in the city would also test patients, but only after 3 miscarriages.

 

Methylation problems such as those caused by this variant and other related variants can cause neural tube defects, increased risk for trisomy, heart defects, and now expanding to schizophrenia and autism.  In many ways, thoughtful and conservative supplementation with methylation support is in the best interest of mom's mood and baby, and is top of my list for perinatal interventions, supported by papers such as this.

One study looked at folic acid supplementation in the women with the C677 mutation and found that there was a decreased incidence of postpartum depression by 21 months after birth.  An interesting study in pregnant patients found an increased incidence of depressed mood in the second trimester in women with the C677TT variant, and that both their and their infant's serotonin transporters were methylated or expressed in ways that could conceivably affect behavior.

Folic Acid is Not Methylfolate
Synthetic folic acid does not exist in the human body.  It is found in vitamins, and thanks to the FDA's wisdom, in enriched flour-based foods (yet another reason to shun flour!).  Multiple enzymatic steps are necessary to convert folic acid into its active form beginning with dihydrofolate reductase in the gut. 

 

Individuals with gene variants, but specifically homozygous C677 should avoid folic acid because of the concern for limited breakdown and subsequent accumulation of this man-made agent.  One study has implicated folic acid in suppression of important immune factors called natural killer cells. Folic acid binds more readily to receptors in the placenta and mammary epithelium, and may competitively inhibit or interfere with the functionv of usable, active folate. Currently, commercial testing of blood folate does not distinguish between metabolized and unmetabolized forms. There is also concern that folic acid supplementation can mask B12 deficiency by resolving the typical blood markers while methylfolate is not as likely to do this (although concurrent B12 supplementation is recommended).

 

Dr. Ben Lynch of MTHFR.net, a tireless researcher on all things related to nutrigenomics, goes as far as to claim that folic acid should not be taken by any pregnant or nursing woman. He suggests that use of folic acid may be disturbing the forces of natural selection:
 

"Since women are now supplementing with increased levels of folic acid, they are more likely to carry to term and have improved methylation; however, once the infant is out of the enriched folic acid womb, it is on its own unless the parents supplement the infant with additional folate, b12 and other methylation support nutrients such as choline, b2 and b6."

 

Why there have never been folic acid vs methylfolate studies in pregnancy and in depression in the general population is unclear.

What's a Girl to Do?
First, get tested.

 

Then, depending on your degree of compromise, you'll want to look for a for a supplement that has says L-methylfolate in the ingredients, with the word Quatrefolic or Metafolin.  Starting with B12 in the form of methylcobalamin, and then introducing small doses of methylfolate and cofactors such as B2, B3, B6, trimethylglycine, and vitamin C is advocated for by Dr. Ben Lynch.  He discusses different products here and points out how unnecessarily riddled with toxic additives the prescription forms are.

 

He also discusses that, if you do have an adverse reaction to methylfolate (agitation, increased anxiety, headache), you can take nicotinic acid or niacinamide in 50mg dosages every 30 minutes until you experience relief.  B3 requires SAMe for its metabolism, and can thereby contribute to a drop in methylation.  It is also a cofactor for COMT, an enzyme that breaks down norepinephrine, epinephrine, and estrogen, all potentially elevated in states of anxiety.

 

It hopefully goes without saying that oxidative stress from environmental pollutants, food allergens, poor sleep, and limited relaxation all increase the demand to the corrective efforts of methylation.  A clean diet, home, body, and mind are a part of this package. ....

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Meimeiquest

I believe it is written that way because her practice (except for people getting off meds) is limited to women and her specialty is perinatal psychiatry.

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Altostrata

Perinatal psychiatry? A scary thought.

 

Dr. Brogan's article implies that the type of folate in broccoli, for example, is undesirable. Not so, according to Chris Kressser http://chriskresser.com/folate-vs-folic-acid

 

The type of folate in good-quality fresh vegetables is equivalent to the 5-MTHF or Metafolin supplement type of folate.

 

People with MTHFR variations have trouble metabolizing the kind of synthetic folic acid that is added to multivitamins and baked goods. Kresser suggests this unmetabolized folic acid is actually dangerous to health.

Edited by Altostrata
changed folate to folic acid

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Meimeiquest

Like post-partum depression, or if you wanted to get off a med to get pregnant, works a lot with thyroid because that often comes up post-partum...I think. She does not prescribe ADs at all, unless a pt. already on wants to stay on.

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Meimeiquest

It seems like Kessler is talking about normal folic acid metabolism and she's talking about abnormal? I don't see her saying those foods are bad, just that the body with abnormal methylation capacity can't utilize the folic acid in them?

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Altostrata

Right, people with the MTHFR variations cannot metabolize folic acid, they need folate, which is the natural form.

This is estimated to be about 40% of the general population.

I think Kelly Brogan knows this, but this sentence is unclear as it implies folate = folic acid:
 

When you eat folate, or B9, in foods like spinach, or you take a multivitamin or eat flour "enriched" with the much-lauded folic acid, your body has to convert that into a usable form.

 

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Meimeiquest

Or is it that the problem makes it difficult to convert folate to methyl folate? Trying to decide if I need to spend the $$ for the test.

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Altostrata

The tests can be ordered by an MD; insurance should cover them.

 

I've found I'm hypersensitive to Metafolin and methylcobalamin -- they'll keep me awake.

 

Here are health consultants who make it explicit that people with MTHFR variations can compensate by eating green leafies:

http://www.gbhealthwatch.com/HotTopic-Green-Folate-MTHFR.php

On the other hand, Ben Lynch says dietary folate is no help:

http://mthfr.net/can-a-homozygous-mthfr-gene-mutation-can-be-managed-by-diet-alone/2011/09/28/

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Meimeiquest

Thank you! You never cease to amaze me, Alto!

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Meimeiquest

Opinions on 23and me? If I understand correctly, they only give ancestral and raw data now? Thinking about MTHFR. My parents both have (different) symptoms.

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Altostrata

Ben Lynch clarification regarding folate in veggies http://mthfr.net/methylfolate-side-effects/2012/03/01/#comment-40944

 

January 12, 2014 at 3:34 am

 

Hello -

If you eat uncooked leafy greens daily, that may be enough support – especially if you reduce your environmental exposures, eat well and sleep well.

 

....You may take creatine and some phosphatidylcholine complex to support methylation – also Glycine helps. Taking these during the day is important – not in the evening.

 

If you have difficulty sleeping, consider taking 1/2 tablet of Niacin along with 1 capsule of GABA prior to sleeping.

 

 

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Altostrata

I am heterozygous for the 677T and 1298C MTHFR variants.

 

This is only a partial block to methylation.

 

Regular MDs can order an MTHFR test, it is often covered by insurance. 23andme is not. There has been some question recently about the accuracy of these popularly available results http://www.nytimes.com/2013/12/31/science/i-had-my-dna-picture-taken-with-varying-results.html

 

It may be cheaper just to take the methylated folate and B12.

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Meimeiquest

I am obviously on an anxiety run here, and my brain is over-linking. I may have had a hefty lead exposure as a child when my parents tore apart and remodeled their circa 1940's kitchen. One of the MTHFR variants impedes heavy metal clearance. A sister goes to a very expensive functional doc; she was supposedly full of heavy metal. I started methylfolate and it seemed to cause nausea (who knows, I have had runs of mild nausea or worse for over a year). So I cut the dose. On 12/26, I increased the dose and a few hours later started severe nausea. Took no more. Have been anxious ever since. I am just afraid taking the supplement will pull out more toxins than I can handle with only my anxious brain to manage it. Also having headaches and upper back pain off and on.

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Altostrata

From what I'm reading, there's a lot of variation in the appropriate dose of methyl folate etc. for each individual. It may be a very small amount is just right for you, meimei.

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Meimeiquest

I don't know what is going to happen next, but this is amazing. First, I have tried niacin before for general WD, to no avail. My last dose of methylfolate was December 26. I have just been getting more and more anxious. Thur. the pdoc was almost begging me to add Klonopin to the oxazepam, she accurately said I radiated anxiety. So a couple of hours ago I took some niacin without expectation...in less than an hour my mind was calm. I have been to the brink so many times, but I am sustained. Thanks again, Alto!

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Altostrata

Uh...you're welcome.

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GiaK

I just had a methylation profile done...I'm all whacked and can't take any of the recommended supplements to correct the whack. 

 

Chris Kresser is my doctor on this one and he's on a book tour so I don't have an appt to talk to him about alternate ways of dealing with the whack until March 27   :(

 

and just FYI...I'm highly reactiive to niacin as well...as all the other suggested supplements...it's a problem. 

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Meimeiquest

What testing did you have done, what company? I am trying to develop a plan since I can't afford a no-insurance doctor. I have had to repeat the niacin several times, but my sudden improvement is still holding. My urine smells like I'm on antibiotics.

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Meimeiquest

Gia, did your testing show how "sick" your system is or just the genes? I'm wishing for a "lots of green smoothies" solution.

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Altostrata

Sounds like it's liver for us all!

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GiaK

I didn't do a gene test Meimeiquest...I'm not fond of gene tests...

 

the methylation profile shows how you process methylators and levels of them etc...

 

this is the one I had done:

 

Lab: Doctor's Data • Methylation Profile; plasma (Not available in NYS)   http://www.seekinghealth.com/methylation-profile-doctors-data.html
 
for those interested in getting labwork that they don't have doctors for there is a franchise lab now that will do ANY lab test you want...it's called...you ready??
 
 
they have a doctor on staff who will order anything you want. The one in my town is run by nice people too, in spite of the fact that i was wondering how it could be legal...still I do believe it's our right to have labs when we want them!!

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JanCarol

Sigh.  None of these "borderline" tests for me.  I don't know how I could get this information.  I have a choice:  mainstream tests with GP doc.  Or whacky weird tests with naturopaths.  And I haven't found one of those who are credible to me.

 

Australia.  The Nanny State.  "We'll tell you what's good for you."  (and most of the time it's okay, Aussies are a healthy lot of people.  But in these fringe sorts of things . . . . )

 

* * *

OMG:  Insight.  I've been wobbly for about a week and a half.  Crying in karate class, getting super sentimental over stupid stuff.  Feeling that old Black Dog pulling on my sleeve.  And what has changed in the past month besides a normal taper?  

 

I've been put on gluten free diet to see if it is the cause of my intestinal distress.  I do take a multivitamin, along with B12 and folic acid.  But B vitamins are easy to get out of complex carbs - and gluten free is worse than white bread.  No nutrition, no fibre.  And likely:  no B vitamins.....

 

This may be slightly off topic, but the insight was caused by reading your methylation experiences.  And while I still don't understand the methlyation thing, and can only find out if I'm "one of those people" by maybe getting a test done next time I'm travelling in the States (geez, bummer), or by trial and error.  I do get that this change in diet could've really mucked up my mood.

 

Also:  my terminal question:  What about people with NO THYROID.  Mine was removed.  I'm on Synthroid.  I can never find out how to supplement for that.  If I up my Synthroid, will that enhance my B vitamin absorption?  Very confusing.  What is the effect of iodine, if I have no thyroid?  (kind of a side question, but okay).

 

Thanks Alto for another stimulating journey.

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Altostrata

There are doctors who specialize in treating unusual thyroid conditions. You might have to hunt for one.

 

The MTHFR tests are well-recognized. Cardiologists and ob/gyns might order them. This might be covered even in Australia.

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cmusic

May I ask about the importance of this in recovery?  I was hetero - in the 70% category - for both genes.  Compound hetero.  This all started for me when a psychiatrist recommended deplin a long time ago.  Did the test at a holistic place.  But there was nothing to do except take supplements which didn't do anything at that time.

 

Since then I've gone through a severe cold turkey withdrawal and all the physical symptoms started.  I am now most likely in the category with GiaK where I won't be able to tolerate the very B vitamins and methylfolate I would need to help with this.  Has anyone figured out something we can do when supplements are too potent?  I also don't know how I would interpret the results of any kind of functional testing on this or where I would go to find a doctor that could help with this sort of thing.

 

Struggling a ton, still, wondering if this is contributing to not getting better.  Would a person have to fix this to heal from withdrawal?  Thanks.

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Meimeiquest

Oops, didn't get the link. You can google "understand COMT and change your life."

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cmusic

Thanks.  Never heard of COMT but is it 'treated' in the same way?

 

The issue is I have severe agitation when I try to take any of the active methylfolate or methyl b12 supplements.  I make smoothies out of spinach or kale every morning but not sure that works if your body has an issue converting natural folate.  So I have sort of resigned to just not doing anything about this other than eating as healthy as I can.  But having seen this thread I'm worried again about this whole topic.  It seems like uncharted waters - and I have never had any success measuring cause and effect with any of this stuff so trial and error is hard for me.

 

Anyway what does someone do who can't take the supplements?

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Meimeiquest

Well, this just blew up for me 8 days ago, so I don't know a lot. I took methyl folate on my own, and half a tablet three times a day seemed to make me nauseated, so I cut to a fourth. I was getting worse, but did not associate.

 

On Dec. 26. I decided I was ready for 1/2, took once, became very nauseated. Did not take any more. Increasing anxiety...by last Sunday had reached match of highest ever. Read the first article, took "antidote" of niacin with zero expectations. Within 45 min. my brain was calm. Normal withdrawal anxiety came back the next day, niacin doesn't help.

 

Someone posted on the MTHFR.net FB page that they learned the extreme anxiety they had after methyl folate was due to another mutation that affects catecholamines. That MIGHT be CORT, I am just fishing around. But my manias have been associated with ADs that affect catecholamines, so I am hoping that the code has been cracked for me.

 

Have you read Eat to Live? He believes extreme nutrition can overcome metabolic genetic errors, so that's what I am trying to do. I want to get to a pint of juice twice daily, but right now a cup twice daily seems to get quite a reaction. And I just feel "different" when I eat (gag) liver so I assume it is helping.

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Meimeiquest

Ok, this is probably silliness, but some say a lot of raw spinach, kale, and some other greens can adversely affect the thyroid. Overall, you might get even more benefit from a variety of veggies. I think (not sure) that when the enzyme system is inefficient, hitting it hard with a lot of the target nutrient will push it through. BUT not sure at all. There is a particular need to avoid folic acid and enriched flour. I think we both have a need for more money to see a dr. with a clue!

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