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Roaccutane caused depression - isotretinoin

Discussion in 'Cognition' started by Gavman, Sep 6, 2011.

  1. Gavman

    Gavman Senior Member

    Since i was 19, i started going downhill stress-wise. I didnt stress more, i just seemed more affected by it. I started taking roaccutane to deal with acne, I think i was on it between 6 months and a year and i really started struggling, i remember water from the bubbler at work started to aggravate my system. What i know now is that roaccutane is a massive dose of vitamin a, which becomes toxic at large amounts. What I don't know is how to deal with it. As my body seems quite dry, dry eyes, ezcema, dandruff, dry throat, all that stuff - taking something like fish oil would make sense, right?

    I had a friend with CFS at the time who had also taken roaccutane and i've read a fair bit on the internet about how it is linked with depression and chronic fatigue. Just not how to deal with it or overcome it. Will vitamin a stay stored in the liver for years to come, should i be taking something to process it out of my liver or are my effects due to low seratonin, also linked to roaccutane. I seem to be very sensitive to vitamin a.

    If anyone knows anything about the effects of vitamin a on the body, or more specifically, what should be done after massive doses have been taken, i'd be quite interested to hear about it.
  2. SpecialK82

    SpecialK82 Ohio, USA

    Ohio, USA
    I have wondered about the CFS connection too. I hope someone knows the answer. Maybe Rich?? I think taking fish oil definitely makes sense.
  3. Gamboa

    Gamboa Senior Member

    I also took accutane. I took it twice for 3-4 month periods a few years apart back in my twenties. I also took antibiotics for many years for acne so I'm not sure if the accutane itself is to blame for my ME if if it was just a bit player. There are now a lot of studies and discussions about antibiotics affecting gut health and how this now leads to illness. Did you also take antibiotics?

    I'll have to look into the accutane and liver toxicity. I hadn't really thought too much about that before.

  4. richvank


    Hi, Gavman et al.

    One of the things Roaccutane (or Accutane or isotretinoin or 13-cis retinoic acid) does is to raise the gene expression of the enzyme glycine N-methyltransferase. This enzyme normally limits the ratio of SAMe to SAH in the methylation cycle. When the activity of this enzyme is increased, the ratio of SAMe to SAH is decreased, and this causes a methylation deficit, so that the many methyltransferase reactions in the body are downregulated. I think this is the connection to ME/CFS. Over the past few years, I have heard from several people who developed ME/CFS after being treated with Accutane. I don't know why this happens to some people, but not to most. I'm aware of one case in which testing indicates that glycine N-methyltransferase has remained upregulated even years after Roaccutane treatment was ended. I don't know why.

    Glycine N-methyltransferase is normally inhibited by 5L-methyl tetrahydrofolate, which is a form of folate used in the methylation treatments. If glycine N-methyltransferase is responsive to it, as it normally is, the methylation treatment should downregulate it. In the case I refer to, this doesn't seem to work, and I don't know why. Perhaps there is a genetic polymorphism in glycine N-methyltransferase in some people that causes it to be unresponsive to methylfolate.

    Best regards,

  5. *GG*

    *GG* senior member

    Concord, NH
    Interesting, I was on Accutane for some time years ago, a short while before coming down with ME. Only diagnosed with CFS though.

  6. gkatz


    I am 37 years old. I have been suffering from CFS for the last 1.5 years. I was a completely healthy person before working, swimming, hanging out with friend etc.
    I started taking Roaccutane a year and a half ago and after 10 days strange symptoms started to appear. after 2 weeks of Roaccutane I stopped taking it due to those symptoms
    now this could be a complete coincidence but during that time I could have sworn it was the drug's fault. there was nothing around that time, no trauma, no virus.
    I am amazed to see that there might be a connection between the two. is anybody studying this? how can this be proved? can someone sue the drug company for something like this? can someone point me to some links where I can read more about this connection?
    thanks in advance.
  7. richvank


    Hi, gkatz.

    Here are some abstracts:

    Arch Biochem Biophys. 2002 May 1;401(1):73-80.
    Activation and induction of glycine N-methyltransferase by retinoids are tissue- and gender-specific.
    McMullen MH, Rowling MJ, Ozias MK, Schalinske KL.

    Department of Food Science and Human Nutrition, Iowa State University, Ames 50011, USA.

    Glycine N-methyltransferase (GNMT) is a key protein in the liver that functions to regulate S-adenosylmethionine (SAM) and the SAM/S-adenosylhomocysteine ratio. Significant GNMT expression is also present in the kidney and pancreas. Inappropriate regulation of GNMT may have negative consequences on methyl group and folate metabolism. We have demonstrated that retinoid compounds significantly elevated hepatic GNMT activity and abundance (approximately 2-fold) in male rats. However, pancreatic GNMT activity and abundance were not altered by retinoid treatment. Likewise, retinoid administration was without effect on renal GNMT activity. Hepatic GNMT activity was also elevated in female rats treated with all-trans-retinoic acid, but to a lesser extent compared to males. Collectively, these results indicate that the modulation of methyl group metabolism by retinoids is tissue- and gender-specific, and may compromise the availability of methyl groups for SAM-dependent transmethylation reactions. In support of this, SAM-dependent synthesis of creatinine was significantly reduced 21% following all-trans-retinoic acid treatment.

    (c) 2002 Elsevier Science (USA).


    (The full article for the following abstract is available free at PubMed. Just type the PMID number into the search box.)

    J Nutr. 2002 Mar;132(3):365-9.
    Vitamin A and its derivatives induce hepatic glycine N-methyltransferase and hypomethylation of DNA in rats.
    Rowling MJ, McMullen MH, Schalinske KL.

    Department of Food Science and Human Nutrition, Iowa State University, Ames, IA 50011, USA.

    Regulation of S-adenosylmethionine (SAM) and the SAM/S-adenosylhomocysteine (SAH) ratio by the key cytosolic enzyme glycine N-methyltransferase (GNMT) is essential in optimizing methyl group supply and subsequent functioning of methyltransferase enzymes. Therefore, inappropriate activation of GNMT may lead to the loss of methyl groups vital for many SAM-dependent transmethylation reactions. Previously, we demonstrated that the retinoid derivatives 13-cis- (CRA) and all-trans-retinoic acid (ATRA) mediated both the activity of GNMT and its abundance. The present study was conducted to determine whether vitamin A had a similar ability to up-regulate GNMT and to assess the biological importance of GNMT modulation by examining both the transmethylation and transsulfuration pathways after retinoid treatment. Rats were fed a control (10% casein + 0.3% L-methionine) diet and orally given retinyl palmitate (RP), CRA, ATRA or vehicle daily for 10 d. RP, CRA and ATRA elevated hepatic GNMT activity 32, 74 and 124%, respectively, compared with the control group. Moreover, the retinoid-mediated changes in GNMT activity were reflected in GNMT abundance (38, 89 and 107% increases for RP-, CRA-, and ATRA-treated rats, respectively). In addition, hepatic DNA, a substrate for SAM-dependent transmethylation, was hypomethylated (approximately 100%) after ATRA treatment compared with the control group. In contrast, the transsulfuration product glutathione was unaffected by retinoid treatment. These results provide evidence of the following: 1) vitamin A, like its retinoic acid derivatives, can induce enzymatically active GNMT; and 2) inappropriate induction of GNMT can lead to a biologically important loss of methyl groups and the subsequent impairment of essential transmethylation processes.


    Vitam Horm. 2008;79:325-45.
    Methyltetrahydrofolate in folate-binding protein glycine N-methyltransferase.
    Luka Z.

    Department of Biochemistry, Vanderbilt University School of Medicine, Nashville, Tennessee 37232, USA.

    In mammals, folate is used as a carrier of one-carbon units (C(1)) in nucleic acids metabolism and biological methylation. Among all forms of folate the most abundant is 5-methyltetrahydrofolate (5-CH(3)-THF), which is of exceptional importance. Its distinctive role among other forms of folate is in its dual function. As a C(1) carrier it is used for synthesis of methionine by remethylation of homocysteine. In addition, 5-CH(3)-THF is bound to and inhibits glycine-N-methyltransferase (GNMT). GNMT is one of the key enzymes in methionine and S-adenosylmethionine (AdoMet) metabolism. It removes excess AdoMet by using it for methylation of glycine. The interaction of 5-CH(3)-THF and GNMT was proposed as an important regulatory mechanism in AdoMet metabolism and biological methylation. The recent discovery of human individuals with mutant GNMT and the study of a mouse model with the GNMT gene knocked out showed that inactivation of that enzyme, indeed, has a significant impact on AdoMet levels in the liver and plasma. The crystal structure of GNMT complexed with 5-CH(3)-THF revealed that there are two folate molecules bound to one tetrameric form of GNMT, which is a basis for establishing of mechanism of inhibition of GNMT. The role of GNMT as a folate-binding protein and how it affects one-carbon folate metabolism is discussed.


    Note that the U.S. FDA has put a "black box" warning on Accutane:

    Best regards,

  8. gkatz


    thanks for the elaborate answer Rich;
    do you know of cases such as the one I described where very short use or Roaccutane had such an impact?
  9. richvank


    Hi, gkatz.

    I don't think so. Most of the people I've heard from who developed ME/CFS from it (maybe half a dozen over the past few years) took it for a longer time than you did, I think.

    I you want to do some testing to see if what I've described is what is going on in your case, here are the tests I would suggest:

    1. The methylation pathways panel offered by Health Diagnostics and Research Institute in New Jersey. It is a blood test, requires an order from a physician or a chiropracter, and costs $295, including the shipper to send the blood samples to the lab. For people outside the U.S., the shipping costs more. The contact info for this lab is pasted below.

    2. The Metametrix 40 plasma amino acids test, which is available from without a doctor's order.

    In the first test, the levels of SAMe and SAH are the items of special interest, though the panel will also evaluate the status of glutathione and the folate metabolism, which are important in determining ME/CFS.

    In the second test, glycine and sarcosine are of most interest.

    If the mechanism I discussed is going on, you will see low SAMe, high SAH, low glycine and high sarcosine. If you have ME/CFS, you will likely also have low glutathione.

    Here's the contact info for the Health Diagnostics lab:

    Health Diagnostics and Research Institute
    540 Bordentown Avenue, Suite 2300
    South Amboy, NJ 08879
    Phone: (732) 721-1234
    Fax: (732) 525-3288

    Lab Director: Elizabeth Valentine, M.D.

    Dr. Tapan Audhya, Ph.D., is willing to help clinicians with interpretation of the panel by phone, or you can use the guide below:

    May 19, 2011

    Interpretation of Results of the Methylation Pathways Panel

    Richard A. Van Konynenburg, Ph.D.
    Independent Researcher

    Disclaimer: The Methylation Pathways Panel is offered by the European Laboratory of Nutrients in the Netherlands and the Health Diagnostics and Research Institute in New Jersey, USA. I am not affiliated with these laboratories, but have been a user of this panel, and have written these suggestions at the request of Tapan Audhya, Ph.D., Director of Research for the Health Diagnostics lab, for the benefit of physicians who may not be familiar with this panel. My suggestions for the interpretation of results of the panel are based on my study of the biochemistry involved, on my own experience with interpreting panel results as part of the analysis of a fairly large number of cases of myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) over the past four years, and on discussion of some of the issues with Dr. Audhya. I am a researcher, not a licensed physician. Treatment decisions based on the results of applying this panel and its interpretation to individual cases are the responsibility of the treating physician.

    Application: In addition to being useful in analyzing cases of ME/CFS, this panel can also be usefully applied to cases of autism and other disorders that involve abnormalities in glutathione, methylation and the folate metabolism.

    The panel includes measurement of two forms of glutathione (reduced and oxidized), S-adenosylmethionine (SAMe), S-adenosylhomocysteine (SAH), adenosine, and seven folate derivatives.

    According to Dr. Audhya (personal communication), the reference ranges shown on the lab reports for each of these metabolites were derived from measurements on at least 120 healthy male and female volunteer medical students from ages 20 to 40, non-smoking, and with no known chronic diseases. The reference ranges extend to plus and minus two standard deviations from the mean of these measurements.

    Glutathione (reduced): This is a measurement of the concentration of the
    chemically reduced (active) form of glutathione (abbreviated GSH) in the blood
    plasma. The reference range is 3.8 to 5.5 micromoles per liter.

    Glutathione plays many important roles in the biochemistry of the body, including serving as the basis of the antioxidant enzyme system, participating in the detoxication system, and supporting the cell-mediated immune response, all of which exhibit deficits in CFS. The level of GSH in the plasma is likely to be more reflective of tissue intracellular glutathione status than the more commonly and more easily measured red blood cell or (essentially equivalent) whole blood glutathione level, which is about three orders of magnitude greater, because red blood cells are normally net producers of glutathione. Also, knowledge of the level of the reduced form, as distinguished from total (reduced plus oxidized) glutathione, which is more commonly measured, is more diagnostic of the status of glutathione function.

    In order to be able to approximate the in vivo level of reduced glutathione when blood samples must be shipped to a lab, it is necessary to include special enzyme inhibitors in the sample vials, and these are included in the test kit supplied by these two laboratories.

    Most people with chronic fatigue syndrome (PWCs), but not all, are found to have values of GSH that are below the reference range*. This means that they are suffering from glutathione depletion. As they undergo treatment to lift the partial methylation cycle block, this value usually rises into the normal range over a period of a few months. I believe that this is very important, because
    glutathione normally participates in the intracellular metabolism of vitamin B12, and if it is low, a functional deficiency of vitamin B12 results, and insufficient methylcobalamin is produced to support methionine synthase in the methylation cycle. In my view, this is the mechanism that causes the onset of ME/CFS. This functional deficiency is not detected in a conventional serum B12 test, but will produce elevated methylmalonate in a urine organic acids test. In my opinion, many of the abnormalities and symptoms in ME/CFS can be traced directly to glutathione depletion.

    Anecdotal evidence suggests that PWCs who do not have glutathione depletion do have abnormalities in the function of one or more of the enzymes that make use of glutathione, i.e. the glutathione peroxidases and/or glutathione transferases. This may be due to genetic polymorphisms or DNA adducts on the genes that code for these enzymes, or in the case of some of the glutathione peroxidases, to a low selenium status.

    Glutathione (oxidized): This is a measurement of the concentration
    of the oxidized form of glutathione (abbreviated GSSG) in the blood
    plasma. The reference range is 0.16 to 0.50 micromoles per liter.

    Normally, oxidized glutathione in the cells is recycled back to reduced glutathione by glutathione reductase, an enzyme that requires vitamin B2 and NADPH. If this reaction is overwhelmed by oxidative stress, the cells export excess GSSG to the plasma. In some (but not all) PWCs, GSSG is elevated above the normal
    range, and this represents oxidative stress. It is more common in CFS to see this level in the high-normal range. This value may increase slightly under initial treatment of a partial methylation cycle block.*

    Ratio of Glutatione (reduced) to Glutathione (oxidized): This is not shown explicitly on the panel results, but can be calculated from them. It is a measure of the redox potential in the plasma, and reflects the state of the antioxidant system in the cells. The normal mean value is 14. PWCs often have a value slightly more than half this amount, indicating a state of glutathione depletion and oxidative stress. This ratio has been found to increase during treatment of a partial methylation cycle block.*

    S-adenosymethionine (RBC): This is a measure of the concentration of S-adenosylmethionine (SAMe) in the red blood cells. The reference range is 221 to 256 micromoles per deciliter.

    SAMe is produced in the methylation cycle and is the main supplier of methyl (CH3) groups for a large number of methylation reactions in the body, including the methylation of DNA and the biosynthesis of creatine, carnitine, coenzyme Q10, melatonin and epinephrine. This measurement is made in the red blood cells because the level there reflects an average over a longer time and is less vulnerable to fluctuations than is the plasma level of SAMe.

    Most PWCs have values below the reference range, and treatment raises the value.* A low value for SAMe represents a low methylation capacity, and
    in CFS, it usually appears to result from an inhibition or partial block of the enzyme methionine synthase in the methylation cycle. Many of the abnormalities in CFS can be tied to lack of sufficient methylation capacity.

    S-adenosylhomocysteine (RBC): This is a measure of the
    concentration of S-adenosylhomocysteine (SAH) in the red blood cells. The reference range is 38.0 to 49.0 micromoles per deciliter.

    SAH is the product of the many methyltransferase reactions that utilize SAMe as a source of methyl groups. In CFS, its value ranges from below the reference range to above the reference range. Values appear to be converging toward the reference range with treatment.

    Sum of SAM and SAH: When the sum of SAM and SAH is below about 268
    micromoles per deciliter, it appears to suggest the presence of
    upregulating polymorphisms in the cystathionine beta synthase (CBS)
    enzyme, though this may not be true in every case. For those considering following the Yasko treatment program, this may be useful information.

    Ratio of SAM to SAH: A ratio less than about 4.5 represents low
    methylation capacity. Both the concentration of SAM and the ratio of
    concentrations of SAM to SAH are important in determining the
    methylation capacity, because they affect the rates of the methyltransferase reactions.

    Adenosine: This is a measure of the concentration of adenosine in the
    blood plasma. The reference range is 16.8 to 21.4 x 10(-8) molar.

    Adenosine is a product of the reaction that converts SAH to homocysteine. It is also exported to the plasma when mitochondria develop a low energy charge, so that ATP drops down to ADP, AMP, and eventually, adenosine. Adenosine in the plasma is normally broken down to inosine by the enzyme adenosine deaminase.

    In some PWCs adenosine is found to be high, in some it is low, and in some it is in the reference range. I don't yet understand what controls the adenosine level in these patients, and I suspect that there is more than one factor involved. In most PWCs who started with abnormal values, the adenosine level appears to be moving into the reference range with methylation cycle treatment, but more data are needed.

    5-CH3-THF: This is a measure of the concentration of 5L-methyl
    tetrahydrofolate in the blood plasma. The reference range is 8.4 to 72.6 nanomoles per liter.

    This form of folate is present in natural foods, and is normally the most abundant form of folate in the blood plasma. It is the form that serves as a reactant for the enzyme methionine synthase, and is thus the important form for the methylation cycle. It is also the only form of folate that normally can enter the brain. Its only known reactions are the methionine synthase reaction and reaction with the oxidant peroxynitrite.

    When there is a partial block in methionine synthase, 5L-CH3-THF drains from the cells into the blood plasma by the so-called methyl trap mechanism. As other forms of folate are converted to 5L-CH3-THF, this mechanism depletes the cells of folates in general.

    Many PWCs have a low value of 5L-CH3-THF, consistent with a partial block in the methylation cycle. Most methylation treatment protocols include supplementation with 5L-CH3-THF, which is sold over-the-counter as Metafolin, FolaPro, or MethylMate B (trademarks), and in the prescription medical foods supplied by PamLab, including Deplin, CerefolinNAC and Metanx. There are some others on the market that include both racemic forms (5L and 5R) of this folate.

    When methylation treatment is used, the level of 5-CH3-THF rises in nearly every PWC. If the concentration of 5-CH3-THF is within the reference range, but either SAM or the ratio of SAM to SAH is below the reference values, it suggests that there is a partial methylation cycle block and that it is caused by inavailability of sufficient bioactive B12, rather than inavailability of sufficient folate. A urine organic acids panel will show elevated methylmalonate if there is a functional deficiency of B12. I have seen this combination frequently, and I think it demonstrates that the functional deficiency of B12 is the immediate root cause of most cases of partial methylation cycle block. Usually glutathione is low in these cases, which is consistent with such a functional deficiency. As the activity of the methylation cycle becomes more normal, the demand for 5-CH3-THF will likely increase, so including it in the treatment protocol, even if not initially low, will likely be beneficial.

    10-Formyl-THF: This is a measure of the concentration of 10-formyl
    tetrahydrofolate in the blood plasma. The reference range is 1.5 to 8.2 nanomoles per liter.

    This form of folate is involved in reactions to form purines, which form part of RNA and DNA as well as ATP. It is usually on the low side in PWCs, likely as a result of the methyl trap mechanism mentioned above. This deficiency is likely the reason for some elevation of mean corpuscular volume (MCV) and mean corpuscular hemoglobin (MCH) often seen in PWCs. This deficit may also impact replacement of cells lining the gut, as well as white blood cells.

    5-Formyl-THF: This is a measure of the concentration of 5-formyl
    tetrahydrofolate (also called folinic acid) in the blood plasma. The reference range is 1.2 to 11.7 nanomoles per liter.

    This form is not used directly as a substrate in one-carbon transfer reactions, but it can be converted into other forms of folate, and may serve as a buffer form of folate. Most but not all PWCs have a value on the low side. It is one of the
    supplements in some methylation protocols. It can be converted to 5L-CH3-THF in the body by a series of three reactions, one of which requires NADPH, and it may also help to supply other forms of folate until the methionine synthase reaction comes up to more normal activity.

    THF: This is a measure of the concentration of tetrahydrofolate in
    the blood plasma. The reference range is 0.6 to 6.8 nanomoles per liter.

    This is the fundamental chemically reduced form of folate from which several other reduced folate forms are synthesized, and thus serves as the hub of the folate metabolism. THF is also a product of the methionine synthase reaction, and participates in the reaction that converts formiminoglutamate (figlu) into glutamate in the metabolism of histidine. If figlu is found to be elevated in a urine organic acids panel, it usually indicates that THF is low. In PWCs it is lower than the mean normal value of 3.7 nanomoles per liter in most but not all PWCs.

    Folic acid: This is a measure of the concentration of folic acid in
    the blood plasma. The reference range is 8.9 to 24.6 nanomoles per liter.

    Folic acid is a synthetic form of folate, not found in nature. It is added to food grains in the U.S. and some other countries in order to lower the incidence of neural tube birth defects, including spina bifida. It is the oxidized form of folate, and therefore has a long shelf life and is the most common commercial folate supplement. It is normally converted into THF by two sequential reactions catalyzed by dihydrofolate reductase (DHFR), using NADPH as the reductant. However, some people are not able to carry out this reaction well for genetic reasons, and PWCs may be depleted in NADPH, so folic acid is not the best supplemental form of folate for these people.

    Low values suggest folic acid deficiency in the current diet. High values, especially in the presence of low values for THF, may be associated with inability to convert folic acid into reduced folate readily, such as because of a genetic polymorphism in the DHFR enzyme. They may also be due to high supplementation of folic acid.

    Folinic acid (WB): This is a measure of the concentration of folinic acid in the whole blood. The reference range is 9.0 to 35.5 nanomoles per liter.

    See comments on 5-formyl-THF above. Whole blood folinic acid usually tracks with the plasma 5-formyl-THF concentration.

    Folic acid (RBC): This is a measure of the concentration of folic acid in the red blood cells. The reference range is 400 to 1500 nanomoles per liter.

    The red blood cells import folic acid when they are initially being formed, but during most of their lifetime, they do not normally import, export, or use it. They simply serve as reservoirs for it, giving it up when they are broken down.

    Many PWCs have low values of this parameter. This can be caused by a low folic acid status in the diet over the previous few months, since the population of RBCs at any time has ages ranging from zero to about four months. However, in CFS it can also be caused by oxidative damage to the cell membranes, which allows folic acid to leak out of the cells. Dr. Audhya reports that treatment with omega-3 fatty acids has been found to raise this value over time in one cohort.

    If anyone finds errors in the above suggestions, I would appreciate being notified at

    * Nathan, N., and Van Konynenburg, R.A., Treatment Study of Methylation Cycle Support in Patients with Chronic Fatigue Syndrome and Fibromyalgia, poster paper, 9th International IACFS/ME Conference, Reno, Nevada, March 12-15, 2009. (

    Best regards,


    Best regards,

  10. redo

    redo Senior Member

    When I took roaccutane I got a vicious response. It exaggerated by CFS symptoms to the Nth degree. Especially the cogitive problems. I only took it for some weeks, and the worsening lasted some time after I quit (between a week and a month, it's a long time ago, so hard to remember). It was really seldom that I got a reaction to anything, so I wouldn't put it into account of being oversensitivity in my case. I am thinking this roaccutane response might be something which is a lot more common in CFS patients than healthy people.
  11. gkatz


    redo, I believe I got CFS due to the roaccutane usage so if I understand you correctly my case is slightly different then yours...
    rich thanks again for the elaborate reply, I live outside the US so I'll check what's the best way for having this test. my question is, assuming what you said will be true in the exam, will I be able to take a treatment that could tackle the specific issues you were addressing? (I currently do exercise and take 10mg a day of SSRI pills). if so, what was the improvement in cases you know?
    thanks in advance
  12. richvank


    Hi, gkatz.

    My current working hypothesis about cases of ME/CFS that apparently result from use of Roaccutane is that this drug causes a shift in the epigenetics (gene expression) of the enzyme glycine N-methyltransferase for some people, raising its activity, and this shift stays "stuck" in these people, so that the activity of this enzyme is then not under normal control. This drains off their methyl groups and thus "starves" the methyltransferase reactions in the body. This would be considered a vicious circle mechanism, because methyl groups are what are needed to silence gene expression, and the high activity of glycine N-methyltransferase prevents them from being available to do this.

    My current hope is that using higher than usual dosages of 5L-methyl tetrahydrofolate (a component of the methylation treatment I have suggested), will eventually shift the epigenetics back to normal by suppressing the activity of glycine N-methyltransferase at the biochemical level, thus raising the available methylation capacity, and hopefully lowering the expression of this enzyme by methylating the DNA that controls its expression and breaking the vicious circle, so that things will come back to normal. This is unproven at this time, but I am hopeful that it will work.

    I recommend that anyone trying this be under the care of a licensed physician, because it would be an experimental treatment and the detailed response in an individual could not be totally predicted. I will note that 5L-methyl tetrahydrofolate is a naturally occurring form of folate in foods, is normally the folate with the highest concentration in the human bloodstream, is an essential part of the metabolism of all the cells of the body, and is the only form of folate than can pass into the brain. The key part of this treatment would be the high dosage. I also note that in the U.S. the PamLab company supplies a prescription "medical food" called Deplin for treating depression that contains 15 milligrams of this folate, which is a much higher dosage than I have recommended as part of the methylation protocol for treating ME/CFS. Note that ME/CFS usually involves a different problem in the methylation cycle than what appears to be the problem in the apparently Roaccutane-caused cases. Most cases involve a partial block of the enzyme methionine synthase, and this same form of folate is a substrate for this enzyme, so it is included in the treatment for most ME/CFS cases, but not at as high a dosage as I think will be necessary to break the imputed vicious circle in the apparently Roaccutane-caused cases.

    I do not know how high the dosage of 5L-methyl THF would have to be to break this imputed vicious circle. I think the prudent approach would be to come up slowly on the dosage, and if symptoms appear that are intolerable, to stop, at least until things calm down. It may take some time for the symptoms to die away, because folates have a long residence time in the body.

    I hope this is helpful, and please consider this simply as biochemical information rather than medical advice. I am a researcher, not a licensed physician. Please work with a licensed physician if you decide to try this.

    Best regards,

    Laurel6123 likes this.
  13. gkatz


    thanks Rich;
    sadly its all Chinese to me. there is a lot of complicated medical terminology involved that I don't really understand. I fear my general physician wouldn't know how to interpret this either...
    Is there a special expertise I need my doctor to have in order to understand what you wrote or would any doctor should be able to understand this? thanks

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