Magnesium, Methylation, and the MTHFR Gene

Magnesium, Methylation, and the MTHFR Gene

Katie Stone - Naturopath

Written By:

Katie Stone - Naturopath
Dr. Nare Simonyan - PhD Pharmaceutical Science

Medical Reviewer:

Dr. Nare Simonyan - PhD Pharmaceutical Science
Kari Asadorian - Bachelor of Science in Nursing

Edited By:

Kari Asadorian - Bachelor of Science in Nursing

Updated On:

February 13, 2025

Table of Contents

    Magnesium, Methylation, and the MTHFR Gene

    Magnesium is essential for the proper functioning of numerous processes within the body. As a cofactor for more than 300 enzymatic reactions, it is involved in muscle contraction, neuromuscular pathways, glucose maintenance, heart contraction, and blood pressure regulation.


    Magnesium is also essential for energy production, nucleic acid synthesis, bone development, and the active transmembrane transport of other ions (i.e., the movement of molecules across cell membranes using ATP).


    Above all, magnesium is a vital cofactor in the methylation cycle, and its deficiency may contribute to other MTHFR-related symptoms.


    This article will discuss the body’s needs for magnesium and its role in methylation. We will explain how to identify and correct a magnesium deficiency and why this is so important for those with an MTHFR gene mutation.

    Essential Benefits of Magnesium

    Magnesium plays a pivotal role in synthesizing ATP1 (adenosine triphosphate). ATP is critical for numerous bodily processes2, including healthy metabolism, muscle contraction and relaxation, glucose utilization, normal neurological function, and the release of neurotransmitters.

     

    Magnesium’s many benefits include:

    • Cardiovascular function3: Healthy cardiovascular function and lipid metabolism4. It contributes to the regulation of vascular tone, heart rhythm, and platelet-activated thrombosis. It’s also required in enzymatic reactions in blood pressure regulation and cardiac excitability.
    • Structural roles5: It’s important for the structure of bones, teeth, proteins, many enzymes, and mitochondria. It is an essential cofactor in almost all enzymatic systems involved in DNA processing6, including RNA and DNA synthesis.
    • Muscle contraction7: Magnesium stimulates calcium reuptake and is required for the active transport of calcium and potassium ions across cell membranes, essential for nerve impulse conduction, muscle contraction, and normal heart rhythm.
    • Nerve function8: Healthy nervous system function and sleep patterns9 rely on magnesium. It’s also required for nerve transmission and neuromuscular conduction.
    • Blood glucose control10: Magnesium regulates insulin action, insulin-mediated glucose uptake, and vascular tone. And assists in daily energy production11.
    • Maintenance of electrolyte balance12 (the homeostasis of minerals within the cell).

    What Role Does Magnesium Play in Methylation?

    Methylation is an important biochemical process13 that “turns on” the biological switches that govern many bodily systems.


    The methylation cycle requires one carbon atom and three hydrogen atoms (CH3) to be transferred from one component to another. CH3 is provided by SAMe (S-adenosylmethionine), the body’s primary methyl donor.


    To produce SAMe, however, the body requires methylfolate. A mutation on the MTHFR gene impairs the body’s ability to create methylfolate, which then impairs the methylation process, causing numerous dysfunctions and subsequent health conditions.


    Magnesium is a cofactor14 in methionine adenosyltransferase 1A (MAT1A), an enzyme that controls the production of SAMe.


    Magnesium is also required for the proper function of catechol-O-methyltransferase (COMT)15, the enzyme responsible for metabolizing catecholamines (neurohormones released in response to stress). Impaired activity has been linked to cardiovascular diseases, particularly hypertension.


    Another critical enzyme with a high magnesium requirement is glutamine synthetase16, which drives glutathione synthesis.

    Identifying a Magnesium Deficiency

    Severe magnesium deficiency17 (hypomagnesemia) can result from chronic disease, excess alcohol intake, gastrointestinal disorders that affect uptake and absorption, and increased renal loss. Redistribution18 and intracellular shifts can occur in acute pancreatitis and pregnancy.


    Other causes19 of low magnesium include low dietary intake (due to low magnesium content in food and high intake of refined/processed foods), chronic diarrhea, chronic stress, and medications such as antacids, proton pump inhibitors, diuretics, and some antibiotics.


    Symptoms20 of a magnesium deficiency may include muscle weakness, muscle cramps, and nervous system excitability (causing tremors or muscle spasms).


    Other symptoms21 may include:

    • Loss of appetite
    • Nausea and/or vomiting
    • Weakness, fatigue
    • Pins and needles
    • Insomnia and/or poor sleep patterns22
    • Heart arrhythmia


    Chronic magnesium deficiency can lead to numerous health conditions, including:

    • Type 2 diabetes
    • Chronic inflammation and metabolic syndrome
    • Osteoporosis and rickets
    • Arrhythmia
    • Coronary Artery Disease
    • Hypertension
    • Neurological Diseases
    • Headache/migraine
    • Seizures
    • Stroke
    • Pulmonary disease
    • Depression

    Supplementing for Magnesium

    Researchers have stated that, along with increasing the risk of various diseases and costing incalculable amounts in healthcare and suffering, subclinical magnesium deficiency “should be considered a public health crisis23.”


    Around 10%–30%24 of a given population has a subclinical magnesium deficiency. Approximately 50% of Americans consume less than their required daily intake25 of magnesium, with some age groups consuming substantially less. This is primarily due to food processing decreases26 in food crop magnesium content.


    Some researchers have argued that a typical Western diet cannot maintain sufficient magnesium levels27 nor reduce the risk of coronary artery disease and osteoporosis. It has also been suggested that the “normal range” of serum magnesium is inaccurate28 and that serum magnesium levels at the lower end of normal are closer to marginal magnesium deficiency.


    Supplementation may be a much more effective and convenient way to restore and support magnesium levels.


    Supplementation may help prevent and treat29 many common health conditions, including metabolic syndrome, migraines, diabetes, preeclampsia, premenstrual syndrome, hyperlipidemia, and some cardiac arrhythmias.


    It may also be used as an adjunct or treatment for depression and as a therapeutic intervention for many other health conditions. Clinicians recommend optimizing magnesium status through supplementation as safe, useful, and well-documented30.


    Magnesium supplementation for depression is shown to be as effective as imipramine31. Supplementation has also shown significant therapeutic effects in heart failure and cardiovascular disease32.

    Dosage Considerations

    The Recommended Dietary Allowance33 (RDA) of magnesium for adults is 400-420 mg daily for men and 310-320 mg for women, while the tolerable upper-level intake from supplements is 350 mg.


    As most people are already subclinically deficient, they would need at least 300 mg of magnesium/day34 to maintain magnesium levels, lower their risk of chronic diseases, and support optimal health.


    Supplementation of 500 mg of Mg35has been associated with significant improvement in the insomnia severity index, sleep time, sleep efficiency, sleep onset latency, serum cortisol concentration, serum renin, and melatonin.


    Diabetic patients treated with 600mg magnesium36 for 12 weeks showed a significant reduction in total cholesterol and LDL with an increase in HDL.


    Supplementation should be increased slowly, as taking large amounts at once can cause gastrointestinal issues. We recommend consulting a health practitioner before starting a supplement regime.

    Which Form of Magnesium is Best?

    Some studies have suggested that organic magnesium compounds37 are more bioavailable than inorganic magnesium oxide. Other research has noted systemic differences in the studies, meaning this is not a reliable conclusion38.


    Many different forms of magnesium supplements are available, including:


    Magnesium citrate

    • Salt form of magnesium with citric acid in a 1:1 ratio.
    • Numerous studies have concluded that citrate shows superior bioavailability39 to other forms of magnesium, particularly oxide.
    • Effective in loosening the bowels, it may be used to treat constipation.
    • May be effective in treating pain and tenderness in fibromyalgia40 when used alongside antidepressants.


    Magnesium malate

    • Compound of magnesium and malic acid.
    • Shown to increase and maintain high levels41 for an extended period.


    Magnesium glycinate

    • Magnesium combined with the amino acid glycine.
    • Case studies have shown that magnesium glycinate with taurinate can provide rapid recovery42 (less than 7 days) from major depression.


    Magnesium threonate

    • Patented form of chelated magnesium clinically shown to cross the blood-brain barrier.
    • Shown to increase neural plasticity43, prevent and restore short-term memory44.
    • May treat cognitive impairment45.
    • Improves executive function, working memory, and attention46.


    Sucrosomial magnesium

    • Magnesium oxide encapsulated within a phospholipid membrane using Sucrosomial® technology
    • Allows active ingredients to pass directly into the bloodstream
    • Sucrosomial® enapsulatoin significantly enhances absorption and bioavailability47.

    What About People with MTHFR Mutations?

    For those with MTHFR gene mutations, magnesium supplementation is especially important.


    Magnesium supplementation may help reduce the risk of stroke and heart failure48, both of which may be higher in those with MTHFR49 due to low folate status and increased levels of homocysteine50.


    Magnesium is also shown to prevent and treat migraines51 and headaches, another common symptom of MTHFR52.


    MTHFR C677T is also linked to an increased risk of developing type 2 diabetes. Magnesium supplementation has improved glucose levels53 and insulin sensitivity in those with diabetes.


    Depression is also a common feature of MTHFR54. However, supplementation with magnesium may be beneficial in treating depression55.


    There is no specific evidence regarding which form of magnesium is “best” for treating MTHFR-related symptoms. However, benefits are more likely to be obtained from a highly bioavailable form that is easily absorbed and utilized in the body.


    Those with MTHFR are advised to supplement with folate and vitamin B12 to assist with methylation. However, a magnesium supplement may help relieve other MTHFR-related symptoms such as muscle cramps, headaches, and depression.

    Choosing the Right Magnesium Supplement for You

    Magnesium’s many roles in the body make it one of our most critical nutrients. Deficient levels are both pervasive and problematic, suggesting that supplementation is necessary for most of the adult population.


    Those with MTHFR are especially likely to benefit from magnesium supplementation to support cardiovascular and neurological health.


    Although a wide range of magnesium supplements are available online and in stores, it is advisable to choose a product with clinically proven high bioavailability—such as that from Methyl-Life’s® magnesium product range.


    Designed specifically for those with MTHFR gene mutations, the Methyl-Life® range includes two highly-rated magnesium products: Sucrosomial Magnesium and Magtein L-Threonate. Each form is backed by scientific research for its excellent bioavailability and efficacy. They can be taken alongside other MTHFR supplements to optimize health and wellbeing.

    Product Recommendations

    Magnesium Complete: Sucrosomial® Delivery - Superior Magnesium - Methyl-Life® Supplements

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    • Liposomal-Like Delivery for Superior Absorption
    • 3rd-Party Tested for Purity, Potency & Safety
    • 90 Vegan, Non-GMO, Gluten-Free Capsules

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    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!

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