Discussion in 'Detox: Methylation; B12; Glutathione; Chelation' started by Freddd, Mar 10, 2011.
Kurt or anyone
what lab markers would indicate a need for electrolytes?
Hi Rich -- thanks so much for joining this conversation.
This is what worries me.
I had bad reactions -- to something -- which got ramped up big time as I took more forms of folate (and more frequent doses) -- but double checking right now...I had been prescribed Folapro (which is similar to Metafolin?) back in late 2009, but I was told this didn't "test" well in March 2010, so it was actually one of the folates I wasn't taking this past fall/winter when things went from bad to worse. Hmmm...
(I'll list what I was prescribed hopefully tomorrow...)
Is folinic acid the only form of folate that helps make new blood (and other) cells? One of the main things I've noticed increasingly during the past four months is that my feet look like they're drained of blood, and quite dehydrated. Seriously. Which also coincides with the icy cold feeling -- and the tingling, twitching etc.
I guess my question is...are we talking about supplemental glutathione (and/or NAC) or are we talking about glutathione that's naturally produced in the body from glutamine, glycine, etc.,?
Thanks Rich, and thanks too to Freddd and Kurt and all for their replies. I'll try to reply to their posts tomorrow, but right now, my clock is SPRINGING FORWARD, so it's already 11:30 and past time for bed.
Competition of folic acid with chemically reduced folates and DHFR reactions
Hi, Freddd and the group.
I think the following is the explanation of why taking folic acid together with one or the other of the chemically reduced folates (either folinic acid or 5-methyl tetrahydrofolate) will interfere with absorption of the latter. My main source of information for the following is the book “Folic Acid and Folates,” edited by Gerald Litwack (2008):
Folic acid is the oxidized form of folate and is the most commonly sold form of folate supplement. It does not occur in significant amounts in natural food sources of folate. It has a long shelf life, which is an advantage commercially, but is not directly usable by the body until it is converted to chemically reduced forms of folate. Since 1999, it has been required that it be added to processed grains in the U.S. in order to decrease the number of neural tube birth defects, such as spina bifida, which are caused by folate deficiency, and this has been found to lower the rate of these birth defects. Some other countries also require this. There is still some controversy, however, over possible disadvantages of adding folic acid to the diet. There has been some published evidence suggesting that the function of natural killer cells can be inhibited by folic acid, and this raises the question of possible increased cancer risk, but the evidence is not very strong for this, and it remains an unsettled issue.
The folic acid molecule incorporates one glutamate molecule in its “tail.” The reduced folates found in natural foods have several glutamate molecules in their tails. When the latter are ingested, all but one of the glutamates are removed by the enzyme glutamate carboxypeptidase II, anchored to the wall of the gut, before the folates are absorbed.
The glutamate molecule is doubly ionized at the pH present in the gut, and this gives folic acid and the folates a double negative charge on their molecules. Because of this charge, they are not able to diffuse very readily through the lipid membranes of the cells lining the small intestine (enterocytes), so they must have active transporters in order to be absorbed in significant amounts when received in food or taken as supplements (unless very high dosages are used, so that the concentration in the gut rises above about 10 micromolar).
There are several types of transporters in the body that can bring folates across cell membranes. It has been found that in humans, most of the folic acid and reduced folates are absorbed by means of the so-called proton-coupled folate transporters (PCFTs). These absorb the folic acid and reduced folates by coupling their transport to transport of a proton (hydrogen ion) and bringing them in together. This takes place primarily in the early part of the small intestine, where the pH is still more acid, because of stomach acid, because of the need for hydrogen ions (acid) in this transport mechanism. The transport is driven by the gradient in hydrogen ion concentration between the lumen (inside space) of the gut and the inside of the enterocytes, where the pH is more nearly neutral (pH 7).
I think the key to the interference of folic acid to absorption of the reduced folates occurs right here. The reason is that the affinities of the PCFTs for folic acid and for the reduced folates are comparable to each other. Therefore, these species are in competition for absorption by the PCFTs, and if there is a high concentration of folic acid in the gut lumen when the reduced folates are taken, there will be less of the reduced folates absorbed.
I’m going to carry this a little further to include what happens after absorption into the enterocytes: Some of the folic acid is reduced by dihydrofolate reductase (DHFR) in the enterocytes, but most of it is transported to the liver as folic acid. On the “back side” (basolateral membrane) of the enterocytes, there are what are called “multiple drug-resistance transporters,” and these are able to transport both folic acid and the reduced folates out of the enterocytes and into the blood in the portal vein, which flows to the liver, again with similar affinities. I haven’t found out yet which transporters are the dominant ones that bring folic acid into the liver cells. I do know, though, that most of the folic acid reduction by DHFR occurs in the liver, so folic acid must be transported into the liver cells.
The DHFR reaction to reduce folic acid to dihydrofolate is a slow reaction in humans in general, and the range of rates of this reaction varies by almost a factor of five among different people, so some people are not able to utilize folic acid very well. The result is that folic acid enters the general blood circulation and can have a half-life there of several hours.
The natural function of DHFR is actually to reduce dihydrofolate to tetrahydrofolate, which is part of the pathway for making thymidylate for DNA synthesis. It happens that this enzyme is also able to reduce folic acid to dihydrofolate, which has made possible the use of folic acid as a supplement, but this is a very slow reaction.
Folic acid competes for DHFR with the normal dihydrofolate reaction and slows it down. This may be another point at which folic acid can interfere with the normal processing of folates in the body. In addition, the DHFR enzyme plays a role in reducing dihydrobiopterin to tetrahydrobiopterin (BH4), which is needed in the synthesis of nitric oxide and the neurotransmitters serotonin and dopamine, as well as in the conversion of phenylalanine to tyrosine. Again, folic acid may slow down these reactions as well.
I think these are the issues involved in the competition of folic acid with the reduced folates and the reactions of DHFR in the body.
In addition to what I've discussed here, there is the possibility of an individual person having various genetic polymorphisms, which can affect the transport and metabolism of folic acid and the folates, and cause changes from the normal functions that I have discussed above.
Rich, thank you for posting this information.
I just started Fred's protocol about a month ago. I was really nervous about starting since I am so sensitive to all supplements. From the start, effects weren't as bad as I anticipated (mostly), not until the last three days.
Three days ago, I decided to up my adb12 to 6 mg a day. I also up my mb12 to 4.5 mg a day from 3 mg. I have also been taking 2 b-right a day for about a week. I am still ramping up on the other vitamins, maybe about half way there.
From what you are reporting, if folic acid has the attached glutamate molecule to the tail, then couldn't by upping my b-right and adb12 that contain folic acid, raise my glumate levels, which are already elevated?
Sorry if this is a dumb question. I am so brain fogged at the moment. I am just trying to understand so I can figure out a way to proceed on with the protocol.
Fred, any thought/suggestions are greatly welcomed by you too. For that matter, anyone's are appreciated.
The bottom line is, when I get start-up symptoms or suffered ill effects from past detox attempts, my anxiety, insomnia, depression, and fatigue greatly increase to intolerable levels.
Thank you for the advice.
Blood test for electrolytes. That will measure levels of Calcium, Magnesium, Sodium and Potassium.
There is a simple indicator you can use if you can see pressure in the blood vessels on the back of your hand. I am lucky and have low body fat and can see the veins protrude well. This is easiest sitting but probably you could stand. So sit and place one hand on a thigh. Notice how much the blood vessels on the back of the hand are puffed-up (this shows blood pressure visually). Now slowly raise the hand, watching the blood vessels. They should 'disappear' around the level of your eyes. This means they stop puffing up, you may still see the discoloration from bloodflow, but the pressure is now lower and they 'disappear'. If the electrolytes are off balance, your blood pressure will be 'off' and the puffy veins will disappear either before reaching the eye level (low BP, presumably from electrolyte imbalance), or well above the eye level (hypertension, also presumably from imbalance). I would only rely on this test though if you have known electrolyte balance problems. I have had the blood test and know my levels can get off, and have learned to tell when I need electroytes. For some years I used the product 'Recoup' with some success, but now I use a less expensive product called '40,000 Volts'. However, I don't follow the directions, which are for severe dehydration cases, I just need a few drops usually to restore balance.
My experience of Mg (I use chloride oil) without a B complex in place was pretty much a train wreck, and I've restarted it now with good results so far.
Rich, thanks from me too for your input. My "initiating event" in 1984 resulted in fairly agressive and lengthy treatment with a DHFR inhibiting drug, and the extra information is very interesting.
Freddd - they've been enriching foods like that since the 60's? What an eye opener!
NZ shelved the idea of mandatory folic acid fortification in 2009 with a review due next year. I'll have to make some more noise
Do you take mag chloride internally, or as mag chloride "oil" externally?
I have the mag oil, which I've used just occasionally. It's probably not going to do much if I don't use it regularily, but it usually hasn't tested as needed (via kiniesology, which may not be very accurate), and most forms of magnesium cause almost instant loose bowels. I know, too much information. I am a little concerned about the trace metals in the mag oil, but perhaps (as usual) I'm overreacting.
I too have found (so far anyway) that I need more sodium than potassium, and used to find a lot of benefit from Recup. But haven't taken it in years -- too expensive. Very puzzling too why Blasi never found a distributor in the USA.
Anyway Kurt -- does the chloride form of magnesium cause less diarrhea? And how much do you take? Also...do you take a calcium supplement to balance it?
p.s. One more question (for now): Do you require as much or as many doses as Freddd is taking of b12, etc., to keep your symptoms reduced? I know the info is here somewhere, but I still don't quite understand why Freddd needs to take so much b12/methylfolate each day before he starts regressing...
Thanks for your reply. A DECREASE in anxiety/tension would be great! I'll try your lozenge 'technique' too.
I just wonder if my salivary glands -- or my overall digestive system is deficient in amylase...?
I'm certainly not Rich or Freddd, and am definitely Mr. Brain Fog, so I want to tell you first that there are no dumb questions!
With that said, I am guessing that it may not be the glutamate (at least not by itself). Glutamate converts into gaba (I think) as long as there's enough manganese and b2, and possible other co-factors. Note that Rich said that folic acid has one glutamate molecule, but that the reduced forms have 'several glutamate molecules'.
It might be the fact that you increased the vitamins that have folic acid in them, which might block the metafolin, which may have caused the increased symptoms...or it may be that the increased adb12 interfered(?) with the methyl-b12? I think Freddd takes the adb12 only once a week, but not certain about that.
Hopefully Rich and Freddd will be able to respond with more authority. I can relate to your symptoms -- "intolerable" says it all.
Just my two cents.
I usually take only one mag chloride tablet by Alta per day. Sometimes a half tablet works as well. If I don't take the mag chloride, the B vitamins do not seem to have as much positive effect on the nerves. No, this does not cause hypermobility in the digestive system for me, I believe mag chloride is better absorbed in the gut than many if not all other forms, and I have tried them all. But I don't generally have that problem anyway, so don't know if that will help in your situation. What I have found is that the effect Rich and Freddd talk about requires magnesium chloride and B6 taken together with the B12, for me and others who have tried this approach. And Vit-C. I suspect some people need B5 instead of or in addition to B6, depends on your genetic details probably. These are all required for methylation, I originally found this from a methylation diagram someone posted, it is right there in the methylation cycle, you must have adequate B6, magnesium, B12 and vitamin C. And all of these can be depleted, in my experience with CFS, for whatever reason. I don't get a benefit from bypassing the proposed methylation cycle block, or simply supplementing with B12, when I am not supporting the entire methylation cycle like this. I have tried the other protocols, this was required to get everything working. I need far less B12/methylfolate this way, but can't speak for Fred or why he needs so much.
Thanks for your reply Kurt.
I just looked again at my nutrEval test results from last summer (already!), and interestingly, under "Nutritional needs", they listed copper at a "2", manganese at "3", iron at a "3", and magnesium at a "7".
b1 - 0
b2 - 2
b3 - 1
Folic acid - 9 (!)
B6 - 9
B12 - 4
A, E, Beta-carotene - 7
Vitamin C - 0 (!)
Lipoic acid - 6
Glutathione - 1
I've never seemed to do well with vitamin c, but perhaps that may be due to the low copper (as they antagonize each other I believe). I'm going to try and get a copper/ceruplasmin blood test -- the other testing for copper has either been through hair or kinesiology...so should have it confirmed.
But I'm wondering Kurt -- in addition to methylation, do you think it's possible that the need for b6 and magnesium may be due to possible PST or sulfation issues that are found in the autism spectrum?
From this link:
"Dr. Waring’s results confirm what ARI had first reported in 1973: whenever extra vitamin B6 is given, it must be accompanied by extra magnesium, or adverse effects may be seen. In our first study of vitamin B6 in autistic children, conducted in the late 1960s, a small number of the autistic children in the experiment showed increased sound sensitivity, irritability and enuresis when the B6 was started. When magnesium was added, these side effects immediately disappeared and the beneficial effects of the B6 were enhanced. Several studies by the research team led by Dr. Gilbert LeLord of Tours University Medical School, in France, confirmed our report that the combination of vitamin B6 and magnesium was markedly more effective than either vitamin B6 or magnesium alone."
And also, do you have a link to that methylation cycle diagram?
Kurt, I asked this in a separate post, but since it's close to what you're saying here, I'll get your input.
Having trouble taking cal./mag. (was taking it at lunch, got a very distinct late pm mental malaise). I realize that magnesium is crucial to the methylation cycle, but what about calcium? Can it be foregone? I'm hoping that I can tolerate magnesium alone.
Also, you said you've tried them all. I'm using "Natural Calm" pure magnesium powder by Natural Vitality. Could that brand be part of the problem? You mentioned magnesium chloride - you find it superior?
Thanks for any advice you can offer.
so they must have active transporters in order to be absorbed in significant amounts when received in food or taken as supplements (unless very high dosages are used, so that the concentration in the gut rises above about 10 micromolar).
So, the sublingual use for 60 minutes to absorb adb12 also would absorb a lot more than usual folic acid? This might be a factor in the folic acid in the Country Life causing worse and quicker deficiency symptoms.
However, I note that you did not respond on the folinic acid. I had the same problem with the folinic acid once a day as 800mcg oral. It just took a month instead of a week. So what is a possible reason that folinic acid is causing the same result? There is no doubt that it is doing so for quite a few people. The question is why?. Your explanation of "why" to use folinic acid was convincing enough for me to try it. Now I want to know why it might be causing a paradoxical folate deficiency in some people. I haven't tried it in isolation yet because I need to get rid of all the other sources of folic acid first. Others here however have the same response to straight folinic acid and have for years, even getting worse over times as deficiencies do.
So is the consensus here that we should be avoiding both folic and folinic acid in using the methylation protocols ? If so doesn't that make some of the supplements used in both Freddd's and Rich's protocols unusable ? Or do we just have to time doses so that mehtylfolate is spaced out and taken away from anything containing folic acid or folinic acid ?
This is the brand I used to rely on -- for years it gave me a 'lift' when things were spiraling downward. But perhaps the folic acid was slowly depleting the active folates? (I used this even before, in fact 5-6 years before I developed CFS...hmmm...)
Is there an ad-b12 without the folic acid?
Drex13 -- I think it's Freddd's position that both folic acid and to a lesser extent folinic acid my be depleting methylfolate in a percentage of folks -- not in everyone.
Ah-ha. I haven't gotten far enough along into methylation to know whether or not this is a problem for me. I can't seem to get past even a 1/4 tab of 5mg mb12 without feeling crummy. As for your question about the adb12, I did see some adb12 drops on the the holisticheal (Yasko's) website. I don't think they contain anything but adb12.
As i mentioned above Source naturals has adb pure sublinguals.
Yasko also carries a sublingual adb12, even though it is currently out of stock. However, it is expensive. $19.50 for 30.
I would say that it is affecting an unknown percentage of folks, and probably not everyone. For me folic acid had to be taqken more often in larger doses to block the methylfolate enough to induce deficiency symptoms. Folinic acid took just 800mcg a day in a single dose. Folinic acid has a longer serum halflife which might account for the difference. There is an awful lot of uncertainty in all this. Unfortuantely the only thing I can be certain of is that I and substantial number of others are affected by both folic acid and folinic acid blocking the Metafolin.
My experience was that the folic acid could be overcome by Metafolin as long as it was taken infrequently enough, which orally turned out to be morning and evening with metafolin and mb12 taken at other times, such as several hours before a B-right, and several hours after, in 3 doses during the day. A single dose of folinic acid on top of the 2x B-right a day was enough to induce deficiency in me.
A mild or strong "detox" reaction appears to be the clue. Since the term "detox" no doubt covers more than one set of reactions we learn to identify those that are actually folate/b12 deficiencies. Correcting the ones that we can might allow a clearer picture of what remains. Ones own leading edge folate deficiency symptoms would be a good indicator but takes multiple expiriences usually to recognize. Nobody can really define this yet. It's going to take the combined experiences of those many of us having this effect to understand how it works. We are just beginning to learn what doesn't work and a few things that might for any given person. Ultimately going to products with all the good qualities without folic/folinic acid is what each of us probably needs to do for best effectiveness, if we are affected by folic/folinic acid.
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