Folate, vitamin B12, one carbon metabolism and the nervous system: Excess folic acid is potentially harmful

Folate, vitamin B12 and one carbon metabolism are fundamental to genetics and epigenetics, and to nervous system development and brain health at all ages. The neuropsychiatric complications of deficiency or inborn errors of folate and vitamin B12 are well documented but there has been controversy about whether excess folic acid is also harmful to the nervous system, especially in the presence of vitamin B12 deficiency. There is now substantial and consistent clinical, epidemiological and experimental evidence that excess folic acid is potentially harmful to the nervous system. Recent experimental evidence confirms that both folate deficiency and excess impair cortical neurogenesis and is greatest when vitamin B12 deficiency is combined with excess folic acid. Excess folic acid increases the demand for vitamin B12 and aggravates the block in the folate cycle resulting from vitamin B12 deficiency. The balance between folate and vitamin B12 is crucial to methylation and to genetics and epigenetics. Both folate deficiency and excess may impair cellular differentiation and nervous system development by hypomethylation or hypermethylation of genes. In countries with folic acid fortification policies many subjects are exposed to excess folate. The long term genetic, epigenetic and transgenerational implications are yet to be clarified. The safe UL of folic acid should be reconsidered in relation to the vitamin B12 status of individuals and populations. The combination of a natural folate together with vitamin B12 would greatly improve the benefits and reduce the harms of current fortification policies.