Differences between Freddd's protocol and the Simplified Treatment Approach
Fredd and Rick, thank you both very much for your detailed replies, they were very helpful.
Ten years back i had a test for gluthathione, it was I recall low. Money is tight so I am not sure whether I can afford to have the test you recommend Rich and if it's available in the UK etc...
Last year I had to have two amalgam fillings removed, had them done separately 8 weeks apart. A few days after the second one i crashed badly (housebound again), from which I still haven't fully recovered 15 months on (still housebound). I take it the release of mercury vapour during the removal was the cause. Does not coping with the amalgam removal possibly suggest that this could be due to a partially blocked methylation cycle?
Finally, Fredd and Rich, hope you don't mind if I ask for another idiot's guide, this time the difference between your protocols?
Many many thanks for your time, it's hugely appreciated.
Hi, anniekim.
I think that having a bad reaction to amalgam removal suggests that glutathione is depleted, because it is normally responsible for binding mercury for excretion. If glutathione is depleted, it is very likely that there is a partial block in the methylation cycle.
With regard to explaining the differences between Freddd's protocol and the one I have suggested, I may be treading on difficult ground!
I'll give you my impressions, but hopefully Freddd will correct anything I say that is not accurate.
The protocol I have suggested was extracted from the full treatment program developed by Dr. Amy Yasko, used primarily to treat children who have autism. Her work in turn is based on her own experience as well as research, performed especially by Dr. S. Jill James and Prof. Richard Deth, which has shown that in autism there is a combination of glutathione depletion and an inhibition of the activity of an enzyme in the methylation cycle, methionine synthase. Dr. James et al. found that treating to lift the activity of methionine synthase also restores glutathione to a more normal level. I found that this same combination is present in ME/CFS, and that similar treatments to those used in autism by Dr. James, Dr. Yasko and the DAN! (Defeat Autism Now!) project will also help most people with ME/CFS.
The substances needed by methionine synthase to carry out its reaction are homocysteine (which does not need to be supplemented) and L5-methyltetrahydrofolate as reactants, methylcobalamin (methyl B12) as a coenzyme, and some cofactor nutrients, including zinc. Methionine synthase is supported by another enzyme that "refreshes" it, called methionine synthase reductase, and this enzyme needs other cofactors, including vitamins B2 and B3. These enzymes are part of the methylation cycle and related pathways, and there are other cofactor nutrients needed by other parts of this cycle and associated pathways.
This is the theoretical biochemical background. From this point, it's a question of deciding which supplements to include in a protocol to best help this part of the metabolism. This question is complicated by the fact that all we humans are unique, in that we have each inherited from our parents our own combinations of versions of the enzymes involved. These are called genetic polymorphisms or SNPs (single nucleotide polymorphisms). Furthermore, different people are deficient in different cofactor vitamins and minerals because of their particular genetics, diets, and health histories up to this point. If we had unlimited amounts of money and testing available, we could test each person thoroughly to see what their genetic polymorphisms are, and what nutrients are deficient, and then we could tailor the treatment to the individual. This is more or less what Dr. Yasko attempts to do in autistic children, and it has been pretty successful. However, it is complex and fairly expensive.
In suggesting the so-called "Simplified Treatment Approach," I attempted to boil this down to a more manageable protocol that could be used by all PWME's/PWC's, without detailed testing. However, I still recommend getting the Health Diagnostics methylation pathways panel to see if there is in fact a partial block in the methylation cycle and glutathione depletion, and thus whether this type of treatment is likely to be of help to the person.
I initially included 7 supplements, in January 2007, with the help of a PWC who was on the full Yasko treatment program. As time went on, I dropped two of them: quite a few people reported that they did not tolerate SAMe well, and others said that the Yasko Methylation RNA formula was too expensive for them. This left five supplements that included the Yasko multi vitamin/mineral formula, the phosphatidyl serine complex, a sublingual hydroxocobalamin supplement, FolaPro (5L-methyl tetrahydrofolate), and Intrinsi/B12/folate.
The Yasko multi was included to supply the whole variety of vitamins and essential minerals, and hopefully to take care of whatever deficiencies different people might have in them. It also includes some nonessential supplements chosen by her particularly to support the methylation cycle and related pathways.
The phosphatidylserine complex was included to supply a variety of phospholipids to repair the cellular membranes, especially the mitochondrial membranes, which are damaged by oxidative stress in ME/CFS. This supplement also supplies the essential omega-3 and -6 fatty acids that everyone needs.
This combination thus supplies all the known essential nutrients for the human body except the essential amino acids, and my hope was that these would be supplied by protein in the person's diet.
With this foundation, I then included 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. Freddd himself has reported that he 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.
I might mention that there are also several other methylation-type treatments in use now, and they have all helped at least some people. They include the following:
The S. Jill James and the DAN! project protocols
The complete Amy Yasko treatment program
The Alan Vinitsky protocol (which uses hydroxocobalamin and high-dose folic acid)
The Derek Enlander protocol
The Sarah Myhill protocol
The Martin Pall protocol (which is moving toward including liposomal hydroxocobalamin and oral 5-methyl tetrahydrofolate
The PamLab prescription "medical foods": CerefolinNAC and Metanx
All these protocols are aiming at boosting the activity of methionine synthase, in my opinion, and all of them are helping some people. It would be helpful if there could be a controlled clinical comparison of these treatments on well-specified ME/CFS patients, but since for the most part these are non-patentable treatments, there is not likely to be funding available for this. In the meantime, we are operating on the basis of projections from available theory, limited clinical testing, and a lot of anecdotal reporting. It does seem to be true that methylation treatment in general is growing among the complementary and alternative physicians who treat ME/CFS and Lyme disease.
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
