The Folllies of Folate in a Nutshell

By Dr. Jen Morganti

Folic acid is one of those nutrients that's easy to take for granted. We only need about 400-1,000 micrograms a day, which is pretty tiny when compared to calcium or magnesium requirements. It's widely available in produce and meat and is supplemented in many processed foods. But despite the micro-requirements, many people are still falling short in their daily needs. And researchers are discovering that this deficiency can lead to a host of health problems that can only be rectified by normalizing folate levels.

Folate deficiency can also be related to cardiovascular disease because it is indirectly related to homocysteine metabolism through the biochemical reaction known as methylation. Low levels of folic acid (as well as Vitamin B6 and Vitamin B12) can lead to elevated homocysteine, which is a known risk factor for developing atherosclerosis or having a heart attack or stroke. It is also critical for proper DNA synthesis, which helps prevent damaged cells and serious disease. Folate deficiency can cause birth defects in pregnancy, depression, macular degeneration, accelerated aging, and other serious conditions.

One of the primary culprits that causes a shortfall is poor absorption. Folic acid needs to go through several enzymatic conversions to become usable by the body. An increasing number of people have trouble metabolizing folate due to a genetic mutation of the MTHFR gene, which interferes with production of the MTHFR enzyme. When that enzyme is dysfunctional, folate is not absorbed or utilized properly. Under these conditions, the person suffers from a folate deficiency despite an abundant supply from food or supplements, because the body just can't utilize it. Also, certain medications, diseases, or alcoholism can impede folate absorption and lead to deficiency in the absence of a genetic mutation.

How do I know if I have the genetic mutation and what do I do?

Your physician can determine if you should be tested for this gene mutation based on the presence of one of these conditions including: elevated homocysteine, IBS, fibromyalgia, depression, or other circumstances. Your doctor can order the test and it will likely be covered by insurance. Some people choose to pay out of pocket rather than go through insurance to keep the information private.

If you discover that you do have the mutation, don't despair— there is a special form of folate that will solve the problem. It's called 5-MTHF, which is the acronym for the chemical name 5-methyltetrahydrofolate and it is the metabolically-active form of folate that can be easily utilized by the body without further conversions. Sounds like the perfect solution, right? It is; however, once you start looking for the right supplement to take, it starts to become very confusing. And there is some information you need to know about dosages and possible side- effects.

The first obstacle in choosing a 5-MTHF supplement is understanding the various names that are used for this ingredient and what they mean. The most common versions you will see are: 5-MTHF, methylfolate, and 5-methyl tetrahydrafolate. Sometimes specific brand names are used; the most common ones are Quatrafolic, Extrafolate, and Metafolin.

Now for the really specific (and somewhat confusing) details. Folinic acid or 5- formyl tetrahydrofolate is the naturally occurring form of folate.The term 5-MTHF is the general term for the type of folate that should be used in the case of genetic mutations. It is important to know the specific chemical structure; the best forms should specify an "L-" or "6S-" in the begining of the word to indicate good bioavailability. The "D" form should be avoided. When you don't see any specific form, it is more likely to be the "D" form and should be avoided.

The specific brands which were mentioned previously are all good quality. Metafolin is made by Merck which is specifically (6S)-5-methyltetrahydrofolic acid, which uses calcium salt, and is also known as L-methylfolate, L-5-methyl tetrahydrofolate or Levomefolic acid. Supplement manufacturers that use this ingredient by Merck are restricted and cannot go over 1 mg per dose. It is also available as a prescription, particularly when higher doses are required.

Quatrafolic is made by Gnosis, and is (6S) 5-methyltetrahydrofolate or L-methylfolate, which uses glucosamine salt, which is the primary differentiation from Metafolin. Some experts claim that a lower percentage of folate is absorbed from this form as compared to the calcium salt version and some say this form is better absorbed. In my opinion, they are probably very similar and can be used interchangeably.

Just to add to the confusion, Gnosis also makes an ingredient called Extrafolate, which is a "racemic" mixture, meaning it is 50% in the "R" form, which is considered inactive, and 50% in the "S" form. Ultimately, this means it is half as potent as the equivalent amount of the "S" only form, so it is less ideal.

Lastly, Gnosis makes an ingredient called Extrafolate-S , which is the calcium salt of (6S)-5-methyltetrahydrofolate. This is most similar to Metafolin, especially regarding bioavailability. This ingredient is only allowed to be sold as a stand-alone ingredient (not in a formula).

Beyond these brands of 5-MTHF, there can be good forms of generic active folate. Just be sure it has the "S" or "L" designation, and avoid those that don't. Also avoid D-5-MTHF = D-5-Methyltetrahydrofolate, 6(R)-L-MTHF and 6(R)-LMethyltetrahydrofolate.


Dosing can be tricky for people with genetic mutations who have severe deficiency. It's wise to find a doctor who has experience and can help determine the appropriate dosage without causing side effects. Some potential side effects that can occur in sensitive people include irritability, insomnia, sore muscles, achy joints, acne, anxiety, palpitations, nausea, or headaches. If this occurs, it may be necessary to lower the daily dosage and later increase it slowly.