What is 5-MTHF? The Ultimate Guide to Folate and Methylfolate

Written by Tom Von Deck
Reviewed by Kimberly Langdon
5mthf label intelligent labs supplement

What is 5-MTHF? This guide is intended to provide you with all of the most helpful and evidence-based information about vitamin B9, folate, folic acid, 5-MTHF, and the supplements and foods that keep your B9 at healthy levels.

You’ll learn about the problems that can lower B9 to unhealthy levels – even if you’re taking supplements or eating folate-rich foods – and how to solve or prevent them. Consider it an FAQ for current and prospective users of folate supplements or for those who are merely curious.

The nutrition of B vitamins is a very nuanced subject. There are many decades of scientific studies about their effects, how they positively and negatively interfere with foods and drugs, the best forms of B9 to take, and so much more. We went digging through these studies so that you don’t have to.

If you have any questions that are important to you that are not answered in this guide OR…

You need more clarity about one of our answers and/or you don’t understand it OR…

You disagree with anything in the guide…

Don’t be a stranger! Let us know! Contact us or leave a comment below.

What is Folate?

Eggs, beans, and bread are sources of folate

The word “folate” describes a family of nutrients found in foods, especially green leafy vegetables, beans, and eggs. These are naturally occurring and water-soluble forms of vitamin B9. (1)

Normally, people use the word “folate” as if it describes a single nutrient. “Folates” might just make you sound funny because this plural form is less common.

Foods high in folate include kale, broccoli, citrus fruits, asparagus, bananas, beans, and liver. (1)

Beans and liver provide far more natural folate than the other foods in the above list.

If a person has high folate needs or is deficient after consuming a lot of it, it is very likely that food is not the best way for them to get folate. There are diseases and genetic factors that can prevent people from metabolizing folate in foods. Keep reading for more details.

What is Folic Acid?

Folic acid is a synthetic and water-soluble form of vitamin B9. It’s normally created for supplementation. Many loaves of bread, pastries, and cereals contain folic acid.

spaghetti is fortified with folic acid in many countries

In 1998, the USA mandated that folic acid be added to particular grains to ensure adequate B9 intake on a mass scale.

As of 2017, 86 countries mandated through law that wheat flour must contain some minimum level of folic acid. (2)(3)

16 of the 86 did the same for maize flour. Six nations also added rice flour to the list.

What is 5-MTHF?

5-methyltetrahydrofolate, or 5-MTHF, is a natural form of vitamin B9 your body is ready to absorb and use for nutritional purposes. It is now a very popular form of folate for this reason, especially among people who have problems metabolizing other forms of B9 from foods and supplements.

5-MTHF Synonyms:

  • L-5-MTHF
  • L-methylfolate
  • L-methylfolate calcium (only if it’s bound to calcium salt)
  • Methylfolate
  • Levomefolic acid

Note the “L” in some of the above names. This letter indicates that the vast majority of human bodies can absorb it. “6(S)” instead of “L” indicates this as well.

If the “L” is replaced with “6(R),” then the formulation probably won’t help you much.

Which Form of Folate Does Your Body Best Absorb & Use?

A study published in the British Journal of Pharmacology compared the body’s absorption of 6(S)-5-MTHF to folic acid. Subjects were healthy women who had problems absorbing food-based folate and folic acid because the genes required to process these nutrients were faulty. 6(S)-5-MTHF was far better at getting usable vitamin B9 into the blood plasma where it can begin working its magic.

In this study, researchers used 6(S)-5-MTHF that was bound to calcium salt. Yes, it did run circles around folic acid in terms of absorption…


Another study compared the calcium-based stuff with another form of 6(S)-5-MTHF bound to glucosamine instead of calcium in rats. Researchers also compared both of them to folic acid. The study showed 1.8 times higher peak blood plasma levels than 5-MTHF bound to calcium salt and 3.1 times higher levels than folic acid. (5)

1mg 5mthf l-methylfolate as quatrefolic acid supplement

This is why Intelligent Labs uses the 6(S)-5-MTHF bound to shellfish-free glucosamine. In our supplements, we use a patented formula called Quatrefolic Acid® and we offer 1mg 5-MTHF and 5mg 5-MTHF.

5-MTHF Brand Names

Metafolin® – A 5-MTHF supplement using L-methylfolate calcium. It’s available only through sellers licensed by its creators.

Deplin® – Available by prescription, this 5-MTHF formulation was created to meet the nutritional needs of depressed patients and enhance the activity of antidepressant drugs.

Quatrefolic Acid® – Again, this is the stuff we use at Intelligent Labs. Patented internationally by Gnosis, it is the most scientifically advanced 5-MTHF formulation on the market. This 5-MTHF is better-absorbed by your body because it’s bound to shellfish-free glucosamine instead of calcium.

Intelligent Labs has two 5-MTHF supplements available with two different dosages. 

What Health Benefits Do Folate & 5-MTHF Provide?

Required for Essential Body Functions

B9 is required for making: (6)(7)(8)

  • Energy from carbs
  • DNA & RNA
  • Red & white blood cells
  • Melatonin, a chemical that regulates sleep
  • Important neurotransmitters like norepinephrine, serotonin & dopamine
  • Your nervous system

bush beans are great sources of dietary folate

Prevent Birth Defects During Pregnancy

Healthcare providers often suggest that pregnant women supplement with folate while pregnant to prevent birth defects such as neural tube defects. This is because the effects of folate shortages on the baby’s development have been well-studied for a long time. (9)

Sufficient folate is required for the development of the nervous system during pregnancy. This is crucial from the beginning of the pregnancy. Women normally don’t realize they’re pregnant until a few weeks in. Even if you’re still trying to conceive, it’s a good idea to make sure your folate levels are up to par. (6)

Read our blog post on why taking 5-MTHF activated folic acid is best for prenatal health.

ATTN Dads: This is for You, Too!

Men trying to conceive should make sure they’re not folate deficient. A 2013 study found that men lacking healthy levels of this vitamin during conception may raise the probability of deformities considerably. (10)

Some women may be advised to start supplementing a few months before conception to increase the certainty of a healthy baby. (11)

Click here to know more about the benefits of folic acid for men.

Scientists have found 5-MTHF to be effective for depression symptoms

May Reduce Depression Risk and/or Enhance Antidepressant Drugs

Deplin®, a prescription form of 5-MTHF, was patented specifically for treating depression and enhancing the benefits of antidepressants in depressed patients. The way 5-MTHF helps with depression is unknown, but studies do show supplements can be helpful. Depression studies typically use very large doses compared to normal nutritional uses.

In a 2013 study of more than 500 patients receiving treatment for depression, automated phone surveys indicated a better average quality of life and increased satisfaction with their depression medications after three months. Satisfaction with relationships with relatives, friends, coworkers, lovers, and strangers also improved. The overall differences after 95 days were pretty dramatic. Subjects used a super-potent prescription form of 5-MTHF. Each dose was either 7.5mg or 15mg. A starting dose for normal 5-MTHF users without depression is typically 1mg or less. (12)

One reason for these benefits in depression patients could be that folate is an essential part of the production of major neurotransmitters like serotonin, dopamine, and norepinephrine and may help regulate them. (13) This is why we added folate to our 18-ingredient natural nootropic stack, Seneca Nootropic. It’s a well-rounded mental health booster and cognitive enhancer that will help you achieve your daily goals! Check out our article on What are nootropics?to learn more about how Seneca and nootropics, in general, can help you!

Additionally, 5-MTHF may work well for some symptoms of bipolar disorder as well.

A six-week study of 10 people with major depression and bipolar disorder showed promising results: (14)

“The investigators found that patients with bipolar disorder taking L-methylfolate showed improvements in depression symptoms, functioning, cognition, and suicidal ideation.”

WARNING: If you suffer from depression, always talk to your doctor before using any form of folate supplement, even at low doses.

Reduce Homocysteine, an Inflammatory Chemical

Homocysteine is a compound in the human body that increases inflammation. Many diseases are rooted in inflammation.

High homocysteine levels may increase the risk of: (18)

  • Blood clots
  • Stroke
  • Alzheimer’s
  • Heart attacks
  • Coronary heart disease
  • Osteoporosis
  • Atherosclerosis

High levels of this compound are associated with low levels of vitamins B6, B9, and B12. This combination is a strong predictor of cognitive decline in men, and probably in women as well. (15)

Healthy levels of all three of these B vitamins are important for keeping homocysteine under control. 5-MTHF can prevent some cognitive decline on its own, but you’ll likely fare much better by keeping the other two at healthy levels as well. (15)(16)(17)

Other causes of high homocysteine levels include: hypothyroid problems, kidney diseases, and psoriasis. This means: don’t automatically blame vitamin B deficiencies. (18)

As you have already read above, laws in dozens of countries lowered homocysteine by mandating that flours be fortified with folic acid. A 24-week randomized placebo study demonstrated that 5-MTHF is a lot better than folic acid at lowering homocysteine levels in healthy humans. (19)

May Reduce Stroke & Heart Attack Risk

5-MTHF could improve heart and circulatory health by reducing homocysteine and through other mechanisms. However, it’s complicated. It might only reduce your risk of heart attack or stroke if you’re folate deficient.

5-mthf and folate may reduce stroke and heart attack risk

Here’s a summary of key evidence that almost reads as a mystery story…

A 2015 study found that men who supplemented with folic acid and took enalapril, a drug that lowers blood pressure, lowered their risk of stroke over a 4.5-year period. The results were significant for the folic acid-enalapril group compared to the enalapril-only group. Old studies from the 70’s also appear to show decreased stroke and heart attack risk from increased folate use. (20)

On the other hand, some U.S.-based placebo studies didn’t show a decrease in stroke or heart attack risk. This could mean that folate only has this effect when people are deficient. Recall that the USA began fortifying grains in 1998, which could explain some results from the 70’s. People had lower folate levels. (20)

China does not fortify grains, which means their population may be deficient as well. Some of the old U.S. studies tracked people who had a history of stroke and heart attack. These people may have decreased their risk with medicines and foods other than folate as a response to these events. (20)

How Do You Know You Have a Folate Deficiency?

Some signs that a lack of folate is causing anemia (red blood cell shortage) Chronic sluggishness & fatigue: (21)

  • Shortness of breath
  • Short temper, annoyance & irritability
  • Your white skin looks extra pale
  • Other signs of low blood oxygen, like memory problems

Other signs of folate deficiency: (22)

  • Premature hair graying
  • Swollen tongue
  • Sores or ulcers in mouth
  • Baby has birth defects & deformities & you’re the mom or dad
  • Diarrhea
  • Growth problems

Self-diagnosis of folate deficiency is tough. This is partly because there is overlap between the symptoms of a lack of folate and a lack of other B vitamins. Your doctor likely has tests to narrow down the causes of the symptoms.

What Causes Folate Deficiency?

A Diet Lacking Folate-Rich Foods

If you’re not eating enough beans, eggs, green vegetables, and other folate-rich foods or supplements, then you’ll likely be short on folate in your body.

kale farmers supply the people with natural folateIssues that Prevent Absorption from Foods & Supplements

A lot of things can cause poor absorption of folic acid and food-based folate, including: (21)

  • Diseases like Crohn’s, Celiac, some cancers & some kidney disorders
  • Defects in the MTHFR gene, which are common
  • Interactions with medications that interfere with folate
  • Excessive use of alcohol or antacids
  • Mutation of Genes Responsible for Metabolizing Folate

Folic acid and natural folate in foods need to go through multiple chemical reactions before they become 5-MTHF, the only useful form.

Most of us metabolize folate and folic acid and transform them to 5-MTHF efficiently. There is a gene that controls this process. It’s called MTHFR, and we each have two copies of it. However, a lot of us have variations of one or both of these gene copies that don’t allow the transformations to 5-MTHF. If one gene copy is bad for folate absorption, your efficiency may take a huge hit. If both copies are bad, you won’t metabolize much of folate or folic acid. (23)

How do you know you have one or two bad copies of the MTHFR gene? You’ll need to take a DNA test and have it sent to a medical lab. You can find labs for this purpose locally and online. Research the lab first or let your doctor choose one.

The easiest way to solve this gene variation problem is to use a 5-MTHF supplement, which doesn’t need a series of chemical reactions for your body to use it properly. In other words, 5-MTHF is already bioactive.


The link between obesity and insufficient folate levels is very strong, but it seems that no one has figured out why.

A review of studies published between 2005 and 2015 examined folate levels in obese women of “childbearing age,” with special attention on pregnant women. The goal of the researchers was to look at possible causes of the high percentage of folate deficiency in these women. They noted a British study that ruled out factors like vitamin supplements, diet, and age. They also pointed out several other studies that ruled out diet as a cause. All they could do was recommend more studies on this matter plus tips on how to design them. (24)

The point is: Obesity itself, or particular causes of obesity, just might lower folate to unhealthy levels. The correlation is strong, and all the questions are about what leads to what.

Another study noted a strong correlation between obesity and folate deficiency:

In 2016, researchers reviewed studies with the intention to update the 2008 American Society for Metabolic and Bariatric Surgery Nutrition in Bariatric Surgery Guidelines. The guidelines are based on studies examining nutrient levels before and after surgical procedures for weight loss. The new 2016 guidelines recommend screening for folate deficiencies before this type of surgery. The reason for this is that up to 54% of obese patients are folate deficient. (25)

Researchers had no intention to investigate cause and effect in this case. They just noted the link, and they responded to it by recommending pre-surgery folate monitoring and supplementation.

Does Cooking Folate-Rich Foods Destroy the Folate?

Kale rich in vitamin b9 in its natural folate form

Whether cooking reduces the folate content in food depends on the food, cooking method, and cooking time.

Normal boiling times can eliminate roughly half of the folate in spinach and broccoli, but steaming does not reduce folate at all. Boiling potatoes and grilling meat don’t seem to reduce folate either, even if you cook them longer than normal. (26)

Boiling onions reduces folate by 35% while baking them only destroys 15% of it. It also turns out that boiling peas retains the most folate compared to other cooking methods. If you boil beans for two hours and then either bake them or fry them, they lose 50%. One study recommends soaking them in saltwater and then boiling them in fresh water to preserve the most nutrients. (27)

Do Pregnant or Expecting Mothers Need to Supplement with Folate?

It is generally accepted in the medical community that keeping folate levels up to par is a good idea. It most likely prevents some types of birth defects, and the strong correlation is well-established.

As mentioned above, you need plenty of bioactive folate in your body from the moment you become pregnant to ensure the baby’s nervous system develops properly. This could mean beginning the process while you’re still trying to conceive.

Supplementation with 5-MTHF is the surest way to know your body will actually absorb enough folate.

If you’re pregnant, take this up with your doctor. Don’t just play around with supplements without guidance that’s custom-tailored to your unique circumstances and based on thorough lab testing.

Can You Have Too Much Folate in Your Body?

This is a controversial issue in medical science. Some researchers say you can have too much folic acid circulating in your body, which can lead to unmetabolized folic acid and even possible health problems (28). Because of the controversy, and the need for more studies, you may find government health agencies refusing to take sides in these debates and advising consumers to err on the side of caution instead.

None of this is likely an issue for 5-MTHF or dietary folate that forms naturally in food.

What can too much folic acid do?

May Hide Signs of B12 deficiency

Too much folic acid in your body may mask signs of megaloblastic anemia caused by vitamin B12 deficiency. This is not a consensus. It’s still a mystery to researchers. If it’s true, then a doctor may miss the diagnosis. This can worsen any blood-related problems and harm your brain and nervous system. The brain damage can cause rapid cognitive decline and confusion. (29)

What is a consensus is that this is not a problem for 5-MTHF, which is what the other forms become when they are metabolized properly. Eating too many beans, oranges, or green vegetables with high folate is also not an issue health experts seem to be worried about. (39)

Vitamin B12 deficiency is thought to be a bigger problem for vegetarians and older adults than for most others. Vegetarian diets don’t supply enough of this vitamin and older adults have a hard time absorbing it. Both groups can supplement with sublingual (under the tongue) B12.

woman sleeping on a sofa

Sleep Disturbances & Mood Problems

Too much folic acid, especially when taken in supplements, could cause sleep problems and irritability. (30)

Nausea & Appetite Loss

Some people may lose their appetites or become nauseous, especially if they get too much folic acid from supplements or multivitamins. (30)

The Solution

When you take a supplement for folate, make sure it’s in the bioactive form: 5-MTHF.

Read the labels on your multivitamins. Do they contain too much folic acid? Most adults should get about 0.5mg of folic acid per day. Read the labels on your breads and cereals, too.

If you’re taking a 5-MTHF supplement, then try to keep the folic acid from fortified foods at a minimum and avoid multivitamins containing folic acid. This may or may not be an issue that interferes with 5-MTHF.

The U.S. National Institutes of Health’s Office of Dietary Supplements has set a recommended daily upper limit of 1mg for folic acid that comes from fortified grains and supplements. They have not set a limit for folate that comes from vegetables or 5-MTHF. (29)

According to the Harvard Health Letter, folic acid from grains can add up quickly (31). See their list below.

Common Foods Fortified with Folic Acid:

  • Bowl of Special K Cereal: 0.394mg
  • Serving of pretzels: 0.172mg
  • 1 cup of cooked spaghetti: 0.166mg
  • 1 multivitamin: 0.4mg

Total = 1.132mg

It’s not hard to blow through that upper limit in one day, so watch your grains and vitamins, especially if you have a hard time metabolizing folic acid. You also want to make sure you’re getting enough B12 and that your body is using it.

grains and vegetables are sources of vitamin b9

Are There Advantages of 5-MTHF Over Other Forms of Folate?

5-MTHF Requires No Chemical Reactions to Become Useful in the Body

Folic acid, which is synthetic, needs multiple chemical reactions before it becomes bioactive 5-MTHF.

Dietary folate, which forms naturally in foods, also requires chemical reactions before it becomes 5-MTHF, but less of them than folic acid does.

In other words, after taking 5-MTHF in a supplement your body has less work to do. No chemical reactions are needed.

Interacts with Less Medications than Folic Acid

Because there is no need for metabolic conversions for 5-MTHF to become bioactive, it is less likely to react with medications and reduce their effectiveness. (33)

Psychiatrists love this because this form of folate can go straight across the blood-brain barrier and into the brain. The blood-brain barrier prevents many substances from entering the brain through the circulatory system. 5-MTHF can go straight to the nervous system. (32)

It is typically the process of metabolism that causes folic acid to interfere with drugs.

Does Not Mask Symptoms of B12 Deficiency

While folate may obscure nervous system damage caused by B12 deficiency-related blood disorders, it’s well established that 5-MTHF does not. (34)

Here’s an infographic showing a clear advantage of taking 5-MTHF over folate and folic acid:

the different forms of vitamin b9: folate vs folic acid vs 5-mthf

What Dosage Should I Start With?

Most people begin with 1mg or less of 5-MTHF daily for normal use. Some situations may require 5mg or more, and a medical professional will usually be well-equipped to guide you through this decision. Just remember that more is not necessarily better when it comes to any form of folate.

Who Should NOT Take 5-MTHF?

If you’re allergic to 5-MTHF, obviously you shouldn’t continue to take it. If you get hives, chest tightness, or shortness of breath, consider it an emergency to be safe.

Talk to your doctor before supplementing with 5-MTHF if you: (35)

  • Are allergic to folic acid in grains or multivitamins
  • Have been diagnosed with B12 deficiency in the past
  • Have bipolar disorder
  • Are pregnant or a nursing mother or you’re trying to conceive (this is to determine proper dosage, which may vary)

Will 5-MTHF React with My Medications?

5-MTHF is less likely to interact with medications than folic acid (33) but don’t use this statement as medical advice. This is something you should discuss with your doctor.

Folic acid can reduce the effectiveness of most seizure medications as well as Pyrimethamine (Daraprim), which treats parasite infections. Methotrexate is a drug that reduces the activity of folate in cells. (36)(37)

On the other hand, a study of folate’s interactions with lamotrigine recommended 5-MTHF supplementation as an alternative way to provide folate for users of the drug. The drug is used to prevent seizures, but the researchers were particularly interested in mood disorders like bipolar depression.

They noted that 5-MTHF doesn’t need to go through chemical reactions before the brain and other systems of the body can use them, so it is less likely to interfere with lamotrigine. (38)

How Should I Store My 5-MTHF Supplements?

Here’s what the reputable Cleveland Clinic recommends on its website:

“Store at room temperature between 59 and 86 degrees F (15 and 30 degrees C). Protect from light. This medicine is quickly broken down and made inactive when exposed to heat or light. Throw away any unused medicine after the expiration date.” (37)

Intelligent Labs uses opaque black bottles to keep all light out.

Please store your supplements where small children can’t access them. 5-MTHF is relatively safe, and an overdose is not fatal. Even with that in mind, the “better safe than sorry” motto should be common practice.

About This Guide

We hope this guide is helpful. Because of the evolving nature of medical science, don’t assume we gave you absolutely all the information you need to know. If you’ve read the whole thing, you know that researchers are debating some of the matters discussed here.

Also, remember that the information is not a substitute for your healthcare provider’s advice. We cannot claim that 5-MTHF is a cure or treatment for any disease. We also can’t claim that our content can help you self-diagnose. Only your doctor can provide proper diagnosis and treatment of health conditions.


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