Hi Dbkita
I find that I need to respond to a piece at a time to do it right. It’s good of you to participate in a stimulating dialog. Thank you. Perhaps a change of understanding will give the clues you need to work it out for yourself the desired balance with healing. Just give this the possibility of a willing suspension of disbelief until this whole thing can be laid out.
Fair enough. I am always open to discussion
The only reason I mentioned that is that there is kind of donut hole induced folate insufficiency. It occurs usually in the startup phase when a person has taken doses of a folate effective for them that are enough to start up a whole lot healing but not enough to maintain it. Then a person develops any number of the folate insufficiency specific things, often angular cheilitis, acne type lesions on scalp and face especially, IBS, mood changes, and such. It is not severe like a methyltrap shutoff or glutathione induced methyltrap. A certain number of symptoms overlap with the hypokalemia. When more effective folate is added then those things heal, promptly.
Then usually the need for potassium goes up in a spiral with the folate. One of the things I have found is that unless a person actually trials L-methylfolate they don’t know if it will actually work better for them. It is very clear that the various polymorphisms are only weakly linked to the effects I’m speaking of. There is a big gap in the interpretation. People that rely on those tests for choosing folate don’t generally have the effectiveness that a person who has trialed theme. They are poor predictors of response. These tests are done in a population which chronic deficiency conditions and the meaning is obscured by that. In at least some of the testing the corruption of the system is evident, the norming population is suffering the effects caused by the lesser activity of the inactive vitamirs and more of the inactive vitamirs are given trying to adjust the test results. As a result a very simple test has had the range of alert for MCV and other measures move in to abnormal territory and that is now “normal”. About 30 years ago > 92 or 93 was alerted. About 15 years ago it moved to > 96 or so. Now it is as high as > 102 depending upon the lab. I talked to a lab rep (labs are, from where I worked, a provider of services). I was told that with the average having moved up to > 96, they adjusted the upper limit to > 100 (2 standard deviations?) so they wouldn’t have to “alert all the tests and have the doctors ignore us”. That is a system corruption. That establishes these deficiency diseases as “normal”.
Another factor, at least with L-methylfolate is a short serum halflife, about 3 hours. I normally take 4 doses a day. Distributed across 4 doses, first thing, last thing and 2 meals I get by on 16 mg. At two doses a day I need 30mg daily to have the same effect.
Just to clarify I have been taking FolaPro 800-1600 mcg for over two years. Folinic acid was used in the first year. I have not used it for a long time. I have not used folic acid or consumed ANY folic acid in my diet for several years now. I am have been taking exclusively methyl b12 sublinguals (Jarrow until Aug 2012, Enzymatic Therapy since then) for 4-5 years. I started adb12 (Source Naturals) only about 9 months ago. I do not take a B-complex, I take all b-vitamins as separate pills to carefully balance them and to avoid too much B6 or B5, and any folic acid. I do take 500 mg of niacinamide and 100 mg riboflavin and B1 per day since they really seem to help me feel better. I used TMG 500 mg for about 18 months and I used SAMe for about six months starting Spring 2012 and had to discontinue both TMG and SAMe due to bad side-effects and harsh potassium balance issues.Of the deadlock quarter I have not taken L-carnitine in any form for some time. That I will freely admit.
Note borderline hypokalemia has been around for about 2 years and was really bad when I added the SAMe and despite 10+ grams per day I was routinely tested below 3.3 or so after a fast in the morning (of course it does oscilate over the course of the day I am sure). Bigger concern was (and to some extent is) my enormous excretion and my routinely low RBC values for intracellular K (low for many years even prior to methylation)
Your point about half-life is intriguing. I am not sure I have the stones to take 5mthf at bed time. But taking all in one dose with my other meds and supplements + food probably leaves something to be desired in terms of absorption and effectiveness. I know B3 will tend to mop up extra SAMe, but vitamin C (especially ascorbic acid) will actually destabilize methylfolate in the gut as I have found by trial and error the hard way.
With folic acid plenty of research has indicated that approximately 20% of USA population can’t convert folic acid to L-methylfolate at all, 30% can do so to more limited degree and 50% to the biological capacity limit of approximately 800mcg/day. I don’t know what the comparable
What can apparently happen, according to many researchers, though I have seen no research supporting it directly, is that folic acid can block the folate absorption and distribution mechanism. That appears to be supported empirically. Many a person taking 400 mcg of folic acid and HyCbl or CyCbl has no folate insufficiency symptoms.
1. Then the person increases to 800 or 1200 or 2500mcg of folic acid. They start getting folate insufficiency symptoms.
2. The switch to MeCbl/AdoCbl and start getting folate insufficiency symptoms.
3. The add 200-800mcg of L-methylfolate and all sorts of epithelial tissues start visibly healing, potassium need goes up and “donut hole” folate insufficiency starts as the Metafolin starts more healing than it can maintain and folate is directed away from some of the epithelial tissues.
4. Folic acid appears to compete directly with L-methylfolate in the absorption and transport systems. L-methylfolate must be taken at a high enough dose with each meal as well as other times per day in order to compete. If Metafolin not taken with meals then the folates in the meal or other supplements taken with food dominate all day and can trigger a person in folate insufficiency. Folic acid appears to clear sufficiently in 24-48 hours for l-methylfolate to have an effect again.
5. Folic acid appears to be most effective at lower doses and effectiveness turns negative as doses increase. This causes all sorts of unreliable, unrepeatable, frustrating, conundrums etc related to interpreting folic acid research. See other post for the reasons folic acid doses is a poor predictor of effects. The results of adding folic acid to food supply (white flour) for neural tube defects was “disappointing”. It is unknown how many additional cases it caused, bringing the returns well below the expected reduction.
6. Folic acid is dependent (enzyme and ATP and methyl groups) upon the Deadlock Quartet being present to be converted to l-methylfolate.
7. Folinic acid competes for absorption.
8. Folinic acid in veggies or supplements, above the level that can be converted to l-methylfolate by the body appears to be able to block the system same as folic acid does causing folate insufficiency symptoms. This appears to be quantity related at least. It appears to take folinic acid about 48-96 hours to clear sufficiently after blockade has been established for l-methylfolate to be effective again.
9. Folinic acid is dependent (enzyme and ATP and methyl groups) upon the Deadlock Quartet being present to be converted to l-methylfolate.
10. Folinic acid and folic acid both only can produce as much l-methylfolate as the keyhole will let them. When more l-methylfolate is required than the body can produce from folic and/or folinic acid, folate insufficiency symptoms appear
Ok I agree with many of your points. I think #10 is a very valid and often overlooked point.
Where I am not sure is #7, especially if the two are taken apart given the very different ways the intestinal lumen works with the two forms (i.e. folinic acid can be converted to 5,10 methylene THF to 5MTHF in the lumen without recourse to the liver, unlike folic acid ... provided a person's folate machinery is operational of course).
Where I disagree is #8.
Folinic acid is a 5-formyl derivative of THF. The folates in vegetables are not folinic or folic acid (a fully oxidized synthetic folate, i.e. pteroylmonoglutamic acid). This is a notorious misconception in the research community. The folates in food are metabolites of THF packed within polyglutamates. In the intestinal lumen these polyglutmate dietary forms are broken down into monoglutamate variants which can then be converted to DHF and then THF by their respective enzymes. The DHFR enzyme is not present in humans for the synthetic folic acid it is present for processing dietary folates. Folinic acid is readily converted to 5,10 methylene THF without use of DHFR. That being said dietary folates parallel more with folic acid than with folinic acid with one crucial difference ... they can be processed in the intestinal lumen and the liver. Folic acid (I am pretty sure) being fully oxidized must be converted in the liver.
I don't think this changes the fact that high dietary folates could be an issue for some people who can not make use of them, have intestinal wall damage, or critical needs for 5mthf but let's be honest while maybe garden feasts are not a good idea, it is not wise probably to eschew vegetables entirely as a general rule. My bigger exclusion on vegetables is to limit high thiol containing ones for other reasons.
Then again as I stated above and in my former post, I don't consume folic acid nor any folinic acid for some time now. And my diet is heavily slanted to animal protein and fats with relatively low carbs and moderate vegeatables. I am also gluten, dairy, corn, and soy free.
The only place where the various polymorphisms come into play in these terms is at what level is the body maxed out for conversion. People that become depleted methylators, those who have been taking methyl competing vitamirs instead of methyl donating vitamirs can watch effectiveness wear off over time and folate insufficiency symptoms appear in many cases. This is the Deadlock Quartet again. Again, it is quite unknown if polymorphisms matter at all in this. It is this “wearing out of response” that was so common in research that what should be GOOD results were viewed as placebo effect, leading to incorrect conclusions.
I don't disagree. I think genes have some importance but it is often overstated. Especially focusing on heterozygote mutations that say 20-40% of the population have anyways. I tend to favor more epigenetic effects, events like infections, etc., or habits like diet, stress, etc. I do think a ensemble of key mutations can lead to certain undesirable fall back patterns when exposed to certain stressors, infections, etc. I only mentioned A1298C heterozygote since unlike most on here I do not have the C677 mutation in any way so my MTHFR production is not handicapped by genetics. I do have a track record of low BH4 levels but instead of blaming that on a heterozygote A1298C that is likely a product of inflammation in the body.
Folate insufficiency symptoms can be caused by any number of medications. They can be caused by some herbs.
I would be interested if you could point me to a list of which medications have this effect. I tend to avoid most herbs since they often have broad spectrum selectivity issues.
Glutathione, NAC and sometimes Whey can cause sudden onset of the most severe folate deficiency symptoms if they are not already present, as a result of the “methyl trap”. It typically starts with inflammation and rapidly add other symptoms. If you are feeling good methyltrap onset feels like that mysterious severe flu like or “viral” disease that starts or worsens FMS, CFS and ME. If a person already has these symptoms severely there is no noticeable change
At one point before methylation treatment was started, I was put on glutathione IVs. And yes I did react very badly to them. But not in the ways you listed. I had hideous reflux, excitotoxicity, and pain. Only later did I figure out what was going on. Glutathione cannot enter the cell unless broken back down and reassembled inside. For this reason most glutathione taken even by IV at best is absorbed in the liver and kidneys. But I was so low on ATP that reassembly was not possible at the GCL stage. Hence I was swimming in glutamate. Given that I have very low GABA production for other reasons, I was overloaded in the CNS (not fun). Even after enduring 8 such treatments over 2 months or so, my RBC glutathione levels were the lowest Rich Vank had ever seen. The solution turned out to be a combination of antioxidatns (vitamin C, etc.), ATP support (d-ribose, creatine, etc.), and later methylation treatment. Within a year my glutathione RBC levels had tripled to high normal. Personally I think glutathione supplementation (of any type) is a bit of a sham given the complicated absorption issues at the cell membrane.
Group 1 – Hypokalemia onset. Symptoms may appear with serum potassium as high as 4.3. May become dangerous if ignored. Considered “rare” with cyanocobalamin it is very common with methylb12 and adensosylb12 and less so with hydroxycobalamin..
IBS – Steady constipation , Nausea, Vomiting, Paralyzed Ileum, Hard knots of muscle, Sudden muscle spasms when relaxed, Sudden muscle spasms when stretching , Sudden muscle spasms when kneeling, Sudden muscle spasms when reaching , Sudden muscle spasms when turning upper body to side, Tightening of muscles, spasms and excruciating pain in neck muscles, waking up screaming in pain from muscle spasms in legs. Muscle weakness, Abnormal heart rhythms (dysrhythmias), Increased pulse rate, Increased blood pressure, Emotional changes and/or instability, dermal or sub-dermal Itching, and if not treated potentially paralysis and death.
Group 2a - Both
IBS – Diarrhea alternating with constipation, IBS – Normal alternating with constipation
Group 2b – Either or both
Headache, Increased malaise, Fatigue
Group 3 - Induced and/or Paradoxical Folate deficiency or insufficiency
IBS – Steady diarrhea, IBS – Diarrhea alternating with normal, Stomach ache, Uneasy digestive tract, increased hypersensitive responses , Skin rashes, Increased acne, Skin peeling around fingernails, Skin cracking and peeling at fingertips, Angular Cheilitis, Canker sores, Coated tongue, Runny nose, Increased allergies, Increased Multiple Chemical Sensitivities, Increased asthma, rapidly increasing Generalized inflammation in body, Increased Inflammation pain in muscles, Increased Inflammation pain in joints, Achy muscles, Flu like symptoms, Depression, Less sociable, Impaired planning and logic, Brain fog, Low energy, Light headedness, Sluggishness, Forgetfulness, Confusion, Difficulty walking, Behavioral disorders, Dementia, Reduced sense of taste, Increase irritability, Loss of reflexes, Fevers, Old symptoms returning, Heart palpitations, Bleeding easily.
Group 4 - Hydroxycbl onset, degraded methylcbl onset, methylcbl after photolytic breakdown onset.
Itchy bumps generally on scalp or face that develops to acne like lesions in a few days from start.
Group 3 symptoms, induced paradoxical folate deficiency or insufficiency are corrected quickly with titrated doses of Metafolin, methylb12 and adenosylb12. If glutathione (precursors) are the cause then larger doses of Metafolin, 7.5-15mg,or maybe more are needed. Different tissues are affected at different levels of methylfolate, it comes or goes in stages. Very strong dose proportionate characteristics are present. Serum folate levels may be high or even very high despite Metafolin responsive deficiency/insufficiency symptoms.
Group 1 symptoms respond readily to potassium. The symptoms and response to potassium may occur at a serum level of 4.3 or less.
I would say that for the last two years I have primarily been in some form of group 1 with occasional flirtations with group 2b. I was in group 3 back in 2008 and 2009 and briefly in 2010 when given glutathione IVs as mentioned above. The problem is when I peaked in terms of 5MTHF, TMG, R5P / P5P, meb12 and adb12, and then added SAMe, the hypokalemia just skyrocketed and I had to eat 4000 calories a day of high potassium food to hit a 10-11 grams target since extended release KCL was suicidal on my GI tract at levels above 2 grams. By dropping the TMG, lowering P5p and r5p, removing SAMe, better balanced meb12 and adb12, and chopped 5mthf in half, suddenly not only did I need less potassium (like now 6-7 grams per day) but a LOT of other things got better. By not doing a proper titration when I started out, I think I had unwittingly overshot the mark for a couple of years and was stuck there suffering many things needlessly. And I am sorry but after two plus years, I was way beyond startup effects.
INDUCED HYPOKALEMIA AND FOLATE INSUFFICIENCY DECISION TREE
Note: ATP startup is not yet in this tree.
IF starting or adding methylb12, adenposylb12 or hydroxycbl, AND OR Metafolin (perhaps 80%)
AND the approximately 3rd day or later onset of symptoms (“Detox”) from Group 1 and/or group2
THEN this can be the onset of Hypokalemia triggered by sudden widespread healing onset. This usually occurs as soon as methylation therapy starts widespread healing process by allowing DNA replications with methylb12 and methylfolate.
IF adding adenosylcobalamin AND OR L-carnitine fumarate AND OR SAM-e to program (perhaps 50%)
AND the approximately 3rd day or later onset of symptoms (“Detox”) from Group 1 and/or group2
THEN this can be the onset of Hypokalemia triggered by sudden healing and /or muscle growth. This usually occurs when the person has experienced muscle shrinkage perhaps from decades of inactivity, as soon as these supplements step up mitochondria functioning.
IF adding or increasing any of Vitamins D, A, E, or C, magnesium, zinc (perhaps 10%)
AND on the approximately 3rd day or later onset of symptoms (“Detox”) from Group 1 and/or group2
THEN this can be the onset of Paradoxical Folate Deficiency (or Insufficiency). Folinic acid is the primary form found in vegetable source. In some unknown percentage of people who appear unable to convert folinic acid adequately to methylfolate the accumulating unconverted folinic acid can actually block the methylfolate.
Thank you for the decision tree.
I selected the three that are relevant potentially to me. The first two I have definitely experienced as already outlined before.
For the third branch, I have taken all of the aforementioned (D, A, C, E, etc.) for several years now. I take 1000 mg magnesium per day in various forms. For a long time I took at Rich Vank's suggestion high dose vitamin C for a while, but have now opted for Na ascorbate 3 grams per day. I take 2500 IU vitamin D now, in the past took higher levels. Sadly both D and A in the gut can elevate inflammation and norepinephrine. For 18 months I was on vitamin A 20000 IU per day and as high as 50 K IU 3 times per week. Those had distinctly different effects than what you listed. I no longer supplement A since I get 5000 IU per day in diet generally. My vitamin D levels are lowish, but the active form 1,25 calcitriol is quite good due probably to the high magnesium.
Could you explain how the third branch ("
IF adding or increasing any of Vitamins D, A, E, or C, magnesium, zinc (perhaps 10%)" leads to Paradoxical Folate problems?
HOW TO INDUCE SUBACUTE COMBINED DEGENERATION and enlarged MCV in humans in 3 months or less.
Causing SCD and macrocytic anemia was NEVER our intention, our intention was to induce health benefits from glutathione or precursors as claimed these days amongst certain practitioners. This is just how it turned out, 180 degrees from what we expected.
Individual results will vary but in an N=10 trial, 100% of subjects had the results to varying degrees, perhaps as they used several different precursor combos or infusions. The subjects were all successful with adb12, mb12 and Metafolin. Those not in this group that had never relieved the deficiency symptoms claimed pain relief from the glutathione as their nerves were damaged further into numbness. I experienced this myself in the glutathione trial as my neurological damage was increased.
Method 1 - feed subjects 1 gram of l-glutamine and 600mg of time release NAC twice a day for duration (or frequent glutathione infusions, or NAC or whey in some). In 3 hours after first dose most of available b12 in the body will be flushed out in the urine. Then within the next few hours methylfolate is expelled from the cells via the "methyl trap". Widespread body, muscle and joint, inflammation and pain start within hours and gets worse by the day. This is responsive to NSAIDS generally. Folate deficiency symptoms appear the first day, mb12 deficiency symptoms in several days and adb12 deficiency symptoms - 3 months or so.
Over the next days and weeks, CPR heads for the roof. Hypersensitivity of all sorts starts, MCS, hyper-immune response, hypersensitivity in nerves, etc. In 3 days angular cheilitis starts up in those who are prone to it. In 2 more days IBS starts. At about the same time acne type lesions start up on scalp and face and often infected follicles in other body areas. Oral lesions usually follow. By six weeks centrally mediated numbness and pain of feet and legs, hands, arms, shoulders etc are all spreading and worsening.
Dr Jeckyl leaves the house and is replaced with Mr Hyde for the duration. Sleep disorders increase. In 3 months macrocytosis is obvious, MCV > 100. MS will be dramatically worsened. If the person is also extremely low on l-carnitine and/or adb12 Parkinson's like symptoms may worsen explosively. Then if l-carnitine is given the subject may go absolutely nuts and a walkthrough of the extreme FFF characteristics of the limbic system will be demonstrated in usually the same order each time, dependent upon rising or falling l-carnitine level.
Reversal, if SCD is not allowed to go too far is multiple 15mg doses of Metafolin (Deplin) and three 50mg mb12 doses or 10mg SC injections of SUITABLE 5 star mecbl until healed for at least a year, and of adcbl the first few days. On day 3, the need for potassium will often increase by 2000-3000mg to avoid dramatic sudden onset of Hypokalemia symptoms when backlogged healing starts up. Also on day 3 Metafolin dosage needs increase. In about a month inflammation will be largely gone if all cofactors are present that are needed, CRP <=1.0, multitudes of pains will be fading. MCV corrects when folate deficiency doesn’t exist for several months. Maintaining folate sufficiency for 3 months straight can be extremely difficult for those with paradoxical folate deficiency. Only the remyelization takes about 9 months to correct to the extent that it can but trails on for years as it is an ongoing equilibrium that is either getting better or worse. By careful active management one can approximately tread water otherwise it gets worse.
Not sure I understand the connection here. Why is the body making its own glutathione a bad thing? Making my own did wonders to help with my autoimmune symptoms.
I routinely take glutamine to prevent muscle catabolism and aid muscle recovery. But glutamine is the most abundant amino acid in the body and I get 230-250 grams of protein anyways. NAC is a different matter and I avoid it (makes me to mentally fogged since the glutamate drop to make glutathione is too mentally fatiguing for me to do scientific research). I figure the body should be left to its own devices to make glutathione as it needs provided there are no nasty blocks. I do not accept glutathione deficit as the central defect in most chronic disorders. But maybe that is just me.
Yes my MCV is higher than I would desire but that has been true for 10+ years and the methylation protocol has not changed that number (always high 90s). Actually looking at my labs, my MCV peaked near 100 for the six months I was at the highest methylation support level. So not sure what to say there (at least for me personally).
Anyways sorry for the lengthy reply.
P.S. I agree that detox is a way over used concept on these forums. But I also think for some of us we are way beyond startup effects when we are deep into the protocols.
P.S.S. I still don't buy the cell growth depletion theory of potassium for the methylation. I do not believe the numbers add up nor can they explain high excretion.