Myalgic Encephalomyelitis and Energy Production


With thanks and reference to Rich Van Koyenburg and Pat Askert’s site


The information is based around the methylation and the use of Co-Enzymes to fuel Mitochondria.


Patients with M.E absorb supplements poorly due to gut malfunctions and infections and thus, many patients report not gaining any benefit from the usual B vitamin supplements from Holland and Barratt and so on.


I personally had the Mitochondrial tests done by Dr Myhill (actually I had them done by the now struck off Dr Wright) and it showed up a deficiency in B3 plus mitochondrial damage, cell death and lack of conversion to ATP plus high oxidated stress.


To learn more about Oxidated Stress please see Byron Hyde's page...


At the point of starting the protocol I was bedbound and could barely lift my head let alone type, I was barely functioning - it was the latter part of 2010 when I began this protocol. I spoke with Rich Van Konyenburg and was interested in how he used Methylation to treat M.E I was particularly interested in how he uses B Vitamins as Co-Enzymes....Pyridoxal (B6), folate and cobalamin and started researching co-enzymes, in particular nicotinamide adenine dinucleotide hydrogen. Within six months I was able to pop to the shops once a week and not suffer from severe crashes that resulted in outbreaks of Shingles. Before, the second I left the house I would explode in shingles. I have more energy than I used to, still feel like I have M.E but it isn’t tying me to my bed although some days are worse than others. Since adding in the Magnesium Malate, my pain has lessened and my cognitive function has improved. It has improved even more since adding the Methyl B12 which I added to the protocol two weeks ago. I am starting to write and research again; I had to stop writing six months ago as I was too unwell and could not focus. I will reiterate the point that this is no magic bullet. I have numerous other health conditions alongside M.E and no two patients are the same. If you are beginning any protocol I would advise you tell your doctor. All the supplements are safe with no side effects but all researchers recommend your doctor supports you through.




NADH is involved in the synthesis of adenosine triphosphate (ATP), the body's primary intracellular energy source. When NADH is oxidized in cellular energy-producing organelles called mitochondria, it forms water and energy.


This energy is preserved as ATP. Every energy-consuming reaction requires ATP, so the more NADH a cell has available, the more energy it can produce.

To keep up with the cellular demand for energy, the body continuously synthesizes NADH (a process that involves niacin, a B-complex vitamin).


Some believe M.E is nothing more than lack of chemical Adenosine Triphosphate (ATP-cellular energy), which provides power to the body. Chronic infections, stress, and other ailments tend to deplete the chemical. NADH is the chemical that jumpstarts the production of ATP in the body’s cells. NADH is known to trigger energy production through ATP generation and is also a great oxidator.


Both support cellular energy production. Coenzyme Q10 is involved in cellular energy production; however, at a much lower level than NADH. Coenzyme Q10 needs NADH to be transformed into its reduced form. Only in its reduced form is CoQ10 active and can transport electrons from NADH to oxygen which then leads to energy production in the form of ATP.


NADH is the fuel for cellular energy production. All living cells require energy to stay alive. Without energy a cell dies because energy production represents the essential prerequisite for every living cell.


How energy is produced involves food being taken in and digested. Its components, proteins, carbohydrates, and fats, are degraded into smaller molecules such as amino acids, sugars and lipids. They are processed leading to a reducing power in the form of NADH, the reduced form of coenzyme 1.


NADH reacts with oxygen, present in every living cell, to produce in a cascade of reactions water (H2O) and energy. This energy is stored in the form of the chemical compound adenosine triphosphate, abbreviated ATP. Scientific studies have shown that a loss of NADH leads to an ATP depletion, which in turn leads to cell death. (Metabolic and Energetic Changes During Apoptosis in Neural Cells, J.C. Mills, D. Nelson, M. Erecinska and R. Pittmanm, Journal of Neurochemistry, 1995). Simply put, the more NADH a cell has available, the more energy it can produce.


NADH is the abbreviation of Nicotinamide-Adenine-Dinucleotide-Hydride. Nicotinamide is another name for vitamin B3. Hence, NADH is the coenzyme form or active form of vitamin B3. Vitamin B3 itself is inactive. As a vitamin it is essential for our body. It is absorbed and converted in the cells to NAD (oxidized form of NADH). NAD is then converted to NADH. However, it cannot be emphasized enough that neither Nicotinamide nor NAD (oxidized form of NADH) shows the energizing effect of NADH not even in very high dosages as we have tested in our numerous studies.]


Despite the dearth of knowledge concerning the cause of CFS, it is generally accepted that there may be a dysfunction of the neuro-crine-endocrinoiogic-immunologic (NEI) network in CFS and several theories have focused on each of the three limbs of the NEI network. One theory suggests that the syndrome results from a dysfunction of the immune system and several subtle immunologic abnormalities have been described in patients with CFS. These include low levels of specific immunoglobulins reported in 17% to 71% of cases, the presence of circulating immune complexes in over 50% of patients, and increased ratios of CD4/CD8 T-lymphocytes. Other abnormalities of the immune system included a decrease in natural killer (NK) cells which appear to play a major protective role in viral infection. A second theory emphasizes the role of neurally mediated hypotension (NHM). Studies utilizing a 3-stage tilt table test have shown an abnormal response in patients with CFS compared with controls and demonstrate an uncompensated NHM which is thought to be the cause of the fatigue. A third, but not mutually exclusive theory, is one that suggests metabolic dysfunction owing to stress, viral infection, allergic disease or a host of other factors. Patients with CFS have increased 2'-5' A synthetase and RNAse L activity. This in turn leads to a depletion of cellular ATP that may be the pivotal metabolic lesion responsible for severe fatigue, cognitive disturbances, and other manifestations of the syndrome. Since stress, allergy, and infections may either trigger or exacerbate the clinical course, control of these factors is critical in the management of patients with CFS. Nicotinamide adenine dinucleotide (NADH), the coenzyme, is known to trigger energy production through ATP generation. This knowledge has provided the rationale for the present study. It consists of the ability of the coenzyme to replenish depleted cellular stores of ATP, thus improving the fatigue and cognitive dysfunction characteristic of the disorder.


The purpose of the present study was to evaluate the efficacy of the reduced form of NADH administered orally to a group of patients with CFS in a double-blind, placebo-controlled crossover study.


A Simplified Treatment Approach Based on the Glutathione Depletion - Methylation Cycle Block Pathogenesis Hypothesis for Chronic Fatigue Syndrome (CFS)


by Rich Van Konynenburg, Ph.D.


The Simplified Glutathione Depletion-Meythlation Cycle Block Treatment Approach.


I will now describe the current version of the simplified treatment approach based on the Glutathione Depletion--Methylation Cycle Block Hypothesis.

(All the supplements used in this approach can be obtained from the site, or all but the Complete Vitamin and Neurological Health Formula can be obtained elsewhere. Please note that I have no financial interest in any of the supplements that I have suggested in the simplified treatment approach.)


Treatment Tip. As I mentioned above, these supplements and dosages have been selected by Dr. Amy Yasko as part of her complete treatment approach, as described in her book "The Puzzle of Autism." Substitutions or changes in dosages may not have the same effect as the combination of supplements and dosages suggested, although it is wise to start withsmaller dosages than those given below, and it is also wise to start with one supplement at a time and work up to the total of five supplements, to test carefully for adverse effects. It will take somewhat longer to reach the suggested combination and dosages by this route, but early experience has shown that this is prudent.

Detoxification and Die-off. As I also mentioned above, this treatment approach should be attempted only under the supervision of a licensed physician, so that any individual issues that arise can be properly dealt with. It's important to "listen to one's body" when doing this treatment. If the detox becomes too intense to tolerate, or if significant adverse effects appear, as described below, the supplements should be discontinued, and the situation should be evaluated immediately by a licensed physician.


This treatment will produce die-off and detox symptoms as the immune system and detox system come back to normal operation and begin ridding the body of accumulated infections and toxins. This appears to be inevitable, if health is to be restored. It may require considerable judgment and clinical experience on the part of the physician to distinguish between inevitable die-off and detox symptoms and possible adverse effects.


While die-off and detox symptoms are occurring, there will also likely be improvement in CFS symptoms over time. The intensity of the expected die-off and detox symptoms can be decreased by lowering the dosages of the supplements. These symptoms probably result from the body's limited rates of excretion of toxins. If toxins are mobilized more rapidly than they can be excreted, their levels will rise in the blood, and it is likely that this will produce more severe die-off and detox symptoms. By lowering the dosages, and thus slowing the rate of mobilization of toxins, their levels in the blood can be lowered, thus ameliorating the symptoms.


Slow and Steady. The temptation to try to get better faster by increasing the dosages suggested by Dr. Yasko must be resisted. In particular, the suggested dosages for the FolaPro and the Intrinsi/B12/folate supplements should not be exceeded. Some who have done this have experienced very unpleasant levels of detox symptoms that had momentum and did not decrease rapidly when the supplements were stopped.


As improvements in energy level and cognition occur, it is tempting for PWCs to overdo activities, which, early in the treatment, can still result in "crashing." It is wise to resist this temptation as well, because complete recovery will not occur overnight with this treatment approach.


Drug Interactions. I am not aware of negative interactions between the five basic supplements and prescription medications used by physicians in treating CFS. However, this treatment approach should not be attempted without considering together with a licensed physician possible interactions between the supplements included in it and any prescription medications that are being taken. This is particularly important if addition of SAMe to the basic five supplements is contemplated.


When this treatment approach is used together with prescription medications, a licensed physician must be consulted before discontinuing any prescription medications. Some of them can cause very serious withdrawal symptoms if stopped too abruptly.


Thyroid. If this treatment approach is begun by a PWC who is taking a thyroid hormone supplement for a hypothyroid condition, the PWC and the supervising physician should be alert to the possibility that HYPERthyroid symptoms, such as palpitations and sweats, can occur, even very soon after starting this treatment. The physician should be consulted about possibly adjusting or eliminating the thyroid hormone supplementation if this occurs.


The Five Supplements


Here are the five supplements, as found in Dr. Yasko's book "The Puzzle of Autism," (p. 49) and as described in detail on her website :


1. One-quarter tablet (200 micrograms) Folapro (Folapro is 5-methyl tetrahydrofolate, an active form of folate, which is sold by Metagenics with a license from Merck, which holds the patent on synthesis).


2. One-quarter tablet Intrinsic B12/folate (This includes 200 micrograms of folate as a combination of folic acid, 5-methyl tetrahydrofolate, and 5-formyl tetrahydrofolate, also known as folinic acid or leucovorin (another active form of folate), 125 micrograms of vitamin B12 as cyanocobalamin, 22.5 milligrams of calcium, 17.25 milligrams of phosphorus, and 5 milligrams of intrinsic factor).


3. Up to two tablets (It's best to start with one-quarter tablet and work up as tolerated) Complete Vitamin and Ultra-Antioxidant Neurological Health Formula from Holistic Health Consultants (This is a multivitamin, multimineral supplement with some additional ingredients. It does not contain iron or copper, and it has a high ratio of magnesium to calcium. It contains antioxidants, some trimethylglycine, some nucleotides, and several supplements to support the sulfur metabolism.)


4. One softgel capsule Phosphatidyl Serine Complex (This includes the phospholipids and some fatty acids)


5. One sublingual lozenge Perque B12 (2,000 micrograms hydroxocobalamin with some mannitol, sucanat, magnesium and cherry extract)


Treatment Tips. The first two supplement tablets are difficult to break into quarters. One of the PWCs who is following the simplified treatment approach has suggested that an alternative approach is to crush them into powders, mix the powders together, and divide the powders into quarters using a knife or single-edged razor blade and a flat surface. The powders can be taken orally with water, with or without food, and do not taste bad.


Some people have asked what time of the day to take the supplements. A few have reported that the supplements make them sleepy, so they take them at bedtime. If this is not an issue, they can be taken at any time of the day, with or without food.


Treatment Components Explained


Since some questions have been asked about which components of this treatment approach are essential, and since some PWCs appear to be taking augmented versions of the simplified GD-MCB treatment approach that I wrote about in my January treatment paper (cited above), I want to offer some comments to help PWCs and their physicians to evaluate which supplements to include in treatment.


FolaPro -- This is included because many PWCs have a genetic polymorphism in their MTHFR (methylene tetrahydrofolate reductase) enzyme that affects the production of 5-methyltetrahydrofolate (which is identical to the product FolaPro). This form of folate is the one used by the methionine synthase enzyme, which is the enzyme that appears to be blocked in many cases of CFS. If PWCs were to have their genetics characterized, as in the full Yasko approach, they would know for sure whether they needed this supplement, but in the simplified approach I suggest simply giving it to everyone.


This should not present problems, because the total folate dose, including the FolaPro and the folates in the Intrinsi/B12/folate supplement, amounts to 400 micrograms per day, which is within the upper limit for folate supplementation for adults and for children four years of age and older, as recommended by the Institute for Medicine of the U.S. National Academy of Sciences.

Intrinsic/B12/folate -- This supplement contains three forms of folate--FolaPro, folinic acid (identical to the drug leucovorin) and folic acid (the most common commercial folate supplement). It also has some cyanocobalamin (the most common commercial vitamin B12 supplement) and some intrinsic factor (identical to that normally secreted by the stomach to enable vitamin B12 absorption by the gut) as well as some other things.


The folinic acid is helpful because some people can't use ordinary folic acid well, as a result of genetic issues. Also, this helps to supply forms of folate that will make up for the low tetrahydrofolate resulting from the block in methionine synthase, until this is corrected. This enzyme normally converts 5- methytetrahydrofolate to tetrahydrofolate, which is needed in other reactions.

This supplement also has some intrinsic factor and some cyano-B12 to help those who have a type of pernicious anemia that results from low production of intrinsic factor in the stomach and which prevents them from absorbing B12 in the gut. Vitamin B12 is needed by the enzyme methionine synthase, in the form of methylcobalamin, but this supplement has cyanocobalamin, which must be converted in the body by glutathione and SAMe to form methylcobalamin. As glutathione and SAMe come up, this should become more effective.


Complete Vitamin and Ultra-Antioxidant Neurological Health Formula -- This is Dr. Amy Yasko's basic high-potency general nutritional supplement. This is a general foundation for the biochemistry of the body. I suspect that this supplement is better for PWCs trying the simplified treatment approach than other high-potency general nutritional supplements, because it has particular things needed for dealing with a methylation cycle block, including some TMG and sulfur metabolism supplements as well as nucleotides. It is also high in magnesium and low in calcium, and has no iron or copper.


As far as I know, there are no other supplements with all these characteristics. I therefore believe that this supplement is important for use in the treatment approach. The TMG helps to stimulate the BHMT pathway in the methylation cycle, and that helps to build SAMe, which is needed by the parallel methionine synthase pathway. The nucleotides will help to supply RNA and DNA for making new cells until the folate cycle is operating normally again.

Phosphatidylserine complex —This contains various phosphatidyls and fatty acids, which will help to repair damaged membranes, including those in cells of the brain and nervous system. It should help with the cortisol response. It also has some choline, which can be converted to TMG (betaine) in the body, to help stimulate the BHMT pathway.


Perque B12 -- This is sublingual hydroxocobalamin. The dosage is fairly large, in order to overcome the blocking of B12 by toxins such as mercury in CFS. As I mentioned above, B12 is needed to stimulate the activity of methionine synthase. Methylcobalamin is actually the form needed, but some people cannot tolerate supplementing it for genetic reasons, and I'm also concerned that people with high body burdens of mercuric mercury could move mercury into the brain if they take too much methylcobalamin.


Methylcobalamin is the only substance in biological systems that is known to be able to methylate mercury. (Note that methylcobalamin is the substance used by bacteria to perform methylation on environmental mercury, and the resulting methylmercury is concentrated in the food chain up to the large predatory fish and enters the human diet.) Methylmercury can readily cross the blood-brain barrier. Methylation of mercury by methylcobalamin has been reported in the literature to occur within the bodies of guinea pigs in laboratory experiments. Perque B12 is sublingual to compensate for poor B12 absorption in the gut of many people.


There are also two other supplements that were included in the earlier version of the simplified approach:


SAMe -- This is normally part of the methylation cycle. Depending on genetic variations (SNPs or polymorphisms) some PWCs can't tolerate much of this, and some need more. If PWCs can't tolerate this, they should leave it out, because stimulating the BHMT pathway, using TMG and choline in the other supplements, will probably make enough SAMe for them naturally. For people who can tolerate SAMe, a dosage of 400 mg per day is suggested.


Methylation Support RNA Formula -- This is a mixture of RNAs that is designed to help the methylation cycle. It is somewhat expensive, and is not essential, but is helpful if people can afford it. Dr. Amy Yasko has since advised me that if a PWC desires to take only one of her RNA Products, she would suggest choosing either the Health Foundation RNA Formula or the Stress Foundation RNA Formula, rather than the Methylation Support RNA Formula, as being most helpful to take the edge off the detox.


The above suggested list of supplements may not be optimum, and future clinical studies may produce an improved protocol. I think that the forms of folate and B12 are probably essential, because they target what I believe is the root issue in the abnormal biochemistry of CFS.


I think the Complete supplement is important to support the general biochemistry and to correct deficiencies that might be present in essential nutrients, as well as to support the methylation cycle and the rest of the sulfur metabolism. I think that some way of stimulating the BHMT pathway is important, also, to bring up SAMe, and the phosphatidyl serine complex provides this, as does the TMG included in the Complete supplement.

Interactions With Other Supplements. With regard to possible interactions between the supplements in the simplified treatment approach and other supplements that PWCs may be taking, I am aware of two:


(1) I would not recommend taking additional folate beyond what is suggested above, since the various forms of folate compete with each other for absorption, and it is important to get enough of the active forms into the body. Also, it is important not to take too much folate, as mentioned above, because this can cause the detox to develop a momentum, so that it will take some time to slow it down if you want to do that.


(2) I would also not recommend taking additional trimethylglycine (TMG, also called betaine) or additional forms of choline, such as phosphatidylcholine or lecithin, since that may stimulate the BHMT pathway too much at the expense of the methionine synthase pathway. The betaine-HCl used to augment stomach acid is something that may have to be omitted while doing this treatment, too, since it will contribute to this stimulation.


Adding glutathione support will help some people, as will adding molybdenum.

As more things are added, though, one is moving toward the full Yasko approach, which is more complicated and expensive. If this is done,I recommend that it be done with the guidance of Dr. Yasko and under the supervision of a personal physician. The simplified treatment approach appears to work well by itself for many PWCs, but others may find that the die-off and detox (or even adverse effects) from this approach used by itself are too severe.


In those cases, the PWCs could consult "The Puzzle of Autism," sold on, to consider together with their doctors what else discussed there might help them. If the simplified approach seems to help to some degree, and it captures one's attention for that reason, but it still either does not accomplish all that is desired, or it is not tolerated, then perhaps the next step would be to consider the full Yasko treatment. At least then there would be stronger motivation to look into it. Otherwise, it can appear very daunting to many PWCs.


Responses Thus Far. The reported responses to this treatment approach have mainly involved a combination of two categories of effects:


(1) improvements in some of the common CFS symptoms (some of them quite rapid and profound), and

(2) intensification or initial appearance of a variety of symptoms that appear to result from increased detoxification and immune system attack on infections.


The former are most welcome, and they are what continue to motivate the people on this treatment, in the face of the detox and die-off symptoms, which are unpleasant but appear to be inevitable, given the large body burdens of toxins and infections that many PWCs have accumulated during their illness, lacking adequate detox capability and cell-mediated immune response during that time.


In addition to these main responses, a few PWCs have reported adverse effects, some of them quite serious. These are discussed below. A few of those who have started the treatment have stopped it for various reasons, including adverse effects. Some have taken breaks from the treatment and have then returned to it or are planning to do so.


While this informal testing of the simplified treatment approach currently is not being carried out in a controlled fashion, and while not all the PWCs trying it are using the complete suggested complement of supplements, it is nevertheless possible to state that the treatment appears to be working for quite a few PWCs, though not all.


Improvements. 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.


1. Improvement in sleep (though a few have reported increased
difficulty in sleeping initially).
2. Ending of the need for and intolerance of continued thyroid
hormone supplementation.
3. Termination of excessive urination and night-time urination.
4. Restoration of normal body temperature from lower values.
5. Restoration of normal blood pressure from lower values.
6. Initiation of attack by immune system on longstanding infections.
7. Increased energy and ability to carry on higher levels of
activity without post-exertional fatigue or malaise. Termination
of "crashing."
8. Lifting of brain fog, increase in cognitive ability, return of
9. Relief from hypoglycemia symptoms
10. Improvement in alcohol tolerance
11. Decrease in pain (though some have experienced increases in pain
temporarily, as well as increased headaches, presumably as a result
of detoxing).
12. Notice of and remarking by friends and therapists on improvements
in the PWC's condition.
13. 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.
14. Return of ability to read and retain what has been read.
15. Return of ability to take a shower standing up.
16. Return of ability to sit up for long times.
17. Return of ability to drive for long distances.
18. Improved tolerance for heat.
18. Feeling unusually calm.
19. Feeling "more normal and part of the world."
20. Ability to stop steroid hormone support without experiencing
problems from doing it.
21. Lowered sensation of being under stress.
22. Loss of excess weight.


Negative Effects. 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:


1. Headaches, "heavy head," "heavy-feeling headaches"
2. Alternated periods of mental "fuzziness" and greater mental
3. Feeling "muggy-headed" or "blah" or sick in the morning
4. Transient malaise, flu-like symptoms
5. Transiently increased fatigue, waxing and waning fatigue, feeling
more tired and sluggish, weakness
6. Dizziness
7. Irritability
8. Sensation of "brain firing: bing, bong, bing, bong," "brain
moving very fast"
9. Depression, feeling overwhelmed, strong emotions
10. Greater need for "healing naps."
11. Swollen or painful lymph nodes
12. Mild fevers
13. Runny nose, low grade "sniffles," sneezing, coughing
14. Sore throat
15. Rashes
16. Itching
17. Increased perspiration, unusual smelling perspiration
18. "Metallic" taste in mouth
19. Transient nausea, "sick to stomach"
20. Abdominal cramping/pain
21. Increased bowel movements
22. Diarrhea, loose stools, urgency
23. Unusual color of stools, e.g. green
24. Temporarily increased urination
25. Transiently increased thirst
26. Clear urine
27. Unusual smelling urine
28. Transient increased muscle pain


I want to reiterate what I wrote near the beginning of this article: This treatment approach must be entered upon only under the supervision of a licensed physician, to make sure that if there are individual issues that arise, they can be taken care of immediately. The treatment approach itself consists only of nonprescription supplements that are normally found naturally in the body and are necessary for normal biochemistry to take place. It would thus appear to be fairly benign on its surface.


However, it must be pointed out that restarting the methylation cycle after it has been blocked for extended periods, particularly in those PWCs whose general health has become quite debilitated, or those who have certain respiratory, cardiac, endocrine or autoimmune conditions, can present some serious challenges. I believe that there is still much more to be learned about the possible hazards of applying this treatment approach to the very heterogeneous CFS population, and this work properly lies in the province of clinicians.


I am not a licensed physician, but a researcher. I believe that I have carried this work as far as a researcher can appropriately carry it. I am hopeful that clinicians will further test this treatment approach in order to learn how it may be safely, effectively, and practically utilized to treat PWCs, and it appears that this is now beginning to occur.


I also hope that physicians or their patients who decide to try this treatment approach will let me know how it works for them, though I may not be able to answer all the emails I receive, as their volume is growing.


Rich Van Konynenburg, Ph.D.
Independent Researcher and Consultant
July 18, 2007


 A Yahoo discussion group is now devoted to these topics. You can find it at


The Krebs Cycle


There are five co-enzymes needed for the Kreb's cycle to function properly. The Krebs Cycle is a series of complex chemical reactions that produce ATP. No ATP = No Energy so it’s vital M.E patients have the Krebs Cycle in place.

The Krebs cycle, also known as the citric acid cycle or the tricarboxylic acid (TCA) cycle, was first identified by Hans Adolf Krebs in 1937. The Krebs cycle consists of a series of enzymatic reactions, which use oxygen to convert carbohydrates, proteins, and fats into carbon dioxide and water. The cycle is also responsible for the generation of cellular energy in the form of adenosine triphosphate (ATP). ATP is a nucleotide utilized to transport energy for cell metabolism. Each turn of the cycle generates one molecule of ATP and two molecules of carbon dioxide (CO2). The Krebs cycle takes place within the mitochondria, distinct organelles found inside every cell and commonly referred to as the “energy powerhouse.”*

The Krebs cycle consists of 8 critical steps involving the creation of 5 intermediate compounds:

1. Acetyl coenzyme A (acetyl CoA), a product of glycolysis (the first step in the breakdown of glucose), is one of the starting components of the Krebs cycle. The acetic acid subunit of acetyl CoA is combined with oxaloacetate to form citrate. The coenzyme subunit of acetyl CoA is released by hydrolysis (a reaction with water) to combine with another acetic acid molecule and begin the Krebs cycle again.

2. Citrate is converted into its isomer isocitrate. Isomers are molecules possessing the same chemical formula, but different structural configurations.

3. Isocitrate is oxidized to form the second intermediate, alpha-ketoglutarate. During this reaction, carbon dioxide (CO2) is released and nicotinamide adenine dinucleotide (NAD+), an important coenzyme and carrier of electrons in the electron transport chain, is reduced to NADH. This transfer of electrons is critical to the generation of cellular energy.*

4. Alpha-ketoglutarate is oxidized to succinyl coenzyme A (succinyl CoA). A second molecule of CO2 is released and another molecule of NADH is formed.

5. A water (H2O) molecule donates its hydrogen atoms to the coenzyme A subunit of succinyl CoA. Then, a free-floating phosphate group (-PO4) displaces coenzyme A and forms a bond with the succinyl complex. The phosphate is then transferred to a molecule of adenosine diphosphate (ADP) to produce an energy molecule of adenosine triphosphate (ATP). It leaves behind one molecule of succinate.

6. Succinate is oxidized by a molecule of flavin adenine dinucleotide (FAD), another compound necessary for the transfer of electrons and generation of energy within the cell. The intermediate fumarate is formed and FADH, the reduced form of FAD, is released.*

7. Fumarate is hydrolyzed (by water) to form the final intermediate, malate.

8. Malate is oxidized by NAD+ to regenerate the Krebs cycle starting component, oxaloacetate. Another molecule of NADH is formed. Oxaloacetate is then free to combine with acetyl CoA and begin the Krebs cycle again.

 Krebs Cycle Abnormalities

Mitochondrial disease can be classified by the effects caused by interferences with the Krebs’cycle has been found in Mitochondrial Disease.

Low production levels of ATP, buildup of nitric and lactic acids and deficiencies of enzymes can contribute to M.E symptoms such as fatigue, cognitive function, heart problems, immune system dysfunction, diabetes and blood sugar problems and hair loss.


Administering Krebs Cycle enzymes can reduce the build-up of lactic acid which can reduce fatigue, muscle pain and cramping.
I like to use brands of methylated folate and vitamin B12 such as Now Foods,
Garden of Life and Pro Health and Metafolin by Solgar.

There are many other (at least 25 genetic errors already identified) that prevent methylation of folic acid--which is actually a complex process: Here is Folate Metabolism There are therefore other theories about enhancing the body's own ability to methylate, involving histamines and orthommolecular treatment, but that is too involved to go into here. You may want to investigate it yourself.

The take home lessons from all this are:


Co-Enzyme B vitamins are critical to neurological health and synthesis of co-enzymes.

Some people have a methylation problem, or other metabolic problem causing a "functional nutritional deficiency."

These people need the methylated and activated forms of B6, B12 and folate.