Understanding the Potential Side Effects of Methylfolate
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 [1] 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.
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.
Studies have evaluated methylfolate as a safe and beneficial nutrient. However, concerns about the potential downside to folate supplementation [2] have been raised. 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.
What Are the Side Effects of Methylfolate?
If you’ve been advised to start taking methylfolate supplements, it’s important to know side effects are generally rare. However, they can happen.
Most people can take methylfolate daily without any issues. Others may find they have to try different dosages before their needs are met.
More Common Side Effects
Let’s take a look at some of the more common side effects of methylfolate usage, or what can happen when your dosage is too high:
- Headaches, aches and pains, fatigue (similar to the flu)
These symptoms can occur when the methylfolate enhances methylation reactions including major detoxification processes. The "clearing out" of accumlulated toxins may occur at a faster rate than the body can respond to.
The best way to deal with these symptoms is to reduce your methylfolate dosage amount and talk to your doctor. - Feeling jittery, hyperactive (as if you’ve had too much caffeine), with a racing heart or palpitations
Again, the sudden increase in methylfolate can mean that your body is now methylating at full speed.
Reduce your methylfolate dosage amount and talk to your doctor. - Feeling aggressive or panicky
This may mean that you have exceeded the methylfolate your body requires for adequate methylation. Talk to your doctor about pausing your methylfolate dosage. You may be advised start with a smaller dosage after your symptoms have resolved. - Burning or tingling sensations throughout the body
Talk to your doctor and consider pausing supplementation until your symptoms clear. - Increased flatulence or loose stools
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 [3]. The increase in glutathione may depend on an adequate supply of B6 [4], as changes in glutathione correlate with vitamin B6 levels. Side effects of increased glutathione might include increased flatulence and loose stools [5].
- Increased flatulence or loose stools
Some more rare but potential reactions could be due to an allergic-like reaction:
- Swelling in unusual areas, especially the face
- Skin reactions including rashes, excessive itching, or hives
- Blistered or reddened skin without any signs of a fever
- Difficulty breathing, wheezing, tightness in the chest or throat
- Difficulty swallowing and talking due to throat swelling
If you have any of the above allergic-reaction type symptoms, it’s best to contact your physician immediately. It’s likely that they will suggest stopping the supplementation for a while, or at least lowering the dosage.
Less Serious Side Effects
Like most other supplements, you could experience some less-serious side effects that may be short term. These won’t typically be cause for concern, but it’s always best to seek help either way. Here are some of the other symptoms you might experience with methylfolate:
- Upset stomach
- Loss of appetite
- Diarrhea
- Acne and pimples
As with taking any supplement, it’s important that you monitor your body's response. Methylfolate has been shown to support healthy cognitive function and numerous other bodily processes, but it can also have negative effects in some people. Consider both your physical and neurological symptoms.
Potential Interactions with Methylfolate
If you are taking other medications, check with your health practitioner before starting a methylfolate supplement.
Some research suggests that L-methylfolate may reduce the efficacy of methotrexate [6], which is used for treating psoriasis. Some cases of people using methotrexate have reported severe aggravation of their psoriasis [7] after taking L-methylfolate 15 mg daily for depression. This is believed to be because methotrexate inhibits the production of certain immune cells [8], while folate drives it.
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[9], 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[10]. 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[11].
Are You Taking Too Much Methylfolate?
Methylfolate performs a crucial role in the central nervous system, and an overdose is not likely to be life-threatening[12].
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[13] (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”[14] continues to progress.
Best Time of Day to Take Methylfolate
Taking the proper dosage of methylfolate at the same time every day will help you achieve 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[15] 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.
How to Prevent the Side Effects of Methylfolate?
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.
Best Methylfolate Supplements
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[16], cancers, and health conditions.
Deficiency in methylfolate is often linked to the MTHFR mutation[17]. 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 best way to reduce the risk of 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.
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-patented L-5-Methylfolate ingredient is crystalline calcium salt-based for superior stability and absorption. Research has revealed that this proprietary form of methylfolate[18] is approximately three times more pure and stable than other L-methylfolate products available on the health supplement market today.
Will Methylfolate Actually Help Me?
Research into the benefits of methylfolate is continuing. However, numerous studies show that for those with a folate deficiency or a MTHFR genetic mutation, methylfolate certainly has many advantages. But it isn't for everyone.
Your doctor will be able to run the necessary tests to determine if you could benefit from methylfolate. Methylfolate is known to support a variety of health issues including depression, schizophrenia, dementia, pregnancy health, neuropathy, fatigue, cardiovascular health, and more.
If you would like to learn more about what to expect when supplementing with methylfolate, you can contact us with any questions you might have.
References
1. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7564482/
2. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4317288/
3. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7996954/
4. https://pubmed.ncbi.nlm.nih.gov/15244101/
5. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3162377/
6. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5192351/
7. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5192351/
8. https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0199574
9. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4679886/
10. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4317288/
11. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4317288/
12. https://www.drugs.com/mtm/l-methylfolate.html
13. https://onlinelibrary.wiley.com/doi/full/10.1002/wps.20672
14. https://www.drugs.com/cdi/methylfolate.html#side-effects
15. https://www.kadlec.org/location-directory/n/neurological-resource-center/resources/mthfr
16. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6147084/
17. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7564482/
18. https://methyl-life.com/pages/methylfolate-types