Folic acid is the form of folate used in food fortification and many supplements. It’s synthetic and different to the natural forms of folate in food.
The folates found in food are used in the body as coenzymes and regulatory molecules. The most bioactive form of folate is methylfolate which issued for methylation processes.
Evidence suggests that the consumption of folic acid can be harmful and can’t fix a folate deficiency due to an MTHFR mutation.
Folic Acid Inhibits Folate Receptors
Folate receptors have a high affinity for folic acid. This means that the folate receptors will bind to folic acid over natural folates causing a reduction in methylfolate available for methylation.
Folic Acid blocks the uptake of methylfolate to the brain
Methylfolate is the only form of folate that crosses the blood brain barrier where it’s used for the formation of important neurotransmitters for mood including dopamine and serotonin.
Folic acid blocks the uptake of methylfolate into the brain via inhibition of folate receptors.
Folic Acid Inhibits DHFR enzyme
Folic acid has no beneficial physiological effect on the body until it’s converted into dihydrofolate and tetrahydrofolate via the DHFR enzyme.
Research indicates that the DHFR enzyme can only convert 200mcg of folic acid into dihydrofolate. Since folic acid is found in supplements, fortified wheat products and many commercial breakfast cereals it’s not difficult to be consuming 200mcg of folic acid per day.
The net result of this is a build up of unmetabolised folic acid and a reduction in the amount of folate available to make methylfolate as the DHFR enzyme also converts folate from food into tetrahydrofolate which will then be converted into methylfolate via MTHFR.
Unmetabolised folic acid disrupts immune function
When folic acid can’t be converted into dihydrofoalte via DHFR it builds up in the blood as unmetabolised folic acid.
Umetabolised folic acid has been shown to cause immune dysfunction including a reduction in Natural Killer cell activity. Natural Killer cells are important in fighting viral infections and can also kill cancer cells.
Unmetabolised folic acid, cognitive impairment and anaemia
Population studies in the USA of elderly people with high levels of unmetabolised folic acid and low vitamin B12 status have a higher risk of cognitive impairment than those with normal folate status.
They also have a higher risk of “folate or B12” deficiency anaemia which causes the body to produce abnormally large red blood cells that don’t function properly.
Folic acid causes Pseudo MTHFR deficiency
A recent case report of a pregnant woman in the USA with infertility issues was tested for MTHFR and homocysteine. Her results were wild type (ie no mutation) on MTHFR and her homocysteine was high at 17.2 umol/L. Homocysteine at this level is higher than expected for someone with no mutation on MTHFR.
Questioning of this patient identified she had been taking 5mg of folic acid per day. Her high homocysteine level indicates she has unmetabolised folic acid which is blocking the uptake of her natural folates via a reduction in folate receptor and DHFR activity. The net result of this is high homocysteine.
High homocysteine is an infertility and miscarriage risk factor in both women and men.
What this suggests is that by simply consuming too much folic acid, you will have a reduction in the functioning of MTHFR whether you have a gene mutation or not. If however, you do have an MTHFR mutation, this effect could be even more problematic.
What about MTHFR and methylfolate?
Folic acid should be avoided in those with MTHFR gene mutation as it requires numerous genes, enzymes and cofactors to be converted into methylfolate. It’s therefore unlikely to fix the methylfolate deficiency in those with MTHFR.
Methylfolate will provide the bioavailable form of folate that is required for methylation processes and overrides a genetic mutation on MTHFR.
Bailey SW et al 2009 ‘The extremely slow and variable activity of dihydrofolate reductase in human liver and its implications for high folic acid intake’, Proceedings of the National Academy of Sciences of the USA, vol. 106, no.36, pp 15424-15429.
Clovis P et al 2017, ‘A daily dose of 5 mg of folic acid for 90 days is associated with increased serum unmetabolized folic acid and reduced natural killer cell cytotoxicity in healthy Brazilian adults’, Journal of Nutrition, vol 147, no.9, pp.1677-1685.
Cornet D et al 2019, ‘High doses of folic acid induce a pseudo-methylenetetrahydrofolate syndrome’, SAGE Open Medical Case Reports, Vol 7, pp 1-4.
Smith DA et al, 2008 ‘Is folic acid good for everyone?, American Journal of Clinical Nutrition, vol. 87, pp. 517-533.
Troen AM et al 2006, Unmetabolized folic acid in plasma is associated with reduced natural killer cell cytotoxicity among postmenopausal women’, The Journal of Nutrition, vol. 136, no. 1, pp189-194.