[Last updated 7th March, 2023]
Folate and folic acid are nutrients required for many critical functions in the body.
Unfortunately, many who have a genetic MTHFR mutation are unable to utilise these nutrients properly.
L-Methylfolate (5-MTHF) has emerged as a popular alternative, and has been used as a complementary medicine in several recent clinical trials.
This article covers what you need to know about it, but explained in human terms.
What is L-Methylfolate (5-MTHF)?
L-methylfolate is the biologically active form of vitamin B9.
That means it is the form the human body can actually use in circulation.
It goes by several other common names including:
- L-Methylfolate calcium (refers to the calcium salt molecule it is attached to)
- Metafolin and Deplin
- 5-MTHF and L-5-MTHF (in this article 5-MTHF refers to L-5-MTHF)
- Levomefolic acid
- (6S)-5-methyltetrahydrofolate and Quatrefolic.
The letters or numbers before the name refers to the 3D chemical structure of that compound.
In this case all you need to know is that L- and 6(S)- indicates biologically active L-Methylfolate (helpful). D- and 6(R)- indicate non-biologically active L-Methylfolate (not helpful).
Some products may only list Methylfolate or 5-MTHF, without specifying if which form it contains. If the label does not state L-Methylfolate, Metafolin or Quartrefolic then it may not be the biologically active form.
Summary: L-Methylfolate, also commonly known as 5-MTHF, is the active form of vitamin B9 the human body can actually use. L- and 6(S)- forms are biologically active, while D- and 6(R)- are not.
L-Methylfolate vs Folic Acid v Folate
The other forms of vitamin B9 you should know are folic acid and folate.
These are the forms we eat, although L-methylfolate is also found naturally in some high-folate food too.
Folate is often called the natural form of vitamin B9, but it actually refers to a family of different compound that occur naturally in some vegetables.
Folic acid is the supplemental or “synthetic” form of vitamin B9 and is typically the first line of treatment for folate deficiency and related health conditions, such as high homocysteine and Neural Tube Defects (1, 2).
In fact, it has been so beneficial for the general population that the addition (fortification) of folic acid to wheat flour is now mandatory in Australia, USA, Canada and several other countries (3).
But note that folic acid is also found naturally in foods, as it is just another compound of folate.
Any folic acid we ingest must be metabolised (converted) into Dihydrofolate (DHF), Tetrahydrofolate (THF), and then finally into L-methylfolate (5-MTHF) to be used in the body. Once in this form it can be transported into cells, tissues and even across the blood-brain barrier.
This is what they look like alongside each other… you can see they are almost identical:
But issues can arise during metabolism for those with an enzyme issue, such as an MTHFR mutation.
These individuals cannot complete the final metabolic step that converts folic acid to the active form L-methylfolate (5-MTHF) (4).
Note that the last step (the last black arrow) requires the MTHFR enzyme and Vitamin B2 to convert 5,10 methylene-THF to L-methylfolate.
This leaves folic acid supplements somewhat useless to you and potentially harmful in the long run (5).
Summary: Any folic acid or folate we ingest must be converted into its active form (L-methylfolate) to be useful. However this becomes a problem if you cannot do this conversion effectively, such as those with an MTHFR mutation.
Benefits of L-Methylfolate (5-MTHF)
Supplementing with L-methylfolate bypasses the entire folic acid metabolism cycle, which is good news if you have an MTHFR mutation.
Think of it like receiving a cooked meal instead of all the raw ingredients. An MTHFR mutation is equal to not having the pots and pans to cook with.
Studies show that L-Methyfolate supplementation is equally (if not more) effective than folic acid for increasing circulating folate in those with an MTHFR mutation. It is also highly effective at reducing homocysteine levels in healthy people (6, 7).
It is also better absorbed and interacts with fewer medications than folic acid (8).
Summary: Research shows it is just as effective as folic acid, if not better absorbed and tolerated.
What should I eat with an MTHFR mutation?
Get your free guide here:
What should I eat with an MTHFR mutation?
Get your free guide here:
L-Methylfolate During Pregnancy
Active folic acid is highly protective against Neural Tube Defects.
This is why all national and international health organisations advocate for folic acid supplementation before and during early pregnancy.
For those who do not metabolise folic acid well, supplementing L-Methylfolate is the clear alternative while pregnant. Especially if you have a homozygous C677T or A1298C mutation, which is thought to increase your folate requirements even more.
The link with miscarriage
Understanding why miscarriage occurs at all is still an active area of research.
Many large observational studies have found a link between MTHFR mutations and increased risk of miscarriage, at least for those of Asian decent (9, 10).
Not all studies found the link, and observational studies do not prove cause and effect, so we cannot say if it’s true for certain. Considering the important role of active folate in fetal growth and development, ensuring adequate L-Methyfolate intake should be your top priority.
Summary: Supplementing with L-Methylfolate while pregnant is the clear alternative for those who suspect an issue with metabolising folic acid.
Other L-Methylfolate Benefits
There are several other areas of health where it has been trialled or used successfully in treatment:
L-Methylfolate (5-MTHF) in depression
L-methylfolate is becoming widely recognised as an effective complementary medicine for patients with severe depression. That is, using it alongside pharmaceutical drugs (SSRI) to enhance the overall effectiveness of treatment (much like fish oil and depression).
Several randomised clinical trials have shown that 15 mg/day of L-methylfolate calcium is a safe, effective and well-tolerated treatment for patients with major depressive disorder who experience partial or no response to SSRIs (11, 12).
It appears to be particular effective in those with certain genetic variations (including MTHFR) and those with elevated inflammatory markers (13, 14).
L-Methyfolate (5-MTHF) in patients with diabetic neuropathy
Diabetic neuropathy is nerve disorder that develops over time in those with poorly managed type 1 or type 2 diabetes.
In a recent study, 544 patients with diabetic neuropathy were given Metanx (L-methylfolate-methylcobalamin-pyridoxal-5-phosphate) to trial for over a year. Based on self-reported surveys, overall pain rating decreased by 32% those previously treated with medications reported a 52% improvement in medication satisfaction (15).
Metanx is a combination vitamin B supplement, so this study did not test the effects of L-methylfolate on its own.
Summary: Early studies show L-Methylfolate supplementation may be beneficial in treating severe depression and diabetic neuropathy.
Important Considerations and Side-Effects of L-Methylfolate
There are several important factors to consider before starting L-methylfolate (5-MTHF).
- Supplementing L-methylfolate bypasses the body’s natural checkpoints for preventing over-methylation. So we must be incredibly cautious with the dosage, as unnatural levels of folate is linked with several issues including cancer risk (16, 17, 18).
- As with almost any supplement, this is not something you should take forever. Nor even everyday in most cases, but rather as a complementary medicine prescribed by your doctor. L-methylfolate also exists naturally in foods, so that should be your preferred source.
- Your vitamin B levels – particularly vitamin B12 (cobalamin) – must be adequate before taking L-methylfolate. Otherwise homocysteine (not good) cannot be broken down and transformed, even with adequate folate. Think of L-methylfolate as the fire, and vitamin B12 as the firewood.
- Minimise intake of folic acid. That means store-bought bread and anything else made with fortified wheat flour.
- L-methylfolate (or any other form of vitamin B9 supplementation) can interact with numerous drugs and medications, so be sure to speak with your doctor first.
- If you have been diagnosed with depression, you must first be screened for risk of bipolar disorder. Folate can enhance antidepressant effects of known antidepressant drugs, and is believed (although not clinically proven) to potentially trigger mixed/manic episodes in those with bipolar.
Potential side effects
As with any biologically active supplement or drug, certain people may experience unwanted side effects.
Unfortunately it is quite common with L-Methylfolate.
These are the most common symptoms and may appear after 2 weeks, 1 week, or even 1 day:
- sore muscles and aches
- acne or rash
- insomnia and irritability
- severe anxiety
- nausea, headaches and migraines
If you experience this then you should speak with your doctor as soon as possible to reduce the dose or take a break. Persistent supplementation through symptoms can be dangerous.
There are also reported steps you can take to relieve some of the L-methylfolate side effects. This includes a small 10-50 mg dose of niacin, or a glutathione supplement (which I’m sceptical actually helps).
Additionally, the idea of taking more supplements to offset side effects of another is the same as taking more pharmaceutical drugs to offset the side effects of another drug.
Summary: There a very important factors to consider before taking L-methylfolate. Side-effects are also common and potentially dangerous if you do not address the problem immediately.
Recommended L-Methylfolate Dosage and Product
The FDA and European Food Standards Agency have approved L-methylfolate (5-MTHF) calcium supplements (16).
It can be obtained with or without prescription, but for non-prescribed supplements ensure the label specifies the amount of active L-methylfolate.
Prescription folate is available in 7 mg and 15 mg dosages which is very high. Unless recommended by your doctor, starting at less than 1 mg (1000 mcg) and then re-assessing is much more sensible if you are using because of an MTHFR mutation. 500 mcg (0.5 mg) or less appears to be the safest starting point.
If this is you, I recommend this supplement (disclosure: this is an affiliate link). The reason is because it contains 800 mcg of L-methylfolate (start with half) plus 1 milligram of vitamin B12 per pill.
It is also gluten, dairy and soy-free for those concerned, but always check with your doctor before taking any new supplements.
Again, there are a lot of risks associated with L-methylfolate supplementation, and it’s not recommended as a long-term solution.
You can get L-methylfolate from natural foods too.
More on MTHFR and other genetic variations
- MTHFR C677T and A1298C: Explained In Plain English
- MTHFR Mutation, Symptoms and Diet: What You Need to Know
- APOE4, Diet and Alzheimer’s Disease: Explained in Human Terms