Different Types of Methylfolate – Apples to Apples Ingredient Comparison
NOTE: The comparisons above are based on the raw material ingredient amounts (which includes “free methylfolate”, salt & water content). If you are comparing two consumer products that are both labeling the “free methylfolate” only (methylfolate minus the salt & water content and are adding in an overage for potency loss, i.e. up to 32% in the case of amorphous based versions), then you can reasonably compare them as 1:1 (and not worry about needing to do any conversions yourself).
Tell me more about the different types of Methylfolate
Alright, let’s paint the methylfolate landscape since, it’s a bit confusing to know what type of methylfolate to buy. There are so many different ways it is labeled and different varieties out there to purchase – how does a consumer know what’s best to get? I am passionate about methylfolate because it has so radically changed my quality of life for the better. And with this information I hope to give you plenty of details that will allow you to make an informed decision based on what is best for you and your family. How do I know so much about the topic, well, I had to research them all to determine which types of methylfolate I would include in my products (and I learned A LOT along the way).
The ingredient Methylenetetrahydrofolate (or its short name: Methylfolate) was first patented and trademarked by a company called Merck in Germany. It was given the name Metafolin®. It is derived by bonding the “active nutritive ingredient”, the (6S) isomer of 5-MTHF, to a calcium salt molecule. The (6S) isomer of 5-MTHF is the actual “free methylfolate” nutrient that your body can directly absorb and immediately use (it’s often denoted as (6S)-5-Methylfolate). Metafolin® is said to be 99.9% pure, this simply means that 99.9% of the ingredient itself is made up of the calcium salt molecule that only the (6S) isomer of 5-MTHF is bound to (there is no (6R) isomer of 5-MTHF in the ingredient). The folks at Merck and PamLabs refer to and market this methylfolate that has only the (6S) isomer of 5-MTHF in it as ‘pure L-Methylfolate’. L and (6S) refer to the same thing in chemistry (they are synonyms when it comes to molecular detail). When you ingest the Metafolin® ingredient, the calcium salt molecule dissolves and only about 72-79% of the active (6S) isomer is available for absorption (the ‘active nutritive ingredient’ that your body can use). This process is called ‘first pass metabolism’ or ‘first pass absorption’. So just be aware that marketing efforts referring to ‘purity’ just mean the ingredient’s isomer type (in this case the calcium-salt base is only bound to the (6S) isomer – 99.9% of the ingredient is (6S)-5-MTHF and only 0.1% is made up of (6R)-5-MTHF). 99.9% purity does not mean the effective (6S) isomer (L-5-Methylfolate or “free methylfolate”) amount available for your body to absorb and immediately use after the first pass absorption. All this basically means is that 1 mg of Metafolin® equals approximately 0.76 mg of the active (6S)-5-MTHF (bioactive “free methylfolate”) that can be absorbed by the body. The other approximately 0.24 mg is made up of the calcium salt and water. Also, it’s worth noting that Metafolin® calcium salt type is a crystalline Type I form, which has solid stability (or potency).
Merck has contracted with Nestlé Health Science – Pamlab, Inc. who creates a number of prescription versions of Metafolin® which are available today for patients in the USA. Check out the prescription chart listing these.
These prescription versions of methylfolate are classified as ‘medical foods’ (since they are technically ‘vitamins’) and approved by the FDA. These contracts for high doses of Metafolin® methylfolate per day have previously been exclusive between Merck and the manufacturers, meaning you will not find a non-prescription, high-dose product sold over-the-counter with Metafolin® in it (none that exceed 1 mg per daily dose). Being under a doctor’s care when taking high dose methylfolate is advised. If you take a product with Metafolin® in it, it should always have the word ‘Metafolin®’ on the product’s label. I have found that Solgar vitamins sells one of the most affordable versions of Metafolin® over-the-counter.
Generic / Racemic Mixtures
I believe that eventually Methylfolate will have a huge impact on people all over the world, but for now, that impact is still being discovered and uncovered. And there are quite a few others who agree with me on this. Here is where the competition enters (as with any great invention – there will be many who compete for a piece of the pie). For those who understand the value of this ingredient, they have been working to circumvent Merck’s patent. Stick with me as we get a little technical for a minute or so. One typical way ‘generics’ can get made chemically is to create a racemic mixture of an ingredient (what we’re talking about is how the ingredient actually gets created from a chemical standpoint). Essentially this results in a chiral molecule, which is a mirror image of the active isomer we want (it’s called an enantiomer). So with a ‘generic’ variety of methylfolate (a racemic mixture version), you would have half of the salt molecules dissolving as the (6S) isomer [so (6S)-5-MTHF] and the other half dissolving as (6R) isomer [(6R)-5-MTHF] (which is an exact mirror image of the (6S) isomer – and assumed to be an ‘inactive’ ingredient). So essentially you’re getting a 50/50 mixture of calcium salt where 50% is the active (6S) isomer your body needs [(6S)-5-MTHF] and 50% is the inactive (6R) isomer that your body shouldn’t need [(6R)-5-MTHF]. You still only get about a 72-79% absorption factor overall, but now you’re talking about half as much ‘active’ (6S) isomer material (as compared to Metafolin® or other (6S) isomer only calcium salt versions). So with a racemic mixture of methylfolate, only about 38% of the ingredient is being absorbed by your body after the first pass absorption vs. ~76% with the Metafolin® or other (6S) isomer only calcium salt versions – we will get to the others in a minute). This means that 1 mg of a generic/racemic mixture equals approximately 0.38 mg of the active (6S)-5-MTHF (bioactive “free methylfolate”) that can be absorbed by your body.
This racemic mixture, substance difference is how other companies have worked around the patent that Merck has for Metafolin®. It is probably most widely known as 5-MTHF (although labeled in many ways – technically it should be labeled as DL-5-MTHF or (6S)/(6R)-5-MTHF). As you can imagine, Merck does not like this competition and has been working hard to stamp it out. A study has been circulated by the Metafolin® folks questioning the (6R) isomer’s health benefit or detriment – it has recently appeared in the pamphlets for the prescription versions that now contain Metafolin®. On the other hand, racemic versions have been used widely and have even been officially tested in a colon cancer trial study where they claim to have found no toxic side effects in the duration of the study (even with daily doses of 100-600 mg) – Check it out here. As you can imagine, an ‘unpatented’ version of methylfolate would be much cheaper than a patented, trademarked version that a company is paying to protect, so you will typically find these racemic versions much more affordable. Though more recently, it seems the use of racemic methylfolate is dying out in the supplement market as doctors are concerned with the study Metafolin® sites.
I personally had a great experience with a calcium-salt based racemic version of methylfolate that my naturopath prescribed me. This is what I was taking when my serotonin levels increased in a normal range (went from 85 to 136), when my anemia went away and some other blood test markers came back into a normal range. Not to mention how great I felt. After fighting 12 years of horrible IBS, I can truly say it’s finally gone now (and I have my life back again). I took a racemic version of methylfolate for 16 months with nothing but fantastic results. But this does NOT mean that I know or am saying the (6R) isomer ‘inactive’ ingredient is not a health issue or may not have negative effects. I am merely relaying my findings and personal experiences with a generic/racemic form of methylfolate. You should take what makes you feel most comfortable/safe, and if you’re concerned about the study the Metafolin® folks are pointing to, then stick with a (6S) isomer only version of methylfolate. These days I only take & make products with the (6S) isomer only. And there are more and more of the (6S)-5-MTHF products available for purchase now.
- Merck manufacturers & sells Metafolin® (as we just discussed)
- Gnosis (who we will discuss next) manufacturers & sells Extrafolate-S® and Quatrefolic®
- Jinkang now on the scene is selling an impressive new Crystalline-C version that is internationally patented, called Magnafolate-C™
- And there are many generics now manufacturing calcium salt versions of (6S) isomer only methylfolate (amorphous forms, mainly) – NOTE: the amorphous form is less stable than the crystalline form of methylfolate, and it affects stability/potency, see Extrafolate-S® below.
Now let’s move on to talk about Gnosis, Merck’s current big methylfolate competitor out of Italy. Gnosis creates patented (6S)-5-MTHF ingredients, one is called Extrafolate-S® and the other is called Quatrefolic®. Quatrefolic® is FDA approved.
Let’s start with Gnosis’ Extrafolate-S®, it is similar in likeness to Merck’s Metafolin® in that it is a calcium-salt based molecule that the (6S) isomer of 5-MTHF is bound to, and it is also a 99.9% pure (6S) isomer-only 5-MTHF ingredient. It also has the same first pass absorption loss rate, making it about 72-79% absorbable. This means that 1 mg of Extrafolate-S® equals approximately 0.76 mg of the active (6S)-5-MTHF (bioactive “free methylfolate”) that can be absorbed by your body. The significant difference between the ingredients Extrafolate-S® and Metafolin® is the salt molecule’s form type. Basically the Extrafolate-S® methylfolate is an amorphous salt form and the Metafolin® methylfolate is a crystalline salt form (Type I).
The difference between these salt form molecules is that a crystalline salt molecule is more stable, whereas an amorphous salt molecule is less stable. What does this mean to you or me? It means that if the amorphous ingredient is manufactured 12 months before use, it can lose up to 16%+ of its potency as compared to a crystalline form ingredient which may lose 1-2% of its potency over that same time period. Extrafolate-S® is not quite as common to find in the marketplace because Gnosis now seems to be pushing its FDA approved Glucosamine salt based version of methylfolate more heavily, Quatrefolic®. It’s worth noting that most other calcium salt based methylfolates that are not patented as Metafolin® or Magnafolate-C™ are amorphous salt versions (including Extrafolate-S®), and if it’s not labeled as one of those three, it’s most likely produced in China as a generic.
Learn more about Gnosis Quatrefolic® methylfolate from their website
Now let’s talk about Quatrefolic®. The difference between this methylfolate and the calcium salt based forms is that Gnosis bound the (6S) isomer of 5-MTHF (the ‘active nutritive ingredient’ we care most about) to a different kind of salt molecule. Instead of using calcium salt, they are using a glucosamine salt molecule. And in 2010 Gnosis was officially recognized and approved by the FDA for its L-Methylfolate – Quatrefolic® (to be officially labeled as (6S)-5-Methylfolate, glucosamine salt). Quatrefolic® is said to be 99.9% pure, which again, just means that 99.9% of the 5-MTHF ingredient is made up of the glucosamine salt molecule that the (6S) isomer is bound to (there is no (6R) isomer in it). However, when you ingest Quatrefolic®, the glucosamine salt molecule dissolves and the first pass absorption rate is only about 54-59%. So only about 56% of the (6S) isomer becomes available for absorption (the ‘active nutritive ingredient’ that your body can use). This means that 1 mg of Quatrefolic® equals approximately 0.56 mg of the active (6S)-5-MTHF (bioactive “free methylfolate”) that can be absorbed. So with this version of methylfolate, you’re actually getting less of the actual (6S) isomer per mg of ingredient after the first pass absorption than you are with a calcium salt based version. It just means that by weight you would need more Quatrefolic® ingredient to equal the same amount of the effective (6S)-5-MTHF that a calcium salt based version contains. The FDA requires 2 mg of the Quatrefolic® ingredient to equal 1 mg of labeled Folate (or (6S)-5-MTHF). It is definitely worth noting that the Quatrefolic® brand has been proven to get absorbed into the bloodstream faster than the Metafolin® brand, so this is something you may see marketed in products selling Quatrefolic® (“it’s the most bioavailable methylfolate” – this just means it becomes available faster for the body to absorb. I like to think of it as the glucosamine salt dissolves faster, therefore freeing the (6S)-5-MTHF to get into your bloodstream quicker, at least quicker than the Metafolin®’s calcium salt dissolves). It’s worth noting that this may make a difference in how one feels symptomatically when taking Quatrefolic® (glucosamine-salt based) vs. Metafolin®. One may experience positive or negative methylation results faster. I have heard of some people encountering side effects based on one vs. the other salt type (so just be aware as you take your methylfolate – you may be fine with one salt type and have trouble with the other, or you may be fine with both salt types). Pay attention to your body and switch to a different type, if you think the salt version might be causing you problems.
Internationally Patented Magnafolate-C™
Now let’s move on to talk about the newest player on the scene, the Crystalline-C brand of methylfolate. It comes from a company called Jinkang which holds an international patent for the ingredient. It is also a 99.9% pure form of methylfolate (meaning a 99.9% pure (6S) isomer only ingredient – no (6R) isomer). It is also a calcium salt based crystalline form, very much like Metafolin® (so it has the solid qualities of a ~76% “free methylfolate” absorption rate). This means that 1 mg of Cyrstalline-C equals approximately 0.76 mg of the active (6S)-5-MTHF (bioactive “free methylfolate”) that can be absorbed by your body. However, it has something special, Crystalline-C is based on a crystalline Type C molecule form, whereas Metafolin® is made with a crystalline Type I molecule. What’s the difference you might ask? Well a type C crystalline molecule form has shown in early lab tests to be more soluble, meaning it should be available to reach the bloodstream faster. So it seems that Crystalline-C may be the best of both worlds … it has the highest concentration of “free (6S) isomer only methylfolate” per mg of the ingredient (like Metafolin® does), and it also has the rock solid stability of the crystalline form (like Metafolin® does). Look for Crystalline-C to begin building more traction in the methylfolate marketplace as it seems to stand out as the best in class for each of the important categories:
Magnafolate-C™ is in the application process for FDA approval, so its manufacturer appears to be in the market for the long haul. Methyl-Life is pleased to be the first company in North America to provide a methylfolate product line using the Crystalline-C ingredient, Magnafolate-C™.
So what does all this information mean to you – how do you make a decision about what brand of methylfolate is best for you to take? For me, I started on a high dose (5-7 mg a day) racemic methylfolate that literally changed my life, then at the same dose, I switched to Solgar’s Metafolin® because when my supplier was out, I found it cheapest over-the-counter (I took that for a couple months). Then one time while on vacation, I couldn’t find Solgar’s Metafolin®, but I found Quatrefolic® and took it for almost 3 weeks (again, my same high dose amounts of 5-7 mg a day). Then I made my own supplement and went back to the racemic for over 10 months (typically taking ~7 mg daily). Then I moved to Quatrefolic® in 2013 and was taking that for a year. And now I have moved to the Magnafolate-C™ based on its solid advantages. All that to say, personally, I haven’t noticed any huge symptomatic differences between the various forms of methylfolate. However, I didn’t pay close attention to any subtle symptom differences, and I am an A1298C MTHFR mutant, so I just have a single mutation. But for me all the versions of methylfolate seem to have worked. I have heard that some folks notice a difference between the two salt types, so if you switch back and forth between a calcium-salt vs. glucosamine-salt based version of methylfolate, just pay attention to your reactions (it seems glucosamine salt for a few can be associated to stomach problems). For health, safety and liability reasons, we now sell both the Magnafolate-C™ & the Quatrefolic® in our products (and I feel very confident recommending those highly).
In the end it’s about peace of mind and your pocketbook. Are you able to get your doctor and insurance to cover a prescription version (if so, you’d be able to take Metafolin® via prescription, if you’re okay with dairy and dyes in the formula)? Are you strapped for cash and need to find the most affordable (6S) isomer-only version of methylfolate out there (check out Methyl-Life)? Do you have a symptomatic sensitivity to a particular salt-based version of methylfolate? Do you want other ingredients/vitamins combined with your methylfolate? Why not try to compare the cost per mg of the active, absorbable amount of the (6S)-5-MTHF your body can directly use after the first pass absorption – the ‘active nutritive ingredient’ (this would allow you to compare apples to apples when determining what to purchase). I have done these calculations in the chart above. At Methyl-Life, we use Magnafolate-C™ and Quatrefolic® in our products (at this time Magnafolate-C™ can’t be combined with other vitamins/active ingredients without infringing upon a Merck patent with Metafolin®, so our multi-vitamin products use Quatrefolic®). I think Methyl-Life has great products at the best prices for purchase, but more than peddling our products, I want to be an advocate for helping you and your family understand all the ingredients well, be able to compare them appropriately, and then purchase what’s best for your needs. I wish you the best of health with your methylfolate journey.