L-Methylfolate Side Effects

What are the bioactive molecules in the folate family?

Folate  - also known as vitamin B9 - is a vital  cofactor in one-carbon metabolism. Folate is the common term used for a group of bioactive molecules in the folate family, which includes folic acid, folinic acid or 5-formyltetrahydrofolate (5-FTHF), 5-methyltetrahydrofolate (5-MTHF) or L-methylfolate, 10-formyl-tetrahydrofolate (10-formyl-THF), 5,10-methylene-THF and unsubstituted tetrahydrofolate (THF).
If your folate levels are low, supplementation may be necessary to support the many processes that depend on this nutrient, such as:

• DNA and RNA synthesis

• the metabolism of amino acids

• regulation of cell division

• the activation of vitamin B12

• reducing homocysteine levels

• support for the production of s-adenosyl methionine (SAMe) and

• reducing the of risk of neural tube defects in the pregnant women

Folate is a key methyl donor, which means it plays a critical role in one-carbon metabolism. One-carbon metabolism is a series of chemical pathways that are important for healthy cellular functions. Folate is particularly important for the synthesis of neurotransmitters such as dopamine, serotonin, melatonin, epinephrine and norepinephrine. These neurotransmitters play an important role in mood, and an imbalance in any one of them can lead to depression and mental health.

Folic acid, folinic acid and 5-MTHF are three different forms of folate used in supplements you find on the shelf today. 

What are the differences between folate and folic acid? 

The major differences between folate and folic acid are all about the forms in which they exist. Folate is the natural form of vitamin B9 that is present in foods such as leafy green vegetables and legumes, while folic acid is a synthetic (mad-made) form. 

The reduced forms of vitamin B9 such as dihydrofolate and tetrahydrofolate are biochemically less stable. Folic acid is  an oxidized form, and is often used in supplements and fortified foods because it remains stable for a longer period of time.

Folic acid consists of a pteroyl group that is connected to a glutamic acid part and shows greater stability than the folates which are in reduced forms. However, it’s important to note that the transformation of folic acid relies on 6 different conversion processes that need to occur within the body before it can be transformed into 5-MTHF which your body can then directly absorb and utilize.

In contrast, folate is a naturally occurring bioactive nutrient and is comprised of polyglutamines in their tails. Folinic acid is also a naturally occurring compound in food, however, it is readily converted into THF even in the absence of the dihydrofolate reductase enzyme (DHFR). This means that the effects of folinic acid are not inhibited by the drug compounds such as methotrexate, which inhibits DHFR in the body. 

Food sources that contain significant amounts of folate include: green leafy vegetables, sprouts, brewer’s yeast, beans, peanuts, sunflower seeds, cruciferous vegetables, fruits, whole grains, liver, seafood, and eggs.

Check out some of the key differences between folic acid and the most active form of folate able to be immediately absorbed and used by the body (without having to undergo any enzymatic conversions), L-methylfolate in the chart below.

L-Methylfolate Side Effects

What is L-methylfolate? Its mechanism of action and clinical indications

L- methylfolate is the active form of 5-MTHF (the chemical structure is given in the figure below). 5-MTHF is the only folate molecule that can cross the blood-brain barrier, which is a big plus when compared to other forms of folate. It's especially important if someone is affected by a cerebral folate deficiency. 

L methylfolate works alongside vitamin B12 in the conversion of homocysteine to methionine, which is vital for maintaining the health and function of the cardiovascular system. 5-MTHF (or methylfolate for short) is a naturally available folate molecule that is used to treat and improve:

• anxiety

• depression

• neural tube defects

• megaloblastic anemia

• elevated homocysteine levels

• vascular endothelial function

• renal malfunction and

• hepatic impairment

Folate deficiency can affect cognitive function and mental health. Chronically low folate levels have been associated with conditions such as depression (including treatment-resistant depression), dementia, schizophrenia, bipolar disorder, peripheral neuropathy, myelopathy, restless leg syndrome, insomnia, irritability and forgetfulness.

Recent studies are even starting to show connections with COVID-19 mortality rates and low folate levels. Two such studies correlated folate levels to immune system health by demonstrating two interesting facts:

1. High homocysteine levels are contributing to a much more severe set of corona virus symptoms and a much more challenging recovery for those individuals (we know that high homocysteine levels are caused by low folate levels, often due to genetic challenges like MTHFR)

2. Folate binds to furin cut sites within the body which helps prevent and slow the spread of COVID-19 as it runs its course, and this makes it much easier for someone who has contracted the virus to fight it and also recover from it (this may be part of the reason why some people have a lot more trouble with symptoms and recovery than others)

Folic acid is readily available, but it's not the easiest source of folate.  It first must undergo six specific enzymatic steps in the body before it becomes l-methylfolate. Each of the enzymes involved in the folic acid pathway is vulnerable to various genetic mutations such as MTHFR.

The MTHFR genetic variation (methylenetetrahydrofolate reductase) means that the body lacks the enzyme required to convert the folate to its most active and absorbable form, L-methylfolate. Low levels of L-methylfolate in the central nervous system can then affect the synthesis of monoamines such as dopamine, norepinephrine and serotonin.

 The enzymatic activity of the MTHFR enzyme can also be compromised by certain drugs. For example, methotrexate can affect the activity of dihydrofolate reductase, which then affects activity of dihydrofolate reductase. Metformin and warfarin can also inhibit L-methylfolate levels. 

L-methylfolate, however, is significantly more bioavailable than synthetic folic acid and doesn't require any further conversion in the body. This means it can be absorbed and used regardless of MTHFR C/T and T/T polymorphisms and drug interactions.

 So the good news is that even if you have folate metabolism mutations (like DHFR or MTHFR or MTHFD) or are taking some of these folate-inhibiting drugs, you can supplement directly with L-methylfolate supplement and bypass the negative effects caused by these issues.

5-MTHF is marketed as Deplin (also known as L-methylfolate) and available in two doses, 7.5 mg and 15 mg. It is prescribed as an ‘adjunct’ to treating depression as it may enhance the effects of antidepressant drug compounds. 

Think of methylfolate as 'boosting' serotonin levels in the body while antidepressant medications target making that serotonin stay around in the body longer by blocking up receptors that clear it. L-Methylfolate assists in the production of thymidine (nucleotide of DNA) from the uracil (nucleotide of RNA), which is very critical for the stability of DNA.

L-Methylfolate is also crucial for regulating homocystiene levels in the body. Homocystiene is an amino acid that can cause serious harm to blood vessels and cardiovascular function if it accumulates in the blood. Elevated homocysteine has been associated with cardiovascular disease as well as cognitive impairment and mental health disorders. 

Methylfolate donates a methyl group for the conversion of homocysteine to methionine, which then leads to the synthesis of S-adenosylmethionine (SAMe). This process also supports nitric oxide production, which is essential for the flow of blood, nutrients, and oxygen to throughout the body. 

Chemical structure of L-methylfolate chart

Role of L-methylfolate in Hyperhomocysteinemia

Homocystiene is a sulfur-containing amino acid formed as a by-product of methyl-transfer reactions in methionine metabolism. Increased levels of homocysteine are a significant risk factor for cardiovascular disease. Hyperhomocysteinemia has been linked to many other diseases such as neural tube defects, schizophrenia, cancer, cognitive impairment, Alzheimer’s disease, rheumatoid arthritis, osteoporosis, and kidney failure.

Taking an L methylfolate supplement can assist with this process if folate levels are low. Methylfolate yields a methyl group to vitamin B12, causing a reaction that creates a methylated form of vitamin B12 (methylcobalamin) which then transfers the methyl group to homocysteine. This process leads to the production of methionine.

The Function of 5-MTHF in Inflammatory Bowel Disease and Irritable Bowel Syndrome

Folate deficiency has been reported as a possible factor in patients with inflammatory bowel disease (IBD). There are a few studies supporting the idea that the drug ‘sulfasalazine’, a prescribed medicine for IBD, actually causes inflammatory bowel disease by inhibiting (at least partly) the folate absorption. 

Research has demonstrated that folate supplementation may have protective effects in patients with ulcerative colitis. Patients have been reported to have a 62% reduced risk of neoplasia upon administering folate supplementation as compared to patients without folate administration. 

It’s worth noting that  the gut produces around 90% of our body’s serotonin, which is why it's referred to as our 'second brain'. We also know that L-methylfolate supports healthy serotonin levels. Those low on serotonin - or who have bowel conditions such as Irritable Bowel Syndrome (IBS) - may benefit from L-methylfolate supplementation.

L-methylfolate may also assist with treating anemia when used in combination with vitamin B12. The dose of 5-MTHF (or L-methylfolate) varies according to the clinical status of the patients, so it's best to seek advice from a health professional first.

5-MTHF and Cardiovascular Diseases 

Poor production of nitric oxide (NO) has been noted as a potential indicator of cardiovascular disease and occurs early in the development of atherosclerosis. Nitric oxide is required for healthy vasodilation, supporting the tone of the blood vessels, preventing platelet activation, limiting plaque buildup, and regulating myocardial contractility.

Elevated levels of homocysteine can compromise the production of NO, which can lead to injury of the endothelial lining and the initiation of atherosclerosis. A lack of NO also increases smooth muscle proliferation, adhesiveness of monocytes and platelets and thrombus formation. 

L-methylfolate increases NO synthesis in vascular epithelial cells, which helps to improve blood flow and supports the function of the cardiovascular system. Taking a L-methylfolate supplement may help to reduce homocysteine levels as well as maintain the production of NO. 

Pharmacokinetics and Advantages of L-Methylfolate

5-MTHF (or L-methylfolate) has many metabolic advantages over folic acid, folinic acid and other folate molecules. The absorption of 5-MTHF is not impaired by any change in the pH of the gastrointestinal tract, which can often happen in conditions such as chronic pancreatitis, cystic fibrosis, ulcerative colitis and Crohn’s disease. Metabolic issues and other metabolic-related diseases (like genetics, i.e. DHFR, MTHFR or MTHFD) do not interfere with the bioavailability of 5-MTHF. 

Supplementation of 5-MTHF is recommended over folic acid to reduce the risk of masking symptoms that occur with a deficiency of vitamin B12.  Taking 5-MTHF also means there is no risk of unmetabolized folic acid (UMFA) in the human body. 

The bioavailability of L-methylfolate superior to folic acid and other molecules in the folate family. In a study involving patients with coronary artery disease who were administered either a single dose (5 mg) of 5-MTHF or of folic acid, levels of 5-MTHF were found to be 700% higher than folic acid. The difference were not dependent on the patient’s enzymatic genotype (in other words, their genetic variant status for certain folate metabolism genes like DHFR, MTHFR, MTHFD).

L-methylfolate plays an active role as cofactor in the synthesis of monoamines such as dopamine, norepinephrine and serotonin, which in turn regulate mood and the pharmacological actions of antidepressants. Research suggests that folate deficiency is directly correlated with the occurrence of depressive symptoms, and that patients with low levels of folate are less likely to respond to anti-depressant medication.

The patients with poor folate levels in red blood cells are 6 times more likely not to respond to antidepressant therapy and to experience depressive symptoms. Again, this may be because antidepressants help serotonin ‘stay in the body longer’ – which only works when the body actually already had serotonin or has made enough serotonin to stay around. 

Methylfolate supplementation may be useful in depression, as it is supports the synthesis of monoamine neurotransmitters. L-methylfolate does not need to be converted before it can help in generating serotonin for the body.

The conversion of folic acid into L-methylfolate, however, requires several stpes. Genetic variations such as DHFR, MTHFR and MTHFD can impair this process further. 

Several factors may be involved in folate deficiency in the human population, including MTHFR gene polymorphisms or drug interactions, malabsorption syndromes such as celiac and Crohn’s disease, long-term medications (folate antagonists, antacids, metformin, warfarin and more), alcoholism, poor absorption of ingested folate and low dietary intake.

In the past, folate deficiency has been treated by recommending folic acid supplements and fortified foods – even though this may be an inferior way to address the deficiency (and unfortunately many are still recommending these poor approaches).

Supplementing with the active form of folate, L-5-Methylfolate (or L-methylfolate), is now preferred for obtaining optimal health benefits. Numerous studies have established the potential use of folate in depression, especially the L-5-MTHF form, which has been shown as an effective molecule for enhancing the effects of antidepressant medication. 

5-MTHF (or methylfolate) plays a key role in the synthesis of monoamines (neurotransmitters) in three active steps. First, 5-MTHF assists in the production of the cofactor tetrahydrobiopterin, BH4.  Next, the enzymes tyrosine hydroxylase and tryptophan hydroxylase are activated and the synthesis of monoamines can occur. If there is no BH4, the enzymes tyrosine hydroxylase and tryptophan hydroxylase become inactive. However,  5-MTHF creates the appropriate amount of BH4 which can in turn activate both enzymes (tyrosine hydroxylase and tryptophan hydroxylase) which leads to the synthesis of dopamine, norepinephrine and serotonin. 

In addition, L-5-MTHF plays a critical role in lowering homocysteine levels. Elevated levels of homocysteine are directly associated with dementia, depression, schizophrenia and stroke, among other diseases. 

What are the side effects of L-methylfolate?

The side effects of L-methylfolate can be:

• Modified sleep patterns

• Issues in focus and concentration on any activities

• Confusion

• Irritability

• Overactivity and excitement

• Fatigue

• Impaired judgment

• Weight loss

• Distended abdomen

• Bronchospasm

• Skin rash

• Erythema

• Taste issues or taste impairment

• Nausea

• Nerves burning and stinging

• Acne

• Palpitations

• Insomnia

• Sore muscles

• Joints ache

• Gastrointestinal discomfort

• Flatulence

• Loss of appetite

• Impaired concentration

Cancer and L-methylfolate 

Research studies have suggested that L-5-MTHF supplementation may have exhibit protective effects. However, methylfolate may also elevate the progression and proliferation of neoplastic lesions if they are pre-existing in the body. 

In other words, methylfolate may cause cancerous cells to grow faster. The dividing cells depend upon the folates to support the methylation reactions and nucleotide biosynthesis required for cell division. Animal studies have revealed that high levels of folic acid in utero could escalate the risk of mammary tumours in the offspring.

Another study has indicated that folate depletion post-weaning has resulted in the protective effects against intestinal neoplasia. A randomized clinical trial found an increased risk of prostate cancer due to folic acid supplementation, whereas baseline dietary natural folate displayed a protective effect against prostate cancer.

Even though the specific mechanisms behind tumorigenesis are yet to be confirmed, some studies showed that the promotion and growth of tumours was ascribed to the dysfunction of DNA methylation (which is in fact the opposite of what L-methylfolate does). 

Treatment for metastatic tumors with antifolate compounds has presented promising results against metastatic mechanisms, which suggests the involvement of folate metabolism in the metastatic processes. In brief, metastasis is the spreading of cancer cells from its original part to other parts of the human body. A case study revealed that patients with hormone-resistant prostate cancer showed an acceleration in metastasis. 

Essentially, folate supplementation could promote cancer cells proliferation, metastatic processes and migration, but further research is pending. 

If you are looking to purchase high quality L-methylfolate, check out Methyl-Life™. When
 compared against other industry-leading brands, Methyl-Life’s™ methylfolate tested as more stable, potent and three times more pure than all of the other top methylfolates in the nutraceutical market. 

Methyl-Life’s™ therapeutically nutritional supplements are available in various methylfolate dosages to support healthy mood, alleviate the symptoms of depression and anxiety, protect against cardiovascular disease and lower homocysteine levels as well as support the immune system. These products are clean, potent and stable - designed to support your genetic and nutritional needs long term.


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