2. Impaired Folate-Methylation Cycle

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Impaired methylation is linked to many unpleasant symptoms, neuroimmune disease, pyrroles and environmental illness, and ill health related to ageing and MTHR gene mutations.

Methylation is a biochemical process used throughout your body like a little light switches for turning on repairing DNA, producing energy, regulating hormones, detoxification, synthesizing neurotransmitters, and more. Most people methylate properly but if your folate/Methylation Cycle is not working properly  you’re going to feel it.

Some people are overmethylators, while some are undermethylators – treatments for each are different as discussed in the Pfeiffer Protocol.

In the Pfeiffer Protocol typically used for ASD, (but most likely also useful for other Neuroimmune Diseases / Environmental Illness like CFS, MCS, GWS),  supplements are used to address methylation problems,  after an initial period of time on a primer  formula. 

These are the key nutritional players in the methylation system:

  • Methionine is an amino acid found in all proteins, but which is especially rich in animal products. After being activated using ATP, the fundamental energy currency of the cell, methionine becomes the universal methyl donor.Once activated methionine donates its methyl group, it becomes homocysteine. Homocysteine needs to be recycled back to methionine so methylation can continue, and homocysteine itself is thought to be harmful by contributing to cardiovascular disease.
  • Vitamin B12 and folate (vitamin B9) recycle homocysteine back to methionine. They take the methyl group from the metabolism of amino acids that we get from dietary protein.
  • Alternatively, betaine (trimethylglycine, TMG), which is mainly derived from choline, recycles homocysteine back to methionine.
  • Several other B vitamins, mainly thiamin (vitaminB1), riboflavin (vitamin B2), niacin (vitamin B3), and pyridoxine (vitamin B6), support B12 and folate in recycling methionine, even though they themselves are not methyl donors.
  • Glycine is our buffer for excess methyl groups.
  • Choline – while most important in methylation are folate, B12, and B6, Choline can be thought of as a partner in the process. (R)
  • A number of minerals are needed to support the enzymes involved in this system: ironphosphorus, sulfur, magnesium, potassium, zinc, and possibly cobaltVitamin A is also needed to produce the enzyme involved in using glycine as a methyl buffer.


If methylation is low (undermethylation), a person will typically experience high levels of histamine in the body, which can cause a wide range of allergic like (Pseudo allergic) reactions to certain medicines (e.g. NSAIDS, cox 2 inhibitor), foods high in histamine, and environmental stressors e.g. temperature, pollutants, smells.  Reducing intakes of foods high in histamine or amines, addressing gut and other chronic infections, and doing the basics to address psychological and lifestyle stress can help with this aspect.

Often people with methylation problems are advised to follow gluten free, grain free, low sugar, yeast free and low carb diets like SIBO, SCD, fodmaps, GAPS, Paleo, Keto. While some people respond very well to these diets, they can worsen symptoms in others. Most likely those experiencing very high histamine levels (histaminosis) – pseudo allergy, or poor sulfation / Fatty acid metabolism impairment PGE1, AA-Eiconasoids – Omega 6 – e.g. Salicylate sensitivity, Pyrrole Disease  and drug resistant depression.  Diets that may help with this include a reduced salicylate and oxalate diet or the RPAH allergy unit (salicylate, amine and glutamate) elimination diet.

Everyone has different issues that impact methylation, so treating it needs to be customised to the individual with the help of a skilled practitioner trained in orthomolecular, integrative, NEM or bio medice or functional medicine. 



Undermethylation is typically addressed with the use of Supplements and also dietary change.

*Note if you have Pyrrole Disorder you should treat this before treating  Methylation problems (R), and you may find the Pfieffer protocol beneficial. Note some people with pyrrole are over methylators rather than undermethylators! this is linked to low histamine


(1) https://www.jillcarnahan.com/2018/07/05/is-undermethylation-keeping-you-down-what-you-can-do/

(1) http://autismcoach.com/the-glutathione-sulfation-methylation-pathway/


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