Problems with B6. Question for Rich Van K.

Discussion in 'Fibromyalgia Main Forum' started by equanimous, May 14, 2011.

  1. equanimous

    equanimous New Member

    So I've still been having problems with what I think is excitotoxicity caused by the methylation protocol. The symptoms have definitely abated somewhat since I decreased the doses of b12 and the folates and added in L-theanine, but I'm still having issues with it. So I decided to add in b6, which was one of your suggestions, and, initially, it made me feel incredibly calm. However, after a couple of days on it, I started to feel the physiological anxiety and tension I associate with the excitotoxicity, and it was much stronger than it had been before I started the b6. I discontinued the b6, and more or less went back to my previous baseline. Any idea what could possibly be going on here? Could the b6 have been helpful, but then somehow some other part of the methylation cycle couldn't keep up and I became depleted in something else? I just wish there were a way to test all of this more scientifically.
  2. Marta608

    Marta608 Member more ways than one, but I have the same problem with many supplements. I even react to D3 in the same way after a month or two of daily doses.

    I'll look forward to Rich's input.

  3. Marta608

    Marta608 Member

    Just bumping for Rich.

  4. Marta608

    Marta608 Member

    I have two notifications about posts from Susan2009 on this thread but don't see them here. I'll check back later.

  5. richvank

    richvank New Member

    Hi, equanimous.

    I'm sorry to hear that excitotoxicity continues to be a problem for you on the methylation cycle treatment.

    This has been a bugaboo for quite a few people on methylation-type treatment for autism as well as ME/CFS. The so-called "step 1" of Dr. Amy Yasko's full treatment program focuses largely on this issue. It seems to become less of a problem as the methylation cycle function improves, but initially it can be a major impediment, as you have experienced.

    Excitotoxicity is caused biochemically by too much excitation of the so-called NMDA glutamate receptors on neurons in the brain and/or not enough excitation of the GABA receptors. The former are excitatory to the neurons, while the latter are inhibitory.

    Why is this happening? In ME/CFS and autism, we know from lab testing that glutathione is depleted. We also know from biochemistry that when glutathione is depleted, a state of oxidative stress develops, and this is also well documented by published studies in ME/CFS. Furthermore, it is known that when oxidative stress is present, it particularly impacts the mitochondria, which are the little power plants in the cells that burn fuel from our food to produce ATP, which is used to power a large number of the biochemical reactions of the cells.
    Dysfunction of the mitochondria in ME/CFS and consequent low availability of ATP are also well established, particularly by the published work of Myhill et al.

    In the brain, one neuron communicates with another by secreting neurotransmitters into the synapse (junction) between them, and these neurotransmitters interact with receptors on the receiving neuron to carry the nerve impulse from one to the next. In the case of those that use glutamate as the neurotransmitter, "helper" cells called astrocytes normally sweep up the glutamate from the synapse after it has done its job, convert it to glutamine, and give it back to the initial neuron to be used again by reconverting it to glutamate.

    If there is a deficiency in ATP production in the mitochondria of the astrocytes, these cells are not able to sweep out and convert the glutamate as rapidly as they should. Therefore, the glutamate level in the synapse remains too high, and it continues to activate the NMDA receptors. This causes the downstream neuron to fire nerve impulses too often, i.e. too rapidly. This causes too much calcium to enter the neurons, and that produces a series of effects that raises oxidative stress in the neurons. The result is called excitotoxicity, which is deleterious to the neurons and can eventually kill them.

    Why would this problem become worse when a person enters upon the methylation cycle treatment? My hypothesis is that this is caused by a temporary further depletion in glutathione when this treatment is begun.

    Why would this happen? Well, when a combination of B12 and folate is taken, this stimulates the activity of the enzyme methionine synthase, which is inhibited (partially blocked) in autism and in ME/CFS. This enzyme is located at a branch point in the biochemical network. When its activity rises, it converts more of the homocysteine into methionine, returning it to the methylation cycle. However, this means that less of the homocysteine is reacted with serine by the enzyme cystathionine beta synthase, at the entrance to the transsulfuration pathway. Therefore, less homocysteine enters this pathway, and therefore less goes on to produce cysteine, which is usually the rate-limiting amino acid for making glutathione. Glutathione production therefore drops, and I suspect that this is what causes excitotoxicity to become worse when methylation treatment is initially entered upon. Over time, as the methylation cycle and the rest of the sulfur metabolism is returned to more normal operation, glutathione does come up, as shown by lab testing, and this problem should therefore be corrected.

    [I want to add here that Prof. Martin Pall has pointed out to me that some of the toxic substances commonly found in people with these disorders can also stimulate the NMDA receptors, so it is possible that improvement in the methylation cycle function, which is expected to improve the operation of the body's detoxication system, may also be causing mobilization of these toxins into the blood, and some may be crossing the blood-brain barrier and impacting the NMDA receptors. So this is another possible way that methylation treatment could initially cause more excitotoxicity.]

    But in the meantime, what can be done about this? I don't have enough feedback from people yet to say what is the best approach, but I will offer some comments.

    If the above hypothesis is correct, it would seem that the most direct approach would be to support the glutathione level in the astrocytes while this treatment is being started. It is known that the brain does not import glutathione directly from the blood, but instead makes its own from cysteine and the other amino acids. Taking cysteine as a supplement has drawbacks, as too high a level can produce auto-oxidation and more oxidative stress. So I think it would be better to use liposomal glutathione, which should be able to reach the liver and kidneys and result in elevating the cysteine supply to the brain. I've been suggesting this only recently, and I think I've heard from only one person who has tried it, but it was a positive report. So that's all the feedback I have so far on that.

    Another possibility is to try to speed up a reaction that converts glutamate directly to GABA,
    and that was what prompted me to suggest supplementing B6, which is needed by this reaction. You reported that this helped initially, but then things went south, worse than before, a couple of days later. Why did this happen? I'm not sure. Maybe the drop in glutathione became greater, and overwhelmed the benefit of this more rapid conversion. It's also possible that you might be one of the people who has one or more upregulating genetic polymorphisms (SNPs) in the CBS (cystathionine beta synthase) enzyme. People with these SNPs tend to have too large a flow down the transsulfuration pathway, and this (somewhat paradoxically) can also interfere with glutathione production. These are SNPs that are included in Dr. Yasko's nutrigenomics panel, and I understand that they are also included in the panel, which is much larger, but less expensive. For people with these SNPs, Dr. Yasko has what she calls the ammonia support protocol, which involves taking some additional supplements. One of the complications here is that taking B6 speeds up the transsulfuration pathway, so taking it can be a double-edged sword for people with these SNPs.

    The following is quoted from Dr. Amy's forum [Note that I don't agree with lowering protein intake in ME/CFS, as she recommends for autism]:

    "PostPosted: Mon Feb 27, 2006 4:32 pm Post subject: Ammonia Protocol CBS Updated 1/09 Reply with quote
    Ammonia/CBS Protocol

    The Ammonia/CBS Protocol is a set of supplement suggestions designed to address biochemical issues associated with CBS + individuals. The level of support is determined by your individual mutations as detailed in the Methylation Pathway Analysis and Urine Amino Acid biochemical test results.

    There is potential for each supplement to add in a layer of detox. It is suggested that you start LOW and SLOW with all recommendations, including the reduction of protein in the diet. If you see regressions in behavior, speech, etc., be sure to take a UTM. The following supplement suggestions should be considered and/or implemented with your physician.

    Biochemical Testing to Determine Individualized Dosing

    Once you receive your nutrigenomic results, it is helpful to run an initial, baseline Urine Amino Acid Test through Dr. Amy to receive her supplement suggestions/adjustments. Comments on UAA results will not be provided until Dr. Amy receives your nutrigenomic testing results. She wants to maximize her feedback on your testing and having your nutrigenomic results in hand is a critical component. Here is the link that can be used to purchase the test:

    The following provides information on how to prepare for a UAA test:

    Implementing the Ammonia Protocol

    The following is an explanation of how to implement specific CBS supports and/or how some of the supplements support the CBS mutation(s). You may need more supports than are listed here, you may also need less. Controlling the CBS is a matter of consistent testing and adjustment of supplementation, even beyond the first 6-8 weeks. These are very general guidelines and you need to utilize your physician, biochemical test results and your individual Methylation Pathway Analysis to implement CBS supports to best support your individual needs.

    • Ammonia Support RNA

    Dosage: 1/4 – 1/3 dropper or 0.25-0.50mL up to 3x a day with meals

    Individual dosage will depend on ammonia /taurine levels as well as the number of mutations. So, the most severe variation, being both copies of CBS C699T would likely need the Ammonia Support RNA closer to 3X’s/day. The least severe variation, being a single CBS A360A may only require it once a day. Ultimately, testing through Dr. Amy will assist you in determining your optimal dose. Ammonia Support RNA should be on board daily with any CBS+ , regardless of ammonia/taurine level. Do not stop giving even if ammonia/taurine level down. Periodic testing through Dr. Amy will help you make necessary adjustments.

    • Low Protein Diet

    Dosage: Protein at one meal/day, do not exceed 3 oz

    If you or your child is on the SCD or high protein, remember to lower protein gradually. If you drastically reduce protein, this may trigger rapid detox and/or result in other gut imbalances. If the SCD or high protein diet is critical to you or your child’s health, then you may wish to address other aspects of the ammonia protocol first.

    • Yucca

    Dosage: (sprinkle - 1 on high protein meals) However, do not rely on yucca alone to help you address high ammonia. - “We are suggesting very low doses of yucca to go along with high protein meals for those who are having ammonia issues in spite of the use of the ammonia support RNA. I do not like to rely only on yucca to pull down ammonia levels for several reasons, most importantly, because while the yucca may help to reduce high ammonia levels it will not help the elevated taurine levels and some of the other biochemical parameters that we follow." - "If taurine is okay and ammonia is high then you might want to focus on the use of charcoal and yucca to help to pull down ammonia without really affecting taurine too much. ”

    • Charcoal and Magnesium Flushes

    Dosage: 1 to 2 capsules of charcoal, followed by enough Magnesium Citrate to produce a Bowel Movement within 8-12 hours. Once per week or more depending on testing and behaviors.

    If indicated on the Methylation Pathway Analysis and/or biochemical testing, charcoal flushes are used if ammonia is high or needs to be kept under control. The purpose of a charcoal flush is to soak up excess ammonia in the body. To complete a charcoal flush, give 1 to 2 charcoal capsules orally followed by enough magnesium citrate to be sure the bowels are moving. You may want to do a “trial run” with magnesium citrate to determine how much you need to use to produce a bowel movement within 8-12 hours. You can do this on a weekend, as that may be more convenient."

    What else can be done? Well, attempts can be made to lower the intake of glutamate (as well as aspartate, which also stimulates the NMDA receptors) from the diet. MSG, hydrolyzed vegetable protein, and Nutrasweet are some of the biggest contributors, and they are included in a wide variety of processed food products. So going to fresh, unprocessed foods is the best way to avoid them, which of course takes more shopping and food preparation, and I know that isn't easy when one is ill, but it could really help.

    Beyond that, one can take various supplements that are known to calm the NMDA receptors or raise the activity of the GABA receptors. Dr. Yasko has offered lists of them. The following is quoted from her forum:

    " Support for Glutamate/GABA Balance
    _ L-Theanine
    _ Pycnogenol
    _ Grape Seed Extract
    _ GABA
    _ Valerian Root
    _ Nerve Calm Formula RNA
    _ Lithium Orotate
    _ Progesterone cream ( Pro-Gest Body Cream)
    _ Taurine (not for CBS + or SUOX Mutation unless suggested on testing)

    Protection from Excess Calcium
    _ Magnesium
    _ Chamomile
    _ Boswellia (Ayur-Boswellia Serrata)
    _ Vinpocetine
    _ Zinc
    _ Paradex "

    I guess that's all I have to offer on this right now. I hope some of this is helpful to you. I hope you will continue to keep us informed about how things go for you.

    Best regards,


    [This Message was Edited on 05/16/2011]
  6. richvank

    richvank New Member

  7. Marta608

    Marta608 Member

  8. Marta608

    Marta608 Member

    Bump for equanimous
  9. hixxy82

    hixxy82 New Member

    Did you ever get any relief from this problem? I'm in the same position. I actually have pyroluria, therefore definitely have a b6 deficiency and should tolerate b6. sigh.