1. Introduction

Magnesium is a critical mineral in the human body governing the activity of hundreds of enzymes encompassing ~80% of known metabolic functions [1,2,3,4]. Despite the importance of magnesium, it remains one of the least understood and appreciated elements in human health and nutrition. It is currently estimated that 45% of Americans are magnesium deficient and 60% of adults do not reach the average dietary intake (ADI) [5,6,7,8]. A daily intake (DI) of 3.6 mg/kg is necessary to maintain magnesium balance in humans under typical physiological conditions, with the ADI for adults estimated at between 320 to 420 mg/day (13–17 mmol/day) [9,10].

The high rate of magnesium deficiency now postulated [5,6,7,8] can be attributed in part to a steady decline in general magnesium content in cultivated fruits and vegetables, a reflection of the observed depletion of magnesium in soil over the past 100 years [11,12,13]. A report to Congress was already sounding the alarm as far back as the 1930s, pointing out the paucity of magnesium, and other minerals, in certain produce [14].

This loss of mineral content across "healthy" food choices has been compounded by a historical rise in the consumption of processed food, which has been shown to impede magnesium absorption and contribute to the current state of magnesium deficiency (defined by serum blood levels, "normal" being considered as 0.7–1 mmol/L and hypomagnesaemia as <0.7 mmol/L) [15,16,17,18,19]. Given the role of magnesium in calcium and potassium transport, cell signaling, energy metabolism, genome stability, DNA repair and replication, it is not surprising that hypomagnesaemia is now associated with many diseases including hypertension, coronary heart disease, diabetes, osteoporosis, and several neurological disorders [1,2,4,20,21,22,23].

Despite its importance to human health, magnesium remains one of least investigated macro minerals, and while it is getting more attention, this still pales in comparison to the level of investigation into other macronutrients such as calcium or iron (Figure 1). The root cause of this oversight likely lies in the fact that iron and calcium deficiency can be diagnosed through a variety of clinically well recognized associated signs and symptoms, and readily supported by commonly used, and clinically validated, diagnostic assays available for verification [24,25,26]. This tie-in is not the case however, for magnesium, where deficiency does not present with unique and identifiable clinical manifestations. Furthermore, even if clinical signs and symptoms are present, they are overshadowed by or taken to be the result of common co-morbidities such as diabetes and cardiovascular disease. The lack of a standardized laboratory test that accurately describes the status of magnesium [27] remains one of the most vexing challenges associated with the magnesium field, and contributes to the relative anonymity of magnesium compared to other macronutrients, which in turn, further contributes to magnesium deficiency and its sequelae.

Figure 1

Number of basic and clinical research papers published (Y-axis) as screened using Web of Science [v.5.28.1] under the search terms "magnesium deficiency" (yellow), "calcium deficiency" (green) or "iron deficiency" (blue) (performed 4 May 2018) over the past 25 years (X-axis; 2017–1992). (Inset) Trend lines show the relatively flat research output on magnesium deficiency relative to calcium and iron.

Moving forward, it is clear that there will be an important role to play for magnesium supplementation across, and within, certain populations. The key to unlocking the benefits of magnesium will be to understand the factors contributing to inadequate dietary intake, including the complexity of absorption, secretion, and reabsorption, and to address the challenges of representative compartment analytics. These factors make most human clinical magnesium supplementation studies are difficult to extrapolate and interpret accurately, leading to magnesium research being described as, "Far from complete and the conclusions that have been drawn are far from clear." [28].

Causes of Magnesium Deficiency

Despite the importance of magnesium to human health and wellness, 60% of people do not meet the recommended DI of 320 mg/day for woman and 420 mg/day for men, with 19% not obtaining even half of the recommended amount [5,6,29]. Magnesium dietary deficiency can be attributed not just to poor mineral intake due to modern diets, but historical farming practices may play a significant role as well. The highest food sources of magnesium are leafy greens (78 mg/serving), nuts (80 mg/serving), and whole grains (46 mg/serving), none of which individually have a high percentage of the recommended dietary allowance (RDA) of magnesium or are eaten consistently or sufficiently for adequate magnesium intake [10,15,30]. Increasing demand for food has caused modern farming techniques to impact the soil’s ability to restore natural minerals such as magnesium. In addition, the use of phosphate-based fertilizers has resulted in the production of aqueously insoluble magnesium phosphate complexes, for example, further depriving the soil of both components [31].

Many fruits and vegetables have lost large amounts of minerals and nutrients in the past 100 years with estimates that vegetables have dropped magnesium levels by 80–90% in the U.S. (Figure 2) and the UK [11,12,13,32,33]. It is important to note that the USDA mineral content of vegetables and fruits has not been updated since 2000, and perhaps even longer, given that the data for 1992 was not able to be definitively confirmed for this review. The veracity of the mineral content to support the claim of demineralization of our food sources should be verified, particularly since farming methods and nutrient fertilization has undoubtedly advanced in the last 50 years. Hence, there is a clear need for a new initiative to study the current mineral content in vegetables and fruits grown in selective markets to get a current and validated assessment of the mineral and nutrient value of commonly consumed fruit and vegetable staples.

Figure 2

The average mineral content of calcium, magnesium, and iron in cabbage, lettuce, tomatoes, and spinach has dropped 80–90% between 1914 and 2018 [30,34,35,36,37]. Asterisks indicate numbers could not be independently verified.

Modern dietary practices are now estimated to consist of up to 60% processed foods [38]. Processing techniques, such as grain bleaching and vegetable cooking, can cause a loss of up to 80% of magnesium content [39]. Beverages, such as soft drinks, which contain high phosphoric acid, along with a low protein diet (<30 mg/day), and foods containing phytates, polyphenols and oxalic acid, such as rice and nuts, all contribute to magnesium deficiency due to their ability to bind magnesium to produce insoluble precipitates, thus negatively impacting magnesium availability and absorption [40,41,42,43]. Magnesium in drinking water contributes to about 10% of the ADI [44], however, increased use of softened/purified tap water can contribute to magnesium deficiency due to the filtering or complexation of the metal [45]. In addition, fluoride, found in 74% of the American population’s drinking water, with ~50% of drinking water having a concentration of 0.7 mg/L, prevents magnesium absorption through binding and production of insoluble complexes [46,47,48]. Ingestion of caffeine and alcohol increase renal excretion of magnesium causing an increase in the body’s demand [49,50]. Common medications can also have a deleterious effect on magnesium absorption such as antacids (e.g., omeprazole), due to the increase in gastrointestinal (GI) tract pH (see Section 2.5) [51,52], antibiotics (e.g., ciprofloxacin) [53], and oral contraceptives due to complexation [54,55], and diuretics (e.g., furosemide and bumetanide), due to an increase in renal excretion (see Section 2.6) [56,57].