Magnesium and MTHFR

Magnesium is the second most abundant mineral in the human body, involved in over 300 biochemical reactions relating to cardiovascular function, energy production, muscle contraction, nerve transmission, and nervous system health.¹

Suboptimal magnesium levels are common due to poor dietary intake, soil depletion, stress, impaired absorption, and many other factors.

Magnesium antagonizes the  N-methyl-D-aspartate (NMDA) receptors and modulates calcium influx, allowing muscles to relax and contract efficiently. This can help reduce cramping and pain. High-dose magnesium has been used clinically as an analgesic for myofascial pain syndrome due to its muscle relaxant and vasodilator properties.²

In addition to supporting muscular relaxation, magnesium interacts with GABA receptors, potentiating GABAergic neurotransmission and subsequently dampening neural excitability, which helps with sleep onset and sleep duration.³

Magnesium also regulates circadian rhythms via daily oscillations in its levels within cells, which are controlled by genes that rhythmically express specific transport proteins. These fluxes peak in the daytime to boost ATP-driven metabolism and circadian gene expression, and decrease at nighttime to conserve energy.⁴
Studies link higher magnesium intake to improved sleep quality.⁵

Magnesium plays a vital role in brain function and mood as it is required for optimal nerve transmission and the formation of membrane phospholipids.⁶ As well as blocking the glutamatergic NMDA receptor, magnesium is also involved in the regulation of serotonergic, dopaminergic and cholinergic transmission. Several studies show that low magnesium is common in those with depression and anxiety, and supplementation may improve these symptoms.⁷

Magnesium inhibits calcium release and increases nitric oxide, which supports vasodilation, reducing high blood pressure and inflammation. It also assists in the breakdown of insulin and glucose, and may have antiplatelet and anticoagulant benefits.⁸

Approximately 99% of Magnesium (Mg) is found in bones, muscles, and soft tissues. Magnesium supports bone health by promoting osteoblast differentiation and suppressing osteoclast activity. Magnesium deficiency can result in an imbalance of calcium, which can increase bone resorption.⁹

Magnesium forms the Mg-ATP complex required for the transfer of energy in nearly all cellular processes, including responses to growth factors, cell proliferation, and carbohydrate metabolism.¹⁰

Magnesium’s interaction with the NMDA receptor and inhibition of glutamate has been linked to migraines. Studies show that people with migraine are often deficient in magnesium, and magnesium supplementation is effective in relieving migraine symptoms.¹¹

Recommended daily requirements (RDI) for magnesium intake depend on age, sex, and life stage.
Adult men: 400-420 mg/day
Adult women: 310-320 mg/day
Pregnant women: 350-360 mg
Boys 14-18 years: 410 mg
Girls 14-18 years: 360 mg

Note: Individuals with certain health conditions (such as diabetes, migraines, or hypertension) or who are physically active may have higher magnesium needs due to increased demands or losses.

Foods rich in magnesium include green leafy vegetables, unpolished grains, and nuts. Meats, starches, and milk are moderate sources.¹²

Food sources of magnesium^13,14

Note: While magnesium should be naturally present in many foods, soil depletion and absorption difficulties may reduce the amount obtained from the diet. Processing and cooking methods further deplete magnesium content. Phytic acid in certain foods can also impair absorption. Organic foods have higher magnesium content.¹⁵

Magnesium deficiency refers to inadequate total body or intracellular magnesium that impairs critical bodily functions. However, reduced serum magnesium levels may also cause various symptoms.¹⁶

Magnesium can be pulled from the bones, muscles, and internal organs to maintain normal serum magnesium levels when intakes are low.¹⁷

Early signs of magnesium deficiency include:¹⁸
Anxiety
Twitching of the facial muscles
Confusion
Depression
Migraines
Muscle cramps or spasms
Irritability
Muscular weakness
Neuromuscular irritability
Photosensitivity
Tinnitus
Tremors
Vertigo

Increased magnesium intake or a high dose can cause loose bowel movements (diarrhea). However, this is usually temporary and will pass as your body adapts. Taking divided doses can help reduce this effect.

Magnesium supplements vary widely in terms of their solubility and molecular composition, which directly relates to how much is absorbed and utilized by the body. 

• Magnesium glycinate: Chelated with glycine (an amino acid), which acts as a major inhibitory neurotransmitter in the central nervous system (CNS). This form is highly bioavailable and may help to calm the mind and relieve stress.¹⁹ Also less likely to cause gastrointestinal distress.
  
  
• Magnesium oxide: Poorly absorbed, best used for short-term relief of constipation.
  
  
• Magnesium L-threonate (MgT): New form of magnesium noted for its ability to cross the blood-brain barrier and support neurological health and cognitive function, including memory and sleep quality.²⁰
  
  
• Magnesium citrate: Well known due to high bioavailability and tolerability. Gentle on the digestive system. Often used in supplements.
  
  
• Magnesium malate: Chelated with malic acid, a compound involved in the body’s energy production cycle. May support muscle health and physical performance.

• Magnesium oils, sprays, lotions, and creams: Topical forms of magnesium are generally a combination of magnesium chloride and water, either used in a spray or added to a cream, lotion, or butter. These products are marketed as a transdermal source of magnesium that enters the bloodstream via passive permeation across the skin. They are purported to relieve muscle cramps, restless legs, and other physical ailments, as well as supporting relaxation and sleep. However, evidence of their efficacy is limited.²¹
  
  
• Magnesium powder: Powdered magnesium supplements are designed to be added to water, juice, or smoothies to support magnesium intake. Powder allows greater flexibility with dosing, but the efficacy of the powder itself depends largely on the type of magnesium and the quality of the formulation. Research comparing magnesium powders with other formulations is limited.

• Magnesium gummies: Magnesium gummy supplements are made with gelling agents, including gelatin and/or pectin) and typically also contain sugar, artificial sweeteners, flavorings and colors. Although popular for their taste and convenience, gummy supplements contain low concentration of magnesium as much of their composition includes fillers and are more prone to degradation from heat, humidity, and pH, which can reduce their effectiveness.
  
  
• Sucrosomial magnesium: A form of magnesium oxide ions encapsulated with phospholipids within a sucrosomial membrane. This formulation allows the magnesium to pass through the digestive system and reach the bloodstream without degradation. Although research is currently limited, some studies suggest that the sucrosomial form improves intestinal absorption of magnesium as well as reducing gastrointestinal side effects usually associated with magnesium.²²

When choosing a magnesium supplement, consider these factors:

Type of magnesium: The bioavailability of the form used in the product will directly impact its benefits. Organic forms (citrate, glycinate, threonate, or malate) are chelated to amino acids or organic acids, which means they are generally more soluble and have higher bioavailability. Inorganic forms (oxide, sulphate, and chloride) are bound to inorganic salts and tend to have lower solubility and absorption rates.²³

Dosage: Your body will excrete any magnesium it cannot absorb at once, so high doses of magnesium are not necessarily beneficial. They are also more likely to cause diarrhea or other gastrointestinal upset. Consider well-absorbed forms in divided doses. Also note the elemental magnesium content rather than the total magnesium, as this is the amount your body is able to absorb.

Cofactors: Many magnesium supplements include nutritional cofactors such as trace minerals, vitamin D3, vitamin B6, vitamin K2, which assist with the uptake and use of magnesium in the body. 

Side effects associated with initial or high dosages of magnesium are generally temporary, and will pass as tolerance increases. However, if side effects are severe and do not improve, stop supplementation and seek advice from a health professional. 

Some side effects may include low blood pressure, tummy cramps, diarrhea, gas, bloating, nausea, and vomiting.

Magnesium plays an essential role in synthesizing S-adenosylmethionine (SAMe), the body’s major methyl donor, via methionine adenosyltransferase (MAT). SAMe forms from methionine using ATP, which requires magnesium binding to become the active Mg-ATP complex. This stabilizes ATP for energy transfer and positions SAMe correctly in the enzyme’s active site for methylation processes involved in DNA synthesis, neurotransmitter production, and more.²⁴

In people with MTHFR variants, the conversion of folate into methylfolate is less efficient, which can lead to impaired SAMe production and homocysteine recycling. Low magnesium may slow this process further by limiting Mg-ATP availability, leading to higher homocysteine and DNA instability.²⁵

People with MTHFR have greater needs for adequate nutrients involved in the methylation cycle, including methylfolate, B12, and choline/betaine. Supplementing with magnesium can help to support this process, so it’s important to choose a highly bioavailable product with nutritional cofactors that the body can use efficiently. Look for products that contain chelated or organic magnesium (citrate, glycinate, threonate, or malate) or the highly absorbable liposomal form, rather than inorganic forms.