1. Patients launch $1.27 million crowdfunding campaign for ME/CFS gut microbiome study.
    Check out the website, Facebook and Twitter. Join in donate and spread the word!
Lessons from ME/CFS: Finding Meaning in the Suffering
If you're aware of my previous articles here at Phoenix Rising then it's pretty clear that I don't generally spend my time musing upon the philosophy of the disease. I find it better to spend my time reading research and trying my best to break it down to its core elements and write...
Discuss the article on the Forums.

CFS,mitochondrial diease, autism

Discussion in 'Other Health News and Research' started by Frickly, Jan 26, 2010.

  1. Gerwyn

    Gerwyn Guest

    Hi JPV I did take both daily subcutaneous 0.5 ml self administered I still take b12 daily and Mg every three days or so but more often if i feel "not right"
  2. Frickly

    Frickly Senior Member

    Messages:
    1,046
    Likes:
    35
    Texas
    Gerwyn,

    I am so glad that you have found releif with this treatment. I would like to try B12 injections but already give my son B12 injections and I get weekly injections of glutathione/ATP and glycyronl plus. I don't think I can take another needle. I do take the oral form of Mg and B12 and think it helps. I had a simular experience with my glutathione/ATP. I went from sitting in my chair all day, unable to cook, shop, shower, ect. to living a fairly normal life. I am a big beleiver that mitochodrial dysfunction is key in CFS.
  3. richvank

    richvank Senior Member

    Messages:
    2,717
    Likes:
    741
    Hi, JPV.

    In my hypothesis (the Glutathione Depletion--Methylation Cycle Block hypothesis) glutathione becomes depleted (which is observed in lab testing), and this leads to lack of protection for B12 (this is based on the current biochemical picture that glutathione normally reacts with B12 at an intermediate stage in its metaboism in the cells, producing glutathionylcobalamin and protecting the B12).

    The B12 is then hijacked by toxins (B12 is known to be very chemically reactive, and toxins build up when glutathione is depleted).

    This shuts down methionine synthase in the methylation cycle (This is based on lab measurements of SAMe and SAH in the methylation cycle, and is consistent with the known requirement of methylcobalamin as a coenzyme for methionine synthase.).

    The folates then leak out of the cells via the "methyl trap" mechanism (This is a known mechanism. The folates in the cell are converted to 5-methyl THF, and since it cannot be used by methionine synthase, it builds up. Since this folate does not have a glutamate tail, it is able to leak out of the cells into the blood plasma. Over time, this lowers the total folate in the cells).

    A vicious circle forms between glutathione depletion and the partial block of the methylation cycle (This is observed in lab testing, but we do not yet understand the exact mechanism). This is the backdrop for everything else in CFS., because it brings down the immune system, the detox system, and several aspects of the endocrine system, as well as the mitochondria (This is based on the known biochemistry of the sulfur metabolism as well as observations that these systems are dysfunctional in CFS).

    In the mitochondria, depletion of glutathione allows the levels of reactive oxygen species to rise (Oxidative stress is perhaps the best known biochemical feature of CFS, based on many measurements). These are produced as a normal part of the oxidation of foods to make ATP, but without sufficient glutathione, they increase in concentration.

    The reactive oxygen species react with enzymes in the Krebs cycle and the respiratory chain (These are known reactions, involving the enzymes that incorporate an iron-sulfur complex), within the mitochondria, de-activating them. Peroxynitrite is one of the reactive species that forms, (and this is one place where my hypothesis shares part of Marty Pall's NO-ONOO model. The reaction with aconitase in the Krebs cycle is supported by measurements of Krebs metabolites in urine organic acids tests on many PWCs).

    This lowers the rate of production of ATP, which impacts the skeletal muscle (causing the observed physical fatigue), the heart muscle (causing the observed diastolic dysfunction), and the brain and nervous system (contributing to the brain-related symptoms of CFS). (Myhill et al. have published a paper reporting testing that shows low ATP in CFS, and ATP is known to power the muscles and the neurons, as well as many reactions in other types of cells).

    Over time, other factors that result from the depletion of glutathione also come into play in causing more dysfunction of the mitochondria (This is based on the known functions of glutathione, including functions involving the detox system and the immune system). These include buildup of toxins, viruses, lactic acid and calcium, and loss of magnesium (Mito dysfunction causes buildup of lactic acid from the glycolysis chain. Disruption of the Ca and Mg levels results from insufficient ATP to power the membrane ion pumps properly). So while the first cause of mito dysfunction in CFS is glutathione depletion, these other factors show up in the Acumen Lab tests that Dr. John McLaren Howard carries out on people who have had CFS for some time. One of the toxins that has been showing up in the women particularly is a chemical that comes from hair dye.

    In my hypothesis, the way to address these issues is to get the methylation cycle operating normally again. When this is done (and we have used the socalled "Simplified Treatment Approach," which was extracted from the full Yasko treatment program), we have found that glutathione comes up automatically. Over time, this should clear out the other problems in the mitochondria. Patients in our clinical study of this treatment reported a significant increase in energy, which suggests that their mitochondria were performing better. We also measured a significant increase in plasma glutathione, whiich I believe is consistent with the hypothesis (This is based on the clinical study carried out by Dr. Neil Nathan and myself, reported at the IACFS/ME conference in early 2009).

    I think that Dr. Yasko's picture of the mechanisms behind mito dysfunction is similar to the one I have outlined above, though she also emphasizes supplementing some of the things that become depleted in the mitochondria as a result of the methylation cycle block. Dr. Yasko's emphasis is on treatment, while mine is on trying to understand the mechanisms, though I am also, of course, interested in treatment, especially treatment that is not too complex or expensive, so that it is feasible for use by most PWCs.

    Best regards,

    Rich
  4. Advocate

    Advocate Senior Member

    Messages:
    506
    Likes:
    14
    U.S.A.
    I allowed myself a fantasy, and did some googling. It seems as though it would be too risky to drive to Panama unless you are young and healthy and adventurous. A chartered medical plane to Panama would cost too much. Flying commercial is too difficult for those with severe orthostatic intolerance, and I didn't find any flights with the kind of seats that flatten out. I suppose one could drive to Miami or a port on the Pacific and take a cruise ship to Panama City. I can't remember the name of the cruise company, but the cruise takes only a week or so. This is just a fantasy, of course.
  5. Advocate

    Advocate Senior Member

    Messages:
    506
    Likes:
    14
    U.S.A.
  6. Gerwyn

    Gerwyn Guest

    Hi Frickly
    Thankyou You can take Mg once a week i.m oral Mg is poorly absorbed but there is an aerosol version available.Alternatively you could try the myers cocktail once a month ----i can't remember the details offhand but i found the effect verging on the miraculous

    I know my ME,not using the enemies terminology anymore, is due to Mito dysfunction -----what caused the prroblem ---who knows?
  7. Gerwyn

    Gerwyn Guest

    It,s a very interesting hypothesis Is there any way to formally test it using improvement in objective parameters, like increased excercise tolerance, that would be exciting! How does it account for the work suggesting that the immune system is hyperactivated in ME and the HPA axis depressed
  8. richvank

    richvank Senior Member

    Messages:
    2,717
    Likes:
    741
    Hi, Gerwyn.

    Yes, that should be done. It's a matter of getting someone interested who is in a position to get funding and carry out an IRB-approved randomized blinded clinical trial with a placebo control group. That is not easy with a treatment that doesn't involve a patented drug.

    The link to the immune system dysfunction is that glutathione depletion shifts the immune response to Th2, and it also inhibits production of perforin by the natural killer cells. The immune system then detects viral and intracellular bacterial infections, and becomes activated, but is not able to defeat them, and a guerrilla war ensues between the immune system and the pathogens. RNaseL is activated. It's supposed to be a temporary holding action, but the cavalry, in the form of the cell-mediated immune response, never arrives, so RNaseL stays activated and chews up messenger RNA in the cells, hindering but not defeating the viruses. The low molecular weight form of RNaseL arises because RNaseL is cleaved by calpain, which becomes activated because of the glutathione depletion.

    The link to the HPA axis dysfunction is that glutathione depletion inhibits the production and regulated release of ACTH, which normally tells the adrenal cortex how much cortisol to secrete.

    These mechanisms are all supported by detailed references in the published literature. However, this is still an unproven hypothesis. The standard for scientific proof is very high, and there are so many steps to this hypothesis that it would require a lot of research to verify that each one is effective in CFS.

    What I've been trying to do is to show that treatment to lift the methylation cycle block is effective in helping PWCs, in hopes that that will attract more interest in the hypothesis behind it. So far I have been able to do an informal clinical study with a physician and 30 women patients, but no control group. It worked out well, and a few physicians have added this treatment to their overall protocols. We are giving talks at medical conferences to recruit more physicians to this treatment, but it's a slow process.

    I'm involved in ongoing dialogues with researchers who have alternative hypotheses, and those get very detailed and sometimes a little "heated." Those with alternative hypotheses also have difficulty getting the support needed to test their concepts.

    If you want to find out more details about this hypothesis, email me at richvank at aol dot com, and I will email you some papers and articles that go into it in glorious detail!

    Best regards,

    Rich
  9. Suzy

    Suzy Guest

    That's really interesting what you said about the adrenal cortex and glutathione. So many of us are on adrenal glandulars or cortisol replacement and it is so difficult to get the right dose. Maybe it would be better to do without and concentrate on raising glutathione.

    I get something new out of each of your posts Rich!
  10. Gerwyn

    Gerwyn Guest

    Thank you very much Rich---I think I,ve got most of that----The only thing I think I,ve missed what causes the glutathione depletion ----I,m sure that you have already said -----Somehow I,ve missed it----Everything seems very plausable---I understand that funding must be very difficult
  11. Gerwyn

    Gerwyn Guest

    I also think that this is a very credible theory I note that a number of viruses directly deplete glutathione levels HIV and swine flu for example----I will check on others I,ve had a look at Sarah Myhills protocol and it looks as though it would be possible to adapt it to include measurements of glutathione any comments?
    Take good care gerwyn
  12. Gerwyn

    Gerwyn Guest

    More on Viruses and glutathione

    oss of GSH, oxidative stress, and decrease of intracellular pH as sequential steps in viral infection.
    J Biol Chem 1997 Jan 31;272(5):2700-8.

    In conclusion, under our conditions of viral infection, oxidative stress is imposed by Glutathione (GSH) depletion, occurring in two steps and following direct virus challenge of the cell membrane without the intervention of reactive oxygen species. These results provide a rationale for the reported, and often contradictory, mutual effects of GSH and viral infection.

    Inhibition of influenza infection by glutathione.
    Free Radic Biol Med 2003 Apr 1;34(7):928-36.

    Infection by RNA virus induces oxidative stress in host cells. Accumulating evidence suggests that cellular redox status plays an important role in regulating viral replication and infectivity. The data suggest that the thiol antioxidant glutathione (GSH) has an anti-influenza activity in vitro and in vivo. Oxidative stress or other conditions that deplete GSH in the epithelium of the oral, nasal, and upper airway may, therefore, enhance susceptibility to influenza infection.

    Evidence for antiviral activity of glutathione: in vitro inhibition of herpes simplex virus type 1 replication.
    Antiviral Res 1995 Jun;27(3):237-53.

    The role of glutathione (GSH) in the in vitro infection and replication of human herpes simplex virus type 1 (HSV-1) was investigated. Intracellular endogenous GSH levels dramatically decreased in the first 24 h after virus adsorption, starting immediately after virus challenge. The addition of exogenous GSH was not only able to restore its intracellular levels almost up to those found in uninfected cells, but also to inhibit > 99% the replication of HSV-1. Data suggest that exogenous GSH inhibits the replication of HSV-1 by interfering with very late stages of the virus life cycle, without affecting cellular metabolism.

    The last study seems to indicate that exogenous glutathione could be a really effective treatment whether or not thr glu deficiency causes XMRV integration or the other way around!
  13. Gerwyn

    Gerwyn Guest

    potential for treatment

    More on Viruses and glutathione

    Loss of GSH, oxidative stress, and decrease of intracellular pH as sequential steps in viral infection.
    J Biol Chem 1997 Jan 31;272(5):2700-8.

    In conclusion, under our conditions of viral infection, oxidative stress is imposed by Glutathione (GSH) depletion, occurring in two steps and following direct virus challenge of the cell membrane without the intervention of reactive oxygen species. These results provide a rationale for the reported, and often contradictory, mutual effects of GSH and viral infection. note the virus is causing the glutathione depletion directly

    Inhibition of influenza infection by glutathione.
    Free Radic Biol Med 2003 Apr 1;34(7):928-36.

    Infection by RNA virus induces oxidative stress in host cells. Accumulating evidence suggests that cellular redox status plays an important role in regulating viral replication and infectivity. The data suggest that the thiol antioxidant glutathione (GSH) has an anti-influenza activity in vitro and in vivo. Oxidative stress or other conditions that deplete GSH in the epithelium of the oral, nasal, and upper airway may, therefore, enhance susceptibility to influenza infection.
    Is this generic for all RNA viruses This could be a missing part of the Puzzle!

    Evidence for antiviral activity of glutathione: in vitro inhibition of herpes simplex virus type 1 replication.
    Antiviral Res 1995 Jun;27(3):237-53.

    The role of glutathione (GSH) in the in vitro infection and replication of human herpes simplex virus type 1 (HSV-1) was investigated. Intracellular endogenous GSH levels dramatically decreased in the first 24 h after virus adsorption, starting immediately after virus challenge. The addition of exogenous GSH was not only able to restore its intracellular levels almost up to those found in uninfected cells, but also to inhibit > 99% the replication of HSV-1. Data suggest that exogenous GSH inhibits the replication of HSV-1 by interfering with very late stages of the virus life cycle, without affecting cellular metabolism.

    The last study seems to indicate that exogenous glutathione could be a really effective treatment whether or not thr glu deficiency causes XMRV integration or the other way around!
  14. richvank

    richvank Senior Member

    Messages:
    2,717
    Likes:
    741
    Hi, Gerwyn.

    Wow! You've really jumped on the viral depletion of glutathione and the effect of raising glutathione on suppressing the viruses!

    In answer to your question, there is a wide variety of stressors that place demands on glutathione, and the combination of stressors that are responsible for glutathione depletion in various individual cases seems to vary quite a bit.
    What I have done is to study the published so-called "risk factor" studies for CFS, as well as to obtain a lot of health histories from PWCs, focusing particularly on what occurred in their lives during the few months just preceding the onset of their illness.
    I have also studied the known functions of glutathione in the body. It was not difficult to put the two together and to infer that the stressors bring on CFS by depleting glutathione.

    The stressors can be put in the categories of physical (such as physical trauma, or surgery, or excessive exercise, as in the "overtraining syndrome"), chemical (such as heavy metals, pesticides, formaldehyde, tung oil, or some drugs), biological (such as infections, including viral as well as others, vaccinations, and blood transfusions), and psychological/emotional (such as deaths in the family or of close friends, divorce, ongoing disputes that are not settled, ongoing financial worry, etc.) Poor diet and lack of sleep are also factors that contribute. These stressors impact glutathione in various ways. Some involve excessive production of oxidative stress, some are toxins that have to be detoxed by using glutathione, some involve activation of the immune system, which uses glutathione, and some involve production of excessive amounts of epinephrine, which can auto-oxidize to adrenochrome, and this uses glutathione to be metabolized and detoxed.

    My hypothesis for the higher prevalence of CFS in women is that many of the women who develop CFS have genetic polymorphisms in CYP1B1, COMT, and one or more of the GST enzymes. The result is that when the time of the month comes that a lot of estradiol must be broken down and eliminated, these women's bodies do not do it via the usual pathways, but instead the process gets caught in a mechanism called "redox cycling," which generates more oxidative stress. Thus, these women have an additional contribution toward oxidative stress. When you add in the fact that the metabolism of epinephrine is also impacted by COMT and GST polymorphisms, so that it also produces oxidative stress in these women, it seems to explain why the combination of being a woman, having these polymorphisms, and then going through a period of severe emotional stress would tend to push them into developing CFS. Again, this is an unproven hypothesis, but the pieces seem to fit together well.

    Concerning the viruses, as Maarten has noted, this hypothesis is compatible either with a virus being an initial cause of the glutathione depletion, or with a virus being reactivated after glutathione is brought down by other causes.

    In the case of the herpes family of viruses (herpes simplex I and II, herpes zoster or varicella zoster, EBV, CMV, HHV-6, etc.) as one of your references noted, glutathione can block proliferation of the virus at a late stage of its cycle. Namely, this family codes for glycoprotein B, and the structure of this protein cannot be finalized until its disulfide bonds are formed. Glutathione prevents formation of these bonds, because it maintains chemically reducing conditions, in which cysteine stays in the sulfhydryl state rather than forming disulfide bonds. As you know, herpes viruses can stay in our cells in the latent state. To come out of the latent state and produce active infection, they must form disulfide bonds. Having a healthy level of glutathione helps to keep them latent, but they are ready to cause trouble if glutathione goes down.

    I guess I'll stop there. Thanks for posting the references. They are consistent with what I've found in the literature, too.

    Best regards,

    Rich
  15. Gerwyn

    Gerwyn Guest

    Hi Rich thanks for the explanation--I was particularily interested in the direct effect of RNA viruses on glutathione depletion----Their replicative pathways are virtually identical I wonder if they all do it and I particularily wonder if it,s an effect on GLU-synthase(or is it synthetase)

    Did you get my idea of adapting sarah myhill's protocol to include a measure of glutathione levels?
  16. richvank

    richvank Senior Member

    Messages:
    2,717
    Likes:
    741
    Hi, Gerwyn.

    Sorry, I don't know whether RNA viruses directly impact the synthesis of glutathione. Maybe they do. They would very likely have an incentive for doing so. It would certainly be interesting if they do! It would be very cool if XMRV does turn out to be the root cause of CFS, and if it does directly deplete glutathione by inhibiting either glutamate cysteine ligase or glutathione synthetase. Normally, glutamate cysteine ligase (formerly called gammaglutamylcysteine synthetase) is the rate-limiting enzyme for the synthesis of glutathione, and its activity is controlled by gene expression, so a virus that integrates itself into the cellular DNA might be able to impact that gene expression. If that works out, it would pull everything together, I think. Time will tell!

    I've tried to get Sarahl on board with the notion that glutathione depletion is what initially causes the mito dysfunction. I don't think she has yet bought into this cause, but I have received test data from some of her patients fairly recently, and they often include red blood cell glutathione measurement among the other things Acumen Lab tests for, and often the RBC glutathione is low. I don't think that measuring the glutathione in the RBCs is the best way to do it, but it is an easier measurement, because there is so much more in the RBCs than in the plasma. Also, only Vitamin Diagnostics (and its parent lab, European Laboratory of Nutrients in the Netherlands) offers plasma glutathione testing. They are able to do it because they have developed proprietary enzyme inhibitors that prevent changes in the reduced glutathione level during shipping and storage of samples. RBCs are normally net exporters of glutathione, so they are able to maintain their glutathione levels when the tissue cells have dropped in glutathione levels. The plasma is more reflective of tissue cell glutathione levels, in my opinion.

    Best regards,

    Rich
  17. spindrift

    spindrift Plays With Voodoo Dollies

    Messages:
    280
    Likes:
    2
    Frickly, where do you get glutathione/ATP shots? What kind of doctor does that and do you have any idea about the cost?
    ( I am just imagining the face of my poor neurologist when I come to him with this one ;)
  18. Gerwyn

    Gerwyn Guest

    hi rich
    I know that HIV directly depletes glutathione as a direct result of it,s replicative process if that helps in any way----I will try and find the mechanismm----It might take a while!
  19. Gerwyn

    Gerwyn Guest

    Hi Rich
    HIV and other RNA viruses encode for a truncated version of glutathione peroxide by a sequence in the env-fs gene in making this enzyme they use the cells selenium ,tryptophan,cysteine and glutamine leading to their depletion(Taylor et al 2000).The vGPx has a protective anti oxidant effect aiding replication(Zioa et al bio factors volume 7 issue 1-4)The coding sequence for vGPx is AAAAGA----a shift in this frame can lead to increased argenine which protects against No generated superoxide again aiding replication.obviously the selenium depletion at the very least will have a deleterious effect on glutathione production---I hope this helps a little

    i will keep digging and post anything intertesting here----best wishes
    Gerwyn
    P.s Sarah,s treatments saved my life!
  20. richvank

    richvank Senior Member

    Messages:
    2,717
    Likes:
    741
    Hi, Gerwyn.

    Thank you for reminding me about Taylor's work. I actually knew about that, from communication with Harry Foster, who has proposed treatment of HIV--AIDS by supplementing with selenium and some amino acids. He has shown that this actually works in Africa to move full-blown AIDS back to only HIV positive.

    It's true that HIV and some other viruses (including Coxsackie and hep C and a few others) do code for a form of glutathione peroxidase which they don't actually use to control oxidative stress. They just use it to sequester selenium, so that the host does not have enough to make its own glutathione peroxidase, and thus cannot control oxidative stress using glutathione. Very clever!

    This is a depletion of glutathione peroxidase, but I don't think it explains the depletion of glutathione itself in AIDS. This may be explained by now. I have not studied the AIDS literature for a few years.

    I asked Judy Mikovits whether XMRV could be using this same mechanism, and she said no, XMRV is a gamma retrovirus, which has a much simpler genome than does HIV, and it doesn't code for glutathione peroxidase.

    I'm really happy to hear that Sarah's treatments saved your life! I don't know if they included methylation cycle treatment or not. I know that she recommends that to some of her patients, and she has a writeup about my hypothesis on her website.

    Best regards,

    Rich

See more popular forum discussions.

Share This Page