Why is potassium supplementation needed in methylation treatmt?

This is a repost from the ProHealth FM/CFS board, in response to a request:

Hi, Mary.

Yes, I agree that potassium deficiency is an important issue to watch for and to correct when a person is doing one of the methylation protocols for ME/CFS.

Freddd is the one who first brought this to our attention, I think because it showed up so strongly with his protocol, which includes relatively high dosages of B12 and folate, compared to what is suggested in the simplified methylation protocol.

It made sense to me from the standpoint of the biochemistry of ME/CFS when he first mentioned it, though I hadn't thought of it before. Here's why:

In 2001, Burnet et al in Australia reported measuring the whole-body potassium content of people with CFS compared to healthy normals. This is possible by using a whole-body gamma ray counter, because all potassium, including that in our bodies, contains a small amount of the natural radioactive isotope, potassium-40, which emits an energetic gamma ray. (This potassium isotope has a very long half-life, and is thought to have been present since the formation of the earth, several billion years ago. It has been decaying ever since, but there is still enough to measure because of its long half-life.) Since the current concentration of potassium-40 in potassium is known, it is possible to calculate the total potassium in the body using this measurement.

Burnet et al. found that the CFS patients who had predominately fatigue but not muscle pain were low in whole-body potassium by more than 10% compared to normal. They also measured the plasma level in the blood serum, and that was found to be normal.

It is known that at least 95% of the potassium in the human body is inside cells. Potassium is the most abundant positive ion inside all cells. So the measurements of Burnet et al. mean that the CFS patients they studied were significantly low in intracellular potassium.

The observation of low intracellular potassium in the presence of normal serum potassium means that there is a problem with the membrane ion pumps that normally pump potassium in (and sodium out) of the cells. These pumps require ATP for their energy supply, and that implies that the mitochondria are not able to supply enough ATP.

We have other evidence now for mitochondrial dysfunction in ME/CFS, so this fits together very well. In the GD-MCB hypothesis, the mito dysfunction is a result of glutathione depletion and a partial methylation cycle block.

O.K., this part was important to explain, because it means that there is no "cushion" in terms of potassium supply in these PWCs.

Now, another thing to note is that it is likely that PWCs have a smaller total number of cells than normal. The reason is that measurements have shown a higher rate of die-off of cells (early apoptosis) in CFS, and also an abnormal arrest in the S phase and the G2/M boundary of the cell cycle (Vojdani et al., 1997). What this means is that the cells are dying off early, and are not being replaced as fast as normal.

According to the GD-MCB hypothesis, the early apoptosis occurs because of damage to the cells by oxidative stress resulting from glutathione depletion.
The arrest of the cell cycle occurs at the stages where the DNA is supposed to be replicated and the cell is supposed to divide, to form two cells. Something is hindering the DNA replication. What is it?

According to the GD-MCB hypothesis, this is caused by the inability of the cells to produce new DNA at a normal rate, which in turn is caused by depletion of the folates in the cells. This in turn is caused by the partial block of the methionine synthase reaction, coupled with the methyl trap mechanism and the catabolism of methylfolate by peroxynitrite, which is elevated because of glutathione depletion.

O.K., so now we have a situation in which the PWC has fewer total cells than normal, and the cells that the PWC does have are lower in potassium than normal.

Now, enter a methylation protocol, which incorporates at least B12 and methylfolate. The effect of this will be to increase the rate of the methionine synthase reaction. One of the effects of this will be to convert methylfolate into tetrahydrofolate more rapidly, and the latter is then converted to other forms of folate, including those needed to make purines and thymidine, which are necessary for making new DNA.

All of a sudden, the cells now have enough DNA to overcome the arrest of the cell cycle, and their rate of cell division goes up, making new cells more rapidly.

These new cells require potassium, and their membrane pumps start pumping it in from the blood plasma. Unfortunately, since the existing cells, which contain 95% of the body's potassium inventory, are already low in potassium, there is no cushion or buffer for the blood plasma potassium level, and if it is not augmented by increased potassium intake from the diet or supplements, the PWC's blood plasma potassium level drops, resulting in hypokalemia. This is hazardous, because it can have detrimental effects on the heartbeat and on other vital processes in the body, such as the use of muscles for breathing.

So that, in my opinion, is why it is important to watch the potassium level when on methylation treatment.

I think this is especially important if large dosages (several milligrams per day) of methylfolate and sublingual or injected methyl B12 are used, because this takes control of the rate of the methionine synthase reaction away from the cells and overdrives the methylation cycle. One result of this is that the folate levels rise rapidly, and cell division also rises rapidly. Under these circumstances, the normal supply of potassium from the diet may not be sufficient to supply the extra potassium that is needed. This is one reason why I do not favor taking high dosages of methylfolate and methyl B12 together by a person who has ME/CFS, but if a person chooses to do this, it is important that they monitor their blood potassium level and augment it as needed.

Note that over-the-counter potassium supplements are limited to 99 mg per pill. The reason for this is that if too much potassium is concentrated in one place in the digestive system, it can damage the wall of the digestive system.
It is preferable to take the potassium in the form of high-potassium foods or juices, or solutions of potassium salts, as tolerated.

Best regards,

Rich

Do you have to worry about potassium falling drastically with high doses of B12 irregardless of dissease? I mean, if you are taking high doses but not diagnosed with CFS but doing it for neuropothy.

My potassium is in "normal" ranges but I am taking 4 of the 1mg B12 Jarrow and Enzymatic Therapy everyday. I take potassium but am not sure if I should be worried about it now.

thanks

Hi, Stacy.

If you are taking B12, but aren't taking any folate, I don't think you will have an issue with potassium deficiency.

Best regards,

Rich

OK great! I take potassium anyway since I am on diuretic for blood pressure, so I didn't wanna get low cuz when i do, I sure feel it in my muscles even before this mess started with me.

I do not take folate, I did not have that checked.

thanks rich!

Thanks for posting this, Rich. So under normal circumstances should patients with CFS/ME ever take more than 200 mcg methylfolate and 2000 mcg of B12, which is the dose you recommend people start with on the Simplified Methylation Protocol? In other words, is there added value to even attempt to increase doses?

Hi, Alice.

Some people need more, and some need to use methyl B12 instead of hydroxo B12. Note that the simplified protocol also includes folinic acid, so there is more than 200 micrograms of total folate in it. There's also some folic acid in the multi, which most people are able to use, though I don't really favor it.

Best regards,

Rich

Hi Rich,

I think a simpler explanation for the need for increased potassium in individuals using very large doses (greater than 2mg) of methylcobalamin (MeCbl, MeB12) and/or L-methylfolate (5-MTHF, Metafolin) is that, by overdriving the Methionine (methylation) Cycle, a large amount of S-adenosylmethionine (SAMe) is being produced that has an aldosterone-related effect via increased methylation capacity as explained in the article below. I think this is actually a better fit for your GD-MCB hypothesis as well.

From, "Toward Understanding the Role of Methylation in Aldosterone-Sensitive Na(+) Transport," News Physiol Sci. 2000 Aug;15:161-165.
http://www.ncbi.nlm.nih.gov/pubmed/11390901 (abstract)
http://physiologyonline.physiology.org/content/15/4/161.full.pdf (full text - direct download):

"Moreover, methylation-promoting agents, such as S-adenosyl-L-methionine (SAMe, also abbreviated SAM and AdoMet), increased Na+ entry across the luminal membrane. That the magnitude of increase in Na+ transport was similar with aldosterone and SAMe and that aldosterone and SAMe were not additive suggests that both work through the same signaling pathway. Several other investigators have also now shown that aldosterone increases substrate methylation in epithelia (9, 10, 12). Also confirmed was that SAMe increases Na+channel activity (4, 6, 9). Several investigators have also reported that a pharmacological inhibitor of methylation attenuates aldosterone-induced Na+ reabsorption, showing further a dependency of transport on methylation (4, 10, 11)."

For the layperson, I suppose this seems to mean that overdriving the methylation cycle - which may not be such a great idea on the whole and over the long term (?) - might have the (unexpected) beneficial effect of increasing blood volume, and therefore blood pressure, which is commonly low in ME/CFS and can lead to many symptoms.

Based on unfortunately very fleeting success I've had with licorice root (effectively a mineralcorticoid potentiator), for example, I was very surprised to find that CFS symptoms that had always felt very nerve-related/neurological to me (weakness, numbness, etc. in the limbs) apparently have a hypotensive origin, since for a brief period (less than a day) they were almost completely resolved by the licorice root, along with my fatigue. I also tried an actual mineralcorticoid, Florinef (fludrocortisone) some years ago, but it wasn't helpful at the time. I've not tried bioidentical aldosterone and am curious if anyone has . . . It's incredibly frustrating (understatement) to know that my body still has the potential to be well again but that I haven't been able to find the key after some 15+ years.

I also have a major mutation (deletion) - not simply an SNP - in the MSH2 caretaker gene that gives a great predisposition to cancer, so I'm reluctant to try for any length of time the much higher doses of MeB12 and methylfolate that Fred, for example, uses for his own unique situation. I'm already an "overmethylator" anyway, and so do much better with hydroxycobalamin, etc. A double conundrum.

As a former research scientist, I do think it's interesting the possibility that megadoses of MeB12 - which are more commonly used for conditions of nerve/CNS damage or dysfunction - may give the appearance of helping with what seem to be neurological issues (but aren't) in the long-standing CFS patient not through an effect of increased concentration of MeB12 in the CSF, for example, but rather (apparently) through an increase in methylation capacity via aldosterone-related pathways - from an overdriven Methionine (methylation) Cycle.

What an amazing finding - I'm surprised I've never heard about that. I have fatigue predominantly but no muscle pain (or at least haven't unless I'm on a b12 protocol and not managing to keep my electrolytes up - then I get sore arm and leg muscles).

SO THIS IS MY HYPO KPP STORY...

MAYBE SOMEONE CAN HELP ME WITH THIS

6 years ago I lived in a moldy house.

I believe I was so susceptible b/c i have had massive amounts of mercury in mouth, from my mom, and vaccines. I believe I have genetic methylation damage as well. I have really been reading a lot about methy and I have experienced so much of what comes with methylation problems...
*depression, low dopamine, GABA, and seratoneine,
*high histamine, sister and mom serious issues with alcoholism (read this is from high histamine) as well as I am allergic to the sun, break out in hives (also read this is related to high histamine and methyl).
*my little brother was born mentally retarded (I am not being politically incorrect on purpose-this is the description from the article I read from Dr A at Health Diagnostic where Rich said to get the methylation testing. He provides you with a diagram and 11 page article, if anyone is interested.
*continuious migraines
*thyroid def
*I and my family have a large amount of sx that were caused by a genetic def or massive amounts of mercury that caused the breakdown in the methyl cycle, but either way I am trying to repair from both ends.

In this moldy house I experienced massive diarrhea for 2 years. We didn't know the house was a wet mold mess and saw doctor after doctor for this gut issue as well as migraines, brain neuro issues, vision problems, etc.

all of a sudden for no apparent reason my muscles would weaken.

It took a few years to really narrow this down, that when ..

*I eat salt and/or sugar my muscles would weaken
*if I exercise and rest after, my muscles weaken
*if I lie still for a long say for acupuncture or an MRI or lying still for the ozone treatments, my muscles will weaken
*sometime when I wake up after a deep sleep (which doesn't happen often) the same thing happens
*If I am in a moldy building or something I am allergic to like dust, my bodies immune must be trying to regulate itself, my muscles weaken.

Through research I discovered Hypo kpp but until recently I didn't connect it with the methylation issue.

So I have this hypo kpp without attempting the methyl treatment.

I am a bit concerned of what will happen when I do and how much and how often will i need to supplement potassium?

does anyone know why this would happen even before i am doing the methyl treatment? it the hypo kip genetic and related to methylation cycle damage?
Rich, I have read the above over and over and wonder if you could shed some light, could this be for the same reasons, The DNA and cellular disfunction? I will re read again until I can understand this better. any help?

I also have very low minerals intracellular except vanadium. high vanadium can be caused by low chromium. high vanadium can cause the salt and potassium pump to malfunction, further messing with the ion channels of calcium, potassium and sodium.

I read a article by mike dessin. He had ion channel disfunction and it leveled out/stopped when he was able to detox and flush and filter this out of his system with acupunture and neual therapy.
I am so toxin, when I do the acupuncture to help flush this out of my system I get bad mobilization of the toxins.

i thought at first this was due to all the potassium i lost with the 2 yrs of diarrhea in the mold house. I read some HYPO KPP isn't caused from a genetic def, people that have bulimia or diarrhea for a long period of time came develop this due to the amount of potassium lost through the stool or vomitting long term.

I also was told that once I ridded my body from the mercury and fixed the methylation cycle I would battle this .

the first day I did mb12/folate, folinic acid and TMG my muscle did relax a bit but I have been supplementing with powder potassium chloride from pure bulk.com. I am trying between 750 and 1500mg a daily. I am having a tough time with eating fruits due to all the yeast-mold, bacteria and parasite infections.

I worry if I am just eating anti candida, meats and veg, no carbs or fruit, so limited potassium from eating and supplementing potassium, if that is dangerous?

Has anyone experienced these types of problems?

thanks for the help

denise

Hi, nan.

Thank you for the link. I read the paper. It's about sodium reabsorption by the kidneys as affected by aldosterone, using methylation. I gather that the relevance of this to potassium is that aldosterone also increases the excretion of potassium into the urine, while increasing the reabsorption of sodium (and with it, water) into the blood, and that you are suggesting that this increased excretion of potassium will require an increase in potassium intake, to maintain balance.

Here are some comments:
1. The kidney is one of the organs that has a rapidly functioning transsulfuration pathway, and thus is able to produce cysteine from methionine. It is thus protected, relative to some of the other organs, from going as low in glutathione, and thus methylation.

(continued)
2. The glycine N-methyltransferase reaction prevents the ratio of SAMe to SAH from going too high, including when high dosages of methylB12 and methylfolate are taken together. I have seen lab evidence for this.
3. Aldosterone has been found in two studies to be low in ME/CFS. This may be due to low output of ACTH by the pituitary, which exerts some control over aldosterone levels.
4. The low blood volume in ME/CFS may be partly due to the low aldosterone. However, the antidiuretic hormone (vasopressin) has also been found to be low, and this may be the dominant cause of the low blood volume. I have suggested that glutathione depletion in the hypothalamus and pituitary is responsible for low output of hormones from these organs. I'm hopeful that this will be corrected by the methylation protocol and that blood volume will come up.

(continued)
How long did you take licorice root? I gather that you stopped. Why did you stop?

With regard to the effect of methylB12 on nerve-related problems, I don't think the mechanism (or mechanisms) are agreed upon. Fundamentally, methylB12 and adenosylB12 are the only known active forms of B12 in humans. MethylB12 is a coenzyme for the methylation cycle, and adenosylB12 is a coenzyme in the mitochondria. So it would seem that either or both of these is involved. Assisting the mitochondria will raise ATP production, which is very importand for powering the membrane ion pumps in neurons. Assisting methylation will help to repair the myelin on the axons, for one thing. Maybe those are involved.

I'm not up to speed on MSH2. Have to check it out. Best regards, Rich

r

Hi, Alice.

Some people seem to need more, but if much more is needed to get an effect, I would suspect that there are deficiencies in other vitamins or in essential minerals, such as can be caused by HPU (hemopyrrolactamuria). If zinc, B6, manganese and biotin are low, I would suspect HPU.

Best regards, Rich

Hi, Denise. It sounds as though you have a very complex case. I'm glad that you discovered that mold exposure was an important factor. I gather that you are not now being exposed to mold toxins.
I wonder if you have done any treatment to remove mold toxins from your body, such as cholestyramine, Questran or Welchol, as recommended by Dr. Shoemaker.

You mentioned that you have gut issues. After the mold toxins have been dealt with, I think that working on the gut should be next. I recommend running a comprehensive stool analysis to see what the issues are, if you can afford it. The Metametrix G.I. Function Profile is a good one. If you can't afford doing that, you might consider trying a series of herbal treatments to clear out possible bad actors in the gut. Paradex or Parastroy will knock out quite a few different parasites. They should be treated first. Then you could try some herbal antibacterials, followed by probiotics to build up the beneficial bacteria.

(continued)
When the mold toxins and the gut issues have been dealt with, then it would be a good idea to take a potent multivitamin-multimineral to get your levels of essential nutrients up. If there are still issues after that, then you could consider the methylation protocol. As always, I recommend working with a physician while on this type of treatment. It would be a good idea to have a comprehensive metabolic blood panel run by your physician to see what your electrolyte levels are. That will tell you if you have hypokalemia, and you can guide your potassium supplementation by the level of potassium in your blood.

Best regards,

Rich

Hi Rich,

Thanks much! I actually wasn't thinking that people following your protocol should have much of a potassium issue. But rather in those using multi-milligram amounts of methylfolate (and methylcobalamin). In that situation, I wonder if GNMT may not be able to keep the levels of SAMe down, since folate (in the usual intracellular glutamated form) is a potent inhibitor of GNMT. The result being (maybe) the extra SAMe causing the potassium loss/drop via the pathway aldosterone uses per the article I cited. I was just having a hard time seeing the drop being due to new cell formation because I thought the K drop was happening pretty quickly in the individuals using 5-MTHF, etc., in amounts above the levels you recommend. The lab results you've seen showing normal SAMe/SAH ratios, does that include people taking, say 5+mg of 5-MTHF and 5+mg MeB12 . . .?

Agree about the vasopressin!

About the licorice root, I've tried it off and on. Seems I usually have a very positive response the first day (feel almost normal) then lose the effect and it makes me feel worse, even with extra potassium. My best guess is that the glycyrrhizin may be reducing my free testosterone levels too much (I'm male). That's a known effect. Free T for me normally runs lowest normal (DHT runs high, though).

Very appreciative of all the work you do!

Hi, nan.

That's a good point about 5-MTHF inhibiting GNMT. I knew that, but forgot it! O.K., so maybe what you suggest is happening to some degree. I don't think I'll abandon my other story, though. I still think it fits.
Yes, the K drop does seem to happen rapidly, and yes, the data I've seen was from people following Freddd's advice, with multimilligram dosages of both. I don't remember the exact amounts. O.K. on the licorice.
Best regards, Rich

HI RICH,

I WROTE TO YOU ON THE DETOX, METHYL BLOG AND TOLD YOU OF MY EXPERIENCE WITH THE CSM-TOTAL GUT IMMOBILITY, SO I HAD TO STOP THAT. I HAVE NOT HAD A BOWEL MOVEMENT SINCE DEC 2010, THE CSM PULLING TOXINS THROUGH THE BILE, STOPPED ALL BILE FUNCTION, I AM TRYING TO GET STRONG ENOUGH TO DO A GALLSTONE FLUSH TO GET THE BILE FLOW BACK AND REMOVE THE STONES AND SEE IF I CAN GAIN GUT MOBILITY.
ANY THOUGHTS ON THIS?

MY HOUSE IS SAFE, HAD CARL GRIMES TOXICOLGIST FROM DENVER COME OUT 2X.

I HAVE DONE THE COMPREHENSIVE DNS STOOL TEST FROM METAWONDER IF I COULD SENT TO YOU PRIVATE E MAIL AND YOU COULD TAKE A LOOK. I FEEL MY GUT IS FULL OF PARASITES, ONE IN PARTICULAR BLASO HOMINUS, YEAST AND MOLD FUNGUS, BACTERIA-LYME-MYCOPLASMA

ONE PROBLEM I HAVE IS NOT HAVING GOOD DR OR NP TO HELP INTERPRET THE TEST SO I AM LEFT TRYING TO UNDERSTAND THE RESULTS MYSELF.

THE HERBS I HAVE TRIED I AM ALLERGIC TO AND FOODS AS WELL. I HAVE BEEN TAKEN OFF THE HERBS, PUT ON A 3 DAY ROTATION DIET. TRYING TO DETOX WITH OZONE SAUNA, OZONE INSUFFIATION, RIFING, AND DOING LIVING STREAMS PROBIOTICS AND ANOTHER FUL SPEC PROBIOTIC. TAKING DIG ENZYMES AND LIQUID MINERALS, DMPS AND ALA FOR CHELATION.
HAVE STARTED SLOWLY THE METHYL NOTED ON OTHER POST.

TRYING SO HARD-AT A LOSS

COULD YOU LOOK AT MY OTHER 2 POST AND ANSWER IF POSSIBLE

THANK YOU SO MUCH

DENISE

Are potassium capsules safer than tablets or should they both be avoided?

@Lotus97
Hi, I think some problems can arise if the capsule or tablet is slow to dissolve. Enough stomach acid is needed, and especially, there needs to be enough fluid to dilute the concentration of the compound. I would take a capsule or tablet with at least 8 oz.of water, probably more. If I were taking multiple caps., I would increase the water.

Some tablets are really slow to dissolve, (fillers), and even with fluids, could cause trouble.
I've been buying potassium compounds in bulk powder. I mix it with water, no problems, very little taste.
For instance, NOW brand sells a potassium gluconate powder by the pound. I've seen that they sell potassium chloride, but I'm not sure if they sell potassium citrate.