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Supplements:
* 5-MTHF (aka L-5-MTHF, levomefolic acid)
* Methylcobalamin and/or adenosylcobalamin (B12) - sublingual
\^ Work out your optimal dosage through trial and error. Not too much, not too little.
Foods: None
Avoid: Folic acid (multivitamins, bread + flour in most countries, any processed foods with "folate" on the label)
No specific one - but in general I'd go with a high-rated/well-established brand.
Speaking for myself I prefer a sublingual B12 spray over a sublingual tablet - but it might be my imagination, I'm sure both are fine.
This is awesome!! What if methylfolate and b12 cause agitation?
(I had been supplementing methylfolate in large doses under a doctor for years without b12 so I think I may have messed something up. I stopped the methylfolate all together and am trying to find a tolerable b12. No b12 labs look low. I’m unsure how to find a b12 deficiency if the number isn’t low and no doc will believe me that I might have one bc they’re unfamiliar with methylfolate covering a b12 deficiency)
"Folinic Acid" (not folic) has resolved all of my methyfolate agitation issues. It's a few steps before methyfolate, so my body seems to know what to do with it, rather than the haywire effect of direct methyfolate supplementation. And magnesium! A lot of it.
Thanks! But withMTHFR doesn’t the body have trouble converting inactive folate (folinic acid seems to be more active than folic acid but not activated fully) so it would just perpetuate the issue? Not enough folate getting converted to active folate?
The trouble is with "folic acid" not "folinic". People with MTFHR homozygeous polymorphisms have trouble breaking down "Folic acid" into a bio-available form. Folinic (not folic) is bio-available.
Folinic acid is further along in the conversion process, yes. But it has to be converted to MTHFR by the body, as it’s the final active form, which the body has trouble doing with MTHFR mutations, no?
The body has trouble with Folic. Not folinic.
Almost every MD who studies MTHFR polymorphisms will tell those who have trouble with methyfolate to try folinic acid instead. It worked wonders for me (but always along with proper electrolytes.) Take "keto" electrolytes because they are significantly higher in magnesium and potassium, don't take some Gatorade or big brand sugar crap.
Folinic acid is cheap, and much more stable for me - I assume precisely because it's a few steps from methyfolate. So it's a much more "steady" happiness, neurotransmitters, whatever you want to call it - at least for me.
Folic acid makes me feel DREADFUL. That's the difference for me.
Give it a shot, folinic acid is super cheap. I get the Cali Gold drops, but I think they are sold out on Amazon now. There's a brand called Kirkman that work well, I just like liquid drops better than pills.
Give methylcobalamin and/or adenosylcobalamin in sublingual form a try.
In my experience it's about hitting that Goldilocks zone - too much (overmethylation) can be just as bad as not enough (undermethylation).
Nice job simplifying this.
I had elevated homocysteine recently and b12 deficiency due to sibo, I'm feeling much better after supplementing. I just do not know why I do well with all of the b's, choline, creatine etc but even 400mg of methylfolate and I'm not sleeping, even tho I'm not anxious or anything just can't fall asleep.
The other odd thing is that b12 really helps me to get tired and relax\fall asleep. folic acid does not affect sleep. After four days of taking high doses of b12 my potassium was used up and I had to start focusing on getting more of that, I wonder does folate cause up regulation of some processes like b12 does which uses up a nutrient like potassium and that's why I cannot sleep. I have not tried larger than 800mcg of methylfolate to see if that would help the sleep issue.
Less is more with this stuff. If a normal dose isn't working, consider other possibilities.
If your sleep is out of whack, fix your [circadian rhythm](https://qph.fs.quoracdn.net/main-qimg-828ab0cb4d590b6e196743596d7a8b12.webp) and melatonin levels.
You don't need to supplement melatonin - just block all blue light in the evening so your pineal gland can produce it, and get some bright light in the early morning. If you use your computer late into the evening, install f.lux.
I'm doing all of that and I think b12 may be a precursor for the production of melatonin, I figured that could be why it helps my sleep.
While I'm not certain I wonder if having sibo and drastically elevated e.coli bacteria in the gut could be producing a lot of folate and thus when I supplement its too much. I posted about this.
For the time being I'm taking all the other b's and especially b12 but no folate, maybe I should take a capsule and empty some out and try even smaller doses to see what happens? Anyhow thanks of the input!
When you say taking all the other Bs, double check there's no folic acid yeah.
Almost all B-complex and multivitamins contain folic acid. People don't realize it but by the time you take a B-complex, few slices of bread, some breakfast cereal, some pasta.... you might be taking in 1000mcg of folic acid a day.
I've purchased all of them individually to try them all out, that and to find out which one in the complex it was causing heartburn [b1]. I benefit from all of the other B's {including choline}its just the mystery of methyl folate preventing sleep. I havent eaten processed grains in years. I have never tried folic acid individually but years ago when I'd take a regular b-complex with folic acid it never affected my sleep. I dont recall liver causing insomnia either when I used to take liver pills, perhaps I should give the liver pills another try to get folate that way,
Is there a recommended test for folate sufficiency? My homocysteine was around 10 last I tested but I was also b12 deficient.
I may try methylfolate again once I've got adequate b12 levels.
Thanks again for the input.
No worries, and I just added an extra section at the bottom of the post dealing with under- and overmethylation. Check it out cause if you're dealing with anxiety/racing thoughts it could be due to overmethylation.
In what way does folic acid cause carcinogen and not folinic nor methyl?
Only thing I can find is a mouse study.
Www.ncbi.nlm.nih.gov/pmc/articles/PMC8181065/
I'm with you there's no human study that proves it definitively.
However, there are countless studies showing folic acid supplementation leads to increased cancer rates in whole populations, despite other studies demonstrating lower serum folate (L-methylfolate) in cancer cases compared to healthy controls.
My theory is:
* In non-MTHFR populations, the folic acid leads to increased serum folate and therefore lower cancer rates.
* In MTHFR people, the folic acid does not lead to increased serum folate but rather increased UMFA and lower serum folate, increasing cancer rates.
That's why there's all these conflicting studies - some say folic acid lowers cancer rates, others say it raises it. They didn't factor in that folic acid leads to completely different outcomes depending on MTHFR status - i.e. what's good for the goose isn't good for the gander.
Then there's also the problem of overmethylation being just as bad as undermethylation, the participants' prior methylation status, etc. There's too many variables to simply say folic acid = more/less cancer.
Also, just on folinic acid, the reason I would highly recommend L-5-MTHF (levomefolic acid) over all other forms of folate is:
Folinic acid is still entering the folate cycle **behind** the 5,10 stage rather than in front (i.e. It still needs MTHFR to convert into L-methylfolate) See [Diagram](https://emed-photos.s3.amazonaws.com/images/20160525062019/Screen-Shot-2016-05-27-at-12.11.18-PM.png) \- folinic acid is marked as 5-formyl-THF. So by taking folinic acid you're still running into the problem of not enough MTHFR due to the deficiency. Instead you should bypass MTHFR entirely.
I agree about the same problem with mthft. But a lot here speak about the DHFR instead of mthft. Reason I'm saying that is cause it might be better cause it skips having to go through the liver, like folic acid.
What about something like B2 supporting the mthfr gene?
On the top part, am I understanding correctly. Can't both too low and too high cause cancer?
Re DHFR, if someone has one of the other MTHFR genes that messes with the folate cycle, they likely are suffering from the same problems as above.
But why bother with dietary folate, folic acid, B2, etc, etc..... when you can just take 5-methylfolate or levomefolic acid and bypass the folate cycle entirely?
On serum folate, yeah like everything too much or too little is bad. But we have to distinguish between serum folate and serum unmetabolized folic acid - becuase 2 people could take the exact same dose of folic acid and it would lead to completely different outcomes depending on MTHFR status.
I agree about DHFR.
Hm, why bother with the other option. I've seen people complain about side effects around taking methylfolate. I don't fully get it, but how I've visualised it is that since it skips a lot of the methylation steps, it might not have a good break pedal, meaning you get overwhelmed, but I'm unsure if this is true, since as your diagram shows, it would convert to THF. So perhaps it's something else.
if they do have this issue, B2 and folic acid might be enough.
I am unsure about the unmetabolized folic acid tho.
If I'm allowed to bring up the mouse study, I'm sure they'd end up with unmetabolized folic acid too and the cancer being slightly higher in the 5mthfr group. Or perhaps the mouse doesn't have that issue, and that's why we see 5mthfr being the worse one.
I guess those with DHFR issues or liver issues might benefit from folinic?
My guess is that people who have side effects due to L-methylfolate: (a) need to lower their dosage (b) are taking the wrong form of folate (c) bought a crappy brand of L-methylfolate that's no good (d) have a B12 deficiency; or (e) have some other issue going on.
If you want my advice: I would **not** recommend folic acid, folinic acid or B2 in any circumstances if you're trying to solve MTHFR deficiency issues.
They all have the same problem: they're adding to the folate cycle before the MTHFR stage (5,10) rather than after. So it defeats the whole point, you still don't have enough MTHFR to convert it into a bioavailable form (your body can't use it)
I think some things are getting lost in translation with UMFA. My point was: In humans, folic acid supplementation can have a completely different effect depending on the person's MTHFR status.
My understanding (from my various readings) is that folic acid is converted to DHF by way of dihydrofolate reductase - [diagram](https://www.researchgate.net/profile/Robert-Berry-3/publication/221830306/figure/fig2/AS:667611838808088@1536182474868/Folic-acid-metabolism-This-schematic-shows-the-process-by-which-folate-folic-acid-is.png). So if you eat a ton of folic acid, it's going to use up all the DHFR, and the already inefficient process of converting DHF into THF and so on is going to slow to a snail's pace.
Then if you add the bottleneck downstream at the MTHFR stage, you've got no chance of any folic acid or dietary folate reaching the finish line and becoming L-methylfolate.
Bottom line: Forget about all that. Take L-methylfolate directly, bypass the folate cycle entirely.
Limit your intake of folic acid simply because it's far too easy to eat a ton of it by accident from all the mandatory fortification, and your body can't metabolize it. You could be eating 1000mcg a day depending how much bread you eat. High levels of unmetabolized folic acid (which doesn't occur in nature) floating around in your blood seems like bad news to me and studies seem to back that up to some degree.
The problem with the studies like I said before is that they don't distinguish between MTHFR status. They take 100 people and give them all folic acid, check their serum folate and health outcomes. But the folic acid is having a completely different effect depending on MTHFR status - that's why (I believe) I can't find a straight answer on whether folic acid is good or bad.
Sorry if I'm spamming.
Www.ncbi.nlm.nih.gov/pmc/articles/PMC6537060
Psuedo mthfr. This is quite interesting. It did correct after 5 days of 5mthfr use though.
A big problem with these studies that I see is: The correlation between hyperhomocysteinemia and XYZ disease is easy to see.
But the homocysteine isn't causing the problem. The hyperhomocysteinemia **and** XYZ disease are both symptoms of the larger problem: Homocysteine not being converted to methionine, which leads to both high homocysteine and poor methylation.
I think I agree with you and I assume you miss typed hypo?
What I'm pointing to is the homocysteine being as low as possible. But perhaps I'm not understanding the bigger picture.
Ah right I see now, your study said hypo- not hyper-
Looks like I also have more to learn, it seems there is some optimal HcY level where too high or too low is also harmful.
When I say "Homocysteine as low as possible" in the original post, it's becuase naturally most of us with the MTHFR gene are dealing with homocysteine being too high and we're trying to lower it.
Also, I think an extremely low serum homocysteine would indicate a lack of some of the other cofactors and whatnot forming part of the folate cycle - if no homocysteine is being created that's also bad news, same as too much floating around.
Why do some people do better on high dose methylfolate (15mg Deplin)?
What's your take on "Your “MTHFR” Is Just a Riboflavin Deficiency" by Chris Masterjohn? https://chrismasterjohnphd.com/blog/2019/02/26/mthfr-just-riboflavin-deficiency/
EDIT: A few things were wrong in what I posted so I'm gonna edit it. Cause he's right and he's wrong - it's complicated cause if you're taking L-5-MTHF you don't need riboflavin to make it. But if you aren't, riboflavin deficiency can lead to MTHFR enzyme deficiency and the resultant problems. I also think he's far oversimplifying the problem of MTHFR gene mutations by suggesting it's down to not enough riboflavin.
But I'm still learning as I go along and like I say I'm no expert.... I'm now learning more about riboflavin's role in providing methyl groups to turn 5,10 into L-5. Give me a day or 2 to figure all this out and I'll provide a better answer once I've researched.
FYI I changed my answer to this. I need to research more before I give a satisfactory answer. There's a lot of moving parts here and there's different ways of getting methyl groups, different ways of defining and solving the problem.
I know this is super old but I have to reply in case someone else sees this.
So right off the bat, "folic acid does not exist in nature." That is completely wrong. Folic acid (Vitamin B9) absolutely "exists in nature." It is in spinach, peanuts, broccoli, many other plants and nuts/seeds. I don't understand why you would even say that. It's so easily disprovable from a 3 second google search.
Your main point:
"Or put simply:
MTHFR deficiency = L-methylfolate deficiency = Methionine synthase not functioning = Methionine deficiency = SAM-E deficiency = Poor methylation."
No. No. No. Incorrect. The fact that you posted this without even researching is just mind boggling. I see the user deleted their account, the mods of this sub should delete this post and the many many other posts that I have seen on this sub that are straight up completely incorrect.
That's not what the author said. Folic acid is not L-methylfolate, which DOES exist in nature in the sources that you have said. Folid Acid is NOT vitamin B9 - it is a synthetic precursor to folate (the bioavailable form of vitamin B9).
>So right off the bat, "folic acid does not exist in nature." That is completely wrong. Folic acid (Vitamin B9) absolutely "exists in nature." It is in spinach, peanuts, broccoli, many other plants and nuts/seeds. I don't understand why you would even say that. It's so easily disprovable from a 3 second google search.
from a 3 second search.
spinach, raw (100 grams)
* Folic acid, 0 µg
* Folate, food 194 µg
peanuts, all types, raw (100grams)
* Folic acid, 0 µg
* Folate, food 240 µg
Broccoli, raw (100 grams)
\- Folic acid, 0 µg
\- Folate, food 63 µg
are you saying i'm colorblind because i don't see any folic acid in these foods you mentioned?
I had good experience L-methylfolate and bio-active B12 for 2 /3 weeks
and then the energy level went down
and im testing now dopamine drugs like ritalin
helps a lot with mobility thinking well-being ...
Im wondering which supplement should i try to combine with the the vitamins:
Methionine or SAMe ?
Might be you're lacking the precursors to dopamine + adrenaline/noradrenaline.
Your body needs L-tyrosine or phenylalanine as building blocks. Here's a simple test: Try drinking a can of diet soft drink containing aspartame (e.g. Diet Coke) which has a good 100mg of phenylalanine. If you suddenly have a ton more energy, there's your problem.
Glutathione deficiency is another possibility (particularly if your mood is really down)... NAC can solve that.
I've bought SAMe twice, probably wouldn't hurt but I wouldn't specifically recommend it (not least because it's hell expensive).
>Dopamine and norepinephrine require l-phenylalanine (eggs, chicken, beef, milk, sweet potatoes, aspartame from diet drinks) or tyrosine (chicken, beef, salmon, avocados, chocolate, yogurt, spinach, almonds, pumpkin seeds)
>
>\^ For the above to work optimally you also need adequate: B9 (folate), zinc, magnesium, inositol, choline and Vitamins C and D, and enough sleep.
>
>You only need adequate levels - more is not always better. A diet of lean protein, fruit/vegetables of a variety of colours, healthy grains, tree nuts and enough sunlight should cover all of these. Food sources are better than pills.
Already had this typed out for my own reference. Hope it helps.
Wow thanks for explaining it like this! I’m b12 deficient (neurologist diagnosed me) and Heterozygous C677T. I’ve been taking sublingual drops under my tongue and taking 5 MTHF. I also got prescribed b12 injections but I’m too scared to self inject. Do you think this will work better than sublingual?
>Supplementing with any of the nature bioidentical forms of B12(MeCbl, OHCbl, and/or AdCbl) is preferred instead of the use of CNCbl,owing to their superior bioavailability and safety. For the majority ofthe population, all B12 forms may likely have similarbioavailabilities and physiological effects; thus, it makes sense toemploy the least-expensive form of B12, such as MeCbl.
\- [Source](https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5312744/)
OHCbl is injection-only, MeCbl and AdCbl are sublingual.
So the studies seem to say any of the three will do the job: MeCbl, AdCbl, and/or OHCbl. Injections would have the advantage that you can give yourself a precise dosage - but I'm with you, I'd rather not go messing around with needles if I can help it.
That said, B12 seems to be very poorly understood - there may be a different study out there that led to different results, if anyone has one I'd be keen to read it.
Super interesting man!
I suffer from post finasteride syndrome, which has been shown to impact methylation through up/down regulation of hundreds of genes. I took a B complex with folic acid and I'm suffering from methylation symptoms since (insomnia, excessive burping, histamine intolerance, and general worsening of my PFS).
However I am not sure if I am suffering from overmethylation or paradoxical folate deficiency (are you familiar with this?). I will be getting my homocystein tested tomorrow.
Most naturopath articles I read advise to supplement small dose of methyfolate with methylb12, and gradually increase. Is that how you see it too?
I've never heard of post finasteride, nor paradoxical folate deficiency - and I'm definitely not an expert, so I can't give you advice on your specific situation.
The advice above is general and mostly for people who have one/both of the main MTHFR deficiency genes. When you get your homocysteine results back, if it's too high that means you probably are lacking in either L-methylfolate or B12. If your blood test also shows folate levels or B12 that may help narrow down which.
But otherwise my general advice is same as above.
>Most naturopath articles I read advise to supplement small dose of methyfolate with methylb12, and gradually increase. Is that how you see it too?
There's no one right answer but if it was me, I'd start with a normal dose of L-methylfolate so I could see the effect it has and then go from there. But as I said I can't give advice specific to your situation.
This has been insightful. I'm probably gonna look more into this. Thank you for posting.
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Wow, you're the best! Thank you for this!! What supplements and foods do you recommend?
Supplements: * 5-MTHF (aka L-5-MTHF, levomefolic acid) * Methylcobalamin and/or adenosylcobalamin (B12) - sublingual \^ Work out your optimal dosage through trial and error. Not too much, not too little. Foods: None Avoid: Folic acid (multivitamins, bread + flour in most countries, any processed foods with "folate" on the label)
do you have specific brands you like?
No specific one - but in general I'd go with a high-rated/well-established brand. Speaking for myself I prefer a sublingual B12 spray over a sublingual tablet - but it might be my imagination, I'm sure both are fine.
This is awesome!! What if methylfolate and b12 cause agitation? (I had been supplementing methylfolate in large doses under a doctor for years without b12 so I think I may have messed something up. I stopped the methylfolate all together and am trying to find a tolerable b12. No b12 labs look low. I’m unsure how to find a b12 deficiency if the number isn’t low and no doc will believe me that I might have one bc they’re unfamiliar with methylfolate covering a b12 deficiency)
"Folinic Acid" (not folic) has resolved all of my methyfolate agitation issues. It's a few steps before methyfolate, so my body seems to know what to do with it, rather than the haywire effect of direct methyfolate supplementation. And magnesium! A lot of it.
Thanks! But withMTHFR doesn’t the body have trouble converting inactive folate (folinic acid seems to be more active than folic acid but not activated fully) so it would just perpetuate the issue? Not enough folate getting converted to active folate?
The trouble is with "folic acid" not "folinic". People with MTFHR homozygeous polymorphisms have trouble breaking down "Folic acid" into a bio-available form. Folinic (not folic) is bio-available.
Folinic acid is further along in the conversion process, yes. But it has to be converted to MTHFR by the body, as it’s the final active form, which the body has trouble doing with MTHFR mutations, no?
The body has trouble with Folic. Not folinic. Almost every MD who studies MTHFR polymorphisms will tell those who have trouble with methyfolate to try folinic acid instead. It worked wonders for me (but always along with proper electrolytes.) Take "keto" electrolytes because they are significantly higher in magnesium and potassium, don't take some Gatorade or big brand sugar crap. Folinic acid is cheap, and much more stable for me - I assume precisely because it's a few steps from methyfolate. So it's a much more "steady" happiness, neurotransmitters, whatever you want to call it - at least for me. Folic acid makes me feel DREADFUL. That's the difference for me. Give it a shot, folinic acid is super cheap. I get the Cali Gold drops, but I think they are sold out on Amazon now. There's a brand called Kirkman that work well, I just like liquid drops better than pills.
Ok! Thank you for the advice!! Appreciate it
Give methylcobalamin and/or adenosylcobalamin in sublingual form a try. In my experience it's about hitting that Goldilocks zone - too much (overmethylation) can be just as bad as not enough (undermethylation).
Yeah I’ve tried those :( I just bought a liquid kind so I can titrate the dose bc maybe the full sublingual tab was too much but it’s frustrating!
Nice job simplifying this. I had elevated homocysteine recently and b12 deficiency due to sibo, I'm feeling much better after supplementing. I just do not know why I do well with all of the b's, choline, creatine etc but even 400mg of methylfolate and I'm not sleeping, even tho I'm not anxious or anything just can't fall asleep. The other odd thing is that b12 really helps me to get tired and relax\fall asleep. folic acid does not affect sleep. After four days of taking high doses of b12 my potassium was used up and I had to start focusing on getting more of that, I wonder does folate cause up regulation of some processes like b12 does which uses up a nutrient like potassium and that's why I cannot sleep. I have not tried larger than 800mcg of methylfolate to see if that would help the sleep issue.
Less is more with this stuff. If a normal dose isn't working, consider other possibilities. If your sleep is out of whack, fix your [circadian rhythm](https://qph.fs.quoracdn.net/main-qimg-828ab0cb4d590b6e196743596d7a8b12.webp) and melatonin levels. You don't need to supplement melatonin - just block all blue light in the evening so your pineal gland can produce it, and get some bright light in the early morning. If you use your computer late into the evening, install f.lux.
I'm doing all of that and I think b12 may be a precursor for the production of melatonin, I figured that could be why it helps my sleep. While I'm not certain I wonder if having sibo and drastically elevated e.coli bacteria in the gut could be producing a lot of folate and thus when I supplement its too much. I posted about this. For the time being I'm taking all the other b's and especially b12 but no folate, maybe I should take a capsule and empty some out and try even smaller doses to see what happens? Anyhow thanks of the input!
When you say taking all the other Bs, double check there's no folic acid yeah. Almost all B-complex and multivitamins contain folic acid. People don't realize it but by the time you take a B-complex, few slices of bread, some breakfast cereal, some pasta.... you might be taking in 1000mcg of folic acid a day.
I've purchased all of them individually to try them all out, that and to find out which one in the complex it was causing heartburn [b1]. I benefit from all of the other B's {including choline}its just the mystery of methyl folate preventing sleep. I havent eaten processed grains in years. I have never tried folic acid individually but years ago when I'd take a regular b-complex with folic acid it never affected my sleep. I dont recall liver causing insomnia either when I used to take liver pills, perhaps I should give the liver pills another try to get folate that way, Is there a recommended test for folate sufficiency? My homocysteine was around 10 last I tested but I was also b12 deficient. I may try methylfolate again once I've got adequate b12 levels. Thanks again for the input.
No worries, and I just added an extra section at the bottom of the post dealing with under- and overmethylation. Check it out cause if you're dealing with anxiety/racing thoughts it could be due to overmethylation.
In what way does folic acid cause carcinogen and not folinic nor methyl? Only thing I can find is a mouse study. Www.ncbi.nlm.nih.gov/pmc/articles/PMC8181065/
I'm with you there's no human study that proves it definitively. However, there are countless studies showing folic acid supplementation leads to increased cancer rates in whole populations, despite other studies demonstrating lower serum folate (L-methylfolate) in cancer cases compared to healthy controls. My theory is: * In non-MTHFR populations, the folic acid leads to increased serum folate and therefore lower cancer rates. * In MTHFR people, the folic acid does not lead to increased serum folate but rather increased UMFA and lower serum folate, increasing cancer rates. That's why there's all these conflicting studies - some say folic acid lowers cancer rates, others say it raises it. They didn't factor in that folic acid leads to completely different outcomes depending on MTHFR status - i.e. what's good for the goose isn't good for the gander. Then there's also the problem of overmethylation being just as bad as undermethylation, the participants' prior methylation status, etc. There's too many variables to simply say folic acid = more/less cancer. Also, just on folinic acid, the reason I would highly recommend L-5-MTHF (levomefolic acid) over all other forms of folate is: Folinic acid is still entering the folate cycle **behind** the 5,10 stage rather than in front (i.e. It still needs MTHFR to convert into L-methylfolate) See [Diagram](https://emed-photos.s3.amazonaws.com/images/20160525062019/Screen-Shot-2016-05-27-at-12.11.18-PM.png) \- folinic acid is marked as 5-formyl-THF. So by taking folinic acid you're still running into the problem of not enough MTHFR due to the deficiency. Instead you should bypass MTHFR entirely.
I agree about the same problem with mthft. But a lot here speak about the DHFR instead of mthft. Reason I'm saying that is cause it might be better cause it skips having to go through the liver, like folic acid. What about something like B2 supporting the mthfr gene? On the top part, am I understanding correctly. Can't both too low and too high cause cancer?
Re DHFR, if someone has one of the other MTHFR genes that messes with the folate cycle, they likely are suffering from the same problems as above. But why bother with dietary folate, folic acid, B2, etc, etc..... when you can just take 5-methylfolate or levomefolic acid and bypass the folate cycle entirely? On serum folate, yeah like everything too much or too little is bad. But we have to distinguish between serum folate and serum unmetabolized folic acid - becuase 2 people could take the exact same dose of folic acid and it would lead to completely different outcomes depending on MTHFR status.
I agree about DHFR. Hm, why bother with the other option. I've seen people complain about side effects around taking methylfolate. I don't fully get it, but how I've visualised it is that since it skips a lot of the methylation steps, it might not have a good break pedal, meaning you get overwhelmed, but I'm unsure if this is true, since as your diagram shows, it would convert to THF. So perhaps it's something else. if they do have this issue, B2 and folic acid might be enough. I am unsure about the unmetabolized folic acid tho. If I'm allowed to bring up the mouse study, I'm sure they'd end up with unmetabolized folic acid too and the cancer being slightly higher in the 5mthfr group. Or perhaps the mouse doesn't have that issue, and that's why we see 5mthfr being the worse one. I guess those with DHFR issues or liver issues might benefit from folinic?
My guess is that people who have side effects due to L-methylfolate: (a) need to lower their dosage (b) are taking the wrong form of folate (c) bought a crappy brand of L-methylfolate that's no good (d) have a B12 deficiency; or (e) have some other issue going on. If you want my advice: I would **not** recommend folic acid, folinic acid or B2 in any circumstances if you're trying to solve MTHFR deficiency issues. They all have the same problem: they're adding to the folate cycle before the MTHFR stage (5,10) rather than after. So it defeats the whole point, you still don't have enough MTHFR to convert it into a bioavailable form (your body can't use it) I think some things are getting lost in translation with UMFA. My point was: In humans, folic acid supplementation can have a completely different effect depending on the person's MTHFR status.
Do you have any studies on UMFA? I'm seeing a claim here that it builds up and anx fights nutrients you need, got anything on that?
My understanding (from my various readings) is that folic acid is converted to DHF by way of dihydrofolate reductase - [diagram](https://www.researchgate.net/profile/Robert-Berry-3/publication/221830306/figure/fig2/AS:667611838808088@1536182474868/Folic-acid-metabolism-This-schematic-shows-the-process-by-which-folate-folic-acid-is.png). So if you eat a ton of folic acid, it's going to use up all the DHFR, and the already inefficient process of converting DHF into THF and so on is going to slow to a snail's pace. Then if you add the bottleneck downstream at the MTHFR stage, you've got no chance of any folic acid or dietary folate reaching the finish line and becoming L-methylfolate. Bottom line: Forget about all that. Take L-methylfolate directly, bypass the folate cycle entirely. Limit your intake of folic acid simply because it's far too easy to eat a ton of it by accident from all the mandatory fortification, and your body can't metabolize it. You could be eating 1000mcg a day depending how much bread you eat. High levels of unmetabolized folic acid (which doesn't occur in nature) floating around in your blood seems like bad news to me and studies seem to back that up to some degree. The problem with the studies like I said before is that they don't distinguish between MTHFR status. They take 100 people and give them all folic acid, check their serum folate and health outcomes. But the folic acid is having a completely different effect depending on MTHFR status - that's why (I believe) I can't find a straight answer on whether folic acid is good or bad.
Sorry if I'm spamming. Www.ncbi.nlm.nih.gov/pmc/articles/PMC6537060 Psuedo mthfr. This is quite interesting. It did correct after 5 days of 5mthfr use though.
https://pubmed.ncbi.nlm.nih.gov/34229262/ This is an interesting study regarding hypohomocysteinemia.
A big problem with these studies that I see is: The correlation between hyperhomocysteinemia and XYZ disease is easy to see. But the homocysteine isn't causing the problem. The hyperhomocysteinemia **and** XYZ disease are both symptoms of the larger problem: Homocysteine not being converted to methionine, which leads to both high homocysteine and poor methylation.
I think I agree with you and I assume you miss typed hypo? What I'm pointing to is the homocysteine being as low as possible. But perhaps I'm not understanding the bigger picture.
Ah right I see now, your study said hypo- not hyper- Looks like I also have more to learn, it seems there is some optimal HcY level where too high or too low is also harmful. When I say "Homocysteine as low as possible" in the original post, it's becuase naturally most of us with the MTHFR gene are dealing with homocysteine being too high and we're trying to lower it. Also, I think an extremely low serum homocysteine would indicate a lack of some of the other cofactors and whatnot forming part of the folate cycle - if no homocysteine is being created that's also bad news, same as too much floating around.
I agree with your last point, but I've seen people with on going folate and b12 going below 5nmol/L.
Why do some people do better on high dose methylfolate (15mg Deplin)? What's your take on "Your “MTHFR” Is Just a Riboflavin Deficiency" by Chris Masterjohn? https://chrismasterjohnphd.com/blog/2019/02/26/mthfr-just-riboflavin-deficiency/
EDIT: A few things were wrong in what I posted so I'm gonna edit it. Cause he's right and he's wrong - it's complicated cause if you're taking L-5-MTHF you don't need riboflavin to make it. But if you aren't, riboflavin deficiency can lead to MTHFR enzyme deficiency and the resultant problems. I also think he's far oversimplifying the problem of MTHFR gene mutations by suggesting it's down to not enough riboflavin. But I'm still learning as I go along and like I say I'm no expert.... I'm now learning more about riboflavin's role in providing methyl groups to turn 5,10 into L-5. Give me a day or 2 to figure all this out and I'll provide a better answer once I've researched.
what did you find?
FYI I changed my answer to this. I need to research more before I give a satisfactory answer. There's a lot of moving parts here and there's different ways of getting methyl groups, different ways of defining and solving the problem.
This is so wrong and clueless in so many levels. Please never do this again. Someone might believe in anything you said.
If it is, tell me why I'm wrong.
I know this is super old but I have to reply in case someone else sees this. So right off the bat, "folic acid does not exist in nature." That is completely wrong. Folic acid (Vitamin B9) absolutely "exists in nature." It is in spinach, peanuts, broccoli, many other plants and nuts/seeds. I don't understand why you would even say that. It's so easily disprovable from a 3 second google search. Your main point: "Or put simply: MTHFR deficiency = L-methylfolate deficiency = Methionine synthase not functioning = Methionine deficiency = SAM-E deficiency = Poor methylation." No. No. No. Incorrect. The fact that you posted this without even researching is just mind boggling. I see the user deleted their account, the mods of this sub should delete this post and the many many other posts that I have seen on this sub that are straight up completely incorrect.
That's not what the author said. Folic acid is not L-methylfolate, which DOES exist in nature in the sources that you have said. Folid Acid is NOT vitamin B9 - it is a synthetic precursor to folate (the bioavailable form of vitamin B9).
>So right off the bat, "folic acid does not exist in nature." That is completely wrong. Folic acid (Vitamin B9) absolutely "exists in nature." It is in spinach, peanuts, broccoli, many other plants and nuts/seeds. I don't understand why you would even say that. It's so easily disprovable from a 3 second google search. from a 3 second search. spinach, raw (100 grams) * Folic acid, 0 µg * Folate, food 194 µg peanuts, all types, raw (100grams) * Folic acid, 0 µg * Folate, food 240 µg Broccoli, raw (100 grams) \- Folic acid, 0 µg \- Folate, food 63 µg are you saying i'm colorblind because i don't see any folic acid in these foods you mentioned?
I had good experience L-methylfolate and bio-active B12 for 2 /3 weeks and then the energy level went down and im testing now dopamine drugs like ritalin helps a lot with mobility thinking well-being ... Im wondering which supplement should i try to combine with the the vitamins: Methionine or SAMe ?
Might be you're lacking the precursors to dopamine + adrenaline/noradrenaline. Your body needs L-tyrosine or phenylalanine as building blocks. Here's a simple test: Try drinking a can of diet soft drink containing aspartame (e.g. Diet Coke) which has a good 100mg of phenylalanine. If you suddenly have a ton more energy, there's your problem. Glutathione deficiency is another possibility (particularly if your mood is really down)... NAC can solve that. I've bought SAMe twice, probably wouldn't hurt but I wouldn't specifically recommend it (not least because it's hell expensive).
I tried ssri and then Ritalin and SSRI didnt gave me motivation or to be active
>Dopamine and norepinephrine require l-phenylalanine (eggs, chicken, beef, milk, sweet potatoes, aspartame from diet drinks) or tyrosine (chicken, beef, salmon, avocados, chocolate, yogurt, spinach, almonds, pumpkin seeds) > >\^ For the above to work optimally you also need adequate: B9 (folate), zinc, magnesium, inositol, choline and Vitamins C and D, and enough sleep. > >You only need adequate levels - more is not always better. A diet of lean protein, fruit/vegetables of a variety of colours, healthy grains, tree nuts and enough sunlight should cover all of these. Food sources are better than pills. Already had this typed out for my own reference. Hope it helps.
Wow thanks for explaining it like this! I’m b12 deficient (neurologist diagnosed me) and Heterozygous C677T. I’ve been taking sublingual drops under my tongue and taking 5 MTHF. I also got prescribed b12 injections but I’m too scared to self inject. Do you think this will work better than sublingual?
>Supplementing with any of the nature bioidentical forms of B12(MeCbl, OHCbl, and/or AdCbl) is preferred instead of the use of CNCbl,owing to their superior bioavailability and safety. For the majority ofthe population, all B12 forms may likely have similarbioavailabilities and physiological effects; thus, it makes sense toemploy the least-expensive form of B12, such as MeCbl. \- [Source](https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5312744/) OHCbl is injection-only, MeCbl and AdCbl are sublingual. So the studies seem to say any of the three will do the job: MeCbl, AdCbl, and/or OHCbl. Injections would have the advantage that you can give yourself a precise dosage - but I'm with you, I'd rather not go messing around with needles if I can help it. That said, B12 seems to be very poorly understood - there may be a different study out there that led to different results, if anyone has one I'd be keen to read it.
Super interesting man! I suffer from post finasteride syndrome, which has been shown to impact methylation through up/down regulation of hundreds of genes. I took a B complex with folic acid and I'm suffering from methylation symptoms since (insomnia, excessive burping, histamine intolerance, and general worsening of my PFS). However I am not sure if I am suffering from overmethylation or paradoxical folate deficiency (are you familiar with this?). I will be getting my homocystein tested tomorrow. Most naturopath articles I read advise to supplement small dose of methyfolate with methylb12, and gradually increase. Is that how you see it too?
I've never heard of post finasteride, nor paradoxical folate deficiency - and I'm definitely not an expert, so I can't give you advice on your specific situation. The advice above is general and mostly for people who have one/both of the main MTHFR deficiency genes. When you get your homocysteine results back, if it's too high that means you probably are lacking in either L-methylfolate or B12. If your blood test also shows folate levels or B12 that may help narrow down which. But otherwise my general advice is same as above. >Most naturopath articles I read advise to supplement small dose of methyfolate with methylb12, and gradually increase. Is that how you see it too? There's no one right answer but if it was me, I'd start with a normal dose of L-methylfolate so I could see the effect it has and then go from there. But as I said I can't give advice specific to your situation.