Methylfolate Side Effects

Methylfolate Side Effects

Katie Stone - Naturopath

Written By:

Katie Stone - Naturopath
Kari Asadorian - Bachelor of Science in Nursing

Medical Reviewer:

Kari Asadorian - Bachelor of Science in Nursing
Jamie Hope - Founder of Methyl-Life

Edited By:

Jamie Hope - Founder of Methyl-Life

Updated On:

April 24, 2025

Table of Contents

    What Are The Side Effects Of Methylfolate? 🤒 Important Side Effects Explained Source: YouTube.com

    Methylfolate has been evaluated as a safe and beneficial nutrient in numerous clinical studies. However, although rare, some people may experience certain side effects. Most of these are mild, but it’s essential to be aware of them and how to correct dosage ranges when experiencing them.


    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? 🤒 Important Side Effects Explained | Video

    Severe side effects of methylfolate

    Methylfolate supplementation is not known to cause severe side effects. Studies show it has similar side effects to placebo (a pill that is not a medicine)1. Methylfolate is generally well-tolerated.


    Methylfolate does not cause adverse reactions commonly associated with antidepressants and other adjunctive mood disorder treatments (e.g., antipsychotics), such as weight gain, metabolic changes and movement disorders.2


    An allergic-like reaction to any medication can lead to:


    • 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 symptoms, it’s best to contact your physician immediately.

    Light side effects of methylfolate

    Some anecdotal evidence about lighter side effects of taking methylfolate have included:


    • Headaches, aches and pains, fatigue (similar to the flu)
      Methylfolate plays a major role in detoxification pathways. For those with MTHFR variants, introducing methylfolate may suddenly enhance methylation activity, leading to temporary symptoms like fatigue, irritability or headaches. These are sometimes perceived as “detox reactions.”

    • Mood changes
      Methylation influences the production and breakdown of neurotransmitters like serotonin, dopamine, and norepinephrine. A sudden change in these levels may cause mood changes, anxiety, or other neurological symptoms.

    • Feeling jittery or 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 more quickly. Pause or 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 to start with a smaller dosage after your symptoms have resolved.

    • Burning or tingling sensations throughout the body.
      This may be due to the folate masking vitamin B12 deficiency, which can lead to nerve damage and tingling (paresthesia).Talk to your doctor and consider pausing supplementation until your symptoms clear.

    Contraindications for methylfolate

    Methylfolate is not known to have contraindications. Unlike folic acid, methylfolate will not mask vitamin B12 deficiency. Methylfolate is also more effective than folic acid supplementation in improving folate levels.3

    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-threatening4.


    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 daily5 (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 damage6” continues to progress.

    Methylfolate Side Effects

    Key takeaways:

    • Icon Methylfolate is safe to take and is not known to cause serious side effects.
    • Icon Some people may experience detoxification symptoms as their methylation increases. However, these are generally temporary.
    • Icon Methylfolate may interact with some medications. Talk to your doctor before starting supplementation.

    How to Prevent the Side Effects of Methylfolate

    Preventing potential side effects of methylfolate is relatively simple:

    • Icon 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.
    • Icon 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.
    • Icon 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.
    • Icon 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.
    • Icon 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.
    • Icon 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.

    How to push through side effects and detoxification

    Most reports of side effects relate to overstimulation of methylation pathways, especially in high doses, rather than actual detoxification processes. However, every individual responds differently to supplementation depending on their health history and previous exposure to toxins, so some may experience side effects and some may not.


    Here’s how to minimize or avoid side effects as much as possible:

    • Icon Take the correct dosage as prescribed by your healthcare provider or as stated on the product. A quality methylfolate supplement will give dosage details and explain how to take the product.
    • Icon Drink plenty of fresh, filtered water and eat a healthy diet with as few processed foods as possible. This will help your body with the detoxification process. Consider nutrients or supplements that support the liver through detox phases I and II.
    • Icon Where possible, minimize your intake of folic acid. This means avoiding supplements and 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.
    • Icon Maintain healthy levels of active vitamin forms B6 (pyridoxal-5-phosphate) and B12 (hydroxo, adenosyl and methyl cobalamins). All 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.
    • Icon Methylfolate can interact with a range of drugs, including methotrexate. Discuss all your other medications and supplements with your medical practitioner before taking methylfolate and the possibility of any interactions.
    • Icon Consider taking NAC or NACET for a week or two before starting your methylfolate supplement and even alongside it if you have had trouble tolerating methylfolate in the past. It can help replenish intracellular glutathione levels that methylfolate may begin to use as you take it.
    • Icon Supplementing with the cofactor nutrients mentioned above can also support your body’s methylation processes. Methylfolate works alongside vitamins B6 and B12 in all of its methylation pathways, and adding these to your supplement regime can help to optimize your overall wellbeing.

    How long do methylfolate side effects last?

    Side effects caused by methylfolate supplementation are generally temporary, and shouldn’t last more than a few days. If you continue to have unpleasant symptoms, stop taking the supplement and consult your healthcare practitioner.


    Nutrients that potentially deplete some of the overmethylation effects and symptoms in the body may include:

    • Icon NAC / NACET
    • Icon Glutathione
    • Icon Nicotinic Acid (B3)

    Product Recommendations

    L Methylfolate 15 mg - A Mood-Boosting Supplement - Methyl-Life® Supplements

    L Methylfolate 15 mg - A Mood-Boosting Supplement
    (156)

    $76.00

    • Professional Strength - Ask Your Doctor
    • High-Dose L Methylfolate 15 Mg for Natural Mood Support2
    • 3rd-Party Tested for Purity, Potency & Safety
    • 90 Vegan, Non-GMO, Chewable Mint Tablets

    Frequently Asked Questions about methylfolate side effects

    Does methylfolate have side effects?

    Methylfolate is unlikely to cause serious side effects and has been clinically proven as safe to take. However, some people may experience detoxification reactions such as headaches, fatigue, and mood changes as their methylation increases. These are usually temporary.

    What should you not take with methylfolate?

    Methylfolate should not be taken with chloramphenicol (an antibiotic), certain anti-seizure drugs (such as phenytoin) and methyldopa (a blood pressure medication).
    Methylfolate can affect the absorption of other drugs such as methotrexate (for autoimmune conditions), bisphosphonates (for osteoporosis), levodopa (for Parkinson’s disease), quinolone antibiotics, thyroid medications (such as levothyroxine), and some tetracycline antibiotics.

    When should you stop taking methylfolate?

    If you experience an allergic reaction or other severe side effects, stop taking methylfolate and consult your health practitioner.

    Who shouldn't take L-methylfolate?

    You should not take L-methylfolate if you are allergic to it. If you have a B12 deficiency (anemia) and choose not to take B12 alongside your L-methylfolate and monitor your levels for both nutrients.
    If you are taking other medications (especially methotrexate, bisphosphonates, antibiotics, or thyroid medications). Talk to your doctor before starting methylfolate supplementation.

    References

    1. George I Papakostas, Richard C Shelton, John M Zajecka, Bijan Etemad, Karl Rickels, Alisabet Clain, Lee Baer, Elizabeth D Dalton, Garret R Sacco, David Schoenfeld, Michael Pencina, Allison Meisner, Teodoro Bottiglieri, Erik Nelson, David Mischoulon, Jonathan E Alpert, James G Barbee, Sidney Zisook, Maurizio Fava; "L-methylfolate as adjunctive therapy for SSRI-resistant major depression: results of two randomized, double-blind, parallel-sequential trials"; The American journal of psychiatry; 2012 Dec

      https://pubmed.ncbi.nlm.nih.gov/23212058/

    2. Vladimir Maletic, Richard Shelton, Valerie Holmes; "A Review of l-Methylfolate as Adjunctive Therapy in the Treatment of Major Depressive Disorder"; The primary care companion for CNS disorders; 2023 May

      https://pubmed.ncbi.nlm.nih.gov/37192264/

    3. Qiangqiang He, Jianping Li; "The evolution of folate supplementation – from one size for all to personalized, precision, poly-paths"; Journal of translational internal medicine; 2023 Jul

      https://pmc.ncbi.nlm.nih.gov/articles/PMC10318921

    4. Cerner Multum; "L-methylfolate"; Drugs.com; 2023 Aug

      https://www.drugs.com/mtm/l-methylfolate.html

    5. Joseph Firth, Scott B. Teasdale, Kelly Allott, Dan Siskind, Wolfgang Marx, Jack Cotter, Nicola Veronese, Felipe Schuch, Lee Smith, Marco Solmi, André F. Carvalho, Davy Vancampfort, Michael Berk, Brendon Stubbs, Jerome Sarris; "The efficacy and safety of nutrient supplements in the treatment of mental disorders: a meta-review of meta-analyses of randomized controlled trials"; World Psychiatry; 2019 Oct

      https://onlinelibrary.wiley.com/doi/full/10.1002/wps.20672

    6. Drugs.com; "Methylfolate"; Drugs.com; [Accessed March 2025].

      https://www.drugs.com/cdi/methylfolate.html#side-effects

    Katie Stone - Naturopath

    About the Author

    Katie is a qualified Naturopath (BNatMed) and freelance writer from New Zealand. She specializes in all things health and wellness, particularly dietary supplements and nutrition. Katie is also a dedicated runner and has completed more half-marathons than she can count!

    Related Articles

    Browse Categories