Different Types of Methylfolate: A Detailed Comparison
Unfortunately, there are as many different ways that Methylfolate is labeled as there are varieties to purchase. How do you know what’s best for your health?!
Here at Methyl-Life, we believe that Methyl-Life has great products at the best prices for purchase, but we also believe it’s part of our job to help you understand all the ingredients, be able to compare them appropriately, and then purchase what’s best for your needs.
We’re passionate about methylfolate and proud to bring you all the information you need to make informed choices about treating your MTHFR deficiency. So, for the more science-y among us, we’ve created this detailed resource for understanding and comparing the key ingredients of methylfolate products on the market today.
Comparing Methylfolate ingredients: the basics
The biggest things that set the different types of methylfolate apart are what kind of salt molecule the active methylfolate isomer is bound to, the “purity” level, and what the absorption rate is. Importantly, purity does not refer to the effective amount available for your body to absorb and immediately use after the first pass absorption, it simply refers to the ingredient’s isomer type (the 6S isomer is what your body can directly absorb and use).
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®. Magnafolate-C® stands out among the various types of methylfolate for its purity, concentration, and stability. We also believe in and confidently sell multivitamins that include Quatrefolic®.
Below is a handy chart, followed by detailed information for each methylfolate type.
NOTE: The comparisons above are based on the raw material ingredient amounts, which includes “free methylfolate,” as well as salt & water content. If you are comparing two consumer products that don’t label the salt & water content, you can compare them as 1:1.
What are the different types of Methylfolate?
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 is made up of the calcium salt molecule that the (6S) isomer of 5-MTHF is bound to. In the body, this means that 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, what does purity mean? Marketing efforts referring to “purity” just mean the ingredient’s isomer type. 99.9% purity does not refer to the effective amount available for your body to absorb and immediately use after the first pass absorption.
All this basically means is that 1mg 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., which creates a number of prescription versions of Metafolin® available for patients in the USA. Check out the prescription chart listing these.
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 methylfolate, 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 that “generics” get made is to create a racemic mixture of an ingredient (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 the (6R) isomer ([6R]-5-MTHF). The 6R isomer is an exact mirror image of the (6S) isomer – and assumed to be an ‘inactive’ ingredient.
Basically, what you get is a 50/50 mixture of calcium salt, where 50% is the active (6S) isomer your body needs and 50% is the inactive (6R) isomer that your body shouldn’t need. You still get about a 72-79% absorption factor overall, but now you’re talking about half as much “active” material. In other words, with a racemic mixture of methylfolate, only about 38% of the ingredient is being absorbed by your body after the first pass absorption, or half of what gets absorbed taking Metafolin® or other the other versions of 6R isomer-only versions.
This means that 1mg 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.
Using this racemic mixture strategy is how other companies have worked around the patent that Merck has for Metafolin®. 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. Yet, 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).
As you can imagine, an unpatented version of methylfolate is much cheaper than a patented, trademarked version that a company is paying to protect. Still, while these racemic versions are typically much more affordable, they seem to be less common in the supplement market due to doctors’ concern regarding the study cited by Metafolin®.
Methyl-Life’s founder, Jamie Horn, shares her own experience with racemic methylfolate:
“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 to being within a normal range (I 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, I felt great! 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.
This is just my personal experience with a generic/racemic form of methylfolate. You should take what makes you feel most comfortable and safe. If you’re concerned about the study the Metafolin® folks are pointing toward, then stick with a (6S) isomer-only version of methylfolate. These days, I only take & make products with the (6S) isomer only.”
Let’s start with Gnosis’ Extrafolate-S®, Merck’s big methylfolate competitor based in Italy. Extrafolate-S is similar to Merck’s Metafolin® in that it is a calcium-salt based molecule that the (6S) isomer of 5-MTHF is bound to. It is also a 99.9% pure ingredient. It also has the same first pass absorption loss rate as Metafolin®, making it about 72-79% absorbable.
1mg 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 in 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, compared to a crystalline form, which will only lose 1-2% of its potency. Extrafolate-S® is not quite as common to find in the marketplace because Gnosis now seems to be more heavily pushing its FDA-approved Quatrefolic®.
The difference between Quatrefolic® and the calcium salt-based methylfolate forms is that the maker, 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 use a glucosamine salt molecule. In 2010, Gnosis was officially recognized and approved by the FDA for its L-Methylfolate, Quatrefolic®, which is 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. 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 1mg 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. This means that, by weight, you would need more Quatrefolic® to equal the same amount of the effective (6S)-5-MTHF that a calcium salt-based version (like Metafolin®) contains.
It is definitely worth noting, however, 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®. When marketing notes that Quatrefolic® is “the most bioavailable methylfolate,” this just means it becomes available faster for the body to absorb.
This faster absorption rate may make a difference in how one feels symptomatically when taking Quatrefolic® vs. Metafolin®: you could 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 that you may be fine with one salt type and have trouble with the other (or you may be fine with both!). 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®
The newest player on the scene is 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®.
Like Metafolin®, it has the solid qualities of a ~76% “free methylfolate” absorption rate. This means that 1mg 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, Crystalline-C 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? The 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 stand out as the best in class for each of the important categories:
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®. Magnafolate-C® is in the application process for FDA approval, so its manufacturer appears to be in the market for the long haul.