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methylation: VERY low, very slow.....results

Messages
514
Hi Rydra,
the day or two before I have had strep, my chemical sensitivities seemed to disappear. It was a very dramatic effect, going from being totally unable to walk into, say, Target, to being able to go in there and actually shop for 15 or twenty minutes...and then there is the effect of doxycycline. Whenever I increase the dose (or the dose isn't consistent) my chemical sensitivities flare.

Determined, I have noticed such things in the past - in my case with inflammation - In fact - I'll have to tell this to Idie - internal trembling would go away as well as any joint pain if I were fighting off a cold - leading me to believe these were caused by inflammatory cytokines which in the event of an actual infection went off to fight THAT instead of me. So...I would guess that chemicals cause inflammatory cytokines for you and I'll bet strategies against those might do the trick. But what are such strategies? Well one is high dose omega-3 (like 7-9g/day) as these use up the enzymes required to produce inflammatory cytokines. When I had a horrible new allergy develop last winter I found 20 Spirulina pills woul do the same thing. Neither is fun as it's so much. There are herbs that are supposed to help with inflammation, thus must target those cytokines, like curcumin. However if you are on meds, and you are, these strategies can be dangerous. Omega-3 thins the blood. I don't know what spirulina does but you can bet there are a lot of constituents in at, any one of which might interact with your meds. Curcumin interacts with 50% of the medicines on the market via CYP3A4...it will PREVENT you from eliminating any medication which is supposed to be cleared via CYP3A4 (50% of the drugs on the market) and this will cause their levels to rise to where they could be toxic. So many herbs do just this sort of thing that I would never take any herbs if I were on drugs. As to blood if your drugs thin your blood or affect clotting this is also something you need to do only under a doctor;s care. For someone NOT on drugs, the above are things I might look into.

Rydra

Sorry, the Yasko report does not contain rs numbers. If I were to research it I would never remember which topic this was under to report back. You could probably look onlin eas well as me for "CBS gene rs" or some such. But it will not necessarily help you find a solution. I mean a lot of CBSers are still sick.
 

determined

Senior Member
Messages
307
Location
USA: Deep South
Interesting, Rydra; I have been taking turmeric for years and I simply can't be without it. It has helped me tolerate fats in my diet for some reason. But even so, I don't tolerate the "good oils" at all, like olive oil, canola, fish oil capsules. So yes, I'm probably deficient in those. Years ago, I used evening primrose oil and tolerated it very well. It helped lessen my chemical sensitivities significantly...it took about a month at the top recommended dose.
 
Messages
514
Interesting, Rydra; I have been taking turmeric for years and I simply can't be without it. It has helped me tolerate fats in my diet for some reason. But even so, I don't tolerate the "good oils" at all, like olive oil, canola, fish oil capsules. So yes, I'm probably deficient in those. Years ago, I used evening primrose oil and tolerated it very well. It helped lessen my chemical sensitivities significantly...it took about a month at the top recommended dose.

Darn-! Unfortunately, Determined, I have just realised I am coming down with a cold or flu so THAT is probably what stopped my internal trembling, as I did notice it goes away upon giving those inflammatory cytokines something else to target. I have noticed in the past that curcumin would take away joint pain. But so does milk thistle. I have to caution you about taking drugs with herbs. Curcumin blocks the CYP3A4 gene which creates the enzyme that clears 50% of the drugs on the market. This means those drugs will reach toxic levels in your system. It is why so many Indian people have great trouble with Western medicine, and often become critically ill from Western drugs. Milk thistle even in small doses greatly increases intestinal absorption, which can affect drug doses also. And so on for most herbs from what I have seen...

I still think you hit on a clue -- I think "things that suppress inflammatory cytokines" (of which there are many) are the things that are likely to stop internal trembling. Indeed I do not always have it and so something I sometimes take or do that is not a regular part of my protocol fixes it...which fits the bill for things like curcumin and milk thistle (for although I swear by milk thistle, I often skip it, and I only take curcumin - if I have particular reason or I just read something good about it...you know - in a dilatant way). It is odd to think that something like trembling could be from cytokines, but I believe cytokines (as oxidants) can dysregulate the methyl cycle, so they do more than irritate and wear down tissues.

Wish I had more. But turns out this time it WAS a cold thing that stopped the trembling for me...
 

Freddd

Senior Member
Messages
5,184
Location
Salt Lake City
Fredd said: I'm not blind. I can see it in urine and how quickly and for how long at visible levels. In addition I can feel a lot of it.

Freddd, tell me again about how you see B12 in your pee? I have never done so. Does that mean you're taking too much or I'm not taking enough?

Ryrda

Hi rRdra,

Based on my various trials with sublinguals I asked my doctor to prescribe injectable mnb12. Since he had watched me come back for the edge of death he was willing to play along. He initially prescribed 5mg a day. I was to try 2x2.5mg and 1x5mg and see if there was any difference. Intially, on folic acid the 2.5mmg injection was just barely noticable as a slight tint to my urine, and only for the forst 3 hours following injection. At 5mg single injection there was a lot more visible b12 in my urine. I then staerted 400mcg of metafolin. The b12 disappeared from my urine at 2.5 mg and reappeared at 4.4mg and above. However, at 5mg the visiblity was about the same as at 2.5mg without metafolin.

I had previously tried 50mg of sublingual mb12 and there was a lot more mb12 visible than what I was seeing with the 2.5 or 5mg injection. I standardizied on 400mcg of metafolin for the first series. I calibrated a series of injections from 1 to 25mg (first series) all subcutaneous. In several additional series I did injections up to 100mg single injections and 60mg 3x per day. I did sublingual form 25mg to 100mg of both mb12 and adb12. For the adb12 series I had to use folic acid with the injectable to have similar results to Country life dibencozide. I tried several different time spans in the sublingual series. So in the Sublingual mb12 and injectable mb12 with metafolin, I found that the sublingual results were the same as the injectable and mached up the amounts. So the 50mg over 3 hours averaging 2 hours per tablet with multiple tablets it worked out that over the span of 45 minutes to 2 hrs per tablet the amount visivble corresponded to 10% to 33% with the typical results 15% to 25%. The 25% of 50mg corresponded to the 12.5mg injection in urine coloration and effectiveness on the CNS. I had corresponding response with folic acid and adb12. The results were quite consistant. When I took the glutathione suddenly the urine from 10mg injection started looking like a 60mg injection with Metafolin. I was still taking the Metafolin with the glutathione but had the most severe folate deficiency symptoms of my life and my urine demonstrated that low folate status.

I would say I was taking quite a bit more. Most people will see some color with a 25mg sublingual dose held for 2 hours or longer.


Does that mean you're taking too much or I'm not taking enough?

No. I'm taking the amount I need, by titration, to keep my CNS from deteriorating more or even healing some. You may not have that damage and may not have the difficulty getting it into the CSF or CNS that I do. If it were not for the CNS I would probably find a sublingual dose of no more than 18mg a day quite sufficient, and maybe not even that much.
 

Freddd

Senior Member
Messages
5,184
Location
Salt Lake City
Thank you for taking the time to give thorough answers.

I don't know what the baseline is, but what I could see from the study was that they doubled the baseline (at the end of the week) with a dose which wasn't large. My question is really, given a 10mg Hydroxy B12 shot once weekly, wouldn't that surpass the levels one get from taking sublingual doses (at the end of the week)? How much high (compared to baseline) would the serum levels go, if one took a couple of drops daily?

If quadruple of the baseline is a good serum level to stay at, I assume a really high IM dose once weekly of hydroxy B12 would be sufficient to achieve that (correct me if I am wrong).

Do you take sub-linguals, sub-cutaneous or intra muscular B12 yourself?



The point of sublingual administration seems to me to get the B12 in contact with mucous membranes, and raise the serum levels that way. Wouldn't the mucous membranes in the nose do just as well? I see that there are other forms of B12 which is given through the nose.

What you think the optimal serum level of B12 would be? 6000 pg/ml? 60000 pg/ml? Higher? If the optimal level for a PWME is 6000+, than I agree that IM shots once weekly most likely wouldn't be the best way to go.

"1mg or 10mg of hydroxcbl produces 10 to 30mcg of mb12/adb12 if at all." What do you mean with this?

Hi Redo,

"1mg or 10mg of hydroxcbl produces 10 to 30mcg of mb12/adb12 if at all." What do you mean with this?


Upon injection the serum half life of b12, with minor differences by variety, is 20-50 minutes for the first few hours increasing to 4 hrs by hour 12. By 24 hours 99% of the cobalamin has been excreted. The halflife increases until the serum level hits about 1500-2000pg/ml and then is at it longest with the kidneys not doing anything and all the excretion done by the liver. In that first 24 hours it is estimated that 10-30mcg is actually converted to either of the two active b12s and a bit more is converted over the next few days before it is all excreted. 1mcg of b12 increases the serum level by 200pg/ml. Raising the serum level from 300 to 1300pg/ml requres a total of about 5mcg. It is estimated that an equal amount enters the tissues for 10mcg retained in all. Mb12 and adb12 result in 3 or more times as much retained cobalamin.

Mb12 affects many symptoms totally unaffected by hycbl. These symptoms start returning on day 3 after an injection. In my CNS an 10mg subcutameous injection produces CNS benefits for 8-12 hours with symptoms returned within 24 hours. It requires 3 x 10mg injections to maintain symptoms reduction without backsliding daily.

What you think the optimal serum level of B12 would be? 6000 pg/ml? 60000 pg/ml? Higher? If the optimal level for a PWME is 6000+, than I agree that IM shots once weekly most likely wouldn't be the best way to go.

So that I don't end up in a wheelchair in diapers I need to maintain about 200,000pg/ml. Other than that I would think that 6000-60,000pg/ml might do the trick.


Do you take sub-linguals, sub-cutaneous or intra muscular B12 yourself?


I take 3x10mg subcutaneous daily for steep diffusion gradiant and currently 33mg of sublingual in a single dose for quality. IM has a 30minute peak and doesn't produce the same degrtee of neurological improvment. I would have to do 1.25mg IM injection each hour to approximate the effectiveness of 3x10mg SC.

If quadruple of the baseline is a good serum level to stay at, I assume a really high IM dose once weekly of hydroxy B12 would be sufficient to achieve that (correct me if I am wrong).

1200pg/ml is poor. People have mb12 responsvie symptoms at well over 1500pg/ml. Looking statistically at it I would guess the symtpom free level of 4 standard deviations is probaly something like 60,000pg/ml of mb12 and adb12. There is no level of hycbl that would ever be symptom free.
 
Messages
514
ok. I never had pink urine. At any dose of mB12. It sounds like you get it if your mB12 dose isn't matched correctly to your mfolate dose. a useful indicator. You know there is a "hyaline cast" to urine if you have that problem from low zinc and low B6 - I forget what it's called. I had the test and dont have it. Hyaline is pink I believe...
 

Freddd

Senior Member
Messages
5,184
Location
Salt Lake City
Hi, Freddd.

I think that what needs to be done is to figure out how people can be separated into groups on the basis of their genetic polymorphisms, so it can be known what treatment is most suited to them. I'm hopeful that the 23andme genotyping will be useful for this. As I've posted before, the folic acid intolerance likely depends on polymorphisms in the DHFR gene. The folinic acid intolerance likely depends on polymorphisms in the MTHFS gene. The inability to use B12 forms other than methyl B12 and adenosyl B12 and the glutathione intolerance are likely due to polymorphisms in the MMACHC gene.

Concerning the difficulty in getting enough B12 into the brain, here's a thought: As you know, in your case, I have suggested that there is a genetic issue with the MMACHC gene, so that your cells are not able to convert other forms of B12 to the two active coenzyme forms, and you have gotten around this problem by raising the concentration of these coenzyme forms in the blood high enough that sufficient amounts of them will get into the cells by diffusion across the cell membranes, without use of the transcobalamin transport mechanism. O.K., now consider the brain. The cells in the brain will likewise have this genetic problem with the MMACHC gene, so they will need to receive methyl B12 and adenosyl B12 directly, also. However, there is an additional hurdle to be overcome for them, because they are behind the blood-brain barrier. So it will be necessary to push the coenzyme B12 forms through the blood-brain barrier first, before they can diffuse into cells in the brain. Perhaps this is the reason that you have found that much larger dosages are needed to help the brain in your case. The B12 forms have to surmount two diffusion barriers to get into the brain cells, and that will require higher concentrations in the blood. What do you think about this?

Rich

Hi Rich,

So it will be necessary to push the coenzyme B12 forms through the blood-brain barrier first, before they can diffuse into cells in the brain

Absolutely. Approximately 1mg sc 3x oer day will effectively penetrate every cell of the body, say about an average serum level of 20,000pg/ml. It takes 10mg sc 3x per day maintaining an approximate serum level of 200,000pg/ml to penetrate the CSF/CNS 24 hrs a day and maintaining effectivenes 24 hours per day. The CNS effectiveness wears off from a single injection between 10 and 12 hours.

Based on the intrathecal injection trial for diabetic neuropathy suggests that the retention of cobalamin in the CSF is highly variable. A single 2.5mg injection into spinal fluid had an effectivenss period of less than 3 months to greater than 4 years. The 50mg/day dose trials indicated that for MS and ALS that effectiveness wore off as sooon as the 50mg doses stopped. The spinal fluid injection indicated that effectiveness ran out as soon as the CSF cobalamin level dropped below a certian level which I couldn't tell you off hand but it is easy to find.

A mix of adb12 and mb12 totalling the same 50mg sublingually or 10mg SC appears to penetrate adequately for both varieties. I don't inject the adb12 currently and via timing it appears to penetrate just as well using a sublingual timed with an injection as a separate injection or a separate 50mg dose. The diffusion gradiant of the two appear additive.

Metafolin somehow keeps the serum level higher longer. The glutathione instantly dropped the cobalamin serum level effectively down to near zero and caused me severe neurological damage.

I would like to add that in both body and CNS there is a bimodal effect. When I started in a single 1mg sublingual, I felt the changes start occuring after no more than 5 minutes. Some things started healing right away. Energy increased somewhat, epithelial tissues healed dramatically in 10 days. Mood was affected. Multi sensory hallucinations were affected, olfactory and taste, hearing and vision were all affected on 1mg total dose. However, peripheral neuropathy continued worsening with 1mg doses and didn't improve until after 3mg injection equivalent doses were had. In the CNS there were many functional changes on body size doses from 1mg to 15mg sublingual. However subacute combined degeneration continued to worsen for several years as everything else healed. It took the 4x7.5mg injections sc or 3x10mg sc injections to improve the nerves and regain feeling and effect myelin repair on the spinal nerves, reduce spinal caused numbness, loss of position sense, dropfoot, brisk reflexes, falling, fecal incontinence. Bascially the nerves needed the higher levels in body and CNS for helaing.
 

Freddd

Senior Member
Messages
5,184
Location
Salt Lake City
Freddd, unfortunately this is not a sufficient test. I can tell you what ELSE is in dark green leafies that affects the methyl cycle -- cadmium. cadmium displaces copper and copper is a cofactor of methionine synthase. Estrogen increases the half life of copper. I believe testosterone does too. So as you get older you have trouble getting enough copper. (Also happens if you take too much zinc). I know you take DHEA and pregnenolone, but it's not replacing what you had when your prostate pumped it out. I am not suggesting a solution, but only a potential snag in your theory for consideration.


Hi Rydra,

I take prescribed weekly injections of testosterone. Whatever effect the DHEA and pregnenlone have is factored into my regiulare testosterone level tests.
 

Freddd

Senior Member
Messages
5,184
Location
Salt Lake City
ok. I never had pink urine. At any dose of mB12. It sounds like you get it if your mB12 dose isn't matched correctly to your mfolate dose. a useful indicator. You know there is a "hyaline cast" to urine if you have that problem from low zinc and low B6 - I forget what it's called. I had the test and dont have it. Hyaline is pink I believe...

Hi Rydra,

I don't vary the zinc. The pink and it is really light magenta, varies directly with the mb12 and or adb12 . This has been confirmed by many people. A large enough injection of b12, any variety is used for testing kidney tubule functioning. If there is a certain type of damage in the kidney, the kidney can't excrete cobalamin.
 
Messages
514
Hi Rydra,

I take prescribed weekly injections of testosterone. Whatever effect the DHEA and pregnenlone have is factored into my regiulare testosterone level tests.

Really?! Is that something new? Last I knew you were only taking DHEA and pregnenolone like me. Did you dial down your DHEA/pregnenolone dose when you started testosterone injections? I have started estrogen injections (twice a year) but only had one so far so dont know what I have to do with my other hormones. Doc told me to lower them significantly but I went into adrenal issue at allergy season and could not then afterward adrenal issues with the flea product for 2 months and somehow never did dial down. So now I take the hormone test and find out if I flunk.

I am not really sure how copper works with testosterone. I thought I mainly was saying that cadmium in leaves blocks copper which is needed for methionine synthase. It would be interesting so see if these people noticing folate food intolerances were finding it was mostly leaves that bother them and bread products (bread is another issue as many are allergic to it or even celiac, so sensitivity to it is more likely that).

Rydra
 
Messages
514
Hi Rydra,

I don't vary the zinc. The pink and it is really light magenta, varies directly with the mb12 and or adb12 . This has been confirmed by many people. A large enough injection of b12, any variety is used for testing kidney tubule functioning. If there is a certain type of damage in the kidney, the kidney can't excrete cobalamin.

I never heard f such a test and I am very interested in kidney issues as my genes make it very likely I will blow mine out -- there are several times a year times in which I cannot pee for lack of BH4 and high blood pressure. I took a Cystatin-C test and my kidneys were fine so far. I understand the creatinine test only tells you your kidneys are bad after it's too late. The Cystatin C test is very expnsive though. :(
 

Freddd

Senior Member
Messages
5,184
Location
Salt Lake City
Really?! Is that something new? Last I knew you were only taking DHEA and pregnenolone like me. Did you dial down your DHEA/pregnenolone dose when you started testosterone injections? I have started estrogen injections (twice a year) but only had one so far so dont know what I have to do with my other hormones. Doc told me to lower them significantly but I went into adrenal issue at allergy season and could not then afterward adrenal issues with the flea product for 2 months and somehow never did dial down. So now I take the hormone test and find out if I flunk.

I am not really sure how copper works with testosterone. I thought I mainly was saying that cadmium in leaves blocks copper which is needed for methionine synthase. It would be interesting so see if these people noticing folate food intolerances were finding it was mostly leaves that bother them and bread products (bread is another issue as many are allergic to it or even celiac, so sensitivity to it is more likely that).

Rydra

I have been on the testosterone since 2000. It helps a lot. On the series of tests that were done when I went with some new docs they found that my testosterone would have been low for an 80 year old man. The Dartmouth study looked at Testosterone in women with FMS. I'm not sure where that ended up. Low b12 wreaks havoc with hormones of many kinds. I left the DHEA and prenenolone alone and titrated the tesosterone according to directions and regular lab tests.
 

Rosebud Dairy

Senior Member
Messages
167
@ Freddd re: testosterone

Did you go by blood levels or saliva on testosterone?

When I was treating this, I felt so much better. It cleared that last little bit of brain fog, I seem to recall. On progesterone already, and doc says my Estrogen prime number is cancer-high - nearly 10,000??? so maybe testosterone isn't so great, since it can convert to testosterone. Maybe I should consider 7 keto DHEA that can't convert.
 

Freddd

Senior Member
Messages
5,184
Location
Salt Lake City
@ Freddd re: testosterone

Did you go by blood levels or saliva on testosterone?

When I was treating this, I felt so much better. It cleared that last little bit of brain fog, I seem to recall. On progesterone already, and doc says my Estrogen prime number is cancer-high - nearly 10,000??? so maybe testosterone isn't so great, since it can convert to testosterone. Maybe I should consider 7 keto DHEA that can't convert.

Hi Rosebud,

I have been getting blood tests, sometimes two, there is a bound and a free T test I believe. Expensive, I avoid them when I can. As my level has been dead even my doc has cut back on testing to once a year. Saliva could be a lot cheaper, what do you know about it? Testosterone can convert to estrogen.
 
Messages
514
I started on estrogen shots 2x/year - I go out of state to get them so glad it is only 2x/year. I have no diea if they help me because these last 6 months have been full of allergy season and months on end of exposure to flea products (which never were an issue with dogs as a 1/year dose would kill everything never to have any worries for the rest of the year) and then exposure to second hand smoke (relative) and me stopping most of my vitamins -- all of which made me feel less than able to judge the effects).

idk if I already said this but I get these wonderful hormone labs - they are very expensive but they assure me I am not headed for cancer, by telling me exactly what my body is making from my hormones. I get this lab on sale every April: http://www.lef.org/Vitamins-Supplements/ItemLCM4098/Urinary-Hormone-Profile-24-hour-Urine-Test.html and here is what the lab says about it (for instance that the 2/16 OH estrogen ratio is predictive of cancer and osteoporosis): http://meridianvalleylab.com/hormon...tests/urinary-216a-estrogen-metabolite-ratio/ . I dont see it advertized at lef, but I know you can order just the 2/16 test because I did it one year to save money. Also this test was twice as much when I got it from a local doctor.

I have a friend my age wh
o just got breast cancer due to hormone replcacement, so I'd like to caution everyone to be safe and test. I think people that take methylation substances are less likely to get hormonal cancers but dont trust me, decide for yourself. It's just that 2-methoxyestradiol is being patented as a carcer cure. http://www.lef.org/magazine/mag2009...er_01.htm?source=search&key=2methoxyestradiol

Rydra
 

Lotus97

Senior Member
Messages
2,041
Location
United States
I just stopped folinic acid and methylfolate. I was only taking 100 mcg of each, but it seems I need to slow things down. I'm also only taking 1000 mcg of hydroxycobalamin. I do get 950 mg of TMG though in the form of betaine hcl which I use a digestive enzyme. I'm also taking at least 300 mg DMG so that my BHMT pathway doesn't get overstimulated by the TMG/betaine hcl. I found out that 100 g of quinoa has over 600 mg of TMG so I need to take that into account too. And I'm taking a small amount of P5P and R5P, but mostly just B6 and B2. I'm taking 320 mg of coenzyme q10 which is a methyl donor, but I don't know exactly how it works.

I'm curious how everyone else in this thread has been doing and if they'd made any progress in increasing the dose. Once I get up to 2000 mcg of hydroxocobalamin I might transition to methylcobalamin. Mostly to save money, but also because I have a sublingual b complex with adenosylcobalamin and I think I can increase the dose if I switch to methylcobalamin since I won't be converting the hb12 into adb12. I'm only getting a low dose of folic acid and some dietary folate. I get 300-400 mcg dietary folate, but I was reading that possibly a significant portion of folate is destroyed in storage and/or cooking of the food. Once I progress with the B12 I'll consider adding folinic acid. It's unlikely that I have an MTHFS mutation, but anything's possible.
 

Freddd

Senior Member
Messages
5,184
Location
Salt Lake City
="Lotus97, post: 340638, member: 8815"]I just stopped folinic acid and methylfolate. I was only taking 100 mcg of each, but it seems I need to slow things down. I'm also only taking 1000 mcg of hydroxycobalamin. I do get 950 mg of TMG though in the form of betaine hcl which I use a digestive enzyme. I'm also taking at least 300 mg DMG so that my BHMT pathway doesn't get overstimulated by the TMG/betaine hcl. I found out that 100 g of quinoa has over 600 mg of TMG so I need to take that into account too. And I'm taking a small amount of P5P and R5P, but mostly just B6 and B2. I'm taking 320 mg of coenzyme q10 which is a methyl donor, but I don't know exactly how it works.

I'm curious how everyone else in this thread has been doing and if they'd made any progress in increasing the dose. Once I get up to 2000 mcg of hydroxocobalamin I might transition to methylcobalamin. Mostly to save money, but also because I have a sublingual b complex with adenosylcobalamin and I think I can increase the dose if I switch to methylcobalamin since I won't be converting the hb12 into adb12. I'm only getting a low dose of folic acid and some dietary folate. I get 300-400 mcg dietary folate, but I was reading that possibly a significant portion of folate is destroyed in storage and/or cooking of the food. Once I progress with the B12 I'll consider adding folinic acid. It's unlikely that I have an MTHFS mutation, but anything's possible.

Hi Lotus,

"and I think I can increase the dose if I switch to methylcobalamin since I won't be converting the hb12 into adb12. "

Contrary to things many believe and even contrary to what I once said based on statements made outside of peer reviewed research (I plead gulity of repeating popular mythology on speculation) the conversion path of HyCbl is first to MeCbl and then to AdoCbl. There is NOT a direct HyCbl to AdoCbl pathway. Generally even with unlimited MeCbl there is insufficient AdoCbl converted to regain lost ground. It is a two step process requiring two enzymes and two rounds of ATP. All that depends on sufficient MeCbl, sufficient AdoCbl, sufficient l-methylfolate and sufficient LCF. HyCbl is not "self booting". Folinic acid is not "self booting". They BOTH require enough of each of the deadlock quartet to generate first the MeCbl AND then the AdoCbl, and of course they need enough of each of the the deadlock Quartet to convert the folinic to L-methylfolate.

MeCbl converts much mor easily to AdoCbl than HyCbl does. You are putting it through multiple keyholes and expect good results?
 

Lotus97

Senior Member
Messages
2,041
Location
United States
Rich has said that some people need higher doses of methylfolate and need to use methylcobalamin and adenosylcobalamin rather than hydroxocobalamin. However, in the methylation study conducted by Rich and Dr. Nathan they found that some people were not even able to tolerate the amount in Rich's protocol. It seems that most of them didn't need to lower the dosage though.
http://www.mecfs-vic.org.au/sites/w...Article-2009VanKonynenburg-TrtMethylStudy.pdf
• GO SLOWLY. Occasionally, as the methylation cycle blockages are released, toxins are
released and processed by the body, and this can lead to an exacerbation of symptoms.

IF THIS HAPPENS, try smaller doses, every other day. SLOWLY work up to the full
dosages. If you have questions, please call our office to discuss them.

As noted earlier, one patient dropped out of the study at 3 months for a reason not related to
response to the treatment. The remaining 29 patients completed 6 months of treatment.

Various patients reported some early exacerbation of symptoms, which in most cases was
followed by a greater improvement in symptoms. Three of the patients found it necessary to
decrease their dosage frequency to every second or third day for several days, until they could
tolerate the full daily dosage schedule.

Sixteen of 30 patients (53%) reported an initial worsening of symptoms, beginning in most of
these cases within 3 or 4 days, but in some cases beginning at up to 2 weeks. Most of the
symptoms were mild, and none of the patients discontinued usage of the supplements during the
first 3 months. The most common side effects were gastrointestinal (pain, cramps, constipation,
or diarrhea), reported by 6 out of 30 patients or 20%; increase in pain, reported by 4 out of 30 or
13%; and increase in fatigue, reported by 3 out of 30 or 10%. Other symptoms, reported by one
patient each, were a decrease in appetite, poor sleep, weak legs, flu-like symptoms, and an
increase in anxiety and depression.

For those who experienced improvement, the time to self-reported improvement on the protocol
was an average of 5.6 weeks, with a range from immediate improvement (which was rare) to as
long as 8 weeks before improvement was experienced.
---------------------------------------------------------------------------------------
As I mentioned above Rich has said that some people do need methylcobalamin and adenosylcobalamin, but Rich believed that hydroxocobalamin was effective for most people. He based this largely on a clinical study conducted with CFS/ME/Fibromyalgia patients using hydroxocbolamin and low doses of both folinic acid and methylfolate. Rich seems to be saying that most people can convert hb12 into an adequate amount of adb12, but I actually get 125 mcg of adb12 from a sublingual b12 complex so I'm covered either way.
B12 and folates, which are specifically needed by methionine synthase. I chose to use hydroxocobalamin on the basis that this would allow the cells to convert it to as much methylcobalamin and adenosylcobalamin that they needed.

In the full Yasko program, Dr. Yasko characterizes certain polymorphisms to decide whether methylcobalamin or hydroxocobalamin are preferable for a given patient.

In making this choice, I realized that there would probably be some people who would not respond as well as others, because of genetic variations. However, I was also concerned that high-dosage methylcobalamin might methylate inorganic mercury and move it into the brain. This is chemically possible, and has been observed in guinea pigs, though not demonstrated in the human body, and I knew that many PWCs have high body burdens of mercury.

An additional concern I have is that high-dose methylcobalamin might overdrive the methylation cycle, since the amount of methylcobalamin will not be under the control of the cells themselves. The possible effects of overdriving the methylation cycle are not known. My concern is that it can prevent flow down the transsulfuration pathway, and thus affect the recovery of the balance of the sulfur metabolism.

Also, if there is not effective control of the SAME/SAM ratio by glycine N-methyl transferase, this ratio may go too high, which would affect gene expression in general as well as other methyltransferase reactions in the body. Since this is unknown territory, I would prefer to avoid it by testing to see how the methylation cycle and related pathways are faring, and limiting methylcobalamin accordingly. But again, there is no proof that this is actually a problem for most people.

This choice is one of the major differences between Freddd's protocol and the one I have suggested. Freddd uses high-dose sublingual methylcobalamin and adenosylcobalamin together, and finds that hydroxocobalamin is not helpful for himself and some others.

For the folates, I included 5L-methyltetrahydrofolate, which is the form needed directly by methionine synthase (and which is also the folate form that Freddd uses), and, following Dr. Yasko, I also included folinic acid and folic acid.

There is some folic acid in the multi, and both folinic and folic acids, as well as additional 5L-methyl tetrahydrofolate, were present in the Intrinsi/B12/folate. This supplement also included intrinsic factor and some additional B12. Over time, the manufacturer changed the formulation of this supplement, so I substituted Actifolate for it, which includes the three forms of folate, but no B12 or intrinsic factor.

Since then, I have come to believe that folic acid does not contribute benefit and may interfere with absorption of the other folate forms, as well as using NADPH, which may be in short supply. I think Freddd has come to agree with this, also. So I have eliminated folic acid, except for what is in the multi, and I think Freddd is trying to eliminate it completely.

I have retained folinic acid, following Dr. Yasko, because it is sort of a "buffer" form of folate that can be converted to other active forms, including those used to make DNA and RNA. I think there is advantage in supplementing this, especially until methionine synthase is more active, so that the 5L-methyl tetrahydrofolate can be converted to tetrahydrofolate, to be used to form other active folate forms. Freddd, on the other hand, has found that folinic acid causes his symptoms to worsen, so he is avoiding it.

I want to emphasize that selecting the supplements for a protocol like this is not an exact science. The biochemical theory, combined with lab testing, gives us guidance about what is not working right, but it doesn't tell us exactly which supplements and at what dosages are most likely to help. And this will actually vary from one person to another because of genetic individuality. So it is a compromise and requires judgment, and what I have chosen is probably not optimum, but it is an attempt to simplify what was initially more complex and expensive than was feasible for many PWCs.

A clinical study performed by Neil Nathan, M.D. and myself (reported at the IACFS/ME conference in 2009) found that this protocol gave significant benefit to at least two-thirds of the ME/CFS patients in the study, and a couple of them were able to return to full-time work.

Freddd has begun from a much different starting point. He has been trying to achieve his own health for many years, and has based his protocol choices on his own experience and that of others, rather than on a theoretical framework or lab testing. [I suspect] Freddd himself has...an inborn genetic error of metabolism in his intracellular B12 processing enzymes. It is not clear how prevalent this is in the general population. The literature suggests that it is rare, but Freddd believes that it is fairly common. Freddd does not have confidence in lab testing, and relies on experience with trying various supplements and combinations of them, to see what the effects are on his symptoms and those of others. He has compiled an extensive list of symptoms and has assigned them to deficiencies of B12 or folate in the body as a whole or in the brain in particular, based on experience.

It is not clear what the actual illness is in many of the people Freddd has worked with. Some may indeed have ME/CFS. Others may suffer from a variety of B12-deficiency conditions, including low B12 in the diet, pernicious anemia, transcobalamin deficiency, or the type of issue Freddd has himself, which involves the enzymes inside the cells that process B12.

Freddd's protocol includes methylcobalamin (methyl B12), adenosylcobalamin (adenosyl B12), 5L-methyltetrahydrofolate, and some other cofactor supplements.
He tends to use larger dosages than in the Simplified Protocol, and favors "pushing through" the symptoms that arise by continuing at the high dosages. He has found that this has led to success for himself and others. He does not believe that methyl B12 at high dosages will cause problems with mercury.

I have taken what I believe is a more cautious approach, advising people to back off on the dosages or stop the protocol for a while if the symptoms become intolerable. In my view, the symptoms that arise on the Simplified protocol are due to restoration of the function of the body's detoxication system and immune system, and that these systems begin to work on the backlog of toxins and pathogens that have accumulated while the person has been ill. Mobilization of toxins into the blood on their way to the kidneys and liver for excretion bathes all the cells in toxins, and I think this is what causes the intensification of symptoms while on the protocol. Slowing down can give the body a chance to rid itself of some toxins before mobilizing more. Freddd attributes the symptoms during treatment to other causes than toxin mobilization, and his view is that backing off on the dosages will cause the person to "lose ground" and have to go through the same issues over again when they resume the treatment at full dosages.

Freddd's protocol essentially bypasses the normal processes of absorption, transport and metabolism of B12 by using large dosages of the final two active coenzyme forms of B12, causing them apparently to diffuse directly into the cells. In principle, this approach is capable of compensating for a wide variety of B12-related disorders. Those benefiting from Freddd's protocol probably do have a wide variety of causes of their B12-related illnesses. My approach, on the other hand, has been directed at trying to understand the pathogenetic and pathophysiological mechanism of ME/CFS specifically, and to design a treatment that counters it, while working with the normal biochemistry of the body to the degree possible.

Freddd's protocol has clearly helped many people, and based on the reports I've received over the past four years, I would say that the Simplified approach has done so as well. I don't have enough controlled treatment data to decide which approach might be best, and as I mentioned above, it probably varies with the individual.

One other thing that I want to emphasize is that my position is that a person needs to be under the care of a licensed physician when on methylation treatment. A small number of people have reported experiencing serious adverse effects while on the Simplified treatment, even though it consists only of nutritional supplements.

I hope this is helpful.

Best regards,

Rich
 

Freddd

Senior Member
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No Longer relevant as the specified piece was removed.

I am preparing an in depth detailing of this entire post as I think it can illustrate just exact what and where the disagreements are.
 

Lotus97

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Lotus,

Freddd himself has reported that he has an inborn genetic error of metabolism in his intracellular B12 processing

THIS IS SOMETHING THAT WAS DISUSSED AT THE BEGINNING AND IS WRONG AS MY REAL PROBLEM WAS LATER IDENTIFED TO BE FOLATE PROBLEMS. EVERYTHING THAT LOGICALLY FOLLOWS BASED ON THIS INCORRECT ASSUMPTION IS ALSO WRONG. MANY UNDERSTANDINGS HAVE CHANGED SINCE THIS WAS WRITTEN AND THE COMMENTS ARE NOT CORRECT ABOUT ANYTHING THAT IS BEING DONE AT THIS TIME. PLEASE STOP REPEATING THESE INCORRECT AND FALSE THINGS. THE MISLEAD EVERYBODY. I HOPE YPOU CAN READ THIS SIZE. I CAN SAY IT AGAIN IN EVEN BIGGER PRINT IF THAT IS WHAT YOU NEED TO SEE IT. SO YOU KEEP FEEDING THIS INCORRECT AND FALSE INFORMATION TO PEOPLE FOR WHAT PURPOSE?

WHY DO YOU KEEP REPEATING THINGS THAT ARE RICH'S MISTAKEN UNDERSTANDINGS. HE ISN'T HERE TO ALTER HIS MISUNDERSTANDING AND BRING THINGS UP TO DATE.
I edited my post and deleted that part. I apologize for the confusion. However, I would also appreciate it if you would also stop bringing up incorrect things about Rich and his protocol since they are also very misleading to the people trying to learn about methylation. Thank you.
 
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