Input requested on possible changes to simplified methylation protocol

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

Hi Rich. I tried Fredd's protocol but had two problems. I found my mental fatigue got worse, but I may have put on muscle and weight (I am contemplating going back on to confirm this). Unfortunately it was very expensive for me, even though Fredd had stipulated relatively low cost products - there were a great many of them.

Mercury mobilization could be an issue with me. I would appreciate a protocol which delivers the benefits but with cost minimization. A $100/mth is more than I can afford, and it seems that to maintain improvement, the protocol must be continued, for some of us. I realise I am suggesting yours and Fredd's protocols are similar. I know this is a simplistic view.

Would there be any problems with the absorption of folinic acid and methylfolate from Thorne Basic Nutrients V, or is that just a B12 problem?

And just as a side question - could you use Thorne IV instead (with copper and iron) if you haven't hit menopause yet?

Hi Rich,
I love the idea of adding the Free Aminos. I have been using them for years. I had a significant decrease in weakness/fatigue when I started them.

The Thorn supplement looks good. It seems to have everything in one place for those who can tolerate everything. Some may have to add one at a time, though. I like it that there are capsules that I can open up and dilute!!

Whatever you decide, I personally feel it's important to go very slowly. I am just now thinking of upping my dose of "diluted specks" of mB12 and methylfolate.

I'm surprised more people haven't responded.

Addressing the issue of change being difficult: I think that most of us realize that the methylation treatment protocols are relatively new and therefore subject to modification as we (you, actually) learn more. It's clear that you are trying to modify the protocol to get better results. As always, we with CFS must be careful and approach any change slowly and cautiously. But keep in mind that almost all of us have a very long history of essentially being on our own. Most of us are used to being careful because we have learned the hard way what happens when we are not.

I must admit that I cringe a bit when I see you mention that the dose "would start at two capsules a day and move up to six, as tolerated." I'm sure I can't be the only one who has to open capsules and ingest a tiny amount. For me, a diluted dose of a speck of mB12 and methylfolate had a big effect. I'm not sure that more is necessarily better. I believe it's better to approach dosing from the low side and move up if there aren't any results.

Hey Rich,
Everyone is so different I'm not sure you can have one protocol. But you may be able to get a basic platform and then customize.
Two years ago, I looked into doing your protocol but many of the required supplements were compounded and had many of my food allergies in them. Mine is Soy, Wheat, Corn, yeast. At the time, I could not find any B's without yeast. These days I am able to find supplements free of many things. I think getting the supplements to its most basic form will help people figure out what is helping or hurting. Also it lets them play with the levels they may need.

People are so different that they have to educate themselves to fix it. I think a matrix with the following catigories would be really helpful:

• Supplement Name
• What it does
• What cycle it works on using Dr Roberts (heart guy in ohio) info packet
• Symptoms that show this deficiency and test results ( low T-cells)
• Symptoms of it working
• When/how to take it
• Amount Range of effectiveness ( b12 .25mcg to 20mg)
• How to titrate up/does up
• What it needs to be taken with to work better
• Genetic/ poly stuff that is indicated
• Great links to resource that people can get more information on it.

I would be more than happy to make this chart but I'm not sure I can attach stuff... oh and I don't know anything =( But more than happy to get it started (I love organization and label makers!)
Also, you mentioned putting in the Rubinex into the mix a couple weeks ago. I have been thinking about it because it is a major piece of the puzzle. I have read that when you increase methlyation you increase your T cells (possible t reg cells) and t-cells decrease or helps regulate your B cells. I suspect that when the immune over reacts to allergins or food or virus, the body tells you to rest so it can fight it. When I wash out my sinus and get infection out, I feel amazing. Something in my body is saying you have infection and makes me feel sick. Similar, when it is out of my sinues (it only takes 30 second) I have more energy (not as much as being on the b12 protocol), brain fog is reduced, I feel happier, the list goes on. So if our B cells are out of control due to T cells being low (in my case my T cells were 4 out of 100, with 50 being good level and B-cells at 50 out of 100). It makes sense that if you wipe out the B cells, people feel better.
Not sure if you have read these studies but I find it interesting from the T-cell stand point.
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2725755/pdf/dmp004.pdf
Mei S, Tan J, Chen H, Chen Y, Zhang J. Changes of CD4(+)CD25(high) regulatory T cells and FOXP3 expression in unexplained recurrent spontaneous abortion patients. Fertil Steril. 2010 Jan 5.
Winger EE, ReedJL. Low circulating CD4 (+) CD25(+) Foxp3(+) T regulatory Cells Predict Miscarriage Risk in Newly Pregnant Women with a history f failure. Am J Reprod Immunol. 2011. Feb. doi:10.1111/j.1600-0897.2011.00992.x.

Nothing to add just lurking around.

I like what Place came up with :

• Supplement Name
• What it does
• What cycle it works on using Dr Roberts (heart guy in ohio) info packet
• Symptoms that show this deficiency and test results ( low T-cells)
• Symptoms of it working
• When/how to take it
• Amount Range of effectiveness ( b12 .25mcg to 20mg)
• How to titrate up/does up
• What it needs to be taken with to work better
• Genetic/ poly stuff that is indicated
• Great links to resource that people can get more information on it.

Hi Rich,

In general, I would say significant improvment. I think the amino acids area good idea. I'm going to do a cost accounting of the active b12 protocol. I know that the Metafolin especially can get expensive if the person has paradoxical folate deficiency from veggie folate but other than that I don't think it is as expnsive as some might think. However Excel will give me the answer. I'm also about to post a new version of the Active B12 protocol that divides things more into stages and balancing points and a more general low start titration method with balancing points by criteria. The cost is something that greatly concerns me having been in the disabled and broke category for a long time.

H

i

Hi Rich

As you know I have been taking Thorne Basic Nutrients III since 2007 and it suits me well but I have only been taking 3 daily so have added extra minerals and other supplements too. I think it is an excellent product.

I thought I would let you know that I am unable to tolerate any extra amino acids. When I do from the very first tablet my brain goes wired and hyper. Its very nasty when this happens and I don’t feel “me” at all. Usually I am quite calm and laid back but if I taking any extra amino acids especially Branch Chain aminos it leads to these horrible symptoms and also severe insomnia and I also become aggressive.

I don’t know why this happens apart from the fact that I feel my neurotransmitters are very balanced and extra aminos throw this balance off. Could it be because my adrenals/thyroids are balanced through medication and these have a very strong positive effect on the brain?

I understand from your post that you don’t think it’s a good thing to go too high with Folapro? Recently I have been taking ½ Folapro as well as the 3 BN. Do you think that might be detrimental? I also take 3000 mcg of the AdnB12 lozenge which contains a little folic acid because I seem to tolerate it better than the Jarrow MB12.

Thanks for all your help.

Pam

A good discussion Rich. I havent tried the full protocol, due to concerns about side effects etc. I have though been prescribed MB12 daily injections by Dr Myhill - I can't tolerate the full dose so take half (250mcg a day) this has been by far my best supplement - much more effective than either HB12 sublingual or MB12 sublingual - real benefits felt.

One of the things that has put me off trying your protocol - apart from not having a doctor to oversee it all- has been the large amount of ingredients in the mulitvits. I am so sensitive to so many different things that i prefer to take my supplements as individual supplements - that way i know what is helping and what i can't tolerate.

Good luck with this, i will be keeping an eye on your good work as usual!
All the best, Justy.

Rich, thanks for your efforts!
I would like to point out some restrictions of the new version - az folate is in the multy-vitamin, it can't be dosed. I'm reacting to all forms of zinc (and may be others) so will try to to the prevoius version of the protocol with all sepatated ingredients.

Thanks for all your work Rich, as always.

I don't have much to contribute I'm afraid, except to say that I think you've made a good case for these changes. It's interesting that a lot of people find it difficult to tolerate some of these supplements - do you have any ideas why this is? For my part, I've never had any problem with any of the supplements you've suggested, even at the highest doses, but they've never given me any improvement either.

I've often wondered though - perhaps we need to be on these things for a very long time before we can expect any results. I believe the trial you published lasted about 6 months. Are you following up any of the patients over a longer period of time?

Perhaps those of us who've been ill for decades need to do this protocol for several years before giving up. Is there any theory that supports this long-term view?

Jenny

Hi Rich,

In my experience, the relatively small amounts of methylfolate in the multi won't be enough, when taking 2mg methylcobalamin. You will notice there is a 2:1 ratio of methylfolate to methylcobalamin in the multi, and this I believe, is for good reason. In Metanx, there is a 1.5:1 ratio. So it is my estimate that people will need 2-3mg of methylfolate with 2mg methylcobalamin.

Another comment is about NT factor. I do not understand the advantage of this supplement. You say it's liposomal. So, phospholipids are encapsulated in...phospholipids? Makes no sense to me. Also the supplement contain a host of ingredients that I would be wary of taking:

I just wonder about the timing issue.

I mean if you have to take such tiny dosages of folate and B12.. you're probably not getting that much benefit.. and you might be better off waiting until you have got yr infectious load down or toxic load some other way.. before going at it.

My Infectious disease doc says methylation comes last.....And he's been wrong about plenty of things..But, I wonder if it would go faster/easier if you have already taken the load off glutatione by taking gcmaf or antivirals or whatever.. because we know that glutathione goes down before it comes up on this protocol.

In retrospect, I think I had a lot of uncontrolled excitotoxicity & supposedly that can kill off brain cells...so I would do it different if I did it again, but knowing what I know now, I would do everything differently! and this was the first thing that gave me any relief from my symptoms...

The best thing is to use it as an adjunctive therapy rather than first line I think....So maybe if you're on something that spares glutathione, it would be easier going.

Chicken or the Egg? did virus/infection load cause the depletion or did the depletion cause the body more receptive?

Hi Jenny,

I was ill for 4 decades and severely so for 17 years. I am not familiar with your situation so what I say is going to be general. First, after 17 years of trying I found ONE thing that was effective. That was the clue I neeeded. It was effective in 5 minutes. What I found is that in general these are not single item deficiencies but rather multiple deficiencies. What that means is that that unless the right combination was taken, nothong works. Also, the itmes I needed to give me a respons have only become available starting in 1998 and the past few years (Metafolin). For, and a lot of people cyanocbl, hydroxycbl, folic acid, and even folinic acid may not be effective at all or even worse, block the things that are effective. If you are willing to fill out a history that is in an Excel speradsheet that I have almost ready to send out, I can will be able to make a reasonable assessment of what supplemnts and COMBINATIONS could work for you. As the right thing(s) can make 100% difference compared to the things that don't work perhaps I can offer you some suggestions. If you are interested post me a private conversation you email address and I will send it out next week. I am still in the process of refining this whole business witth the help of people like you. The other thing I will be able to tell is if you fit the pattern of those who can benefit.

If I succeed at identifying what could work and it does, you could be ready to start rehabilitation in a year or so. Often the problem has been that it works so well that it does too much all at once and I've been working at breaking that down so things can happen at a more tolerable level.

Hi Adreno,

I don't believe that the ratio idea of mb12 to methylfolate has any relavance at all. 50mcg of mb12 can trun on healing needing 2400mcg or more of Metafolin and 2000mg or more of potassium. 50,000mcg of mb12 requires no more, it just penetrates the brain better. That said, I agree, more methylfolate is needed.


DISCLAIMER

I am a self taught systems analyst and consultant. I am not credentialed, certified or licensed to do anything besides drive a car. I have been disabled by the disease processes being discussed and affecting neurology in a multitude of ways for 10 years and impaired in a variety of ways and levels for 54 years before that. Everything I say is my opinion, synthesis, understanding or otherwise of my own creation except direct attributed quotes. Approximate paraphrases are also my interpretation of what I have read. All of this is at best my data analysis, understanding, synthesis and hypotheses and not to be construed as medical advice. I am not responsible for anything you do with any information provided in any way. Anything you do is your own responsibility and at your own risk. There are no published peer reviewed studies backing up my opinions or statements, except the incidental ones quoted or implicit in my synthesis or understanding, and then only in so far any reading of such papers may confer. Your interpretations, actions and variations of what I say are strictly at your own risk.

Thanks Freddd but I have given you lots of details over the last few months, and you've made suggestions. I've tried most of them, but haven't experienced any improvement, and nothing gives me any bad reactions either.

I find it striking that all multivitamins and drugs that contain both b12 and folate have higher levels of folate. The healthy human body also contains higher levels of folate than b12. That said, it is possible that there is a threshold dose, which we do not need to go beyond. I have already posted a study showing that methylation and neuronal healing peaks at ~1000 mcg folate for a 80 kg human, so maybe taking something like 800-1000 mcg 3-4 x daily might be optimal. In any case, I highly doubt that the methylfolate contained in the Thorne multi will be enough, when taking an additional 2 mg methylcobalamin.