5-LMTHF vs. Folinic Acid. Which is Best For MTHFR?

I am sure everyone would like a simple answer so they can just buy a product and move on with their lives, but like everything else about MTHFR, this is an individual question.

The very short answer, is both forms will get you there in the end. Don’t worry, I’ve got the much longer answer all ready for you too.

One caveat before we get going – we are entering into unresearched territory here. The effects of 5-LMTHF vs. folinic acid in MTHFR mutants have never actually been studied as a comparison, so the only useful data I can use here in my own clinical experience with myself and my clients. MTHFR is a reasonably new area for scientific research and the research has focused primarily on health risks and disease correlations, as well as basic information about how disease risk changes with folate status, but we are nowhere near the point where we are actually looking at how MTHFR folks feel well.

Fast vs. Slow

In a very real sense, what we are dealing with here, is incredibly fast action, vs. slower steadier action. 5-LMTHF is the active form of folate. As soon as it absorbs, it is useable in a very rapid way. For some MTHFR folks, this is a miracle, but it’s all too much for others. Folinic acid, on the other hand, still has to be converted to the active form, and so has a much slower action because you can only use it as fast as you convert it. For some people, this isn’t enough. For others, it gives the benefits of methylfolate without the scary burst of energy (which can feel like anxiety, heart palpitations, or restlessness if it’s too high.)

If you look at the diagram above, the enzymes are highlighted in grey. You can see that 5-LMTHF is the end-product of all of this. It doesn’t need to be changed into anything else, because it’s already what we’re after. Folinic acid, on the other hand, still needs the MTHFR enzyme, but bypasses “DHFR Slow,” which only folic acid uses (and you know what I think of folic acid) and the “DHFR Fast” which is used by other forms of natural folate. It’s an efficient way to get good active folate even if your MTHFR is slow, just as long as you don’t have folic acid in your diet slowing everything down.

Doesn’t Every MTHFR mutant Need The Active Form?

No. Every MTHFR mutant needs good sources of natural folate, but this could be food sources of natural folate (NOT FOODS FORTIFIED WITH FOLIC ACID), folinic acid, or 5-LMTHF. Ultimately, they are all working on solving the same problem they just do so with different levels of efficiency. Here are some quick facts for you.

  • Natural folate, folinic acid, and 5-LMTHF are all useable by MTHFR mutants as long as they don’t have folic acid in their diet.
  • Folic acid makes natural folate and folinic acid less useful because it blocks receptor sites and slows down the methylation pathway.
  • 5-LMTHF is the only form of folate that bypasses the MTHFR enzyme entirely,
  • Natural folate, folinic acid, and 5-LMTHF are all-natural forms of folate.
  • Folinic acid is easier for many MTHFR mutants to tolerate because it is metabolized more slowly.
  • Often, taking folinic acid for several months will help a person who couldn’t tolerate 5-LMTHF to tolerate a low dose.
  • Some MTHFR folks will never be able to tolerate any forms of folate.
  • Because folinic acid metabolizes more slowly, it typically generates fewer side-effects than 5-LMTHF.

Do MTHFR Mutants Need Both Folinic Acid and 5-LMTHF?

The short answer is that we think so, but maybe not.

Here’s why. Folinic acid converts to 5-LMTHF reasonably easily (using the MTHFR enzyme) but 5-LMTHF has to go through a much more complex backward process to convert back to folinic acid. WE think it is important because these two substances feed into different pathways most easily.

5-LMTHF

  • Bypasses the MTHFR enzyme
  • Supports methylation and production of SAMe
  • Can cross the blood-brain barrier easily
  • Methylates substances like serotonin (to make melatonin), norepinephrine (to make epinephrine)

Folinic Acid

We are nowhere near the point where research is actually asking the question, “How do MTHFR mutants feel well.”

Amy Neuzil, tohealthwiththat.com

Next week we’re going to talk about what to expect when you’re starting to supplement with folate, what symptoms you might see, what is going on in your body an what to do about it.

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Pssst. There Are Different Types of Folate. And One of Them is TOXIC.

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.

Did you have any idea there were different types of folate?

Folate

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

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

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)

5-LMTHF

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.
Not all types of folate are created equal, and certainly not folic acid! This is why it matters to get the right type for you..

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 B12deficiency, 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.)

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