L-Methylfolate Side Effects

What are the bioactive molecules in the folate family?

Folate and folic acid are represented as vitamin B9, which is a significant cofactor in one-carbon metabolism. Folate is the common term used for a group of bioactive molecules in the folate family including 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). Folate supplementation is vital to maintain sufficient levels of folate which plays an active role in many important dependent processes 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

Besides the fundamental functions mentioned above, folate is a key methyl donor and involved in the synthesis of neurotransmitters such as dopamine, serotonin, melatonin, epinephrine and norepinephrine (many of which play an important role in depression and mental health).

Not to mention that cancer, cardiovascular diseases (CVD), neural tube defects, depression, anxiety and cognitive impairment are the possible consequences of folate deficiency. Folic acid, folinic acid and 5-MTHF are three different forms of folate that can be found in folate 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 a reduced form while folic acid is an oxidized form. The reduced forms of vitamin B9 such as dihydrofolate and tetrahydrofolate are less stable biochemically, whereas the oxidized form, folic acid (found in supplements and fortified foods) remains stable for a longer period of time.

Folic acid is a synthetic (man-made) water-soluble compound that does not exist in nature. 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 entity and is comprised of polyglutamines in their tails. As compared to folate, 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).

Consequently, the effects of folinic acid are not inhibited by the drug compounds, for instance, 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, a methyl group donor for many biological functions in our human bodies, is the active levo isomer 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 considered advantageous when compared to other biomolecules in the folate family (and especially important if one is dealing with cerebral folate deficiency). 

L-methylfolate in conjunction with vitamin B12 is involved in the conversion of homocysteine to methionine (an important indicator of cardiovascular health). 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

The administration of folate as a part of a nutritional regimen has displayed promising results in the treatment of vitiligo (a medical condition that causes white patches on your skin) and reducing inflammation of the gums. Also, research studies have demonstrated that folate supplementation plays a critical role of in the management of cervical dysplasia and neoplasia in ulcerative colitis.

 Folate deficiency causes the loss of cognitive function, neurological and psychological activities. This impairment consequently leads to quite a lot of disease conditions such as depression, endogenous depression, treatment-resistant depression, dementia, schizophrenia-like syndromes, bipolar disorder, peripheral neuropathy, organic psychosis, 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. how 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)

The enzymatic conversion of folic acid brings about the formation of L-methylfolate through six specific enzymatic steps. Each of these enzymes involved in the folic acid pathway is vulnerable to various genetic mutations that disrupt L-methylfolate plasma levels.

 Of these enzymatic steps, the most vulnerable enzyme to polymorphism and genetic variations is methylenetetrahydrofolate reductase (MTHFR), which helps to convert the folate to its most active and absorbable form, L-methylfolate. Low levels of L-methylfolate in the central nervous system affect the synthesis of monoamines such as dopamine, norepinephrine and serotonin.

 In addition, the enzymatic activity of folate-reducing enzymes is compromised by the drugs that can interact with these enzymes. For example, methotrexate interferes with and inhibits dihydrofolate reductase, thus affecting the enzymatic activity of dihydrofolate reductase. Another example is metformin and warfarin, these types of drugs can inhibit L-methylfolate levels in the body as well. 

 However, the important thing to note is that L-methylfolate is seven times more bioavailable than synthetic folic acid and remains unaltered by these enzymatic differences including MTHFR C/T and T/T polymorphisms and unaffected by the drug interactions.

 So the good news is, even if you have folate metabolism mutations (like DHFR or MTHFR or MTHFD) or are taking some of these folate-inhibiting drugs, if you’re able to supplement directly with L-methylfolate, then you can by-pass 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 as an ‘adjunct’ to treating depression. L-methylfolate is marketed as an antidepressant-helper, as it may boost the effects of antidepressant drug compounds. 

On a very basic level you can think of methylfolate as essentially 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.

 In the case of cancer, sufficient levels of folate inhibit the expression of oncogenes (or tumour-causing cells), followed by the promotion of DNA stability prior to cancer initiation (so you can really think of it a little like a cancer protector). 

However, it’s worth noting that 5-MTHF could also trigger cell division and growth of cancer cells once the cancer cells have been established in our bodies. Think of L-methylfolate as the “life-giver” – it really helps give your body the fuel, energy and basic life building blocks it needs for regeneration, however, if your body is full of cancer cells, it can also give fuel to them – so talk to your oncologist if you have active cancer cells in your body and wish to take L-methylfolate.

L-Methylfolate donates a methyl group for the conversion of homocysteine to methionine, and ultimately the synthesis of S-adenosylmethionine (SAMe) ensues. 

This methionine conversion is a very significant biochemical process as the elevated homocysteine has often been associated with cardiovascular disease as well as cognitive impairment and mental health disorders. 

The beneficial role of 5-MTHF on cardiovascular disease comes from lowering homocysteine levels and increasing nitric oxide production. These things reduce endothelial dysfunction and demonstrate the protective effects of 5-MTHF for better managing cardiovascular disease.

Chemical structure of L-methylfolate chart

Role of L-methylfolate in Hyperhomocysteinemia

The increased levels of homocysteine, as a de-methylated product from the folate pathway, is a significant risk factor for cardiovascular disease. In addition, hyperhomocysteinemia has been considered a pathogenic process in many diseases such as neural tube defects, schizophrenia, cancer, cognitive impairment, Alzheimer’s disease, rheumatoid arthritis, osteoporosis, kidney failure, and is even being looked at regarding COVID-19 morbidity. 

An ideal homocysteine metabolism requires a methyl donor, and , L-methylfolate serves just this purpose of methylation as it yields a methyl group to vitamin B12. As a result of this reaction, a methylated form of vitamin B12 or methylcobalamin is formed, and this then transfers the methyl group to homocysteine.

Finally, this process leads to the production of methionine. So in short, L-methylfolate helps us turn homocysteine (a dangerous amino acid when it builds up to levels higher than 10) into methionine, (a more healthy amino acid).

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

Folate deficiency has been reported as a pathogenic marker 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 evidence has demonstrated the protective effects of folate supplementation as observed in a dose-dependent manner against colonic neoplasia in patients with ulcerative colitis. Neoplasia 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 we now know so much more about our gut being considered our ‘second brain’. And because we know our gut produces around 90% of our body’s serotonin and we also know that L-methylfolate increases our serotonin levels, if we’re low on serotonin, it stands to reason that our ‘guts’ could definitely benefit from L-methylfolate supplementation.

Irritable Bowel Syndrome (IBS) has been connected to low serotonin levels, so IBS is certainly an area where folate supplementation may make a significant impact on improving symptoms.

L-methylfolate in Anemia:

In combination with vitamin B12, folic acid has been used for the treatment of macrocytic anemia. The dose of 5-MTHF (or L-methylfolate) varies according to the clinical status of the patients, however, the therapeutic dose is typically 800 – 1000 mcg each day.

5-MTHF and Cardiovascular diseases 

Malfunction of endothelial nitric oxide (NO) production is one of the pathogenic indicators in cardiovascular disease and happens early in the development of atherosclerosis. Modest vasodilation due to deficient NO production has been deemed as a key pathogenic factor in atherosclerosis.

L-methylfolate increases the NO synthesis in vascular epithelial cells, thereby improving the blood flow. The elevated levels of homocysteine continuously exposed to vascular epithelium compromise the production of appropriate amounts of NO.

As a result, injury to the endothelial lining and the initiation of atherosclerosis, which also includes increased smooth muscle proliferation, adhesiveness of monocytes and platelets and thrombus formation. 

Mechanistically, L-methylfolate alleviates nitric oxide production by reducing homocysteine levels, maintaining the availability of key endothelial NO cofactors and minimizing the concentration of superoxide anions. 

Pharmacokinetics and Advantages of L-Methylfolate

5-MTHF (or L-methylfolate) has many metabolic advantages over folic acid, folinic acid and other folate molecules. As a major advantage, the absorption of 5-MTHF is not impaired by any change in the pH of the gastrointestinal tract, which can often happen with 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.

It is recommended that the supplementation of 5-MTHF instead of folic acid is required to diminish the possibilities of masking hematological symptoms that occur with a deficiency of vitamin B12. Also, 5-MTHF is believed to reduce the probable adverse effects caused by unmetabolized folic acid (UMFA) in the human body. Cancer is one such question that has come up in studies regarding UMFA which tends to be a direct result from supplementing with synthetic folic acid which does not always convert well in the body. Methylfolate supplementation does not produce this UMFA, only folic acid supplementation.

The bioavailability of L-methylfolate is higher than folic acid and other molecules in the folate family. To support the high bioavailability claim, a lot of research studies were conducted. For instance, a pharmacokinetic study involving the patients with coronary artery disease were administered a single high dose (5 mg) of 5-MTHF or of folic acid. The results revealed a remarkably high bioavailability of 5-MTHF, which was 700% higher for plasma folate levels after 5-MTHF administration as compared to the folic acid administration. The difference recorded in the study was not dependent on the patient’s enzymatic genotype (in other words, their genetic variant status for certain folate metabolism genes like DHFR, MTHFR, MTHFD).

Of all the folates mentioned, only L-methylfolate plays the role of cofactor in the synthesis of monoamines such as dopamine, norepinephrine and serotonin, which in turn actively participate in the regulation of mood and pharmacological actions of antidepressants. Research studies revealed that folate deficiency is directly correlated with the occurrence of depressive symptoms, consequently, the patients with low levels of folate hardly respond to anti-depressant therapy and finally with relapse of the symptoms of depression. 

The patients with poor folate levels in red blood cells are 6 times more likely not to respond to the antidepressant therapy and the likelihood of depressive episodes is high. Again, if antidepressants help serotonin ‘stay in the body longer’ – that only works when the body actually already had serotonin or has made enough serotonin to stay around. 

If the body needs more serotonin to be made, that’s where the methylfolate supplementation comes in and does the heavy lifting. The administration of L-5-MTHF (or L-methylfolate) is useful in depression, as it is suggested to exert its mechanism of action by increasing the synthesis of monoamine neurotransmitters. L-methylfolate does not need to be converted before it can immediately start on the task of generating serotonin for the body.

The conversion of folic acid into L-methylfolate, however, is required and is a long, multi-step process. Again, this is where our genetic challenges can cause a lot of impairment to these conversions – as various gene mutations on polymorphisms like DHFR, MTHFR and MTHFD inhibit the transformation of folic acid to L-methylfolate.  

Several problems have been blamed for folate deficiency in the human population such as disruption in folate metabolism due to genetic shortcomings like MTHFR gene polymorphisms or any 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. Folate studies conducted to date have established the potential use of folate in depression, especially the L-5-MTHF form, which has been shown as an effective molecule for augmenting neurotransmission. L-5-MTHF plays a critical role in the homocysteine cycle and improving health by lowering homocysteine levels. Elevated levels of homocysteine are directly associated with dementia, depression, schizophrenia and stroke to mention a few.

5-MTHF (or methylfolate) plays a key role in the synthesis of monoamines (neurotransmitters), which is comprised of three active processes. In the first step, 5-MTHF supports the production of an important cofactor, called tetrahydrobiopterin, BH4. 

Secondly, the activation of the rate-limiting enzymes tyrosine hydroxylase and tryptophan hydroxylase for the synthesis of monoamines takes place. In the absence of BH4, the enzymes tyrosine hydroxylase and tryptophan hydroxylase become inactive; this condition does not support the binding of enzymes with their amino acid substrates such as tyrosine and tryptophan which are the necessary precursors for monoamines. 

Finally, the presence of 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. Thus, L-5-MTHF is classified as a trimonoamine modulator that is essential for the production of monoamines (neurotransmitters) which are responsible for a balanced brain and mental health.

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 

The association between folate supplementation and cancer has always been up for debate in the nutraceutical field. Research studies have shown that L-5-MTHF supplementation to normal cells exhibit protective effects, however, methylfolate may elevate the progression and proliferation of neoplastic lesions if they are pre-existing in the body. 

Basically the idea is, if you don’t have cancer, methylfolate could help protect you from getting it, however, if you do have cancer, methylfolate might cause it to grow faster. The dividing cells depend upon the folates to support the methylation reactions and de novo nucleotide biosynthesis that is required for cell division. The following findings from the studies supported the notion of promoting tumorigenesis. 

Animal studies have revealed that high levels of folic acid in utero could escalate the risk of mammary tumours in the offspring (now we want to remember that folic acid due to its complex conversion steps can often result in UMFA which poses a different question about cancer altogether). 

Another study has demonstrated that folate depletion post-weaning has resulted in the protective effects against intestinal neoplasia. A randomized clinical trial has unveiled the increased risk of prostate cancer due to folic acid supplementation (again, remember folic acid is the synthetic, non-bioactive form of folate), whereas baseline dietary natural folate displayed a protective effect against prostate cancer.

Even though the specific mechanisms behind tumorigenesis are yet to be discovered, 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-resistance prostate cancer were found to have an acceleration in metastasis. Taken all studies together, folate supplementation could promote cancer cells proliferation, metastatic processes and migration, nevertheless, a significant number of randomized clinical trials are required to verify this association of cancer and folate.Publish

If you are looking to purchase the purest form of active (fully-converted) folate, L-5-MTHF (or L-Methylfolate), check out Methyl-Life™ as they are selling the ultimate L-methylfolate on the market today. In a recent study when compared against the other industry-leading brands, Methyl-Life’s™ tested more stable, potent and even 3 times purer than all of the other top methylfolates in the nutraceutical market. 

Methyl-Life’s™ therapeutically nutritional supplements are available in various doses and are optimized to help you balance and elevate your mood, alleviate the symptoms of depression and anxiety, protect against cardiovascular disease and lower homocysteine levels as well as boost the immune system to optimize your overall health and wellbeing. So check them out if you’re looking for clean, potent and stable products which will serve your genetic and nutritional needs long term.


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