Hi, all.
I’m writing this post to ask for advice. I’m considering making some new changes to the Simplified Methylation Protocol for the treatment of ME/CFS. Many of you have experience with methylation-type treatments, favorable, or in some cases, unfavorable. I would like to have the benefit of your experience in considering these changes.
Why make changes? Several reasons. I think we have learned more about this type of treatment of ME/CFS from experience. Also, I would like to change the treatment to make it effective for more PWMEs. And I would like to make it more convenient to use. Also some new forms of supplements have come out recently, and they may offer advantages over what we have used in the past.
What are the disadvantages of making changes? There is still a lot we don’t know, and there is some uncertainty about the effects that changes would have. Also, it can be confusing to people to have yet another modification of the protocol, when the previous versions can still be found on the internet at various sites. And, the more the new version departs from the version used in the clinical study by Dr. Nathan and myself, the more people may wonder how relevant that study is to the new version.
But my opinion is that the pros outweigh the cons, so I want to proceed.
The guiding philosophy for this modification is still the same as it has always been. The new modification will still be based on the Glutathione Depletion—Methylation Cycle Block hypothesis for the pathogenesis and pathophysiology of ME/CFS, because this hypothesis, in my opinion, has continued to hold up as research into ME/CFS has continued and new information has come to light.
The new version will still seek to minimize the number of supplements and keep the cost reasonable from the viewpoint of most PWMEs. It will still consist only of nonprescription nutritional supplements. While it will not be possible to obtain all the supplements in the new version from a single source, they will still all be available via the internet, at least in the U.S.
With that background, I will start from where we are now. Here is the version of the protocol that I proposed on March 30, 2011:
1. General Vitamin Neurological Health Formula: Start with ¼ tablet and increase dosage as tolerated to 2 tablets daily
2. Hydroxy B12 Mega Drops: 2 drops under the tongue daily (2,000 micrograms)
3. MethylMate B: 3 drops under the tongue daily (210 micrograms of methylfolate)
4. Folinic acid: ¼ capsule daily (200 micrograms)
5. Phosphatidyl Serine Complex: 1 softgel capsule daily (500 milligrams) (or lecithin,
1200 milligrams)
Considering first the General Vitamin Neurological Health Formula, the purpose of this multi was to compensate for nutritional deficiencies that might be present in vitamins and essential minerals, and also to supply other nutrients particularly helpful for the methylation cycle and related pathways. For many PWMEs, this formula has apparently been adequate for these purposes. However, for others, it has not. The dosages of some of the vitamins and minerals in this supplement have not been sufficient to compensate for the deficiencies in quite a few people, based on lab testing after extended treatment with the existing protocol in some cases, and based on improved response when certain nutrients were added in other cases. In addition, some people have been sensitive to certain of the ingredients in this formula and have therefore not been able to take it. Finally, this formula includes both cyanocobalamin and folic acid, and I would like to eliminate these forms of vitamin B12 and folate, for various reasons. I am therefore considering replacing this formula with Thorne Basic Nutrients V (http://www.thorne.com/Products/Multiples/prd~VM5.jsp) .The dosage would start with two capsules per day and move up to six per day, as tolerated. This supplement does not have all the ingredients that are found in the Neuro Health formula, but it does have the essential nutrients, and hopefully the body would be able to synthesize the others that it needs.
Next, the Hydroxy B12 Mega Drops. Since the first version of the simplified protocol, I have specified hydroxocobalamin as the form of B12 to use. The actual form of B12 that is needed by methionine synthase, the enzyme that is partially blocked in ME/CFS, is methylcobalamin. The cells must convert hydroxocobalamin to methylcobalamin. This requires both glutathione and S-adenosylmethionine (SAMe). Many PWMEs are able to make this conversion, but some are not. In lab testing, I have found some people to be extremely low in both glutathione and SAMe, which makes this conversion very slow. Dr. Amy Yasko bases the choice of hydroxo- or methyl-B12 on genetic polymorphisms. Since I have not relied on polymorphism characterization, I simply chose one of them, i.e. hydroxo B12. I was initially concerned that methyl B12 could methylate inorganic mercury and move it into the brain. Although this is theoretically possible from a chemical standpoint, there does not seem to be evidence that it occurs to a significant extent in humans treated with methyl B12 at the relevant dosages. I have also been concerned that use of high dosages of methyl B12 together with high dosages of methylfolate can overdrive the methylation cycle and slow the recovery of glutathione. I still believe this is the case, based on lab test results I have seen. However, if the dosage of methyl B12 is not too high, I don’t think this will be an issue. In view of all of this, I am now considering replacing Hydroxy B12 Mega Drops with Methyl B12 Mega Drops, at the same dosage, i.e. 2000 micrograms. Note that the Thorne Basic Nutrients V contains methylcobalamin as well as adenosylcobalamin, but since it is an oral supplement, their absorption will be limited, and additional sublingual B12 is needed to get enough into the blood to overcome the functional B12 deficiency in ME/CFS.
Next, MethylMate B. This supplement contains methylfolate, which is the form of folate needed by methionine synthase. I am considering eliminating this one, because the Thorne Basic Nutrients V contains methylfolate.
Now, folinic acid. The reason I have included this form of folate is that in most people it serves as a buffer for the folate metabolism, and can readily be converted to other forms of folate, which methylfolate cannot. Including folinic acid allows the other forms of folate (including those necessary for producing new DNA and RNA) to rise, while the methionine synthase reaction, which forms tetrahydrofolate, also convertible to other folate forms, has not yet come up to full speed. I am considering eliminating this supplement, because the Thorne Basic Nutrients contains folinic acid.
Next, the phosphatidylserine complex. This supplement has had several purposes. It contains a range of phospholipids, which can help in the repair of cellular membranes that have been damaged by oxidative stress. It also provides some choline, which can be converted in the body to betaine to support the alternate BHMT pathway for methylation, thus helping to build up SAMe until the methionine synthase reaction comes up. Finally, Dr. Yasko favors the use of phosphatidyl serine to support the nervous system in autistic patients. In the previous version, I suggested lecithin as an alternative for PWMEs who have low cortisol, since phos. serine has the effect of lowering cortisol, at least at first. Over time it has become more clear to me that low cortisol is much more of an issue in ME/CFS than in autism. Also, by switching hydroxo B12 to methyl B12, raising SAMe via the BHMT pathway is not as important. There has been some concern that the phospholipids will be digested and not absorbed intact. I have also learned of a liposomal form of the phospholipids that is likely to be more effective in delivering them to the cells. Therefore, I am considering replacing the phosphatidylserine complex and its lecithin alternate with the product called “Smart Youthful Energy,” made by NT Factor (http://www.ntfactor.com/nt-factor-lipids/). I’m not sure of the dosage yet. It comes in bottles with a serving size of 2 fluid ounces, and perhaps that would be appropriate.
This is a nested liposomal phospholipid supplement that can deliver the phospholipids directly to the cells, including the mitochondria. It is a soy-based product, so there may be a problem for those with sensitivity to soy, and an alternative may have to be used by them.
Finally, I am considering adding a free-form amino acids supplement to the protocol, because I have found that some PWMEs are very low in the essential amino acids. I am considering Free Aminos, made by Allergy Research Group, and the dosage would be two capsules per day.
Those are my thoughts for now. I would be interested in input from anyone who would like to comment. I don’t have a set time schedule for making changes. I want to get input and think about it for a while, to try to avoid changes that wouldn’t be helpful.
Best regards,
Rich
I’m writing this post to ask for advice. I’m considering making some new changes to the Simplified Methylation Protocol for the treatment of ME/CFS. Many of you have experience with methylation-type treatments, favorable, or in some cases, unfavorable. I would like to have the benefit of your experience in considering these changes.
Why make changes? Several reasons. I think we have learned more about this type of treatment of ME/CFS from experience. Also, I would like to change the treatment to make it effective for more PWMEs. And I would like to make it more convenient to use. Also some new forms of supplements have come out recently, and they may offer advantages over what we have used in the past.
What are the disadvantages of making changes? There is still a lot we don’t know, and there is some uncertainty about the effects that changes would have. Also, it can be confusing to people to have yet another modification of the protocol, when the previous versions can still be found on the internet at various sites. And, the more the new version departs from the version used in the clinical study by Dr. Nathan and myself, the more people may wonder how relevant that study is to the new version.
But my opinion is that the pros outweigh the cons, so I want to proceed.
The guiding philosophy for this modification is still the same as it has always been. The new modification will still be based on the Glutathione Depletion—Methylation Cycle Block hypothesis for the pathogenesis and pathophysiology of ME/CFS, because this hypothesis, in my opinion, has continued to hold up as research into ME/CFS has continued and new information has come to light.
The new version will still seek to minimize the number of supplements and keep the cost reasonable from the viewpoint of most PWMEs. It will still consist only of nonprescription nutritional supplements. While it will not be possible to obtain all the supplements in the new version from a single source, they will still all be available via the internet, at least in the U.S.
With that background, I will start from where we are now. Here is the version of the protocol that I proposed on March 30, 2011:
1. General Vitamin Neurological Health Formula: Start with ¼ tablet and increase dosage as tolerated to 2 tablets daily
2. Hydroxy B12 Mega Drops: 2 drops under the tongue daily (2,000 micrograms)
3. MethylMate B: 3 drops under the tongue daily (210 micrograms of methylfolate)
4. Folinic acid: ¼ capsule daily (200 micrograms)
5. Phosphatidyl Serine Complex: 1 softgel capsule daily (500 milligrams) (or lecithin,
1200 milligrams)
Considering first the General Vitamin Neurological Health Formula, the purpose of this multi was to compensate for nutritional deficiencies that might be present in vitamins and essential minerals, and also to supply other nutrients particularly helpful for the methylation cycle and related pathways. For many PWMEs, this formula has apparently been adequate for these purposes. However, for others, it has not. The dosages of some of the vitamins and minerals in this supplement have not been sufficient to compensate for the deficiencies in quite a few people, based on lab testing after extended treatment with the existing protocol in some cases, and based on improved response when certain nutrients were added in other cases. In addition, some people have been sensitive to certain of the ingredients in this formula and have therefore not been able to take it. Finally, this formula includes both cyanocobalamin and folic acid, and I would like to eliminate these forms of vitamin B12 and folate, for various reasons. I am therefore considering replacing this formula with Thorne Basic Nutrients V (http://www.thorne.com/Products/Multiples/prd~VM5.jsp) .The dosage would start with two capsules per day and move up to six per day, as tolerated. This supplement does not have all the ingredients that are found in the Neuro Health formula, but it does have the essential nutrients, and hopefully the body would be able to synthesize the others that it needs.
Next, the Hydroxy B12 Mega Drops. Since the first version of the simplified protocol, I have specified hydroxocobalamin as the form of B12 to use. The actual form of B12 that is needed by methionine synthase, the enzyme that is partially blocked in ME/CFS, is methylcobalamin. The cells must convert hydroxocobalamin to methylcobalamin. This requires both glutathione and S-adenosylmethionine (SAMe). Many PWMEs are able to make this conversion, but some are not. In lab testing, I have found some people to be extremely low in both glutathione and SAMe, which makes this conversion very slow. Dr. Amy Yasko bases the choice of hydroxo- or methyl-B12 on genetic polymorphisms. Since I have not relied on polymorphism characterization, I simply chose one of them, i.e. hydroxo B12. I was initially concerned that methyl B12 could methylate inorganic mercury and move it into the brain. Although this is theoretically possible from a chemical standpoint, there does not seem to be evidence that it occurs to a significant extent in humans treated with methyl B12 at the relevant dosages. I have also been concerned that use of high dosages of methyl B12 together with high dosages of methylfolate can overdrive the methylation cycle and slow the recovery of glutathione. I still believe this is the case, based on lab test results I have seen. However, if the dosage of methyl B12 is not too high, I don’t think this will be an issue. In view of all of this, I am now considering replacing Hydroxy B12 Mega Drops with Methyl B12 Mega Drops, at the same dosage, i.e. 2000 micrograms. Note that the Thorne Basic Nutrients V contains methylcobalamin as well as adenosylcobalamin, but since it is an oral supplement, their absorption will be limited, and additional sublingual B12 is needed to get enough into the blood to overcome the functional B12 deficiency in ME/CFS.
Next, MethylMate B. This supplement contains methylfolate, which is the form of folate needed by methionine synthase. I am considering eliminating this one, because the Thorne Basic Nutrients V contains methylfolate.
Now, folinic acid. The reason I have included this form of folate is that in most people it serves as a buffer for the folate metabolism, and can readily be converted to other forms of folate, which methylfolate cannot. Including folinic acid allows the other forms of folate (including those necessary for producing new DNA and RNA) to rise, while the methionine synthase reaction, which forms tetrahydrofolate, also convertible to other folate forms, has not yet come up to full speed. I am considering eliminating this supplement, because the Thorne Basic Nutrients contains folinic acid.
Next, the phosphatidylserine complex. This supplement has had several purposes. It contains a range of phospholipids, which can help in the repair of cellular membranes that have been damaged by oxidative stress. It also provides some choline, which can be converted in the body to betaine to support the alternate BHMT pathway for methylation, thus helping to build up SAMe until the methionine synthase reaction comes up. Finally, Dr. Yasko favors the use of phosphatidyl serine to support the nervous system in autistic patients. In the previous version, I suggested lecithin as an alternative for PWMEs who have low cortisol, since phos. serine has the effect of lowering cortisol, at least at first. Over time it has become more clear to me that low cortisol is much more of an issue in ME/CFS than in autism. Also, by switching hydroxo B12 to methyl B12, raising SAMe via the BHMT pathway is not as important. There has been some concern that the phospholipids will be digested and not absorbed intact. I have also learned of a liposomal form of the phospholipids that is likely to be more effective in delivering them to the cells. Therefore, I am considering replacing the phosphatidylserine complex and its lecithin alternate with the product called “Smart Youthful Energy,” made by NT Factor (http://www.ntfactor.com/nt-factor-lipids/). I’m not sure of the dosage yet. It comes in bottles with a serving size of 2 fluid ounces, and perhaps that would be appropriate.
This is a nested liposomal phospholipid supplement that can deliver the phospholipids directly to the cells, including the mitochondria. It is a soy-based product, so there may be a problem for those with sensitivity to soy, and an alternative may have to be used by them.
Finally, I am considering adding a free-form amino acids supplement to the protocol, because I have found that some PWMEs are very low in the essential amino acids. I am considering Free Aminos, made by Allergy Research Group, and the dosage would be two capsules per day.
Those are my thoughts for now. I would be interested in input from anyone who would like to comment. I don’t have a set time schedule for making changes. I want to get input and think about it for a while, to try to avoid changes that wouldn’t be helpful.
Best regards,
Rich