Magnesium B6 Supplement

Magnesium belongs to the group of mineral compounds. This group includes:

• Mineral salts, found in abundance, such as magnesium, calcium, or potassium
• Trace elements, which are present in trace amounts, such as iron, copper, and manganese.

Magnesium is the 5th most abundant mineral salt in our body, after calcium, phosphorus, potassium, and sodium. It is involved in over 300 enzymatic reactions in humans (metabolism of ATP, lipids, proteins, and DNA), which says a lot about its importance.

A healthy person has a magnesium stock of around 25 grams, though this varies depending on body weight. Since our body excretes magnesium every day, a continuous supply is necessary, through both diet and supplementation.

A lack of magnesium can affect fatigue, protein synthesis, and muscle recovery. Athletes have higher needs, and many turn to supplementation to meet them.

Magnesium is often paired with vitamin B6, which contributes to:

• Normal protein and glycogen metabolism,
• Normal functioning of the nervous system,
• Normal psychological function,
• Normal energy-yielding metabolism,
• Reduction of tiredness and fatigue.

Magnesium is the 5th most abundant mineral salt in our body. It is involved in over 300 enzymatic reactions in humans (metabolism of lipids, proteins, and DNA), which says a lot about its importance. Dietary magnesium is mainly found in cereal bran (whole grains), dried herbs, seeds, and oilseeds (nutritional composition data for foods is available on the website of ANSES, the French Agency for Food, Environmental and Occupational Health & Safety).

About 99% of the body's magnesium is stored in our tissues, while 1% circulates in the serum and red blood cells (erythrocytes). Bone tissue contains the largest share (50 to 60%). The rest is stored in skeletal muscles and soft tissue. Storage (retention), absorption, reabsorption, and excretion result from exchanges between different compartments of the body (small intestine, colon, kidneys, muscles, and bones) based on dietary magnesium intake [1] (see diagram of storage and exchange).

Figure 1: illustrating the storage and exchange sites of magnesium (de Baaij JH, et al., 2015) [2]

Magnesium is mostly intracellular. In the body's electrolyte balance, it acts mainly inside our cells, just like potassium.

Figure 2: illustrating the body's electrolyte balance.

Magnesium is involved throughout our body, hence a very broad range of health claims (see the benefits tab). Here are the main areas where it plays a role:

• Bone health, notably because it's a cofactor for calcium, alongside vitamin D and vitamin K.
• It's an essential element in stress management.
• It's an important part of the Krebs cycle, meaning aerobic energy production.
• It's also a key mineral for good cardiovascular health, particularly for maintaining healthy blood pressure and preventing strokes.
• Lastly, it's an important element in protein synthesis.

Magnesium is also part of the structure of many physiological components of our body beyond bones and proteins: notably in a large number of enzymes, in mitochondria, and in DNA and RNA. In short, magnesium is everywhere, and its benefits are just as numerous. Let's look at a few of its main actions.

The benefits of magnesium for improving overall sleep quality were demonstrated in a randomized, double-blind, placebo-controlled trial conducted among 46 adults suffering from insomnia. Participants received either 500 mg/day of elemental magnesium or a placebo for eight weeks.[3] Sleep was assessed using sleep diaries and the Insomnia Severity Index questionnaire, and physical activity was recorded.[3] Blood samples for magnesium, cortisol, melatonin, and renin were also taken before and after the trial.[3] Magnesium supplementation significantly increased sleep time (p = 0.002) and sleep efficiency (p = 0.03), while improving sleep onset latency (p = 0.02).[3] Serum cortisol levels decreased (p = 0.008) alongside increases in serum melatonin and renin (p = 0.007 and p < 0.001 respectively), indicators of improved sleep quality.[3] Researchers also noted that decreased renin levels were associated with lighter sleep, while improved renin was associated with non-REM (NREM) sleep.[3]

A second trial, randomized, placebo-controlled and crossover, looked at the impact of magnesium supplementation on nighttime hormone secretion in 12 healthy volunteers aged 60 to 80.[4] Magnesium supplementation significantly decreased cortisol levels (p<0.01) during the first part of the night. Aldosterone increased (p<0.05) during the second half of the sleep cycle, with renin increased (p<0.05) throughout the cycle.[4] This demonstrates that magnesium can help offset the changes that can occur with aging and their impact on the sleep cycle.

Magnesium is also highly present in the stress pathway, where the body produces epinephrine and norepinephrine that trigger a calcium influx into muscle nerve endings to keep them tense. This action enables the muscle contraction needed to respond to danger. The calcium influx into nerve endings drives magnesium out of its intracellular environment, leading to its excretion once in the bloodstream. Adequate magnesium intake is therefore essential to avoid an imbalance between calcium and magnesium (a Ca:Mg ratio of 2:1 is ideal) and to prevent chronic stress from taking hold over the long term.

Magnesium supplementation has been shown to reduce muscle pain associated with tension and cramps. In a randomized, double-blind, placebo-controlled trial conducted among 43 pregnant women, for example, 300 mg/day of magnesium bisglycinate for four weeks reduced the intensity and frequency of cramps by 50% (p<0.05).[5] Magnesium citrate (300 mg/day) over six weeks (n = 17) was also found to be effective in improving patients' assessments of muscle cramps, with 78% of patients reporting improvement compared to 54% in the placebo group (p < 0.03).[6] These results therefore point to the benefits of magnesium in moderating cramps and muscle spasms.

Because of its affinity with phosphate, magnesium (in its ionized form) plays a role in ATP phosphorylation and therefore in energy metabolism. In muscle, magnesium is a cofactor of phosphocreatine, essential for ATP resynthesis (an energy intermediate molecule). This gives it a key part in muscle contraction, since the process is "ATP-dependent." More broadly, magnesium as a cofactor is essential to protein synthesis, muscle nerve transmission, neuromuscular conduction, and carbohydrate homeostasis.

Studies have linked magnesium deficiency to congestive heart failure, arrhythmia, myocardial infarction, and, perhaps most notably, hypertension.[7] In a randomized, double-blind, placebo-controlled trial involving 91 middle-aged and older women with mild to moderate hypertension, 480 mg/day of elemental magnesium was administered for six months. This resulted in a decrease in diastolic blood pressure (DBP) of 3.4 mmHg (p = 0.003) in the magnesium group, compared to no change in the placebo group.[8]

A 2017 systematic review and meta-analysis of randomized controlled trials also studied the effect of magnesium supplementation on blood pressure.[9] Subjects included people with insulin resistance, prediabetes, or noncommunicable chronic diseases.[9] Doses ranged between 365 and 450 mg/day. Magnesium supplementation significantly reduced blood pressure and demonstrated clinical effects on overall cardiovascular health. Systolic blood pressure (SBP) was reduced by an average of 4.18 mmHg, while DBP decreased by an average of 2.27 mmHg.[9]

A separate 2017 systematic review and meta-analysis of randomized controlled trials assessed the benefits of magnesium supplementation on cardiovascular risk factors associated with type 2 diabetes (T2D), in both diabetic and non-diabetic individuals. Results showed that magnesium supplementation reduced SBP by 3.056 mmHg and decreased the risk of CVD associated with T2D.[10]

In France, the maximum authorized daily dose on supplement labels is set at 300 mg per day, or 80% of the NRV, which is established at 375 mg per day [11].

The NRVs, formerly known as RDAs (Recommended Daily Allowance) defined by EFSA are values based on the average needs of the European population as a whole, regardless of age, sex, or physical activity level. For more precision, it's possible to calculate in milligrams per kg of body weight.

In 1995, Maastricht University in the Netherlands published research proposing 6 mg per kg of body weight per day to maintain the body's stock. A 60kg woman therefore needs 360mg per day, and a 75kg man needs 450mg per day. Someone wanting to rebuild a low stock should therefore increase the dose, while keeping in mind that a large part comes from diet, and that the magnesium in food and dietary supplements is absorbed at an average of only 40% (up to 70% for certain nutrients in some cases, see below).

Dietary magnesium is mainly found in:

• Cereal bran (i.e. whole grains)
• Dried herbs
• Seeds and oilseeds
• Sardines
• Mineral water (sipped throughout the day)
• Dark chocolate
• Hard cheeses such as beaufort, comté, or emmental, which also have a good magnesium content
• (Nutritional composition data for foods is available on the website of ANSES, the French Agency for Food, Environmental and Occupational Health & Safety: https://ciqual.anses.fr/).

Western diets tend to be low in magnesium, for several reasons:

• First, fast cooking methods at very high temperatures (over 95°C) tend to strip foods of certain micronutrients.
• Second, cereal refining removes the bran, which is rich in magnesium.
• Lastly, dried herbs, seeds and oilseeds, or hard cheeses aren't present at every meal.

Optimal nutritional intakes of natural magnesium are determined by the body's needs, its absorption, excretion, and retention. This is why occasional magnesium shortfalls can be multifactorial [1,12]:

• A shift in food choices away from "whole" foods and toward more processed products (refined products),
• Reduced absorption due to intestinal disorders, vitamin D deficiency, or the use of proton pump inhibitor medications,
• Gastrointestinal losses resulting from diarrhea, vomiting, malabsorption, fistulas, or laxative use,
• Renal losses due to alcohol consumption, diabetes treatments, or hypercalcemia,
• Losses through sweating,
• Genetic conditions (FHHNC type 1 or type 2, Bartter syndrome, Gitelman syndrome, etc.) [12]
• Unmet needs in particular physiological situations (such as intense stress).

Recognizing a deficiency is still a debated question. Today, there are three approaches of varying complexity that can be used at the individual level:

First, the symptom-based approach: noting the classic eyelid twitch, but above all cramps that occur quickly and often without even having done physical activity. Difficulty falling asleep (tense muscles) is also an indicator. The catch is that this approach remains uncertain. It's more intended to confirm one of the following approaches. A consultation with a healthcare professional can help identify Chvostek's sign or Trousseau's sign. More generally, several studies have shown a positive relationship between magnesium stock and maintaining a relaxed state [13].

You'll often read online that a magnesium deficiency can't be identified through a blood test. That's only half true. There are actually two ways to go about it:

First, by analyzing serum magnesium content, meaning the level of Mg2+ ions in the bloodstream, but not in red blood cells. The problem is that magnesium is stored at 55% in bones and 44% in soft tissue and muscles, so less than 1% of magnesium is in the blood, split between serum (the extracellular medium) at 0.2% and erythrocytes, meaning red blood cells, at 0.8%. Magnesium is a mineral that likes to be inside cells, so a serum-level analysis doesn't provide reliable information about the intracellular stock, which is what matters most.

There is therefore a second approach, analyzing erythrocyte content, meaning the amount of magnesium in red blood cells. At the individual level, this test (not reimbursed by French national health insurance) is unquestionably the most reliable given the intracellular nature of this mineral. There is, however, debate over whether erythrocytes are good indicators for assessing overall magnesium stock. But the consensus today is that a deficiency observed in red blood cells is already strong evidence of a broader deficiency and therefore of the need for supplementation.

Finally, there are approaches based on analyzing magnesium content in urine, but these tests are complicated to carry out, because 1: measurements need to be taken over 24-hour cycles and compared to daily intake, and 2: part of the excretion happens through the fecal route, which makes the analysis somewhat unreliable, and it generally needs to be done in a hospital setting.

Beyond testing, several observational studies such as Su.Vi.Max 1 and 2 have shown that around 75% of the French population has a magnesium deficiency, a quarter of which is considered severe. Three populations are more likely to experience such deficiencies:

• Athletes, who have above-average excretion
• Pregnant women, since part of their magnesium stock is transferred to the fetus
• Older adults (60 and over), whose intestinal magnesium absorption sometimes works less well

Magnesium supplementation therefore appears to make sense, especially since the risk of magnesium excess remains extremely rare.

A good magnesium formula is evaluated on three criteria:

• Elemental magnesium content, which needs to be high enough to avoid taking an unreasonable number of capsules
• Digestive tolerance
• And finally, absorption from the intestine into the bloodstream

Elemental magnesium Mg2+ is an ion that needs to be bound to another molecule to be stabilized. This molecule is called a "transporter" because it affects the three parameters above. There are 3 main families of transporters.

1/ Inorganic magnesium salts

These are called inorganic because they don't contain any carbon atoms. They include magnesium oxide, marine magnesium, magnesium carbonate, magnesium hydroxide, as well as magnesium chloride and magnesium sulfate. Here is how they score on the three criteria:

• Content: this is the strong point of this family, with salts providing elemental magnesium content in the range of 40 to 60%. Magnesium chloride is an exception, however, with a rate of 12%.
• Digestive Comfort [14]: the main issue with magnesium, as a free element in the intestine, is that it's very hydrophilic (it loves water) and therefore attracts a large amount of H2O molecules. This effect can cause diarrhea. The transporters in this first family don't have a strong bond with elemental magnesium, which quickly becomes free in the intestine. Their digestive tolerance is therefore generally poor when ingested in large quantities, as is the case with a magnesium capsule formula. In an electrolyte-type formula, however, where magnesium intake is more spread out and long-term, digestive tolerance is better.
• Absorption [14]: free dietary elemental magnesium uses the ionic pathway (DMT-1, TRPM6/7) for 20% and the paracellular pathway for 80%. But magnesium competes with other minerals such as calcium, zinc, or iron at these pathways. The whole challenge of a good magnesium formula is therefore to open other absorption pathways, and inorganic magnesium salts can't do that. These salts are also only very slightly soluble in water, which prevents them from reaching the molecular scale at which absorption occurs at the enterocyte level. All this explains why their absorption, when provided in large quantities, remains low: under 20%.

Conclusion: while inorganic salts can have some value in diffuse-intake electrolyte-type formulas, they aren't the solution to favor in a high-concentration magnesium formula.

2/ Organic magnesium and chelates

As their name suggests, these transporters contain carbon atoms, and the body loves carbon, offering assimilation pathways specific to this type of molecule. This makes it possible to reduce the pressure on the ionic and paracellular pathways and improve absorption. That's the great strength of this family. It includes the famous magnesium bisglycinate, but also magnesium malate, magnesium citrate, magnesium lactate, as well as magnesium taurinate and magnesium glycerophosphate. Same three criteria:

• Content: this is the main weakness of this family. The acids and amino acids that make up these transporters have a significant molecular weight, which reduces the elemental magnesium content to a range of only 6 to 12% at most.
• Digestive Tolerance [16]: except for magnesium citrate, all these transporters show good (lactate) to very good digestive tolerance (bisglycinate, malate, in particular). One reason is that the magnesium ion is kept captive by its transporter for longer, so it captures fewer water molecules. The organic salts with the strongest bonds are chelates like bisglycinate. Glycerophosphate also has a unique feature: this transporter is fat-soluble, which further distances the magnesium ion from H2O molecules [13].
• Absorption: the great strength of this family lies, without question, in its absorption level, nearly three times higher than inorganic salts (up to 70%) [17]! Three main reasons explain this success. First, these transporters are highly soluble in water or fat, which allows them to reach the molecular scale at which absorption mechanisms take place. Second, a fraction of these transporters keeps the magnesium ion captive (notably in the case of chelates) and opens new absorption pathways, such as the peptide pathway (PepT1) with bisglycinate (formed by two glycine molecules, hence a dipeptide) or the MCT pathway (monocarboxylates with malate). Lastly, once the transporters have separated from the elemental magnesium, they help acidify the digestive tract, a key factor both for keeping Mg2+ ions free and facilitating their absorption via ionic pathways, and for increasing paracellular absorption, which is also pH-sensitive.

Conclusion: this second family is an interesting solution for effective magnesium formulas. Its only weakness is that it requires taking a large number of capsules per day, or large capsules, to reach recommended intakes.

3/ Liposomal or microencapsulated magnesium

A new family of magnesium transporters has emerged in recent years. It takes a first-generation salt (generally oxide) and micro-encapsulates it in a phospholipid sphere, itself sometimes coated with a layer of sucrose ester or similar. It was developed to check all three boxes: content, assimilation, and digestive comfort. Two patents currently dominate the market: MagShape® Microcapsules, developed in Spain and manufactured in France, and UltraMag®, from the well-known Italian company Alesco. Let's see how they score:

• Content [18]: this family offers a relatively high content, between 30 and 35% elemental magnesium. That's well above the organic salt family, even if slightly below the average of inorganic salts. It's enough to avoid taking a large number of capsules or oversized capsules.
• Digestive Tolerance [18]: liposomes are small spheres made of phospholipids that encapsulate magnesium oxide. They form a protective barrier that shields it from the acidic stomach environment and prevents the Mg2+ ions from separating from the oxide and attracting a large number of water molecules, as mentioned above.
• Absorption [19]: this is where the liposome is most innovative, through the absorption pathway it opens for magnesium, known as endocytosis. The phospholipids of the liposomal capsule are the same as those forming the membrane of enterocytes, which is why these cells capture the liposomes via specific receptors or membrane invaginations. Once inside the cells, the liposomes release their active ingredient, allowing it to pass into the cytoplasm and then into the bloodstream.

Figure 3: how a liposome works.

Conclusion: liposomes offer a highly innovative approach that combines absorption, digestive tolerance, and high content [20]. It's a very relevant solution for a magnesium formula. Two things need checking, though: the size of the liposomes and their stability. The ideal size for absorption is around 50 to 500 nanometers (nm) [20]. Stability matters just as much, since a liposome remains a fragile compound: if the phospholipid sphere is destroyed, the vehicle loses all its value. The MagShape® and UltraMag® trademarks provide guarantees of optimal average size and stability.

You'll often read online that bisglycinate is the best magnesium salt, and countless brands offer this single transporter in their formula. Yet, as we've seen, bisglycinate has a major flaw: its low content, which forces these brands to use oversized capsules or offer doses with an unreasonable number of capsules to reach 300 mg per day. A single transporter may also not suit every digestive tract, for various reasons (genetics, state of the gut flora, etc.).

The multi-transporter approach reduces these risks and offers two advantages:

• Optimized content thanks to the addition of liposomes, avoiding an unreasonable number of capsules per dose,
• Optimized assimilation by stimulating as many absorption pathways as possible, including less competitive assimilation pathways.

B6 is a cofactor for magnesium in absorption and in enhancing its action, notably in the stress pathway, in energy production (Krebs cycle), and in the protein pathway. However, this cofactor role is only observed at mega-doses of 30 mg [21], whereas in France the maximum safe dose is 25 mg and the NRV for B6 is 1.4 mg. It's therefore necessary to stay close to the maximum safe dose to aim for scientific effectiveness and achieve an effect. In any case, a little bioactive B6 never hurts a formula, especially as its cost remains low and won't significantly affect the final price!

Taurine is also praised for its role as a cofactor for magnesium. This non-proteinogenic amino acid is perceived by the general public as a stimulant, when it is in fact rather sedative. It's presented as a cofactor for magnesium in two ways:

• First, taurine bound to magnesium can serve as a transporter for it. This organic magnesium offers very good absorption and can be a relevant choice in a multi-transporter approach.
• Second, free taurine, meaning not bound to magnesium as a transporter, is recognized for its ability to increase magnesium retention within cells. But this effect is only achieved at large quantities, around 5 grams per day! In capsule form, this would push the daily dosage to more than 10 capsules, which is unreasonable. While still of interest, it's probably wiser to get this as a separate addition to a magnesium formula, directly in powder form.

These findings suggest that combining a soluble organic salt (magnesium malate), a chelate (bisglycinate), and a liposome is one of the most effective nutraceutical strategies for getting the best magnesium capsule, since it stimulates up to 5 absorption pathways for this essential element!

Figure 4: absorption pathways of different magnesium transporters

Alongside magnesium malate, Nutri&Co chose two manufacturing patents for greater effectiveness:

• TRAACS® patented magnesium bisglycinate from the American firm Albion Minerals. This ingredient guarantees a form that is 99% pure and therefore unaltered, unlike some opaque sourcing. There are two grades within Albion Minerals: the form with 11% elemental magnesium and the form with 18%, which is "buffered" with oxide to increase the content. At Nutri&Co, we chose the 11% form, meaning 100% chelated. We wanted an all-terrain formula that can potentially be taken with a meal without excessively harming absorption. As we've seen, oxide remains relevant in small doses if intake is spread out over time, which adds a constraint.
• MagShape® Microcapsules liposomal magnesium, whose trademark guarantees us an ideal liposome size of 100 to 200 nanometers, as explicitly indicated in research on magnesium microcapsules. Adding this transporter allows us to offer 100 mg of elemental magnesium per capsule, making calculations easy.

In addition to these transporters, our formula also provides vitamin B6 in its coenzyme form, meaning directly usable by the body: pyridoxal-5-phosphate.