Everything You Needed To Know about Methylation and Methylfolate
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The terms methylation, L-Methylfolate, and MTHFR have received a good deal of attention in recent years. However, much of the information found online is conflicting, confusing, or incorrect.
Your health matters. It’s vital that you know how to distinguish fact from fiction.
We here at Methyl-Life are experts on methylation, L-Methylfolate, and health issues caused by MTHFR. We’d like to help you understand the importance of proper methylfolate supplementation - and the right product for you - without the scientific jargon.
Common questions about Methylation:
What is methylfolate?
To understand methylfolate, it’s important to first understand B vitamins, the importance of folate, and the process of methylation.
Why vitamins B1, B2, B3, B5, B6, B7, B12 are important
There are 13 vitamins that are essential to the proper functioning of your body. Among these is a group of vitamins called the B vitamins, which include thiamin (B1), riboflavin (B2), niacin (B3), pantothenic acid (B5), pyridoxine (B6), biotin (B7), folate (B9), and cyanocobalamin (B12).
While all the B vitamins have a similar molecular structure, they each have very different roles within the body. Together, they help your body break down glucose (blood sugar) and create energy in the form of ATP molecules. Without ATP, your most crucial organs such as your heart and brain would not be able to function.
Folate is the natural form of vitamin B9 in food, while folic acid, on the other hand, is the synthetic (man-made) form of folate that is added to fortified foods or dietary supplements.
Folate is vital to your health no matter what age you are or what stage of life you’re at. It’s required for many different functions within the human body, particularly the production of red blood cells. Folate occurs naturally in many foods such as legumes and leafy greens.
Deficiency or low levels of folate can be caused by genetics, certain diseases, medications, or by not obtaining folate from your food. Folate deficiency can lead to decreased red blood cell count, also known as anemia. In serious cases, folate deficiency can lead to a condition called hyperhomocysteinemia: high levels of a certain amino acid in the blood.
Key point: the folate vitamin is most active when converted into methyl folate.
Common questions about methylation
Methylation is a metabolic process crucial to every cell and organ in your body. It’s like billions of little switches turning on and off every second, controlling everything from your metabolism and your stress response, to your brain chemistry and detoxification.
In short, methylation is life: you would not exist without it.
From a scientific perspective, methylation is the transfer of a methyl group (one carbon atom and three hydrogen atoms) onto the amino acids, proteins, enzymes, and DNA within your body.
Adding a methyl group to these molecules is necessary for certain biochemical reactions that allow important functions such as thinking, repairing DNA, turning genes on and off, fighting pathogens and triggering detoxification (especially in the liver).
Methylation is also crucial for the proper functioning of the Hypothalamic-Pituitary-Adrenal (HPA) axis, as well as the creation of all neurotransmitters. For example, the conversion of norepinephrine to epinephrine depends on an enzyme that must first be activated by methylation.
What is methylfolate used for?
L-methylfolate is a dietary supplement that may be prescribed for people who have conditions related to folate deficiency. This is also the most common name for the nutrient.
L-methylfolate is a cofactor in the production of monoamines (serotonin, dopamine, and norepinephrine), which are involved in the regulation of mood and the mechanism of action for antidepressants. The bioavailability of L-methylfolate is much higher than folic acid alone.
Why do people need methylfolate rather than folic acid?
We all have two genes called the MTHFR gene (methylenetetrahydrofolate reductase) which we inherit from our parents (one from each parent). The MTHFR gene is important because it provides instructions to your body for making an enzyme called methylenetetrahydrofolate reductase.
This enzyme plays many important roles in your body, including the processing of amino acids. More importantly, it’s required for the conversion of a form of folate called 5,10-methylenetetrahydrofolate to a form called 5-methyltetrahydrofolate. This is the primary active form of folate in your blood, and it’s absolutely necessary for the conversion process of the amino acid homocysteine into methionine.
Unfortunately, the MTHFR gene has the potential to mutate. A mutation will either affect the enzyme’s ability to function normally or it can completely inactivate it. This can lead to a variety of health issues, particularly related to the nervous system.
Up to 70% of people with depression are found to have a genetic variant of the methylenetetrahydrofolate reductase enzyme that compromises their ability to convert dietary folate and particularly synthetic folic acid into L-methylfolate.
Supplementation with L-methylfolate has been found to help improve response to antidepressants in depressed patients who otherwise do not respond adequately. L-methylfolate has also been used to treat patients with clinical depression who have folate deficiency, as well as those with schizophrenia who have also hyperhomocysteinemia related to folate deficiency.
Why is B12 also important?
With so much focus on folate, it’s easy to forget the importance of B12.
Unlike folate, B12 is best absorbed via the sublingual glands under the tongue. Deficiency in B12 is a major cause of fatigue and low red blood cell production. More importantly, however, low B12 is also associated with neurological symptoms such as mood disorders, anxiety, and/or nerve pain. Research has shown a fundamental link between low B12, folate, and major depression.
What is the difference between L-methylfolate and folate?
L-methylfolate or 6(S)-5-methyltetrahydrofolate [6(S)-5-MTHF] is the primary biologically active form of folate and the primary form of folate in circulation. It is also the form that is transported across membranes into peripheral tissues, particularly across the blood-brain barrier.
As the active form of the B-vitamin folate, L-methylfolate is able to penetrate into the blood-brain barrier and influence mood. This form is able to bypass the conversion step mediated by the MTHFR enzyme (methylenetetrahydrofolate reductase). This means that L-methylfolate supplements can be given as a means of improving serum and CNS folate levels, particularly in assisting with the response to antidepressant medication.
In fact, several studies have shown that taking L-methylfolate alone or alongside antidepressants reduces depressive symptoms. Supplementation with folic acid, on the other hand, have had mixed results. Some studies show an improvement in depression while others show no clinical benefit. Some studies have even suggested synthetic folic acid may be linked to cancer.
What time of day should you take methylfolate?
Many doctors and natural health practitioners recommend a split dose in which the patient takes half of their prescribed dosage in the morning and half in the afternoon. Folate has a limited half-life in the body, so a split dosage helps to maintain a steady level of folate in the bloodstream throughout the day.
What is the recommended daily methylfolate dosage?
Prescription methylfolate will be given with dosage instructions from your doctor. These instructions will take into account your individual health history, condition, body weight, other medications, and any other factors that could affect your response.
We recommend seeking a doctor or naturopath who is familiar with MTHFR and methylation. If you’d like to hear more about what some of the doctors we work with suggest, check out our short YouTube video on L-methylfolate dosage, How methylfolate much should I take?
How long does it take for L-methylfolate to work?
Again, this will depend on your dosage, as well as your unique body chemistry and health history. Some people may see results within days or weeks, while for others it may be up to four months.
It should be noted that if you have been taking a large daily dose (for example, 15 mg) for four consecutive months without improvement, it’s not likely you will notice the benefits from this nutrient.
What are the different types of methylfolate?
There are a number of different types of methylfolate, as well as many different terms. Some of these terms include:
- Methylfolate
- L-MTHF
- L-Methylfolate
- L-Methylfolate Calcium
- D-Methylfolate (inactive form)
- D-5-Methylfolate (inactive form)
- Levomefolic Acid
- Metafolin
- 5-MTHF
- 5-Methylfolate
- 5-Methyltetrahydrofolate
- L-5-MTHF
- L-5-Methyltetrahydrofolate
- 6(S)-5-MTHF
- 6(S)-5-Methyltetrahydrofolate
- 6(R)-5-MTHF (inactive form)
- 6(R)-5-methyltetrahydrofolate (inactive form)
- Quatrefolic (6S)-5-methyltetrahydrofolate
- Quatrefolic
What does methylfolate do for the body?
As explained above, folate is involved in neurotransmitter synthesis (i.e. increasing serotonin) and numerous enzymatic reactions throughout the body. One of folate’s most crucial roles is in ridding the body of excess homocysteine, which is vital for the health of the cardiovascular system, immune system, and central nervous system function.
Ordinary folic acid supplements will not provide the full spectrum of effects if an individual is unable to convert folate to its biologically active form called 5-methyltetrahydrofolate (5-MTHF).
Because a large proportion of the population has the genetic enzyme deficiency that prevents the proper conversion of folate to 5-MTHF, many people are vulnerable to low blood folate levels and subsequently, higher than desired homocysteine.
For this reason, taking bioactive folate 5-MTHF directly has been shown to significantly increase blood serum folate levels compared with folic acid supplementation.
Key point: This form of folate is vital for people who have a genetic enzyme deficiency because it requires no conversion to become metabolically active.
Methylfolate is an important cofactor in the healthy production of DNA and neurotransmitters. It also assists with cardiovascular function, hormone production, and many responses within the cells, liver, and reproductive system.
Methylfolate is crucial for:
- Normal growth and renewal of cells, tissues, and organs.
- Healthy cognitive function including balanced mood, memory, and behavior.
- Facilitating the activity of SAMe (S-adenosylmethionine)
- Synthesis of the key neurotransmitters serotonin, dopamine, and norepinephrine.
- Production of the sleep hormone melatonin
- Assisting with the regulation of homocysteine, a potentially toxic human metabolic product
- Promoting healthy pregnancy and fetal development.
- Repairing the myelin sheath for nerve integrity
What are the side effects of L-methylfolate?
While L-methylfolate is a powerful and essential nutrient, supplementation can result in noticeable side-effects in some people. The most common of these include:
- Changes to sleep patterns and/or insomnia
- Difficulty concentrating
- Irritability
- Hyperactivity and excitement
- Brain fog or confusion
- Impaired judgment
- Weight loss
- Nausea
- Gas, bloating, and abdominal distention
- Bitter or bad taste in the mouth
- Sore muscles and/or aching joints
- Skin reactions such as acne or a rash
- Anxiety and/or palpitations
- Headaches or migraines
- Tingling or stinging in the nerves
- Runny nose
How much methylfolate should I take for depression?
Methylfolate dosage for depression requires an assessment from a qualified healthcare provider or naturopath.
Studies involving patients with depressive disorders who are given the prescription medical food L-methylfolate (Deplin) may have to take anywhere from 7.5 mg to 15 mg to achieve its benefits.
A 2012 study published in the American Journal of Psychiatry showed that L-methylfolate at 15 mg/day showed significant improvement in response rate and degree of change in depression scores as compared to continued SSRI therapy plus placebo. This result was established over two randomized, double-blind trials to evaluate the effect of increasing L-methylfolate supplementation to treat major depressive disorder in patients who had a partial response or no response to selective serotonin reuptake inhibitors (SSRIs).
Where to buy methylfolate
Methylfolate supplements are now available in health stores, at pharmacies, and online. Folate 5-MTHF has been declassified as a ‘medical food’ and is now available as a dietary supplement.
However, with so many products to choose from, it’s difficult to know which is good - and which isn’t.
Top methylfolate products on Amazon
Some of the best methylfolate products on Amazon with reviews include:
- Jarrow Formulas Methyl B-12/Methyl Folate and Pyridoxal-5-phosphate (P-5-P) Lozenges
- Jarrow Formulas Methyl Folate 5-MTHF
- One Elevated Methyl Folate+
- Life Extension Optimized Folate (L-Methylfolate)
- Thorne Research - 5-MTHF 1 mg Folate - Active Vitamin B9 Folate
- Esquared Vitamin B12 - 5000 MCG Supplement with Methylcobalamin (Methyl B-12) - Max Strength Vitamin B 12
- NOW Supplements, Methyl Folate 1,000 mcg, Metabolically Active Folate*, Co-Enzyme B Vitamin
Best methylfolate prenatal
It’s vital for women to get adequate folate both before and during pregnancy. Due to the high prevalence of the genetic enzyme deficiency, MTHFR, which prevents proper cellular uptake of folate, supplementation with L-Methylfolate is highly recommended.
The best methylfolate supplement for pregnancy is one that includes the bioactive form of folate (5-MTHF). Some examples include:
- Thorne Basic Prenatal
- Mama Bird Prenatal Multi+, Methylfolate (Folic Acid), Methylcobalamin (B12), Natural Whole Food Organic Herbal Blend
- NATURELO Prenatal
- Methyl-Life Methylated Multivitamin + Cognitive Nutrients (without iron or Vitamin C)
Best methylfolate for depression
As previously mentioned, prescriptions for medical conditions such as depression should be given by a doctor or qualified naturopath. However, some recommended methylfolate supplements for depression include:
- Methyl-Life products - Methylfolate 7.5+, Methylfolate 10, & Methylfolate 15
- One Elevated Methyl Folate+
- Jarrow Formulas Methyl Folate 5-MTHF 400 Mcg
- Jarrow Formulas Methyl B-12/Methyl Folate and Pyridoxal-5-phosphate (P-5-P) Lozenges
What supplements to take if I am vegan with MTHFR?
Most Methy-Life methyl folate supplements mentioned below are vegan, apart from the Methylated Multivitamin + Cognitive Nutrients.
Methyl-Life Product Range
Active Ingredients
Folate: 15,000 mcg from (6S)-5-Methylfolate,Calcium – Magnafolate® PRO
Methylfolate 15 is a high dose (15 mg) of internationally-patented Magnafolate® PRO [(6S)-5-methyltetrahydrofolic acid, Calcium salt, Type C Crystalline molecule (L-Methylfolate)]. It is our best-selling, serotonin-enhancing supplement, providing essential support for healthy mood, immune system function, and nervous system function.
This unique and internationally-patented L-5-Methylfolate ingredient is crystalline calcium salt-based for superior stability and absorption. This proprietary form of methylfolate offers greater purity: approximately 3x more pure than any other competing form of methylfolate. It is also known as L-MTHF, L-Methylfolate, L-5-MTHF, and (6S)-5-Methylfolate.
Folate must be reduced to tetrahydrofolate (THF) within the body before it can become metabolically active with its conversion into 5-Methyltetrahydrofolate (5-MTHF). This is the fully-activated folate derivative normally found in healthy circulation of those who do not have MTHFR genetic variants. Most importantly, it is the already-converted form of folate that can be absorbed and used by the body’s cells immediately.
Benefits of Methylfolate 15
- Formulated specially for people with heightened need for folate due to genetic (MTHFR) defects, dietary deficiencies or drug-induced need (i.e. taking warfarin, coumadin, metformin, etc.)
- Bypasses MTHFR gene mutations to optimize the body’s methylation process
- Boosts energy and motivation
- Helps protect against toxins and disease by boosting glutathione
- Supports overall wellbeing
- May reduce symptoms of depression by promoting SAMe and therefore serotonin
- May help manage homocysteine levels caused by folate deficiencies
- May reduce the risk of cardiovascular disease
- Third-party testing to ensure safety and efficacy
Methyl-Life Product Range
Active Ingredients
Folate: 10,000 mcg from (6S)-5-Methylfolate,Calcium – Magnafolate® PRO
Methylfolate 10 is a high dose (10 mg) of internationally-patented Magnafolate® PRO [(6S)-5-methyltetrahydrofolic acid, Calcium salt, Type C Crystalline molecule (L-Methylfolate)]. It is one of our best supplements for the brain, providing essential support for healthy mood, immune system function, and nervous system function.
This unique and internationally-patented L-5-Methylfolate ingredient is calcium salt-based for superior stability and absorption. This crystalline form of methylfolate offers greater bioavailability over many competing forms of methylfolate. Magnafolate® PRO is the purest methylfolate you can buy, it’s approximately 3x purer than the other leading brands. It is also known as L-MTHF, L-Methylfolate, L-5-MTHF, and (6S)-5-Methylfolate.
Folate must be reduced to tetrahydrofolate (THF) within the body before it can become metabolically active with its conversion into 5-Methyltetrahydrofolate (5-MTHF). This is the fully-activated folate derivative normally found in healthy circulation of those who do not have MTHFR genetic variants. Most importantly, it is the already-converted form of folate that can be absorbed and used by the body’s cells immediately.
Benefits of Methylfolate 10
- Formulated specially for people with heightened need for folate due to genetic (MTHFR) defects, dietary deficiencies or drug-induced need (i.e. taking warfarin, coumadin, metformin, etc.)
- Bypasses MTHFR gene mutations to optimize the body’s methylation process
- Boosts energy and motivation
- Helps protect against toxins and disease by boosting glutathione
- Supports overall wellbeing
- May reduce symptoms of depression by promoting SAMe and therefore serotonin
- May help manage homocysteine levels caused by folate deficiencies
- May reduce the risk of cardiovascular disease
- Third-party testing to ensure safety and efficacy
Active Ingredients
Folate: 5,000 mcg from (6S)-5-Methylfolate,Calcium – Magnafolate® PRO
Methylfolate 5 is a moderate dose (5 mg) of internationally-patented Magnafolate® PRO [(6S)-5-methyltetrahydrofolic acid, Calcium salt, Type C Crystalline molecule (L-Methylfolate)] for highest stability and potency.
This unique and internationally-patented L-5-Methylfolate ingredient is calcium salt-based for superior stability and absorption. This crystalline form of methylfolate offers greater bioavailability over many competing forms of methylfolate. Magnafolate® PRO is the purest methylfolate you can buy, it’s approximately 3x purer than the other leading brands. It is also known as L-MTHF, L-Methylfolate, L-5-MTHF, and (6S)-5-Methylfolate.
Folate must be reduced to tetrahydrofolate (THF) within the body before it can become metabolically active with its conversion into 5-Methyltetrahydrofolate (5-MTHF). This is the fully-activated folate derivative normally found in healthy circulation of those who do not have MTHFR genetic variants. Most importantly, it is the already-converted form of folate that can be absorbed and used by the body’s cells immediately.
Benefits of Methylfolate 5
- Formulated specially for people with heightened need for folate due to genetic (MTHFR) defects, dietary deficiencies or drug-induced need (i.e. taking warfarin, coumadin, metformin, etc.)
- Bypasses MTHFR gene mutations to optimize the body’s methylation process
- Boosts energy and motivation
- Helps protect against toxins and disease by boosting glutathione
- Supports overall wellbeing
- May help manage homocysteine levels caused by folate deficiencies
- May reduce the risk of cardiovascular disease
- Third-party testing to ensure safety and efficacy
Active Ingredients
L-Methylfolate 7,500 mcg (as Magnafolate® PRO)
Hydroxocobalamin 1,500 mcg
Adenosylcobalamin 1,000 mcg
Methylfolate 7.5 is a high dose (7.5 mg) of internationally-patented Magnafolate® PRO [(6S)-5-methyltetrahydrofolate acid, Calcium salt, Type C Crystalline (L-Methylfolate)] PLUS 2.5 mg active B12 (as both Hydroxocobalamin and Adenosylcobalamin).
These highly-bioavailable nutrients are delivered in a great-tasting chewable tablet that dissolves under the tongue for maximum B12 absorption.
The unique and internationally-patented L-5-Methylfolate ingredient is calcium salt-based for superior stability and absorption. This crystalline form of methylfolate offers greater bioavailability over many competing forms of methylfolate. It is also known as L-MTHF, L-Methylfolate, L-5-MTHF, and (6S)-5-Methylfolate.
Numerous studies of depressive patients have shown both low folate and low vitamin B12 status, and there is an established link between depression and low levels of these two vitamins in the general population.
Folate must be reduced to tetrahydrofolate (THF) within the body before it can become metabolically active with its conversion into 5-Methyltetrahydrofolate (5-MTHF). This is the fully-activated folate derivative normally found in healthy circulation of those who do not have MTHFR genetic variants. Most importantly, it is the already-converted form of folate that can be absorbed and used by the body’s cells immediately.
Benefits of Methylfolate 7.5+
- Formulated specially for people with heightened need for folate due to genetic (MTHFR) defects, dietary deficiencies or drug-induced need (i.e. taking warfarin, coumadin, metformin, etc.)
- Bypasses MTHFR gene mutations to optimize the body’s methylation process
- Boosts energy and motivation
- Helps protect against toxins and disease by boosting glutathione
- Supports overall wellbeing
- May reduce symptoms of depression by promoting SAMe and therefore serotonin
- May help manage homocysteine levels caused by folate deficiencies
- May reduce the risk of cardiovascular disease
- Third-party testing to ensure safety and efficacy
Active Ingredients
L-Methylfolate 3,000 mcg (from [6S]-5-Methyltetrahydrofolate, Calcium - as Magnafolate® PRO)
Vitamin B-12 3,750 mcg (as Methylcobalamin)
B-Methylated II is a moderate-dose combination of B-9 (as Methylfolate) and B-12 (as Methylcobalamin).
It contains the internationally-patented Magnafolate-CTM [(6S)-5-methyltetrahydrofolic acid, Calcium salt C Crystal (L-Methylfolate)]. This unique and internationally-patented L-5-Methylfolate ingredient is calcium salt-based for superior stability and absorption. This crystalline form of methylfolate offers greater bioavailability over many competing forms of methylfolate. It is also known as L-MTHF, L-Methylfolate, L-5-MTHF, and (6S)-5-Methylfolate.
B-Methylated II lozenges are taken under the tongue and absorbed through the mucous membranes. B12 absorption is maximized when taken sublingually because it is not well-absorbed via the gut.
This is the purest and most stable form of L-Methylfolate, which most closely resembles the pharmaceutical version of methyl folate.
Active Ingredients
Vitamin B-12 5,000 mcg Total
(as Methylcobalamin) 2,500 mcg
(as Hydroxocobalamin)1,250 mcg
(as Adenosylcobalamin) 1,250 mcg
B12 Complete contains a combination of the most bioactive forms of B12 for maximum delivery and absorption.
Bioactive simply means that the B12 has already been converted into a form that can be absorbed and used by the body’s cells immediately. This makes B12 Complete suitable for people who have MTR, MTRR, COMT, or other gene mutations that may be affecting B12 absorption).
Benefits of B12 Complete
Methylcobalamin is an active form of vitamin B12 that helps in synthesis of methionine and S-adenosylmethionine (SAMe). It is also required to maintain integrity of myelin, neuronal function, proper red blood cell formation and DNA synthesis. It may also help in lowering homocysteine levels and reducing the risk of anemia.
Hydroxocobalamin is a precursor to methylcobalamin and Vitamin B12 and often recommended in conditions where B12 cannot be properly absorbed in the gut. Hydroxocobalamin is essential for DNA replication and synthesis, proper function of the nervous system, cellular energy, as well the conversion of homocysteine into methionine. It’s known to help with brain fog, pernicious anemia and mopping up excess peroxynitrites. It’s also known to be the most well-tolerated form of active B12.
Adenosylcobalamin is the form of B12 stored in the mitochondria and selected when your body requires a biologically active form of vitamin B12 to support the Krebs cycle and cellular energy production. Adenosylcobalamin helps in muscle recovery, myelin sheath integrity, and reduces the risk of anemia.
The Chewable Methylated Multi is a comprehensive multivitamin made with the nutrients required for optimal methylation in the body.
This research-based formulation includes methylfolate and hydroxocobalamin to promote your body’s production of glutathione, your most powerful antioxidant.
It also promotes healthy pregnancy and may protect against neural tube defects.
The Methylated Multi supports energy production with a host of B vitamins and their cofactors, TRAACS® minerals, Vitamins A, D3, E and bioactive K2.
It also contains a new ATP energy combination, Panmol® NADH + MicroActive® CoQ10.
Cognitive support has been added with a specialized soy-free form of choline which is able to cross the blood brain barrier for optimal uptake in the body. Another important nutrient to benefit brain health is a soy-free phosphatidylserine derived from sunflower lecithin which provides essential phospholipids for improved memory, attention, mood and behavior.
The Chewable Methylated Multi can be taken along with other Methyl-Life products containing methylfolate as a means of increasing your daily intake.
This high-quality multivitamin is suitable as a prenatal supplement and for children (at a lower dose: 1-2 tablets instead of 3).
Methyl-Life’s Non-Methylated Multivitamin is a comprehensive multivitamin specifically formulated WITHOUT methylfolate or Vitamin B12. This makes it suitable for those taking a customized dose of methylfolate and/or Vitamin B12 prescribed by a doctor. It is also ideal for people who do not tolerate methylfolate or active B12.
We created this formula following requests from customers and doctors seeking a multivitamin that could be safely taken alongside their prescribed higher methylfolate and B12 doses.
Methyl-Life’s Non-Methylated Multivitamin is an excellent supplement to complement many of our other methylfolate-only products, B12 products or other active prescriptions.
The Non-Methylated Multi supports energy production with a host of B vitamins and their cofactors, TRAACS® minerals, Vitamins A, D3, E, bioactive K2, along with Trimethylglycine [TMG] for supporting your body’s ability to lower homocysteine levels.
It also contains a new ATP energy combination, Panmol® NADH + MicroActive® CoQ10.
Cognitive support has been added with a specialized soy-free form of choline which is able to cross the blood brain barrier for optimal uptake in the body. Another important nutrient to benefit brain health is a soy-free phosphatidylserine derived from sunflower lecithin which provides essential phospholipids for improved memory, attention, mood and behavior.