After discovering some new facts on B12, I noticed that folate was often cited in the same articles. As with B12 — there are two versions, just like B12:

• methylfolate
• folate

There is no harm in taking methylfolate, but if you have the TT MTHFR genotype then plain folate will have little impact.

• “We assayed serum folate levels of 60 patients with chronic fatigue syndrome (CFS) and found that 50% had values below 3.0 micrograms/l. Some patients with CFS are deficient in folic acid.” [1993]
  • “Our findings indicated that the average serum folate concentration in IBD patients was significantly lower than that in control patients, whereas the mean serum vitamin B12 concentration did not differ between IBD patients and controls. ” [2017]
• Response to vitamin B12 and folic acid in myalgic encephalomyelitis and fibromyalgia[2015].
  • “. In ME patients, hypomethylation is seen in a majority of certain immune cells [1] and of DNA in genes associated with immune cell regulation [2]. Although the reason for such hypomethylation can only be speculated upon, for the time being, it is interesting that the combined action of the vitamins B12 and folate (Fig 1) play a fundamental role in providing methyl groups to hundreds of substrates in various elementary cell processes. ”
    • A common genetic variant affecting folate metabolism is not over-represented in chronic fatigue syndrome [1997].
  • ” Good responders (6.7±6.6 mg per day) and Mild responders (1.9±2.0 mg per day). ” –> 6.7+6.6 = 13.3 mg  or 13,000 mcg
• Vitamin D deficiency changes the intestinal microbiome reducing B vitamin production in the gut. The resulting lack of pantothenic acid adversely affects the immune system, producing a “pro-inflammatory” state associated with atherosclerosis and autoimmunity.[2016]
  • “Vitamin D blood levels of 60-80ng/ml promote normal sleep. ” – bad sleep patterns may be an indicator of low Vitamin D levels.
  • “These results suggest that the combination of vitamin D plus B100 creates an intestinal environment that favors the return of the four specific species, Actinobacteria, Bacteroidetes, Firmicutes and Proteobacteria that make up the normal human microbiome.”

B12 / Folate Balance

The issue arises when B12 levels are low… from [2007] review: “Simply put, if your vitamin B-12 status is good, folate supplementation is good for you!”

• “Those with a low vitamin B-12 status (serum cobalamin <148 pmol/L) and high serum folate (>59 nmol/L) had an odds ratio for cognitive impairment of 5  [times higher] compared with those whose vitamin B-12 status and folate status were both normal. “
• ” In agreement with current knowledge, they found that a low vitamin B-12 status is associated with macrocytosis, anemia, and cognitive impairment. “
• “The “good news” is that, in subjects with a normal vitamin B-12 status, high serum folate (>59 nmol/L) was associated with protection from cognitive impairment. This finding is remarkable in a population with a much higher mean folate concentration (39 nmol/L) than that seen in countries where there is no mandatory folate fortification. “

Bottom Line

For methylfolate, a dosage between 6,000 mcg and 13,000 mcg have been tried with good results. Unlike Vitamin B12 (cost around $.06/day), looking at Amazon we are looking at a cost of $130+/day. With some brands, the capsules are just 400 mcg which means 15 –> 30 capsules per day. There is one brand that sells in 15mg (15,000 mcg) at $39.00 for a 30 day supply – that’s just one capsule per day.

• A remarkable 81% of CFS patients experienced subjective improvement of their symptoms after treatment with folinic acid” [2006] [Full Text] “Folinic acid should be distinguished from folic acid (vitamin B₉). However, folinic acid is a vitamer for folic acid, and has the full vitamin activity of this vitamin. ” [wikipedia]
• NOTE: folinic acid dosage is much smaller that folate (folic acid) because it is bioactive.

Additionally, adequate Vitamin D3 supplementation (likely 15,000 IU/day for many) may be needed to restore natural B-vitamin production

My gut feeling is that 95% of CFS patients are taking less than the level required for a mild responder.

WARNING: Some people can respond with severe anxiety, see this external post.