Magnesium Glycinate - an overview (original) (raw)

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Chronic Fatigue Spectrum

Jacob Teitelbaum MD, in Integrative Medicine (Third Edition), 2012

Nutritional Support

Patients with CFS or FMS are often nutritionally deficient. This occurs because of (1) malabsorption from bowel infections, (2) increased needs because of the illness, and (3) inadequate diet. B-complex vitamins, ribose, magnesium, iron, coenzyme Q10, malic acid, and carnitine are essential for mitochondrial function.10,40 These nutrients are also critical for many other processes. Although blood testing is not reliable or necessary for most nutrients, I do recommend checking vitamin B12, iron, total iron-binding capacity, and ferritin levels.

I begin patients with CFS or FMS on the nutritional regimen described next.

Multivitamin

A high-quality multivitamin suited for their needs should contain at least 50 mg of B-complex vitamins, 150 mg of magnesium glycinate, 900 mg of malic acid, 600 units of vitamin D, 500 mg of vitamin C, 15 mg of zinc, 50 mcg of selenium, 200 mcg of chromium, and amino acids. A powdered vitamin is generally better tolerated, better absorbed, and less expensive than tablets.

d-Ribose

Because CFS and FMS represent an energy crisis, patients must have what is needed for optimal mitochondrial function. If you remember your biochemistry training on the Krebs citric acid cycle, the key energy molecules are adenosine triphosphate, reduced flavin adenine dinucleotide, and reduced nicotinamide-adenine dinucleotide. These molecules are made up predominantly of ribose in addition to B-complex vitamins and adenosine. Some of my patients improved markedly with improved energy and decreased pain when they were given one scoop (5 g) of ribose three times a day for 3 weeks, followed by one scoop twice a day (Corvalen, Bioenergy Life Science; see Key Web Resources). Two studies with a total of 298 patients with CFS or FMS that were conducted by 53 health practitioners showed an average 61% increase in energy at 3 weeks.41,42 If ribose is going to help, improvement is usually seen within 1 month (a 280-g container is a fair therapeutic trial). Ribose is a very powerful new addition to our therapeutic armamentarium for treating fatigue, pain, and cardiac dysfunction.

Dosage

Give 5 g (one scoop of Corvalen) of ribose three times a day for 3 weeks, followed by 5 g twice a day.

Precautions

d-Ribose is natural, quite safe, tastes good (sweet like sugar), and is very low in side effects. Rarely, it can cause a mild drop in blood glucose as it stimulates energy production. If patients feel overenergized or hyperactive when they take ribose, simply have them take it with a meal or lower the dose. This response also suggests the need for adrenal support.

Widespread nutritional deficiencies are common, and no single tablet will address them all. Patients should consider a good multiple vitamin, with the addition of ribose at 5 g two to three times daily, coenzyme Q10 at 200 mg daily, and acetyl-l-carnitine at 1000 mg daily for approximately 4 to 9 months, then PRN.

Iron

If the patient's iron percent saturation is less than 22% or the ferritin is less than 60 mg/mL, supplement with iron (taken on an empty stomach because food markedly decreases iron absorption). Iron should not be taken within 6 hours of thyroid hormone because iron blocks thyroid absorption. Continue treatment until the ferritin level is greater than 60 mg/mL and the iron percent saturation is higher than 22%.

Vitamin B12

If the vitamin B12 level is less than 540 pg/mL, I recommend vitamin B12 injections, 3000 mcg intramuscularly three times a week for 15 weeks, then as needed based on the patient's clinical response. Studies of CFS are showing absent or near-absent cerebrospinal fluid vitamin B12 levels despite normal serum vitamin B12 levels.43 Metabolic evidence of vitamin B12 deficiency is seen even at levels of 540 pg/mL or more.44 Severe neuropsychiatric changes are also seen in vitamin B12 deficiency even at levels of 300 pg/mL (a level higher than 209 is technically normal).45 As an editorial in the New England Journal of Medicine suggested, the old-time doctors may have been right about giving vitamin B12 shots.46 Compounding pharmacies can make vitamin B12 at 3000 mcg/mL concentrations. I use hydroxycobalamin, although methylcobalamin may be more effective, albeit more expensive.

Coenzyme Q10

The dose of coenzyme Q10 is 200 mg a day. This conditionally essential nutrient improves energy production in patients with CFS or FMS. It is especially critical in patients taking statin-family cholesterol treatments (which can actually cause FMS pain and which I avoid using in patients with FMS).

Acetyl-l-Carnitine

Treating with acetyl-l-carnitine, at 500 mg twice daily for 4 months, is strongly recommended. Biopsies show that intracellular levels are routinely low in patients with CFS. This not only causes weakness, but also contributes to the average 32-lb weight gain seen in CFS or FMS.

Diet

No one diet is best for everyone. I recommend that patients eat those things that leave them feeling the best (which is not always the same as what they crave). Having said this, however, most patients with CFS find that they do best with a high-protein, low-carbohydrate diet. They should avoid sugar, as well as excessive caffeine (which is a loan shark for energy) and excess alcohol. Warn the patient about a possible 7- to 10-day withdrawal period when eliminating sugar and caffeine. If patients have low blood pressure or orthostatic dizziness, increasing salt intake markedly should also be considered.

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Dysmenorrhea

Greta J. Kuphal MD, in Integrative Medicine (Third Edition), 2012

Supplements

Magnesium

Magnesium has been found to be beneficial in the treatment of arrhythmias, severe asthma, migraine, dyspepsia, and constipation. Its role in dysmenorrhea may be related to its effect on intracellular calcium concentration,18 a reduction in prostaglandin synthesis,19 or its muscle relaxant properties. A Cochrane Review found three studies showing that magnesium was more effective than placebo in decreasing menstrual pain and the use of analgesic medications. The studies were small, but the results encouraging.20a

The form of magnesium is important because some forms are more likely to cause diarrhea (see the section on dosage). Foods rich in magnesium include fish, nuts, leafy greens, whole grain cereals, and baked potatoes with the skin.17 Magnesium is a largely intracellular cation, so red blood cell magnesium may be a more accurate measure of nutrient status than the typically used serum magnesium.

Dosage

Unless constipation is present, consider doses of 200 to 600 mg daily of forms of magnesium less likely to cause loose stools: magnesium glycinate (chelated magnesium), magnesium gluconate, or magnesium chloride. See Table 54-1 for dietary sources of magnesium.

Precautions

Use magnesium with caution in individuals with impaired renal function. If diarrhea develops, decrease the dose until this condition is relieved because diarrhea is one of the first signs of magnesium toxicity.

Vitamin B6 (Pyridoxine)

A series of small studies (N = 21 to 24) in 1988 compared various permutations of vitamin B6 versus magnesium versus vitamin B6 and magnesium versus placebo and found that vitamin B6 was better than placebo and better than a combination of vitamin B6 and magnesium at decreasing visual analogue pain scores and tablets of ibuprofen used.20a A mechanism offered to explain the possible beneficial effect of vitamin B6 is its role in increasing the influx of magnesium into the cell, thereby supporting the effects of magnesium described earlier.

Dosage

The dose is 100 mg daily. If a higher dose is used, close monitoring is needed. See Table 54-1 for dietary sources of vitamin B6.

Precautions

Vitamin B6 toxicity typically manifests as neuropathy that reverses with decreased intake.17 Doses described were 100 mg twice daily; however, the Institute of Medicine established the upper tolerable intake level for vitamin B6 as 100 mg daily for adults.

Vitamin B6 and magnesium may work synergistically because vitamin B6 increases the influx of magnesium into the muscle cell.20b

Vitamin B1 (Thiamine)

One of the largest double-blind placebo-controlled studies investigating the effect of a nutritional supplement on dysmenorrhea was a trial of vitamin B1. This crossover trial involved 556 Indian adolescents who were randomized to receive 100 mg of vitamin B1 daily for 90 days, followed by placebo for 60 days or placebo for 60 days, followed by 100 mg daily of vitamin B1. In both groups, complete resolution or significant improvement in pain did not occur until the participants had received thiamine for at least 30 days. “Cure” rates by the end of the trial were approximately 90% in both groups.21 This overwhelming success at “curing” dysmenorrhea certainly raises the question of whether the results could be confirmed with another study in a different population. The mechanism by which this treatment works may simply be reversal of a deficiency that can manifest with decreased pain tolerance, muscle cramping, and fatigue, which are symptoms similar to those of premenstrual syndrome.19

Dosage

The dose is 100 mg daily for 90 days. Consider continuing treatment if symptoms recur after initial improvement. See Table 54-1 for dietary sources of thiamine.

Precautions

Orally, thiamine is usually well tolerated. It rarely can cause dermatitis or a hypersensitivity reaction.22

Vitamin E

Vitamin E has been proposed to provide relief from dysmenorrhea through antiinflammatory action and through induction of a marked rise in beta-endorphin level.23,24 Several randomized placebo-controlled studies including a total of 383 women 15 to 21 years old, showed a significant decrease in the severity and duration of pain with vitamin E compared with placebo. Doses used varied from 150 to 500 units daily for either 2 days before and 3 days after or for 10 days before and 4 days after the onset of menses.25–27 The tolerable upper intake level in healthy people is 1000 mg/day, equivalent to 1100 units of synthetic vitamin E (d-l-alpha-tocopherol or alpha- tocopherol or SRR-tocopherol) or 1500 units of natural vitamin E (d-alpha tocopherol or RRR-tocopherol).28,29

Dosage

The dose is 400 units daily for a few days before and a few days after the onset of menses. See Table 54-1 for dietary sources of vitamin E.

Precautions

Doses higher than 400 units of vitamin E have higher potential for adverse effects in unhealthy individuals.

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Dysmenorrhea

Greta J. Kuphal MD, in Integrative Medicine (Fourth Edition), 2018

Therapies to Consider

Aromatherapy with Massage

A study of 57 Korean college women with dysmenorrhea compared abdominal massage with aromatherapy (a mixture of two drops of lavender, one drop of clary sage, and one drop of rose in 5 mL of almond oil), abdominal massage with almond oil only, and no intervention. The aromatherapy group showed a significant decrease in menstrual discomfort based on scoring using a visual analogue scale compared with massage alone or no treatment. Massages in the study took place for approximately 15 minutes daily for 1 week before the start of menses. No side effects were reported.74

Aromatherapy Massage for Dysmenorrhea

Use slow, smooth, and continuous strokes with mild to moderate pressure and a mixture of lavender, clary sage, and rose oils in almond oil (see previous section). The strokes should start with the masseur’s left hand on top of the right in the right lower quadrant of the abdomen, go up to the ribs, and then across the abdomen to the left lower quadrant. The masseur can then provide gentle kneading of the left and right lower abdomen, followed by stroking across the abdomen. This sequence can be repeated for a total of 15 minutes and performed daily for 1 week before the expected onset of menses.

Prevention Prescription

•

Maintain a healthy weight.

•

Follow an antiinflammatory diet.

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Participate in regular, moderate-intensity aerobic exercise.

•

Avoid use of tobacco.

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Avoid alcohol in excess.

•

Employ effective stress management techniques.

Therapeutic Review

Exercise

•

The benefits of exercise on stress reduction and maintenance of a healthy weight may reduce risk factors for dysmenorrhea.

Nutrition

•

Diets rich in omega-3 fatty acids can reduce menstrual pain. Supplement with 1500–2000 mg daily of docosahexaenoic acid and eicosapentaenoic acid. Through diet, omega-3 fatty acids can be obtained with two to three servings of cold-water fish weekly and other, plant-based sources.

Supplements

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Magnesium (glycinate, gluconate, or chloride): 600 mg daily, decreased if diarrhea develops. Use with caution in patients with kidney disease.

•

Vitamin B6 (pyridoxine): 100 mg daily (may work better with magnesium)

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Vitamin B1 (thiamine): 100 mg daily for 90 days, or longer if symptoms recur after cessation

•

Vitamin E: 400 units daily

Botanicals

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French maritime pine bark extract/Pycnogenol: 30 mg twice daily. The effect may last for at least 1 month after cessation.

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Fennel: 30 drops of extract at the onset of menses, then every 6 hours for the first 3 days of menses. Avoid during pregnancy or lactation.

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SCA (saffron, celery, and anise, by Gol Daro Herbal Medicine): 500 mg three times daily for 3 days, starting with onset of pain or bleeding.

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Willow bark extract: 240 mg daily of salicin in divided doses, starting on the day before expected symptoms.

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Cramp bark and black haw: 2–3 mL of a tincture made in 1:3 proportion every 2 hours or as needed; or 4–8 mL of fluid extract (1:1) three or four times daily; or simmer one tablespoon of bark in 12 oz of water for 15 minutes, one-third cup consumed every 2–3 hours as needed.

•

Other herbs per Table 57.2.

Pharmaceuticals

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Nonsteroidal antiinflammatory drugs such as ibuprofen, 400–600 mg with food every 6 hours, starting the day before symptoms expected to occur until symptoms cease

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Combined contraceptive pills

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Levonorgestrel-containing intrauterine device

Mind-Body Therapy

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Consider counseling or health psychology referral for relaxation techniques, biofeedback, or pain management training, for example, if determined relevant given the individual’s history.

Bioenergetic Therapy

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Use a heating pad or microwavable bean bag on the low back or abdomen for up to 8–12 hours.

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Consider purchasing a magnet therapy device (e.g., mn8; see Key Web Resources).

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Consider using a transcutaneous electrical nerve stimulation unit.

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Consider acupuncture.

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Consider acupressure.

Biomechanical Therapy

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Consider spinal manipulation therapy (chiropractic or osteopathic treatment).

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As a last resort, laparoscopic presacral neurectomy may be more effective than laparoscopic uterine nerve ablation.

Other Therapies to Consider

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Aromatherapy with abdominal massage using a mixture of two drops of lavender, one drop of clary sage, and one drop of rose in 5 mL of almond oil

Key Web Resources

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Type 2 Diabetes

Richard Nahas MD, in Integrative Medicine (Third Edition), 2012

Supplements

Table 32-1 describes the glycemic effects and cardiovascular benefits of different treatments for type 2 DM.

Vitamin D

For more than 1 million years, Homo sapiens lived outdoors. Modern lifestyles severely restrict sun exposure, a drastic change in the human environment that has been ignored until recently. Vitamin D synthesis in the skin is triggered by exposure to ultraviolet (UV) light. This stimulus damages DNA, so it should not be surprising to learn that vitamin D activates DNA and cellular repair systems. By binding to nuclear vitamin D receptors, vitamin D actually regulates many aspects of physiology. Investigators now know that vitamin D does more than make bones.

Low serum 25-hydroxyvitamin D (25-OHD) levels are associated with a growing list of serious chronic diseases, including cardiovascular disorders, neurologic diseases, allergic and autoimmune problems, several cancers, and all-cause mortality. Whether this is a cause-and-effect relationship or whether low vitamin D is simply a marker of chronic inflammation, oxidative stress, or some other physiologic disturbance is unclear. Nonetheless, vitamin D trials have reported improvements in chronic pain, blood pressure, pregnancy outcomes, and autoimmune disease risk.

Vitamin D deficiency increases mortality risk in type 2 DM,68 but the evidence that treating this deficiency improves outcomes in type 2 DM should be considered preliminary.69 One small study reported that improvements in vitamin D status were associated with reductions in HbA1c in patients with type 1 DM.70 Large single doses given to patients with type 2 DM significantly reduced blood pressure in a reported trial,71 and another trial reported improvements in endothelial function.72 In a study of 24 patients with type 2 DM who were given low doses of vitamin D (400 and 1200 units) for 4 months to treat deficiency, none of their glucose or metabolic parameters improved, but their 25-OHD levels were still low at the end of the study period.73

Guidelines for vitamin D supplementation vary widely, and at this time they should be considered in process. I advise patients to supplement in a manner that mimics sunlight exposure. Patients are told to take 10,000 to 15,000 units at a time, one to three times per week, until their 25-OHD levels are at the middle of the normal range. Although this range appears to vary from person to person, a reasonable maintenance dose may be 1000 to 4000 units daily. Toxicity is rare unless daily doses of more than 20,000 units are taken for several months. Large, long-term studies will certainly be forthcoming and will help clarify this very important potentially modifiable risk factor.

Dosage

The dose is 1000 to 4000 units daily or 10,000 to 15,000 units one to three times a week. Monitor serum 25-OHD levels to keep them between 30 and 80 ng/mL.

Precautions

Side effects are rare, but hypercalcemia with subsequent calcification of blood vessels with prolonged use of high doses has been observed.

Chromium

This trace element has several effects on carbohydrate and lipid metabolism. A complex containing trivalent chromium is known as glucose tolerance factor. Evidence suggests that it acts to reduce tissue lipid content and that chromium responders are more likely to be more obese, more insulin-resistant, and have poorer glycemic control regardless of baseline chromium status.74

A meta-analysis of 41 trials that evaluated the glycemic effects of various formulations found 14 trials involving patients with type 2DM.75 The evidence is difficult to interpret because of low study quality and differences in formulation and dose, but the best results were reported in trials that used chromium picolinate or brewer's yeast at doses of at least 200 mcg daily. In these trials, the mean reduction in HbA1c was 0.6% compared with placebo.

Dosage

A dose of 200 to 1000 mcg daily is recommended.

Precautions

Chromium has no known side effects.

Alpha-Lipoic Acid

Also known as thioctic acid, alpha-lipoic acid (ALA) is a potent lipophilic antioxidant that is found in most eukaryotic cells. It also acts as a cofactor for several mitochondrial and cytosolic enzymes, with the R+ enantiomer being the active form. In addition to its antioxidant activity, it can also regenerate other antioxidants by reducing them; this list includes vitamins C and E, coenzyme Q10, and glutathione. ALA also chelates mercury, arsenic, iron, and other metals that act as free radicals. It is present in trace amounts in organ meats and some vegetables, but these amounts are negligible as compared with usual therapeutic doses.

ALA has been used to treat several diseases in Europe and Japan since the 1950s. A large body of preclinical research supports the potential benefit of ALA in liver disorders, cardiovascular disease, cancer prevention, and neuropsychiatric disorders and for heavy metal and general detoxification.

Good evidence indicates that ALA reduces painful diabetic neuropathy. First used parenterally, ALA in oral form was effective in a multicenter trial involving 181 patients with type 2 DM who received varying doses for 5 weeks. All doses provided overall 50% symptom reduction, with the lowest dose (600 mg daily) causing the fewest side effects.76 This finding may be related to reduced lipid peroxidation in neuronal cell membranes or improved endothelial function and microvascular blood flow.77 ALA also may improve insulin sensitivity through enhanced GLUT4 translocation and glucose uptake in muscle and fat cells.78 This last effect was seen in intravenous ALA trials and is not yet firmly established with the oral form, but it provides further support for the use of ALA in patients with type 2DM.

Most published trials have used regular ALA (an R-S racemic mixture). R-Lipoic acid is marketed as a superior product because it is the endogenously produced form, but little evidence supports this claim. A sustained-release form is also marketed as superior based on the short half-life of regular ALA, but whether peak levels or total levels are most important is unclear, and evidence of safety and efficacy is similarly lacking. At this time, regular ALA is the recommended form.

Dosage

The best dose for neuropathy is 600 mg daily, but a dose of 50 to 100 mg is sufficient for antioxidant purposes. Absorption is best on an empty stomach.

Precautions

The most common side effect is nausea, but insomnia, fatigue, diarrhea, and rashes have also been reported.

Omega-3 Fatty Acids

Fish and other marine species are the main sources of eicosapentaenoic acid (EPA) and docosahexanoic acid (DHA) in the human diet. Alpha-linoleic acid is an omega-3 precursor found in walnuts, flax, and other grains. Although they do not affect glycemic control, these fats have antiinflammatory, antithrombotic, and antiarrhythmic effects that appear to prevent and treat cardiovascular disease. For this reason, they offer important benefits to patients with type 2 DM.

A Cochrane Systematic Review of 23 trials involving 1075 patients who used omega-3 fatty acids at an average dose of 3.5 g daily reported improved lipid parameters and platelet function.79 Small trials have also reported improvements in endothelial function; in one study, impaired flow-mediated dilatation improved significantly after subjects consumed 2 g of omega-3 fatty acids.80

Dosage

Most cardiovascular benefits of omega-3 fats occur at doses of 1000 mg (EPA and DHA) daily, but higher doses are often used.

Precautions

Fishy repeats and mild gastrointestinal upset are the only side effects. Although bleeding in aspirin or warfarin users is often cited as a reason for caution, the literature contains no reports of this effect.

Magnesium

Magnesium affects insulin secretion and action, and it also influences lipid parameters and endothelial function. A systematic review identified 9 trials that evaluated magnesium supplementation for 4 to 16 weeks in 370 patients with type 2 DM and noted improvements in fasting glucose and high-density lipoprotein cholesterol. In the five trials of sufficient duration to evaluate HbA1c, a nonsignificant reduction of 0.31% (95% CI, − 0.81 to 0.19) was reported.81 A separate review of magnesium for the prevention of type 2 DM found seven cohort studies and reported an overall benefit; an average daily dose of 100 mg decreased risk by approximately 16%.82 How accurately routine tests reflect total body stores is unclear.

Dosage

Usual starting doses are approximately 100 mg daily and can be increased as desired or to bowel tolerance. Magnesium is available as oral liquid or tablets, transdermal lotion, or Epsom salts, as well as in parenteral formulations.

Precautions

Gastrointestinal intolerance, mainly diarrhea, is the most common side effect. Chelated magnesium (magnesium glycinate) causes less diarrhea than do other forms of magnesium.

Antioxidants

People who eat diets that are rich in antioxidants have a greatly reduced type 2 DM risk, but commonly used antioxidant supplements do not appear to have the same preventive effect. In 8171 women who were followed for 9.2 years in the Women's Antioxidant Cardiovascular Study, only mild benefit was suggested by a nonsignificant trend with vitamin C, whereas vitamin E increased risk and beta-carotene offered no benefit.83 The Prevention of Progression of Arterial Disease and Diabetes (POPADAD) trial found no significant benefit in 1276 Scottish adults who took a low-dose mixed antioxidant supplement or placebo for 8 years.84

The benefits of antioxidant-rich foods are probably more attributable to the dozens of phytomedicines they contain that we are only beginning to understand. Although antioxidants and multivitamins are commonly prescribed by integrative practitioners as “insurance against deficiency,” this practice may not be safe. High doses of vitamins have been shown to interfere with absorption and use of lesser-known but potentially more powerful antioxidants in food; high-profile examples include tocopherols and carotenoids.

Whole food supplements may be a reasonable alternative approach. In one study, an antioxidant supplement derived from pomegranate, green tea, and ascorbic acid improved lipid parameters and markers of oxidative stress in a placebo-controlled trial involving 114 patients with type 2 DM in Turkey.85

Vitamin E

Vitamin E is one of the most commonly used specific antioxidants, but no real evidence indicates that it helps patients with type 2 DM. Negative results reported in large cardiovascular and cancer trials have been the subject of media reports, controversy, and debate among integrative medicine practitioners. Alpha-tocopherol supplementation did not decrease the risk of type 2 DM in the large Alpha-Tocopherol Beta-Carotene (ATBC) cancer trial.86 One small trial actually reported prooxidant effects shortly after ingestion of a single 1200-unit dose.87

Although several tocopherols and tocotrienols have vitamin E–like activity, most vitamin E supplements only contain alpha-tocopherol. Some investigators believe that negative results in vitamin E trials can be explained by the decreased absorption of the other, more potent molecules in this family whose absorption is inhibited by alpha-tocopherol supplementation.88 In fact, one study comparing the effects of alpha- and gamma-tocopherol on markers of oxidative stress and inflammation in patients with type 2 DM found no differences between the two.89 Single trials reported that gamma-tocopherol increased blood pressure90 and did not change platelet function.91

Greater benefit from alpha-tocopherol has been demonstrated in people who are homozygous for a haptoglobin gene variant that is present in 3% to 4% of the population and increases oxidative stress. In an Israeli double-blind study involving 1434 people with type 2 DM who were homozygous for haptoglobin-2, alpha-tocopherol actually reduced the risk of a combined cardiovascular end point by more than 50%.92 This is an example of how genetics may improve treatment outcomes in future personalized medicine.

Vitamin E supplements containing mixed tocopherols and trienols are increasingly available, but we cannot provide clear dosing guidelines for their use for type 2 DM. Vitamin E has no known side effects.

l-Carnitine

l-Carnitine shuttles fatty acids into mitochondria. It has been proposed as a potential therapy for type 2 DM based on the known intracellular lipid accumulation that occurs in the disease. A pilot study found no improvements in glycemic control after 4 weeks of l-carnitine use in 12 patients with type 2 DM,93 but several trials reported that it improved lipid parameters and significantly reduced lipoprotein (a), an important independent inherited cardiac risk factor for which few effective therapies exist.94

Dosage

The usual dose is 500 to 1000 mg three times daily.

Benfotiamine

Postprandial endothelial dysfunction has been proposed as the link between metabolic syndrome and atherosclerosis. This state is linked to oxidative stress, hyperglycemia, hypertriglyceridemia, and altered nitric oxide function. It is attributed to glucose-protein complexes in food, named advanced glycation end products (AGEs). These complexes are formed at high temperatures and activate AGE-specific receptors, which activate monocytes and endothelial cells and ultimately promote inflammation. Benfotiamine is a synthetic analogue of thiamine that is much more bioavailable. It activates transketolase, an enzyme that helps clear AGEs, thus improving postprandial endothelial function.

In a pilot study, 350 mg of benfotiamine after meals completely eliminated the vascular measures of postprandial endothelial dysfunction in 13 patients with type 2 DM.95 This important finding has not been replicated since it was reported in 2006, but corroborating evidence seems like a high priority. Several trials suggested that benfotiamine improves diabetic neuropathy,96,97 a finding that is not surprising considering the neurologic symptoms seen in thiamine deficiency. One trial found no improvement in some markers of diabetic nephropathy,98 but another reported improvements in microalbuminuria.99

Dosage

The 350-mg dose used in the pilot study is higher than that found in most formulations.

Precautions

This early evidence is very promising, but it is probably premature to recommend widespread use of this synthetic thiamine analogue because long-term safety results are not available.

Vitamin K

This fat-soluble vitamin exists as phylloquinone (K1) in plants and menaquinone (K2) in animals and in a fermented soybean product named natto. Vitamin K2 is considered more biologically active and is a cofactor for carboxylation of proteins. It helps make osteocalcin, which strengthens bones by forming a protein scaffold on which it is laid. It also makes matrix Gla protein, which prevents vascular calcification by repairing smooth muscle and endothelium. Vitamin K2 is receiving growing attention as a target for treatment of diverse disorders in addition to its established role in coagulation factors biosynthesis.

Early studies suggest that vitamin K2 also stimulates beta cell proliferation and enhances insulin sensitivity. Vitamin K deficiency, as suggested by low levels of carboxylated osteocalcin, is also associated with type 2 DM risk.100 Recommending vitamin K2 for glycemic control is premature, but its endothelial and cardiovascular benefits may make it an appealing addition to an integrative type 2 treatment plan.

Dosage

The starting dose of vitamin K2 is usually 100 mcg daily, but higher doses have been commonly used.

Precautions

Patients taking warfarin will need close monitoring and dose adjustment after starting vitamin K2, but this ultimately reduces the fluctuations in international normalized ratio results seen in vitamin K2–deficient patients.101 Vitamin K has no other known side effects.

Risks of Specific Supplements

Although evidence indicates that selenium has insulin-like actions and may delay microvascular complications, integrative practitioners should know that selenium is associated with increased risk of type 2 DM. In the Nutritional Prevention of Cancer trial, 1202 people with localized melanoma were randomized to receive selenium or placebo for cancer prevention. After 7.7 years of follow-up, selenium users developed type 2 DM more often (hazard risk, 1.55; 95% CI, 1.03 to 2.33), with the greatest risk in people with the highest baseline selenium levels (hazard risk, 2.70; 95% CI, 1.30 to 5.61).102 Selenium supplementation should be considered only in patients with low baseline selenium levels. The maximum daily dose is 200 mcg. The way in which inorganic and organic forms differ in their effect on type 2 DM risk is unclear.

Practitioners should also exercise caution when using B vitamins in patients with nephropathy. In the Canadian Diabetic Intervention with Vitamins to Improve Nephropathy (DIVINe) trial, 238 patients with type 1 DM and type 2 DM were given a tablet containing folic acid 2.5 mg, vitamin B6 25 mg, and vitamin B12 1 mg daily or placebo for almost 3 years to treat elevated homocysteine. Although the treatment group had lower plasma homocysteine levels, they had worse kidney function and more cardiovascular events.103 The investigators postulated that this finding may be explained by cell proliferation induced by folic acid, increased methylation from folic acid and vitamin B12, or nitric oxide–related mechanisms. Earlier reports noted poorer cardiovascular outcomes associated with B vitamins, and one hopes that further study will clarify this issue.

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Effect of magnesium supplementation on women's health and well-being

Debora Porri, ... Hellas Cena, in NFS Journal, 2021

4 Climacteric and menopause, the second stage of life

The fertility cycle ends with menopause, which begins when the menstrual cycle finishes and is a transition into a new phase of women's life.

During this period women experience climateric symptoms, including vasomotor ones, changes in mood, sleep disturbances, etc.… which may significantly impair quality of life [81–83]. Those symptoms largely depend on the decline in circulating endogenous oestrogens, but recent evidence suggested a role of magnesium supplementation in reducing the duration and intensity of those unpleasant manifestations, as well as typical risk factors.

It's worth to notice that an inverse association between dietary magnesium intake and the risk of depression was recently found in a representative sample of the general population, 17,730 adults from the 2007–2014 National Health and Nutrition Examination Survey [84]. During an observational study on postmenopausal women Authors observed the lowest magnesium levels in women with depressive symptoms and the highest in women without depressive symptom, indicating higher vulnerability to depression in women with inadequate magnesium level [85]. To reinforce this hypothesis, a recent systematic review [86] provided evidence of magnesium involvement in mood disorders highlighting that magnesium supplementation was associated with a decline in depressive symptoms. Future studies should aim to reduce confounding and measurement errors in order to increase strength of evidence.

4.1 Bone health

Low serum magnesium has been demonstrated to be associated with low bone density both in pre and postmenopausal women [87] and evidence shows lower magnesium levels in osteoporotic postmenopausal women compared with non-osteoporotic ones [88].

Furthermore, it is known that dietary intake of magnesium has a beneficial role in inflammation and oxidative stress, both risk factors for osteoporosis: it is therefore reasonable to assume a protective effect of magnesium on conceivable osteoporotic fractures [89–92].

In the last decade, only one trial by Aydin et al. [93] evaluated magnesium supplementation on bone reabsorption markers in 30 postmenopausal osteoporotic women. Half of them received a daily oral dose of 1830 mg magnesium citrate for 30 days while the other half received placebo. This study showed that magnesium supplementation suppressed bone turnover. Particularly, oral magnesium supplementation led to a significant reduction in urinary deoxypyridinoline levels and to a significant increase in osteocalcin level [93].

Furthermore, magnesium plays another critical role in the prevention of osteoporosis: it's well recognized that insufficient Vitamin D levels contribute to the onset of osteoporosis through reduced calcium absorption [94] and Vitamin D nutritional status is accurately represented by serum 25-hydroxyvitamin D (25(OH)D) level [95].Both in vitro and in vivo studies have indicated that magnesium deficiency affects 1α-hydroxylase (i.e., CYP27B1) and 24-hydroxylase (i.e., CYP24A1), which synthesizes and metabolizes 25(OH)D and 1,25(OH)2D, respectively [96–98]. Findings from a recent clinical trial suggested that optimal magnesium status may be important for optimizing 25-hydroxyvitamin D status [99]. This study included 180 subjects aged 40–85 y who were randomly assigned to receive a customized dose of magnesium glycinate supplementation that would reduce the calcium-to‑magnesium intake ratio to ~2.3 based on their baseline calcium and magnesium intakes, according to previous result [100,101].

4.2 Cardiovascular risk

4.2.1 Hot flashes

Another common symptom of menopause and peri-menopause is hot flashes, which are uncomfortable and have also recently been supposed to be associated with adverse cardiovascular risk factor profile, including elevated blood pressure, higher blood lipids and insulin resistance [102]. It's well known that magnesium has been used in cardiovascular disorders treatment and prevention and that this mineral plays a pivotal role in the regulation of blood pressure, insulin metabolism and cardiac excitability [103].

In addition, hot flashes are mediated by an imbalance in serotonin and norepinephrine in the brain that causes vasomotor instability and magnesium is known to be neuroactive, vasoactive, affecting serotonin in many body cells, including brain. Evidence suggests that magnesium is likely to be a reasonable causal link between vasomotor symptoms and menopause [104,105].

Two recent and consecutive trials tested magnesium supplementation in reducing hot flashes in menopausal women with a history of breast cancer, taking into consideration that hot flashes are commonly experienced during chemotherapy [107].

In the pilot phase trial on 25 subjects were supplemented with magnesium oxide 400 mg for 4 weeks, 56% of women had a >50% reduction in hot flash score (frequency × severity). Results from this trial allowed to plan a double-blind, placebo-controlled randomized trial with a sample size of 289 postmenopausal women with a past diagnosis of breast cancer [107]. Subjects were randomly assigned into three groups: one received 1200 mg of daily magnesium oxide, the other one received a daily dose of 800 mg magnesium oxide and the last group received placebo. At the end of 8 weeks trial period, serum magnesium levels were unchanged after treatment with magnesium, and supplementation failed to improve hot flash scores, concluding that further studies are needed to better define role, timing, dosage and kind of magnesium supplementation in these patients.

4.2.2 Hypertension

After menopause, the prevalence of hypertension in women rises due to different mechanisms in aging compared with men [108].

Hypertension is a major risk factor for cardiovascular disease in women at this stage of life [109] and evidence shows that blood pressure may be well less controlled in women then in men [110].

Several studies support a positive relationship between menopause and hypertension [111,112] especially in women reporting vasomotor symptoms with a greater risk of hypertension [113].

The role of magnesium deficiency in the development of hypertension is well supported [114,115] but to date, findings on the relationship between magnesium supplementation and blood pressure are inconsistent. A recent meta-analysis [116] has highlighted a statistically significant inverse relationship between dietary magnesium intake and hypertension risk, despite no association between the risk of hypertension and per-unit increment of serum magnesium concentration was found.

Moreover, recent data showed evidence that a combined deficiency in magnesium and vitamin D is detected in essential hypertension [117,118] and may be of special pathogenetic importance, especially in patients with diabetes mellitus type IIb in which decreased magnesium concentrations and vitamin D levels are related to increased interleukin levels that are complicit in the development of arterial stiffness and arteriosclerosis. Evidence suggests that both magnesium and vitamin D in hypertensive patients with diabetes mellitus type IIb should be carefully considered and eventually corrected immediately [119].

Ana Rosa Cunha [120] and colleagues carried out a double-blind randomized clinical trial on 35 women with uncontrolled hypertension treated with diuretics, aged 40–65 years, in order to evaluate the effect of magnesium supplementation on functional vascular changes and blood pressure control. Subjects were randomized to receive oral 600 mg of magnesium chelate twice a day for 6 months or placebo. Finally, supplementation was associated with a better blood pressure control, improved endothelial function and enhanced of subclinical atherosclerosis.

Risk factors for hypertension also include obesity; many women report gaining weight as they transit through menopause [121] and this could be one of the contributors to hypertension development. In the second Nurses' Health Study [122] authors found that the strongest risk factor for developing hypertension was an increased body mass index (BMI) and obese women had 4.7 times higher incidence of hypertension than women with BMI < 23.0 kg/m2. In this study, 40% of new hypertension cases were attributed to overweight or obesity.

Moreover at this age, there's an increase of weight-promoting drugs prescription, which establish a vicious circle increasing both risk of NCDs as well as risk of micronutrient inadequacies, [123] including magnesium, which is already pretty common in western population despite the apparent good health status [124].

Nevertheless, a recent meta-analysis [125] aimed at evaluating the effects of magnesium supplementation on blood pressure and obesity among patients with type IIb diabetes mellitus found that magnesium supplementation had beneficial effects on blood pressure regardless of body weight status.

There is currently evidence suggesting beneficial effects of magnesium supplementation in menopausal women, but extensive studies are needed to establish treatment characteristics, taking into account lifestyle and medications use.

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