Folic Acid, Folate & Methylfolate: Potential Problems & Critical Distinctions

Folate, folic acid, folinic acid and 5-methyl folate are not the same. Knowing the difference between the different types of folates could have very important implications for your health.

The terms “folic acid” and “folate” are often used interchangeably to describe Vitamin B9. The truth, however is that they are not the same. Folic acid, is actually a synthetic form of Vitamin B9, which is not found in nature, nor is it naturally found in the human body. In order for folic acid to be metabolized, it must undergo metabolism via the enzymes FOLR2 and DHFR, primarily in the liver. However, natural folates found in whole foods appear to be metabolized via the intestinal mucosa.

A study discussed the specific metabolism of folic acid and proposed that there may be associated risks (1). Two separate studies found that folic acid is an oxidized form of B9, and in order to become biologically active, the nutrient must be reduced via the DHFR (di-hydrofolate reductase) enzyme in the liver (1, 2). The major problem here is that the liver and other human tissues lack significant amounts of DHFR enzymes to metabolize folic acid (3).

As a result of the fortification of refined flour products with synthetic folic acid, plasma and red blood cell levels doubled the predicted target saturation of folic acid in these blood markers. Synthetic, oxidized folic acid is poorly metabolized, and has a high propensity towards accumulating in the body in a non-metabolized state. Other studies have found a correlation between high levels of un-metabolized folic acid as well, following the consumption of folic acid fortified foods or folic acid supplements (5). Further studies on folic acid-fortified bread consumption have found elevated levels of non-metabolized folic acid following consumption of a single slice of bread (6).

What Are The Possible Implications of Un-Metabolized Folic Acid?

Statistical correlations have been found between folic acid consumption and the formation of cancer (7, 8). One study actually found low folate levels may protect against colorectal cancer (9). An epidemiological study conducted in 2007 found that men and women with previous colorectal adenomas, who took 1000 mcg of folic acid daily for 6-8 years had increased risk factors for colorectal cancer (10).

It is certainly plausible to consider the possible cancer risks associated with excessive folic acid, considering that folate methylation is critical for cell proliferation, including in the formation of neoplastic cancer cells. It is for this reason that certain conventional cancer treatments use folate-blocking drugs such as methotrexate. Folic acids and folates all consist of varying numbers of glutamic acid conjugates. Glutamaic acid is well established to increase growth factors in various cancers.

From a clinical perspective, folic acid, folate and 5-methylfolate are a common cause of adverse reactions. Some of the  common symptoms of Folate include:

• Headaches
• Insomnia
• Anxiety
• Agitation
• Heart palpitations

These are likely at least partially caused by the increasing pool of free glutamate in the system. Some of the adverse symptoms of folate may be linked to the effects on the serotonin pathway.

Folate is known to affect serotonin activity. One study reported an increase in the cerebrospinal fluid (CSF) metabolite of serotonin, 5-HIAA, following folate supplementation (12). Folate is known to increase the activity of a cofactor known as BH4, biopterin (13). This cofactor is necessary for the synthesis of catecholamines as well as serotonin. In the case of folate-induced adverse reactions, BH4 levels may be increased leading to higher serotonin turnover.

Others Forms Of Vitamin B9

The richest naturally-occurring sources of Vitamin B-9 are:

• Animal liver
• Dark green leafy vegetables (such as kale, collards, chard, spinach)
• Whole cereal grains
• Legumes

Folates appear to be heat labile nutrients, so be aware that over-heating your food may reduce the amount of folate present.

Supplementally, aside from folic acid, there are 2 forms of Vitamin B9 commercially available: Folinic acid (5-formyl tetrahydrofolate) and 5-methyltetrahydrofolate. Folinic acid is a metabolically active form of folate, a downstream folate metabolite, and a precursor to the active form of folate known as 5-methyltetrahydrofolate (or 5-MTHF for short).

5-MTHF is the most popular form known today. Individuals with MTHFR gene mutations are often recommended to supplement with this form of folate, because in certain cases (primarily +/+ homozygous gene carriers of MTHFR SNPs A1298C and C677T) these individuals may not be able to generate this important methylated form of folate.

As mentioned previously, folates in general are prone towards inducing adverse reactions and various symptoms. An important quote by Paracelsus is:

“the dose makes the poison”.

It’s significant to address that how much, or which type of folate (or for that matter any nutrient) your body needs may be unique to you. Too much, too little, or the wrong form of a nutrient could become problematic.

Remember also that Vitamin B12 and folate are intrinsically connected. A B12 deficiency can actually cause a folate deficiency, because B12 is necessary to properly methylate folate.

Further research on the deleterious effects of folic acid are critically needed, as well as the metabolic distinctions between folic acid, folinic acid and 5-methyltetrahydrofolate.

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