This can be such a confusing distinction, made far worse by the fact that supplement companies and nutritional information labels often use “folate” and “folic acid” interchangeably. Thanks, regulatory agencies.
Folate is the general name for a group of natural related substances, all in the category called “vitamin B9.” They are essential to the human diet because we can’t make them for ourselves (hence “vitamins”) and are best found in foods. Great sources include dark leafy greens, lentils, chickpeas, yeast extracts like marmite, and legumes. Folates are not shelf-stable and can’t be used to fortify other foods because they degrade quickly so the only sources are natural sources. This form is not stable enough to be made into supplements or prescriptions. Folate must go through the MTHFR enzyme to be converted into 5-LMTHF and so this might be slow or impaired in MTHFR mutants.
Folic acid is the crystalline, shelf-stable, entirely man-made form of folate. It functions in the same way that folate does, but has to go through an initial enzyme in the liver, called dihydrofolate reductase, in order to be useful. This enzyme is slow and because of this, high doses of folic acid often build up as unmetabolized folic acid in the blood. Folic acid has been shown to be toxic at high doses – you can read a whole post about it here. When foods are fortified, they are fortified with folic acid. This includes foods like bread, pasta, cereal, and baking flour. Folic acid doesn’t absorb well for people with inadequate stomach acid. This is everyone who takes antacids, heartburn medications, or prescriptions for reflux. Folic acid also masks symptoms of a B-12 deficiency and so can prevent you from getting the treatment you need if your B-12 is low. This is the most common form in supplements and there are prescription folic acid formulas as well.
Folinic acid is the only shelf-stable form of natural folate. It is naturally occurring in some bacteria, although the forms sold as supplements are man-made. Also, there is a prescription form of folinic acid called leucovorin which is used to counteract methotrexate and fluorouracil toxicity as well as folate deficiency and methanol poisoning. Folinic acid is easier to tolerate, for some MTHFR mutants, than 5-LMTHF and does convert to the more active forms (like THF and 5-LMTHF) although it still needs the MTHFR enzyme to do it. This form leads most easily into:
- DNA base pair production (purine synthesis)
- DNA repair
- BH4 pathway and neurotransmitter formation
- ATP synthesis (cellular energy production)
This is the most biologically active form of folate – it doesn’t have to undergo any conversions in the body to be used. It is found in both supplements and prescriptions like Deplin (labeled for depression, but off-label for weight loss and MTHFR issues) and Cerefolin NAC (for Alzheimer’s dementia or in pregnancy), and Metanx (for diabetic neuropathy). Oddly, none of these are actually intended for MTHFR polymorphisms. Go figure. 5-LMTHF is well-absorbed even when your stomach pH isn’t what it should be (like if you’re taking antacids or prescriptions for reflux or heartburn). 5-LMTHF also doesn’t mask symptoms of B-12 deficiency as readily as folic acid does, and so you are able to get appropriate treatment. Also, 5-LMTHF is the only form that is able to cross the blood-brain-barrier to increase levels of folate in the cerebrospinal fluid. Crossing the blood-brain-barrier is extremely important during pregnancy (and fetal development) and in those with severe MTHFR mutations. 5-LMTHF can convert to folinic acid but does so extremely slowly and in a difficult manner, so it’s best to take both. This form is best for:
- Bypassing the MTHFR enzyme for MTHFR mutants
- Supporting methylation of DNA, proteins, lipids, and toxins.
Naturally occurring 5-MTHF has important advantages over synthetic folic acid – it is well absorbed even when gastrointestinal pH is altered and its bioavailability is not affected by metabolic defects. Using 5-MTHF instead of folic acid reduces the potential for masking hematological symptoms of vitamin B12 deficiency, reduces interactions with drugs that inhibit dihydrofolate reductase, and overcomes metabolic defects caused by methylenetetrahydrofolate reductase polymorphism. Use of 5-MTHF also prevents the potential negative effects of unconverted folic acid in the peripheral circulation.Scaglione F, Panzavolta G. Folate, folic acid and 5-methyltetrahydrofolate are not the same thing. Xenobiotica. 2014;44(5):480-488. doi:10.3109/00498254.2013.845705
Key Points to Notice about the Different Types of Folate
- Folic Acid is the only form that has to use the “Slow DHF” enzyme, and the only one that often lingers in the blood as unmetabolized folic acid (which is toxic).
- Naturally occurring folate from unfortified foods can convert to folinic acid or 5-LMTHF, but the conversion to 5-LMTHF in MTHFR folks is slow or impaired.
- Folinic acid can convert to 5-LMTHF, but it still needs to go through the MTHFR enzyme and so it might be slow or impaired in MTHFR folks
- 5-LMTHF is the most active form, but it doesn’t convert back to folinic acid very easily.
The Best Folate For MTHFR Mutants
Those of us with the MTHFR mutations do have to be mindful of our types of folate. Natural food sources of folate are great for us and for many people it can be enough to eat a diet high in natural folate. This means lots of dark green leafy vegetables, pulses like lentils and chickpeas, beans, and yeast extracts like marmite. We’ll talk more about food sources of natural folate next week. Some MTHFR folks will find they need a supplement as well, which should be folinic acid or 5-LMTHF or ideally, a combination of both because they can interchange, but they lead to different pathways. Folinic acid leads most easily into purine synthesis and the BH4 pathway which helps to make your neurotransmitters.
Next week we’ll do a deep dive into food sources of folate because for everyone with the MTHFR mutation, trying food sources and ramping those up should be step one (step two, actually. For all the steps, check out our Start Here for MTHFR guide.)