Can The Methyl Folate Trap and DHFR Cause Strong Reaction From Taking Methylfolate?

[Lotus97]

I had heard that folic acid can block methylfolate, but when I started taking methylfolate I had a strong reaction to it even though I was taking at least 1000 mcg of folic acid so I assumed that for myself folic acid wasn't a problem. But then I read about The Methyl Trap and DHFR. Correct me if I'm wrong, but if you take folic acid in high doses then it slows or blocks DHFR which converts folic acid into methylfolate and folinic acid. If this happened to me then I would have been depleted of methylfolate. If I was depleted of methylfolate when I started taking methylfolate could that be part of the reason I reacted so strongly to it?

 

[Lotus97]

Could the Methyl Trap also have caused my low HGB/hemoglobin? I found this quote by Rich

The reason why red blood cells are larger and contain more hemoglobin than normal in ME/CFS is that the cells in the bone marrow that produce new blood cells do not have enough folate. Certain forms of folate are needed to make DNA and RNA, which are needed to make new cells. Since the bone marrow is not able to make red cells in normal numbers, it stuffs more hemoglobin into each one it does make, and that raises both MCV (their size) and MCH (their hemoglobin content).

The reason why these cells do not have enough folates is that there is a partial block in methionine synthase, which links the methylation cycle to the folate metabolism. Because of this block, folates continue to be converted to methylfolate (this is called the "methyl trap" mechanism), but it cannot be used by the methionine synthase reaction. Instead, peroxynitrite, which rises because of the depletion of glutathione, breaks down the methylfolate, and that depletes the folates in general.

 

[jeffrez]

That all sounds very likely, Lotus, and in fact sounds exactly like what just happened to me. I was taking my last bottle of B-Right and thought I was safe in adding 5mthf since the B-Right already has folate and Quatrefolic. But it's possible there was either a block or a methyl trap and it whacked out my glutathione & redox balance and caused a crash. As I recall, I also have increased MCV. Very interesting, would be interested to hear more about this from people more in the know about methylation.

 

[Malachy]

Yes, that all seems correct to me. Taking too much folate in any form can both mimic and mask symptoms of B12 defiency and anaemia. Whether or not it's directly related to the methy-folate trap is debatable because there is no clinical/pathological testing available (other than in university research labs) that could prove the methyl-trap is actually happening inside your cells.

I hope someone can correct me if I'm wrong, but my understanding is as follows:

DHFR is one of the enzyme's responsible for converting folic acid to active forms of folate. Methylfolate is not the only active form of folate. Because folic acid does not occur in nature, our bodies are not designed to process it. When the cellular machinery in the mitochondria are using up energy and equipment to process folic acid, it prevents the proper metabolism of other forms of folate, so if you have too much folic acid circulating, any extra methylfolate will saturate the cellls and also build up in the blood (outside the cells), most of it will do nothing and get excreted, but some of it will speed up other processes and make you feel sick. So it's not really correct to say that folic acid blocks methylfolate, but it's a good enough analogy for most people to understand. Too much folic acid prevents the natural/active forms of folate from accessing the parts of the machine that make our cells work correctly, and forces folate into other biochemical pathways that are not necessarily contributing to anything useful and can make you feel worse.

To say that the extra circulating folate is making you feel sick because you are "healing" is a fallacy. It's really just your body reacting to something that shouldn't be happening. If it makes you sick, change the dose!

For most of the population who are folate deficient, then taking folic acid is perfectly fine. Folic acid in low amounts get's converted at a slow rate and helps to replenish active forms of folate. That is why it is useful to prevent neural tube defects and helps to rebuild nerve damage in trauma patients. It's only when too much folic acid and active folate (methylfolate) are circulating at the same time that problems occur.

 

[Lotus97]

That all sounds very likely, Lotus, and in fact sounds exactly like what just happened to me. I was taking my last bottle of B-Right and thought I was safe in adding 5mthf since the B-Right already has folate and Quatrefolic. But it's possible there was either a block or a methyl trap and it whacked out my glutathione & redox balance and caused a crash. As I recall, I also have increased MCV. Very interesting, would be interested to hear more about this from people more in the know about methylation.

My problem actually happened with the B-Right and Quatrefolic too. I had never heard about methylation or methylfolate and had been taking the B Right b complex over a year without any problems then they add the Quatrefolic to the formula and it blows me away. For the next month or two I was in a state of extreme anxiety/overstimulation with heart palpatations and tachycardia. I also seemed to develop POTS-like symptoms (I don't think I actually have POTS, but I'm not sure). My experience led to my discovery of Phoenix Rising and methylation. By a strange coincidence I began taking it a few days after my tooth with an amalgam cracked so at first I thought I had mercury toxicity. I might have been exposed to some mercury, but it was probably mostly the methylfolate.

How much folic acid were you taking at the time? It could just be that you took too much methylfolate, because Quatrefolic is supposed to be a particularly potent version of methylfolate and combined with more methylfolate on top of that could just be too much methylfolate, but I'm not really sure how much folic acid is needed to cause the methyl trap. Also, it's a bit annoying that Jarrow doesn't specify how much folic acid and methylfolate is in the B Right so we don't really know how much folic acid we were getting?

 

[jeffrez]

How much folic acid were you taking at the time? It could just be that you took too much methylfolate, because Quatrefolic is supposed to be a particularly potent version of methylfolate and combined with more methylfolate on top of that could just be too much methylfolate, but I'm not really sure how much folic acid is needed to cause the methyl trap. Also, it's a bit annoying that Jarrow doesn't specify how much folic acid and methylfolate is in the B Right so we don't really know how much folic acid we were getting?

I was only taking whatever folate/QF is in the B-Right. I added tiny, tiny crumbs of Metafolin thinking such small amounts would be safe, but apparently it overloaded me like Malachy described and crashed me somehow. It's really strange because I've taken 2 B-Rights by accident a couple times, which would DOUBLE the amount of folate/QF, and was fine with it. I also stopped taking B-Right when I learned about the folate problem, but then almost immediately felt worse from not taking it. I had one bottle left, so a couple months ago I started taking them again to use up the bottle while trying to figure out what brand to try next, and I was fine with it. The amount of Metafolin I added this week couldn't have been much more than 10mcg each, for a total of 2 doses on two consecutive days. I'm having a hard time getting my head around the idea that such a small amount could backfire like this, but I felt the depression kick in almost right away, and there was nothing else added to explain the crash.

 

[drex13]

Any idea which SNP on the DHFR enzyme we may be talking about here ? I wonder if maybe more attention should be paid to DHFR than to the one that gets all the attention MTHFR. I don't seem to get along well with either Folinic acid or with Methylfolate. They seem to produce different symptoms when I take them, but either way, I feel crappy. Methyl b-12 is also not my friend, but Hydroxy seems ok. I also like the Phosphatidyl Serine, per Rich's SMP. I think it clears my head up. I'm getting off topic, but I am interested to hear about others who don't do well with the methylfolate .

 

[Lotus97]

Any idea which SNP on the DHFR enzyme we may be talking about here ? I wonder if maybe more attention should be paid to DHFR than to the one that gets all the attention MTHFR. I don't seem to get along well with either Folinic acid or with Methylfolate. They seem to produce different symptoms when I take them, but either way, I feel crappy. Methyl b-12 is also not my friend, but Hydroxy seems ok. I also like the Phosphatidyl Serine, per Rich's SMP. I think it clears my head up. I'm getting off topic, but I am interested to hear about others who don't do well with the methylfolate .

There's a thread about that:
http://forums.phoenixrising.me/index.php?threads/snps-for-dihydrofolate-reductase-dhfr.19563/

That's why I started taking PS. I didn't even know it was involved in methylation when I started. I'm not sure if helped me or not with brain fog, but I'm glad it's working for you. It's supposed to also lower cortisol which is why Rich removed it from his newest methylation protocol.

 

[Freddd]

To generally clarify, the methy (folate) trap, methyl-trap in the literature, happens when there is a lack of sufficient MeCbl in the cell for a transaction requiring l-methylfolate. This can ovccur becasue there is just enough MeCbl to get used up in these transactions before running out of l-methylfolate so the methyltrap occurs and there are folate deficiency symptoms despite having a surplus of folate and the real deficiency is b12. When the methylfolate gets kicked out of the cell, then folate deficiency symptoms are exhibited, usually with a hard onset but not usually as hard as glutathione can cause. When only l-methylfolate is given and the person has no trouble with veggie folates, then a "donut hole" type folate insufficiency happens. More is needed than was given to start the healing.

When too much folic acid, whatever that means for the person involved, there are one or more mechanisms that can block l-methylfolate from being delivered to where it is needed when it is needed. The same can occur with folinic and veggie folates in some unknown percentage of people under essentially unknown causes. All of these types of folate insufficiency appear paradoxical in nature.

 

[Lotus97]

To generally clarify, the methy (folate) trap, methyl-trap in the literature, happens when there is a lack of sufficient MeCbl in the cell for a transaction requiring l-methylfolate. This can ovccur becasue there is just enough MeCbl to get used up in these transactions before running out of l-methylfolate so the methyltrap occurs and there are folate deficiency symptoms despite having a surplus of folate and the real deficiency is b12. When the methylfolate gets kicked out of the cell, then folate deficiency symptoms are exhibited, usually with a hard onset but not usually as hard as glutathione can cause. When only l-methylfolate is given and the person has no trouble with veggie folates, then a "donut hole" type folate insufficiency happens. More is needed than was given to start the healing.

When too much folic acid, whatever that means for the person involved, there are one or more mechanisms that can block l-methylfolate from being delivered to where it is needed when it is needed. The same can occur with folinic and veggie folates in some unknown percentage of people under essentially unknown causes. All of these types of folate insufficiency appear paradoxical in nature.

Unfortunately, I didn't know about methylation when I started methylfolate. Jarrow's B Right changed their formula and added methylfolate. And the only methylcobalamin I was taking was the 100 mcg oral dose from the B Right. Are you saying the lack of B12 is part of the reason why I had the bad reaction?

 

[Malachy]

Reactions to methylfolate could be caused either by too much methylfolate or not enough B12. Inborn errors of metabolism and enzyme dysfunction could also cause reactions to methyfolate. If lowering the methylfolate or increasing your b12 intake does not relieve symptoms, you should seek advice from a qualified medical practitioner who can investigate further. Despite popular opinion, there is a lot more going on in your body than just methylfolate and B12.

 

[Lotus97]

True. This is all a working hypothesis until I test out these theories. I will post my results as things develop. There definitely is a lot going on in my body besides B12 and folate deficiency. Before my crash I made a significant recovery without B12 or methylfolate supplementation. Even if methylation will only speed up my recovery by 5-10% I'll take all the help I can get.

 

[Malachy]

I thought that mehtylfolate and methylcobalamin were causing my symptoms after reading all the misinformation on these forums. Then I stopped taking B6 for a day, and my symptoms went away. I added b6 back in this-afternoon and BANG, the headaches and nausea returned within 30 minutes... so not every adverse reaction should automatically be assumed to be folate b12 folate b12 startup startup startup etc. I really don't see any evidence to support many of the creative theories posted with abandon on this forum.

 

[Lotus97]

I thought that mehtylfolate and methylcobalamin were causing my symptoms after reading all the misinformation on these forums. Then I stopped taking B6 for a day, and my symptoms went away. I added b6 back in this-afternoon and BANG, the headaches and nausea returned within 30 minutes... so not every adverse reaction should automatically be assumed to be folate b12 folate b12 startup startup startup etc. I really don't see any evidence to support many of the creative theories posted with abandon on this forum.

I have heard of a few other people having problems with B6. Some people were able to tolerate P5P, but others couldn't take B6 or P5P. I don't think the issues were related to overmethylation though. Maybe you could start a thread to let people know that B6 can cause issues for some people.

That said, I have read many more accounts of people having adverse reactions to B12 and folate. Some people have to start at a very low dose of either of these and slowly increase their dose. That's why Rich has people start with hydroxocobalamin and 200 mcg of methylfolate. He also has people start only B12 first, then add folinic acid, and then finally add methylfolate. I'm not sure about Freddd's active B12 protocol, but in his micro titration protocol he has people start at 200 mcg methylfolate and a very low dose of methylcobalamin. Even though B12 and methylfolate are the most likely to lead to overmethylation/overdriving the methylation cycle, B6/P5P, B2/R5P, choline, TMG, phosphatidylserine, and SAMe could also lead to overmethylation.

 

[Freddd]

I thought that mehtylfolate and methylcobalamin were causing my symptoms after reading all the misinformation on these forums. Then I stopped taking B6 for a day, and my symptoms went away. I added b6 back in this-afternoon and BANG, the headaches and nausea returned within 30 minutes... so not every adverse reaction should automatically be assumed to be folate b12 folate b12 startup startup startup etc. I really don't see any evidence to support many of the creative theories posted with abandon on this forum.

Hi Malachy,

B6 is one of the three items needed to convert homocycteine back to methione. It can cause a breakdown if not effective and can cause low potassium and/or low mehthylfolate and/ort low b12 when processing starts because of low b6/p5p. It's in the third tier of croitical cofactotrs be3caseu it is usally in b-complex, and the prefered ones have p5p.

 

[Freddd]

Unfortunately, I didn't know about methylation when I started methylfolate. Jarrow's B Right changed their formula and added methylfolate. And the only methylcobalamin I was taking was the 100 mcg oral dose from the B Right. Are you saying the lack of B12 is part of the reason why I had the bad reaction?

Hi Lotus,

The problems with the methyltrap is that the symtpoms appear backwards. When the MeCbl is not where it is needed in the cell then methylfolate is flusyhed from the cell and the pr0cess breaks fo lack of methylb12, not MeCbl, give merthylfolate deficiency symptoms. Then a little bit of effective MeCbl cause b12 deficiency symptoms when the process no longer breaks at the methylfolte. This appears very contrratictory, paradoxical in fact, and confuses most everybody.

Methylfolate doesn't help a person out of a methyl-trap. MeCbl does, in sufficient quantity. In small (10mcg active absorbiton, doses it just changes the symtpoms to b12 deficiencies sysmtpoms for a few hours until depleted then back to methyltrap. It makes things look backwards.

Perhaps I can help distinguish between different level of things.

Partial methylation block creeps up on you.
Paradoxical folate deficiency, several levels, creeps up on you except when induced
MeCbl body and/or CNS creeps up on you
AdoCbl body and/or CNS partial mito blockage creeps up on you

When MeCbl gets low enough Methyl-trap (severe mfolate deficiency symptoms, CNS and/or body) - hits like a ton of bricks.
When AdoCbl/LCF gets low enough below a certain ATP generation level, sometimes muscles switch to workaround with lactic acid, prodcution, 1/6 energy. A different group of researchers from Rich (local to where I live) was looking for this situation, I had it. It hits like a ton of bricks
Methy-trap and Partial mito block (or something) together may set off each other or by the same stress; combined hits like 10 tons of bricks.

And there are likely other variations that I haven't identified yet.

The day I woke up able only to crawl to the toilet to vomit, changed my life. I had a total all system failure, total collapse. It was diagnosed as misc entero virus likely. There was a lot going on there. In 10 days I had 100 symptoms more than before it had hit. They stayed and worsened for 17 years for me. Who here was hit with a sudden onset like a ton of bricks and looking for what happened? I think I have much of this whole thing mapped out in a way that all the pieces fit as they fit into place. What keeps it from happening easily are the many complications and paradoxical symtpoms.

Part of the puzzle is that this crash, this "tipping" appears to occur with all sorts of stresses, bacteria, virus, exhaustion, physical trauma, vaccine,

Then people don't recover well because their immune system is trashed by these breakdowns. Things get more and more out of kilter.

 

[Lotus97]

I made a recovery during a period where I was taking over 1000 mcg of folic acid. It wasn't until I took methylfolate that I had adverse effects. I was just trying to figure out why I reacted so strongly to the methylfolate. My symptoms were probably from overmethylation, but I'm going to try stopping or at least drastically reducing my folic acid intake and at the same time slowly bring up my B12 levels and very slowly add methylfolate. Maybe I'm just really sensitive to methylfolate, but we'll see what happens.

 

[jeffrez]

Hi Lotus,

The problems with the methyltrap is that the symtpoms appear backwards. When the MeCbl is not where it is needed in the cell then methylfolate is flusyhed from the cell and the pr0cess breaks fo lack of methylb12, not MeCbl, give merthylfolate deficiency symptoms. Then a little bit of effective MeCbl cause b12 deficiency symptoms when the process no longer breaks at the methylfolte. This appears very contrratictory, paradoxical in fact, and confuses most everybody.

This is a very interesting post (snipped for brevity), and I wonder if it finally explains the paradoxical depression I and some others get from 5mthf. High dose methylfolate is actually considered a secondary line of treatment for treatment resistant depression by mainstream med, in doses of 15mg and higher, for example: http://www.medscape.com/viewarticle/739246

I used to respond to folate with decreased anxiety and depression, then after a couple of crashes it stopped working that way and instead now produces really awful depression. If what you're saying is the case, then it would appear that what's actually happening is not that the methylfolate itself is causing the symptoms, but that it's creating a further L-MF deficiency because of lack of mb12. I think in the initial paragraph above you meant: "the process breaks for lack of methylb12, not methylfolate," is that right? Which then leads to the MF deficiency symptoms (in this case, depression) and indicating that the fix is actually to increase mb12, not methylfolate? That would appear to follow from how you've laid it out.

Great post, that really clarified some things for me - again, if it's true. I'm starting to have a suspicion that my cells are not absorbing or using B12 properly, so even though the serum levels are high, I'm still getting problems when I add the L-MF. Does that sound plausible to you, or would it be impossible for the cells or tissues not to use the b12 with sufficient blood levels? If it is possible, what factors could account for insufficient tissue saturation or absorption?

Waiting now for the Enzymatic Therapy b12, really interested to see what effects that has.

 

[Freddd]

This is a very interesting post (snipped for brevity), and I wonder if it finally explains the paradoxical depression I and some others get from 5mthf. High dose methylfolate is actually considered a secondary line of treatment for treatment resistant depression by mainstream med, in doses of 15mg and higher, for example: http://www.medscape.com/viewarticle/739246

I used to respond to folate with decreased anxiety and depression, then after a couple of crashes it stopped working that way and instead now produces really awful depression. If what you're saying is the case, then it would appear that what's actually happening is not that the methylfolate itself is causing the symptoms, but that it's creating a further L-MF deficiency because of lack of mb12. I think in the initial paragraph above you meant: "the process breaks for lack of methylb12, not methylfolate," is that right? Which then leads to the MF deficiency symptoms (in this case, depression) and indicating that the fix is actually to increase mb12, not methylfolate? That would appear to follow from how you've laid it out.

Great post, that really clarified some things for me - again, if it's true. I'm starting to have a suspicion that my cells are not absorbing or using B12 properly, so even though the serum levels are high, I'm still getting problems when I add the L-MF. Does that sound plausible to you, or would it be impossible for the cells or tissues not to use the b12 with sufficient blood levels? If it is possible, what factors could account for insufficient tissue saturation or absorption?

Waiting now for the Enzymatic Therapy b12, really interested to see what effects that has.

Hi Jeffrex,

You caught my uninterntional word substitution that starts with the same letter. Quite right, methytrap casues paradoxical bouncing back and forth symptoms and can hit like a ton of bricks. Yes one has to increase MeCbl and then standby when both donut hole folate insufficiecncy hits AND low potassium. Then these things bounce around a bit until they all balnce out, only to unbalance all over again with AdoCbl. Actually everything can be stuck becasue of lack of sufficient ATP (AdoCbl, to start and then an appropriate LCF ittration) and not start. OCcasionally something else yet is the cause, but only about 5% total. Instead, other things add to the response rather than holding then up entirely.

Generally you need to add both in siufficient quatity becasue when the MeCbl hits, it sucks down avialable folate rapidly and goes almost immeditately into folate insufficiency. Insufficiency generally doesn't hit as hard as methyltrap.

 

[dbkita]

Hi Jeffrex,

You caught my uninterntional word substitution that starts with the same letter. Quite right, methytrap casues paradoxical bouncing back and forth symptoms and can hit like a ton of bricks. Yes one has to increase MeCbl and then standby when both donut hole folate insufficiecncy hits AND low potassium. Then these things bounce around a bit until they all balnce out, only to unbalance all over again with AdoCbl. Actually everything can be stuck becasue of lack of sufficient ATP (AdoCbl, to start and then an appropriate LCF ittration) and not start. OCcasionally something else yet is the cause, but only about 5% total. Instead, other things add to the response rather than holding then up entirely.

Generally you need to add both in siufficient quatity becasue when the MeCbl hits, it sucks down avialable folate rapidly and goes almost immeditately into folate insufficiency. Insufficiency generally doesn't hit as hard as methyltrap.

So let me see if I got this straight.

If someone were to say take only 400-800 mcg of methylfolate (and maybe to make things worse at the same time eat a couple hundred micrograms of vegetable folate a day) but take a dose of say 5000-10000 mcg of 5 star sublingual mb12 they will in fact probably burn through their methylfolate rapidly and end up with a donut hole methyfolate insufficiency but also get hit with the high need for potassium?

On the other hand if they take high doses of methylfolate and say get only a 100 mcg of mb12 absorbed they run a high risk of a methyl trap?

So if someone is kind of near a balance point between the too, but wants to increase they are better off raising both mb12 and methylfolate together (provided there is enough ATP via LCF and adb12 to go along for the ride)?