Humans have a much lower capacity to metabolize folic acid (FA) than other animals in nature, and are affected by dihydrofolate reductase (DHF), which is only 1/56th of the capacity of rats and much lower than other mammals in nature, making it difficult to obtain sufficient folic acid from the synthetic folic acid route.

The activity of the enzyme 5,10-methylenetetrahydrofolate reductase varies between ethnic groups, regions and ages, resulting in differences in the ability to metabolise folate, and CT and TT groups have low enzyme activity and are unable to fully metabolise ingested folic acid (FA) into live 5-methyltetrahydrofolate, which is truly useful, resulting in widespread folate deficiency in humans.