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Revised Simplified Methylation Protocol (August 25, 2012 Revision)

richvank

Senior Member
Messages
2,732
Hi, all.

Various versions of the Simplified Methylation Protocol have been in use now for about five and a half years, and we have gained considerable experience with it. It is currently being used by clinicians and people with ME/CFS (PWMEs) in several other countries in addition to the U.S. Most who try it report benefit from it. A few have reported complete recovery, but most will need additional types of treatment to achieve complete recovery, and this is an area of ongoing research.

On May 30, 2012, I posted a request for input on possible changes to the Simplified Methylation Protocol (SMP) on the Phoenix Rising ME/CFS forum and to the Yahoo cfs_yahoo group. Quite a few people tried supplements that I was considering and posted comments about their experiences. Several offered advice. Thank you to all who responded.

As expected, different people had different experiences, and not all the comments were in agreement with each other. This is inherent, given that each person is unique, though we all share the same basic biochemical scheme, and it makes the formulation of a “one-size-for-all” protocol very challenging.

I have reached conclusions about what I will recommend for now. There may be additional changes in the future, as more experience is gained and we learn more about how to treat ME/CFS. I will present the “bottom line” first, and then discuss the rationale behind the choices, together with some additional options, for those who are interested.

Here is the revised Simplified Methylation Protocol as of today, August 25, 2012:

(AS ALWAYS, I RECOMMEND THAT ANYONE ON THIS TYPE OF TREATMENT BE UNDER THE CARE OF A LICENSED PHYSICIAN. Even though this protocol consists only of nutritional supplements, a small number of people have reported experiencing serious adverse effects while on it. If this occurs, the protocol should be discontinued.)

1. Neurological Health Formula (Holistic Health, Inc.) (Multivitamin-multimineral, plus
additional nutrients): Swallow one-quarter tablet and increase to 2 tablets daily. Go
up to 6 tablets daily if tolerated. [Moderator Note: As of Sept/Oct 2013, Neurological Health Formula was discontinued, and replaced with:
ALL-IN-ONE Multi Vitamin/Mineral (120 caps Holistic Health )]

2. Activated B12 Guard (Perque) (2,000-microgram lozenge of hydroxocobalamin):
Take one lozenge per day, sublingually.
3. FolaPro (Metagenics) (800-microgram tablet of 5L-methyltetrahydrofolate): Swallow
one-quarter tablet daily, which amounts to 200 micrograms per day.
4. Folinic acid (800 micrograms of 5-formyltetrahydrofolate): Swallow one-quarter
tablet or one-quarter of the contents of a capsule daily, which amounts to 200
micrograms per day.
5. Lecithin (1200-milligram softgel): Swallow one softgel per day, which amounts to
1200 milligrams of lecithin. If finances permit, instead of lecithin, drink a 2-ounce
bottle of Smart Youthful Energy (NT-Factor)(Pure liposomal glycophospholipids)
daily.

All these supplements except Smart Youthful Energy can be obtained from www.holisticheal.com, or all but the first one can be obtained from other sources. I do not have a financial interest in any of these supplements. A pill splitter (available from drugstores) will be needed to split tablets. These supplements can be taken with or without food. Different times of the day work better for different people, in regard to effects on sleep. It is best to start with lower dosages than those suggested above and to work up slowly, to check for tolerance. Some people have found that they are very sensitive to these supplements, and can take only much smaller dosages. Others find that they need somewhat larger dosages than those suggested. For those who wish to start the supplements one at a time, I suggest starting with the Neurological Health Formula first, then adding the lecithin, then the B12, and finally the folates, with FolaPro last.


In making this revision, I have been guided by the following goals:

1. To provide effective treatment to correct the vicious circle mechanism that I believe to be the core of the pathophysiology of ME/CFS, involving glutathione depletion, a functional B12 deficiency, a partial block of the methylation cycle, and loss of folates from the cells. This vicious circle mechanism is described by the Glutathione Depletion—Methylation Cycle Block hypothesis for the etiologies, pathogenesis and pathophysiology of ME/CFS. This hypothesis cannot be regarded as scientifically proven, but as far as I know, it is consistent with the current body of published research on ME/CFS.

2. To use only nonprescription nutritional supplements that are available via the internet.

3. To use supplements that are available from a single source, where possible.

4. To keep the protocol simple, with a minimum number of supplements, while preserving its effectiveness.

5. To keep the cost low while preserving effectiveness.

6. To improve the effectiveness of the protocol over that of the previous version, and in particular to increase its likelihood of being effective for more of the ME/CFS population.

7. To preserve the ability of individuals to adjust dosages of individual supplements to match their tolerances and needs.

8. To preserve the relevance of the clinical study of an earlier version of the protocol by Dr. Neil Nathan, M.D., and myself, to the degree possible.

With those goals in mind, I will discuss each of the supplements in the revised protocol.

1. Neurological Health Formula: I have decided to continue recommending this multi for a variety of reasons. First, we have a track record with it that shows that it is helpful to most PWMEs. It contains the vitamins and essential minerals to cover possible nutritional deficiencies, as well as several supplements to support the methylation cycle and related pathways that are not in other multis. Use of this multi allows the active folates to be given separately, so that people can adjust their dosages separately from that of the multi. The cost is reasonable.

This formula does have some disadvantages as well, in my opinion. It lacks copper and iron, which are essential nutrients, and which are deficient in some PWMEs, but which are also capable of promoting oxidative stress if present in excess as free ions. This formula is also rather low in some of the other essential nutrients. Thus, it would be wise to test for levels of vitamins and essential minerals and add appropriate supplements if some are low (see below).

This formula includes some folic acid and some cyanocobalamin, which I do not prefer.
Folic acid is not utilized well by some people, and it competes for absorption and transport with the active forms of folate. Cyanocobalamin contains cyanide, but the amount in this multi should be well dealt with, especially since so much more hydroxocobalamin will enter the blood with this protocol.

The fact that this formula includes several extra nutrients can be a disadvantage for some PWMEs who have sensitivities to one or more of the ingredients, and thus are not able to
take the formula. These people will need to explore other alternatives for covering possible deficiencies in vitamins and essential minerals, and they may also need some of the additional nutrients that are in this formula.

I had considered use of the Thorne Basic V supplement, and some people tried it and reported that they did well with it. However, others did not respond well to it, and use of it does not allow separate adjustment of dosages for the active folates, which some PWMEs must limit to very small amounts because they react very strongly to it. Also, this multi does not include some of the helpful nutrients that are in the Neuro Health Formula, and it does include lipoic acid, which reportedly can mobilize and redeposit mercury if not dosed frequently enough.

2. Activated B12 Guard: This was used in earlier versions of the protocol to supply the high dosage of B12 that is needed to overcome the functional B12 deficiency. In the previous version of the SMP, I changed the recommendation to Hydroxy B12 Megadrops taken under the tongue. Several people have reported that this has not been as effective as the Perque Activated B12 Guard, so I am now changing back to that. Perhaps the length of time that the liquid drops are in contact with the mucosa is just too short to allow enough absorption sublingually.

I had also considered changing the form of B12 to methylcobalamin. Some PWMEs do need to use this form, particularly if their glutathione and/or S-adenosylmethionine are very low. However, use of hydroxocobalamin is a “gentler” approach to lifting the partial methylation cycle block, and many PWMEs need such an approach. Use of hydroxocobalamin also keeps the cells in control of the rate of the methylation cycle, preventing it from being overdriven, which slows the rise of glutathione. So I have decided to stay with hydroxocobalamin as the first form of B12 to try. For people who do not get a response from the SMP within a couple of months, switching to methylcobalamin would be an option to try. Another option would be to try adding some adenosylcobalamin (dibencozide). However, I do not favor raising the overall dosage of B12 very much above 2,000 micrograms per day, and especially not when it is combined with dosages of methyfolate that are much above the RDA range of 400 to 800 micrograms per day. This combination can overdrive the methylation cycle and hinder the rise of glutathione.

3. FolaPro: This was also used in earlier versions. In the previous version, I changed the recommendation to the liquid MethylMate B, on the basis of convenience, not having to split tablets. However, I have received reports that some PWMEs have a sensitivity to something in MethylMate B. Therefore, I am now changing back to FolaPro. Solgar Metafolin could be used instead, and it is probably less expensive, but it also contains additional additives, including mannitol and magnesium stearate, which may cause sensitivity problems for some people. The function of this supplement in the protocol is to replenish the form of folate directly needed by the methionine synthase reaction, which is partially blocked. This form has been depleted by reactions with peroxynitrite, and some people are not able to convert other forms of folate into methylfolate readily.

4. Folinic acid: This is a buffer form of folate that most people can readily convert to other active forms of folate. Its role in the protocol is to supply these other forms while the methionine synthase reaction has still not come up to normal. This is particularly important for making new DNA and RNA for replacing cells. In the early versions of the protocol, Actifolate was used to supply folinic acid. However, it also contains some folic acid, which I would prefer to minimize. Folinic acid can be obtained either in tablet or capsule form.

5. Lecithin: The role of lecithin is to help with repair of cell membranes, especially mitochondrial membranes, which have been damaged by oxidative stress. I suspect that the damaged mito membranes are one of the main reasons why many PWMEs have found that recovering their energy status is one of the slowest aspects of recovery from ME/CFS. In early versions of the SMP, I recommended phosphatidylserine complex to fill this role. However, the phosphatidylserine component tends to lower cortisol initially, and most PWMEs already have below-normal cortisol. Most lecithin is derived from soy, but for those who do not tolerate soy, lecithin is also available that is derived from sunflower, canola or eggs.

I have also recommended that if finances permit, it would be preferable to use Smart Youthful Energy rather than lecithin. This is more costly, but I think it would be worth it, for those who can afford it. Smart Youthful Energy is composed of a liposomal form of pure glycophospholipids of the types needed by the cell membranes, including the mitochondrial membranes. This product has the capability to deliver these lipids to where they are needed, unchanged. Unlike other NT Factor products, there are no additional supplements besides the lipids in this product. It is derived from soy, but it does not contain soy protein, and should not provoke any reactions. Use of these lipids constitutes what has been called “Lipid Replacement Therapy,” a trademarked name.
This approach has been tested by Dr. Garth Nicolson and others, and has been found to be very beneficial in conditions that involve fatigue, including ME/CFS.

6. Amino acids supplementation: I considered adding this to the protocol, because I have found that some PWCs are depleted in amino acids, but issues were raised by commenters, including the possibilities that this would provoke yeast growth or increased excitotoxicity or ammonia generation. Since I don’t have much experience with supplementation with free amino acids, I have decided not to add this now. Hopefully PWMEs can consume enough protein in their diets to supply the amino acids they need.
Those who are able to do lab testing will be able to determine their amino acids levels and correct them if necessary.


I want to add that I have written the above keeping in mind that many PWMEs are not able to do much if any lab testing, largely for financial reasons. However, I do want to note that my preference would be for people to do lab testing before entering upon this protocol, as well as other additional treatments that may be needed, as indicated by the results of testing.

I particularly favor running the methylation pathways panel that is offered by the Health Diagnostics and Research Institute in New Jersey, USA, and the European Laboratory of Nutrients (ELN) in the Netherlands. This panel will identify whether there is glutathione depletion, a partial methylation cycle block and folate depletion, and thus whether methylation treatment is likely to help. It will also provide baseline data
for comparison later, to gauge the progress of the treatment.

If there are problems with the digestive system, I favor running comprehensive stool analyses to identify them so that they can be treated. I particularly like the Metametrix G.I. Function Profile and the Diagnos-Techs Expanded G.I. Panel. If finances permit running both of them, I think it would be worthwhile. If not, I think I would choose the Metametrix panel. It is important to have the digestive system operating fairly well in order for the methylation protocol to work properly, because it is necessary to have sufficient absorption of nutrients and sufficient ability to excrete toxins, rather than recirculating them. Friendly bacteria produce some of the vitamins needed by the body. Also, correcting a “leaky gut” will take a major load off the immune system, which is dysfunctional in ME/CFS.

I also believe it is helpful to test for deficiencies in the vitamins, minerals and amino acids and augment those that are low. They can either be measured directly, as in the vitamin,minerals and amino acids panels offered by Health Diagnostics or the ELN, or by metabolic-type testing, such as with the Metametrix ION Profile or the Genova Diagnostics NutrEval Profile.

For people who suspect high body burdens of toxic metals, tests involving feces, urine and hair are available. High levels of some toxic metals can block enzymes in the methylation cycle and related pathways. Chelation treatment may be necessary to lower the levels enough to permit normal operation of this part of the metabolism.

People who are sensitive to biotoxins and are being exposed to them in their homes will need to correct this situation in order for the methylation protocol to be helpful to them.
I would particularly refer you to Dr. Ritchie Shoemaker’s website www.survivingmold.com.

I also want to note that increased excitotoxicity (causing anxiety, insomnia, nervousness and a “wired” feeling) has been reported by many people on the SMP. I believe that this is caused by an initial further drop in glutathione in the brain when this protocol is started. I have suggested that supplementing with L-cystine (not the same as L-cysteine) may help with this. However, people who have a high mercury body burden should not do this, because L-cystine has the potential to move mercury into the brain.

Best regards,

Rich Van Konynenburg
 
Last edited by a moderator:

richvank

Senior Member
Messages
2,732
Hi, all.

Sorry, I omitted a discussion of potassium deficiency. Can't get the edit feature to work on this long post, so here is the additional paragraph. Rich

Finally, some people have experienced potassium deficiency while on this and other methylation protocols. I believe that this is caused by accelerated cell division when the folates are restored to the cells, making it possible to produce new DNA more rapidly. PWMEs are low in whole body and intracellular potassium, so that they do not have much reserve. Symptoms of low potassium can include muscle cramps, arrhythmia, and extreme fatigue and lethargy. If these are experienced, potassium intake should be increased, either using supplements or eating more fruits and vegetables.
 

alice

Senior Member
Messages
109
Location
No. CA, USA
Hi, all.

Sorry, I omitted a discussion of potassium deficiency. Can't get the edit feature to work on this long post, so here is the additional paragraph. Rich

Finally, some people have experienced potassium deficiency while on this and other methylation protocols. I believe that this is caused by accelerated cell division when the folates are restored to the cells, making it possible to produce new DNA more rapidly. PWMEs are low in whole body and intracellular potassium, so that they do not have much reserve. Symptoms of low potassium can include muscle cramps, arrhythmia, and extreme fatigue and lethargy. If these are experienced, potassium intake should be increased, either using supplements or eating more fruits and vegetables.


Hi Rich,

Thanks very much for this great updated methylation protocol.

I would like to try supplementing additional potassium - what dose do you suggest? Most K supplements are 98 mg or so, is that about correct? Label says 98 mg is only 3% of daily value.
 

jstefl

Senior Member
Messages
250
Location
Brookfield, Wisconsin
Rich:

I have tried, with very little success, to cut the Folapro into four pieces. It seems to me, and I certainly could have this wrong, that your original protocol called for a whole tablet.

Would there be any harm in taking a whole tablet, or is this dosage important?

John
 

alice

Senior Member
Messages
109
Location
No. CA, USA
Rich:

I have tried, with very little success, to cut the Folapro into four pieces. It seems to me, and I certainly could have this wrong, that your original protocol called for a whole tablet.

Would there be any harm in taking a whole tablet, or is this dosage important?

John


John,
The Folapro (Metafolin) whole tablet is 800 mcg. Rich suggests starting with 200 mcg. One way to cut it is by using a 4 inch End Cutting Hobby Pliers that you can get at the hardware store or craft shop. I actually did not have much luck with that tool., but it does work The tablets are very hard to break up. A pill cutter will not work - anyway not the ones I tried. Probably a strong butcher knife would work too ( on a cutting board) - but watch your fingers:eek: !

What I am using is a cheese cutter for hard cheeses. It is about 4 inches long, round oak handle ,and the blade part about 2 inches wide, very sturdy and has a sharp cutting edge (maybe something like this is available at a place like Williams-Sonoma or Sur Le Tables)

Even so, the tablets break every which way, so I guestimate as close as possible the small pieces I have into four doses (now 3 doses as I have just upped the dose a bit).. I've been doing it this way for about 3 years now.

I did substitute the MethylMate drops for awhile, but have gone back to the tablet because I think Folapro is more efficacious. Good luck.

alice
 

juniemarie

Senior Member
Messages
383
Location
Albuquerque
I read on a site for children on the Yasko protocol that the way the mothers deal with this to crush the entire tablet in a coffee grinder or with a special pill grinder.....then they give the powder.
 

richvank

Senior Member
Messages
2,732
Rich:

I have tried, with very little success, to cut the Folapro into four pieces. It seems to me, and I certainly could have this wrong, that your original protocol called for a whole tablet.

Would there be any harm in taking a whole tablet, or is this dosage important?

John

Hi, John. Sorry about how hard it is to split Folapro tablets. I've heard that doing the first split along the diameter (longest dimension) works best. Or crushing it into a powder and dividing it in fourths.
A whole tablet has been too much for some people. I don't know how it would work for you. Rich
 
Messages
18
With regards to testing - is it going to skew test result of the Methylation Pathways panel or the GI Effects Complete Profile if I have been taking Hydro b12? If so, how long should I stop before taking the tests?

Would I be able to get enough information from the TRIAD test from Metametrix (Organix and Amino Acid) to give me answers mixed with the other two? I am trying to get as many answers as I can from different places on a budget.
 

richvank

Senior Member
Messages
2,732
Hi, Kimfm.

It's O.K. to keep taking hydroxoB12 when you run these tests.

The TRIAD panel plus the other two would give you a lot of information. It would be nice if you could measure chemical elements, both essential ones and toxic ones, too, either with a blood or urine test. That would show up deficiencies in essential minerals, which can be important, as well as toxins.

Best regards,

Rich
 

maddietod

Senior Member
Messages
2,859
I've been on various methylation protocols for a year and a half. My brain fog is (recently) completely gone. Obviously I can't be sure it's the methylation, but the last iteration involved using mb12 instead of hb12, and the dose has to be 1K, not 2 or higher.

I have 2 questions. It's cheaper for me to buy vitacost B100 (with folic acid) and add vitacost metafolin. How bad for me could this be? Is there a place I should look on my Yasko or NJ lab results to answer this question?

Also, when I ran out of lecithin I stopped using it - over a month ago. Where in the cycle is this critical? Meaning, how important it it for me to remember to go buy some?

Madie
 
Messages
41
hi Rich

What do you mean "high mercury body burden" ? you mean high levels of mercury? how does one know this without testing?

thanks
 

richvank

Senior Member
Messages
2,732
I've been on various methylation protocols for a year and a half. My brain fog is (recently) completely gone. Obviously I can't be sure it's the methylation, but the last iteration involved using mb12 instead of hb12, and the dose has to be 1K, not 2 or higher.

I have 2 questions. It's cheaper for me to buy vitacost B100 (with folic acid) and add vitacost metafolin. How bad for me could this be? Is there a place I should look on my Yasko or NJ lab results to answer this question?

Also, when I ran out of lecithin I stopped using it - over a month ago. Where in the cycle is this critical? Meaning, how important it it for me to remember to go buy some?

Madie

Hi, Madie.

I think it comes down to the question of how well your first DHFR reaction works, i.e. how readily your cells are able to convert folic acid to tetrahydrofolate. I'm not sure that can be determined from your lab tests. The Yasko panel does not include DHFR, and in the NJ lab panel the tetrahydrofolate can also come from other sources, including the methionine synthase reaction.

I suppose you could try it for a while to see if it seems that you are getting benefit from it. What about starting with a B50 instead of a B100? That would have less folic acid.

The lecithin is intended mainly to repair phospholipid membranes that have been damaged by oxidative stress, especially the mitochondrial membranes. I think that using it will help to bring the ATP production of the mitochondria up sooner, which will mean more energy. In the latest revision, I am suggesting use of the NT Factor phospholipid formulation, Smart Youthful Energy. It is more expensive, and several people have mentioned a less expensive powder version of this. As far as I know, that would be O.K., too, but I don't have feedback from people on this yet.

Best regards,

Rich
 

richvank

Senior Member
Messages
2,732
hi Rich

What do you mean "high mercury body burden" ? you mean high levels of mercury? how does one know this without testing?

thanks

Hi, Pegasus.

Yes, I mean high levels of mercury in the body. Testing is the best, and while there is no perfect test for mercury body burden, probably the urine collection test after challenging with a chelator is best, if the person can tolerate the chelator.
Such tests are offered by Doctor's Data Lab and are available from some physicians or from www.directlabs.com

If testing is not feasible, one has to try to guess at whether there is a high mercury body burden. The factors that would tend to cause this are an extended period of illness during which the person had amalgam fillings in their teeth or consumed a significant amount of fish that are near the top of the marine food chain. This includes tuna.

Best regards,.

Rich
 

leela

Senior Member
Messages
3,290
Hi Rich,
THank you, as always, for continuing to refine and revise your protocol, and for being so open to patient feedback.

I have long been concerned about the effects of GMOs, and having recently watched the documentary "Genetic Roulette" (which is streaming free online this week by the way) I am even more committed to eliminating GMOs and the inevitabe pesticides associated with them, from my diet.

When I tried my own modified modified [sic] methylation protocol, I noticed both soy and sunflower lecithins didn't feel good, and both tested badly through bioresonance/muscle testing with different practitioners.

I wonder of this has anything to do with GMOs/pesticide residues? The phospholipid product you recommend sounds great--except that it does not include the GMO-free certification, and with soy being something like 94% GMO now, I would be very hesitant to take in concentrated amounts of not only the modified genetic material, but the pesticides used in heavy amounts on those crops. (There are other reasons I avoid soy in general as well.) It's a shame, because I inherently feel the need for these substances. I just can't seem to find a source that works for me. No idea why sunflower lecithin didn't do the job--unless sunflowers are also heavily sprayed--I have no idea.

As someone who suffers from MCS as a delightful side-effect of having this disease, I suspect this may be why I did not notice improvement after 9 months of trying to improve methylation. It seems possible that the addition of concentrated amounts of toxic material in the supplements themselves could cancel out the benefits of the protocol.
Something to consider, anyway.
 

richvank

Senior Member
Messages
2,732
Hi, Leela.

I'm sorry that the lecithins didn't work out for you. Perhaps you could tolerate lecithin derived from eggs.

I don't know whether genetic modification would affect the composition of the phospholipids, or what the level of pesticide residues might be in these products.

If it is not possible for you to find a phospholipid source that you can tolerate, maybe you could drop down to a source of the essential fatty acids, and rely on your cells' ability to make their own phospholipids. Perhaps a high-purity fish oil would work. I believe that some of them are distilled now, to remove impurities.

Non-response to methylation treatment might be caused by a variety of factors. I think the main one is deficiencies in some of the essential cofactor vitamins and minerals. Severel people appear to be low in B-complex vitamins, and also in some of the minerals such as zinc, magnesium, manganese, or selenium.

Best regards,

Rich
 

leela

Senior Member
Messages
3,290
Thank you, Rich.

In the spirit of furthering this important approach (I continue to believe you're onto something here) I'll add that as a vegetarian, I don't do eggs or fish oil, but did, in my modification of the protocol, add vegetarian EFA/DHA once I realized I wasn't tolerating the lecithins. At the time I was doing the protocol, I did not add the multi-vitamin (for various reasons.) Your point about that is well-taken.

Essential elements on a provoked urine test showed reasonable mineral levels except for low selenium. Having taken the metals test for monitoring of insanely high lead levels and the chelation thereof, I wonder if having crazy high heavy metals might be something that prevents the methylation reboot?
 

richvank

Senior Member
Messages
2,732
Hi, leela.

Thanks for the encouragement!
O.K. on the vegetarian EFA/DHA and on the metals testing.

Yes, high heavy metals body burdens can interfere with rebooting the methylation cycle, the reason being that several of the heavy metals bind to sulfur atoms, and the methylation cycle is at the beginning of the sulfur metabolism. So if heavy metals are high, they can block several of the enzymes in this part of the metabolism. In our clinical study, we had an 84-year-old lady who didn't respond to several months of methylation treatment, but then, when Dr. Nathan added chelation with DMPS and DMSA, she bounced right up, and was able to go on a trip to Paris with her friends. So, yes, heavy metals can be a big blocker of this type of treatment.

Best regards,

Rich