Study Confirms CFS Patients Benefit from Folate

19518Folinic acid (a derivative of Folate) was found to be effective according to a study (PDF).

Folinic acid was used at 25 mg a day for 1-2 months. Because there was already an established association between ME/CFS and Folate deficiency, this study did not look at the folate status of their participants. Nevertheless, 81% of patients reported significant improvement in pain and energy level within these one to two months.

This level of improvement is significant for CFS because CFS patients don’t respond favorably to many treatments. Furthermore, contrary to popular belief, CFS patients of a low placebo-response rate at only 19.6% after meta-analysis.

This study also showed immune problems such as marked depletion of their CD19 B-Cell mature B-cell population. This comes as no surprise as this been replicated in many other studies.

This study that I am referencing was done in 2006. Since then, according to what’s indexed in PubMed, nobody has looked at folate in ME/CFS. No, this wasn’t a huge study with a huge number of participants, but the 81% response rate should prompt further research and studies.

You may be wondering: If this data isn’t new, why am I talking about it?

This is a call to researchers. So many researchers with CFS research things that come to a dead-end. The patient community can tell you that supplementing B12 and Folate works, but you (researchers) have to listen to the clues from patients. If you listen to the clues patients have been presenting for years, you can make new discoveries.

An idea for the research community

Here is my study idea for the research community (Stanford, Harvard, Johns Hopkins, UCLA, Columbia University, UCSF, or whoever happens to be listening to this blog post).

Please do a medical study where you look at various genes such as MTHFR, MTR, MTRR. Use the methylcobalamin form of B12 with L-methylfolate (most preferable) or folinic acid. Do not use folic acid.

Look at markers such as serum and RBC folate (and compare differences), serum B12, serum methylmalonic acid (a better indicator of B12 status), homocysteine, total glutathione, reduced glutathione, and oxidized glutathione.

If patients have normal B12 and folate status, still treat them the same as the rest of the patients in the study. In other words, if levels are normal, still treat.

The treatment group may be difficult because some patients can’t handle large doses of B12 and Folate, and some patients need large doses of folate and B12. Careful study design in this regard is important. I would suggest using sublingual methyl B12 tablets instead of injections because they work just as well, and patients are likely to be more compliant. It wouldn’t be wise to use pharmaceutical doses of folate, as you will be likely to have a significant patient drop out rate. 800 mcg of Folate may be a good dose.

Also, to see if this protocol changes immune markers, assess CD19, CD56+/CD57 Natural Killer Cells along with any other immune related paramaters gathered from studies. The study should be minimum of 3-6 months (the longer the better). Re-evaluate all markers at the end of the study, and have patients assess how much improvement they experienced.

It’s very important to treat these patients whether or not they present with a B12/Folate deficiency or not.

Use strict inclusion criteria such as ICC or CCC criteria.

Finally, if this study demonstrates improvements, try using a similar study on other neurodegenerative diseases. I think a study like this could possibly be successful in Autism and on controversial patient populations such as those with chronic Lyme Disease.

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David Geffeney

Near full remission from debilitating ME/CFS first performing homemade fecal transplant (centrifuge and isolate the probiotic material, encapsulate for mid small intestine delivery due to SIBO.

Then administration of 3.25 mg 2x/days l-methylfolate. I also added methylated b12 and b6, potassium, cal-mag-zinc….recovered nicely.

Discontinued the b9 and indeed fell again. Reintroduced methyl b9 and got the expected flu like symptoms for a few days. Like a whole body and mind reset.

In short, I am now certain that Folate was an issue. I predict that absorbtion is the problem as when I have GI inflammation, I dont absorbe supplements, thus I make (ill advised I know) Injectables of these vites. Once inflammation gone, I can absorbe orally again.

Lastly, elevated homocysteine is a better test than genetic IMO.

Max Smith

I have found, and read, that the jarrows brand is really good for methylated vitamins


Can you please suggest a reliable supplement Brand for the b12 and folinic. There are so many it’s hard to know
Thanks, Amy


If 23andme no longer test certain genetic health mutations, is there a better testing company to go to?


The second sentence in your article states, “Folinic acid was used at 25 mg a day for 1-2 months.”

However, the dose in the study you are referencing is not once a day, but rather 3-4 times daily. Big difference! The study states, “Folinic acid was used at a 25mg dose level 3-4 times daily for 1-2 months”


Look at and Amy Yasko’s work. Depending on a grouping of an individuals genetic mutations – they have discovered what TYPE of B-12 works best. Individuals with COMT, VDR and CBS mutations all process methyl groups differently and there are methyl groups in methyl-b12 and methylfolate that will make these patients noticeably (and terribly) worse. They need the hydroxy or adenyl form of b-12. Methyl groups are a double edged sword – helping some and harming others.


If you have CFS you Must get a sleep study!!!


FMS and CFS are multifactoral, but can, likely in many or most cases, be cured or vastly improved by a combination of supplements targeted to genetic defects in metabolic pathways that you so graciously provide for us, addressing heavy metals such as mercury amalgam dental fillings with a biologic dentist and detoxing appropriately, and by treating hidden infections like lyme or low-grade dental/jaw infections that may not show up in blood or urine but can respond to the right antibiotics. In my case, autonomic response testing confirmed these issues, and also that I needed doxycyline monohydrate INSTEAD OF THE GENERIC I’D HAD MANY TIMES BEFORE plus zithromax. One week of the right Rx, soon after addressing metals and the right supplements, and my FMS of 20 years disappeared.


I fit the above criteriaand have the MTHFR and some MTRR’s…but folate makes me absolutely worse as does methyl-folate as is suggested for those with the defects. My folate levels on lab results are very high. Likewise, my B12 levels are normal, and nearly all B12 supplements make me worse or have no affect…all except one, hydroxy-B12, which I just cannot get enough of.

My genetic doctor says that those whith methylation issues (which I suspect that many with CFS have) will do poorly on other forms of B12 for various reasons.

By the by, there is another study showing those with Fibromyalgia have an 80% improvement rate with anti-virals.

My suspect is that most people with hard to treat chronic low-grade conditions would respond well to: 1) supplying them with the missing nutrient/s (which is not nearly as straight forward as it may seem); and 2) rx’ing anti-bacterials/virals/fungals/paracitics.

Best of luck.


I believe Dr. Rich van Konynenburg did use Folinic acid in his small study with Dr. Neil Nathan.

I do know that Dr. Rich includes folinic acid in his Simplified Methylation Protocol. He passed away last fall, but he left a wealth of articles, videos and postings on this.

My partner and I have MCS and we have benefited greatly from his research and the SMP.


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