CFS - The Methylation Cycle

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NOTE - I am aware that Rich van Konynenburg has updated his ideas but I have found that the regime as described below has worked reliably well on my patients.


Chronic Fatigue Syndrome is a symptom, not a diagnosis, and the name of the game is to identify the underlying causes. In fatigue syndromes we don't see macro-pathology, we see micro-pathology - that is to say the problems are bio-chemical and occur at the molecular level.

There are several cycles, which I now know to be centrally important in causing fatigue. All these cycles interlink with each other like Olympic rings and getting one cycle going will drive another. The important cycles which I know to be major players include blood sugar wobbles, allergy problems, sleep cycles, mitochondrial function, anti-oxidant status, the NO/OONO cycle, thyroid and adrenal hormones cycles and de-toxification. I am greatly indebted to Rich van Konynenburg for updating me on a new player which interlinks with many of the above, namely the methylation cycle.

The Methylation Cycle

Rich van Konynenburg's idea is that ineffective methylation is a major cause of fatigue. There are many possible reasons but those that he's identified for which methylation is essential are:

  • To produce vital molecules such as Co Q-10 and carnitine.
  • To switch on DNA and switch off DNA. This is achieved by activating and deactivating genes by methylation. This is essential for gene expression and protein synthesis. Proteins of course make up the hormones, neurotransmitters, enzymes, immune factors and are fundamental to good health. When viruses attack our bodies, they take over our own DNA in order to replicate themselves. If we can't switch DNA/RNA replication off then we will become more susceptible to viral infection.
  • To produce myelin for the brain and nervous system.
  • To determine the rate of synthesis of glutathione which is essential for detoxification.
  • To determine the rate of synthesis of glutathione which is an essential anti-oxidant as glutathione-peroxidase. Furthermore oxidative stress blocks glutathione synthesis - yet another vicious cycle!
  • To control sulphur metabolism of the body, not just glutathione but also cysteine, taurine and sulphate. This is an important process for detoxification.
  • As part of folic acid metabolism. This also switches on synthesis of new DNA and RNA.
  • For normal immune function. The methylation cycle is essential for cell mediated immune function and blockages here will mean that infections will not be adequately dealt with. I know this clinically because many patients tell me that once they get on to their B12 injections (an essential co-factor for methylation) this seems to protect them from getting infections.

The overall effect here is that if the methylation cycle doesn't work, the immune system malfunctions, the detoxification system malfunctions, our ability to heal and repair is reduced and the anti-oxidant system malfunctions.

The Bio-chemistry

(You can ignore this bit if you like because it's not essential to know but it's interesting.)

There are four cornerstones to the methylation cycle and on each cornerstone sit four molecules namely homocysteine, methionine, S-adenosylmethionine (SAMe) and S-adenosylhomocysteine. Each of these molecules leads into the next one by means of enzymes. The important co-factors that allow this to happen are the B vitamins such as folic acid, vitamin B12 and vitamin B6. In converting from S-adenosyl methionine into S-adenosyl homocysteine, a methyl group is given up and this can be used to stick on to other molecules - hence the name, the methylation cycle.

However, there is a particular bio-chemical glitch here. In order for the methylation cycle to work these B vitamins have to be in their activated form, namely methylcobalamin, folinic acid and pyridoxyl-5-phosphate. In order to get cobalamin into methylcobalamin, the methylation cycle has to be working. So if this cycle has crashed completely, the body can't make methylcobalamin in order to get it up and running again. Since this cycle is so fundamental to other biochemical cycles including trans-sulphuration and folate metabolism, it can't change the vitamin B6, folic acid and cobalamin into the active forms necessary for the methylation cycles to work.

This means that in order to get this cycle up and running initially we have to prime the pump with the activated vitamins, but hopefully once the methylation cycle is up and running, it can function on the vitamins in their normal states.

Testing for how well the methylation works

We don't have a simple test to see how well the methylation cycle works. What we can do is measure levels of homocysteine and SAMe. If these were raised this would show a blockage in one part of the pathway. Indeed, a raised homocysteine we know to be a major risk factor for arterial disease, almost certainly because this represents blockages in the methylation cycle. However, one could have a normal homocysteine and normal SAMe but blockages elsewhere in the system, which would still impair the ability to methylate. So there is no simple test.

One can also measure urinary MMAs (test for methylated B12) and FIGLu (test for methylated folate) but these can only be done as part of an Organic acids present in urine (Metabolic Analysis Profile).

How do we go about treating this?

Rich van Konynenburg has identified a package of micronutrients specifically to support the methylation cycle. He recommends the activated form of vitamins. These are more expensive than the basic forms, but I think that the idea here is that they are necessary in the short term to get the cycle working and in the longer term they can be dropped off. In addition to the basic three B vitamins Rich van Konynenburg has one or two other additions which you may also like to choose to use, but my initial suggestions would be as follows.

The Methylation Cycle - which supplements to take to support

This is the package of supplements to support the methylation cycle. It needs to be taken in addition to everything else, i.e. the standard nutritional package (multivits, multiminerals, EFAs, vits C + D) and the mitochondrial rescue package (D-ribose, acetyl-L-carnitine, CoQ10, etc.)! But the methylation package will change with time because as the methylation cycle starts to work again, it will start to stand on its own feet. Everyone”s package will be a bit different depending on how poorly their cycle is working. One day we will have the biochemical tests to tailor make each package for each person, but until then I suggest the following regime for those sufferers who have been taking vitamin B12 in oral form (as either hydroxocobalamin or cyanocobalamin):

For two months a daily dose of

If you are better - fine! If you are worse - it may be the reaction to the methylation package because it may cause an acute detox reaction (see below). Slow down the regime - take smaller amounts of the supplements and build up slowly. If you are unchanged - swap the sublingual B12 for injected B12 ie:

  • Daily subcutaneous injections methylcobalamin 0.5mgs (this is a bit more expensive than cyanocobalamin). Some CFSs will not respond clincially until 5mgs daily is injected. B12 is very safe with no known toxicity- as a colleague commented - the only way you could kill yourself with B12 would be to drown in the stuff! I would prefer people to start with this regime but I know many do not fancy the idea of injections - actually I am a wimp too, but they are easy and almost painless.
  • Methyltetrahydrofolate 800mcg (ActiFolate)
  • Pyridoxal-5- phosphate 100mgs (50mgs twice daily)
  • Glutathione 250mgs daily
  • Phosphatidyl Serine 200mgs (100mgs twice daily) - BioCare

If you are better - fine! If you are worse - it may be the reaction. If you are unchanged, add in:

  • Tri-methylglycine or TMG (not to be confused with betaine hydrochloride, so always ensure that you are taking pure-grade TMG)
  • Lecithin (phosphatidyl choline) and Phosphatidyl Ethanolamine.
  • S-adenosyl methionine (SAMe) directly as a supplement 400mgs daily

For those sufferers who have already tried B12 by injection as either hydroxocobalamin or cyanocobalamin before starting the methylation cycle protocol, go straight on to injections of methylcobalamin.

Once you are substantially better

Then the regime can be relaxed. Once you are a good methylator, then methyl B12, ActiFolate and glutathione could be tailed off. Injections could be swapped for oral supplements. However, do this slowly - some people need a small supplement long term in order to stay well.

  • Methyltetrahydrofolate 800mcg (ActiFolate).
  • Hydroxocobalamin 5000mcgms sublingually (or cyanocobalamin sublingually as Shot-0-B12). It may be necessary for some people to continue with B12 by injection to get the best effect (easy to self inject 0.5 - 5mg daily - once you have improved on methylcobalamin, then switch to the less expensive cyanocobalamin). Then the injections can be spaced out and the frequency adjusted according to clinical response.
  • Pyridoxyl-5-phosphate 50mgs (this is present in the BioCare multivitamin)
  • Phosphatidyl Serine 200mgs (100mgs twice daily) - BioCare

These should be taken in addition to my basic package of supplements, namely multivitamins, Mineral Mix, essential fatty acids, vitamins C and D - these are the supplements I like all people to take on a regular basis. See Nutritional Supplements - what everybody should be taking all the time even if nothing is wrong

Problems with starting this package of treatment

Rich van Konynenburg has been in contact with patient and support groups and about 60 so far have gone through this regime. He seems to see two categories of effect - firstly sometimes a quite rapid and profound improvement in some of the common symptoms, or secondly symptoms worsening or new symptoms arise because in getting the methylation cycle going one suddenly starts to get detox and die off symptoms. The reason for this is that when the methylation cycle was not working the body was unable to detox properly and unable to produce cell mediated immune responses to get rid of chronic infections. Once the methylation cycle is up and running, suddenly the body can swing into action with respect to detox and cell mediated immune responses and this can make the person much worse. The reasons for this are fairly obvious - as soon as one starts to detox one mobilises chemicals and toxins into the blood stream, this makes people ill. Secondly, remember that it is not viruses and chronic infections that make one ill, it is the immune reaction against them. Cell medicated immune responses make you feel sick! So it is really important to go into this regime gently, be mindful that it may make things worse initially but see this as a good sign.

Rich tells me that the following symptoms of CFS have been reported to have been corrected and so I have taken his list and repeated it at length so you can see the sort of things to expect. PWC means People With Chronic fatigue syndrome.

"The following symptoms of CFS have been reported to have been corrected by various PWCs on this treatment. Note that these are gathered from reports from many PWCs, so that not all have been reported by a single person.

  • Improvement in sleep (though a few have reported increased difficulty in sleeping initially).
  • Ending of the need for and intolerance of continued thyroid hormone supplementation.
  • Termination of excessive urination and night-time urination.
  • Restoration of normal body temperature from lower values.
  • Restoration of normal blood pressure from lower values.
  • Initiation of attack by immune system on longstanding infections.
  • Increased energy and ability to carry on higher levels of activity without post-exertional fatigue or malaise. Termination of "crashing."
  • Lifting of brain fog, increase in cognitive ability, return of memory.
  • Relief from hypoglycaemia symptoms.
  • Improvement in alcohol tolerance
  • Decrease in pain (though some have experienced increases in pain temporarily, as well as increased headaches, presumably as a result of detoxing).
  • Notice of and remarking by friends and therapists on improvements in the PWC's condition.
  • Necessity to adjust relationship with spouse, because not as much caregiving is needed. Need to work out more balanced responsibilities in relationship in view of improved health and improved desire and ability to be assertive.
  • Return of ability to read and retain what has been read.
  • Return of ability to take a shower standing up.
  • Return of ability to sit up for long times.
  • Return of ability to drive for long distances.
  • Improved tolerance for heat.
  • Feeling unusually calm.
  • Feeling "more normal and part of the world."
  • Ability to stop steroid hormone support without experiencing problems from doing it.
  • Lowered sensation of being under stress.
  • Loss of excess weight.

The following reported symptoms, also gathered from various PWCs trying this simplified treatment approach, are those that I suspect result from die-off and detox:

  • Headaches, "heavy head," "heavy-feeling headaches"
  • Alternated periods of mental "fuzziness" and greater mental clarity.
  • Feeling "muggy-headed" or "blah" or sick in the morning.
  • Transient malaise, flu-like symptoms.
  • Transiently increased fatigue, waxing and waning fatigue, feeling more tired and sluggish, weakness.
  • Dizziness.
  • Irritability.
  • Sensation of "brain firing: bing, bong, bing, bong," "brain moving very fast".
  • Depression, feeling overwhelmed, strong emotions.
  • Greater need for "healing naps."
  • Swollen or painful lymph nodes.
  • Mild fevers
  • Runny nose, low grade "sniffles," sneezing, coughing.
  • Sore throat.
  • Rashes.
  • Itching.
  • Increased perspiration, unusual smelling perspiration.
  • "Metallic" taste in mouth.
  • Transient nausea, "sick to stomach"
  • Abdominal cramping/pain.
  • Increased bowel movements.
  • Diarrhoea, loose stools, urgency.
  • Unusual colour of stools, e.g. green.
  • Temporarily increased urination
  • Transiently increased thirst.
  • Clear urine.
  • Unusual smelling urine
  • Transient increased muscle pain.

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What to do if you're not getting better

If you are still struggling then there must be another cause of fatigue that has not been addressed. Remember, fatigue is just a symptom! There are many parallels between chronic fatigue syndrome and autism and many of these ideas have already been used in the treatment of autistic children with excellent results. This work has been pioneered by Dr Amy Yasko N.D., Ph.D. in America. Please see Dr Amy Yasko's website

For further information go to:

Townsend Letter for Doctors and Patients, Oct, 2006 by Richard A. Van Konynenburg

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