Western Societies have seen a steady escalation in their calcium to magnesium ratio, due in large part to increasing dietary calcium relative to magnesium and decreasing magnesium content in their food. The mineral content of vegetables has declined by as much as 80% - 90% in the last 100 years [1]. There has also been considerable controversy over what blood level of 25(OH)D and intake of D3 constitute adequacy for skeletal and extraskeletal health [2].

This controversy has only become more heated with the advent of Covid-19 and the pandemic. D3 intake directly affects the iCa:iMg ratio. But this has garnered little attention and the interplay has been overlooked. The benefits of vitamin D are slowly adulterated as this ratio rises and is reflected in rates of colorectal cancer [3] [4] [5], prostate cancer [5] [6], esophageal cancer [5], cardiovascular disease (CVD) [5], metabolic syndrome [5], total mortality [5], and cognitive function [7] [8].

Like calcium, only the ionized form of magnesium (Mg⁺⁺ or iMg) is physiologically active. Unlike calcium, magnesium is primarily an intracellular resident. Magnesium is not a hormone like vitamin D, but does play an integral role in the function of neurotransmitters and intracellular signaling.

Vitamin D not only identifies as a hormone with endocrine features but also boasts intracrine and paracrine capabilities. The latter are vital to both innate and adaptive immune function. Vitamin D deficient rickets was first discovered in the 1920s. Not until the 1970s was the entity vitamin D resistant magnesium deficient rickets recognized.

Is magnesium integral to optimal immune function as well? Or is its primary role only to support vitamin D? Is there a vitamin D resistant magnesium deficient immune dysfunction? And if so, at what level of magnesium is this problem avoided? We know that magnesium is vital to immune function independent of vitamin D. Its role in methylation to prevent mutations and to stabilize DNA are under-appreciated. Is there a way to evaluate the vitamin D/magnesium partnership directly? Using widely accepted laboratory reference ranges for serum Ca, Mg, PTH and several clinical studies involving Ca, Mg, PTH, and 25(OH)D, this article will demonstrate the critical roles in immune function both magnesium and vitamin D play, together and independently. A serum iCa:iMg of about 2.0 with a 25(OH)D of at least 50 ng/mL translates to optimal health.

Establishing magnesium sufficiency in the hospital setting can be difficult. Most of the authorities on the topic cannot agree on the best method. Evaluating the urine for the concentration of magnesium after a loading dose seems to be the most popular at present. However, this is expensive and time consuming, not to mention inconvenient. Many others prefer to measure magnesium content within RBCs (red blood cells) and/or PBMCs (peripheral blood mononuclear cells). In the healthy (no meds, no renal disease, normal albumin, no known relevant polymorphisms) establishing magnesium sufficiency is much easier. Serum iMg can be calculated, as will be shown.

The Ca:Mg appears to differ depending on the population studied, and diet seems to be the primary determinant of this variance. Jean Durlach, founder of the Society for the Development of Research on Magnesium (SDRM) over 50 years ago recommended 2.0 as the proper target.

The active forms of calcium and magnesium are its cations (iCa, iMg). The screening serum lab value for each includes both bound and unbound components. Normal range for serum calcium is about 2.2 - 2.7 mM (8.5 - 10.5 mg/dL or 4.3 - 5.3 mEq/L) with a median of about 2.45 mM (mg/mL). If serum albumin is midrange, then ~50% is ionized => median iCa is about 1.22 mM. Normal range for serum magnesium is about 0.75 - 0.95 mM (1.8 - 2.2 mg/dL or 1.5 - 1.9 mEq/L) with a median of 0.85 mM. Serum iMg is 55% - 70% of total serum Mg (tMg) [9] [10] [11]. What % is “normal”?

Serum iMg is held within a narrow range (0.53 - 0.67 mmol/L by ion sensitive probe) in normal, healthy subjects [12]. Therefore, in normal, healthy subjects about 70% of serum magnesium must be ionized in order to remain within the reference range, i.e., 70% of 0.75 mM = 0.525 mM (v 0.53 mM) and 70% of 0.95 mM = 0.665 mM (v 0.67 mM). This implies a median iMg of about 0.60 mM and a median iCa:iMg of 2.03 (1.22/0.60), close to Durlach’s recommendation of twice as much dietary calcium as magnesium. This number is not some government derived result, but one derived physiologically based on millions of control specimens. Therefore, in normal, healthy subjects with normal renal function and without medications, when serum Mg is within normal limits, most of the time serum iMg can be easily determined from tMg without ion sensitive probes.

Serum tMg and iMg can be further refined in a healthy population by reconfiguring the lower reference limit of serum magnesium from 0.75 mM to 0.85 mM. Serum magnesium values of less than 0.85 mM are associated with increased health risks. The lower limit of the reference range should be raised to 0.85 mM [13] [14]. This reference interval (0.75 - 0.95 mM) was derived from NHANES (National Health and Nutrition Examination Survey) I data (1974) and the recommended iCa:iMg of 2.6 was derived from NHANES II (1977). Both were based on the distribution of serum magnesium in a normal population rather than one based on clinical outcomes. Due to funding shortages NHANES has not determined serum magnesium levels in its participants since 1974 [15]. All data is based on food frequency questionnaires.

Many have called for a change in the serum tMg reference range, all have been ignored [16] [17]. Many have noted that using a cut-off of 0.75 mmol/L for magnesium deficiency misses 50% of those with true magnesium deficiency. For example, no change of iMg in plasma was observed during the menstrual cycle in controls and PMS (premenstrual syndrome) patients. However, in the PMS group the overall monocyte iMg and to a lesser extent the RBC iMg were significantly lower than in controls [18]. Another study on migraine patients, as compared to controls, demonstrated a lower intracellular magnesium content only [19]. Subsequent increase in magnesium intake only increased intracellular content (erythrocytes and lymphocytes) without any change in plasma magnesium.

Any serum iMg shortfall is seemingly replenished in part from intra-erythrocytic iMg stores, where iMg varies between 0.4 - 0.6 mM [20] [21]. This is close to the serum iMg range of 0.53 - 0.67 mM [12], which suggests simple passive diffusion. Interestingly, intra-erythrocytic iMg also reflects memory and recognition [22] and intra-erythrocytic iMg appears to decline with age [23]. Changing the reference range lower limit for serum magnesium would uncover these diagnostic shortfalls. Mansmann christened this occult (migraines) and subclinical (PMS) normomagnesemia magnesium deficiency (MgD) [24]. Normomagnesemia MgD can also be seen in pre-eclampsia [25]. Even below the existing lower limit of 0.75 mM, symptoms may be absent [26].

PTH, which responds to both blood iCa and iMg, should be about 20 - 30 pg/ml (see Figure 1), when serum (or plasma) tCa (total calcium) is at its median of 2.45 mM or 9.5 mg/dL.

One study [27] evaluated a group with “high” magnesium intake (n = 19) in which 1) the RDA for magnesium was met by FFQ (food frequency questionnaire), 2) the calcium intake was twice that of magnesium, 4) the vitamin D was 27 ng/mL (near its official sufficiency level of 30 ng/mL), 5) iMg was 0.537 mM,

and 5) the iCa:iMg ratio was an optimal 1.85 (=> iCa was about 1.0 mM, since serum calcium was not measured). Both iCa and iMg were low, despite a PTH of 60 pg/mL. The sufficiency level of 30 ng/mL 25(OH)D requires a PTH of 40 pg/mL (see Figure 2). This indicates some degree of secondary hyperparathyroidism in this “high” mag group. Ca and Mg need to increase and a vitamin D level of 30 ng/mL is insufficient to meet that need. The set point (27-D, 60-PTH) in this group represents their mean in this study. The PTH of 60 pg/mL on the curve (see Figure 2) corresponds to a 25(OH)D of less than 10 ng/mL (not 27 ng/mL). This level of PTH is too high (secondary hyperparathyroidism) and must be suppressed by increasing magnesium and calcium intake and their absorption/resorption. Increasing intake of D3 both increases calcium/magnesium and suppresses PTH. This shifts the curve to the right by about 20 ng/mL (27 ng/mL - ~7 ng/mL). The recommended 30 ng/mL 25(OH)D becomes about 50 ng/mL and the PTH becomes about 30 pg/mL. But the 2:1 intake ratio must be maintained. The 25(OH)D can then approach its minimal adaptation of 50 ng/mL (see Figure 2). This 50 ng/mL is not some arbitrary number determined by the Institute of Medicine (IOM) (mathematically proven to be in error by an order of magnitude) [28]. This number has been determined physiologically by serum samples from a large control group (n = 14,681). About 75% of all adults worldwide have serum 25(OH)D levels less than 30 ng/mL [29]. According to the NHANES (2003-6) about 95% of Americans have serum 25(OH)D levels less than 40 ng/mL [30].

Another recent study of 180 participants (see Figure 3) [31] revealed that increasing magnesium intake, when serum 25(OH)D > 30 ng/mL, may be ineffective and even counterproductive.

In this study magnesium supplementation was beneficial if initial baseline 25(OH)D3 was between 15 ng/mL and 30 ng/mL, but had a negative effect if baseline was between 30 and 50. But closer scrutiny reveals that the Ca:Mg ratios for the target group and the placebo group were 3.7 and 3.9 respectively (serum calcium must be elevated and PTH must be suppressed). Any increase in either calcium or magnesium further suppresses PTH (negative feedback) and with it the synthesis of vitamin D, which is degraded to 24,25(OH)₂D3 at a 3.5 + Ca:Mg. The PTH (not measured) must be allowed to increase by decreasing Ca intake. An elevated Ca:Mg cannot be lowered by increasing magnesium supplementation alone. An isolated increase in magnesium intake will only further depress PTH. A combined approach will facilitate the availability to Mg of CaSRs in the intestines, kidneys, bone, and parathyroids, shared by both calcium and magnesium. Increased Mg intake can be accommodated with less risk of the laxative effect. But calcium intake must be curtailed simultaneously!

As has been shown, midrange iCa and iMg and a 2:1 ratio cannot be attained at a level of 40 ng/mL for 25(OH)D. From this graph (see Figure 1, Figure 2) the difference in PTH values above or below 30 pg/mL reflects a Ca:Mg ratio below or above 2.0 respectively. If iCa and iMg are midrange and dietary calcium to magnesium intake approaches 2 to 1, then the full benefit of increasing vitamin D can be realized even to 80 ng/mL without increasing serum calcium [32].

The beneficial effect of lowering the Ca:Mg ratio below 2.6 (see Figure 4) applies to many forms of cancer, CVD, total mortality, and cognitive function.

But there is a lower limit and it appears to be 1.7 [3] [4] [33] [34]. In a study on Chinese [33] with a low Ca/Mg intake ratio (a median of 1.7 vs around 3.0 in US populations), intakes of Mg greater than US Recommended Daily Allowance (RDA) levels (320 mg/day among women and 420 mg/day among men) were related to increased risks of total mortality for both women and men. Mortality was predominantly CVD and CRC [33], which were also seen in those who increased calcium intake, when their Ca:Mg exceeded 2.6. Perhaps the dairy diet of the West (more disposed to calcium) might explain this discrepancy. Increasing calcium intake has been encouraged in China [34]. Increased magnesium intake has been encouraged in the West [35].

According to NHANES (1999-2000), 79% of US adults did not meet the RDA of magnesium. US population Ca:Mg for 2000 and later has been greater than 3.0 with a mean ratio as high as 3.7 in women supplementing with calcium [36].

The inverse association between calcium and distal CRC was found only in participants with a Ca:Mg ratio between 1.7 and 2.5. Interestingly, in one study on this 25(OH)D levels were higher in those with Ca:Mg greater than 2.636 in both the placebo and target groups [4]. Clearly vitamin D supplementation in a vacuum has drawbacks.

According to NHANES 2009-2010 data, more than 76% had calcium-to-magnesium intake ratios ≥2.6… A Ca:Mg ratio range of 1.70 - 2.60 has been proposed as an optimum range. Data from NHANES surveys have shown the mean Ca:Mg intake ratio from foods alone for US adults has been >3.00 since 2000. Furthermore, a review of supplements containing calcium or magnesium available to the American public found a mean ratio of 2.90 [5].

The journey to determine optimum Ca:Mg and its relationship to vitamin D has been tortuous and torturous.

1) The RDA for D3 determined by the IOM of the National Academy of Sciences, issued in 2014, was shown to be in error by an order of magnitude [28]. Instead of 600 to 800 IUs D3 per day, it should be 6000+. Instead of 30 ng/mL blood level of 25(OH)D, it should be 50+ ng/mL.

2) Calculation of the NNT (number needed to treat) reveals the efficacy of vitamin D for viral respiratory infections during the flu season [37] to be ten times that of the flu shot, according to the CDC’s own data for 2017-18 [38]. Yet this fact languishes in clinical application.

Many conditions challenge magnesium adequacy. Dehydration triggers aldosterone, which has a magnesiuretic effect [39]. The symptoms of dehydration overlap with those of magnesium deficiency―headaches, cramps. Stress triggers cortisol, which also causes magnesiuresis [40]. Due to these factors and many others, e.g., alcohol, proton pump inhibitors, certain antibiotics, …, magnesium status can slowly deteriorate, yet remain unrecognized. Many of its signs and symptoms are nonspecific and overlap with those of aging, including alopecia, a common symptom in Long Covid. Magnesium deficiency is an underappreciated and unwelcome diagnosis hiding in plain sight. It has as deep a connection to vitamin D, as does calcium. The serum iCa:iMg serves as a reliable proxy for their working partnership [41]. Calcium and magnesium compete for the same receptor (CaSR) in the intestines, bone, kidney, and the chief cells of the parathyroid glands. Vitamin D and magnesium are also inextricably linked. Magnesium is required for multiple enzymes in the synthesis of vitamin D and PTH (see Figure 5). Even the substrate (7-dehydrocholesterol), utilized by the sun to produce D3, requires magnesium as a cofactor.

Magnesium can also act independent of vitamin D. We know that it is critical for natural killer (NK) and CD8+ cell activation [42] [43] [44]. Magnesium is also required for synthesis of SAMe (S-adenosyl methionine), the universal source for the body’s methylation needs, essential to cancer prevention and other probable long term complications of Covid-19 and/or its vaccines, including cognitive function. DNA is hypomethylated in both Alzheimer’s [7] and Lewy Body Dementia [8].

Magnesium is essential to the synthesis of the powerful antioxidants glutathione (see Figure 6) and melatonin. These two antioxidants are frequently mentioned in the treatment of Covid-19 [45] [46]. NAC (N-acetyl cysteine) efficacy has also been reported [47] [48]. Magnesium (and B6) are also required cofactors for aromatic L-amino acid decarboxylase (AAAD), which directly produces serotonin and dopamine. An imbalance or deficiency between the two is closely associated with depression and many symptoms that overlap with Long Covid.

To produce melatonin requires methylation (with B5 as cofactor) of serotonin. SAMe is the sine qua non for synthesis of both glutathione (see Figure 6) [49] and melatonin. NAC can replenish glutathione [47] [48]. Glutathione also regulates transforming growth factor-beta (TGFβ) [50], a cytokine critical to Covid-19 and some forms of Long Covid.

Myalgic encephalomyelitis/chronic fatigue syndrome (CFS) [51], fibromyalgia [52], Epstein-Barr virus (EBV) [53], cytomegalovirus [54], mast cell activation syndrome (MCAS) [55], and postural orthostatic tachycardia syndrome (POTS or dysautonomia) are all associated with magnesium deficiency. Excess histamine characterizes MCAS. Magnesium is required for both pathways to degradation

of histamine (SAMe and diamine oxidase (DAO)). There are reports of successful treatment of Long Covid with antihistamines. Autoimmune diseases (multiple sclerosis, systemic lupus erythematosus, rheumatoid arthritis, diabetes mellitus (DM)) [56] [57] [58] are also directly or indirectly associated with magnesium deficiency.

The CD147 epitope on the spike protein S of SARS-CoV2 or its vaccines [59] [60] combines with CD147 receptors on immune cells, erythrocytes, platelets, and endothelial cells. ACE2 receptors are prominent in the lungs, but the CD147 receptor becomes the major player once the blood-gas barrier has been breached. Vaccination bypasses this immune barrier. Increasing D3 supplementation in the face of an imbalanced calcium intake, three times greater than that for magnesium, impedes the contribution of magnesium to immune function and can compromise the benefits of vitamin D. Calcium and magnesium are both integral to immune function, but as the iCa:iMg increases above its natural, Mother Nature derived ratio of 2.0, efficacy slowly decreases.

The magnesium dependent 1α-hydroxylase, which produces the active form of vitamin D, is active not only in renal cells but also in lung, prostate, brain, immune cells, and placenta for synthesis of active vitamin D with paracrine and intracrine effects that are not impacted by circulating PTH [61]. These cells need plenty of intracellular Mg⁺⁺ to enable intracellular reactions, e.g., PTH production in the cytosol and vitamin D related hydroxylations in the mitochondria. Increasing intracellular iCa compromises this [62] via competition for mitochondrial membrane CaSRs. This might explain why so many symptoms of magnesium deficiency involve smooth, skeletal, or cardiac muscle, all rich in mitochondria.

・ “Every known illness is associated with a magnesium deficiency”. Norman Shealy (father of holistic medicine);

・ “Magnesium is involved in ~80% of known metabolic functions”. Jayme Workinger.

In summary, calcium, magnesium and vitamin D are essential to good health. The iCa:iMg ratio is the best measure of the efficacy of this working partnership. The present reference range for normal serum tMg (0.75 - 0.95 mM) includes many with subclinical diseases. In healthy, normal individuals tMg can provide specific insight to iMg, especially if the tMg normal range is modified to 0.85 - 0.95 mM. The laboratory reference range values for serum Mg and Ca imply a midrange iCa:iMg of about 2.05 which contradicts official RDA recommendation from the IOM for calcium and magnesium, which is about 3.0 (1200 mg/400 mg). A review of supplements containing calcium or magnesium available to the American public found a mean ratio of 2.90 [5]. Furthermore, the RDA of 600 - 800 IU/d for vitamin D from the IOM was discovered to be in error by an order of magnitude (2014) and has not been rectified over the ensuing 8 years [30]. The target ratio of 2.0 cannot be attained at this RDA.

To attain the laboratory reference range dictated ratio of 2.05 for iCa:Mg requires a PTH of about 30 pg/mL (see Figure 1), a similar 2.0 dietary intake ratio for calcium and magnesium, and a 25(OH)D level of at least 50 ng/mL. Any PTH above this level implies some degree of secondary hyperparathyroidism (elevated PTH and depressed 25(OH)D). Any PTH level below this implies some degree of secondary hypoparathyroidism (depressed PTH and elevated iCa:iMg). Some symptoms of mild hypoparathyroidism, e.g., fatigue, weakness, cramps, fasciculations, overlap with those of magnesium deficiency.

Indeed both the correction of the IOM error [30] and evidence presented in this article point to a sufficiency level of at least 50 ng/mL 25(OH)D (see Figure 9).

Magnesium deficiency, including that associated with an elevated iCa:iMg, combined with CD147 receptor mediated consumption of NK cells and CD8+ T cells, creates severe Covid-19. The CD147 epitope, present on the spike protein S [59] [60], engages CD147 receptors on these two classes of immune cells.

NK cells and CD8+ T cells produce the predominance of IFN-γ and its removal activates the KKS, brain fog type Long Covid [84]. The other less frequent comorbidity type Long Covid is characterized by increased TGFβ. This cytokine opposes IFN-γ and is increased in all with comorbidities. Its release is triggered by angiotensin II and AT1Rs, and arises in an upregulated RAS environment.

Maintaining a dietary Ca:Mg intake roughly 2:1 (dairy has a Ca:Mg of about 12:1) and a 25(OH)D level of at least 50 ng/mL optimizes the vitamin D, calcium, magnesium interplay. Between 1977 and 2012, US calcium intakes increased at a rate 2 - 2.5 times that of magnesium intakes [118]. Got milk?

Perhaps a “Long Covid panel” or “immune panel” with serum 25(OH)D, calcium, and magnesium might become popular. This approach shields the individual from not only the crown viruses and their vaccines but also DNA mutations and cancer, cardiovascular disease, and immune dysfunction in general.

The author declares no conflicts of interest.

Chambers, P. (2022) Ca:Mg + D, the Shield that Interdicts the Crown Viruses and Vaccines. Open Access Library Journal, 9: e9249. https://doi.org/10.4236/oalib.1109249