Folate vs Folic Acid vs Folinic Acid vs 5-MTHF

Key Takeaways 

• All are considered forms of vitamin B9 – an essential nutrient 
• Dietary Folate forms are either natural or synthesized, but that’s not the real problem — the chemical form of Folate, Folic Acid, is the real potential troublemaker.
• 5-MTHF is the most biologically active form of folic acid/folate.

When a cold hits and with it the miserable plaguing of a runny nose, do you reach for Puffs, Kleenex, Scotties or the store brand of facial tissues?  If ever there were a case of same-but-different, this is it. Even if you did a blind grab for a tissue, you’d be able to tell the difference between the coveted Puffs with lotion and those coarse, sorry-excuse-for-a-tissue you find in excess at your doctor’s office. 

What is Folate, Folic Acid?

In a similar vein, that list of words atop this article are all considered forms of vitamin B9.  But they are not the same thing. Knowing how they differ could have important ramifications in your health.  Folate and folic acid are used interchangeably to describe vitamin B9, but that is not completely accurate.  Folates are found in whole foods and are metabolized by intestinal mucosa. Folic acid is synthetic, is not found in nature and is used to make supplements and to fortify food.  For folic acid to be useful to the body, it is metabolized by the enzymes FOLR2 and DHFR, primarily in the liver. Natural folates, on the other hand, are handled by the gut. FOLR2 is a gene with a high affinity for folic acid and its reduced derivatives.  It mediates delivery of 5-methyltetrahydrofolate to the interior of cells, possibly transporting methotrexate in synovial macrophages in persons with rheumatoid arthritis. DHFR converts dihydrofolate to tetrahydrofolate, which is a methyl group shuttle responsible for the de novo synthesis of purines and certain amino acids.  Dihydrofolate reductase deficiency is linked to megaloblastic anemia.   

So, long story short, vitamin B9 is an essential nutrient.  It’s important to cell growth and the manufacturing of DNA. Several health conditions are associated with its deficit, including elevated homocysteine (linked to elevated risk for CVD) (Wierzbicki, 2007), birth defects (neural tube abnormalities) (Czeizel, 2013) and risk of some cancers (Choi, 2002) (Blount, 1997).  While the CVD and cancer risks take some time to present, neural tube defects show up in nine months or less. Among these are cephalic disorders that stem from damage to, or abnormal development of, the growing nervous system, usually occurring very early in pregnancy. The infant may be plagued by chronic illness, a physical disability or even death.   In cases where disrupted closure of the neural tube occurs, a process that normally takes place between the 3rd and 4th weeks of pregnancy to form the brain and spinal cord, parts of the brain, skull and scalp are often absent.  This condition, called anencephaly, results in an infant who is deaf, blind, unconscious and unable to feel pain.  For these reasons, some countries mandate food fortification with folic acid. And that is where problems can start.  The U.S., Canada and Chile mistakenly use folic acid instead of folate or folinic acid. 

Let’s Talk About 5-MTHF

The word folate derives from the Latin word for leaf.  Leafy vegetables are, in fact, one of the best dietary sources of folate.  The name applies to a group of related compounds with similar nutritional properties.  Levomefolic acid or 5-methyltetrahydrofolate is the active form.  The digestive system transforms food folate into 5-MTHF before it enters the bloodstream (Patanwala, 2014). Unmethylated, oxidized folic acid must undergo enzymatic reduction to become biologically active meaning when folic acid enters a cell, it needs to be converted into 5-MTHF before your body can use it. This enzymatic reduction can be hindered by the fact that many people carry gene variants that can hinder the last step of the conversion.  If one of the primary recommendations for this essential nutrient is during pregnancy, that means that many women may struggle to get the full benefits from folic acid. Unfortunately, most mainstream prenatal supplements still use folic acid. 

Although it is such that the bioavailability of folate from food is only 80% of that from folic acid, the food source is a safer alternative (Winkels, 2007).  The concept of a dietary folate equivalent (DFE) acknowledges that difference (Hannon-Fletcher, 2004). 

Unmetabolized folic acid has been found to reduce the efficacy of natural killer (NK) cells in immune activity.  Study at Tufts University noted a metabolic difference between folate and folic acid influence on immune function, with NK cytotoxicity almost one-fourth lower in persons with unmetabolized folic acid (Troen, 2006).  This study alone tells us that something is rotten in Denmark following doses of the synthetic compound. The low rate of conversion to the reduced form questions the efficiency of using it as the sole source of vitamin B9, especially in early pregnancy, and then especially in individuals possessing lower than average conversion capacity (Bailey, 2009). 

The U.S. is not the only place to show concern about folic acid over-accumulating in plasma as a result from mandated fortification in foods.  Even in Ireland there has been an examination of safety after the mandate was added to an extensive voluntary folic acid enhancement program. There was a well-founded worry that overconsumption of folic acid would mask vitamin B12 deficiency and a possible acceleration of cancers in the elderly (Boilson, 2012).  It is generally accepted that any B-vitamin taken away from the rest of that complex acts like a drug, and that side effects are to be anticipated in many, if not most, instances. Where the entire B-complex accompanies folic acid supplementation, unmetabolized folic acid is not realized, especially in the presence of vitamin B6, pyridoxine (Obeid, 2016).  One way to minimize the worries with folic acid use is lowering intake from the common 400 mcg to 200 mcg or 100 mcg (Sweeney, 2007). 

In cases where folate supplement intake is encouraged, though not only in pregnancy, 5-MTHF is deemed more effective than folic acid in raising plasma levels of the nutrient (Prinz-Langenohl, 2009) while allowing a more easily assessed plasma value (Wright, 2010).  Folinic acid is known as 5-formyl tetrahydrofolate, used where the drug methotrexate is employed in cancer therapy. Methotrexate is an anti-metabolite that interrupts the action of the reductase enzyme that guides the methylfolate pathway. Since folinic acid does not need enzyme activity for its conversion, its function as a nutrient is unaffected by enzyme inhibition.  You see, methotrexate impedes the non-biological nature of folic acid that possibly encourages tumor growth, especially in matters where colorectal disease risk is heightened with folic acid (Cole, 2007). An increased hazard ratio was seen in Norwegian patients whose diets were augmented with folic acid, not only in colorectal disease, but also in lung cancer (Ebbing, 2009).  Scientists at USC’s Keck School of Medicine, based on the results of an aspirin/folic acid study, found folic acid to be implicated in the incidence of prostate cancer, while folate was not (Figueriredo, 2009).  

Chemically, folinic acid is the active metabolite of folic acid; the Rx form is called leucovorin, a calcium-salt form acting as an antidote to the entities that block the conversion of folic acid to its downstream metabolites.  5-MTHF is the most biologically active form of folic acid/folate. It is well-absorbed, even when gastric pH is less than optimal, and its bioavailability is not compromised in the face of metabolic missteps (Scaglione, 2014). In the company of vitamin B12 it helps to convert the inflammatory marker homocysteine to methionine, the sulfur-containing essential amino acid important to the endogenous manufacture of several vital substances, including epinephrine and choline.   5-MTHF lowers homocysteine (HCY), prevents neural tube defects, and improves vascular endothelial function (Antoniades, 2006). High doses of folic acid can hide a vitamin B12 deficiency, causing neurological injury secondary to undiagnosed pernicious anemia, but supplementing with 5-MTHF appears to be able to avoid this problem. Since 5-MTHF can only be converted to 5,10 methylenetetrahydrofolate—involved in DNA synthesis—after recycling HCY with vitamin B12, it does not mask B12 deficiency because it does not synthesize DNA without it.

If there is any apprehension about the same-but-different situation, it is that 5-MTHF costs a lot more than plain folic acid, andolinic acid isn’t exactly inexpensive, either. But your health shouldn’t come at a cost. BodyBio’s Multi-Vita-Min contains folinic acid in the company of methylated B12 – the best of both worlds.