A Simple Explanation of the Glutathione/Methylation Depletion Theory of ME/CFS by Rich Von Konynenburg

1. To get an isolated case of CFS (I’m not talking here about the epidemics or clusters), you have to have inherited some genetic variations from your parents. These are called polymorphisms or single-nucleotide polymorphisms. We know what some of the important ones are, but we don’t know all of them yet. This is a topic that needs more research.

2. You also have to have some things happen in your life that place demands on your supply of glutathione. Glutathione is like a very small protein, and there is some in every cell of your body, and in your blood. It protects your body from quite a few things that can cause problems, including chemicals that are toxic, and oxidizing free radicals. It also helps the immune system to fight bugs (bacteria, viruses, fungi) so that you are protected from infections by them.

3. Oxidizing free radicals are molecules that have an odd number of electrons, and are very chemically reactive. They are normally formed as part of the metabolism in the body, but if they rise to high levels and are not eliminated by glutathione and the rest of the antioxidant system, they will react with things they shouldn’t, and cause problems. This situation is called oxidative stress, and it is probably the best-proven biochemical aspect of chronic fatigue syndrome.

4. There are a variety of things in your life that can place demands on your glutathione. These include physical injuries or surgery to your body, exposure to toxic chemicals such as pesticides, solvents, or heavy metals like mercury, arsenic or lead, exposure to infectious agents or vaccinations, or emotional stress that causes secretion of a lot of cortisol and adrenaline, especially if it continues over a long time. Just about anything that “stresses” your body or your mind will place a demand on glutathione. All people experience a variety of stressors all the time, and a healthy person’s body is able to keep up with the demands for glutathione by recycling used glutathione molecules and by making new ones as needed. However, if a person’s body cannot keep up, either because of extra-high demands or inherited genetic polymorphisms that interfere with recycling or making glutathione, or both, the levels of glutathione in the cells can go too low. When glutathione is properly measured in most people with CFS (such as in the Vitamin Diagnostics methylation pathways panel), it is found to be below normal.

5. One of the jobs that glutathione normally does is to protect your supply of vitamin B12 from reacting with toxins. If left unprotected, vitamin B12 is very reactive chemically. If it reacts with toxins, it can’t be used for its important jobs in your body. A routine blood test for vitamin B12 will not reveal this problem. In fact, many people with CFS appear to have elevated levels of B12 in their blood, while their bodies are not able to use it properly. The best test to reveal this is a urine organic acids test that includes methylmalonic acid. It will be high if the B12 is being sidetracked, and this is commonly seen in people with CFS.

6. When your glutathione level goes too low, your B12 becomes naked and vulnerable, and is hijacked by toxins. Also, the levels of toxins rise in the body when there isn’t enough glutathione to take them out, so there are two unfortunate things that work together to sabotage your B12 when glutathione goes too low.

7. The most important job that B12 has in the body is to form methylcobalamin, which is one of the two active forms of B12. This form is needed by the enzyme methionine synthase, to do its job. An enzyme is a substance that catalyzes, or encourages, a certain biochemical reaction.

8. When there isn’t enough methylcobalamin, methionine synthase has to slow down its reaction. Its reaction lies at the junction of the methylation cycle and the folate cycle, so when this reaction slows down, it affects both these cycles.

9. The methylation cycle is found in all the cells of the body (not counting the red blood cells, which are unusual in a lot of ways). The methylation cycle has some important jobs to do. First, it acts as a little factory to supply methyl (CH3) groups to a large number of reactions in the body. Some of these reactions make things like creatine, carnitine, coenzyme Q10, phosphatidylcholine, melatonin, and lots of other important substances for the body. It is not a coincidence that these substances are found to be low in CFS, so that people try taking them as supplements. Not enough of them is being made because of the partial block in the methylation cycle. The methylation cycle also supplies methyl groups to be attached to DNA molecules, and this helps to determine whether the blueprints in the DNA will be used to make certain proteins according to their patterns. The “reading” of DNA is referred to as “gene expression.” Methyl groups prevent or “silence” gene expression. Overexpression of genes has been observed in CFS patients, and I suspect this is at least partly due to lack of sufficient methylation to silence gene expression.

10. Another thing that the methylation cycle does is to regulate the overall use of sulfur in the body. Sulfur comes in from the diet in the form of amino acids in protein (methionine and cysteine) and as taurine and some as sulfate. The methylation cycle regulates the production of the various substances that contain sulfur that are needed by the body. The levels of various sulfur metabolites are often found to be abnormal in people with CFS.

11. One of the most important sulfur-containing substances in the body is glutathione, so now you can see how this is starting to look like a dog chasing its tail! The thing that causes chronic fatigue syndrome to be chronic, and keeps people ill for years and years, is this interaction between glutathione, vitamin B12, and the methylation cycle. When glutathione goes too low, the effect on vitamin B12 slows down the methylation cycle too much. The sulfur metabolites are then dumped into the transsulfuration pathway (which is connected to the methylation cycle) too much, are oxidized to form cystine, pass through hydrogen sulfide, and are eventually converted to thiosulfate and sulfate and are excreted in the urine. This lowers the production of glutathione, which requires cysteine rather than cystine, and now there is a vicious circle mechanism that preserves this malfunction and keeps you sick.

12. That’s the basic biochemical mechanism of CFS. I believe that everything else flows from this. As you know, there are many symptoms in CFS. I won’t discuss all of them in detail here, but here’s how I believe the fatigue occurs: The cells have little powerplants in them, called mitochondria. Their job is to use food as fuel to produce ATP (adenosine triphosphate). ATP acts as a source of energy to drive a very large number of reactions in the cells. For examples, it drives the contraction of the muscle fibers, and it provides the energy to send nerve impulses. It also supplies the energy to make stomach acid and digestive enzymes to digest our food, and many, many other things.

When glutathione goes too low in the muscle cells, the levels of oxidizing free radicals rise, and these react with parts of the “machinery” in the little powerplants, lowering their output of ATP. So the muscle cells then experience an energy crisis, and that’s what causes the fatigue. Over time, because of the lack of enough glutathione, more problems accumulate in the mitochondria, including toxins, viral DNA, and mineral imbalances. These have been observed in the ATP Profiles and Translocator Protein test panels offered by Acumen Lab in the UK.

13. There are explanations that flow from this basic mechanism for other aspects of CFS. I haven’t figured out explanations for all of the aspects of CFS, but I do think I understand a large number of them in some detail, and I’ve been able to explain enough of them that I believe this mechanism will account for the rest as well, if we can figure out the underlying biochemistry. My 2007 IACFS conference poster paper presented outlines of many of these explanations.

14. The involvement of infections by bacteria, viruses and fungi appears to have two aspects in CFS. First, as mentioned above, infectious agents can act as one of the stressors that initially bring down the level of glutathione and produce the onset of isolated cases of CFS in people who are genetically susceptible. I suspect that the clusters or epidemic occurrences of CFS (such as at Incline Village in the mid-80s) were caused by particularly virulent infectious agents, such as powerful viruses, and the genetic factor is less important in these cases.

15. Second, when a person’s glutathione, methylation cycle, and folate cycle are not operating normally because of the vicious circle described above, the immune system does not function properly. In this case, viruses and bacteria that reside inside our cells and that are always in the body in their dormant, resting states are able to reactivate and produce infections, which the immune system is not able to totally put down. This accounts for the observation that most of the viral and intracellular bacterial infections seen in CFS patients are caused by pathogens that most of the population is carrying around in their dormant states.

16. Third, when the immune system’s defenses are down, a person can catch new infections from others or from the environment, and the immune system is not able to defeat them, so they accumulate over time. Dr. Garth Nicolson has found that the longer a person has been ill, the more infections they have, on the average.

17. Other things that accumulate over time are various types of toxins, because the detox system depends to a large extent on the sulfur metabolism, and it will not be operating properly as long as the person has CFS. The body stores much of these toxins in fat, but as the levels get higher, they begin cause problems throughout the biochemistry of the cells. Many people with CFS have been tested for toxins (most commonly the heavy metal toxins, which are the most easily tested) and they are commonly found to be elevated.

18. The longer a person is chronically ill with CFS, the more toxins and infections accumulate in their body, and the more symptoms they experience. This explains why the disorder changes over time, and why some people become extremely debilitated after being ill for many years.

19. The main key to turning this process around is to help the methionine synthase enzyme to operate more normally, so that the partial block in the methylation cycle and the folate cycle are lifted, and glutathione is brought back up to normal. That is what the simplified treatment approach is designed to do, and so far, the evidence is that it does do these things in most people who have CFS. I recommend that people with CFS have the Vitamin Diagnostics methylation pathways panel run to find out if they do in fact have a partial methylation cycle block and glutathione depletion before deciding, with their doctors, whether to try this treatment. This also provides a baseline so that progress can be judged later on by repeating it every few months during the treatment. Symptoms may not be a good guide to judge progress during treatment, because detoxing and die-off can make the symptoms worse, while in fact they are exactly what is needed to move the person toward recovery.

20. The main question I’m working on now is what else needs to be done to bring people to recovery? I don’t have complete answers to this question yet. Many people may recover from this treatment alone, but it is proving to be a slow process, and we will need more time to see how this will work out. It does appear that people who suffer from illness due to toxic molds do need to remove themselves from environments where these are present. The small amount of evidence I have so far suggests that people who have Lyme disease will need to have that treated in addition. I’m not sure about certain viral infections. They may also need to be treated. We still have a lot to learn, but I’m convinced that the mechanism I have described above is the core of the abnormal biochemistry in CFS, and correcting it needs to be cornerstone of the treatment.

Back to the Glutathione/Methylation Treatment Main Page

nicky elsworth April 24, 2012 at 5:05 am

Dear all, I suffered from ME/CFS some 4 years ago. I was told about Glutathione and how low levels worsen or ‘bring on’ M.E./CFS . Luckily my practitioner (a bio-chemist kiniesiologist) tested me for a product called Recancostat/Glutacyan. It was only available in Germany, but i managed to get hold of it. After just 3 months i was back to normal. As this was so remarkable, i ensured i secured the distribution rights for the UK and Australasia. The product (I call it Empower Life in the UK) is a patented, unique supplement as it transports the Glutathione to the cell WITHOUT wastage and oxidisation. If you’d like any more information, please get in touch via my website , or email me on nickyelsworth@rocketmail.com. I have launched this product in the UK and many people with ME are now benefitting from this honest product. regards Nicky Elsworth. Empower Health UK.

Rob August 3, 2013 at 1:53 pm

Do you have any medical lit on these products? The only one i was able to find was this. http://www.ncbi.nlm.nih.gov/pubmed/10472575

Cort May 5, 2012 at 9:31 am

This question came in the contact us section:

I am an acupuncturist and health coach and recently found your site. I am very curious about a couple ingredients in the supplements recommended by Dr. Van Konynenburg for treating Methylation Cycle Block. As I understand it, cyanocobalamin is not biologically active and must be converted to methylcobalamin in the body. Also, ingesting the cyano- form of B-12 is much more likely to cause side effects compared to the readily available methy- form supplement. I would like to know why a B-12 supplement is used that has the cyano- form? Also, folic acid must be converted in the body, in fact methylated. And there is some research indicating the possibility of increased cancer risk from taking the common folic acid supplements. Why is this in the recommended supplements rather than using something that only has methylated forms of folate?

Thank you,
Geoffrey Levens, L.Ac.

Rich Van Konynenburg May 19, 2012 at 1:25 pm

Hi, Geoffrey.

I agree with your comments on cyanocobalamin and folic acid. The reason they are in the protocol is that they are part of Dr. Amy Yasko’s multi, which was designed for supporting methylation cycle treatment. I extracted the simplified protocol from her complete treatment program. I agree that it would be better if other forms of B12 and folate were in this supplement, but it was developed some time ago, and that’s what she put in it.

Please note that most of the B12 in the protocol is actually hydroxocobalamin, and most of the folate is in the active forms, folinic acid and methylfolate. Only two tablets of the multi are included, and the dosages specified for it at holisticheal.com are for six tablets, so they should be divided by three to see what is in the simplified protocol.

This protocol is definitely not optimized. More clinical study is definitely needed to improve it. When I proposed the first version of it in January 2007, my main goal was to test the GD-MCB hypothesis. Over time there have been some changes in the protocol, but I’m sure it could use more improvement.

Thanks for your comments.

Best regards,

Rich Van Konynenburg

Claudine November 9, 2013 at 12:45 pm

I believe that this is exactly what has been happening to me. I also believe that with those symptoms that often times we go to the doctor and the doctor will prescribe psychiatric meds. I believe this is what happened to me, I believe that I suffer from the methylation issues and was low on b12 even though my labs indicates that I was high and out of range. The doctors presumed that I had mental problems, anxiety, depression and they put me on a benzodiazepine. Ever since being on the benzo I have endured debilitating chronic illness and can trace back to the day that I started taking them and how it has devastated my life. I think this is a huge realization and that are getting prescribed psychiatric drugs and it makes them worse than they don’t realize that that’s what’s happening. My hole thought processes that my initial sickness came from the methylation problems but the benzo has annihilated it.

Claudine November 9, 2013 at 12:47 pm

I apologize for the typos. :)

Linda November 16, 2013 at 10:26 pm

“The main question I’m working on now is what else needs to be done to bring people to recovery?”

Removing heavy metals from the body through proper chelation. I am recovering through chelation with Andy Cutler’s protocol. As I continue to chelate fatigue lessens and frequency and severity of infections lessen. Supplements are essential to supporting the body during chelation. Mercury interferes with enzymes and accounts for many of the biochemical problems that you notice. Take a look around you to see how many heavy metals, especially mercury, we are all exposed to. Yes, some people are genetically less able to clear heavy metals and can be the sickest ones. The genetic mechanisms are not all clearly understood. Some people are exposed to larger quantities than others or at susceptible times in development. See the frequent dose chelation and adult metal chelation groups on yahoo.


puppy training June 18, 2014 at 4:35 pm

It’s amazing designed for me to have a website,
which is good for my know-how. thanks admin

Michelle June 26, 2014 at 12:03 am

I have been diagnosed with me /Cfs and fibro. What do I need to take and where do I get these meds? I’m so miserable!

Willow August 21, 2014 at 2:12 pm

I see your cry for help. Unfortunately there is not a one-size-fits-all solution. There is no list of meds to order that will cure you. Because we haven’t truly figured out what is going on with those of us who are suffering from these conditions, the treatment is different for everyone. Two resources to check out, in addition to the Phoenix Rising website are the Dr. Amy Yasko methylation cycle treatment protocol and the Dr. Shoemaker biotoxin treatment protocol. These are two things which are helping me to recover. They may help you or you may find that your answers lie elsewhere. Best of luck in your healing process from a sister sufferer.

Robin September 2, 2014 at 2:29 am

CFS and fibro can be Lyme disease, a bacterial infection often acquired from an infected tick bite. See http://www.lymenet.org for more info and referrals to Lyme-literate doctors. It is possible to treat the bacterial infection – we’re all different in what treatments we respond to.

Deb October 1, 2014 at 3:54 pm

I recently got a b12 shot. The next day I had an ulcer come up in my mouth suddenly and very painfully. It lasted a week even with treatment. Could this be indicative of anything to do with this subject?

fprefect October 17, 2014 at 9:03 am


if you have ME/CFS, this might be related to your methylation status. I recommend posting on the Phoenix Rising forum in the Methylation section. someone there might be able to help.


Suzi December 2, 2014 at 2:47 am

Hello Rich,
Thank you for taking the time and trouble to write up all this explanation. Very good and useful.
I am a therapist in the UK and always looking to improve Methylation pathways.
I am interested in Geoff’s comments on B12 and Folic acid. Although someone may be a good biochemist they may not still have the deeper knowledge how to produce the best quality nutritional products. It just means maybe people have to find their own way through this. Liposomal Glutathione is very gentle and gets into the system more easily without aggravation to the body. I take a general vitamin mineral and extra Alpha Lipoic Acid from AOR who seem to make the best ALA I have found. This is the first info I have read on repairing the Methyl pathway from a different perspective.
I have only ever ran a normal detox protocol but this all looks to be that bit more involved so I am grateful for all the information from everyone.

nicole January 16, 2015 at 7:43 pm

Hi my name Nicole, Im very passionate about CFS as ive had it on and off for 15 years.. I have now found chemical free and safe patches which naturally signal your body to produce more of its oen Glutathione. I have been using these for 4 months and feel great. If you want to know more please email me. Supplements dont get absorbed and IV Glut is so expensive, This is a cheap and safe option and it works fast.
God bless

Kris Sebor February 15, 2015 at 3:05 pm

Nicole i am very interested in these patches as well. I have been working with a Dr but still no relief from chronic pain and feeling like i am 90 years old. I am a hair dresser and thd Dr thinks i am toxix from all the chemicals I am exposed to topluplus i have a lot of histamine release going on which are all indicators of ME from what i have been reading if you would please e-mail me the info @ thewrightkut@att.net i would appreciate it thanks

Theunis April 12, 2015 at 8:41 am

Hi Nicole,
Trust you are well please would you send me more info on the patches.
Thanks a mill.

louise April 19, 2015 at 12:10 am

hi Nicole,
im interested in these opatches can you send me more information etc

Hilary May 31, 2015 at 1:27 am

Hi Nicole could you email me the website of the patches.
Many thanks

Kris June 1, 2015 at 11:08 am

Hi Nicole, can you give me the information on the patches?
Thank you!!!

kim July 2, 2015 at 10:48 pm

I suffer from fybromylagia and hashimotoes. I am very interested in the patches you mentioned. Would love it if you could send me the link

Maria July 5, 2015 at 11:17 pm

Hi Nicole. I’m interested in trying those patches you mentioned. Could you please send me the link. TIA!

Gav January 18, 2015 at 11:07 am

I have been taking high doses of Vitamin C (ascorbic acid). About 60 grams per day spread throughout the day mixed in water. I notice that my Candida symptoms decreased dramatically by doing this. I am also taking antifungal medication. I know that Vitamin C chelates heavy metals, is an antihistamine, responsible to neurotransmitter production and regenerates antioxidants. In studies animals that were deprived of glutathione levels increased their own internal production of Vitamin C. Glutathione also recycles Vitamin C so it can continue to work. I was wondering if the main reason for feeling better was due to the high levels of Vitamin C compensating for the low levels of glutathione or if the high levels of Vitamin C somehow improved glutathione levels by not having to recycle Vitamin C as much since it is taken throughout the day. Can anyone answer these questions?

Are there any other ways to replenish glutathione or since we have some genetic disposition to low levels of glutathione are we stuck and unable to recover?

Note: Please read “Vitamin C: the Real Story, the Remarkable and Controversial Healing Factor” by Steve Hickey for more information regarding this amazing vitamin.

Monte Monfore February 7, 2015 at 3:17 pm

Hi Nicole,

I’m interested in the patches you mentioned, but I don’t see an email address in your comment. If you will consider responding pls, you can either reply here or email me at monteswimmer@yahoo.com.

Much appreciation,

Monte Monfore

veronica February 15, 2015 at 4:01 pm

Nicole, I’m interested in the patches you mentioned, but I don’t see an email address in your comment. if you can email me at tristenlove2007@hotmail.com or reply here. thanks so much!

Roxanne February 17, 2015 at 2:09 pm

Please also e-mail me the info on the patches! I would love to try them!!! rstoneburg@tds.net


Crystal February 27, 2015 at 11:46 pm

A few years after Lyme disease I am now struggling with Graves disease. Do you have any suggestions? Thanks for all the info!

Elissa Palser April 2, 2015 at 11:51 am

Hi, firstly I am injecting hydroxocobalanin-acetate – should I stop before starting this protocol, or does it potentially replace the B12 in the protocol?
Secondly, how much of each thing should one take, how often, etc? I think there could be clearer titration guidance.
Thirdly, what’s your response to Nicky’s expensive product? Does it side step the protocol and go straight for the kill, or is it irrelevant to this protocol?

Vari April 15, 2015 at 10:20 pm

Has anyone heard of taking Wild Orange essential oil as a natural means to raise Glutathione? DoTerra claim theirs does this.

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