Revised Simplified Methylation Protocol (August 25, 2012 Revision)

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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,

2010:

(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.

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 , 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

(as pointed out by Professor Pall), 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