Folate (vitamin B9) is an essential water-soluble nutrient naturally found in food. Because the body cannot synthesize folate and stores it only in limited amounts, a deficiency can develop within weeks to months on a low-folate diet. Inadequate folate impairs cell division, disrupts methylation processes vital for gene regulation, and leads to the buildup of toxic metabolites, making consistent dietary intake essential.
Understanding the Key Differences Between Folate & Folic Acid
Among all the research I’ve done on the biochemical differences between folate and folic acid, this stands out as the clearest and most accurate representation of their distinct forms –
“The bioavailability and metabolism of the different folate forms vary due to their respective chemical structures. All forms of folates, natural or synthetic, must be converted to the circulating form 5-MTHF to exert their biological activity. The structurally related compounds included in the folate group are FA, natural folates, and 5-MTHF.
Folic Acid
Folic acid is the oxidized, monoglutamate precursor form of folate that was synthesized in pure crystalline form for the first time in the 1940s. Many dietary supplements include it as do fortified foods, such as cereal-based products, pasta, enriched bread, and fruit juice. Folic acid doesn’t occur in nature and has no biological functions. To be utilized, the human body must metabolize and reduce it to 5-MTHF using a multistep enzymatic conversion.
Natural folates
Natural folates occur in foods and also exist in many chemical forms of polyglutamate. Food folates are hydrolyzed to the monoglutamate form in the gut before absorption by active transport across the intestinal mucosa. Therefore, before entering the bloodstream, the monoglutamate form is reduced to tetrahydrofolate (THF) and converted into methyl forms (5-MTHF).
5-MTHF
The biologically active form 5-MTHF, the predominant physiological form of folate found in blood and in umbilical cord blood, is also available in small amounts in foods. It’s widely available as a food ingredient and doesn’t require metabolization.”
-Active Folate Versus Folic Acid: The Role of 5-MTHF (Methylfolate) in Human Health, Lorena Carboni
Folate & Pregnancy
Folate is essential for both men and women throughout life, but its importance is especially heightened during early human development. During pregnancy—particularly in the first trimester—folate needs increase significantly to support rapid cell division and the growth of fetal, placental, and maternal tissues. This is due to its critical role in DNA, RNA, and protein synthesis. Maintaining adequate folate levels during pregnancy is vital for both maternal and fetal health, as folate deficiency has been linked to several adverse outcomes, including neural tube defects (NTDs), neural crest disorders (such as congenital heart defects), fetal growth restriction, low birth weight, preterm delivery, and neonatal folate deficiency.
MTHFR – The Perfect Storm
Since the late 1990s, folic acid fortification in numerous foods began in many developed countries after strong evidence showed it significantly reduces neural tube defects (NTDs). Today, people commonly consume folates in three forms: natural folate from food, synthetic folic acid from fortified food products, and supplementation. As a result, circulating levels of total folate—particularly unmetabolized folic acid—have risen to levels likely unprecedented in human history.
MTHFR is a key enzyme in methylation, a process essential for regulating gene expression and detoxification. Impaired methylation has been associated with a wide range of health concerns, including birth defects, fatty liver disease, cardiovascular problems, mood disorders, poor recovery, and possibly cancer. These MTHFR variants are extremely common—most people carry at least one.
For individuals with MTHFR gene variants, such as C677T and A1298C, the ability to convert folic acid into its active form is significantly reduced. This can lead to unmetabolized folic acid build up in the bloodstream, a pattern that more recent research has linked to potential health risks.
Risks of Folic Acid Intake in Excess
Like other water-soluble vitamins, folic acid is not stored in significant amounts in the body, so toxicity is generally not a major concern. However, increasing research has initiated a broader conversation about the possible risks linked to high levels of folic acid consumption.
High doses of folic acid can lead to elevated levels of unmetabolized folic acid (UMFA), which has been linked in peer-reviewed studies to immune dysfunction, cognitive issues, and increased cancer risk—particularly colorectal and prostate cancers. Folic acid may also epigenetically alter gene expression, with long-term effects.
The WHO recommends 400 µg/day of folic acid during the periconceptual period, which effectively prevents neural tube defects. However, many prenatal supplements contain 1 mg or more, and some prescriptions go as high as 5 mg/day. This can push intake above the tolerable upper limit (UL), resulting in elevated UMFA in both maternal and fetal blood samples.
Excessive folic acid intake during pregnancy—especially beyond the first trimester—has been associated with altered DNA methylation, impaired neurodevelopment, and a possible increased risk of autism. Data from the CDC’s Vaccine Safety Datalink reported an association between prenatal folic acid supplementation and higher autism risk, even after adjusting for confounding variables.
These findings suggest that while adequate folic acid is essential for healthy fetal development, excessive intake may pose risks—highlighting the importance of balanced supplementation.
Understanding the difference between folate and folic acid—and how genetic factors like MTHFR can impact their metabolism—is essential for making informed decisions about supplementation, especially during pregnancy. While folate plays an undeniable role in supporting healthy development, emerging research on unmetabolized folic acid is prompting a closer look at the current protocols surrounding vitamin B9 supplementation.