Fortification, folate and vitamin B12 balance, and the nervous system. Is folic acid excess potentially harmful?

The benefits of folic acid fortification are well known but less understood or acknowledged is the growing evidence of potential harms to the nervous system from excess folate, primarily because of a combination of fortification and/or high and sustained intake of folic acid supplements. We have summarised the historical, clinical, epidemiological and experimental evidence accumulated over the last 60 years in the pre and postfortification eras, which consistently and substantially suggests that excess folate, in particular in folic acid users, can have direct harms to the nervous system, especially in the presence of vitamin B12 deficiency. The harms are related both to the dose and duration of exposure to excess folic acid. Recent experimental evidence suggests that impaired cortical neurogenesis with excess folic acid is similar to that of folate or vitamin B12 deficiency and greatest when folate excess is present with vitamin B12 deficiency. Excess folate leads to a fall in vitamin B12 levels and aggravation of the block in folate metabolism resulting from vitamin B12 deficiency. The balance between folate and vitamin B12 is crucial to the functioning of one carbon metabolic pathways, the methylation cycle and ultimately to DNA and RNA structure and function, genetic and epigenetic stability. Vitamin B12 deficiency is an independent risk factor for NTDs and accounts for the increased risk of NTDs in some countries where B12 deficiency is more common than folate deficiency. A more prudent and balanced approach to fortification with folic acid, or preferably a natural reduced folate, combined with vitamin B12 would potentially improve the benefits and reduce the harms, including epigenetic and transgenerational risks, associated with current public health policies.