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CFS, Methylation and Creatine

Chronic Fatigue Syndrome (CFS) or Myalgic Encephalomyelitis (ME)

Chronic Fatigue Syndrome (CFS) or Myalgic Encephalomyalitis (ME) is an ill defined disease that is characterized by a post exercise tiredness or malaise. The condition usually lasts for more than six months and in affected individuals is very disabling. Symptoms include muscle soreness, inability to concentrate (brain fog), headaches and severe mental and physical fatigue. In addition these symptoms may be accompanied by sensitivity to light, sounds and smells,  digestive disturbances, depression, painful and often slightly swollen lymph nodes, and it may also be accompanied by cardiac and respiratory problems.

Causes of CFS

A wide variety of immune, endocrine, cardiovascular and central nervous abnormalities have been reported in CFS. Among the causes suggested for CFS include damage to parts of the brain governing cognition, memory, mood, energy and perception, an altered stress response, an unbalanced immune system, a hidden chronic infection, excessive production of free radicals, reduced intracellular glutathione, abnormal sympathetic nervous system activity, cardiac dysfunction and others. Many CFS sufferers are found to have sub-normal levels of vitamin D in their serum. Several researchers believe that CFS is a mitochondrial disease in which excessive, uncontrolled production of nitric oxide damages proteins in the mitochondria, and particularly in the electron transport chain. Whilst the exact cause of CFS may vary, a major group of CFS sufferers have also been found to have one or more mutations in the enzymes responsible for methylation. In these individuals it would appear that whilst they were able to exist as relatively healthy individuals, often not knowing that they had methylation associated mutations, some initiating factor such as a prolonged infection, combined with low vitamin D levels resulted in gradual loss of their vitamin B12 supplies leading to the CFS symptomatology being apparent, and the subsequent discovery of their methylation status. A recent study by Russell-Jones (2022) has shown that every individual studied had a deficiency in functional vitamin B2. This deficiency appears to have been caused by an inadequate intake of Iodine, Selenium and/or Molybdenum, which in turn resulted in lower activation of vitamin B2. The functional vitamin B2 deficiency, in turn, resulted in gradual inactivation of vitamin B12. Individuals were found to be deficient in both Adenosyl and Methyl B12, yet serum vitamin B12 levels were normal or elevated. Thus a situation of Paradoxical B12 deficiency was universal.

Causes of Fatigue

The primary symptom of CFS/ME is fatigue, but few researchers appear to address this issue, however, resolving the fatigue would appear to be the primary aim of treatment. We have identified several known causes of fatigue and have outlined them in the cartoon below

Most would be familiar with the fatigue that one feels after over-exercising, when stores of muscle glycogen and creatine-phosphate are used up. Fatigue can also occur in vitamin B12 deficiency, due to the lack of production of the electron-transport vehicle CoQ10 (a methylation product) and due to lack of production of the ATP shuttle vector creatine. Fatigue is also common in hypothyroidism, in which lack of Iodine and/or Selenium results in lack of activation of vitamin B2, and that then affects the activation of vitamin B12, with functional vitamin B12 deficiency resulting. A feature of Chronic Fatigue is lack of functional B2 and functional B12, which can occur to prolonged infection, and/or constant over-training or over-work, the two most common causes of CFS/ME. The most likely cause of the fatigue is lack of production of creatine due to functional vitamin B12 deficiency (see below).

Vitamin B2 deficiency in CFS

Activation of vitamin B2 in the body requires all of Iodine, Selenium and/or Molybdenum, and at the top of this cascade is the requirement for an active thyroid. Our Data shows a very high level of hypothyroidism in women with CFS. This is in line with the observations that conditions such as fatigue, headaches, low body temperature, anxiety, panic attacks, PMS, hair loss, depression, low motivation, IBS, insomnia, decreased memory and concentration are all common symptoms in hypothyroidism.

Vitamin B12 deficiency in CFS

The main cause of CFS is functional vitamin B12 deficiency, however, vitamin B12 levels may be normal or higher than normal and present as Paradoxical B12 deficiency.

Synthesis of Creatine

Synthesis of creatine occurs in two steps

1. Conjugation of glycine, and arginine, via  the enzyme, l-arginine:glycine amidinotransferase (AGAT), to produce guanidinoacetate acid (GAA),

2. Methylation of Guanidinoacetate by the enzyme Guanidinoacetate-N-Methyl transferase (GNMT, GAMT)

 In many individuals a reduced production of the energy shuttle vector, CoQ10 is also found. CoQ10 production involves three methylation steps.

Functional B12 deficiency correlates with functional B2 deficiency.Functional vitamin B2 deficiency as determined by levels of glutaric acid in urine, correlated with both the classical marker of AdenosylB12 deficiency, as MMA gradually increased as glutaric acid levels increased, and with neurological markers of Methyl B12 deficiency.

Similarly, other markers of Methyl B12 deficiency, Homovanillic acid, Vanillyl Mandelic acid, Quinolinic Acid and Kynurenic acid all increased as glutaric acid increased.

In contrast, initially levels of 5-hydoxyindole acetic acid increased as glutaric acid increased, however there was an inflection point at glutaric acid levels of 2 or above. This presumably reflects the requirement for functional vitamin B6 in the synthesis of serotonin. However, if functional B2 deficiency is great enough, then vitamin B6 activation (which requires FMN) will not occur.

Synthesis of melatonin requires methylation of N-AcetylSerotonin.  

Synthetic pathway for Melatonin

Lack of vitamin B12 pushes the pathway to both degradation of serotonin, but also to the metabolic destruction of high levels of intracellular tryptophan with increased in KA and QA. In addition, the lack of B12 also results in reduced production of melatonin, contributing to poor gut health - often seen in CFS and also to poor sleep patterns, also characteristic of CFS.

Not only is there reduced production of melatonin and adrenalin in vitamin B12 deficiency, because of the requirement for methylation, there is also reduced production of CoQ10 and creatine, which are arguably the main contributing factors to the chronic fatigue seen in CFS, as these result in poor energy conversion, and gradual loss of stored muscle creatine.

The reduction in the rate of methylation also reduces the transfer of homocysteine into the sulphation cycle thereby resulting in lower production of Glutathione and increased production of pyroglutamate

The primary reason for the chronic fatigue seen in CFS is the reduced production of creatine, the energy transfer molecule within the cytoplasm of the cell. Given that over 40% of all methylation goes to the production of creatine, this would be consistent with this mechanism (see https://b12oils.com/creatine.htm). Mutations in the enzyme GAMT are associated with conditions such as autism. Deficiency in GAMT activity has been associated with conditions  such as epilepsy, mental retardation and pyrimidal movement disorders (Ensenauer  etal, 2004).

Iron Deficiency and CFS

Contributing to lower energy in CFS can be lower levels of iron, as this will reduce the amount of oxygen that can be used in oxidative phosphorylation, further it reduces the efficiency of the Electron Transport Chain (ETC). Of greater significance, though, is the uncoupling of the enzyme aconitase, the major enzyme involved in the metabolism of citrate in the citric acid. As ferritin levels drop below 70 ug/L, aconitase starts to reduce it ability to metabolize citric acid with the result that energy (as unmetabolized citrate) appears in urine. As ferritn drops to around 20 ug/L as much as 80-90% of citrate can be lost into urine. Optimal levels of iron, therefore should be with ferritin >70 ug/L, Haemoglobin >14.5 and Haematocrit >0.45.

Genetic Linkage

Recently it has been found that CFS may be related to defects in either folate metabolism and/or the methylation cycle, with a high incidence of sufferers have genetic mutations in the MTHFR, MTR, MTRR, MTS and/or SHMT genes. In addition many CFS individuals have genetically similar vitamin D receptor genes. It is possible that CFS sufferers have had these "inborn errors of metabolism" for much of their life, without experiencing any significant problem until some precipitating event such as stress or a chronic infection has triggered chemical changes inside the body thereby resulting in CFS.

Treatment of CFS

Many, many different treatments have been tried in an attempt to cure CFS, with little success. However, there is some independent published clinical evidence that suggests potential benefits from repeated dose treatment with high levels of injected vitamin D3, adenosylcobalamin and methylcobalamin (both forms of Vitamin B12).  It is believed that this repeated high dose supplementation is required to stock both the body’s methylcobalamin levels but also the adenosylcobalamin. Over time, and with the addition of high dose vitamin D supplementation the majority of subjects appear to return to their pre-fatigue status.

The RnB protocol has been found to be highly effective in reversing the symptoms of CFS (RnB protocol)

Creatine supplementation has also proven to have some success in some individuals (Allen, 2012).

Current Treatments of CFS

The majority of treatments as outlined by "Experts in the field" do not address generation of creatine, rather are aimed at treating the symptoms. These treatments are expensive (over $50K pa) and generally useless and include

Chelation therapy,

Graded exercise therapy guided by exercise physiologists

Cognitive behavioural therapy guided by clinical psychologists

Treatment of sleep disorders - by a sleep consultant

Treatment of depression, by a clinical psychiatrist, generally with the use of SSRIs, or SNRIs or other addictive anti-depressants



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Russell-Jones, GJ 2022 Functional vitamin B12 deficiency in CFS. Int J. Psychiatry 27 Jul 2022 PDF

Russell-Jones, GJ 2022 Paradoxical vitamin B12 deficiency PDF


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