How to Titrate to Get Out of Donut Hole Insufficiency

[adreno]

My doctor told me he has tested quite a number of patients and found a high number who have antibodies to the folate receptors.

Thank you for posting this, very interesting.

 

[dbkita]

I gradually worked my way up on the dose of Metafolin over 5 months to about 14-15 a day. Then went to a trial on 15 mg Deplin. I had a very quick positive leap forward and have so far done well on the 15 mg/day for the past 4 months. I had been able to gradually increase my B12 dosage, but once I reached the 15 mg/day folate level, I had enough to support a fairly rapid move to high dose injected MB12 (35-40 mg injected daily divided into 3 doses). I am making progress on this so far.

My doctor told me he has tested quite a number of patients and found a high number who have antibodies to the folate receptors. He said that the person has to take enough folate to overcome this resistance. He also told me he suspects that I *might* have a defect in the transporter function for carrying B12 around in the body.

So I wonder if a person takes a small amount of folate, whether it activates the antibody response? Could this sometimes be an explanation for symptoms?

The way an autoimmune disease works, the antibodies will be bombing the folate receptors provided their "trigger" is active. The folate receptors are located on the outside of the cell membrane where the antibodies can "see" them.

Those receptors are about bringing THF into the cells. So you probably would need higher concentration of folate to get a certain effect since active receptor density on the cell surfaces would be lower. Taking folinic acid or l5mthf would bypass this in principle I think. BUT ... taking lots of precursors to THF may makes things worse ... maybe.

We are presumably talking about antibodies to a receptor that binds a substrate to transport it into cells and NOT the production of the substrate. For example, I have glutamic acid decarboxylase antibodies. That means they attack the enzyme that produces GABA. Not the GABA receptors themselves. If I stimulate in my case GAD activity, I get worse. But why would the presence of THF and its precursors trigger the antibodies any worse unless the body adaptively creates more folate receptors in response to high plasma concentrations, which sadly I do not know the answer to. l5mthf and folinic acid however, do not bind to the folate receptors in question to my knowledge.

Still not sure how the body would handle lots of floating THF or its precurors in the bloodstream and not much ability to dock those to make folinic acid and l5mthf. That could have its own issues

I would be cautious about jumping to the conclusion that this a common problem. CFS is not uncommon yes. But once you ignore Hashiimoto's, Celiac's and type 1.5 diabetes, autoimmune disease are pretty rare. It is an interesting concept though. I will discuss with one of my doctors.

I would also think this would have some sort of signature pattern on an HDRI methylation panel or equivalent. Just not sure what the pattern would be. Depends on their testing methods also I suppose.

From their website:

"Methylation Pathway Parameters Tested:

Glutathione (oxidized), Glutathione (reduced), S-adenosyl-methionine (RBC), S-adenosyl-homocysteine (RBC), Tetrahydrofolate (THE), 5-methyl-THF, 10-forrnyl-THF, 5-formyl-THF, Folic Acid, Folinic Acid, Folic Acid (RBC), Adenosine"

Here is Rich Vank's explanation of the test:

http://forums.phoenixrising.me/index.php?threads/methylation-pathways-panel.4711/

So if you have antifolate receptor antibodies would you not expect high plasma THF and low 5mthf and probably low folinic acid since the latter two cannot be generated well from transported THF? Just a thought.

 

[EastWest]

Adreno and Dbkita, unfortunately you are both way beyond my understanding so I can't further contribute though I read with interest and attempt to understand. The autoimmune does apply to me though, both Hashi's and celiac. My doc didn't check my folate receptor antibody level. I also don't have pre-protocol levels of THF, 5 mthf and folinic from the panel above. I did have low GSH, low cysteine, taurine and glycine levels which have corrected since being on the current folate/B12 regimen but did not correct on MB12 injections only at 5 mg a week. My MMA and Figlu were indicative of the issue but not indicative of my need for such high doses as far as I know. I should have mentioned in my post above that I also take ADB12 at high doses, 60mg daily.

I'm located in China and have been helping a local Chinese woman to try this treatment. She seems to show the paradoxical folate deficiency just like Freddd describes it happening. After reading this thread, I understand that she may need to go up more quickly than she has been on the dose.

 

[dbkita]

Like Freddd says, hypokalemia takes some time to develop (3-4 days in my case). You can probably go as high as you want with folate on a single day, without getting into trouble. But if you continue the high folate doses for several days in a row, K will start to drop. It least this is what happens to me.

Btw, I have done pretty high doses lately, without any hypokalemia. As I have said before, I do not believe the hypokalemia is induced by healing (or the creation of new cells). It's simply that more K is being excreted (for whatever reason). In my case it seems to have something to do with ALCAR. I am not supplementing any K at the moment, and even avoid high K foods. Still my pulse has been low and I need extra salt.

Is this still holding true with 500 mg ALCAR or a higher dose?

I wish I could take more methylfolate. Crushes me with hypokalemia if I do. I recently raised p5p to 50 mg and riboflavin (by dose splitting) and within a few days my telltale signs of hypokalemia came crashing back. And that was keeping methylfolate fixed. Gah!

 

[dbkita]

Adreno and Dbkita, unfortunately you are both way beyond my understanding so I can't further contribute though I read with interest and attempt to understand. The autoimmune does apply to me though, both Hashi's and celiac. My doc didn't check my folate receptor antibody level. I also don't have pre-protocol levels of THF, 5 mthf and folinic from the panel above. I did have low GSH, low cysteine, taurine and glycine levels which have corrected since being on the current folate/B12 regimen but did not correct on MB12 injections only at 5 mg a week. My MMA and Figlu were indicative of the issue but not indicative of my need for such high doses as far as I know. I should have mentioned in my post above that I also take ADB12 at high doses, 60mg daily.

I'm located in China and have been helping a local Chinese woman to try this treatment. She seems to show the paradoxical folate deficiency just like Freddd describes it happening. After reading this thread, I understand that she may need to go up more quickly than she has been on the dose.

Lithium is important to b12 transport especially if you have MTRR defects. Be careful with lithium though. Maybe something to bring up with your doctor. Good luck!

 

[Xara]

Thanks pela, Freddd and adreno, for the information given, for sharing your personal experiences, I am much more confident now about figuring out what my best methylfolate dose might be by trippling each dose.

I do keep potassium handy for when I need it, and normally eat a high potassium diet--5000-5500 mg per day. Why are you waiting until Friday?

Thanks for those figures as well, pela, it's nice to know, it's nice to have some guidelines, despite the fact reactions and intakes needed are indeed very personal.
On Fridays I always make a new intake schedule, I usually take a week to see how things develop, unless things deteriorate seriously of course.
Being in Europe I am in a different time zone. I wrote yesterdays message at 1.30 AM local time, so officially Thursday had already started over here. Things were/are not that urgent that I can't take a day to think about what to do and read the opinions, suggestions and experiences of the experts.

The low potassium symptoms (...)I hope this is clear. Some of these things are just fuzzy.

Very clear, Freddd. This technical info, the third day, the comparison with blood falling sugar, the (relative low) potassium need of CNS, food potassium helping tomorrow not today, (how much) potassium in water will help (when) (with what) today, rather quickly thank heavens for that, more potassium needed to reverse the insufficiency momentum than needed to maintain that reversal - it's all very interesting and all very helpful to understand what to expect and what to do. Your explanation has been very reassuring, Freddd. Thank you so much.
I am improving slowly, I am healing, without your protocol and the people who improved following your suggestions I would not have started improving myself (hB12 worsened my condition).

Like Freddd says, hypokalemia takes some time to develop (3-4 days in my case). You can probably go as high as you want with folate on a single day, without getting into trouble. But if you continue the high folate doses for several days in a row, K will start to drop. It least this is what happens to me.

That's a relief to know, adreno. Thanks. I noticed you and I share some similarities so I am always keen on how to learn how something worked out for you.

Btw, I have done pretty high doses lately, without any hypokalemia. As I have said before, I do not believe the hypokalemia is induced by healing (or the creation of new cells). It's simply that more K is being excreted (for whatever reason). In my case it seems to have something to do with ALCAR. I am not supplementing any K at the moment, and even avoid high K foods. Still my pulse has been low and I need extra salt.

ALCAR? No LCF? (I missed a post of yours?)
I am having less trouble with K as well. I think my last troubles (fasciculations, muscle spasms, electrical shocks, high pulse when active, weak muscles) were caused by a disbalance in K, Ca, Mg and Na - thanks dbkita, he was right (naturally ) It seems I took too much K compared to the other elements.
A couple of weeks ago I used 2700 mg of potassium gluconate on top of my diet (about 3000 mg). Now I'm taking no supplemental K when having my smoothies at breakfast and lunch (they contain K rich fruits), and nothing with my afternoon snack, I am only taking some (300 mg or so) at dinner and late in the evening. So I have room now to increase - if needed.

I'm really glad to read you're doing better, adreno. How much of everything are you taking ATM? Are you planning an increase soon?

 

[adreno]

Is this still holding true with 500 mg ALCAR or a higher dose?

Yes, this is at 500mg ALCAR. There might be other factors involved, as we discussed before. My point is that it seems it is possible to take high doses of methyl donors without getting hypokalemia, although I do not understand the exact mechanism.

 

[adreno]

I'm really glad to read you're doing better, adreno. How much are you taking ATM? Are you planning an increase soon?

Thanks I change things quite a lot, so I realize it can be hard to keep up with that. Since my pulse dropped to low 50s almost 2 weeks ago, I have been experimenting with higher doses of mb12 and mthf. At the moment I take 5mg, 5mg adb12 and 5mg mthf. I am trying to find out how ALCAR and maybe a few other nutrients influence methylation and K balance. LCF has no noticeable effect on me.

 

[Xara]

Thanks I change things quite a lot, so I realize it can be hard to keep up with that. Since my pulse dropped to low 50s almost 2 weeks ago, I have been experimenting with higher doses of mb12 and mthf. At the moment I take 5mg, 5mg adb12 and 5mg mthf. I am trying to find out how ALCAR and maybe a few other nutrients influence methylation and K balance. LCF has no noticeable effect on me.

Interesting! Since so many supplements affect blood sugar and blood pressure and since I am not high in both of these I am regularly checking them at home. Last Friday for instance I started taking Jarrow Formulas' R-ala five times a day but I had to go back to three times a day, because sugar went as low as 2.7 mmol/L on empty stomach, at least according to this device I have at home. Blood pressure was a minute ago: 91 and 61, pulse: 55, which is not an exception in my case.
I am curious what will happen in these areas next week when I'll start upping mfolate, mb12 and ab12 tomorrow, I am taking Dr's Best LCF 3 x 1 capsule, but did not notice much thus far. Please, adreno, would you be so kind to keep me updated on the (non) effect of ALCAR and the other ones on BP, methylation and K balance? Thanks!

 

[Xara]

I should have mentioned in my post above that I also take ADB12 at high doses, 60mg daily.

Hi EastWest,
60 mg of aB12 - that's quite a bit. I'll start trying 2 x 10 mg of AN Dibencoplex tomorrow, since a friend of mine, she told me that after taking that amount of aB12 the aching in her muscles disappeared. So I'd like to know: how come you're taking 60 mg? Any improvements related to that?
Thanks!

 

[Freddd]

Interesting! Since so many supplements affect blood sugar and blood pressure and since I am not high in both of these I am regularly checking them at home. Last Friday for instance I started taking Jarrow Formulas' R-ala five times a day but I had to go back to three times a day, because sugar went as low as 2.7 mmol/L on empty stomach, at least according to this device I have at home. Blood pressure was a minute ago: 91 and 61, pulse: 55, which is not an exception in my case.
I am curious what will happen in these areas next week when I'll start upping mfolate, mb12 and ab12 tomorrow, I am taking Dr's Best LCF 3 x 1 capsule, but did not notice much thus far. Please, adreno, would you be so kind to keep me updated on the (non) effect of ALCAR and the other ones on BP, methylation and K balance? Thanks!

Hi Xara,

Not everybody responds or has need for LCF. And part of the time a person response best to ALCAR. I tried 4 or 5 forms including the mix of 4 from Jarrow. The ONLY one that worked, and that was gangbusters, was LCF. Some people find it is ALCAR. I've not heard of any other than those two being tremendously effective.


Your pulse sounds like mine was when I was in excellent condition skiing and jogging.

 

[Freddd]

Adreno and Dbkita, unfortunately you are both way beyond my understanding so I can't further contribute though I read with interest and attempt to understand. The autoimmune does apply to me though, both Hashi's and celiac. My doc didn't check my folate receptor antibody level. I also don't have pre-protocol levels of THF, 5 mthf and folinic from the panel above. I did have low GSH, low cysteine, taurine and glycine levels which have corrected since being on the current folate/B12 regimen but did not correct on MB12 injections only at 5 mg a week. My MMA and Figlu were indicative of the issue but not indicative of my need for such high doses as far as I know. I should have mentioned in my post above that I also take ADB12 at high doses, 60mg daily.

I'm located in China and have been helping a local Chinese woman to try this treatment. She seems to show the paradoxical folate deficiency just like Freddd describes it happening. After reading this thread, I understand that she may need to go up more quickly than she has been on the dose.

Hi EastWest,

China, there is another place I would love to visit while I can still travel. My partner went to China with a Utah Choir a few years ago and spent 10 days there. They gave some performances at some kind of large get together and it was on TV. They had a great time My health problems kept me from traveling.

So how are you taking the AdoCbl of 60mg? That is a CNS penetrating dose if enough is absorbed. Have you tried l-carnitine fumarate? This kind of dose being effective indicates to me certain CNS problems. I believe that they can be managed and kept in remission for decades as long as the qualitative aspects of the needed cobalamins are in order. As far as MeCbl goes, you may not have found an effective one. Some batches of crystal are great and others are not.



Congratulations on finding the combination that works for you. It's good of you to help a woman there.

 

[Freddd]

The way an autoimmune disease works, the antibodies will be bombing the folate receptors provided their "trigger" is active. The folate receptors are located on the outside of the cell membrane where the antibodies can "see" them.

Those receptors are about bringing THF into the cells. So you probably would need higher concentration of folate to get a certain effect since active receptor density on the cell surfaces would be lower. Taking folinic acid or l5mthf would bypass this in principle I think. BUT ... taking lots of precursors to THF may makes things worse ... maybe.

We are presumably talking about antibodies to a receptor that binds a substrate to transport it into cells and NOT the production of the substrate. For example, I have glutamic acid decarboxylase antibodies. That means they attack the enzyme that produces GABA. Not the GABA receptors themselves. If I stimulate in my case GAD activity, I get worse. But why would the presence of THF and its precursors trigger the antibodies any worse unless the body adaptively creates more folate receptors in response to high plasma concentrations, which sadly I do not know the answer to. l5mthf and folinic acid however, do not bind to the folate receptors in question to my knowledge.

Still not sure how the body would handle lots of floating THF or its precurors in the bloodstream and not much ability to dock those to make folinic acid and l5mthf. That could have its own issues

I would be cautious about jumping to the conclusion that this a common problem. CFS is not uncommon yes. But once you ignore Hashiimoto's, Celiac's and type 1.5 diabetes, autoimmune disease are pretty rare. It is an interesting concept though. I will discuss with one of my doctors.

I would also think this would have some sort of signature pattern on an HDRI methylation panel or equivalent. Just not sure what the pattern would be. Depends on their testing methods also I suppose.

From their website:

"Methylation Pathway Parameters Tested:

Glutathione (oxidized), Glutathione (reduced), S-adenosyl-methionine (RBC), S-adenosyl-homocysteine (RBC), Tetrahydrofolate (THE), 5-methyl-THF, 10-forrnyl-THF, 5-formyl-THF, Folic Acid, Folinic Acid, Folic Acid (RBC), Adenosine"

Here is Rich Vank's explanation of the test:

http://forums.phoenixrising.me/index.php?threads/methylation-pathways-panel.4711/

So if you have antifolate receptor antibodies would you not expect high plasma THF and low 5mthf and probably low folinic acid since the latter two cannot be generated well from transported THF? Just a thought.

Hi Dbkita,

So now we come to an autoimmune situation. Classic IF insufficiency Pernicious Anemia is thought to be caused by autoimmune antibodies. However, fewer than 50% with PA have antibodies to IF or parietal cells. The longer a person continues in PA the more likely they are to have antibodies. This causes a conundrum because according to the theories of the last 50 years it "should be" the other way around and was always assumed to be. However, with a large percentage of macrocytic anemia MeCbl doesn't fix it but l-methylfolate does, as with me. As the immune system appears to go weird and hyper when a person is in methyltrap or maybe methyltrap with partial ATP block, it makes sense that the longer a person has macrocytic anemia the more likely to have autoimmune antibodies.

 

[dbkita]

Yes, this is at 500mg ALCAR. There might be other factors involved, as we discussed before. My point is that it seems it is possible to take high doses of methyl donors without getting hypokalemia, although I do not understand the exact mechanism.

Hmmm if there was a way to figure out those other factors it could be very enlightening. What dose schedule perchance are you using for methylfolate and mb12 / adb12? Also is the 5mg of adb12 a dose escalation or did you try that in the past to no avail?

 

[adreno]

Hmmm if there was a way to figure out those other factors it could be very enlightening. What dose schedule perchance are you using for methylfolate and mb12 / adb12? Also is the 5mg of adb12 a dose escalation or did you try that in the past to no avail?

The last time I tried similar dosing I needed 10g of supplemental K. So something is definitely different. I had some hypokalemia show today, so have supplemented a bit (less than 1g). I have a cold so that might be why. Also I have stopped the manganese a few days ago, to see if this would have an effect. Although it is nice to be free of hypokalemia, having hyponatremia and brachycardia isn't much fun either. There where also a few other factors; I changed my dosing from 1 x 15mg MK-4 to 3 x 5mg. Still, I'm stumped why any of these factors would have such a profound effect. It'll take some time to sort it out, I'm afraid.

 

[Xara]

Hi Xara,

Not everybody responds or has need for LCF. And part of the time a person response best to ALCAR. I tried 4 or 5 forms including the mix of 4 from Jarrow. The ONLY one that worked, and that was gangbusters, was LCF. Some people find it is ALCAR. I've not heard of any other than those two being tremendously effective.


Your pulse sounds like mine was when I was in excellent condition skiing and jogging.

You're kiddin'! All this effort to get a pulse like mine? All I have to do is sit on the couch all day.

I'll look into ALCAR, Freddd, don't know much about it, thanks for mentioning it, much appreciated.

 

[dbkita]

The last time I tried similar dosing I needed 10g of supplemental K. So something is definitely different. I had some hypokalemia show today, so have supplemented a bit (less than 1g). I have a cold so that might be why. Also I have stopped the manganese a few days ago, to see if this would have an effect. Although it is nice to be free of hypokalemia, having hyponatremia and brachycardia isn't much fun either. There where also a few other factors; I changed my dosing from 1 x 15mg MK-4 to 3 x 5mg. Still, I'm stumped why any of these factors would have such a profound effect. It'll take some time to sort it out, I'm afraid.

Yeah something is very different. I don't see vitamin k as the driver. I also wonder why the hyponatremia. Are your fluid retention capabilities ok? Is urination normal? I like 5 mg Mn but I don't see it altering my potassium balance in an obvious way.

 

[Victronix]

Like Freddd says, hypokalemia takes some time to develop (3-4 days in my case). You can probably go as high as you want with folate on a single day, without getting into trouble. But if you continue the high folate doses for several days in a row, K will start to drop. It least this is what happens to me.

Btw, I have done pretty high doses lately, without any hypokalemia. As I have said before, I do not believe the hypokalemia is induced by healing (or the creation of new cells). It's simply that more K is being excreted (for whatever reason). In my case it seems to have something to do with ALCAR. I am not supplementing any K at the moment, and even avoid high K foods. Still my pulse has been low and I need extra salt.

Just wondering, are you still having less hypokalemia? And do you still think it is related to ALCAR? Is your pulse still low?

I'm seeking a roadmap for coping with K, of course.

The idea that more K may just be being excreted is very interesting. I have experienced real healing of damaged tissues with both B-12 and methylfolate (even at just 50 mcg), so I do know that actual healing is going on, but I don't know if the mechanism does or doesn't involve K.

 

[adreno]

Just wondering, are you still having less hypokalemia? And do you still think it is related to ALCAR? Is your pulse still low?

My pulse started going up again when I dumped the ALCAR. I am now on 1000mcg x2 mfolate, and 5mg mb12/ab12. For that I do get some hypokalemia at times, and I need to supplement around 1g K daily. But the loss of K is not anywhere near what I experienced last year on the same doses. Why that is, I don't know, but I have changed my regimen quite a lot since then. Maybe something else I'm taking has improved things. Manganese might be a factor, I have been taking 5mg daily recently, and that seems to help.

 

[Victronix]

Thanks, that's helpful. Interesting about Manganese. I've never considered it.