Folic Acid, Folate, Folinic Acid, Methylfolate
How these may impact people with energy production issues
Please note the information provided in this article is not to be considered medical advice. The purpose is to provide a general overview of this topic and share my experience.
Having myalgic encephalomyelitis (ME) has led me down a lot of rabbit holes looking for treatments. Theories abound about why bodily processes have gone awry.
In my journey to manage ME, I learned about the MTHFR gene mutation that affects how the body processes folate. Through genetic testing I learned I have this gene mutation which may contribute to my health issues.
The science behind this gene mutation has been confusing. We have a lot more information than we did 20 years ago but there is still conflicting information.
What I learned led me to avoid synthetic (man made) folic acid, and aim to include foods high in folate. I think this dietary adjustment may be one reason my energy levels improved.
I have taken the supplement methylfolate, but adding that to my diet didn’t seem to make much difference. My guess is that my diet provides enough folate so the extra supplement was not needed.
Basic Facts
Folate is Vitamin B9 and is needed for healthy liver, skin, hair and eyes, and to keep the nervous system working properly.
Folate is required for breaking down homocysteine and making DNA.
Man made folic acid and natural folate are not identical substances
Folic acid is a synthetic substance (often labeled as folate) that has been mandated to be added to wheat and other grains in many countries to help prevent birth defects.
The MTHFR gene mutation changes the way the body processes synthetic folic acid.
Folinic Acid is a natural form of folate - also known as leucovorin.
The different versions of folate are not processed the same
AI ChatGPT description (April 2025):
Folic Acid – A synthetic form of vitamin B9 used in supplements and fortified foods. It requires conversion in the body to become active.
Folate – A naturally occurring form of vitamin B9 found in foods like leafy greens, legumes, and citrus fruits. It is essential for DNA synthesis and cell function.
Folinic Acid – A bioactive form of folate that does not require as much conversion as folic acid. It is often used in medical treatments, such as for folate deficiency and chemotherapy support. (See more at StatPearls Folinic Acid)
Methylfolate (5-MTHF) – The most active form of folate that is readily used by the body. It bypasses the need for conversion and is especially beneficial for individuals with MTHFR gene mutations.
Why is folic acid added to enrich grains?
Folate is vital during pregnancy to prevent neural tube defects (birth defects of the brain and spine such as spina bifida). By adding folic acid to a portion of the food supply that most people eat, it has greatly reduced the risk of these birth defects.
Where is folic acid found?
Man made folic acid is not found in nature. It is a man made substance added to enriched foods and supplements. The main foods with folic acid are enriched wheat flour as well as enriched rice and corn cereal products. Many multi-vitamins and B vitamin complexes include this synthetic folic acid.
MTHFR gene mutation
“The MTHFR gene mutation is a variation in the MTHFR gene. This gene normally tells your body how to make the MTHFR protein. You need this protein to process folate, which helps your body make DNA.”
“Folate is required to break down homocysteine, an amino acid. If you have an MTHFR gene mutation, your body may not break down folate as well as it should. This leads to increased levels of homocysteine, which potentially could cause health problems.”
Risks of taking too much synthetic Folic Acid
From NHS Website:
What happens if I take too much folic acid?
“Taking doses of folic acid higher than 1mg can mask the symptoms of vitamin B12 deficiency, which can eventually damage the nervous system if it's not spotted and treated.
This is particularly a concern for older people because it becomes more difficult to absorb vitamin B12 as you get older.”
“Even though synthetic folic acid may be more bioavailable, it is not sufficiently metabolised to form 5-methyltetrahydrofolate.
This is because its metabolism depends on the dihydrofolate reductase enzyme that becomes saturated easily beyond 200–300 μg dose of folic acid instead of converting to dihydrofolate or tetrahydrofolate.
Hence, intact folic acid accumulates in the serum. This increase in amount may inhibit the formation and reuptake of 5-methyltetrahydrofolate.”
Folic acid buildup
I have come across information about folic acid buildup. This possibility is concerning since so much of the American diet is fortified with synthetic folic acid.
A person who eats wheat products and fortified cereal along with vitamin supplements may not realize how much folic acid they are ingesting.
The article, Do MTHFR Mutations Cause Folic Acid Build Up? offers some insight. It states:
“A buildup of unmetabolized folic acid (UMFA) in the blood may lead to a range of health concerns. It may also worsen the symptoms of an MTHFR mutation.
Studies in mice have shown that high doses of folic acid can cause some patients to develop a “pseudo MTHFR”3 syndrome, in which elevated unmetabolized folic acid leads to higher levels of homocysteine.
High blood concentrations of folic acid may decrease the toxicity of natural killer cells4 .
However, when folic acid cannot be converted to its usable form, methylation cannot happen2 . Worse still, the presence of an MTHFR SNP means the unmetabolized synthetic folic acid accumulates and can actually become hazardous.”
The information that high blood concentrations of folic acid may decrease the toxicity of natural killer (NK) cells is very concerning considering that low NK cell function is a known symptom in myalgic encephalomyelitis.
Unmetabolized Folic Acid in Plasma Is Associated with Reduced Natural Killer Cell Cytotoxicity among Postmenopausal Women from 2006 states:
“Our data showing that unmetabolized FA [folic acid] in plasma is associated with decreased NK [natural killer] cytotoxicity are a cause for concern. This association with FA was independent of circulating 5-methyl-THF and total folate.”
Which countries mandate folic acid added to food supply?
US - FDA Website
New Zealand - Science Media Centre
UK - UK.gov (coming end of 2026)
Australia - Food standards Australia/New Zealand
Canada - Science Direct
Many other countries don’t mandate it, but it looks like some producers add folic acid in their products anyway.
Individual states may also mandate food fortification. A recent article, Georgia Senate considers mandatory folic acid fortification for corn products, from March 2025 discusses the state of Georgia considering mandating folic acid be added to corn products.
“The committee heard compelling testimony highlighting the ease with which manufacturers can incorporate essential nutrients like folic acid into corn products, a process that is already in practice for wheat flour.”
Foods with natural folate
List taken from Cleveland Clinic website:
Beans and peas, including black-eyed peas, lentils, chickpeas and kidney beans.
Beef and chicken liver.
Dark, leafy green vegetables, such as spinach, asparagus, Brussels sprouts and beets.
Fruit (and fruit juice), including avocados, tomato juice, oranges and orange juice, and melons.
Nuts, such as walnuts and peanuts.
Eggs and dairy.
Seafood, including dungeness crab and halibut.
Meat and poultry, including chicken.
Folic acid and autism
Synthetic folic acid has been implicated in making autism symptoms worse. From The Autism Community in Action:
“Should I supplement folic acid?
No. Folic acid use is not advised. Folic acid is the oxidized form of folate. It can block folate receptors in some kids, making problems worse.”
I am including information about autism, as there are some overlapping neurological symptoms that indicate ME and autism may have similar biological abnormalities.
Conclusion
The following conclusion from The hazards of excessive folic acid intake in MTHFR gene mutation carriers: An obstetric and gynecological perspective sums up my understanding:
“Folic acid should no longer be considered a “one-size-fits-all” supplement.
More ingestion of leafy greens like kale, spinach, arugula and swiss chard that provide natural folate forms, including 5-methyl-THF, should be encouraged, while synthetic forms in vitamins and starch additives should be monitored.
This is especially important in those carrying the MTHFR SNPs.
In these patients, it is imperative to use the active 5-methyl-THF derivative, in a dosage of 600-800mcg QD, to bypass the mutated enzyme and receive the complete benefits of folic acid.
Therefore, the replacement of folic acid with 5-methyl-THF in prenatal vitamins should be strongly considered as universally beneficial.”
Managing Myalgic Encephalomyelitis
My lifestyle is severely limited because of ME, but I have been able to maintain a baseline that allows me to get dressed daily, write these articles, as well as leave the house once a week for IV fluids.
My fatigue issues are significantly reduced compared to the earlier years of having ME, but I am still severely restricted by post-exertional neuroimmune exhaustion.
This stable baseline may, or may not, have to do with avoiding folic acid. I am doing a variety of things to boost my energy production. My article, ME - Management & Treatment, discusses why I think antioxidants are also an important part of improving my energy production.
While the issue of folic acid may apply to only a subset of patients, it is worth noting that the experts who wrote the IC Primer for Myalgic Encephalomyelitis state that some diet changes have been known to help patients improve quality of life. Page 14 of the IC Primer offers dietary guidance that coincides with reducing products that have the folic acid additive:
…“Sensitivities/intolerance to gluten, milk & dairy, and eggs are common. Do elimination trials as indicated.
Reduce refined foods: e.g. white sugar & flour….”
As with everything to do with ME, this is a complicated topic. There is more to understand about how folic acid/folate affect our B12 levels. I have not included that aspect in this article. You can find more information in the links provided in this article and in the Extra Links section below.
I hope this has been helpful. When it comes to managing ME, knowledge is power.
Aiming for a better future…
Colleen
Information provided here or in comments is not to be considered medical advice.
Sources
Gristan YD, Patel P, Moosavi L. Folinic Acid. [Updated 2024 Feb 28]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2025 Jan-. Available from: https://www.ncbi.nlm.nih.gov/books/NBK545232/
Tafuri L, Servy EJ, Menezo YJ (2018) The hazards of excessive folic acid intake in MTHFR gene mutation carriers: An obstetric and gynecological perspective. Clin Obstet Gynecol Reprod Med 4: doi: 10.15761/COGRM.1000215 https://www.oatext.com/the-hazards-of-excessive-folic-acid-intake-in-mthfr-gene-mutation-carriers-an-obstetric-and-gynecological-perspective.php#Article
Troen AM, Mitchell B, Sorensen B, Wener MH, Johnston A, Wood B, Selhub J, McTiernan A, Yasui Y, Oral E, Potter JD, Ulrich CM. Unmetabolized folic acid in plasma is associated with reduced natural killer cell cytotoxicity among postmenopausal women. J Nutr. 2006 Jan;136(1):189-94. doi: 10.1093/jn/136.1.189. PMID: 16365081 https://pubmed.ncbi.nlm.nih.gov/16365081/
The hazards of excessive folic acid intake in MTHFR gene mutation carriers: An obstetric and gynecological perspective Laura Tafuri1 *, Edouard J Servy1 and Yves J R Menezo2 1 The Servy Massey Institute, 812 Chafee Ave, Augusta, GA, USA 2 Laboratoire Clement, Paris, France and London Fertility associates, Harley St, London UK https://www.oatext.com/pdf/COGRM-4-215.pdf
Extra links
Video explanation about MTHFR gene mutation by a chiropractic doctor. I don’t know enough about this doctor to endorse him or the products he mentions. MTHFR MUTATIONS: DO THIS NOW #161 | https://drstephenstokes.com
Wien TN, Pike E, Wisløff T, Staff A, Smeland S, Klemp M. Cancer risk with folic acid supplements: a systematic review and meta-analysis. BMJ Open. 2012 Jan 12;2(1):e000653. doi: 10.1136/bmjopen-2011-000653. PMID: 22240654; PMCID: PMC3278486.
“Prostate cancer was the only cancer type found to be increased after folic acid supplementation (meta-analyses of six RCTs). Prospective studies of cancer development in populations where food is fortified with folic acid could indicate whether fortification similar to supplementation moderately increases prostate cancer risk.”
Carboni L. Active Folate Versus Folic Acid: The Role of 5-MTHF (Methylfolate) in Human Health. Integr Med (Encinitas). 2022 Jul;21(3):36-41. PMID: 35999905; PMCID: PMC9380836.
“Testing every pregnant woman for the existence of a mutated MTHFR gene isn’t a standard medical protocol, but women expressing MTHFR polymorphism may not experience the perceived advantage of FA supplementation and can be at potential risk because they are less able to transform FA.”
Frye RE, Slattery J, Delhey L, Furgerson B, Strickland T, Tippett M, Sailey A, Wynne R, Rose S, Melnyk S, Jill James S, Sequeira JM, Quadros EV. Folinic acid improves verbal communication in children with autism and language impairment: a randomized double-blind placebo-controlled trial. Mol Psychiatry. 2018 Feb;23(2):247-256. doi: 10.1038/mp.2016.168. Epub 2016 Oct 18. PMID: 27752075; PMCID: PMC5794882.
“Thus, in this small trial of children with non-syndromic ASD and language impairment, treatment with high-dose folinic acid for 12 weeks resulted in improvement in verbal communication as compared with placebo, particularly in those participants who were positive for FRAAs.”
Christensen KE, Faquette ML, Leclerc D, Keser V, Luan Y, Bennett-Firmin JL, Malysheva OV, Reagan AM, Howell GR, Caudill MA, Bottiglieri T, Rozen R. Folic Acid and Methyltetrahydrofolate Supplementation in the Mthfr677C>T Mouse Model with Hepatic Steatosis. Nutrients. 2024 Dec 28;17(1):82. doi: 10.3390/nu17010082. PMID: 39796516; PMCID: PMC11723006.
“MethylTHF and folic acid supplementation had limited benefits for TT mice, while folic acid supplementation had negative effects on CC females. Further investigation is required to determine if these effects are relevant in humans.”
Fardous AM, Heydari AR. Uncovering the Hidden Dangers and Molecular Mechanisms of Excess Folate: A Narrative Review. Nutrients. 2023 Nov 6;15(21):4699. doi: 10.3390/nu15214699. PMID: 37960352; PMCID: PMC10648405.
“Given the widespread folic acid supplementation, it is imperative to further research its optimal intake levels and the molecular pathways impacted by its excessive intake, ensuring the health and well-being of the global population.”
Thank you for great information once again!
Interesting article thank you. I wondered if Methylfolate is only naturally occurring or can be synthesised / man made? If it could, would it be better to subtract that for food production than Folic acid? I understand there are other issues but is it possible? I’m guessing it’s much more costly or something 🤔.