Methylfolate Side Effects and How to Prevent Them

Methylfolate is an essential nutrient required for a wide range of processes in the body. Usually, we can obtain adequate folate and folic acid from food and supplements, which the body then converts to methylfolate.

However, some people cannot process folic acid properly due to a MTHFR polymorphism. This typically leads to lower levels of folate in the body. In these cases, methylfolate must be restored through supplementation or medication.

Unlike folic acid, L-methylfolate can pass through the “blood-brain barrier” and enter the central nervous system. Folic acid cannot be metabolized in the body.

Prescription methylfolate is available as Deplin®, classified as a ‘medical food.’ Deplin® is commonly prescribed for treatment-resistant depression and can be used off-label for megaloblastic anemia and renal and hepatic impairment.

Methylfolate is also available over-the-counter (OTC) as a health supplement, and dozens of brands are now available for consumers. 

In general, methyl folate is regarded as a harmless nutrient based on studies evaluating the safe upper limits of folate intake. In recent years, however, concerns have been raised with respect to a potential downside to folate supplementation. As with any supplement, methylfolate can have some side effects. Most of these are mild, but it’s essential to be aware of the correct dosage ranges.

This article will cover the most common side effects associated with taking methylfolate and how to avoid them. We’ll also explain dosage requirements and the best options for taking methylfolate safely.

Certain individual factors make some people more likely to experience side effects than others. Since methylfolate is a medical food, the most significant factor that influences side effect rate includes the magnitude of absorption. For example, if you have a condition that prevents the absorption of methylfolate into the bloodstream, side effects are less likely.

The most common side-effects of methylfolate include:

● Allergic reactions like:

    ○ Bronchospasm (trouble breathing)

    ○ Hives

    ○ Itching

● Swelling of the face, mouth, tongue, or throat

Some research suggests that L-methylfolate may reduce the efficacy of methotrexate, which is used for treating psoriasis. Some cases of people using methotrexate have reported severe aggravation of their psoriasis after taking L-methylfolate 15 mg daily for depression. This is believed to be because methotrexate inhibits the production of certain immune cells, while folate drives it.

Methylfolate helps in the conversion of homocysteine to methionine. Increasing methylfolate intake may reduce homocysteine levels, which in turn may lead to an increase in glutathione. The increase in glutathione may depend on an adequate supply of B6, as changes in glutathione correlate with vitamin B6 levels. Side effects of increased glutathione might include increased flatulence and loose stools.

Methylfolate enhances the effects of antidepressants, which can be problematic if the patient also has bipolar disorder. In patients with unipolar depression, antidepressant treatment is associated with an increased risk of subsequent mania/bipolar disorder, though the effect is small These findings highlight the importance of considering risk factors for mania when treating people with adjunctive methylfolate for depression.

The precise molecular mechanisms by which folate influences cellular functioning are still being studied, but some researchers have noted that folate causes alterations in nucleotide levels via nucleic acid biosynthesis and methionine biosynthesis affecting SAMe levels.

While folate deficiency can reduce the production of nucleotides and SAMe, an increase in folate may elevate their production. SAMe is a universal methyl group donor in more than a hundred reactions in the cells, including DNA, RNA, and protein methylation, and the biosynthesis of numerous key metabolites such as polyamines, epinephrine, creatine, and phosphatidylcholine. This suggests that the cellular response to these changes may produce a wide range of effects that are not easy to predict.

Methylfolate performs a crucial role in the central nervous system, and an overdose is not likely to be life-threatening.

However, rare side effects include allergic reaction, like rash; hives; itching; red, swollen, blistered, or peeling skin with or without fever; wheezing; tightness in the chest or throat; trouble breathing, swallowing, or talking; unusual hoarseness; or swelling of the mouth, face, lips, tongue, or throat. This may be a response to the glucosamine salt form of methylfolate, which can cause shellfish-related allergies.

Prescription methylfolate in the form of Deplin is available in dosages of 7.5 mg and 15 mg. The recommended dosage for adjunctive treatment to antidepressant medication is 7.5 - 15 mg per day. The greatest effects from high-dose methylfolate in treatment-resistant depression are seen from taking methylfolate 15 mg daily (as adjunctive to antidepressants).

The dosage for treating megaloblastic anemia is also 7.5 - 15 mg per day, while the dosage for renal and hepatic disorders (moderate) is not to exceed 40 mg per day.

Other methylfolate prescription medications include Metanx, Cerefolin, and NeevoDHA. These are available in 3 mg, 5.6 mg, and 1 mg L-methylfolate respectively, along with additional nutrients.

It’s important to note that doses greater than 0.1 mg/day may mask pernicious anemia. Doctors advise that this may cause normal blood cell count to show up in blood tests while “irreversible nerve damage” continues to progress.

Taking the proper dosage of methylfolate—at the right time—may help obtain the most effective results while also reducing the risk of side effects. For most people, the best time of day to take methylfolate is when it fits their schedule.

Prescription methylfolate in dosages of 7.5 mg or 15 mg are usually taken by mouth once a day, with or without food.

Dr. Neil Rawlins suggests taking a 1/2 dose twice a day(morning and early afternoon) in order to keep the folate serum levels more even in the bloodstream throughout the day.

Preventing potential side effects of methylfolate is relatively simple. 

● To start with, take the correct dosage as prescribed by your doctor or as recommended on the supplement. A quality supplement designed by experts will be formulated in a way that provides a specific dosage.

● Where possible, minimize your intake of folic acid. This means avoiding foods that contain folic acid, such as fortified cereals, flours, and other products. Those with an MTHFR mutation cannot process folic acid efficiently, and the poor conversion of folic acid to methylfolate has its own negative symptoms.

● Maintain healthy levels of active vitamin forms B6 (pyridoxine) and B12 (cobalamin). Both of these nutrients are required for the conversion of homocysteine to methionine. Deficiency in either B6 or B12 can lead to an increase in homocysteine levels, which also increases the risk of many negative health issues.

● Advise your doctor if you are taking medication for psoriasis, particularly methotrexate. Methylfolate appears to interact with methotrexate, causing a flare-up of psoriasis symptoms that may have been absent for some time.

● Folate enhances the antidepressant effect of certain antidepressant drugs, which may trigger episodes of mania in those with bipolar disorder. It is advised that you are screened for bipolar disorder before commencing adjunctive methylfolate and antidepressant treatment.

● Methylfolate can interact with a range of drugs. Discuss all your other medication and supplements with your medical practitioner before taking methylfolate and the possibility of any interactions.

Methylfolate is absolutely essential for normal bodily function due to its involvement in an enormous range of processes- the most important being methylation. Aberrant DNA methylation has been widely observed in many diseases, cancers, and health conditions.

Deficiency in methylfolate is often linked to the MTHFR mutation. Low levels of methylfolate can lead to a variety of negative health issues, including elevated homocysteine, depression, and dementia.

Methylfolate may be prescribed by doctors or natural health practitioners where a deficiency is detected. In most cases, the side effects of methylfolate supplementation are quite rare.

The most commonly reported side-effects are allergic reactions and minor drug interactions.

The best way to reduce the risk of these side effects is to ensure you are taking a quality methylfolate supplement. Confirm with a medical professional that you aren’t taking any medications that may interact with methylfolate and whether you have medical conditions that may interfere.

A great many methylfolate supplements are now available over-the-counter and online. The trick is to find one that contains pure, bioactive methylfolate. Methylfolate supplements are often known or labeled as L-MTHF, L-5-Methylfolate, L-5-MTHF, and (6S)-5-Methylfolate or L-methylfolate.

Some of the most highly recommended methylfolate supplements are in the Methyl-Life® product line, which includes a range of dosage levels: Methylfolate 5, Methylfolate 7.5+, Methylfolate 10, and Methylfolate 15.

Each of the methylfolate products in the Methyl-Life’s range contains the internationally-patented Magnafolate® PRO [(6S)-5-methyltetrahydrofolate, Calcium salt, Type C Crystalline molecule (L-methylfolate)]. These best-selling products are formulated especially for people with a heightened need for bioavailable folate due to MTHFR defects, dietary deficiencies (such as vegans or vegetarians), or other conditions in which nutritional absorption is impaired. 

This unique and internationally-patentedL-5-Methylfolate ingredient is crystalline calcium salt-based for superior stability and absorption. Research has revealed that this proprietary form of methylfolate is approximately three times more pure and stable than other L-methylfolate products available on the health supplement market today.