B-12 - The Hidden Story

[soulfeast]

Thanks, Freddd. I crashed yesterday. Was able to have a wonderful day from 9-4 running errands and shopping.. felt somewhat near normal. Got home and knew I was toast. I didnt know adenyl is not used up.. was thinking maybe I need more and maybe I do for reserves.. ?? Took 4 1 mg jarrow M12s today and will take one more at least. I was taking 4 mg total per day. Also took half a AB12 (4.3 mg) and more methionine, which has helped me in the past.

Wondering now if daily activity, pushing the muscles.. which i did... I could feel them working and flexing like when i used to work out and took such things forgranted.. what a great feeling. At the same time, I could tell they were not recovering well.

I've been looking int o my genetics. I am MTR++ which means both genes in the pair are defective. This gene is supposedly responsible for "using" MB12 specifically. ++ indicates I am a MB12 guzzler and use too inefficiently, too fast. One MTRR gene is hetero +-. This one is involved in recycling B12.. so this can be slowed down due to this gene. So despite my COMT++, ++ status which honestly I am abit confused about though am warned not to take too many methyl groups because of, I may very well need a continual supply of MB12.

I dont understand how small amounts of MB12 can make up a deficiency or what exactly defines that. It seems to me if one is always needing to "reload" then one is at least dependent. If the body needs to function and one constantly needs to reload to do that, then are we talking repair stage or to function stage? If you stopped MB12 would you go downhill or stop progressing?

Regarding your RBCs.. are you sure your methylation cycle is balanced?

Thank you Lena and Sunday for your updates. It helps to hear.

 

[soulfeast]

Freddd, what do you think about Neubrander's 25mg/ml solution 60-90 degree angle subcutaneous for sustained prolongued release MB12? He uses this with autistic children. He played with concentrations and came up with this one, dose per weight, but specifically this concentration because it is thick enough to stay suspended in the fat for more of a time release effect. He says we lose what does not bind to receptor sites and this is more efficient. He also only doses on average every three days. No neuro damage in the sense we are talking about. It is to keep the brain fed MB12 and methylated. But I am wondering how this might apply to us as well.

 

[soulfeast]

Active B12 Titration Methods

These methods can be applied to either active b12; adenosylb12 and methylb12. If a person is having a lot of startup reaction to mb12 then I would suggest starting with adb12. Either should be started on a base of the basic vitamins and minerals; A, D, C, E, B-complex that includes P-5-P and pantethine and without Cyanob12 (Jarrow B-Right, twice a day), methylfolate, magnesium, calcium, zinc (50mg) and Omega3 oils. These are so essential that they often go without saying or being taken. They are absolutely essential for healing and tissue formation. There are many other things that may be beneficial and aid healing tremendously and some critical cofactors that are essential but after the active b12s are started as they dont work as well or at all when the b12 is short.


I will use mb12 as an example but this applies in the same way to adb12 (dibencozide). First there are a few general things to consider.

1. Our nervous systems notice difference
2. Unbound active b12s diffuse into our systems
3. Higher serum levels of unbound active b12s diffuse deeper more quickly making more intense change.
4. Maintained serum levels diffuse wider but less intense change.
5. After a period at a given dosage level equilibrium is reached and change is maintained but not increased, healing continues at that level but not more. Healing is dose proportionate but not linearly so.
6. An estimated 250mcg of unbound active b12 accounts for almost all of the perceived intensity until very high levels are reached. That is a 5mg tablet is not particularly perceived as more intense than a 1mg but a 1mg is more intense than ¼ of a 1mg.
7. If a particular level is maintained all day equilibrium is reached more quickly that if that level happens once a day for 1 hour.
8. When equilibrium is reached, perceived intensity diminishes quickly.
9. When a sublingual tablet is removed from the mouth via physical removal or chewing and swallowing the increase in intensity stops within minutes. One can actually hold at a certain level of intensity this way.
10. Approximately 15% is absorbed in the first 45 minutes of tissue contact time, about 1% each 3 minutes. After 45 minutes that drops to about an additional 1% each 5 to 10 minutes until gone. Maximum absorbtion appears to be in the area of 25%. This applies only to the 5 star brands. A fine degree of control can be obtained via a timed method as well as cutting the tablets.

Slow titration
Start on day 1 with 1 quarter tablet of Enzymatic Therapy 1mg or Jarrow 1mg mb12 or Country Life adb12. This can amount to a 30-60mcg absorbtion, 3x that for the adb12. Much of this will go into the tissues within the actual period of absorbtion. Taking additional quarters can be timed so as not to increase intensity. Taking a half will increase the intensity. If one only takes 1 quarter a day it is unlikely to ever reach equilibrium. I would suggest, that as long as the intensity is tolerable to take at least 8 quarters a day. After a few days, as long as comfort is maintained try ½ tablet. Its not that there wont be symptoms shifting and intensification, there will be. We are just trying to keep the intensity under control.

Rapid titration
Do as above with ½ or whole tablets. Over the days increase to ¼ of a 5mg, then ½ of a 5 mg tablet and finally to a 5mg tablet. At 5mg tablet 4 times a day most people will reach a stable equilibrium that is at the maximum short of injections or multiple tablets per dose. However, once one reaches this point, 2 x 5mg tablets at a time or 4x5 may be a just barely noticeable difference from 1 tablet, if there is any additional effect at all. At around the point of 50mg in 2-3 hours with multiple tablets at a time a threshold effect may be noticed. This is the point approximately equivalent to a 7.5mg injection, the point at which the Japanese research and my own experience indicates up regulated neurological healing may occur. Above that dose no additional noticeable effect occurs at up to at least 25mg injection. This may only apply to people with CNS/CSF deficiencies. That is unknown at this time. There are current Japanese studies being done with 50mg IV infusions that may define this zone more clearly. This is the area Ive labeled as ZONE 3 on some other posts which Ill repost here. A fast high dose repeated for several days will soon loose its startup effects and will rapidly diminish that of smaller doses. Approximately 20mg on day one may cause a lack of startup effect on day two for any dose less than approximately 2-5mg.

Freddd, regarding rapid tiration.

"However, once one reaches this point, 2 x 5mg tablets at a time or 4x5 may be a just barely noticeable difference from 1 tablet, if there is any additional effect at all. At around the point of 50mg in 2-3 hours with multiple tablets at a time a threshold effect may be noticed. "

This doesnt mean that you lose the results youve gained does it? Just means you stop progressing like reachign a plateau?

Isnt this an extreme deficiency? Or it takes more MB12 than one can store to repair the nerves?

Do you know if its the MB12 acting in the methylation cycle that promotes healing of nerves? If so then one is feeding the methylation cycle and it seems that there is a threshold of MB12 required for that then thats it.. no more. Just time???

 

[Freddd]

Freddd, what do you think about Neubrander's 25mg/ml solution 60-90 degree angle subcutaneous for sustained prolongued release MB12? He uses this with autistic children. He played with concentrations and came up with this one, dose per weight, but specifically this concentration because it is thick enough to stay suspended in the fat for more of a time release effect. He says we lose what does not bind to receptor sites and this is more efficient. He also only doses on average every three days. No neuro damage in the sense we are talking about. It is to keep the brain fed MB12 and methylated. But I am wondering how this might apply to us as well.

Hi Soulfeast,

The compounding pharmacy I work with says that getting 25mg/ml into solution doesn't happen with a many batches of mb12. When they try for 25mg/ml they have difficulty getting to more than 20mg/ml and much comes out in the filter. SO I have standardized on 20mg/ml. Also, with the attempted 25mg/ml there was a lot of polynucleation and the solution kept crystalizing on me making it difficult to draw. The thing about higher concentration and absorbtion rates is that the rate absorbed from SC injections depends upon the surface area of the spheroid of solution. As the surface area goes up by the square and concentration goes up linearly, an injection of solution with half the concentration has more surface area per mg for faster absorbtion. It's not that a denser solution stays suspended longer, it's that it makes a smaller shape with less surface area per mg and is absorbed more slowly thereby.

Having tried both 20 and 25mg/ml concentration I noticved no difference at all. I have an 8-10 hour peak I can feel in the effects on nerves from each injection of 10mg. Three per day of 10mg keeps it constant or 4 per day of 7.5mg.

If you ask people who have been doing this for a while, 3 days is the period one has from a single dose before symptoms start returning noticably. It doesn't matter whether the dose is sublingual, IM or SC for that 3 day period.

What has been documented is thgat with CFS/FMS there is a depressed cobalamin level in the cerebral spinal fluid. It appears to be either a restriction on the intake from the serum or a speeding exiting from the CSF or both.

My changes of neurological symptoms in my feet that I am aware of with each injection if I take 2 or fewer per day is completely separate from the return of other symptoms which takes 3 days. There is also no assurance that autism involves a reduced CSF level of cobalamin. From the 3 day effect it doesn't sound like it does. That puts it into the class with other symptoms.

From an injection or sublingual usage, when the b12 first hits the blood serum halflife is about 20-50 minutes. Over the next 12 hours it reduces to 4 hours or so and then averages 12.9 hours from hrs 12-48. The halflife increases as the concentration in blood falls. Repeated injections keeps the serum high enough on the average that the serum halflife is typically less than 4 hours.

I have read everything I can get hold of by Dr Neubrander and have adopted many useful things. I've added to that what I have learned through actual injection usage as well and corrwespondence with others doing such injections. I personally have not found that angle of injection, from shallow to normal, makes any difference at all in the length of time of absorbtion. However, I am not a small child being injected in the buttocks but rather self injection on my stomach which has more than ample subcutaneous fat for the purpose but may have a different rate of absorbtion.

Also, it appears that once neurologically damaged rather more mb12 is needed at a higher level to maintain functionality.

 

[Freddd]

Freddd, regarding rapid tiration.

"However, once one reaches this point, 2 x 5mg tablets at a time or 4x5 may be a just barely noticeable difference from 1 tablet, if there is any additional effect at all. At around the point of 50mg in 2-3 hours with multiple tablets at a time a threshold effect may be noticed. "

This doesnt mean that you lose the results youve gained does it? Just means you stop progressing like reachign a plateau?

Isnt this an extreme deficiency? Or it takes more MB12 than one can store to repair the nerves?

Do you know if its the MB12 acting in the methylation cycle that promotes healing of nerves? If so then one is feeding the methylation cycle and it seems that there is a threshold of MB12 required for that then thats it.. no more. Just time???

Hi Soulfeast,

This doesnt mean that you lose the results youve gained does it? Just means you stop progressing like reachign a plateau?


I have not lost the results gained, but I have reached a plateau at which there are diminishing returns from increased doses. There is one discontinuity in that at about 7.5mg SC of mb12.


Isnt this an extreme deficiency? Or it takes more MB12 than one can store to repair the nerves?

The Japanese who have done the high dose research hypothecize and threshold of "upregulation of neurological healing" at greater amounts. Or maybe it is just the amount needed to penetrate the cerebral spinal fluid by diffusion to provide sufficient for healing. Experiments with intrathecal injections of 5mg of mb12 into the CSF indicates that period of increased healing action ranges from 2-12 months in the trials that have been done so far. THe healing of the nerves involves healing of the neural damage itself as well as the repair of myelin and that appears to take both kinds of active b12 plus omega3 oils plus other cofactors. It doesn't appear directly related to methylation for the most part.

 

[soulfeast]

Depressed concentration in spinal fluid makes sense as a difference between "us" and autistic children. More than a methylation issue as well.

Are there links to the Japanese study (ies)?

When you mean diminishing returns from increased doses, do you mean less progressive healing effect for more higher doses.. it seems you do not mean you lose what you gained whe you say "dimished returns." (I have a feeling this is technical language that I am clueless to.) Its not like you form whatever it is that you form to a drug over time.. sorry brain fog.. not resistance. ugh I should know this term.

Thank you for all this information, Freddd.

 

[soulfeast]

My symptoms came back today.. gait issues, puppet feeling, weak arms and muscle fatigue like lead weights. I had quite a few good days then crashed. The crash was not terrible.. one bad day then able to get out and do a few things, though with pacing, then the gait issues, feet that feel like they are not feeling the ground properly, etc. Does the body just use more b12 during stress?

This is either lyme of b12, spinal fluid defiency (or both). Wish I could figure it out quicker. I am not using abx because I dont want to treat a b12 issue with abx.

Is there any info on how these b12 CNS/spinal fluid deficiencies develop>? Is it the genetics, stress, diet.. does it just happen so gradually then BAM.. you notice it too late then spend more years losing ground trying to get a "diagnosis?"

 

[Freddd]

My symptoms came back today.. gait issues, puppet feeling, weak arms and muscle fatigue like lead weights. I had quite a few good days then crashed. The crash was not terrible.. one bad day then able to get out and do a few things, though with pacing, then the gait issues, feet that feel like they are not feeling the ground properly, etc. Does the body just use more b12 during stress?

This is either lyme of b12, spinal fluid defiency (or both). Wish I could figure it out quicker. I am not using abx because I dont want to treat a b12 issue with abx.

Is there any info on how these b12 CNS/spinal fluid deficiencies develop>? Is it the genetics, stress, diet.. does it just happen so gradually then BAM.. you notice it too late then spend more years losing ground trying to get a "diagnosis?"

Hi Soulfeast,

When I say "diminishing returns I DO NOT mean reversal of results. Going from 0mcg to 100mcg BIG BIG changes, going from 100 to 1000 mcg BIG changes, from 1000mcg to 6000mcg medium additional changes, going from 6000mcg to 10,000 mcg no additional changes in body, one increment of change in CNS healing, 10,000mcg to 50,000 mcg - no additional changes becasue of more. I refer to injected dose, not sublingual. The amount of change approaches a limit. After it reaches the maximum, more doesn't change the rate of healing.

I don't have current copies of the Japanese studies. However, Google scholar will bring up a few studies with things like 50mg methylcobalamin, high dose methylcobalamin and so on. You might find some I haven't seen yet. They arfe not real informative. They are not very specific and indicate an improvment in function with ALS and MS patients as long as the high dose is maintained and then reversion to previous condition when discontinued. However, all the studies were short, 1 month or so. I have found that a round of neurological healing takes at least a year, and Neubrander suggests that it takes 5 years for neurological healing to mecome permanent. So far, becasue of various problems encountered I have never actually maintained any one run of CNS healing for more than about 3 months before getting a not so good batch of mb12 or a light exposed batch or other problems. I'm working on it. When I fall back however, it doesn't go as far as it used to be though fartyher than I would prefer at times.

The depressed CNS cobalamin levels are still being verified and replicated in repeated research with variations. The cause is unknown. Those doing the research hypothecize some impediment in the the unknown transport system through the brain blood barrier. Dirrect intrathecal injection of b12 for a study on diabetic neuropathy appears to indicate part of the problem may be rate of loss too or instead of rate of gain. In that study improvment lasted as long as CSF level of cobalamin stayed high. It went low in 2 to 12 months or more. Causes are unknown. The leading edge experimental protocols are being done right here and at wrongdiagnosis by me and a few others. We are the only people I know of actually experienced in this and who have been doing it for any length of time.

Is there any info on how these b12 CNS/spinal fluid deficiencies develop>? Is it the genetics, stress, diet..

Unknown.

does it just happen so gradually then BAM.. you notice it too late then spend more years losing ground trying to get a "diagnosis

Exactly. I can trace my problems back to childhood. Everybody who goes to very low body levels also goes to low CNS/CSF levels. However, some folks sucvh as with CFS/FMS have low CSF/CNS level even with "normal" body levels. From my personal experience and some others, there can be both mb12 and adb12 CNS/CSF deficiencies or maybe only one kind. The manifestations differ a bit based on single type or both.

As of now, NOBODY gets diagnosed with it unless you luck into a study, and even then they have no idea how low is too low or how it corresponds with symptoms and damage or any idea at all how to fix it, except Japanese, and then they are only a few studies beginning to feel arond. The Japanese studies were done before the low CSF/CNS levels were discovered. They hypothecize an upregulation of neural healing but it may actually be a normalization instead of people who have a depressed level.

I have given a pragmatic test that appears to work, burt again entirely experimental and praqgmatically based. It appears to work equally well for people wheter they appear to have my supposedly rare hypothecized genetic enzyme lack or not. It does not appear related to that and appears quite separate.

 

[JPV]

Rich, I have a few questions about your Simplified Methylation Protocol.

Freddd calls for the usage of various (what he calls "essential") supplements, such as Zinc, Calcium Magnesium, A, D, E, C Vitamins and Fish Oil as a foundation for his protocol.

Your protocol calls for similar supplements in the form of Yasko's "Neurological Health Formula".

The difference is, that he recommends a much higher dosage of these "essential" supplements than you do. Unless I'm mistaken, your protocol calls for one tablet a day. Even on the label of Yasko's product, it recommends "six (6) tablets daily with meals".

In your opinion, is it OK to take more and would there be any benefit from doing so? Do you have a reason for recommending such a low dosage?

Actually, do you have upper limit recommendations for all of the supplements on your protocol? This is one aspect that I am very unclear about when reading about your recommendations. I get the impression that the dosages you mention are primarily meant as a starting point.

Also, I read elsewhere, that you recommend avoiding usage of Betaine HCI while on your protocol. I firmly believe that proper digestion is essential to recovery from CFS. Are other digestive aids suitable for use with this protocol, and if so, do you have any recommendations that might serve as an adequate substitute for Betaine HCI?

 

[richvank]

Rich, I have a few questions about your Simplified Methylation Protocol.

Freddd calls for the usage of various (what he calls "essential") supplements, such as Zinc, Calcium Magnesium, A, D, E, C Vitamins and Fish Oil as a foundation for his protocol.

Your protocol calls for similar supplements in the form of Yasko's "Neurological Health Formula".

The difference is, that he recommends a much higher dosage of these "essential" supplements than you do. Unless I'm mistaken, your protocol calls for one tablet a day. Even on the label of Yasko's product, it recommends "six (6) tablets daily with meals".

In your opinion, is it OK to take more and would there be any benefit from doing so? Do you have a reason for recommending such a low dosage?

Actually, do you have upper limit recommendations for all of the supplements on your protocol? This is one aspect that I am very unclear about when reading about your recommendations. I get the impression that the dosages you mention are primarily meant as a starting point.

Also, I read elsewhere, that you recommend avoiding usage of Betaine HCI while on your protocol. I firmly believe that proper digestion is essential to recovery from CFS. Are other digestive aids suitable for use with this protocol, and if so, do you have any recommendations that might serve as an adequate substitute for Betaine HCI?

Hi, JPV.

Thank you for your interest in the Simplified Treatment Approach (STA). You have asked some very good questions, and I wish I had some very good answers to them! I'll first try to give you some short answers, as I can, and then give you some background so that you will understand why these answers aren't better than they are.

On the Yasko multi, it's true that on the bottle the specified daily dosage is 6 tablets per day. Dr. Yasko's own recommendation in her treatment program for autism and other neurological diseases, is only 2 tablets per day, which is the same as in the STA. The low dosages are specified because it has been found that some people with these disorders (particularly children with autism) are not able to tolerate higher dosages, especially at first, because they experience rather strong symptoms, presumably due to die-off of pathogens and/or mobilization of toxins. In my opinion, it is O.K. to take more, if a person can tolerate more. People seem to vary quite a bit in terms of what they can tolerate.

As far as upper limit dosages are concerned, I would suggest as a first cut observing the Tolerable Upper Limit dosages for the essential nutrients recommended by the Institute of Medicine of the National Academy of Sciences. Some of these are conservative, but I think that's a good place to start in determining upper limit dosages.

Some people do benefit from taking higher dosages of some of the supplements than are specified in the protocol I have suggested. If a person has the resources, I recommend doing some testing to see what their nutritional status is for the various essential nutrients, and then supplementing more of the ones that are found to be deficient. Before deciding (with one's physician) whether to try the STA, I favor running the Vitamin Diagostics Methylation Pathways Panel to find out if there is a partial methylation cycle, draining of folate metabolites from the cells, and glutathione depletion. This will indicate whether this treatment is likely to help, and it will also give baseline values for comparison later, to help in determining the progress of treatment, if the person enters upon the treatment. Symptoms aren't always reliable for determining the progress, because of die-off and detox symptoms. As a minimum set of tests to see what nutrients are needed, I favor the ones used by Dr. Yasko: The Genova Diagnostics metabolic analysis profile (which is a urine organic acids panel), the Doctor's Data urine amino acids panel, and the Doctor's Data urine toxic and essential elements panel. I think it's better to test to see what's needed than to just be shooting in the dark.

With regard to use of betaine-HCl, it's true that I recommended avoiding it while on the STA. The reason was that in the liver and kidneys, there is an alternate pathway that converts homocysteine into methionine, beside the methionine synthase pathway. The alternate pathway uses betaine. I made that recommendation based on Dr. Yasko's concern that overstimulation of the alternate pathway would shunt too much flow away from the main pathway, which is partially blocked and which needs to be stimuated because it is also associated with the folate metabolism, which in turn is needed for other purposes, including making DNA and RNA. I don't know of any objective clinical testing of this recommendation, and it's possible that my concern was unfounded. An alternative to betaine-HCl is the properly diluted HCl solution that is offered by Allergy Research Group. Note that it is very important that the correct concentration of HCl be used. Too high a concentration will damage the throat and esophagus. On the other hand, if it is too dilute, it won't serve its purpose well in the stomach.

O.K., now some background:

I'm a researcher, not a clinician. I developed a hypothesis to explain CFS, called the Glutathione Depletion--Methylation Cycle Block hypothesis, and presented it at the 2007 conference of the IACFS. It was based on work done by others in autism, which I applied to CFS because of the similarities I saw in the biochemistry in these two disorders. At the conference, Dr. David Bell, who has been involved with CFS since the outbreaks in the 80s, told me that he believed my hypothesis was valid, and he asked me for a treatment protocol to test it.

I had been exploring the existing biomedical treatments for autism, including those of the DAN! project and of Dr. Yasko, and had already been encouraging people with CFS to try these treatments. I had not seen much success with the DAN! treatments, at least the way I had been suggesting that they be applied, and the Yasko treatment was quite complex, expensive, and time-consuming, as it was genetically tailored to each patient. Knowing what I knew about the "managed care" under which physicians in the U.S. had to work, I was pretty sure that most physicians would not find the full Yasko treatment to be something they could implement in their practices.

I consulted with one of the people with CFS who was on the Yasko treatment program, and she suggested that I extract the part of the full Yasko treatment that deals specifically with lifting the methylation cycle block, the so-called "Step 2." I thought this was a good idea, and I selected 7 of the supplements in this step. I wrote to Dr. Bell, suggesting this "stripped-down" version of the full Yasko treatment program, and I also posted it to some CFS internet groups.

One person decided to try it, and she experienced some benefits right away, which she reported on the Pro-Health board in the spring of 2007. This led to an avalanche of others who decided to try it, and before long there were more than 60 people who had reported that they were trying it. After some experience, I removed two of the seven supplements, one because about half the people did not tolerate it well, and the other because of the cost. This made the protocol simpler, with only 5 supplements, and the cost was in the range of $2 to $3 per day. Most PWCs seemed to be able to deal with this degree of complexity and cost.

Also in 2007, Vitamin Diagnostics independently began to offer their Methylation Pathways Panel, primarily based on its potential use in autism. I found this panel to be very helpful in CFS as well, and began to encourage people with CFS to run it.

Shortly after this, the Ratna Ling Working Group on CFS was formed, and I was fortunate to be selected to participate in it. I was permitted to give a short talk to the group about my hypothesis and treatment and the early results. Neil Nathan, M.D., was also a member of the group. He believed what I had to say was worth trying, and went home and tried this protocol on some of his CFS and autism patients. The results were very favorable, and he then proposed a clinical study of this treatment. We were fortunate to be able to obtain financial support from an anonymous donor, and we carried out the clinical study in his practice in Springfield, MO. The results were again very favorable, and we presented them at the 2009 conference of the IACFS/ME.

Just after this study was completed, Metagenics, the supplier of two of the supplements in the protocol, changed the formulation of one of them (Intrinsi/B12/folate), eliminating folinic acid. I therefore replaced this supplement with another of their products, Actifolate, which still contains folinic acid, and this is in the revised protocol.

O.K., so this is the history of this treatment protocol. Is it optimum? Probably not, and probably the optimum treatment varies from one person to another, because of their unique genetic makeup, their nutritional status, and the characteristics of their particular version of CFS. As you can see from the above, this protocol was initially selected as a means of testing my hypothesis for CFS. In my opinion, it has successfully done that, though I can tell you that there are others with their own hypotheses who don't agree with me on that!

One can go only so far with biochemical theory. To optimize a treatment would require considerable additional testing of alternative protocols, which has not been done, and, I might add, which would be difficult to find funding to do, because the treatment does not involved patented drugs.

What can be said for this protocol is that it is based on Dr. Yasko's treatment experience, and it does have a clinical study behind it that includes objective lab test data.

As you know, there are other treatments advocated by others that are somewhat different from this one, though they all impact the partial methylation cycle block. You mentioned freddd's protocol. There are also the full Yasko treatment program based on genetic testing, the DAN! protocol for autism which is not a fixed protocol, and the Vinitsky protocol (which uses folic acid instead of the reduced forms of folate). Each of these has its adherents, and some have been used by large numbers of people. As far as I know, none of them have been subjected to what I would call objective testing, nor have they been compared with each other in controlled testing. The clinical study we ran on the STA did not have a placebo control group and was not blinded. So, unfortunately, we are left with trying to make decisions based on biochemical theory and a lot of anecdotal information on clinical results. I have expressed my views, based on whatever theory or observations I have, as to what I think are the pros and cons of these protocols, elsewhere in this forum and in other CFS internet groups, but my views have not been objectively tested. So that's where things stand, at least from my point of view.

Best regards,

Rich

 

[JPV]

Rich, thank you so much for taking the time to give such a thoughtful and thorough response. Frankly , I don't know how you manage to keep up with responding to so many people on the various message forums that you frequent. You are truly a major asset to the entire CFS community and I am grateful for your presence here.

 

[richvank]

Rich, thank you so much for taking the time to give such a thoughtful and thorough response. Frankly , I don't know how you manage to keep up with responding to so many people on the various message forums that you frequent. You are truly a major asset to the entire CFS community and I am grateful for your presence here.

Hi, JPV.

You're very welcome, and thank you for writing such nice things about me! The fact is, I really do not keep up with all the message traffic! I know that there are some messages that I miss, some I don't know how to answer without doing more study, and some that I just haven't had time to get to yet. I hope people do not feel hurt or offended when I don't respond to all their emails, or don't respond right away. I'm several months behind on some of them. I feel like a one-armed paper hanger most of the time! I find that posting to the internet groups is more efficient, because many people can read the same message, but some people have personal issues that they prefer not to post to the groups, and some request a detailed analysis of their individual cases, and I try to deal with those one-on-one.

These dialogs actually result in a two-way benefit. Trying to answer questions forces me to study issues that I haven't thought of, and I receive many inspirations from PWCs who raise issues or suggest answers to questions raised by others. I find this very beneficial in trying to develop a better understanding of CFS.

I want to add that the tests for nutrient levels that I suggested above can be ordered through some physicians, or they can also be ordered without a physician's order from www.directlabs.com. Since they are urine tests, they can be run at home and the person can ship their own samples to the labs and have the results returned directly to them. The Vitamin Diagnostics test does requiire an order from a physician or a chiropracter.

Best regards,

Rich

 

[JPV]

Yeah, I prefer asking questions of this sort in public so it's available to others that may be interested. Since I try to remain anonymous, I have no qualms sharing personal information.

 

[Freddd]

Yeah, I prefer asking questions of this sort in public so it's available to others that may be interested. Since I try to remain anonymous, I have no qualms sharing personal information.

Hi Jpv,

There is a reason for the simpliefied protocol and that is "simpified". Going all the way with a lot of different supplements each of which needs to be titrated and adjust against the backround of all the others gets quite complicated. For instance, I speak of retesting the need and effects of TMG and SAM-e and other items after an intial equilibrium is reach, of fine tuning all the various nutrients, of trying different brands and forms and quantities to see what actually works best.

Portassium is something that must be monitored. At first if a person undergoes a sudden startup of healing serum poatassium can plumet causing serius pproblems and conceivably even death. However, six months later the amount of potassium needed to get a person through a startup might be too much. The same with ZINC, A, C and who knows what else. Many things might be adquate with lack of b12 keeping a lid ony everything, it being the most limiting factor. A few days after starting mb12/adb12 all sorts of things besides potassium may be in short supply that was fine when not healing. A year later after most healing is done smaller amounts may again be adequate. However, rehab may take several years of muscle formation after basic healing is done. Being in the most effective balance can be difficult to find and maintain. There is not one answer only even for only one person as that answer varies over time with stages of healing.

 

[JanisB]

Hi JBV, You asked Rich

Also, I read elsewhere, that you recommend avoiding usage of Betaine HCI while on your protocol. I firmly believe that proper digestion is essential to recovery from CFS. Are other digestive aids suitable for use with this protocol, and if so, do you have any recommendations that might serve as an adequate substitute for Betaine HCI?

Rich answered:

With regard to use of betaine-HCl, it's true that I recommended avoiding it while on the STA. The reason was that in the liver and kidneys, there is an alternate pathway that converts homocysteine into methionine, beside the methionine synthase pathway. The alternate pathway uses betaine. I made that recommendation based on Dr. Yasko's concern that overstimulation of the alternate pathway would shunt too much flow away from the main pathway, which is partially blocked and which needs to be stimuated because it is also associated with the folate metabolism, which in turn is needed for other purposes, including making DNA and RNA. I don't know of any objective clinical testing of this recommendation, and it's possible that my concern was unfounded. An alternative to betaine-HCl is the properly diluted HCl solution that is offered by Allergy Research Group. Note that it is very important that the correct concentration of HCl be used. Too high a concentration will damage the throat and esophagus. On the other hand, if it is too dilute, it won't serve its purpose well in the stomach.

I want to add a few things I've used that have helped increase digestive acid:
1-2 tsp of apple cider vinegar
a few drops of cayenne tincture
20-30 drops of gentian tincture

None of these will burn your esophagus either, and the tinctures both increase gastric parietal cell secretions.

 

[Freddd]

Hi Rich

could you clarify in which way B12 deficiency differs from CFS? I agree with you, and think it may be why so many CFSers experience detox, which is long and difficult rather than a short-lived start-up.

thanks

Nicola QUOTE]


Hi, Nicola.

Please note that I said that I don't "believe" B12 deficiency is synonymous with CFS, not that I have proven it (yet!)

With that understanding, I'll tell you what I think at this point, based on the available evidence of which I'm aware.

I believe that the the hallmark of CFS (and of autism, which I believe is the same disorder, the obvious differences being due to the earlier age of onset) is a chronic vicious circle mechanism that includes a partial block of the enzyme methionine synthase in the methylation cycle, draining of folate metabolites from the cells, and depletion of glutathione.

I also believe that this disorder usually begins with depletion of glutathione by any combination of a variety of physical, chemical, biological and/or psychological/emotional stressors, and in order for it to develop in an individual, there must usually be a genomic predisposition toward development of this vicious circle.

Vitamin B12 deficiency, as freddd alluded to, is a heterogeneous disorder.

Its most common cause is a malabsorption disorder, which can have a variety of causes, including celiac disease, Crohn's disease, or surgeries that have removed the latter part of the small intestine.

The second most common cause is pernicious anemia, which is an autoimmune disorder that destroys the cells in the stomach that produce intrinsic factor, and which is often genetically related.

Low intake of vitamin B12 is another frequent cause, particularly in vegetarians and especially vegans.

Extensive exposure to nitrous oxide anesthesia in dental procedures or surgery oxidizes B12, and can be a cause of B12 deficiency.

Drugs such as proton pump inhibitors, histamine H2 receptor blockers, metformin, and Questran can deplete B12.

Just getting older is also a factor, because the stomach lining tends to degrade as we get older, producing less stomach acid, which is necessary to free B12 from protein in our food, so that it can be absorbed.

There are also inherited genetic issues, such as a deficiency of transcobalamin or inborn errors of metabolism in the intracellular cobalamin-processing enzymes, such as the one freddd has.


If a person has the genetic predisposition toward developing CFS, I believe that the above processes can also be a cause of CFS for that person, as can anything that interferes with they body getting enough folate.
I believe that it is possible to have both B12 deficiency and CFS in such cases, though I suspect that the formal case definitions for CFS would rule this out on the basis that the exclusionary diagnosis requires that other known medical causes for the symptoms must be ruled out before CFS can be diagnosed.

But in my mind, the crucial aspect for defining a case of CFS is that vicious circle mechanism, which is what I believe makes CFS chronic.

Many of the cases of B12 deficiency can be corrected by giving vitamin B12 in a way that it can reach the cells. Conventional doctors do this by injection of cyanocobalamin or hydroxocobalamin, and that corrects most of the cases. I realize that it does not correct cases such as freddd's, because the problem in those cases is inside the cells themselves, not in the absorption into the body or the transport of B12 to the cells.

CFS, on the other hand, cannot be corrected by providing B12 alone, even in large dosages, as was pioneered by Paul Cheney and Charles Lapp several years ago, though it does help to relieve symptoms temporarily.
In order to break the vicious circle, enough folate must also be given, and the chemically reduced forms are best.

I suspect that this stable vicious circle mechanism is not present in most cases of B12 deficiency. If it were, I don't believe that just injecting B12 would correct this disorder.

I would love to see some methylation pathways panel results on people who have ordinary B12 deficiency to test out this hypothesis. It would also be interesting to see such results on people who have the type of inborn errors of metabolism that freddd has, but I would not put them in the same cohort with the other B12 deficiencies that involve low intake, malabsorption, pernicious anemia, transcobalamin deficiency, drugs, or the other causes.

Best regards,

Rich

Hi Rich,

I'm working up a much more complete piece on the problem of defining and identifying "b12 deficiency". This specific post of yours was the inspiration. It demonstrates so well the problems of those who actually suffer from it in getting diagnosed and effectively treated. Most everything most medical persons think they know about b12 and b12 deficiency is demonstrably wrong despite some of the things being technically correct.

Vitamin B12 deficiency, as freddd alluded to, is a heterogeneous disorder

This is very true. It has a multitude of contributing causes and 300 or more symptoms, signs (including reducndency of technical and common terms and expansion of peripheral neuropathy into numerous symptoms and paresthesias) and co-correlates. A person might have just about any combination possible of those 300 symptoms and signs thereby having enough different symptoms for 10 specialists all at once with not a single one able to solve the problem.

Its most common cause is a malabsorption disorder, which can have a variety of causes, including celiac disease, Crohn's disease, or surgeries that have removed the latter part of the small intestine.

Just getting older is also a factor, because the stomach lining tends to degrade as we get older, producing less stomach acid, which is necessary to free B12 from protein in our food, so that it can be absorbed.

Less acid causes malabsorbtion so these ought to be considered together, along with tapeworms, bacterial overgrowth and a host of minor causes. Probably considerably more than half the people never find out any specific cause for b12 deficiency. Having constructed a model of b12 and the enterohepatic reciculation loop I have found that there is one high sensitivity factor. That one high sensitivity factor is the reabsorbtion efficiency of the bile excreted cobalamin. If this drops just a little, not enough to be noticably pathological for any reason, the equilibrium represented by the serum cobalamin level drops like a rock.

The second most common cause is pernicious anemia, which is an autoimmune disorder that destroys the cells in the stomach that produce intrinsic factor, and which is often genetically related.

That is just plain not even remotely true. It is a widely repeated statement. It is a commonly believed myth. Many physicians say "You don't have macrocytosis, you can't possibly have b12 deficiency". Because of the origins of the knowledge of b12 for many it is linked to P.A. Having spoken with and corresponded with some thousands of b12 deficiency sufferers, the only cause I have seen less common than P.A. is tapeworms.

Drugs such as proton pump inhibitors, histamine H2 receptor blockers, metformin, and Questran can deplete B12.

Quite true, and each of these is more common than PA in my experience.

There are also inherited genetic issues, such as a deficiency of transcobalamin or inborn errors of metabolism in the intracellular cobalamin-processing enzymes, such as the one freddd has.

True, though the actual incidence is unknown because adults are virtually never tested. Also, folate deficiency also appears to hinder cobalamin absorbtion, retention and/or utilization. And Folic acid conversion defects are present in 50% of the population. Even when not present and people can convert folic acid to active folates at the full channel capacity of about 800mcg per day that may not actually be sufficient for many. Folic acid appears to be a major contributor to a person becoming locked into a depleted methylator state. Whether this is identical with your "methylation block" state or not is unknown to me. This depleted methylator state can be induced by taking Hycbl or Cycbl with or without folic acid.

Extensive exposure to nitrous oxide anesthesia in dental procedures or surgery oxidizes B12, and can be a cause of B12 deficiency.

With very sudden onset. A person right on the edge can be tipped over that edge by a single dental procedure's duration of N20. The amount required isn't nearly so extensive as popularly believed. In my experience this cause is far more common than PA. And a person often can't get out of this state once they are in it without sometimes sizable supplements. The Nitrous Oxide depletes methylb12 from the brain where it is most critical for neurological functioning and that is the most difficult to replace for many.

Many of the cases of B12 deficiency can be corrected by giving vitamin B12 in a way that it can reach the cells. Conventional doctors do this by injection of cyanocobalamin or hydroxocobalamin, and that corrects most of the cases. I realize that it does not correct cases such as freddd's, because the problem in those cases is inside the cells themselves, not in the absorption into the body or the transport of B12 to the cells.

The problem with this statement is that while techically true, even in people who respond to Cycbl and./or Hycbl, these two cobalamins are AT BEST effective for about 1/3 of symptoms in 2/3 of people. This is the problem with the definition of "b12 deficiency". If you define it as the symptoms that respond to Hycbl and/or Cycbl ONLY then the 80% or so of the people with adb12/mb12 responsive symptoms that don't respond to Hycbl/Cycbl don't have "b12 deficiency". What they have is an untreatable selection of mysterious undiagnosable conditions. By having that "Only" clause present then most macrocytic anemia is not B12 deficiency since it very often requires BOTH methylfolate and a cobalamin the person responds to. The HCY test often used to detect "b12 deficiency" actually detects methylb12 defciency and/or methylfolate deficiency and/or p-5-p deficiency. Becasue of how totally common, 50% or so, genetic problems converting folic acid to methylfolate are, at least 50% of all b12 deficiencies are also tied to folate inadequacies. So

Wikepedia:
Megaloblastic anemia, the most common cause of macrocytic anemia, is due to a deficiency of either vitamin B12, folic acid (or both). Deficiency in folate and/or vitamin B12 can be due either to inadequate intake or insufficient absorption. Folate deficiency normally does not produce neurological symptoms, while B12 deficiency does.

So how does this differ from CFS in consideration of whether it is a b12 deficiency disease or not. Like most b12 deficiency diseases the specific set of symptoms is determined by a whole group of missing cofactors. That is what makes the understanding so complicated.

So when you say that a methylation block can't be lifted by b12 alone, that statement is ambigusous. If you were to say that the methylation block can't be lifted by (using a functionally descriptively named object) MethylConsumingHycbl alone I would agree with you since Hycbl competes for methyl groups forcing a mutual lockout competing for the methyl group one must also take a methyl source and since a likely majority of b12 deficient folks are also folate deficient, methylfolate looks like an excellent candidate. However that mutual lockout state may not exist if one is using MethylDonatingMethylb12 instead of MethylConsumingHycbl. When you merely say "b12" that simply obfuscates the situation through lack of specificity.

I suspect that this stable vicious circle mechanism is not present in most cases of B12 deficiency. If it were, I don't believe that just injecting B12 would correct this disorder.

I suspect that this stable vicious cycle can't exist with MethylDonatingMethylb12 instead of MethylConsumingHycbl. However, there still exists in at least 50% of b12 deficient people a coexisting folate deficiency no matter what the serum folate test says. Again, people can demonstrate benefit from Metafolin even if the test says that they should not be deficient. So if we define b12 deficiencies by the actual functional b12 missing we could say that high MMA is a result of Adenosylb12ResponsveDeficiency. By the same token then we can say that high HCY can be the result of Methylb12ResponsiveDeficiency and/or MethylFolateResponsiveDeficiency and/or P5PResponsiveDeficiency.

If you are referring to Hycbl in saying "just injecting b12", it leaves 2/3 of symptoms untouched as compared to a combination of Mb12 and Adb12 in 2/3 of people and near 100% of symptoms untouched in 1/3 of people. This comes down to a defintional problem of what constitutes "b12 deficiency". If those 2/3 of symptoms (or whatever the exact percentage is in any given person or group of people) relieved by mb12-adb12 but not by Hycbl/Cycbl are not part of "b12 defciency" then what are they?

Do we have to have a separate definition of MecblAdocblDeficiencySyndrome as a separate entity from CycblHycblDeficiencySyndrome? So why should we have a separate subset definition of CycblHycblDeficiencySyndrome as it is 100% contained within MecblAdocblDeficiencySyndrome? If it would actually get the 80% or so of people who are currently undiagnosable and untreatable properly diagnosed and treated I'm all for it. However an awful lof of stealth deficiency diseases that right now are mysterious syndromes would disappear. That would disappoint a whole lot of constiuancies for these mysterious diseases and irritate a lot of pharmaceutical companies hoping to hit the next multi billion dollar drug for a disease that never is cured and so goes on indefinitely generating revenues.

I realize that it does not correct cases such as freddd's, because the problem in those cases is inside the cells themselves, not in the absorption into the body or the transport of B12 to the cells.

I didn't get into real trouble until I became a vegetarian and dependent upon Cycbl for my b12 needs. Milk, eggs, cheese and occasional fish wasn't anywhere near enough.

It was Cycbl that gave me the final clue I needed to solve the problem, You see, Cycbl is not 100% ineffective in me, just 99.9999% ineffective. After I went off it and B-50 complex for 6 months, too much nausea, I couldn't deal with all those pills that didn't seem to do anything, it made a minute noticable difference. My beef-red burning sore tongue got the tiniest little bit less burning when I started the Cycbl again. It minutely affected 1 symptom out of 200 by a very small just barely noticable amount. One day later my first methylb12 sublingual affected 150 or so symptoms hugely. While this amount of differential effect is somewhat more for me than some others, it is a very similar effect to the majority of people.


You make a good case for including Folinic acid and I'll try that.

 

[Sunday]

I've seen an ATP supplement and am wondering if it would do any harm to add it to my protocol (like fooling my body into making NO ATP of its own, instead of the little it must be cranking out).

I've definitely seen improvements on the B12 protocol, but I'm still bad off with the OI and the PEM, so in many ways those improvements don't have a lot of practical use for me. It's nice that the brain fog seems to be clearing and great not to be nauseated, but I'm still not functional and never know when I can count on myself to do something or I'll just have to crash. I suppose it's better than being in total whiteout, but I still don't have a life.

 

[soulfeast]

Thank you for all of your replies, Freddd and Rich as well.

 

[Freddd]

I've seen an ATP supplement and am wondering if it would do any harm to add it to my protocol (like fooling my body into making NO ATP of its own, instead of the little it must be cranking out).

I've definitely seen improvements on the B12 protocol, but I'm still bad off with the OI and the PEM, so in many ways those improvements don't have a lot of practical use for me. It's nice that the brain fog seems to be clearing and great not to be nauseated, but I'm still not functional and never know when I can count on myself to do something or I'll just have to crash. I suppose it's better than being in total whiteout, but I still don't have a life.

Hi Sunday,

Let's review what you have tried with the adenosylb12. I assume you have tried that. Then have you tried l-cartnitine fumarate? If that hasn't done the trick have you tried several other forms of l-carntine, and maybe a couple of brands, taken at least 30 minutes before food. Taken with food does nothing. In addithion, Alpha lipoic acid. Ths assumes a base of b-complex, magnesium/calcium, 50mg of zinc and Metafolin, at least 800mcg but maybe much more is needed, espcially if you have done anything with glutathione, perhaps 5000mcg or more daily for a while needs to be tried. Also 51mg sublingual for 2 hours needs to be tried along with the 5000mcg or so of Metafolin and everything else. Some of these things can be very specific as to timing or brand and all the right combinations. It's not always simple. Let's talk some details and see what you have and haven't tried.


"OI" is what?
"PEM" is what?

 

[Sunday]

Thanks for your reply, Freddd. And sorry about the mysterious acronyms; I learned them on this forum. OI = orthostatic intolerance; PEM = post-exertion malaise (kind of a dumb term, as has been discussed on other threads, but for now it's what we've got).

Here's what I'm currently taking:

first thing, on an empty stomach (per your recommendation before):

Solgar methylfolate 3200 mg
acetyl-l-carnitine 500 mg (I used this originally; switched to l-carnitine fumarate for about a month, but it didn't seem to make an appreciable difference, so I switched back)
Jarrow sublingual mb12 4 mg
Country Life sublingual adb12 3 mg
(and right now, I'm experimenting with adding nattozimes to this section, with hopes that it might do my circulation some good).
The sublinguals usually last about 1.5 hours or more.


second thing, with food (the food is usually homemade kefir; lately I've been adding d-ribose, agave syrup, a hint of salt, cinnamon, ginger, and something called Vivix, which has extracts of muscadine grape, elderberry, purple carrot, and polygonatum cuspidatum. Resveratrol content 100mg)

vitamin C 2,000 mg
vitamin E 400 IU
B-Right capsule
potassium 99 mg
zinc 50 mg
fish oil 1,000 mg
krill oil 500 mg
vitamin D3 5,000 IU + 400IU in my vitamin A
vitamin A 10,000 IU
magnesium complex 400 mg (350 mg magnesium oxide, 40 mg magnesium citrate, 10 mg magnesium aspartate)
ubiquinol 300 mg
alpha lipoic acid 300 mg
Drenamin (Standard Process adrenal support; no hormones in it, just organic adrenal extract)

until I ran out recently, I was also taking a cal-mag supplement. Besides my daily pint of kefir, I drink raw milk pretty copiously, and eat cheese and ice cream, so I worry less about calcium intake. I admit this is not scientific, just based on the fact that I eat a lot of dairy. (And yes, I have given dairy up and no, it didn't make an appreciable difference.)

I also took selenium for a few months. When I ran out, I didn't notice it, so I left it out. I may add it again. After all, taking pills is already a part-time job for me.


later in the day, with food:

B-Right capsule
krill oil 500 mg
fish oil 1000 mg
ubiquinol 300 mg


at night, for the last few days I've been taking Dr. Lazlo's Heavy Metal Shield, supposed to be a mild form of detox for heavy metals.

I also am on a course of acupuncture (I go on and off, for financial reasons) and taking some Chinese herbs. My acupuncturist did have me on glutamine last fall for a few weeks. That was just before I discovered your protocol, so when I read your adventures, I quit the glutamine. I also took some NAC for a month or so about two years ago. I do have an especially rough time when I add more folate, so it may be that more is required. If I added it, would it be much worse to do 2 at a time than it is to do one? Knocked me back for about 2 weeks each time I upped the dosage 800 mg. The discouraging thing is that I don't necessarily feel improved (I mean, past what I was before upping the dosage) after the two weeks are up.

3 mg of adb12 seemed like a pretty high dose compared to what others take, which is why I thought a more direct approach to ATP might help. The ubiquinol seems to be making a difference, but I started with much smaller doses and have only been doing the more therapeutic 600mg for about a week.

I'm not sure how long I can keep up buying all this stuff. I would love to eliminate some things, because I just can't afford hundreds of dollars a month. I've been going on the premise that it would get me well enough to work and earn the money, but that isn't happening.

Any thoughts that might lead me to a winning combination would be greatly appreciated. I am pleased at my improvement in brain function with the B12, augmented I think by ubiquinol and acupuncture; my brain's back at about 60-70%. But my energy level remains at around 20%, more or less. And of course when my energy goes, my brain goes too; this post may be a testament to that...