Natural Folate vs Synthetic Folic Acid

The form of folate that is used in food fortification and most dietary supplements is a synthetic form; pteroylmonoglutamate. In supplements and fortification it is commonly called simply ‘folic acid‘ and in common usage the terms ‘folate‘ and ‘folic acid‘ are considered interchangeable. However, there are important differences between naturally occurring and synthetic forms of folate. This article explains some of those differences.

Folate in any form is not used directly within the body. It is metabolised to an active co-enzyme, tetrahydrafolate (tetrahydrafolic acid).

Pteroylmonoglutamate (synthetic folic acid) differs from the naturally occurring forms of folate in the diet because it is in an oxidised state and contains only one conjugated glutamate residue. Interestingly, it has much greater bioavailability than the natural folates and is rapidly absorbed across the intestine. This may lead to high amounts of unmetabolised folic acid in the blood stream[1]. Supplementation and fortification of foods[2] is likely to cause increases in blood levels of synthetic folic acid. Synthetic folates when overloaded into the blood in this fashion could interfere with the metabolism, cellular transport and regulatory functions of the natural folates that occur in the body by competing with them binding with enzymes, carrier proteins and binding proteins.“[3]

The folate receptor has a higher affinity for synthetic folic acid than for methyl-THF (the main natural form of folate that occurs in the blood.) This may result in:

• Reduced levels of active folates for use as co-enzymes in brain function
• Down-regulation of folate receptors[4]
• Change in gene expression of folate dependent enzymes

There also is considered to be a risk of liver capacity saturation with high dose folic acid supplementation, leading to higher levels of unmetabolised folic acid entering the general circulatory system. This would compound the potential negative effects mentioned above[5] and may have direct effects on other functions such as immunity[6], and although high folate diets are considered to reduce risk of cancer, high intakes of supplemental folic acid may actually increase carcinogenesis[7]. In fact, many cancer drugs are anti-folates due to their ability to inhibit the growth of rapidly dividing cell types found in tumours.

Is natural folate supplementation justified?

The benefit of folate supplementation in reducing neural tube defects is undeniable and the vital role of folate for overall health is clear. However, the potential risks associated with synthetic folic acid make natural folates a more prudent supplemental choice.

Natural folate supplements using L-5-methyl-THF may also reduce the effects of Vitamin B12 deficiency masking (folic acid taken in large doses can mask the effects of a B12 deficiency so that it often remains undiagnosed for a longer time, resulting in neural damage) and may reduce interactions with drugs that inhibit dihydrofolate reductase[8].

Recent research has shown that the actual amount of folate in foods may be approximately 25% lower than what was previously thought[9], and so supplementation of a natural form of folate may be warranted for many, especially those that are not eating the recommended 6+ servings of vegetables per day, pregnant and breastfeeding women and active or highly stressed individuals.

References

1 Ashokkumar, B., Mohammed, Z. M., Vaziri, N. D., & Said, H. M. (2007). Effect of folate oversupplementation on folate uptake by human intestinal and renal epithelial cells. The American journal of clinical nutrition, 86(1), 159-166.

2 Kelly, P., McPartlin, J., Goggins, M., Weir, D. G., & Scott, J. M. (1997). Unmetabolized folic acid in serum: acute studies in subjects consuming fortified food and supplements. The American journal of clinical nutrition, 65(6), 1790-1795.

3 Smith, A. D., Kim, Y. I., & Refsum, H. (2008). Is folic acid good for everyone?.The American journal of clinical nutrition, 87(3), 517-533.

[5] Wright, A. J., Dainty, J. R., & Finglas, P. M. (2007). Folic acid metabolism in human subjects revisited: potential implications for proposed mandatory folic acid fortification in the UK. British Journal of Nutrition, 98(4), 667-675.

[6] Troen, A. M., Mitchell, B., Sorensen, B., Wener, M. H., Johnston, A., Wood, B., ... & Ulrich, C. M. (2006). Unmetabolized folic acid in plasma is associated with reduced natural killer cell cytotoxicity among postmenopausal women. The Journal of nutrition, 136(1), 189-194.

[7] Ulrich, C. M., & Potter, J. D. (2006). Folate supplementation: too much of a good thing?. Cancer Epidemiology Biomarkers & Prevention, 15(2), 189-193.

[8] Pietrzik, K., Bailey, L., & Shane, B. (2010). Folic acid and L-5-methyltetrahydrofolate. Clin Pharmacokinet, 49(8), 535-548.

[9] Konings, E. J., Roomans, H. H., Dorant, E., Goldbohm, R. A., Saris, W. H., & van den Brandt, P. A. (2001). Folate intake of the Dutch population according to newly established liquid chromatography data for foods. The American journal of clinical nutrition, 73(4), 765-776.