Good question!

Choosing the right dietary supplement is now more difficult than ever. A saturated market along with overblown marketing campaigns can blur our understanding of what’s good and what’s not.

Brands will often use unfamiliar jargon and visual effects to “sell” their products, ultimately confusing the consumer. Too often, this strategy is about gaining credibility through alluring claims in the hope that consumers won’t feel compelled to compare products.

Well, we’re about to clear things up once and for all by explaining exactly what makes a methylfolate supplement good, and how to choose the best.

At Methyl-Life®, we believe in helping our customers understand exactly what’s best for their health. This detailed resource will explain and compare the industry-leading methylfolate nutrients competing on the market today.

Different types of methylfolate may be used in different products. Each type can vary in terms of its structure, which can then affect its delivery and uptake in the body.

The majority of all L-methylfolates on the market are bound to one of two major salt molecules: calcium salt or glucosamine salt. The salt molecule has a lot to do with how much “free methylfolate” can be delivered to the body. 

Some methylfolates have a crystalline molecular salt structure and others an amorphous salt structure. This molecular structure correlates directly to a methylfolate’s stability and therefore also its purity and potency. 

Methylfolates with a crystalline molecule structure are more potent and pure and remain so for longer due to their stable structure.

The most bioavailable forms of methylfolate are L-Methylfolate, L-5-MTHF, L-5-Methyltetrahydrofolate, (6S)-L-MTHF, and (6S)-L-Methyltetrahydrofolate. 

The “L” or “(6S)” forms are chemically identical. This form is also the most biologically active and the form the human body will be able to utilize directly.  On supplements, these may be labeled as:

• L-5-Methyltetrahydrofolate, Calcium
• (6S)-5-methyltetrahydrofolic acid
• calcium salt L-methylfolate
• (6S)-5-methyltetrahydrofolic acid monosodium salt
• L-methyltetrahydrofolate, glucosamine salt

• Folic acid
• D forms and (6R) forms of methylfolate are exactly the same (these are less biologically active and are referred to as D-5-MTHF or D-5-Methyltetrahydrofolate, (6R)-5-MTHF, (6R)-5-Methyltetrahydrofolate). This is a cheap form that can be substituted in lower quality products.When individuals have symptoms or medical conditions linked to folate deficiency, such as anemia, fatigue, or mood disorders
• 5-Methyltetrahydrofolate- if labeled this way a product can contain the D/6R isomer form of methylfolate which would actually be considered a “contaminant” in a pure active L-methylfolate.

Both the natural L-isomer and the inactive D-isomer of 5-MTHF have two chiral centers. However, both chiral centers in L-MTHF have the natural L-configuration (6S, αS), whereas in the D-isomer (D-5-MTHF) the configuration of the chiral carbons is the inactive (6R, αS).

Chemically speaking, the L/(6S) and D/(6R) isomers are mirrors of one another.

One is usually considered the “active” ingredient in a compound and the other is often considered “inactive”, "unnatural" or a “contaminant”.

The (6S, αS) isomer of calcium L‐methylfolate corresponds to the natural form of folate. This simply means that the (6S, αS) isomer is considered the pure form the body can use.

Any form of methylfolate that does not specify the L isomer form (or (6S) isomer form) of methylfolate may not be 99% pure biologically active methylfolate.

Folates degrade under light, heat, oxygen, moisture, and acidic pH, which is why stability is so important.

Crystalline salt molecules are considered extremely stable due to their regular structure, lower energy state, efficient packing, and long-range order. Amorphous salt molecules are known to be much less stable due to a more disordered atomic arrangement, resulting in higher energy states, greater potential for atomic movement, and higher exposure to oxygen. Chemical degradation can also affect high-energy amorphous molecules.

The purity of an ingredient refers to the percentage made up of only the 6S or L-isomer. In a pure L-methylfolate such as Cerebrofolate™, 98-99% of the ingredient is made up of the calcium salt molecule that the (6S) isomer of 5-MTHF is bound to. This means it contains less of the 6R or D inactive isomer content in the raw ingredient. 

When you ingest a product that is said to be ~98-99% pure L-Methylfolate, after the calcium salt, water and impurities all dissolve, 80% of the total raw ingredient amount (for Cerebrofolate™) is actually the active (6S) or L-isomer of 5-MTHF that’s available for the body to absorb. 

This is referred to as the “free methylfolate” percentage of a nutrient. During ingestion, methylfolate becomes available for use in the body through a process called “first-pass metabolism” or “first-pass absorption.” Cerebrofolate™ has been tested and confirmed to have the highest potency percentage of any other methylfolate on the market.

Cerebrofolate™ is superior to other L-methylfolates for many reasons.

Cerebrofolate™ is a crystalline (Type I) calcium salt form of (6S)-5-methyltetrahydrofolate (or L-5-MTHF). Most clinical studies on methylfolate so far have used a bioidentical crystalline form, Type I calcium salt structured methylfolate.

Cerebrofolate™ has a molecular weight of 497.5g/mol, which facilitates its transfer through intestinal cells. L-5-MTHF glucosamine is almost twice as heavy at 817.8g/mol, which can slow down the transfer.

Cerebrofolate™ comprises 80% “free methylfolate”, while L-5-MTHF glucosamine comprises only ~52% “free methylfolate”. This makes Cerebrofolate™ the most potent L-methylfolate on the market today. Ingesting just 1 mg of the raw ingredient provides 0.80 mg of absorbable L-methylfolate.

Cerebrofolate™ is produced in a cGMP facility which is FDA registered and audited, FSSC22000, Kosher, Halal and ISO9001 certified. FSSC22000 represents the highest level of quality and certification for ingredients used in dietary supplements. While most companies employ skip-batch testing (testing once every determined number of batches), every single batch of Cerebrofolate™ is tested for impurities and heavy metals.

Cerebrofolate™ has been shown to retain its stability for up to two years when stored at room temperature.

Some L-methylfolate products are now available as a prescription in the USA under the classification “medical food”. 

These are prescribed for people who have conditions related to folate deficiency. Examples include Deplin®, Metanx®, Cerefolin®, NeevoDHA®, Enlyte® and XaQuil XR®.

When comparing products, look for a CofA (Certificate of Analysis) detailing the exact amount of the 6R or D-isomer (as tested) in their methylfolate. 

This should be considered an ‘impurity’ and should show up as less than 0.15%. In the CofA for Cerebrofolate™, this value is reported in our test results as undetectable.

So, a product previously labeled as providing 1,000 mcg of folate now must be labeled as 1,700 mcg DFE. On the other hand, a product previously labeled as providing 1,000 mcg that now shows 1,000 mcg DFE may have reduced the amount of folate from 1,000 mcg of ingredient down to ~590 mcg of ingredient.

Methyl-Life® formulas have not changed at all.Our products still carry the exact same amount of methylfolate that they always have, but the new DFE labeling on our products may suggest that amounts are much higher.