Supplements 101: Magnesium

Magnesium is the 4th most common mineral in the body with calcium, sodium, and potassium taking the lead. While most are familiar with how vital sodium, calcium, and potassium are to every function of the body, magnesium is a lesser-known player.

Magnesium is important. It is required for the functioning of over 300 enzymes in humans! In addition to acting like the key to activating so many enzymes, the mineral also helps balance other minerals like calcium and potassium. It is involved in tissue health and repair. It helps make DNA, RNA, and proteins. It is also vital for the mitochondria to make cellular energy, ATP.

Magnesium Deficiency is Common to All

Modern times have seen a rise in magnesium deficiency. Soils have been depleted of magnesium with the overuse of pesticides which bind Mg and limits its uptake in crops. Water processing plants further deplete the mineral before it comes to our taps. Refinement of foods, like grain, also dramatically reduces food’s magnesium content by upwards of 300%. Boiling foods reduces the magnesium content.

In the gut, absorption of magnesium can be reduced if taking certain medications. Antacids, antibiotics, antihistamines, and blood pressure-lowering drugs are chief culprits. Absorption is also reduced if there is a vitamin D deficiency. With normal aging, magnesium absorption is reduced by as much as 30%.

In the US, the magnesium intake of the average adult in 1900 was 540mg, compared to just 250mg today. These statistics are also consistent with other countries. It is thought that chronic, subclinical magnesium deficiency is associated with an increased risk of cardiovascular disease and depression. Perhaps others.

Testing Magnesium Levels is Tricky

As much as 90% of the total magnesium content of the body is housed in muscle tissue and bone. So when taking a blood test, only a small window of magnesium status is sampled. Magnesium levels can also be detected by analyzing hair.

In the blood, a large proportion of magnesium is bound to carrier proteins where it is not readily detected on a routine blood test. Serum magnesium is most commonly tested. However, magnesium deficiency can be present despite normal serum magnesium levels. Testing the magnesium content of the red blood cell is a preferred method but all blood markers lack sensitivity of detection compared to a muscle biopsy for instance.

To make matters worse, many doctors and researchers agree that the current reference ranges of serum and red blood cell magnesium are not sensitive enough to detect those with marginal deficiency. So if you’re values are on the low end of normal, you could have a subclinical deficiency.

Typical labs use a reference range of serum magnesium of 75–95 mmol/L. However, researchers suggest that any serum value below 85 mmol/L is considered a clinical deficiency.

Magnesium Deficiency may be Common to ME/CFS

Some studies have shown low levels of magnesium in ME/CFS patients. However the study designs were poor and testing methods not highly sensitive. There are also few trials to show that supplementing with magnesium benefits symptoms or quality of life in ME/CFS. Again these studies were poorly designed and used dosages and forms of magnesium that were less than ideal.

Severe ME/CFS patients are likely at highest risk of deficiency. In a study of hospitalized patients, 6.9%–11% were noted to have low magnesium levels on their routine exam. The immobilization of bed rest and all other physiological effects of it (excess cortisol), likely deplete the mineral further. More details on these factors below…

Magnesium Deficiency Promotes Inflammation

Even short periods of magnesium deficiency can trigger inflammatory pathways. With inadequate magnesium, cells produce Substance P—a molecule that is involved in pain and acute inflammation. Substance P also has the effect of stimulating the head honcho of the inflammatory cascade, NFkB. 

In human studies, those with the lowest magnesium levels also had the highest markers of systemic inflammation. This included high levels of CRP and TNF. In cells, the absence of magnesium causes mast cells to pump out histamine and perpetuate an inflammatory response. On the flip side, high levels of magnesium reduce the release of inflammatory cytokines from blood cells.

Magnesium Acts in the Brain

Magnesium readily and easily crosses into the brain through the blood-brain barrier. Once there, it can bind to the NMDA receptor—a key receptor that triggers neurons to be excited. Magnesium works counter to calcium and glutamate in the brain which stimulates NMDA to excitation. Overactivation of this receptor has been implicated in autism, depression, and neurodegenerative diseases like Alzheimer’s. What causes overactivation? Well, it could be too much glutamate and calcium, or too little magnesium to keep these in check.

Magnesium Plays a Vital Role in the HPA Axis

Magnesium can alter the entire stress response cascade—the message from the brain that tells the adrenal glands to release the stress hormone cortisol. This is the hypothalamic-pituitary axis (HPA). Magnesium acts at the top of this cascade to hinder the release of hormone (ACTH) from the hypothalamus of the brain so that the message doesn’t reach the adrenal glands. When magnesium is deficient, the hypothalamus produces excess ACTH (no check and balance) to force the adrenal gland to pump out more hormones. Not enough magnesium means serious disruption of the HPA axis.

A double-blind randomized clinical trial was conducted in 46 elderly subjects taking 50mg of magnesium oxide or placebo. Their sleep was assessed in this trial but also blood markers of stress including cortisol. After 8 weeks, there were significant decreases in cortisol and also better sleep. A thought provoking study but it’s a total shame they used the oxide form! Learn all the forms of magnesium below.

Magnesium is Effective for Migraine

A Cochrane review graded magnesium supplementation as an effective, evidence-based approach to reduce migraine headaches. Supplementation has been shown to reduce the frequency, duration, and intensity of migraines by 41% compared to placebo. Another study with a 3-month treatment period of oral Mg citrate at 600 mg/day resulted in significant improvement in attack frequency and severity.

How to Get More Magnesium

As is always the case, nutrition from whole food sources is best. Around 30-40% of the magnesium from foods is absorbed in the gastrointestinal tract. However, absorption is increased even further if there is already a deficiency. High-fiber foods stimulate gut bacteria to enhance magnesium absorption.

Foods highest in magnesium are hemp and pumpkin seeds, spinach, chard, yogurt, oily fish, avocado, dark chocolate, and mollusks. Get extra magnesium from drinking high-quality mineral water.

Supplementing with Magnesium

Some experience GI upset when supplementing with magnesium. The Institute of Medicine has set an upper tolerable limit at 350 mg/day, as this amount has no risk of gastrointestinal side effects in almost all individuals. Keep in mind that GI upset may be an indicator that the form of magnesium is not right for you or it could mean that you are taking too much.

Magnesium toxicity is rare but can occur. Symptoms to watch out for include back or pelvic pain, drop in blood pressure, difficulty breathing, irregular heartbeat, and confusion. Those with kidney disease should not take magnesium outside of medical guidance.

If you can’t tolerate oral forms of magnesium, topical applications, liquid drops, bath products, or inhalants are also effective at increasing levels. For those that are bedridden with illness or have severe deficiency, injectable magnesium may be prescribed.

Which Form of Magnesium is Best?

Magnesium comes in numerous forms so it is no wonder that confusion surrounds which one to choose. Typical forms recommended by doctors are oxide and citrate. Yet these have the worst bioavailability. Let’s break the various forms down:

• Magnesium oxide: this is often found in effervescent tablets. Poorly absorbed

• Magnesium citrate: significantly better absorbed than oxide since it is more soluble but still not great

• Magnesium chloride, lactate, and aspartate: bioavailability better than citrate and oxide

• Magnesium sulphate: common preparation for intramuscular or intravenous administration, good delivery

• Magnesium orotate: does not have GI upset effect, orotate helps shuttle Mg into the cell, best studied in cardiovascular diseases

• Magnesium taurate: good absorption and ability to pass through to the brain easily, best for migraine

• Magnesium malate: used in clinical trials of Fibromyalgia (though poor design), minimal GI side effects

• Magnesium glycinate: better bioavailability and fewer GI side effects

If you have a clear magnesium deficiency, even subclinical, choose any of the last 4 forms of magnesium listed here. Shoot for less than 350mg per day in a divided dose or as tolerated. If you don’t have a clear deficiency and want to trial therapeutic magnesium supplementation for ME/CFS, then magnesium taurate seems like the best option as it has more potent effects on the brain.

References

DiNicolantonio JJ et al. (2018) Subclinical magnesium deficiency: a principal driver of cardiovascular disease and a public health crisis. Open Heart. 5(1): e000668.

Uysal N et al. (2019) Timeline (Bioavailability) of Magnesium Compounds in Hours: Which Magnesium Compound Works Best? Biol Trace Elem Res. 187(1):128-136.

Innerarity S. (2000) Hypomagnesemia in acute and chronic illness. Crit Care Nurs Q. 23(2):1-19.

Tarleton EK, Littenberg B, MacLean CD, Kennedy AG, Daley C (2017) Role of magnesium supplementation in the treatment of depression: A randomized clinical trial. PLoS ONE 12(6): e0180067.

Schwalfenberg GK (2017) The Importance of Magnesium in Clinical Healthcare. Scientifica (Cairo). 2017: 4179326.

Dibaba DT, Xun P, He K. (2014) Dietary magnesium intake is inversely associated with serum C-reactive protein levels: meta-analysis and systematic review. Eur J Clin Nutr. 68(4):510-6.