Folic Acid

Folic acid is the chemically synthesized form of folate or vitamin B9. In humans, folates are converted to tetrahydrofolic acid, which is the active form.

folicacid and tetrahydrofolate

Folate deficiency has been implicated to have a wide variety of health effects. In particular, normal development during gestation, heart disease, stroke, cancer, and depression have all been linked to folic acid levels in the body. Folate is an essential vitamin, and can be found in many leafy-green vegetables. In the US, it is mandatory for cereal grains to be "fortified", or supplemented with folic acid, at a level of 140 micrograms of folic acid per 100 grams of grain.

Molecular and Cellular Roles of Folic Acid

Folic acid is responsible for the molecular process of methylation, whereby a -CH3 chemical moiety is added to molecules. Folic acid has also been shown to reduce oxidative stress by reacting with free radicals and this effect translates to human studies, wherein folic acid supplementation has been shown to reverse oxidative DNA damage due to arsenic in the water supply.1,2At a cellular level, folic acid is neuroprotective, as deficiency is associated with high incidence of lead poisoning in children. This causal relationship was recently confirmed by experiments with rats.3,4

Overall, folic acid plays a crucial role in the ubiquitous process of methylation and has been shown to be protective, particularly, in the face of oxidative stressors.

Cognitive Effects

Low blood folic acid levels are associated with poor cognitive performance, especially during age-related cognitive decline.5However, the results of randomized control trials investigating folic acid supplementation have been mixed. Early results have suggested supplementation may be beneficial for healthy adults, while more recent meta-analyses have largely been negative.

In a randomized control trial published in 2007, 818 participants were randomly assigned to either folic acid or 800 micrograms of daily folic acid for three years. The folic acid group demonstrated significantly improved performance on memory scores, information processing speed, and sensorimotor speed, as compared to placebo.6In a 2010 meta-analysis of 9 placebo-controlled trials, comprising 2835 participants, folic acid was not found to improve cognitive function. In a 2012 meta-analysis of 19 studies, it was found that folic acid supplementation does not influence cognitive function in healthy individuals or individuals with cognitive impairment.7In a third meta-analysis, of 11 placebo-controlled trials and 22,000 individuals, it was found that folic acid supplementation did not significantly impact cognitive function.8

Our recommendation

Based on the multitude of individual trials and the results of many meta-analyses, we do not recommend folic acid supplementation to improve cognitive function in most healthy adults. However, if folic acid levels are below normal then supplementation to reach normal levels should be undertaken. Normal plasma concentration of folate in adults is 2-20 ng/ml, in children is 5-21 ng/ml, and in infants is 14-51 ng/ml.

  1. Joshi, R., Adhikari, S., Patro, B., Chattopadhyay, S., & Mukherjee, T. (2001). Free radical scavenging behavior of folic acid: evidence for possible antioxidant activity. Free Radical Biology and Medicine, 30(12), 1390-1399.

  2. Guo, X., Cui, H., Zhang, H., Guan, X., Zhang, Z., Jia, C., . . . Mao, G. (2015). Protective Effect of Folic Acid on Oxidative DNA Damage: A Randomized, Double-Blind, and Placebo Controlled Clinical Trial. Medicine (Baltimore), 94(45), e1872. doi:10.1097/md.0000000000001872

  3. Solon, O., Riddell, T. J., Quimbo, S. A., Butrick, E., Aylward, G. P., Lou Bacate, M., & Peabody, J. W. (2008). Associations between cognitive function, blood lead concentration, and nutrition among children in the central Philippines. J Pediatr, 152(2), 237-243. doi:10.1016/j.jpeds.2007.09.008

  4. Quan, F. S., Yu, X. F., Gao, Y., & Ren, W. Z. (2015). Protective effects of folic acid against central nervous system neurotoxicity induced by lead exposure in rat pups. Genet Mol Res, 14(4), 12466-12471. doi:10.4238/2015.October.16.13

  5. Michelakos, T., Kousoulis, A. A., Katsiardanis, K., Dessypris, N., Anastasiou, A., Katsiardani, K. P., . . . Petridou, E. T. (2013). Serum folate and B12 levels in association with cognitive impairment among seniors: results from the VELESTINO study in Greece and meta-analysis. J Aging Health, 25(4), 589-616. doi:10.1177/0898264313482488

  6. Durga, J., van Boxtel, M. P., Schouten, E. G., Kok, F. J., Jolles, J., Katan, M. B., & Verhoef, P. (2007). Effect of 3-year folic acid supplementation on cognitive function in older adults in the FACIT trial: a randomised, double blind, controlled trial. The Lancet, 369(9557), 208-216.

  7. Ford, A. H., & Almeida, O. P. (2012). Effect of homocysteine lowering treatment on cognitive function: a systematic review and meta-analysis of randomized controlled trials. J Alzheimers Dis, 29(1), 133-149. doi:10.3233/jad-2012-111739

  8. McCaddon, A., & Miller, J. W. (2015). Assessing the association between homocysteine and cognition: reflections on Bradford Hill, meta-analyses, and causality. Nutr Rev, 73(10), 723-735. doi:10.1093/nutrit/nuv022

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