The Human Operating Manual

Micronutrient Cheat Sheet

Micronutrient Cheat Sheet

Just to rehash once again, I am not a doctor. My qualifications are in neuroscience and science communication. Don’t take any of this as medical advice. Also, I found all this information in other people’s books. So, please go read the original sources, which I have listed on the Summaries page. This is not my own personal research. I have, however, combed through countless books and papers to find common trends. Don’t be stupid. Use this to generate ideas and then go do your own research.


Recommended, Upper Limits, & Relationships
Fat-Soluble Vitamins and Related Minerals

Vitamin A

Vitamin D



D, Calcium, & Phosphorus Interactions


Vitamin K

B Vitamins Involved in Energy Metabolism

Thiamin (Vitamin B1)

Riboflavin (Vitamin B2)

Niacin (Vitamin B3)

Pantothenic Acid (B5)

Vitamin B6

Biotin (Vitamin B7)

Vitamins Involved in Methylation

Folate (Vitamin B9)

Cobalamin (Vitamin B12)

Choline and Betaine

Serine, Glycine, Methionine



Antioxidant Vitamins and Minerals

Vitamin E

Vitamin C







Electrolytes: Sodium, Potassium, and Chloride
Other Minerals







Essential Fatty Acids

Arachidonic Acid

Alpha-Linolenic Acid (ALA)

Eicosapentaenoic Acid (EPA)

Docosahexaenoic acid (DHA)

Vitamin & Mineral Summary (The Mineral Fix)
Index of Signs and Symptoms (Testing Nutritional Status)

Recommended, Upper Limits, & Relationships

Nutrient: Recommended Dietary Allowances (RDA), Upper Limit, Synergistic Relationship (SR), Varies Based on Nutrient Levels (VBNL), Antagonistic Relationship (AR)

Vitamin A:

  • RDA: 700-900 mcg
  • Upper: 3000 mcg
  • SR: Iodine, Iron, Zinc
  • VBNL: Vitamin E
  • AR: Vitamin K, Vitamin D

Vitamin C:

  • RDA: 75-90 mg
  • Upper: 2000 mg
  • SR: Vitamin E
  • VBNL: Copper, Iron, Selenium
  • AR: Vitamin B12

Vitamin D:

  • RDA: 600-800 IU
  • Upper: 4000 IU
  • SR Vitamin K, Calcium, Magnesium, Selenium
  • AR: Vitamin A, Vitamin E

Vitamin K:

  • RDA: 90-120 mcg
  • Upper: Not Established
  • SR: Calcium
  • VBNL: Vitamin D
  • AR: Vitamin A, Vitamin E

Vitamin E:

  • RDA: 15 mg
  • Upper: 1000 mg
  • SR: Vitamin C, Selenium, Zinc
  • VBNL: Vitamin A
  • AR: Vitamin D, Vitamin K

Vitamin B1 (Thiamine):

  • RDA: 1.1-1.2 mg
  • Upper: Not Established
  • SR: Magnesium
  • AR: Vitamin B6

Vitamin B2 (Riboflavin):

  • RDA: 1.3 mg
  • Upper: Not Established
  • AR: Calcium

Vitamin B3 (Niacin):

  • RDA: 14-16 mg
  • Upper: 35 mg
  • SR: Zinc

Vitamin B5 (Pantothenic acid):

  • RDA: 5 mg
  • Upper: Not Established
  • AR: Copper

Vitamin B6 (Pyridoxine):

  • RDA: 1.3-1.7 mg
  • Upper: 100 mg
  • AR: Vitamin B1, Vitamin B9, Zinc

Vitamin B7 (Biotin):

  • RDA: 30 mcg
  • Upper: Not Established
  • VBNL: Vitamin B5

Vitamin B9 (Folate):

  • RDA: 400 mcg
  • Upper: 1000 mcg
  • AR: Vitamin B6, Vitamin B12, Zinc

Vitamin B12 (Cyanocobalamin):

  • RDA: 2.4 mcg
  • Upper: Not Established
  • AR: Vitamin B9, Vitamin C


  • RDA: 1000-1200 mg
  • Upper: 2000-2500 mg
  • SR: Vitamin D, Potassium
  • AR: Magnesium, Phosphorus, Sodium, Iron, Manganese, Zinc


  • RDA: 425-550 mg
  • Upper: 3500 mg


  • RDA: 1800-2300 mg
  • Upper: 3600 mg


  • RDA: 35 mcg
  • Upper: Not Established


  • RDA: 900 mcg
  • Upper: 10,000 mcg
  • VBNL: Vitamin C
  • AR: Iron, Molybdenum, Selenium, Zinc


  • RDA: 3-4 mg
  • Upper: 10 mg


  • RDA: 150 mcg
  • Upper: 1100 mcg
  • SR: Vitamin A, Selenium


  • RDA: 8-18 mg
  • Upper: 45 mg
  • SR: Vitamin A, Vitamin C
  • AR: Vitamin E, Calcium, Copper, Manganese, Zinc


  • RDA: 300-450 mg
  • Upper: 500 mg
  • SR: Vitamin B1, Vitamin B6, Vitamin D, Potassium
  • AR: Calcium, Phosphorus, Zinc


  • RDA: 1.8-2.3 mg
  • Upper: 11 mg
  • AR: Calcium, Iron


  • RDA: 45 mcg
  • Upper: 2000 mcg
  • AR: Copper


  • RDA: 700-1250 mg
  • Upper: 3000-4000 mg
  • AR: Calcium, Magnesium


  • RDA: 4700 mg
  • Upper: Not Established
  • SR: Calcium, Manganese, Sodium


  • RDA: 55 mcg
  • Upper: 400 mcg
  • SR: Vitamin D, Vitamin E, Iodine
  • VBNL: Vitamin C
  • AR: Copper


  • RDA: 1200-1500 mg
  • Upper: 2500 mg (this is likely too low)
  • SR: Potassium
  • AR: Calcium


  • SR: Molybdenum


  • RDA: 8-11 mg
  • Upper: 40 mg
  • SR: Vitamin A, Vitamin B3
  • AR: Calcium, Magnesium, Copper, Iron

Fat-Soluble Vitamins and Related Minerals

Vitamin A


Vitamin A is a group of fat-soluble nutrients that includes 3 active forms: retinol, retinal and retinoic acid, and the inactive forms: carotenoids such as alpha-carotene, beta-carotene and beta-cryptoxanthin from plants. It is essential for proper physical development, growth and immune system functioning. Vitamin A has been known to provide anti-inflammatory and anti-infectious activity.

Most of the benefits of vitamin A come from its active form, such as retinol, retinal and retinoic acid. You can only get these from animal sources. Even though some pre-vitamin A from beta-carotene can be converted into its active form, the absorption rate is determined by other fat-soluble nutrients and the conversion is poor. This is why you can’t rely on a low-fat, carrot rich diet to acquire adequate levels of vitamin A. 

The best sources of vitamin A are organ meats, with liver giving you about 5000-7000 mcg-s from just 100 grams. That’s why it’s better to eat liver only a few times per week. Higher doses of vitamin A, like 12,000 mcg-s, can become toxic, causing drowsiness and coma.

The Inuit are known for developing hypervitaminosis A due to eating polar bear liver. Because polar bears feed exclusively on seals and fish, their liver contains extremely high amounts of vitamin A. Even just a mouthful has nearly 9000 mcg-s, which is why you’d probably die if you ate polar bear liver. If you eat meat and some organ meats, then you don’t need to supplement vitamin A.

Immune Health

Immune organs, like the thymus, need vitamin A to promote and regulate thymocytes. Studies link vitamin A deficiency with increased susceptibility to infections.

Vitamin A helps to form epithelial and mucosal tissue, which is the first line of defense against pathogenic invaders. Vitamin A is part of the mucus layer of both the respiratory tract as well as the intestine, improving the antigen immunity of these tissues. 

Retinoic acid (RA) has a crucial role in regulating the function of immune cells, including the release of interferons. RA regulates the differentiation of dendritic cells (DCs), which are potent antigen-presenting cells that modulate the adaptive and innate immunity. RA has a crucial role in regulating tolerance to bacteria and food antigens. RA also suppresses IgE, which may reduce autoimmunity and allergic reactions. Finally, retinoic acid controls signaling of innate lymphoid cells (ILC) located on the surface of intestinal mucosa where they enhance immunity and maintain barrier function.

Signs and Symptoms of Deficiency

Poor night vision; dry eyes; hyperkeratosis around hair follicles, or appearing as bumps on the skin that can be mistaken for goosebumps or acne, or on the surface of the conjunctiva (Bitot’s spots); poor immunity to infectious diseases.

  • A 2017 study showed that vitamin A deficiency is dose-dependently associated with tuberculosis. Epidemiology shows that healthy people have higher serum vitamin A than patients with tuberculosis or HIV. In vitro, RA, together with vitamin D3, inhibits the proliferation of M tuberculosis bacteria and reduces its survival. Vitamin A supplementation has been shown to reduce the incidence of tuberculosis in Botswanan HIV patients. Fixing vitamin A deficiencies have been shown to reduce the risk of dying from malaria and measles.
  • Vitamin A also has therapeutic effects in respiratory diseases like pneumonia and measles in children. Vitamin A reduces mortality, morbidity and vision problems in children between the ages of 6 months and 5 years. The RDA of vitamin A for children is 1665 IU/day. Infections can also make you lose vitamin A through urine.

Less Well Established but Plausible Signs and Symptoms of Deficiency

Kidney stones; disrupted circadian rhythm and an inability to use light therapy to entrain a healthy circadian rhythm; autoimmune disorders; asthma and allergies; food intolerances; low sex hormones; and delayed puberty.

Risk Factors for Deficiency

  • Diets that do not contain at least one of the following: a weekly serving of liver; regular use of cod liver oil, a multivitamin, or another supplement providing 100% of the US RDA for vitamin A as retinol.
  • If the diet is also poor in dairy products and eggs, and does not contain several servings per day of red, orange, yellow, or green vegetables.
  • Diets where fats come from polyunsaturated vegetable oils are more likely to produce vitamin A deficiency than diets where the fat is mostly saturated or monounsaturated.
  • A low-fat diet will not intrinsically produce vitamin A deficiency, but it will increase its likelihood by leading to lower absorption of vitamin A from food.
  • Long-term use of glucocorticoids, high-protein diets, and high-dose vitamin D may contribute to vitamin A deficiency in combination with poor dietary intake.

Signs and Symptoms of Toxicity

Most commonly, nausea, vomiting, and headache. In extremes, anorexia, blurred vision, scaling skin, hair loss (alopecia), organ damage, death.

Osteopenia and osteoporosis can be worsened by vitamin A at non-toxic levels when vitamin D and calcium are deficient. You should keep vitamin A below 10,000 IU per day during the first eight weeks of pregnancy due to a possible risk of birth defects unless blood measurements, signs, and symptoms justify higher intakes to prevent deficiency.

Risk Factors for Toxicity

  • Months or years of consistently taking at least 165 IU per kilogram body weight per day, and in the majority of cases greater than 2300 IU per kilogram body weight per day.
  • Fat-soluble vitamins like A and D work synergistically. Vitamin A can reduce vitamin D toxicity and vice versa. Supplementing vitamin D in humans greatly increases the required dose needed to induce vitamin A toxicity. Thus, a vitamin D deficiency may increase the potential for vitamin A toxicity. To prevent vitamin A toxicity, make sure you are not deficient in vitamin D.
  • A vitamin D deficiency, on top of an increased vitamin A intake, can lead to the accumulation of endogenous retinoids, triggering viral activation and promoting susceptibility to novel influenza strains. Although normal physiological amounts of retinoids in conjunction with vitamin D help to inhibit influenza pathogenesis, a lower vitamin D to A ratio could worsen the disease. Giving vitamin A supplements alone can increase the incidence of respiratory tract infections and in high doses cause influenza-like symptoms. Because retinoids regulate cell growth, they also affect viral replication.
  • Higher doses of vitamin A, such as 12,000 mcg, can become toxic and cause drowsiness and a coma (hypervitaminosis A). Too much vitamin A during pregnancy can also lead to birth defects. The RDA of 700-900 mcg of retinol activity equivalents in adult women and men, respectively is probably not optimal and there may be benefits from 5000 mcg a day from whole foods. The best sources of vitamin A are liver, cod liver oil, egg yolks and salmon. If you eat meat and some organ meats or eggs, then you do not need to supplement vitamin A.

Testing for Vitamin A Deficiency

  • Serum vitamin A: This should be kept toward the middle of the reference range (third quintile) and low-normal results do not necessarily rule out a problem.
  • Retinol-binding protein: Can be measured alongside serum vitamin A, but may be affected by a greater number of variables unrelated to vitamin A status (it is increased in insulin resistance and type 2 diabetes, and decreased in type 1 diabetes, systemic inflammation, and a variety of liver and kidney diseases).

Testing for Vitamin A Toxicity

  • Serum vitamin A will be high in most cases.
  • In descending order of likelihood, the following tests may show elevations:
    • γ-glutamyltransferase, triglycerides, alkaline phosphatase, prothrombin time, cholesterol, aspartate aminotransferase, bilirubin, and calcium.

Testing Caveats

  • Zinc is necessary for almost every step during vitamin A metabolism, including blood transport. Zinc deficiency should always be considered as an explanation for an apparent case of vitamin A deficiency that does not respond well to dietary and supplemental strategies, regardless of whether serum vitamin A is altered.
  • Adiposity may cause cellular vitamin A deficiency without lowering serum levels. Fatty liver disease compromises the liver’s ability to store vitamin A and may raise serum levels.
  • Drugs that are vitamin A derivatives (known as retinoids; e.g., isotretinoin, marketed as Accutane) may cause vitamin A deficiency signs by hurting the body’s utilization of natural vitamin A.
  • Chronic alcohol abuse and protein deficiency also hurt vitamin A utilization.

Correcting Vitamin A Deficiency

You should rule out deficiencies of other nutrients, especially vitamin D and zinc, before taking high-dose vitamin A.

Supplements providing 25,000-50,000 IU per day appear to be well within the margin of safety for short-term use (several weeks) in an adult, and may help resolve a deficiency more quickly, but should not be used without close monitoring of serum vitamin A. More importantly, try to get your vitamin A from food first. 

Correcting Vitamin A Toxicity

The only well-established treatment for vitamin A toxicity is the removal of the toxic dose of vitamin A.

Vitamin D


The most bioavailable source of vitamin D is the sun. Vitamin D is a hormone that gets synthesized when your skin gets exposed to sunlight. You should get daily sunlight exposure as often as you can without getting burnt. The best time for sunlight is in the morning to help with balancing the circadian rhythm, which also influences the function of the immune system. The immune system has circadian clocks and when disturbed, the immune system is also disrupted.

There are many benefits to vitamin D:

  • Higher levels associated with a lower risk of cardiovascular disease
  • May reduce the risk of getting influenza in schoolchildren
  • Higher levels are associated with a lower risk of multiple sclerosis
  • May help to maintain a healthy mood
  • Deficiency is associated with anxiety and depression in fibromyalgia
  • Higher levels are associated with a lower risk of cancer
  • Higher levels are associated with a lower risk for type 1 diabetes
  • May help with weight loss by suppressing appetite
  • May protect against osteoporosis and arthritis
  • Improves muscle strength in limbs
  • May reduce the risk of dying

Immune Health

Deficiencies in vitamin D are linked with increased risk of infections and autoimmune diseases. Most cells in the body and all white blood cells have vitamin D receptors on their surface. Vitamin D receptors regulate the essential functioning of all cells. In fact, vitamin D regulates more than 5% of the human protein-encoding genome. Vitamin D acts as a buffer for the immune system by reducing proinflammatory cytokines and increasing anti-inflammatory cytokines. It also stimulates the expression of anti-microbial peptides and improves barrier function.

Mutations in the vitamin D3 gene CYP27B1 are correlated with increased risk of type-1 diabetes, Addison’s disease, Hashimoto’s thyroiditis and Graves’ disease. Most cells, including T and B cells, have receptors for vitamin D, which regulate the immune system. It’s important to note however, that these receptors are stimulated by active vitamin D (calcitriol), which requires adequate magnesium.

  • Low sunlight exposure and living at high latitudes are thought to contribute to multiple sclerosis (MS) risk. Declining UV light due to seasonality has been noted to increase MS activity. Occupational and childhood exposure to sunlight is inversely correlated with the risk of MS and mortality.
  • Low sunlight exposure is considered a major component to type-1 diabetes (T1D) risk. T1D onset peaks between October and January and reaches its low point during the summer in the northern hemisphere, while the southern hemisphere shows the same reverse pattern. T1D risk appears to be greatly affected by UV irradiation. Regular supplementation with vitamin D3 in children has been correlated with an 88% reduced risk of T1D. In T1D, CD4+ T lymphocytes become pathological and autoreactive, damaging healthy tissue. The same is found in multiple sclerosis.
  • Current guidelines for calcium homeostasis show that vitamin D levels below 30 nmol/L cause deficiencies, 30-50 nmol/L is insufficient, and above 50 nmol/L sufficient. Appropriate ranges for autoimmunity are not known, however, 2,000 IU/day of vitamin D that reached 75 nmol/L is associated with maintenance of intestinal permeability, improved quality of life and reduced disease markers in people with Crohn’s disease compared to those who were below 75 nmol/L.

Vitamin D and Decreased Infection Risk

Vitamin D has bactericidal properties against some bacteria and pathogens like M. Tuberculosis by increasing interferon gamma. Toll-like receptor activation of human macrophages up-regulates vitamin D receptor expression and vitamin D-1-hydroxylase genes, which induces the antimicrobial peptide cathelicidin and leads to the killing of intracellular Mycobacterium tuberculosis. Calcitriol is a direct inducer of antimicrobial peptides in various cells like myeloid cells, keratinocytes, neutrophils and bronchial epithelial cells. This has an antibacterial effect on pathogens like Pseudomonas aeruginosa that cause cystic fibrosis.

  • In a study among 19,000 people, those with lower levels of vitamin D were more likely to suffer from upper respiratory tract infections. A 2017 meta-analysis showed that supplementing with vitamin D decreases the odds of developing a respiratory infection in people with 25-hydroxyvitamin D below 25 ng/mL by 70%. Among 11,321 individuals, supplemental vitamin D decreased the risk of acute respiratory infections (ARI) by 12% in subjects who were deficient, as well as those at normal levels. Vitamin D3, but not vitamin D2, supplementation has been shown to reduce mortality in older adults who are vulnerable to respiratory diseases.
  • Low vitamin D is associated with frequent colds and influenza. It’s well-established that the seasonality of influenza correlates with the reduced vitamin D levels during winter months. Prophylactic vitamin D supplementation for influenza has been shown to prevent illness and reduce secondary asthma in children. There’s a high prevalence of vitamin D deficiency among children with asthma and allergies.

Availability from Food

The richest vitamin D foods are wild salmon (988 IU per 3.5 oz or 100g) vs 250 IU in farmed salmon, herring (1600 IU per 3.5 oz), cod liver oil (450 IU/tsp), egg yolks (commercial eggs have 18-39 IU, whereas pastured eggs have 3-4 times more) and some fortified foods like milk, cereal or orange juice. Mushrooms synthesize vitamin D2 not vitamin D3. Vitamin D2 can raise blood vitamin D levels but the effects aren’t equal to D3. The amount of vitamin D in a given food depends on how much exposure to natural sunlight it receives. 

Less Well Established but Plausible Signs of Vitamin D and Calcium Deficiency

High blood pressure, poor immunity to infectious diseases, autoimmune conditions (especially psoriasis, multiple sclerosis, and type 1 diabetes), asthma and allergies, certain cancers (estrogen-responsive breast cancer, and cancers of the prostate, colon, rectum, ovary, and endometrium), low sex hormones, high androgens in women, insomnia, and cardiovascular disease.

Primarily driven by vitamin D deficiency. CVD, asthma, allergies, and cancer are also possible consequences.

Vitamin D deficiency is associated with increased HMGB1-mediated inflammation in coronary arteries. Supplementing with vitamin D decreased this response in pigs. Deficient vitamin D status is also linked to a higher risk of severe COVID-19 outcomes and mortality in African Americans. Early vitamin D treatment (calcifediol, a partially activated vitamin D analog) in hospitalized patients significantly reduced intensive care unit necessity.

Risk Factors for Vitamin D Deficiency

An indoor lifestyle combined with a low dietary fatty fish, pasture-raised egg yolks, cod liver oil, and vitamin D supplements. If you spend a lot of time outdoors, you may still develop deficiency if you use sunscreen and sunblock, clothing that covers most or all of your skin, or if environmental factors such as clouds, pollution, atmospheric ozone, and tall buildings block your exposure to UV-B rays. Inflammation (from infection or from recovery from injury or surgery), excess phosphorus or vitamin A, and calcium deficiency can all deplete vitamin D levels. Disorders of fat malabsorption hurt the ability to absorb vitamin D in the diet, but do not hurt the ability to obtain it from sunlight.

Obese people have 50% less bioavailable vitamin D compared to non-obese individuals and are 3-times more likely to be deficient in vitamin D.

Signs of Deficiency

  • Mood disorders and depression
  • Chronic fatigue syndrome and exhaustion
  • Frequent infections
  • Slow wound healing and frequent injuries
  • Low bone density and rickets
  • Hair loss
  • Muscle pain and fibromyalgia


Hypercalcemia is the hallmark of vitamin D toxicity. Case reports have associated it with 25(OH)D levels as low as 56 ng/mL, but most cases are associated with levels higher than 200 ng/mL.

Vitamin D toxicity is quite rare and typically only happens if supplementing with extremely high doses (> 10,000 IU) over a long time period.

Correcting Vitamin D Imbalances

  • Get a blood test to check your vitamin D levels. The optimal range is between 40-60 ng/ml. If you’re under 30-40, then consider taking a vitamin D3 supplement.
  • Add vitamin D rich foods. Get more egg yolks, supplement cod liver oil, eat fatty fish especially wild salmon, liver and salmon roe.
  • Take a vitamin D supplement. The dosage depends on your level of deficiency.
    • If you’re under 20 ng/ml, then 6,000-10,000 IU will likely be needed every day for a few weeks until you reach a level of 30 ng/ml to 50 ng/ml. Usually, 2,000-4,000IU daily thereafter is required to maintain sufficient levels.
    • If your vitamin D level is between 20 ng/ml and 29 ng/ml, then 4,000-6,000 daily for a few weeks is likely needed to reach 30 ng/ml or higher. A maintenance dose of vitamin D 2,000-4,000 IU/day thereafter is likely needed to maintain sufficient levels.
    • If you’re at sufficient levels between 30-50 ng/ml, then stick to 2,000-4,000 IUs daily.
    • If you’re over 50 ng/ml, then you probably don’t need to take additional vitamin D supplements but would still want to continue eating vitamin D rich foods.
  • If you live in darker climates, then take more vitamin D. During the winter months it’s good to take about 4,000 IUs and some may require up to 7,500 IUs, especially if living in northern parts of the world. During the summer, less vitamin D is typically needed, i.e., perhaps 1,000-2,000 IUs.
  • Get other fat-soluble vitamins. It’s also a good idea to optimize the other fat-soluble vitamins like A, K and E to get the full benefits of vitamin D. Foods for that include organ meats, fatty fish, fermented foods and meat.
  • Get enough magnesium. Aim for about 400-500 mg a day to help activate vitamin D. It may be best to supplement with magnesium before taking a vitamin D supplement to see if this is the true cause of inactive vitamin D. 
  • Spend more time outside. The sun provides many other benefits and getting appropriate levels of sunlight without burning can have numerous health benefits, especially boosting nitric oxide, which can help maintain a healthy blood pressure.



It is required for muscle contraction, vasodilation and bone health. However, only 1% of total body calcium is needed for carrying out these roles. The remaining 99% is stored in bones and teeth for structural support. The skeleton and bones are a readily available source of calcium to meet this baseline requirement. When calcium intake is low or malabsorbed, the body will pull stored calcium from bones to maintain normal functioning, which can eventually lead to osteoporosis and fractures. Low calcium levels in the body can cause muscle cramps, convulsions, abnormal heartbeat and eventually death.

Calcium homeostasis is regulated by parathyroid hormone, calcitriol and calcitonin. When blood calcium levels drop, the parathyroid glands secrete parathyroid hormone (PTH), which stimulates the conversion of vitamin D in the kidneys into its active form calcitriol. This decreases urinary excretion of calcium but raises urinary excretion of phosphorus. Elevated PTH also promotes bone resorption or breakdown, which releases calcium and phosphorus into the serum from bones. Higher calcitriol concentrations increase intestinal absorption of calcium and phosphorus. As calcium levels normalize, PTH secretion stops and the thyroid gland secretes a peptide hormone called calcitonin. Calcitonin inhibits PTH, reduces bone resorption as well as calcium absorption and promotes urinary calcium excretion.


The current RDA for calcium in women is 1,200 mg/d and for men 1,000 mg/d. The tolerable upper limit is 3,000 mg/d for 9-18-year-olds, 2,500 mg/d for adults 19-50 years old and 2,000 mg/d for 51+ years of age.

Healthy non-growing adults require 550-1,200 mg of calcium a day to maintain balance. For growing boys, the minimal intake to achieve maximal retention is 1,140 mg/d and 1,300 mg/d for growing girls. Intakes greater than 1,400 mg/d achieve a positive calcium balance in people with both normal renal function as well as in those with end-stage renal disease.

Females, especially adolescent girls, are generally less likely to get adequate amounts of calcium from food. Replacing milk with carbonated soft drinks high in phosphorus has been associated with a rise in bone mineral density loss and fracture risk. Soft drinks that contain phosphoric acid have been a major source of phosphorus over the past quarter century.

Calcium from food is not correlated with increased CVD risk, whereas supplemental calcium is. Among calcium supplement users, taking more than 1,400 mg/d of calcium total (from diet and supplements) is associated with higher all-cause mortality, including cardiovascular disease. Dietary calcium intake and the association with cardiovascular mortality follows a U-shaped pattern with intakes < 800 mg/d or > 1,200 mg/d sharply associated with an increased risk of cardiovascular mortality.

Eating calcium-rich foods should not contribute to cardiovascular disease, unless magnesium deficiency occurs, or high-dose calcium supplements are taken. The recommended ratio of calcium to magnesium is ~2:1 both for daily dietary intake and supplementation. In Western countries, the ratio of calcium to magnesium is much higher than it is in China (3 vs 1.7).

Urinary calcium excretion is limited to 4 mg/kg of bodyweight per day. For an average-weight person that would equate to a limit of 280-350 mg per day. Because of that, the kidneys are not able to lower hypercalcemia during excess calcium intake. In the elderly and people with renal dysfunction, the arteries become a calcium sink because the kidneys are not able to excrete extra calcium. Hypercalcemia also increases the risk of developing kidney stones.

Calcium Overload and Calcification

Osteoporosis occurs when bone resorption is chronically higher than bone formation, which promotes the risk of fractures.

  • The risk of osteoporotic hip fracture is determined by one’s peak bone mass and the rate of bone loss after that peak has been reached. Low calcium and low protein diets, age, female gender, estrogen deficiency, smoking, hyperthyroidism and high alcohol consumption increase the risk of developing osteoporosis.
  • Estrogen deficiency reduces the absorption of calcium, whereas estrogen therapy enhances calcium absorption.
  • Excessive calcium intake (>1,500 mg/d) can decrease parathyroid hormone (PTH), which increases the risk of low bone turnover. Too much calcium also reduces bone growth stimulating effects of PTH.
  • However, for the elderly or for someone with impaired calcium absorption, optimal calcium intake may be around 2,400 mg/d due to impaired absorption.

Hyperparathyroidism is the most common cause of elevated calcium in the blood (hypercalcemia). Patients with kidney disease on high calcium intakes experience low bone turnover and PTH suppression. Parathyroid hormone suppression caused by high calcium intake is also thought to reduce magnesium absorption. Sweden is the highest dairy and calcium consuming countries, but it also has the highest rate of hip fractures among developed nations. Meta-analyses find calcium supplementation does increase bone mineral density modestly but does not result in reduced incidence of fractures. Ultimately, the optimal level of calcium intake will also depend on the background intake of magnesium, vitamin D and vitamin K.

Phosphate has a role in the accumulation of calcium by activating the calcium uniporter and inhibiting calcium efflux. One of the contributing factors for arterial calcification is high serum phosphate, which has been shown to promote calcification in animal models and cell studies. In humans, high serum phosphate is associated with increased cardiovascular disease events. For every 1 mg/dL increase above normal in phosphorus levels, the risk of coronary artery calcification has been seen to increase by 21%. A low calcium to phosphorus ratio in diet has adverse health effects, starting with arterial calcification and ending with bone loss.

Excessive supplemental calcium can contribute to calcium overload, increasing urinary calcium excretion and possibly soft tissue calcification.

Excess calcium converts smooth muscle cells into bone-forming cells or osteoblasts that promote arterial calcification. High calcium intake also suppresses kidney synthesis of calcitriol, which raises cardiovascular risk.

Cellular Level

Extracellular calcium is constantly maintained at 1.25 mM by parathyroid hormone and 1,25-dihydroxyvitamin D (calcitriol) activity, except after supplementation over a 3-4-hour period.

Intracellular calcium levels are maintained around 100 nM (nanomolar) and can rise up to 1 mcM (micromolar) upon activation, whereas extracellular calcium sits at 1.2 mM.

Intracellular calcium homeostasis is regulated by the mitochondria’s tightly regulated calcium transport system. The mitochondria also produce ATP, which generates reactive oxygen species as an inevitable by-product. In healthy subjects, this basal oxidative stress should be dealt with by the body’s endogenous antioxidant systems. However, during pathophysiological states the balance is offset, causing calcium dysregulation, oxidative stress and eventually cell death. In vitro studies find that calcium in the brain inhibits mitochondrial respiration by inhibition of Complex I and thus reduces mitochondria-generated reactive oxygen species in a dose-dependent manner. Calcium can also inhibit free radical production in the presence of ATP and magnesium.

When intracellular calcium reaches 1 mcM it is taken up by the mitochondria and through a uniporter it is released once levels drop below 1 mcM. Concentrations >1 mcM may inhibit mitochondrial respiration and trigger pro-cell death signals. The mitochondria can accumulate a lot of calcium, exceeding 1000 nmol/mg of mitochondrial protein. This ability is an intrinsic component of ATP production.

Heart mitochondria have a sodium-calcium exchanger in addition to the calcium uniporter. Intracellular calcium is kept at a balance by the influx and efflux of calcium by voltage-operated channels or agonist binding (glutamate, ATP, acetylcholine) via receptor-operated channels. Calcium can also be released from internal stores such as the endoplasmic reticulum.

Increased calcium intake decreases the gastrointestinal absorption of lead and can prevent it from being mobilized from bone during bone demineralization. Average dietary calcium intake of 900 mg/day and supplementation of 1,200 mg/d during pregnancy can reduce maternal lead concentrations by 8-14%. Similar results were found in the blood and breast milk.

Dairy, in particular, promotes insulin-like growth factor (IGF-1), which regulates cell proliferation and growth. Circulating IGF-1 levels are positively correlated with cancer risk, especially prostate cancer. Prostate cancer risk has been observed to be the highest in people who consume the most dairy and animal protein. However, it has also been found that individuals with a higher dairy/calcium consumption are more likely to engage in healthy lifestyle practices like exercise or seeking of medical help, which might mitigate the association with increased prostate cancer risk.

A recent meta-analysis estimated that a high calcium intake (1,300 mg/d) increases fat oxidation by 11% compared to a low intake of 488 mg/d. Dietary calcium may also bind to fat from food in the digestive tract and prevent its absorption. Vitamin D sufficiency could also help with lipolysis as vitamin D deficiency is associated with obesity.

Calcium signaling also regulates autophagy, which is the recycling of cellular material that is beneficial in moderation but can also lead to cell death when in excess.

Activation of the NMDA-selective glutamate receptors causes a massive influx of calcium into neurons, leading to their death. This is the result of excess mitochondrial superoxide production that damages organelles. Beta-amyloid proteins involved in Alzheimer’s disease cause sporadic intracellular calcium signaling and calcium influx that results in neuronal death.

Calcium-Dependent Enzymes, Functions and Consequences of a Deficit

Calcium-Dependent Enzymes/Proteins: Function: Consequences of Deficit

  • ATP Synthase: Produce and activate ATP: Energy shortage, not enough energy to carry out vital bodily processes
  • Fatty Acid Oxidation: Burn triglycerides and lipids for fuel: Hyperlipidemia, hypercholesterolemia
  • Lipolysis: Breakdown of fat cells: Obesity, visceral adiposity
  • Glycolysis: Burn glucose for fuel: Hyperglycemia, glycation, insulin resistance
  • 5-HTP: Melatonin production, serotonin production, relaxation, REM sleep: Sleeping problems, insomnia, arousal, anxiety, poor memory consolidation
  • Parathyroid Hormone (PTH): Bone turnover, bone mineral density: Osteoporosis, increased bone loss, decreased bone density
  • Calcitriol: Active form of vitamin D, promote bone density, support immunity, govern hormone regulation: Osteoporosis, decreased bone density, increased risk of fractures, weaker immunity
  • Calcitonin: Regulate calcium balance, reduce calcium absorption: Calcium overload, calcification, atherosclerosis

Calcium Food Sources

Dairy products, edible bones (e.g., those in canned fish), and green vegetables.

Things that Reduce Calcium Absorption and Increase Calcium Demand

  • Certain plant foods, even those rich in calcium like spinach and kale, inhibit calcium absorption due to their oxalic acid or oxalate content. Oxalates are found the most in spinach, rhubarb leaves, bok choy, sweet potato, cassava and beans. Citric acid or lemon juice helps to break down oxalate crystals.
    • Supplemental calcium increases the risk of calcium oxalate kidney stones. Higher dietary calcium intake, however, does not appear to promote kidney stone formation and may even lower the risk. Adequate calcium intake reduces the absorption of dietary oxalate and reduces urinary oxalate by forming insoluble calcium oxalate salts. 
  • Phytates are weaker inhibitors of calcium absorption than oxalates. Wheat bran or dried beans can substantially reduce calcium absorption, whereas regular wheat does not appear to do so. To reduce the phytate and oxalate content of these foods, you can soak and sprout them beforehand. Yeast also contains a phytate-breaking enzyme called phytase that helps to break down phytate during fermentation.
  • High sodium and protein intake can increase urinary calcium excretion but also calcium absorption. Sodium and calcium appear to compete in the kidneys for reabsorption. Every gram increment of sodium (2.5 g of sodium chloride) excretion by the kidneys has been found to draw 26.3 mg of calcium into the urine. However, higher sodium intakes are associated with fewer hip fractures. Thus, the increased absorption of calcium may offset any calcium loss out the urine. At the same time, high protein intake increases intestinal calcium absorption. Metabolic acidosis, which may result from excess animal protein or cereal consumption, also increases calcium excretion. Bicarbonate from fruits, vegetables or bicarbonate mineral water can help to offset that.
  • Lactose intolerance increases the risk of calcium deficiency due to the avoidance of dairy. Some lactose intolerant people can tolerate small amounts of dairy without side-effects. Consuming dairy with other foods or spread throughout the day may improve tolerance. Low-lactose dairy products include aged cheeses, yogurt or lactose-free milk.
  • Vegan diets may not provide adequate amounts of calcium due to the avoidance of dairy as well as the reduced bioavailability of calcium from the increased phytonutrient content of plants. Bone fracture risk is higher in vegans compared to omnivores or vegetarians. 
  • Caffeine from coffee, tea or soda can also raise urinary excretion while reducing the rate of absorption of calcium. However, one cup of coffee causes a loss of only 2-3 mg of calcium. Doses of 400 mg of caffeine do not change 24-hour urinary calcium excretion. Moderate coffee consumption (1-2 cups a day) is not associated with poor outcomes on bone but when no milk or other calcium foods are consumed it is. Thus, habitual coffee consumption requires compensation in the form of increased calcium consumption from food. The increased urinary calcium excretion seen from the consumption of carbonated beverages is attributed to their caffeine content, not the carbonation or phosphorus.
  • Alcohol reduces calcium absorption directly and by inhibiting enzymes that convert vitamin D into its active form. 
  • Menopause promotes bone loss due to lower estrogen levels increasing bone resorption and reducing calcium absorption. During the first year of menopause, bone mass may decrease 3-5% per year, but it drops down to 1% after the age of 65. Increasing calcium intake does not completely offset this loss.
    • Low calcium intake is associated with premenstrual syndrome (PMS) and supplemental calcium decreases the symptoms. 
  • Amenorrhea, which is a condition wherein menstruation stops or fails to begin, causes a drop in circulating estrogen, which has a negative effect on calcium balance. Usually, it is associated with the “female athlete triad” – disordered eating or anorexia, amenorrhea and osteoporosis. Menstrual irregularities and low bone mineral density are associated with the risk of future fractures. 
  • The rate of gastrointestinal calcium absorption is about 10- 30% for adults and as high as 60% for growing children. Antacids increase urinary calcium excretion and glucocorticoids promote calcium depletion.

Osteopenia and Osteoporosis

  • Osteopenia is a less severe form of osteoporosis and both involve decreased bone mineral density and increased risk of fracture.
  • A DXA scan is required for early diagnosis and without one signs and symptoms may not be apparent.
  • Elevated parathyroid hormone (PTH) is a major factor in these conditions, and it is raised by deficiencies of vitamin D or calcium, or by excess phosphorus.
  • These disorders are caused by deficiencies of calcium or vitamin D, or an excess of phosphorus.

Rickets and Osteomalacia

  • Rickets is the childhood version of osteomalacia.
  • Key signs and symptoms include bone pain, muscle weakness, fragile bones, and skeletal deformities such as thickened wrists and ankles, compressed vertebrae and pelvis, and bowed legs. Skeletal deformities are more common and obvious in children.
  • An X-ray would show poorly mineralized, overgrown bone matrix, and, in children, expanded growth plates. These are driven by hypocalcemia (low blood calcium) or hypophosphatemia (low blood phosphorus),
  • Deficiencies of vitamin D, calcium, or phosphorus can cause rickets.


A neuromuscular condition resulting from hypocalcemia. It can involve muscle twitching, tremors, or spasms; confusion; and in extreme cases seizures, coma, and death.

Since tetany is driven by hypocalcemia, deficiencies of vitamin D or calcium may cause it. A large excess of phosphorus may also contribute to tetany by depleting blood levels of calcium. It is low ionized calcium rather than low total calcium that drives the condition, and alkalosis or high albumin may decrease ionized calcium even when total calcium is normal.

Soft Tissue Calcification

Deposits of calcium in tissues other than the bones and teeth can take many forms, including kidney stones and cardiovascular disease. In children, early calcification of cartilage interferes with growth. Soft tissue calcification can be caused by hypercalcemia or hyperphosphatemia. In the urinary system, it may be caused by high levels of calcium or phosphorus in the urine, known as hypercalciuria and hyperphosphaturia.

Excesses of vitamin D, calcium, and phosphorus can cause it. Nevertheless, calcium at healthy intakes protects against kidney stones because it prevents excess phosphorus absorption and favors net movement of phosphorus into bone rather than kidney.


  • High levels of ionized calcium in the blood can be caused by excess calcium or vitamin D, but not phosphorus. They are usually driven by a high amount of total calcium, but acidosis or low albumin may increase ionized calcium even when total calcium is normal.
  • Chronic excess of vitamin D will cause more persistent hypercalcemia than chronic excess of calcium when either are present on their own. However, excess calcium can cause persistent hypercalcemia in the presence of alkalosis and impaired kidney function.
  • In addition to soft tissue calcification, hypercalcemia can lead to frequent thirst and urination, confusion, lethargy, fatigue, depression, bradycardia (slow heart rate), arrhythmia, palpitations, or fainting.
  • Hypercalcemia may be driven in part by calcium moving from bone to blood, especially in response to vitamin D toxicity, in which case it will be accompanied by lower bone mineral density.

Risk Factors for Calcium Deficiency and Excess


A diet low in dairy products, edible bones (e.g., those in canned fish), green vegetables, calcium-containing multivitamins, or calcium supplements is the primary risk factor. Excess phosphorus inhibits calcium absorption and may aggravate a dietary deficiency.


The tolerable upper intake limit (TUIL) set by the Institute of Medicine for calcium is 2.5 grams per day for adults under the age of 50 and 2 grams per day for adults over this age. This is based on the risk of calcium-alkali syndrome, where hypercalcemia occurs alongside alkalosis and impaired renal function. This requires causes of alkalosis and impaired renal function in addition to high calcium intakes.

Populations at risk for this syndrome are pregnant women, elderly women, and bulimics.

In these populations, calcium supplementation contributes to the syndrome when it takes the form of calcium oxide, hydroxide, or carbonate, or when it is accompanied by antacids, diuretics, ACE inhibitors, or NSAIDs.

Caveats for Supplementation

Before supplementing, you should know whether or not you’re actually deficient because too much calcium promotes atherosclerosis and plaque formation. Especially if you’re not getting enough vitamin K2. Calcium and Magnesium absorption compete with each other in doses higher than 250 mg-s so you shouldn’t supplement them together. Consuming more dairy and calcium isn’t healthier and won’t strengthen your bones. Regions with the highest dairy consumption also have the highest rates of bone fractures and osteoporosis because they’re not getting enough vitamin K. It’s not recommended to supplement calcium if you’re eating meat and veggies.

Calcium itself decreases the absorption of some drugs, such as bisphosphonates (used for osteoporosis), fluoroquinolones and tetracycline antibiotics, levothyroxine, phenytoin (an anticonvulsant), and tiludronate disodium (for Paget’s disease). Consuming 600 mg of calcium with a meal cuts the absorption of zinc in half from that meal. Taking calcium supplements together with thiazide diuretics increases the risk of hypercalcemia because of increased calcium reabsorption by the kidneys. It can also promote abnormal heartbeat in people taking digoxin for heart failure.

Calcium supplementation is not recommended for those who do not need it as dietary calcium comes in safer amounts and with other nutrients. However, it might be necessary for those who are having difficulties consuming calcium foods, like in those who are lactose intolerant or for postmenopausal women. To avoid calcium overload and increased urinary excretion, it is better to take no more than 500 mg per meal and not exceed 1,500 mg/d. Supplementing calcium (600-2,000 mg/d for 2-5 years) has been associated with gastrointestinal disturbance, constipation, cramping, bloating and diarrhea. The most cost-effective calcium supplement is calcium carbonate. Calcium citrate is best for those who have poor stomach acid or are on histamine-2 blockers or protein-pump inhibitors.

Calcium retention is higher in people with renal dysfunction and/or kidney disease. As a result, they may also need to aim for the lower end of the RDA and be more cautious with calcium supplementation to prevent soft tissue calcification.



Phosphorus is another essential mineral component of bones and teeth as well as DNA and RNA. Calcium and phosphorus make up hydroxyapatite, which is the main structural component of bones, the collagen matrix and tooth enamel. In humans, phosphorus makes up ~1-1.4% of fat-free mass (approximately 700 grams). Out of this amount, 85% is located in bones and teeth as hydroxyapatite, 14% exists in soft tissue and 1% is present extracellularly.

Inorganic phosphorus, as phosphate (PO 4 3−), is required for all known life forms. Phosphorus is a part of cell membranes, ATP and phospholipids. Phosphorylation is the addition of a phosphoryl group to an organic molecule, which affects many proteins and sugars in the body. The phosphorylation of carbohydrates is involved with many steps in glycolysis. Glucose phosphorylation is needed for insulin-dependent mTOR activity in the heart, regulating cardiac growth. Without phosphorus, or phosphorylation, glycogen resynthesis and glycolysis do not work as well. Phosphorylation also affects amino acids and proteins like histidine, lysine, arginine, aspartic acid and glutamic acid.

Phosphorus deficiency can cause anorexia, muscle wasting, rickets, hyperparathyroidism, kidney tubule defects, and diabetic ketoacidosis. Genetic phosphorus disorders include X-linked hypophosphatemic rickets, which promotes rickets, osteomalacia, pseudofractures, dental damage and enthesopathy (mineralization of ligaments and tendons). Hypophosphatemic rickets may also be accompanied with hypercalciuria.

  • In preterm infants, phosphorus and calcium deficiency are one of the main causes of osteopenia. Most of the fetal bone mineralization occurs during the third trimester of pregnancy, which is why preterm babies are born with low calcium and phosphorus in their bones.
  • Phosphorus deficiency occurs in 21.5% of chronic obstructive pulmonary disease patients, 30.4% chronic alcoholics, 33.9% of ICU patients, 75% of severe trauma or burn victims and up to 80% of people with sepsis.
  • Prolonged starvation or malnutrition can cause refeeding syndrome, which is characterized by hypophosphatemia but can also include abnormal balances in sodium and fluids, changes in metabolism, thiamine deficiency, hypokalaemia, and hypomagnesaemia.

Phosphorus homeostasis is regulated by the kidneys, bones and intestines. In kidney failure, the body cannot excrete phosphate efficiently and its levels rise. Phosphorus resorption by the kidneys also increases. Patients with moderate kidney dysfunction have higher serum phosphate levels (4.12 ml/dL) compared to those with normal kidney function (3.74 mg/dL). Higher phosphorus retention promotes chronic kidney disease (CKD) and bone disorders. High as well as low bone turnover are common in CKD.

Refeeding Syndrome

In early starvation, the body will shift from using carbs to using fat and protein for fuel, which can decrease metabolic rate by up to 20-25%. During refeeding, the increase in blood glucose increases insulin and decreases glucagon, which stimulates synthesis of glycogen, fat, and protein. This process requires phosphate, magnesium, and vitamin B1. Insulin stimulates the absorption of potassium, magnesium, and phosphate into the cells via the sodium-potassium ATPase pump, which also shuttles glucose into cells. This process decreases serum levels of these minerals because the body is already depleted of them.

  • Refeeding syndrome can cause electrolyte deficiencies, fluid retention, cramps, heart palpitations, hypoventilation, respiratory failure, heart failure, impaired blood clotting, coma and even death. It is more likely to develop in patients who are underweight, anorexic, have a low-nutrient diet or with a history of drug/alcohol abuse.
  • Administration of phosphorus and thiamine can help to prevent refeeding syndrome. However, electrolytes and sodium are also vital because an actual phosphorus deficiency is rare. For most people to become deficient in phosphorus, you would have to be ingesting close to zero phosphorus for a month or longer, which is why it most commonly occurs in third world malnutrition victims. Refeeding syndrome while fasting or calorie restriction occurs mostly because of dehydration, lack of potassium, sodium, and magnesium.

Normal serum phosphate in adults is 2.5-4.5 mg/dL or 0.81-1.45 mmol/L. Hypophosphatemia is defined when phosphate drops below the lower end of the normal range and hyperphosphatemia is when it is above the high end. However, serum or plasma phosphate does not necessarily reflect whole-body phosphorus content.

Phosphorus-Dependent Enzymes, Functions and Consequences of a Deficit

Phosphorus-Dependent Enzymes/Proteins: Function: Consequences of Deficit

  • ATP Synthase: Produce and activate ATP: Energy shortage, not enough energy to carry out vital bodily processes
  • Phosphorylation: Burn triglycerides and lipids for fuel: Hyperlipidemia, hypercholesterolemia
  • Glycolysis: Burn glucose for fuel: Hyperglycemia, glycation, insulin resistance
  • Glucokinase: Catalyze the phosphorylation of glucose: Risk of hyperglycemia and insulin resistance
  • Hexokinase: Catalyze the phosphorylation of glucose: Risk of hyperglycemia and insulin resistance
  • Glucose 6-Phosphate: Convert glucose into glycogen, glycogenolysis, glycolysis, gluconeogenesis: Risk of hyperglycemia and low glycogen storage
  • Fructose-6-Phosphate: Store glucose in the cells, glycolysis, gluconeogenesis: Risk of hyperglycemia and insulin resistance
  • Fructose-1-Phosphate: Store fructose in the cells, glycolysis, gluconeogenesis: Risk of hyperglycemia and insulin resistance
  • Parathyroid Hormone (PTH): Bone turnover, bone mineral density: Osteoporosis, increased bone loss, decreased bone density
  • Calcitriol: Active form of vitamin D, promote bone density, support immunity, govern hormone regulation: Osteoporosis, decreased bone loss, decreased bone density, increased risk of fractures, weaker immunity
  • Calcitonin: Regulate calcium balance, reduce calcium absorption: Calcium overload, calcification, atherosclerosis


The RDA for phosphorus is 700 mg for adults, 1,250 mg for teens 9-18 years of age, 500 mg for 1-8-year-olds and < 275 mg for infants. Tolerable upper intake levels (Uls) are set at 3,000-4,000 mg/d. Estimated Average Requirement (EARs) for basal requirements are deemed to be 580 mg/d for ages above 19. The RDA for phosphorus is being exceeded greatly and it may be even higher than currently estimated. NHANES data from 2015-2016 shows that adults get on average 1,189 mg/d for women and 1,596 mg/d for men, while children and teens get 1,237 mg/d. In 2013-2014, NHANES showed the average phosphorus intake from both food and supplements was 1,744 mg/d for men and 1,301 mg/d for women. However, this may not be adequate as these surveys don’t take into account the phosphate additives in many foods.

High intake of phosphorus can contribute to calcium overload and magnesium deficiency. Cell studies find excess phosphorus can cause vascular calcification and endothelial dysfunction. A high intake of phosphorus (>1,400 mg/d) in relation to calcium keeps parathyroid hormone elevated constantly, which decreases bone mineral density. Over the long term, it can lead to an increased risk of skeletal fractures and cardiovascular disease mortality.

However, if calcium intake is adequate, high intake of phosphorus doesn’t seem to have a negative effect on bone mineral content. Excess phosphorus, however, may promote the formation of kidney stones and calcium oxalate.

The recommended ratio of Ca/P is 1-2:1. Increased phosphoric acid consumption from soft drinks may have a negative effect on bone health. Diets with a low Ca/P ratio (≤0.5) have an increase in parathyroid hormone and urinary calcium excretion.

Food Sources

High dietary calcium and phosphate intake inhibit the absorption of magnesium. People eating refined low magnesium diets also tend to get a lot of phosphorus from those same foods. Dairy, especially cheese, has a high phosphorus to magnesium ratio. 

Phosphorus is found in many different types of foods, such as dairy, meats, fish, eggs, legumes, vegetables, grains and seeds. Infants fed cow-milk formulas have a 3x higher phosphorus intake and higher serum phosphate levels compared to those fed human milk. These levels seem to normalize after 6 weeks but infants less than 1 month old may be at a risk of hypocalcemia when fed exclusively high phosphorus formulas.

Phosphate additives like phosphoric acid, sodium phosphate and sodium polyphosphate are added to processed foods for preservation and they have been shown to reduce bone mineral density in humans. These additives can provide 300-1,000 mg to the total daily phosphorus intake with an average of 67 mg of phosphorus per serving. That is about 10-50% of the phosphorus intake in Western countries.

Absorption of phosphorus from whole foods is anywhere from 40-70% with animal foods being more bioavailable than plants. The absorption rate of phosphate additives added to foods is anywhere from 70-100%. Unenriched meat and cottage cheese are better choices than hard cheeses or sausages that tend to have added phosphate additives. In seeds and grains, phosphorus is stored as phytic acid. Because humans lack the phytase enzyme, phytic acid is not absorbed and it actually inhibits the absorption of other nutrients.

Calcium from foods and supplements may bind to phosphorus and reduce its absorption. A high intake of calcium (2,500 mg/d) can bind 0.61–1.05 grams of phosphorus. Replacing high phosphorus foods like animal protein and phosphate additives with more calcium foods can reduce serum phosphate levels.

Reducing phosphorus containing foods, which are often high in protein, in CKD patients may not outweigh the benefit of controlling phosphorus levels and may lead to higher mortality because of protein restriction. Instead, getting higher calcium proteins foods like cottage cheese or whey protein might be a better approach.


Phosphate binds to calcium, causing the calcium phosphate to leave the blood as it deposits in other tissues, both in healthy ways (e.g., bone) and unhealthy ways (e.g., kidney stones). Thus, hyperphosphatemia can cause tetany (deficient calcium available to the nervous and muscular systems) and soft tissue calcification (excess calcium phosphate deposited in soft tissues) but not osteomalacia (deficient calcium phosphate available to bone). Symptoms will primarily be those associated with tetany.

Plausible Signs of Phosphorus Deficiency

Fatigue, weakness, and carbohydrate intolerance.

Risk Factors for Phosphorus Deficiency and Excess


  • High levels of calcium in the diet may interfere with phosphorus absorption, but the reverse problem is far more likely.
  • Hungry bone syndrome involves the movement of phosphorus into bone when bone mineral content starts increasing suddenly after the correction of a bone resorption disorder, for example by surgical removal of the parathyroid gland. Hypocalcemia and low levels of magnesium (hypomagnesemia) also develop during hungry bone syndrome.
  • Refeeding syndrome occurs after aggressive correction of starvation or of chronic malnutrition, as might occur in alcoholism, eating disorders, or illnesses that impact food intake.
  • Dietary phosphorus drops to low levels or even zero, the loss of lean mass causes loss of phosphorus stores, and the drop in carbohydrate metabolism causes the loss of the phosphorus needed for that process. Serum phosphate tends to remain stable during malnutrition. During refeeding, however, insulin and the rise in carbohydrate metabolism bring phosphate into cells, causing hypophosphatemia to develop. This is aggravated by the large demand for cellular repair and rebuilding of phosphorus stores. Hypomagnesemia and low levels of potassium (hypokalemia) also occur during refeeding syndrome.
  • Antacids can bind to phosphorus and over the long-term lead to hypophosphatemia. If the antacids contain calcium carbonate, they can also decrease the intestinal absorption of phosphorus. Laxatives that contain sodium phosphate can increase serum phosphate levels. When taken at high doses, laxatives that contain sodium phosphate may even lead to death, especially in those with kidney failure, heart disease or dehydration.


  • The principal cause of hyperphosphatemia is chronic kidney disease.
  • Excess dietary phosphorus, however, contributes to low bone mineral density and the risk of kidney stones.
  • Phosphorus is more bioavailable from animal products than from plant products, and unlike bones and dairy products, animal flesh contains very little calcium. A diet rich in animal flesh may therefore provide sufficient phosphorus to aggravate a deficient level of calcium. The main dietary risk factor, however, is a diet rich in processed foods.

D, Calcium, & Phosphorus Interactions

Testing for Vitamin D, Calcium, and Phosphorus Status

25(OH)D (calcidiol)

Recommended to maintain this marker between 30-40 ng/mL, and to be concerned if under 25 ng/mL or over 50 ng/mL. To convert these units to nmol/L, multiply by 2.5. To convert nmol/mL back to ng/mL, divide by 2.5. 25(OH)D is very responsive to vitamin D status, but is decreased by calcium deficiency, excess phosphorus, vitamin A, inflammation, and genetic factors that increase its conversion to calcitriol or its inactivation.

Parathyroid Hormone (PTH)

  • Calcium and vitamin D suppress PTH, while phosphorus raises it. If PTH is maximally suppressed, the body perceives calcium and vitamin D as adequate and does not perceive any crisis of excess phosphorus. The point of maximal suppression appears to be approximately halfway through the normal range (around 30 pg/mL) and may be as low as 20 pg/mL.
  • A PTH higher than 35 pg/mL is a cause for nutritional action.
  • If PTH is maximally suppressed, there is likely no need for action even if 25(OH)D appears low (unless magnesium deficient).

1,25(OH)2D (calcitriol)

  • During vitamin D deficiency, calcitriol remains normal until the deficiency is beyond the degree needed to cause serious rickets and osteomalacia, at which point it may become elevated briefly and finally become low. By contrast, in calcium deficiency calcitriol rises linearly with the degree of deficiency. Phosphorus tends to have no net effect on calcitriol levels.
  • If low, but in range, vitamin D is likely more deficient. If high, but in range, calcium is more likely deficient. If PTH is high, excess phosphorus may be the issue regardless of calcitriol level. Elevations are best interpreted when high-sensitivity CRP is measured.

High Sensitivity C-Reactive Protein

  • Inflammation causes the conversion of calcidiol to calcitriol.
  • Values of 1-3 suggest chronic, low-grade chronic inflammation, and values above 3, especially those above 10, suggest an acute infection or serious inflammatory disorder. hs-CRP values associated with low-grade inflammation could be considered likely to make a modest contribution to low 25(OH)D, especially if calcitriol is on the higher end of normal.

Calcitonin and FGF23

Excess calcium will raise calcitonin, and excess phosphorus will raise FGF23.

Total Calcium, Ionized Calcium, and Phosphorus
  • Serum calcium declines in deficiencies of vitamin D or calcium that are severe enough to cause rickets. It rises in clinical hypercalcemia caused by excesses of these two nutrients.
  • Only ionized calcium is biologically relevant. Total calcium usually reflects ionized calcium, and we usually use it because it is easier to collect blood and is cheaper. Nevertheless, total calcium will underestimate ionized calcium during acidosis or in the presence of low albumin, and it will overestimate it during alkalosis or in the presence of high albumin.
  • Phosphorus levels decline in phosphorus deficiency and rise in phosphorus excess.

Other Nutrient Deficiencies

  • Although zinc is not as prominent in vitamin D metabolism as it is in vitamin A metabolism, the activity of the vitamin D receptor is dependent on zinc, so zinc deficiency may cause resistance to vitamin D and cause clinical signs of deficiency to develop at normal 25(OH)D levels.
  • Magnesium is critical to all aspects of vitamin D and calcium metabolism, and deficiency of magnesium will cause hypocalcemia (thereby contributing to tetany and osteomalacia) and interfere with the interpretation of the blood markers. For example, PTH may be low in magnesium deficiency even though the hypocalcemia that accompanies this deficiency should raise it.
  • A deficiency of vitamin K will contribute to osteopenia or osteoporosis without affecting any of these blood markers.


  • Pregnancy lowers 25(OH)D, calcium, and PTH, and raises calcitriol. These are probably adaptations to supply calcium to the fetus while minimizing the risk of bone loss to the mother. Total calcium may drop as low as 8.2 mg/dL, which is below the typical bottom of the reference range.
  • Pregnancy may induce a mild acidosis that keeps ionized calcium normal while total calcium drops. PTH is typically between 10 and 25 pg/mL. Alterations to 25(OH)D and calcitriol mainly occur in the second and third trimesters, where 25(OH)D is cut in half and calcitriol is doubled.

Kidney Disease

The excretion of phosphate declines, which causes calcium levels to fall. The hyperphosphatemia and hypocalcemia elicit a rise in PTH.

Requires medical treatment and nutritional management.


A poorly understood overactivation of the immune system. Calcitriol is high, 25(OH)D is often low, and hypercalcemia may occur. It requires medical attention.

Tumors and Genetic Disorders

Blood markers that otherwise do not seem to make sense. For example, a deficiency of vitamin D or calcium will cause a rise in PTH that brings calcium levels up to normal. High PTH should therefore be associated with normal or low calcium. If high PTH is associated with high calcium, PTH is being overproduced, raising calcium higher than normal, and this is likely the result of a medical condition.

Excess phosphorus will raise FGF-23 and this will bring phosphorus levels down to normal. High FGF-23 should be associated with normal or high phosphorus. If high FGF-23 is associated with low phosphorus, FGF-23 is being overproduced, causing hypophosphatemia, and this is another likely case of a medical condition.

Correcting Nutritional Imbalances in Vitamin D, Calcium, and Phosphorus

  • Low 25(OH)D, indoor lifestyle, low dietary vitamin D, normal calcium intake, low hs-CRP, and middle-of-the-range calcitriol. Vitamin D deficiency is most likely.
  • Low 25(OH)D, outdoor lifestyle, adequate dietary vitamin D, low calcium intake, low hs-CRP, and calcitriol on the high end of the range. Calcium deficiency is most likely.
  • Low 25(OH)D, outdoor lifestyle, adequate dietary vitamin D, adequate calcium, high hs-CRP, and calcitriol on the high end of the range. Inflammation is most likely.
  • Low or normal 25(OH)D, outdoor lifestyle, adequate dietary vitamin D, adequate calcium, high intake of processed foods, calcitriol normal or low, calcium normal or low, phosphorus normal or high, and high FGF-23. Excessive intake of phosphorus is most likely.
  • Alternatively, PTH may be normal or low in the case of excess vitamin D, and the earliest sign may be an elevated 25(OH)D. Very elevated 25(OH)D and hypercalcemia would be the principal markers of vitamin D toxicity.



Magnesium is the 4th most common cation (positively charged ion) in the human body, the 2nd most common intracellular cation and the most common intracellular divalent cation. It is required for over 300 enzymes in the human body. The main functions of magnesium include regulation of sodium, calcium and potassium levels, ATP generation, modulation of inflammation, DNA/RNA protein synthesis and neurotransmitter production.

Extracellular magnesium contributes only ∼ 1% of total body magnesium, which is concentrated primarily in the serum and red blood cells. The human body contains roughly 25 grams of magnesium with 50-60% of it being in bones and the remainder in soft tissue. Out of that amount, 90% is bound and 10% is free. In the blood, 32% of magnesium is bound to albumin and 55% is free.

Immune Health

Magnesium is important for all bodily processes, including immunity. Magnesium deficiency elevates pro-inflammatory cytokines like TNF-alpha and reduces CD8+ T cells. Magnesium deficiency also activates macrophages, neutrophils and endothelial cells, which increase inflammation further. A deficiency in magnesium also promotes the degradation of the thymus by increasing apoptosis and oxidative stress.

During viral infections, strategies that improve CD8 T cell cytotoxicity may lead to a healthier immune response. Potential strategies would include magnesium and selenium. During magnesium deficiency, monocytes release more inflammatory cytokines, whereas supplemental magnesium may reduce cytokines released by activated toll-like receptors.

Intracellular free magnesium regulates the cytotoxicity of NK cells and CD8 T cells. Reduced intracellular free magnesium causes dysfunctional expression of the natural killer activating receptor NKG2D in NK and CD8 T cells as well as defective programmed cell death in NK and CD8 T cells.

Magnesium is essential for base excision repair enzymes, which is a type of DNA damage response. In large quantities, magnesium can suppress N-Methylpurine-DNA glycosylase (MPG) that initiates base excision repair in DNA. However, magnesium is required for all the downstream actions of base excision repair proteins like apurinic/apyrimidinic endonuclease, DNA polymerase β and ligases. Thus, magnesium regulates repair processes to ensure a balanced repair of damaged DNA bases.

Type 2 diabetics have been found to have low intracellular free magnesium, which might partially explain why they are more susceptible to RNA viruses. Additionally, magnesium supplementation can inhibit NF-kB, which regulates tissue factor expression. Magnesium deficiency also promotes oxidative stress and depletes intracellular glutathione.

Therefore, intracellular magnesium plays a key role in immune function and magnesium supplementation, especially in those with low magnesium levels in their immune cells, may support a healthy immune response.

Intracellular magnesium deficiency = decreased cytotoxicity of NK cells and CD8 T cells -> Increased viral/cancer replication.

Benefits of Magnesium for Stress and Immunity

  • Magnesium supplementation improves fasting blood glucose in people with diabetes and glucose tolerance in those who are at a high risk of diabetes. Magnesium deficiency has been implicated in reduced pancreatic beta cell function, reduced DNA repair capacity, insulin resistance, cardiovascular disease, type-2 diabetes, osteoporosis, hyperglycemia and hyperinsulinemia.
  • Magnesium regulates neurotransmitters and improves neurological health. It may protect against neurodegeneration and neurological disorders. Magnesium can stabilize mood in bipolar disorder and mania.
  • Magnesium promotes relaxation and stress relief. Magnesium is needed for creating serotonin in the brain, which promotes relaxation and wellbeing. It also supports the function of GABA, which is the main inhibitory neurotransmitter.
  • Magnesium helps muscles to relax by reducing calcium influx (NMDA receptor). Calcium promotes muscle contraction and tightness, whereas magnesium counteracts this process. Magnesium also promotes sleep efficiency, onset and quality.

Exercise Performance

Epsom salt baths or float tanks can decrease muscle soreness, enhance relaxation, and displace the calcium ions that can accumulate in muscle tissue during workout. But concentrated magnesium chloride is even more effective than Epsom salts. Magnesium is essential for nerve and cardiac function, muscle contraction and relaxation, protein formation, and the synthesis of ATP-based energy. A magnesium deficiency can result in muscle cramping, excessive soreness, low muscular force production, disrupted recovery and sleep, immune system depression, and even potentially fatal heart arrhythmias during intense exercise.

Studies have shown magnesium to be effective for buffering lactic acid, enhancing peak oxygen uptake and total work output, reducing heart rate and carbon dioxide production during hard exercise, and improving cardiovascular efficiency. Supplementing can also elevate testosterone and muscle strength by up to 30%, as well as combat calcium buildup from muscle micro-tearing. Magnesium citrate powder is the best oral version but topical magnesium chloride may be better (to avoid liver enzyme breakdown and gastrointestinal issues).

Availability from Food

Some of the top magnesium rich foods (per 100 grams):

  • Pumpkin Seeds = 534mg
  • Sesame Seeds = 351mg
  • Brazil Nuts = 376mg
  • Dark Chocolate = 327mg
  • Almonds = 268mg
  • Black Beans = 160mg
  • Mackerel = 97mg
  • Dark Leafy Greens; Spinach, Swiss Chard or Kale = 79mg
  • White Beans = 53mg
  • Bananas = 27mg

Magnesium Deficiency and CVD, DNA Repair, and Blood Sugar Control

Magnesium deficiency has been implicated in pancreatic beta-cell function, reduced DNA repair capacity, insulin resistance, cardiovascular disease, type-2 diabetes, osteoporosis, hyperglycemia and hyperinsulinemia.

  • Magnesium supplementation improves fasting blood glucose in people with diabetes and glucose tolerance in those who are at a high risk of diabetes. Supplementing magnesium for 4 months or more significantly improves insulin resistance and fasting glucose in both diabetic and non-diabetic subjects. Magnesium improves insulin resistance in those with low blood levels of magnesium.
  • Hyperglycemia and hyperinsulinemia increase mitochondrial reactive oxygen species (mtROS) production that reduces the antioxidant capacity of glutathione. Magnesium deficiency also reduces glutathione, which is an important antioxidant that helps protect the lungs, especially during viral infections. Insulin resistance and hyperinsulinemia, as found in those who consume high sugar diets, promote renal excretion of magnesium and reduce intracellular magnesium levels.
  • Lower serum magnesium increases thrombotic risk, which makes it important surrounding COVID-19, as COVID-19 increases thrombotic risk. In vivo, magnesium has anti-thrombotic effects and reduces mortality in pulmonary thromboembolism suggesting that magnesium is a natural anticoagulant.
  • Metformin, diuretics, and proton pump inhibitors, which are commonly prescribed to type-2 diabetics, have been shown to cause low magnesium by reducing gastric acidity and magnesium solubility, thus decreasing absorption of magnesium in the gut. Diuretics also increase the elimination of magnesium out of the urine.

How Magnesium Affects the Pathogenesis of Cardiovascular Disease

  • Magnesium activates ATP, which is essential for energy production and cell function. The sodium-potassium pump is magnesium-ATP-driven, and it affects blood pressure as well as sodium accumulation in the cell. ATP is required for heart muscle contraction and oxidative phosphorylation in heart mitochondria.
  • Magnesium deficiency leads to intracellular sodium and calcium accumulation, which promotes arterial vasospasms, blood vessel constriction and hypercoagulability. Increased intracellular calcium can lead to hypertension and vasospasms. Coronary vasospasms are thought to be one of the causes of sudden cardiac death.
  • Magnesium deficiency reduces membrane potential polarization through intracellular sodium accumulation, which can cause arrhythmias.
  • Magnesium deficiency results in increased oxidative stress and low antioxidant defense, which leaves the heart vulnerable to myocardial injury.
  • Magnesium supports glutathione synthesis and glutathione deficiency promotes the accumulation of calcium.
  • Low magnesium status is associated with hypertension.
  • Magnesium deficiency increases inflammatory cytokines and interleukins, which promotes metabolic syndrome, cardiovascular disease and endothelial dysfunction.
  • Low magnesium promotes endothelial dysfunction, thrombosis and atherosclerosis.
  • Magnesium lowers clotting factors and inhibits ADP-induced platelet aggregation.
  • Magnesium deficiency causes myocardial lesions through calcium overload and catecholamine excess.
  • Magnesium depletion increases vasoconstriction and worsens cardiac contractility.
  • Vasoconstrictor hormones, such as angiotensin, serotonin and acetylcholine increase when extracellular magnesium is low.
  • Low serum magnesium is associated with atrial fibrillation in people without cardiovascular disease by modulating the inflow of calcium into the cell.
  • Magnesium reduces the inhibition of plasmin, which is an enzyme that degrades fibrin clots.
  • Magnesium deficiency results in an increase in triglycerides and blood lipids. Three months of magnesium therapy in patients with ischemic heart disease decreases apolipoprotein B concentrations by 15% and VLDL concentrations by 27%.
  • Hypomagnesemia is the result and cause of insulin resistance. Higher magnesium intake is associated with a reduced risk of diabetes.

Magnesium supplementation in patients of coronary heart disease has been found to decrease platelet-dependent thrombosis, improve flow-mediated vasodilation and increase VO2 max.

Magnesium-Dependent Enzymes, Functions and Consequences of a Deficit

Magnesium-Dependent Enzymes/Proteins: Function: Consequences of Deficit

  • ATP Synthase: Produce and activate ATP: Energy shortage, not enough energy to carry out vital bodily processes
  • Fatty Acid Oxidation: Burn triglycerides and lipids for fuel: Hyperlipidemia, hypercholesterolemia
  • Pyruvate Dehydrogenase: Convert pyruvate into acetyl-CoA and enable the burning of glucose for fuel: Hyperglycemia, insulin resistance
  • Glycolysis: Burn glucose for fuel: Hyperglycemia, glycation, insulin resistance
  • TCA Cycle: Direct acetyl-CoA into ATP production, NAD/NADH: Energy shortage, mitochondrial dysfunction
  • Insulin Production: Produce insulin to enable cells to pick up glucose from the blood: Insulin resistance, hyperglycemia
  • GLUT4 Translocation: Enable cells to pick up glucose without insulin: Hyperglycemia
  • Thyroid Hormones: Regulate metabolic rate and energy production: Hypothyroidism, chronic fatigue, brittle skin and hair, hypercholesterolemia
  • Glutathione Synthesis: Protect against oxidative stress: Increased oxidative stress and weaker immunity
  • Glutathione Peroxidase: Removes hydrogen peroxide: Increased oxidative stress and weaker immunity
  • Serotonin Production: Enable melatonin production, govern relaxation and docility: Chronic stress, anxiety and sleep problems
  • Melatonin Production: Promote sleep, relaxation and antioxidant repair: Oxidative stress, sleep problems, chronic stress
  • Dopamine Production: Regulate motivation, mood, attention and behavior: Depression, attention deficit disorders, procrastination
  • Steroid Hormone Production: Physical repair, protect against stress, regulate sex hormones: Frailty, aging and muscle loss, chronic stress
  • Testosterone Production: Affect bone density, muscle mass, fat burning, mood, and stress: Increased risk of obesity, cardiovascular disease, frailty, and chronic stress
  • DNA Repair: Repair damaged DNA: Cell senescence, increased DNA mutations
  • T-cell Regulation: Balance anti-inflammatory and proinflammatory immune responses: Autoimmunity, inflammation, infection

Frequency of Deficiency

Mild deficiency is very common.

Many factors can increase magnesium loss, such as disease states (diabetes, heart failure and insulin resistance), medications (insulin, proton pump inhibitors and diuretics) and aging itself. So, it is plausible you may need up to 500 mg/day or more of magnesium, especially if you’ve been deficient for a while. The negative side-effects of excess magnesium intake are often gastrointestinal upset and diarrhea.

Unfortunately, it is one of the hardest nutrients to get from just whole foods because of soil depletion and food processing. On top of that, stress, insulin resistance, exercising, sweating, metabolic syndrome and environmental factors can deplete magnesium further by activating the sympathetic nervous system.

Magnesium depletion from food is primarily caused by pesticides and fertilizers that deplete the soil of vitamins and minerals. They kill off beneficial bacteria, earthworms and bugs that create nutrients into the soil. A great example is vitamin B12, which is created by bacterial metabolism. Fertilizers also reduce the plant’s ability to absorb minerals. There are also processing methods like refining oils and grains that remove even more magnesium. The refinement of oils eliminates all their magnesium content.

Signs and Symptoms of Deficiency

  • Cardiac arrhythmia, palpitations, weakness and fatigue, ataxia (loss of full control over body movements), muscle twitches and spasms, low blood levels of calcium (hypocalcemia) and related disorders such as tetany and osteomalacia, low blood levels of potassium (hypokalemia), apparent vitamin D deficiency and resistance to standard treatment.
  • More moderate magnesium deficits may contribute to the following disorders: osteopenia and osteoporosis, soft tissue calcification (such as kidney stones), high blood pressure (hypertension), preeclampsia and eclampsia, migraines, and many aspects of cardiovascular disease.
  • Magnesium deficiency increases the susceptibility of tissues and lipoproteins to oxidation and reduces glutathione levels. Getting enough magnesium is critical for managing overall levels of inflammation and oxidative stress. Because of that, magnesium deficiency is one of the main drivers of cardiovascular disease, because of the increased oxidation of tissues, lipids and chronic systemic inflammation.
  • Magnesium deficiency can cause immune dysfunction, as found in those with ‘XMEN syndrome’. These individuals have a genetic defect in transporting magnesium into their immune cells, which is thought to contribute to their increased risk of upper respiratory tract infections, sinusitis, uncontrolled Epstein-Barr virus replication, lymphoma, autoimmune diseases and reduced immunity.
  • Magnesium deficiency reduces the cytotoxicity of natural killer cells and CD8 killer T cells. This can increase viral replication and may promote the proliferation of malignant growth.
  • Magnesium deficiency promotes oxidative stress and depletes intracellular glutathione. Therefore, intracellular magnesium plays a key role in immune functioning against pathogens and magnesium supplementation may reverse immune dysfunction.
  • Low magnesium is associated with increased risk of thrombosis. Magnesium has antithrombotic effects and low magnesium promotes platelet-dependent thrombosis. In vivo, magnesium reduces mortality in induced pulmonary thromboembolism. Magnesium deficiency also promotes endothelial dysfunction and oxidative damage to endothelial cells, while supplementing magnesium improves endothelial function.
  • Magnesium deficiency promotes symptoms of depression and anxiety. Supplementing magnesium may be helpful for anxiety symptoms. Magnesium deficiency induces anxiety and HPA axis dysfunction.
  • Magnesium is needed to activate vitamin D and move it around the body. Deficient magnesium can reduce the active form of vitamin D, also known as calcitriol, and impair the parathyroid hormonal response. This can lead to magnesium-dependent vitamin-D-resistant rickets. Thus, optimizing vitamin D levels requires an optimal magnesium status. Importantly, active vitamin D is needed to produce vitamin K dependent proteins and helps to activate them, which requires magnesium.
  • Women with osteoporosis have been found to have lower serum magnesium compared to those with osteopenia and healthy individuals. A short-term study on 20 postmenopausal women saw that 30 days of 290 mg/d of magnesium citrate suppressed bone turnover, indicating reduced bone loss.
  • Seizures
  • Pain or hyperalgesia
  • Photosensitivity
  • Tinnitus (ringing in the ears)
  • Hearing loss
  • Cataracts

Risk Factors for Deficiency

  • Poor diet and a lack of vegetables
  • Low stomach acid and low salt intake
  • High sugar/fat intake
  • High refined carbohydrate intake
  • Vitamin B6, selenium or sodium deficiency
  • High calcium, vitamin D or phosphorus intake
  • Albuminuria
  • Malabsorption of magnesium: proton pump inhibitors and other antacids, vomiting and diarrhea, ulcerative colitis, pancreatitis, and any gastrointestinal disorders that cause fat malabsorption.
  • Urinary magnesium excretion is proportional to urinary volume and is increased by anything that causes increased urination, such as diabetes or diuretics. A number of other pharmaceutical drugs including epidermal growth factor blockers and some antibiotics and antifungal medications increase urinary magnesium loss.
  • Chronic alcohol abuse causes both malabsorption and urinary wasting of magnesium.
  • Sweating and burn injury cause loss of magnesium through the skin.
  • Hungry bone syndrome involves the movement of magnesium into bone when bone mineral content starts increasing suddenly after the correction of a bone resorption disorder, for example by surgical removal of the parathyroid gland. Low levels of calcium (hypocalcemia) and phosphorus (hypophosphatemia) also develop during hungry bone syndrome.
  • Refeeding syndrome results from the aggressive correction of starvation or chronic malnutrition. Dietary magnesium drops to low levels and possibly zero, and loss of lean mass causes loss of magnesium stores. During refeeding, insulin brings magnesium into cells, causing hypomagnesemia to develop. This is aggravated by the large demand for cellular repair and rebuilding of magnesium stores. Low levels of hypophosphatemia and low levels of potassium (hypokalemia) also occur during refeeding syndrome.
  • Kidney failure and kidney diseases
  • Hemodialysis and peritoneal dialysis
  • Acetaminophen toxicity
  • Aluminum exposure
  • Metabolic syndrome
  • High aldosterone
  • Emotional and psychological stress
  • Enzymatic dysfunction by impairing magnesium distribution
  • Estrogen therapy by shifting magnesium to soft and hard tissues, lowering serum magnesium
  • Excessive or prolonged lactation
  • Excessive menstruation
  • Prolonged fasting
  • Foscarnet, gentamicin and tobramycin
  • Heart failure
  • Low selenium intake
  • Vitamin B6 deficiency

Testing for Magnesium Status

  • Serum magnesium declines in deficiency and rises in toxicity, but it is less sensitive than red blood cell and urine to changes in magnesium status.
  • Red blood cell magnesium may be low when serum is not, and while this could indicate an early deficiency, it could also indicate a deficiency in factors needed for bringing magnesium into cells, such insulin signaling, energy production, and sodium.
  • Urine magnesium will be low in nutritional deficiency, but high in deficiencies caused by urinary loss.

Normal serum magnesium is considered to be 0.7-1.0 mmol/L, but the optimal range has been proposed to be>0.80 mmol/L. About 10-30% of a given population experiences subclinical magnesium deficiency based on serum magnesium levels below 0.80 mmol/L.

An elevated retention of an intravenous or oral magnesium load is likely the best way to test for magnesium deficiency. It suggests that the body is trying to hold onto more magnesium because the tissues are depleted. However, the tests assume a normal kidney function for the IV test and normal gastrointestinal/kidney function for the oral test. If you do not have normal kidney function for the IV load or gastrointestinal/kidney function for the oral test, then the measurements can be inaccurate. Measuring hair, bone, lymphocyte, urinary or fecal magnesium excretion may be easier and cheaper, but they are less reliable methods. For the most reliable assessment, multiple methods need to be used. The easiest way to identify magnesium deficiency is from a low-normal blood level (< 0.82 mmol/L), especially if the 24-hour urinary magnesium is low (< 80 mg/day). This is not 100% accurate but it is highly suggestive of magnesium deficiency.

Healthy magnesium-sufficient subjects have an IV magnesium load retention of just 2-8%. On average elderly people retain around 28% of an IV magnesium load, suggesting that many older individuals have marginal magnesium deficiency.

Testing Caveats

Since RBCs are higher in magnesium than serum levels, hemolysis will falsely elevate serum magnesium. Hemolysis can occur inside your body if you have certain medical disorders, but it can also occur during blood collection due to poor positioning of the needle or other technical difficulties. If serum is implausibly high, especially when urine and RBCs are normal, the serum measurement may have been falsely elevated from hemolysis and should be repeated.

There is a collection of rare genetic disorders that cause poor magnesium absorption, urinary magnesium loss, or both. Many of the signs and symptoms of magnesium deficiency are results of hypocalcemia or disordered calcium handling, and many result from hypokalemia.

Correcting Magnesium Deficiency

If your diet is low in unrefined plant foods, your first approach should be to eat more magnesium-rich foods. If this is not possible, practical, or sufficient to reverse signs, symptoms, and blood work, you can use a supplement.

  • The most absorbable forms of magnesium are L-threonate, citrate, glycinate, taurate and aspartate. Avoid magnesium carbonate, sulfate, gluconate and oxide because they are poorly absorbed and mostly used as fillers. The RDA for magnesium in adults is approximately 350-420 mg per day, which around 50-75% of the population is not meeting. Stress, insulin resistance and coffee make you burn through magnesium, requiring higher intakes, potentially above 500 mg per day.

How to Restore Your Magnesium Levels: A 4 Step Plan

  1. Determine the factors that are causing you to become depleted in magnesium and fix them.
  2. Eat a high magnesium diet.
  3. Determine if you are still magnesium deficient (low-end of normal serum magnesium levels plus low 24-hour urine magnesium level).
  4. Consider magnesium supplementation.

Supplement Overview

  • Magnesium L-threonate is the best form of magnesium for increasing magnesium levels in the brain. It has been shown to improve cognition in those with cognitive impairment, ADHD symptoms and IQ scores in those with ADHD and memory in people with Alzheimer’s disease and in mice with dementia. It has very good bioavailability and a low risk of diarrhea. Some people prefer taking magnesium L-threonate in the morning for focus and alertness, whereas others prefer to take it at night for relaxation and sleep. Different people experience different effects when taking magnesium L-threonate as the benefits will depend on a person’s baseline magnesium level in the brain. LTP seems to be better if you lower the background activity (noise) of neurons. This can be improved by increasing the amount of magnesium in the ECF in a tissue culture. Mice with more magnesium had higher cognitive function. Magnesium, in the form of other supplements, needs to be in too high of a concentration for cognitive effects, which results in diarrhea. Magnesium threonate is more effective at crossing the BBB. Threonate is a metabolite of vitamin C, which may supercharge the transporter. People usually report better sleeping. About 5% don’t tolerate threonate well.
  • Magnesium Glycinate is one of the safest forms of magnesium with some of the least side-effects such as diarrhea. The added glycine, at least in children, may help with relaxation, pain and sleep by lowering body temperature. To be fair, the amount of glycine provided from magnesium glycinate supplements for adults is likely too low to have any real benefit. Doses of 125-300 mg of magnesium glycinate have been shown to rapidly resolve major depression in less than 7 days. Magnesium diglycinate seems to be a good alternative to magnesium oxide in patients with intestinal resection.
  • Magnesium Malate has been used for chronic fatigue syndrome and fibromyalgia. Malic acid boosts ATP levels, which is a magnesium-dependent molecule. In animal studies, magnesium malate is highly bioavailable and stays elevated in the serum for hours.
  • Magnesium Chloride is the best magnesium for digestion issues because extra chloride helps to produce stomach acid, which is why it is used to treat digestive disorders. Magnesium chloride has been shown to improve insulin sensitivity and metabolic control in type-2 diabetics. It has also been shown to improve symptoms of depression. Transdermal magnesium chloride may improve pain and quality of life in fibromyalgia.
  • Magnesium Citrate has fairly good bioavailability. It can withstand the acidic environment of the gut and can thus be absorbed over a longer period of time. Magnesium citrate has also been seen to improve arterial stiffness. Too much magnesium citrate can cause loose stools.
  • Magnesium Taurate is used for cardiovascular conditions as taurine helps the heart to work properly. Taurine can benefit congestive heart failure patients. Both magnesium and taurine have vascular-protective properties.
  • Magnesium Sulfate is mostly found in Epsom salt. It contains sulfur, which is a potent antioxidant needed for making glutathione. In pregnant women at imminent risk for delivery, magnesium sulfate supplementation has been shown to reduce the rate of cerebral palsy by 45%.
  • Magnesium Arginate helps with vasodilation and blood flow thanks to arginine.
  • Magnesium Lysine contains lysine, which has anti-viral effects. It can also support skin health.
  • Magnesium Ascorbate contains vitamin C, which is why it can cause loose stool in large doses. It is a good bioavailable source of vitamin C and magnesium.
  • Magnesium Gluconate is chelated with gluconic acid, which is the by-product of glucose fermentation. Together with potassium gluconate it has been shown to benefit myocardial function.
  • Magnesium Orotate is a magnesium salt of orotic acid. In patients with coronary heart disease, magnesium orotate improves heart function and exercise tolerance. It might be the best one for cardiovascular conditions. Even 25-50 mg/d of magnesium orotate has benefits in adolescents with syndromes of cardiac connective tissue dysplasia. Magnesium orotate has even been shown to improve survival in heart failure patients.
  • Magnesium Oxide has a fairly low bioavailability compared to other magnesium supplements. It is also one of the most commonly used forms of magnesium, but it can cause negative side-effects as it is not chelated and has poor water solubility. However, there is a case report of hypo-magnesaemia due to malabsorption wherein oral magnesium oxide supplementation elicited a response whereas magnesium glycerophosphate didn’t. This may be because magnesium oxide is high in elemental magnesium compared to most magnesium supplements and if it does not cause diarrhea then it can provide a fairly large amount of magnesium.

When taking magnesium supplements, it is better to take smaller doses more frequently rather than large doses at once because of improved total absorption.

Signs and Symptoms of Toxicity

  • Hypermagnesemia can lower blood pressure to dangerous levels. Both bradycardia (slow heart rate) and tachycardia (fast heart rate) may occur. Paradoxically, hypermagnesemia can cause hypocalcemia, one of the major features of clinical magnesium deficiency.
  • In those with poor kidney function, supplementation can cause hypermagnesemia. One example of this is administration of magnesium to prevent convulsions in preeclampsia and eclampsia.
  • For magnesium as a nutritional supplement, the upper limit of 350 mg/d should be used as a rough indicator of potential risk in the context of poor kidney function.

Correcting Toxicity

If hypermagnesemia is found, poor kidney function is a likely cause and must be addressed with appropriate medical treatment. Nutritionally, supplemental magnesium should be removed.

Vitamin K


Vitamin K2 and D work in synergy and co-dependently. Vitamin D regulates calcium levels in the blood and vitamin K directs it into the right place such as the bones and teeth. Vitamin D toxicity and vitamin K deficiency are associated with soft tissue calcification. Low levels of vitamin K are also linked to cardiovascular disease. Supplementing with vitamin K has been shown to reduce coronary artery calcification.

Vitamin K2 deficiency is associated with worse outcomes in COVID-19 patients. This may have to do with vitamin K2’s ability to reduce calcification of elastin, which forms cable networks around the alveoli in the lungs allowing for equal oxygen exchange, which is extremely important in severe SARS-CoV2 infection. Poor vitamin K2 status is associated with a higher level of pro-inflammatory cytokines. Vitamin K2 also acts as a co-factor in inflammatory responses mediated by T cells.

Frequency of Deficiency (K2 specific)

A large proportion are deficient. One of the leading causes is the use of antibiotics

Availability from Food (K2 specific)

Given you don’t need that much K1 from vegetables and K2 is much more difficult to come by, here is a list of foods richest in Vitamin K2, starting with the highest:

  • Natto is a Japanese fermented soybean dish with a foul smell. It’s the richest source of vitamin K2 with a whopping 1103.4 micrograms of Vitamin K2 MK-7 in 100 grams.
  • Goose Liver Paste – a pâte type of cream used a lot in French cooking and similar cultures. It’s an easy way of making organ meats more palatable and tastier. MK-4 content 369 mcg/100g.
  • Hard Cheeses – cheese should be fermented and unpasteurized for the greatest health benefits. A lot of the vitamins and minerals get lost during processing. MK-7 content 76.3 mcg/100g.
  • Soft Cheeses (Brie) – maybe one of the reasons the French didn’t get atherosclerosis had to do with the K2 rich cheeses and pâtes that protected them against plaque formation. MK-7 content 56.5 mcg/100g.
  • Egg Yolks – specifically the cholesterol-rich egg yolks which where the entire egg gets its nutritional value from. MK-4 content 32 mcg/100g.
  • Dark Poultry – meat that’s darker in color such as geese and duck. Much richer in vitamins than white chicken. MK-4 content 31 mcg/100g.
  • Butter – MK-4 content 15 mcg/100g.
  • Liver and Organ Meats – probably the most nutrient dense foods on the planet are liver, heart, and other organ meats. One of the best sources of dietary vitamin A and D, which are essential for vitamin K utilization. MK-4 content 14 mcg/100g.
  • Sauerkraut and Fermented Foods – another form of bioavailable vitamin K1 as well as K2. Paradoxically, the K2 and B vitamin content of fermented foods comes from the live bacteria in them, not the cabbage itself. So, sauerkraut is still actually an animal-based food. MK-7 content 5 mcg/100g.
  • Raw Milk and Kefir – more unprocessed food that’s rich in vitamins and some live bacteria. Pasteurized milk just kills all the juice, figuratively speaking. MK-4 content 2 mcg/100g.

Intestinal bacteria produce a small amount.

Signs and Symptoms of Deficiency

  • Defective blood clotting. Easy bruising or blood accumulating at the surface of the skin may be most apparent, but widespread internal bleeding and hemorrhage are possible.
  • May contribute to osteopenia, osteoporosis, short stature in children, soft tissue calcification (e.g., calcified atherosclerotic plaque; calcification of the vascular media that occurs in diabetes, kidney disease, and with age; kidney stones).
  • Even less well established but plausible signs and symptoms include insulin resistance, inadequate insulin and hyperglycemia, low testosterone and fertility in men, high androgens in women, poor exercise performance or tolerance, and cancers of the liver, lung, and prostate.

Risk Factors for Deficiency

  • Vitamin K1 occurs mainly in greens. Vitamin K2 refers to a collection of compounds known as menaquinones that are individually designated menaquinone-n, abbreviated MK-n, where n is a number between 4 and 13. MK-4 is found primarily in animal products, and MK-7 through MK-13 are found primarily in fermented foods.
  • A severe vitamin K deficiency of dietary origin is rare, and would require a diet devoid of green plants, animal foods, and fermented foods. However, far less vitamin K2 is present in the diet than K1, and K2 is more effective at supporting most functions of vitamin K besides clotting. Most diets contain inadequate K2 to support these functions and, in this sense, moderate vitamin K deficiency may be the norm.
  • Humans are able to convert other forms of vitamin K into MK-4, but cholesterol-lowering statins decrease this conversion and presumably make it more important to obtain MK-4 in the diet.
  • High-dose vitamin E supplementation increases the breakdown of vitamin K and may contribute to deficiency.
  • Vitamin D, chronic kidney disease, and anything else that causes soft tissue calcification raises the need for vitamin K. Any disorders leading to fat malabsorption may induce deficiency. The vitamin K status of newborns is often deficient because of inadequate intake by the mother during pregnancy.
  • Drugs known as 4-hydroxycoumarins, such as warfarin (Coumadin), inhibit vitamin K recycling.
  • Severe deficiencies of vitamin K can be produced by an overdose of anticoagulant medication, or accidental poisoning with rodenticides in the case of children and pets.

Special Note on Anticoagulant Medication

Vitamin K2 better supports the non-clotting functions of vitamin K than K1 does, and since it is present in the diet in much lower quantities than K1, low-dose K2 supplementation (e.g., 45 micrograms per day of MK-7) may be a safe way of supporting these other functions.

It doesn’t appear to interfere with warfarin like K1 does (Bruce Ames Triage Theory). Eat natto.

Excess and Toxicity

High-dose vitamin K stimulates the breakdown of vitamin E and has the potential to deplete glutathione, both of which are critical components of the antioxidant system. High doses also inhibit bone resorption, which may help preserve bone mass but may also interfere with blood sugar control, sex hormone balance, and energy utilization during exercise.

Testing for Vitamin K Status

Serum Vitamin K

  • Reflects recent intake. Also, low even after intake or supplementation if deficiency is caused by malabsorption.

Prothrombin time

  • A functional marker of blood clotting. It is used to calculate the international normalized ratio (INR), a value used to adjust the dose of anticoagulant medication. In the absence of 4-hydroxycoumarin treatment, it could reflect vitamin K deficiency, but could also reflect many other factors that interfere with blood clotting.

Des-γ-carboxy Prothrombin

  • DCP or protein induced by vitamin K absence or antagonism-II (PIVKA-II) rises when the vitamin K status of the liver is inadequate to support blood clotting. In the absence of 4-hydroxycoumarin treatment, high PIVKA-II strengthens the interpretation that prothrombin time is elevated because of vitamin K deficiency. PIVKA-II will rise during treatment with 4-hydroxycoumarins and this is expected. In the absence of 4-hydroxycoumarin treatment, elevated PIVKA-II suggests a relatively severe deficiency of vitamin K.

The vitamin K status of extrahepatic tissues

  • The ideal tests of vitamin K status for routine screening and disease prevention. Not yet available clinically.

Correcting Vitamin K Deficiency

The RDA for vitamin K is 90 mcg for women and 120 mcg for men, however, no distinction is made between K1 and K2. Vitamin K1 can easily be obtained from leafy green and cruciferous vegetables. Vitamin K1’s absorption from vegetables can be greatly increased by combining them with healthy fats like pastured butter or extra virgin olive oil. For vitamin K2, an optimal daily intake seems to sit at around 150-200 mcg/day, which can be obtained from animal foods like organ meats, fermented foods like sauerkraut and natto, egg yolks, dark poultry and fermented cheese.

If this is not possible or practical, supplemental vitamin K1 (phylloquinone) can be added at a dose of 100-500 micrograms per day. Most people who do not consume natto or goose liver, and do not consume a lot of egg yolks and cheese, would benefit from supplementing 200-1000 micrograms per day of K2, preferably as a mix of MK-4 and MK-7. Individuals with chronic kidney disease, and diseases involving soft tissue calcification, need at least 500 micrograms per day of supplemental K2 and probably more than one milligram per day.

Consuming trans fats blocks the actions of Vitamin K2, which would make everything even worse regards to arterial health and inflammation.


Thiamin is required for the recycling of vitamin K and should be considered if there is a reason to suggest thiamin deficiency. Glucose 6-phosphate dehydrogenase (G6PD) deficiency can also impair vitamin K recycling.

B Vitamins Involved in Energy Metabolism

B vitamins are essential water-soluble vitamins that have to be obtained on a regular basis. They are involved with both the innate and adaptive immune responses and help with nerve functioning, energy production and methylation. It has been found that B vitamins can reduce pro-inflammatory cytokines, improve respiratory functions, maintain endothelial integrity and prevent hypercoagulation. Deficiencies in B vitamins can cause hypersensitivities. Because of their adaptogenic properties, B vitamins can also help to manage stress.

Thiamin (Vitamin B1)

Vitamin B1 or thiamine sufficiency has been shown to reduce the risk of cardiovascular disease, kidney disease, mental disorders and neurodegeneration. High-dose thiamine therapy improves early-stage diabetic nephropathy. Deficiencies in thiamine cause inflammation and inhibit the antibody response.

Symptoms of Deficiency

  • Beriberi. Peripheral neuropathy (weakness, numbness, pain, or tingling in the hands and feet), impairment of reflexes, with or without cardiovascular signs that include enlarged heart, elevated heart rate (tachycardia) and cardiac output, and congestive heart failure.
  • Wernicke’s Encephalopathy. Weakness, paralysis, or disordered movement in the muscles around the muscles of the eye (ocular palsies, ophthalmoplegia, nystagmus) ataxia (loss of full control over body movements), confusion, often with peripheral neuropathy.
  • Korsakoff’s Psychosis. Amnesia, confabulation (fabricated, distorted, or misinterpreted memories), decreased spontaneity and initiative. This is often but not always a progression of Wernicke’s encephalopathy.
  • Very severe thiamin deficiency may cause seizures, paralysis, and death.
  • Poor glucose tolerance may occur in less severe thiamin deficits. Less well established but plausible signs and symptoms include improvements in energy or neurological health on a low-carbohydrate diet, low levels of neurotransmitters, and apparent deficiencies of folate and vitamin K that do not respond well to dietary or supplemental corrections.

Risk Factors for Deficiency

  • Dietary thiamin deficiency occurs when the diet does not contain several 100-gram servings per day of meat, legumes, whole grains, or enriched grains.
  • Persistent vomiting, alcoholism, gastrointestinal diseases that cause malabsorption, liver diseases that impair hepatic thiamin storage, and HIV/AIDS.
  • Diabetes increases the need for thiamin. Also, a potential cause for depleted vitamin K levels. 
  • Less common but well-established causes of thiamin deficiency include thiamin antagonists that occur in raw fish and shellfish, seasonally in ferns, and in the edible larvae of the African silkworm.
  • Less well established but plausible causes include sulfite accumulation, which may be driven by molybdenum deficiency and high intake of animal protein or sulfite used as a food additive; thiamin-destroying bacteria and fungi in the human gut; thiamin-destroying amoebas that may pollute water; and perhaps thiamin antagonists produced during infections or from exposure to toxic indoor molds.

Testing for Thiamin Status

  • Whole blood thiamin pyrophosphate: Low
  • Erythrocyte transketolase activity: Low
  • Alanine measured on a plasma amino acid profile: High
  • Lactate and possibly pyruvate are elevated in the blood.
  • Alpha-ketoglutarate, also known as 2-oxoglutarate, lactate, and possibly pyruvate is elevated on a urinary organic acid analysis

Testing Caveats

Transketolase activity is subject to genetic polymorphisms that may impact its activity, and alcoholism may cause epigenetic decreases in its activity; these caveats do not rule out the sensibility of supplementing thiamin when transketolase activity is low, since it may be responsive to extra thiamin, but they complicate a straightforward interpretation of thiamin deficiency.

If only one or two metabolites are high, the interpretation is less clear. Most thiamin-dependent enzymes also depend on lipoic acid and are subject to inhibition by oxidative stress and heavy metals, which may mimic the metabolite pattern of thiamin deficiency.

Correcting Thiamin Deficiency

  • If the diet is poor in thiamin, thiamin-rich foods should be introduced.
  • Many disease states cause thiamin deficiency that must be addressed independently with appropriate medical care. Thiamin supplementation is safe even at high doses and may help resolve a dietary deficiency more quickly or compensate for poor absorption or a high rate of urinary loss.
  • If deficiencies of other B vitamins have not been adequately screened for, you should include a B complex alongside thiamin.
  • Thiamin hydrochloride is likely adequate in most cases. Benfotiamine may be beneficial for the neuropathy of diabetes and alcoholism but its superiority over thiamin hydrochloride has not been clearly demonstrated. Thiamin pyrophosphate (thiamin diphosphate) is the active form of thiamin, and supplements of this form could plausibly overcome impairments in thiamin activation, which are known to occur in alcoholism.

Riboflavin (Vitamin B2)

Vitamin B2 or riboflavin is an essential nutrient for the integrity of mucous membranes, the skin, eyes and nervous system. Riboflavin deficiency is associated with depression. Supplemental riboflavin has been shown to help lower neurological disability in multiple sclerosis. UV radiation, together with riboflavin, damages the DNA/RNA of viruses, bacteria and pathogens, reducing their replication. This combination of riboflavin and UV light in human plasma and whole blood has been shown to reduce SARS-CoV2 viral titers. Riboflavin can also inhibit HMGB1, which is a likely contributor to cytokine storms. The most abundant sources of riboflavin are organ meats, eggs, fish and some vegetables (although plants only contain the precursors).

Signs and Symptoms of Deficiency

  • Red, crusty skin on the outer edges of the lips (cheilosis) or cracks at the corners of the mouth that may fissure (angular stomatitis); inflammation of the tongue (glossitis); redness, bleeding, and swelling inside the mouth (hyperemia and edema of the oral cavity); seborrheic dermatitis (red, scaly, itchy, painful, greasy skin affecting the outer edges of the nostrils, outer ears, eyelids, and genitals); pain or hypersensitivity to touch or temperature in the hands and feet (peripheral neuropathy); conjunctivitis; normocytic, normochromic anemia (low red blood cells but normal hemoglobin and MCV).
  • Suboptimal riboflavin status may cause iron deficiency anemia that responds poorly to iron, elevated homocysteine, cataracts, high blood pressure, oxidative stress, migraines, fatigue, exercise intolerance, preeclampsia, and difficulty using fat for fuel.
  • Riboflavin deficiency causes pathological activation of macrophages, expressing excessive HMGB1 and TNF-alpha. Foods high in riboflavin include liver, eggs, dairy, salmon, mushrooms, meat, spinach and almonds. Riboflavin combined with UV light has effectively inactivated the Middle East respiratory syndrome coronavirus (MERS-CoV) in human plasma.

Risk Factors for Deficiency

  • Diets low in animal products, especially organ meats, and enriched flours, especially if they are also high in sugar or fat and do not include riboflavin supplements or riboflavin-containing multivitamins. Vegetarians and vegans have lower intakes and a greater risk of deficiency.
  • Anorexics and alcoholics have poor intake, and alcohol impairs the absorption and utilization of riboflavin.
  • Low stomach acid, impaired protein digestion, and intestinal inflammation impair riboflavin absorption.
  • Light therapy, tanning beds, and extensive sun exposure deplete riboflavin.
  • Exposure of food to light depletes riboflavin from food.
  • Low thyroid and adrenal hormones impair the retention and use of riboflavin in the body.
  • Diabetes, trauma, stress, and dialysis increase the excretion of riboflavin. Diabetes, cancer, and heart disease can precipitate or exacerbate a deficiency.
  • The ideal riboflavin intake is likely to be higher than the RDA, at 2-5 mg/d. High-fat diets, exercise, and weight loss each increase the riboflavin requirement by 20-60% and have an additive effect when combined.

Testing for Riboflavin Status

  • Whole blood total riboflavin, which is mainly intracellular riboflavin in its active form, is low in deficiency.
  • Whole blood total riboflavin and a CBC at the same time: The author has a calculator that estimates the erythrocyte riboflavin concentration and correlates it with the gold standard marker of riboflavin status, the erythrocyte glutathione reductase activity coefficient (EGRAC). Values above 0.7 are good, while 0.5 indicates early deficiency and 0.4 indicates severe deficiency.

Testing Caveats

  • Rare genetic disorders in fatty acid oxidation or riboflavin metabolism may induce signs of riboflavin deficiency but require highly specialized diagnosis and medical treatment.
  • Some of the signs and symptoms of riboflavin deficiency, especially the skin lesions, are due to deficient metabolic activation of the form of vitamin B6 found in plant foods, and are seen in vitamin B6 deficiency as well.

Correcting Riboflavin Deficiency

  • Organ meats
  • Free riboflavin is preferable over riboflavin 5’-phosphate. 5 mg would be an ideal dose but most supplements have 100-400 mg and these high doses are harmless. Doses of 200-400 mg have been used to reduce migraine frequency and duration. Riboflavin should always be taken with food and should be spread out across meals as evenly as possible to maximize absorption and retention.

Niacin (Vitamin B3)

Vitamin B3 or niacin (nicotinic acid) is a precursor of nicotinamide adenine dinucleotide (NAD), which is a co-enzyme for many physiological processes, including immunity and redox status. NAD is used during the early stages of an infection to suppress inflammation and reduce pro-inflammatory cytokines. Niacin can improve dyslipidemia and cardiovascular disease outcomes, especially if patients are not on statins already. The highest vitamin B3 foods are brewer’s yeast, red meat, fish, and coffee. The RDA for niacin is 16 mg/day for men and 14 mg/day for women. Doses of over 3 grams a day can be toxic, causing insulin resistance.

Nicotinamide Riboside (NR):

  • A form of vitamin B3 and a precursor to NAD. When taken orally, NR is highly bioavailable and aids in mitochondrial energy production. It exists in high levels in cow’s milk (unpasteurized and A2 is ideal).
  • Shown to restore NAD+ levels, provide more NAD+ activity than from diet alone, can slow cellular aging, and improve many age-related metabolic problems, including diabetes and neurodegenerative problems.
  • NR appears under the name ChromaDex. Tru Niagen, Elysium Basis, and Thorne ResveraCel. One in the morning and one in the afternoon, allowing NR to match the body’s circadian rhythm pulsing of NR.

Signs and Symptoms of Niacin Deficiency

  • Dermatitis, diarrhea, dementia.
  • The dermatitis of niacin deficiency occurs only on sun-exposed tissue. It begins with reddening and progresses to scaling and dark color. It most commonly impacts the backs of the hands and the wrists, forearms, face, and neck.
  • Diarrhea is associated with generalized malabsorption that might cause deficiencies of many other nutrients and celiac-like atrophy of the intestinal villi.
  • The so-called “dementia” can be simple depression in its earliest stages, but progresses to schizophrenia-like psychosis, with auditory and visual hallucinations, and paranoid, suicidal, or aggressive behavior. Insomnia, headaches, and dizziness may be present early on. Later, tremors or muscular rigidity, loss of tendon reflexes, numbness and weakness may occur.
  • Suboptimal niacin status may contribute to fatigue, exercise intolerance, or poor exercise performance; accelerated aging, especially of the skin in response to the sun, cancer and inflammation of the esophagus, vulnerability to leukemia, increased genetic mutations, and skin cancer.

Risk Factors for Niacin Deficiency

  • Niacin is found in the diet and also synthesized from tryptophan using iron, riboflavin, and vitamin B6.
  • Niacin in grains and seeds is poorly bioavailable unless they are soaked in an alkaline solution or fermented for 8 or more hours.
  • Diets based on unprocessed whole grains, or based on sugar or fat, or that are very low in non-collagen protein, are likely to lead to poor niacin status.
  • Hartnup’s disease is a rare genetic disorder of tryptophan malabsorption.
  • Crohn’s disease and megaduodenum also cause malabsorption.
  • Serotonin-producing tumors known as carcinoid tumors can divert tryptophan to serotonin and away from niacin. Drugs that impair niacin synthesis include isoniazid (anti-tuberculosis), Imuran and 6-mercaptopurine (immunosuppressives), 5-fluorouracil (anti-cancer), levadop/carbidopa (Parkinson’s) and alcohol.
  • Alcoholism is also associated with poor intake.
  • HIV/AIDS is associated with poor niacin status as a result of cellular damage that depletes niacin.
  • Anything that lowers ATP levels (e.g., hypothyroidism, metformin, berberine) theoretically may hurt niacin status.
  • Anything that directs tryptophan into building muscle tissue (e.g., working out or taking leucine or its metabolite, HMB) or serotonin synthesis (e.g., using carbohydrate to boost mood and improve sleep) may hurt niacin status.
  • Any form of cellular damage, ranging from normal sunlight exposure to injury, disease states, and aging, depletes niacin for repair processes.

Niacin Excess and Toxicity

  • Niacin, used to lower blood lipids, causes a flushing reaction involving redness and itching, possibly progressing to a brown color of the skin. It also may raise homocysteine, worsen glucose tolerance, and occasionally contribute to diabetes. Very high doses cause liver toxicity, resulting in nausea, vomiting, headache, elevated liver enzymes, hepatitis, jaundice, and in extreme cases encephalopathy and liver failure. Occasionally it results in blurred vision or lazy eye that reverses upon withdrawal.
  • Excess niacin is detoxified through methylation, and the liver results from severe drainage of the methyl pool. At non-toxic doses, niacin still drains methyl groups, which might lower creatine synthesis or interfere with the regulation of neurotransmitters.

Risk Factors for Niacin Toxicity

  • Both nicotinic acid and nicotinamide are toxic to the liver, but nicotinic acid is more toxic. Among preparation of nicotinic acid, slow-release is the most hepatotoxic form, while immediate release and extended release are less toxic.
  • Elevated liver enzymes and jaundice have occurred at intakes as low as 750 mg/d nicotinic acid, but almost all severe cases 3-9 g/d. Nausea, vomiting, and headache have been reported from nicotinamide at doses as l ow as 3000 mg/d but severe signs very rare and only reported over 10 g/d.
  • Toxicity has not been characterized for newer supplements such as nicotinamide mononucleotide (NMN) or nicotinamide riboside (NR), but they probably are similarly but slightly less toxic than nicotinamide. Individuals are most likely to experience toxic effects of niacin if they have a history of liver disease, diabetes, active peptic ulcers, gout, cardiac arrhythmia, IBD, migraines, alcoholism.
  • To minimize toxicity, pair nicotinic acid with glycine (100 mg of glycine or 300 mg of collagen for every 200 mg of nicotinic acid) and pair all forms of niacin with trimethylglycine (TMG, 100 mg TMG for every 100 mg nicotinic acid or nicotinamide; 100 mg TMG for every 200 mg NMN or NR).
  • High-dose nicotinic acid appears to have a 1 in 43 chance of causing diabetes and the best protection against this is likely to avoid snacking on carbohydrates in the 2–6-hour period after each dose.

Testing for Niacin Deficiency

In deficiency, NADP(H) stays constant while NAD(H) falls. The “niacin number” can be calculated by dividing the concentration of NAD(H) by NADP(H) and multiplying by 100. Healthy adults not taking niacin supplements have a niacin number close to 175. Niacin supplementation can raise this over 600, while 5 weeks of moderate, experimental niacin deficiency drops it to 60.

As the niacin number declines under 175, deficiency should be considered progressively more likely, and this can be used as a target for correcting deficiency.

Correcting Niacin Deficiency

  • Niacin-rich foods, protein, vitamin B6, or iron, depending on what the cause of deficiency is.
  • Nicotinamide riboside (NR) supplements are the best choice for improving tissue levels, but high doses will tax the methylation system so care taken to optimize methylation status should be used in this approach, and he recommends supplementing 100 mg trimethylglycine (TMG) for every 200 mg NR.

Pantothenic Acid (B5)

Vitamin B5 or pantothenic acid is mostly involved in energy metabolism and lipid homeostasis. Nasal sprays with pantothenic acid analogs have been shown to reduce nasal congestion, allergies and inflammation. Liver and organ meats are packed with all the B vitamins. A 3.5 oz (100g) serving of beef liver provides around 163% of the RDA for B2 and 1,122% of the RDA for B12.

Signs and Symptoms of Pantothenate Deficiency

  • Numbness, especially in the toes, burning in the feet, irritability, restlessness, disturbed sleep, and gastrointestinal distress.
  • Considered extremely unlikely.
  • Additional signs that should be considered plausible in more moderate deficits could include a vulnerability to hyperammonemia (which would make someone feel sick and fatigued on a high-protein diet), general fatigue and weakness, improved health and well-being on a low-fat diet, and the pain associated with rheumatoid arthritis.

Risk Factors for Deficiency

  • Pantothenate is also produced by gut microbes, which may protect against deficiency on low-pantothenate diets.
  • Yeast, liver, eggs, and mushrooms stand out as excellent sources.
  • Diets high in refined grains and devoid of pantothenate-rich foods will be low in pantothenate and this may contribute to moderate deficits when pantothenate supplements or pantothenate-containing multivitamins are not used. The contribution of gut pantothenate production to nutritional status is not well characterized, but gut dysbiosis might be seen as a plausible contributor to deficiency.

Testing for Pantothenate Status

Plasma levels of pantothenate decline in nutritional status.

Correcting Pantothenate Deficiency

If other B vitamin deficiencies have not been ruled out, supplementation is best as a component of a B complex. Nevertheless, there is no known toxicity and supplements of one gram per day of calcium pantothenate have shown promise in rheumatoid arthritis. Calcium pantothenate is about half pantothenate and one gram of it provides approximately 50 times the RDA.

Vitamin B6

Vitamin B6, the inactive form is pyridoxine (found in plants) and the active form is pyridoxal 5- phosphate (found in animals) has many roles in sleep, mood and inflammation. People with depression and anxiety have low levels of B6. Low B6 status is associated with inflammatory conditions like inflammatory bowel disease (IBD), diabetes and cardiovascular disease. In COVID-19, pyridoxal 5-phosphate supplementation might alleviate pro-inflammatory cytokines and prevent hypercoagulability. During infections and inflammation pyridoxal 5-phosphate is depleted and low levels of this essential vitamin can result in immune dysfunction, increased cytokine production, renin release and platelet aggregation, reduced type 1 interferons, reduced lymphocyte movement and disrupted endothelial integrity. Animal studies show that supplementing with active B6 shortens the duration and severity of viral pneumonia. This may be because of how vitamin B6, B2 and B9 upregulate the anti-inflammatory IL-10. The active form of vitamin B6 is also needed for the functioning of diamine oxidase (DAO), which is an enzyme that breaks down histamine.

Signs and Symptoms of B6 Deficiency

  • Convulsive seizures; cognitive symptoms such as irritability, depression, and confusion; vulnerability to infection, lesions similar to those of riboflavin deficiency (cheilosis, angular stomatitis, glossitis, oral hyperemia and edema), and sideroblastic anemia (normal hemoglobin concentrations that accumulate around the edges of red blood cells, seen under a microscope).
  • More moderate deficits of B6 elevate homocysteine, contribute to cardiovascular disease, and contribute to chronic low-level inflammation.
  • Less well established but plausible signs and symptoms of moderate B6 deficits include cognitive decline, depression, anxiety, insomnia, hypoglycemia, oxalate kidney stones, and the morning sickness of pregnancy.
  • Vitamin B6 is needed for the endogenous synthesis of niacin, and may contribute to niacin deficiency in the presence of other predisposing factors. It is also needed for the metabolic activation of essential fatty acids, and may contribute to essential fatty acid deficiency in the presence of other predisposing factors.

Risk Factors for B6 Deficiency

  • There are rare genetic defects that cause dramatic increases in the need for vitamin B6 to prevent either seizures or sideroblastic anemia.
  • Diets low in animal foods, low in riboflavin, low in raw foods, or dominated by overcooked foods may contribute to deficiency.
  • Gut flora and the enzyme pyridoxine 5’-phosphate oxidase (PNPO) are important for deriving B6 from plant foods, and variations in these factors may contribute to deficiency.
  • Inflammation raises the need for B6 and also increases its degradation.
  • Oral contraceptives, high estrogen levels, NSAIDs, and drugs used to treat tuberculosis and Parkinson’s increase the need for B6.
  • Sulfite accumulation, which may be driven by molybdenum deficiency and a high intake of animal protein or sulfite used as a food additive, contributes to B6 deficiency.

Vitamin B6 Toxicity

Long-term use of doses above 500 milligrams per day of pyridoxine may cause ataxia (loss of full control over body movements), and sensory neuropathy, with symptoms such as numbness to touch or temperature change, tingling, burning, or pain in the extremities.

Testing for B6 Status

  • Plasma B6: Low
  • Erythrocyte transaminase activity: Low
  • The combination of elevated xanthurenate, k ynurenate, and quinolinate on a urinary organic acids profile is robust evidence of B6 deficiency. In early deficits, xanthurenate is most likely to be elevated and quinolinate is least likely.

Testing Caveats

Oral contraceptives, and presumably high estrogen, may cause the signs of B6 deficiency to appear on an organic acid profile, but it is not clear whether higher doses of B6 will correct them. It is therefore unclear whether this should be regarded as B6 deficiency. Nevertheless, anecdotally, 100 mg/d of pyridoxal 5’-phosphate seems to mitigate insomnia that sometimes accompanies high estrogen levels.

Correcting B6 Deficiency

  • Increasing the proportion of animal foods in the diet, using more gentle cooking techniques, and including more raw foods may all help improve B6 status. Among plant foods, bananas are an excellent source of B6 because it is easy to eat them raw and because their B6 is absorbed more effectively than the B6 in most other plant foods.
  • Pyridoxal 5’-phosphate is the ideal supplement because it does not require riboflavin-dependent metabolic activation in the liver. 5 milligrams per day should be adequate to correct a deficiency that results from poor dietary intake. However, many factors disrupt B6 metabolism, and doses between 30-100 milligrams per day may be needed to reverse signs of deficiency in some individuals. Because of the risk of toxicity, doses this high should be used with care and only when there is clear justification. 

Correcting B6 Toxicity

Neurological problems induced by toxic doses of B6 generally resolve when B6 is withdrawn. Nevertheless, signs and symptoms of toxicity should always be reported to a physician as they could require medical care or be mistaken for other conditions that require medical care.

Biotin (Vitamin B7)

Signs and Symptoms of Deficiency

  • Scaly, red dermatitis around the nose, mouth, and perineum (between the anus and genitals), hair loss (alopecia), conjunctivitis, ataxia (loss of full control over body movements), depression, lethargy, paresthesia (tingling, numbness, or a feeling of something crawling on the skin).
  • Biotin deficiency during pregnancy may contribute to birth defects.

Risk Factors for Biotin Deficiency

  • Egg yolks and liver, which are far more abundant in biotin than any other foods; egg whites, which contain a heat-sensitive compound known as avidin that impairs biotin absorption; and pregnancy, which raises the need for biotin.
  • The consumption of egg white, especially raw and when consumed without equal numbers of egg yolks and without biotin supplements or biotin-containing multivitamins. Even though cooking degrades avidin, substantial proportions remain in cooked egg white. Whole eggs do not pose a risk of deficiency, and this is probably true even if raw. On the other hand, egg whites should not be consumed without the yolks unless biotin supplements are also used. The same is true for egg white protein powders.
  • Pregnancy raises the need for biotin, and about one-third of mothers become temporarily biotin deficient during pregnancy.

Testing Biotin Status

  • Urinary 3-hydroxyisovalerate (beta-hydroxyisovalerate): The most sensitive and robust marker of marginal biotin deficiency.
  • Blood levels of biotin decline in deficiency, but they are less sensitive than urinary 3-hydroxyisovalerate.

Correcting Biotin Deficiency

Thoroughly cooking egg whites or consuming fewer of them. Liver and egg yolks are the best food sources of biotin. Liver can be consumed up to two 3.5-ounce servings per week, and 3-4 egg yolks per day can be used for most people, but may need to be moderated for individuals with elevated blood cholesterol.

Vitamins Involved in Methylation

Methylation is the process of transferring a methyl group from one molecule to another, a crucial biological process involved in removing toxins, growing and repairing cells, and metabolic functioning. Methylation deficits are linked to a number of health conditions, including diabetes and cancer, and are caused by a variety of factors, including stress, nutrient deficiencies, and genetics.

A methyl group is a carbon atom attached to three hydrogen atoms. It is an abundant organic compound derived from methane. Methylation occurs when a methyl group is taken from one compound or molecule and is transferred to another. For example, a methyl group can be added to your DNA from a methyl donor like methionine (high amounts in meat tissue). The process is largely responsible for switching genes on and off and silencing viruses. When your body experiences methylation, less desirable genes, such as those that code for cancers and autoimmune diseases are switched off while helpful genes are switched on. Methylation is required for cell division, neurotransmitter synthesis and metabolism, detoxification, cellular energy metabolism, the formation of protective myelin sheaths, and early CNS development.

Signs and Symptoms of Deficient Methylation

Undermethylation occurs when your body is unable to adequately transfer methyl groups or because you are not consuming enough methyl donating foods. This can cause you to be dopamine-seeking, hard-charging, high achiever, as it can keep serotonin levels low. It is associated with being an over-achiever, having OCD tendencies, a low threshold for pain, and ritualistic behaviors. A few ways to deal with this are to eat more meat and less folate (it acts as a serotonin reuptake inhibitor). 

  • Fatty liver disease, neural tube birth defects, elevated homocysteine and associated cardiovascular risk, fatigue, poor exercise capacity, histamine intolerance, difficulty ignoring negative thoughts and thought patterns, depression, anxiety, obsessive compulsive disorder, histamine intolerance, inability to adequately eliminate arsenic, inability to properly utilize selenium or excrete excess selenium.
  • Severe deficiencies in methylation could contribute to deficiencies of zinc, copper, and perhaps other positively charged minerals. As with excessive methylation, possibly cancer.

Signs and Symptoms of Excessive Methylation

Over-methylation is associated with creativity and sensitivity. If you are prone, you may exhibit high levels of empathy for others but also experience sleep issues, food and chemical sensitivities, hyperactivity, panic attacks, and a tendency to gain unwanted weight. Highly correlated with schizophrenia. Eat less meat (vegetarianism and veganism may be beneficial). You need to consume adequate protein but don’t go overboard with muscle meat.

Among the best supported: distractibility, difficulty focusing, impulsivity, and substance abuse.

More speculative: difficulty breaking free from psychological conditioning, difficulty falling asleep or poor-quality sleep, and faster aging skin. As with deficient methylation, possibly cancer.

Signs and Symptoms Specific to B12 and Folate Deficiencies

Macrocytic, megaloblastic anemia. This is independent of their role in methylation. This may be asymptomatic, or may make you feel tired, weak, short of breath on exertion, and cause heart palpitations and paleness.

If deficient remethylation of homocysteine is found, the cause may be deficiencies of folate, B12, or betaine/choline.

The following points should be considered:

  • Assessing folate and B12 deficiencies.
  • If betaine and choline are deficient in the diet, they will both be low.
  • If the betaine/choline ratio is high, this is likely from deficient folate or B12, or from poor MTHFR activity.
  • If the betaine/choline ratio is low, this is likely from low choline dehydrogenase activity, and is a strong argument for using trimethylglycine (TMG, betaine) instead of choline to support methylation.
  • If betaine and choline are both high, this could be from low BHMT activity and suggests that neither choline nor TMG may be able to adequately support remethylation, increasing reliance on folate and B12.
  • If both MTHFR and BHMT activity are low, however, it may be harder than expected to use folate, B12, TMG, or choline to support remethylation. If methionine levels are also low and undermethylation symptoms are the primary concern, this is an argument for increasing dietary methionine, which can be achieved through increased total protein, increased animal protein (which is twice as rich in methionine as plant protein), or supplementation with L-methionine. However, if lowering homocysteine is the primary concern, it may be necessary to decrease dietary methionine. If high homocysteine, low methionine, and undermethylation symptoms are all important concerns, the best strategy would be to use vitamin B6 to try to increase the amount of methionine that can be tolerated without a rise in homocysteine, and to adjust the dietary methionine to what best achieves the balance between fixing undermethylation and keeping homocysteine low.

If excess methylation of glycine is found, it could reflect high levels of SAMe and inadequate glycine, or it could reflect low levels of methylfolate.

The following points should be considered:

  • If methionine and S-adenosylmethionine are elevated, the best strategy is to improve the balance of methionine to glycine within the diet. A good default is 5 grams of glycine for every 75 grams of non-collagen protein. 5 grams of glycine can be obtained from glycine powder, or from 15 grams of gelatin or collagen.
  • If excess methylation of glycine accompanies deficient remethylation of homocysteine as described earlier, then the likely cause of the glycine methylation is low levels of methylfolate, due either to folate deficiency or to low MTHFR activity. This could be confirmed using markers of folate status. In this case, the primary strategy should be to restore methylfolate levels. If serum folate is low, this indicates that methylfolate levels are low. If it is also true that RBC folate is low or FIGlu is high, then more dietary folate is needed. If these others markers are normal, however, the problem is likely to be mainly with MTHFR activity. 

If a high rate of transsulfuration is found, this could reflect high levels of SAMe or oxidative stress.

The following points should be considered:

  • If methionine and S-adenosylmethionine are elevated and glutathione is normal or high, then this may not be a problem (unless it causes sulfur intolerance).
  • If glutathione is low, then the high rate of transsulfuration is likely due to oxidative stress. If this is accompanied by low methionine, S-adenosylmethionine, and homocysteine, then oxidative stress is likely severe enough to be compromising methylation and contributing to undermethylation symptoms. 
  • If a high rate of transsulfuration accompanies symptoms of sulfur intolerance, such as allergy-like symptoms or symptoms of glutamate intolerance, regardless of the other methylation markers, see Molybdenum and Sulfur Catabolism.

If a low rate of methionine activation is found, this could be caused by magnesium deficiency, any deficiencies or disorders of energy metabolism, or impairments in the MAT enzyme. If the underlying cause is genetic or cannot be easily resolved, this is a strong argument for supplementing with SAMe at doses ranging from one tablet or up to 1600 milligrams per day.

Testing Caveats

Numerous reactions in the methylation pathway require magnesium and ATP. Magnesium deficiency or metabolic disruptions that affect ATP production such as hypothyroidism, diabetes, insulin resistance could contribute to methylation imbalances, and this becomes more likely if no nutrient deficiencies can be supported. Extra niacin is excreted in methylated form, and high-dose niacin supplements (in any form: niacin, niacinamide, or nicotinamide) may be the cause of an apparent deficiency in methylation.

Correcting Imbalances in Methylation-Related Nutrients

  • There are no satisfactory tests of choline status, but most people do not consume enough choline. Lack of evidence for deficiencies of other nutrients should also point attention to choline when the data suggest a deficiency of methyl donors.
  • If the cause is a medical issue, such as a malabsorption disorder, it will need appropriate medical treatment.
  • If the cause is poor diet, the dietary targets, or supplements within the ranges listed in “Causes of Deficiencies and Imbalances” should be used, with doses adjusted over time to bring blood markers in range.
  • If creatine is used to reduce the methylation demand, it should be noted that, anecdotally, some people develop over-methylation symptoms such as insomnia. This appears to have a temporary effect, and it may take up to 6 weeks for the full effects of creatine to settle in.

Folate (Vitamin B9)

Vitamin B9 or folic acid or folate is essential for methylation and DNA and protein synthesis. Regarding the immune system, the role of methylation is to maintain the function of immune cells like T-cells and activate the immune response. Improper methylation is linked with autoimmune conditions. Folate, also known as 5-methyltetrahydrofolate (5-MTHF), increases the methyl donor called SAMe (S-adenosylmethionine). Deficient or broken methylation raises homocysteine, which is associated with cardiovascular disease. Other nutrients that support methylation are the amino acid methionine, vitamins B12 and B6, glycine, betaine or trimethylglycine (TMG), creatine, choline, N-acetylcysteine (NAC) and sulfur-rich foods like cruciferous vegetables.

  • Mutations in the MTHFR gene can cause errors in homocysteine regulation and methylation. MTHFR is a gene that helps to form methyl groups with folate and recycle homocysteine into methionine. We all have 2 MTHFR genes from both of our parents. If one of the MTHFR genes is mutated, you’re “heterozygous.” If two are mutated, you’re “homozygous.” A single mutation isn’t a medical concern and not everyone with two mutations develop hyperhomocysteinemia. Those with MTHFR mutations, especially MTHFR 677 TT genotype, may benefit from around 1.6 mg of riboflavin (vitamin B2) per day.

Folate Deficiency

  • Meeting the folate requirement requires two to three 100-gram servings of liver, legumes, or greens per day. Liver should not be used more than twice a week in most cases and legumes and greens can be used to meet the remainder of the requirement. Folate is stable in liver when frozen and in legumes when dried, but not in frozen vegetables.
  • Reliance on frozen vegetables as a source of folate without realizing that most of the natural folate in these foods has degraded before consumption may also be a major contributor.
  • Preventing deficiency may take 3-5 servings of plant foods rather than 2-3 if they are cooked and the cooking water is discarded.
  • There is also a rare genetic defect in the primary intestinal folate transporter known as hereditary folate malabsorption.

Folate Excess

  • First, it can mask B12 deficiency by preventing the associated anemia without doing anything to prevent the degeneration of the nervous system.
  • Second, although the mechanism is poorly understood, folate supplementation has been associated with the onset of nervous system degeneration in B12-deficient patients and could be the factor that provoked the degeneration.
  • Third, supplementation with as low as 1 milligram per day of folate has provoked hypersensitivity reactions in some individuals.

Cobalamin (Vitamin B12)

Vitamin B12 or cobalamin is essential for cellular growth, nerve functioning and myelin synthesis. Low levels of B12 raise homocysteine, inflammation and oxidative stress. Deficiencies in B12 can cause gastrointestinal, respiratory and central nervous system issues. Vitamin B12 is nearly impossible to get from plant foods (a noted exception is Nori) and vegan diets are commonly deficient in it. A deficiency in vitamin B12 is also known for causing nerve damage and neuropathies. Methylcobalamin supplementation has been theorized to be a potential strategy for reducing organ damage and symptoms in COVID-19. In Singapore, COVID-19 patients given 500 μg of B12, 1000 IUs of vitamin D and magnesium had fewer severe symptoms and they needed less intensive care.

Frequency of Deficiency

Vegans but increasingly common for other diets.

Availability from Food

Bovine liver, sardines, salmon, eggs, soil.

Signs and Symptoms Specific to B12 Deficiency

  • Vitamin B12 deficiency causes neurological degeneration that is largely independent of its role in methylation and does not involve folate. Mental changes include memory loss, changes of personality or mood, and in the most severe cases delirium and psychosis.
  • Changes generally begin in the feet and work their way upwards with lost sense of position and vibration and paresthesia (tingling, numbness, or a feeling of something crawling on the skin), possibly progressing to ataxia (loss of full control over the muscles), spasticity (constant contraction) and gait abnormalities (difficulty walking correctly).
  • Other signs and symptoms include optic neuritis, visual disturbances, and autonomic dysfunction, which may manifest as dizziness or faintness upon standing in the case of orthostatic hypotension, or exercise intolerance if the heart rate does not appropriately adjust to exercise.

Vitamin B12 Deficiency

  • The major cause of vitamin B12 deficiency is poor absorption.
  • Pernicious anemia occurs in 0.1% of the general population and close to 2% of the elderly. It consists of an autoimmune attack on components of the digestive system specific to B12 absorption. Chronic gastritis, on the other hand, is usually caused by H. pylori, may affect half or more of the population, begins in childhood, and advances with age. In the elderly, gastritis may be severe enough to cause vitamin B12 deficiency in 10-15% of the population.
  • Signs of B12 deficiency are found in over 70% of vegetarians and 90% of vegans, due to low intake without supplementation. B12 is found almost exclusively in animal products, and the bioavailability in eggs is low, making milk the only food source for most lacto-ovo-vegetarians.
  • Some research indicates that there is B12 in a small selection of vegan foods: shiitake, chanterelle, and black trumpet mushroom; and chlorella and green or purple nori (laver). Nevertheless, most mushrooms and edible bacteria or algae do not contain B12 and the levels found in chlorella have been shown to be extremely inconsistent.
  • Some animal products, such as liver and clams, have far more than the RDA for B12, but you can only absorb one day’s worth of B12 in each meal. If you eat one large serving of clams, your data may indicate that you’ve eaten enough for at least the week and maybe even the month, but you’ve only absorbed enough for the day. Thus, a diet that does not contain, on average, at least seven B12-rich meals per week and meet the RDA for an average intake, is at risk of suboptimal B12 status.

Choline and Betaine

Choline – RDA is 425-550 mg-s. Choline is a precursor to acetylcholine – a neurotransmitter responsible for cognitive functioning and attention. It’s also vital for cell membrane, methyl metabolism, and cholesterol transportation. Foods rich in choline are eggs, meat, and fish. If you eat these foods, then you don’t have to supplement with choline. On a plant-based diet, it may be a good idea to take choline and inositol.

Choline and Betaine Deficiency

  • Within the methylation system, choline is converted to betaine, and betaine acts as the direct methyl donor.
  • Choline is much more abundant in liver and egg yolks than in any other foods. Meeting the requirement for choline requires 2-3 egg yolks per day if obtained exclusively from egg yolks. One 100-gram serving of liver provides the equivalent of two egg yolks, and one 100-gram serving of most cruciferous vegetables or nuts provides the equivalent of half an egg yolk.
  • Choline fulfills other functions outside of methylation that betaine cannot fulfill.
  • One egg yolk’s worth of choline can be obtained in betaine using any of the following: 100 grams of spinach (measured raw), 100 grams of raw beets or 50 grams of cooked or canned beets, or 25 grams of wheat germ.

Choline Excess

Excess choline may be converted in the colon to trimethylamine oxide (TMAO), which may contribute to cardiovascular disease. This can be minimized by 1) spreading choline out across meals rather than taking it all at once, and 2) getting choline mainly from food, and if using supplemental choline to use phosphatidylcholine.

Serine, Glycine, Methionine

Amino Acid Deficiencies

  • Serine and glycine can be synthesized by the body, while methionine cannot. Nevertheless, endogenous synthesis of any amino acids only occurs adequately when total protein requirements are met.
  • As long as the protein comes from animal products or from plant products that are well diversified (does not come exclusively from legumes), methionine and serine needs will be met.
  • Methionine, present in all proteins and especially rich in animal protein, increases the need for glycine. Therefore, this extra glycine requirement is best fulfilled by the inclusion of collagen in the diet, which is much higher in glycine than other proteins and quite low in methionine. 5 grams of glycine could be obtained from ⅔ of an ounce of bone meal, or with one to two servings of hydrolyzed collagen. 
  • In short, eat nose to tail and try to source wild or free-range/pasture raised meat.

Amino Acid Excesses

  • Excess protein generates ammonia, which is toxic if it accumulates but is usually safely converted to urea. Rare genetic disorders or urea-degrading microbes in the gut may impair the disposal of ammonia but for most people the ability to dispose of ammonia is not overwhelmed until protein intakes reach 8 grams per kilogram body weight, which cannot be obtained from food and would be extremely difficult to achieve even with protein supplements.
  • Methionine increases the need for glycine, and high intakes of animal protein or supplementation with S-adenosylmethionine (SAMe) may deplete glycine to suboptimal levels.
  • Collagen supplementation has the potential to increase oxalate accumulation and could pose a risk of kidney stones. Individuals at risk of kidney stones should be careful with collagen and preferably monitor oxalate levels. Oxalate excretion in response to collagen is more likely to occur if you are deficient in B6.
  • The oxalate is produced mainly from the hydroxyproline in collagen, not the glycine, so if you cannot resolve increased oxalate excretion in response to collagen supplementation, you should try supplemental glycine as an alternative.



Molybdenum cofactors (Moco) are complexed to a pterin, forming molybdopterin, which is a cofactor for many important enzymes in the body including sulfite oxidase, xanthine oxidase, dimethyl sulfoxide (DMSO) reductase, aldehyde oxidase, carbon monoxide dehydrogenase (CODH), nitrate reductase and mitochondrial amidoxime reducing component (mARC). They metabolize sulfur-containing amino acids and heterocyclic compounds, including purines and pyrimidines. Xanthine oxidase, aldehyde oxidase, and mARC also help to metabolize drugs, alcohol and toxins. The only molybdenum enzyme that does not contain molybdopterin is nitrogenases that fix nitrogen (protein) in all life forms. The cofactor for nitrogenase is called FeMoco (iron-molybdenum cofactor) that converts atmospheric nitrogen into ammonia.

Genetic mutations of a molybdenum cofactor deficiency cause an absence of molybdopterin, which leads to the accumulation of sulfite and neurological damage due to a lack of sulfite oxidase. Some people with a molybdenum deficiency may also have trouble dealing with sulfites in food because of a poorly functioning sulfite oxidase. Molybdenum cofactor deficiency is not the same as molybdenum deficiency.

Molybdenum cofactors cannot be obtained as a nutrient from dietary sources and need to be synthesized by the body. One of the enzymes that catalyzes this process is radical SAM (an enzyme that uses iron-sulfur clusters to cleave Sadenosyl-L-methionine (SAM) to generate a radical). The other option for molybdopterin, besides molybdenum-sulfur pairing, is to complex with tungsten(wolfram)-using enzymes, which requires selenium for its action.

Molybdenum-Dependent Enzymes, Functions and Consequences of Deficient Molybdenum Intake

Molybdenum-Dependent Enzymes/Proteins: Function: Consequences of Deficit

  • Molybdopterin: Molybdenum cofactor used in molybdenum and tungsten containing enzymes: Sulfite accumulation and toxin buildup
  • Sulfite Oxidase: Oxidize sulfite and sulfate via cytochrome C, transfer electrons to the electron transport chain and allow the generation of ATP: Sulfite and sulfate accumulation, poor energy production
  • Xanthine Oxidase: Break down xanthine and purines into uric acid, generate reactive oxygen species and superoxide: Insufficient ROS signaling, in excess promotes gout
  • Dimethyl Sulfoxide (DMSO) Reductase: Catalyze the reduction of dimethyl sulfoxide (DMSO) to dimethyl sulfide (DMS): Excess sulfoxide accumulation
  • Aldehyde Oxidase: Oxidize aldehydes into carboxylic acid, eliminate alcohol toxicity: Alcohol toxicity, liver damage
  • Carbon Monoxide Dehydrogenase (CODH): Partake in the carbon cycle as a source of energy and fixate CO2: Poor energy metabolism and growth
  • Nicotinate Dehydrogenase: Partake in nicotinate and nicotinamide (NAM) metabolism. NAM and nicotoniate are forms of vitamin B3, like niacin and NAD+: Poor energy production, lack of enzymatic reactions.
  • Nitrate Reductase: Reduce nitrate to nitrite, which is critical for producing protein in plants: Poor nutritional quality and low protein crops
  • Nitrogenase: Fixate nitrogen, facilitate growth, biosynthesis of nucleotides and amino acids: Poor growth, physical deterioration
  • Mitochondrial Amidoxime Reducing Component (mARC): Reduce amidoximes to amidines, help with cholesterol metabolism: Poor lipid profile, liver damage


The RDA for molybdenum is 45 mcg/d for adults 19 years of age and older and 43 mcg/d for teenagers 14-18 years of age. During pregnancy and lactation, it is recommended to get 50 mcg/d of molybdenum and for children 9-13 years old 34 mcg/d. Infants from birth to 6 months of age should get 2 mcg/day and from 6 to 12 months of age 3 mcg/d. Children aged 1-3 years of age should get 17 mcg/day and children 4-8 years of age should get 22 mcg/day. The tolerable upper intake level (UL) for adults 19 years of age and older is 2,000 mcg/d. The UL for children 1-3 years old is 300 mcg/d, 4-8 years old is 600 mcg/d, 9-13 years old is 1,100 mcg/d and 14-18 years old is 1,700 mcg/d. Consuming a reasonably high molybdenum diet does not pose a threat to health because it gets rapidly excreted through urine. The minimum requirement for molybdenum for adults is deemed to be 22-25 mcg/d and estimated average requirement is 34 mcg/d.

The human body contains roughly 0.07 mg of molybdenum per kilogram of bodyweight. Molybdenum is stored in the liver, kidneys, adrenal glands and bones in the form of molybdopterin. It is also found in tooth enamel, helping to prevent tooth decay. The ability to synthesize molybdopterin, which is an iron-sulfur and selenium-dependent process, seems to be necessary for retaining molybdenum in tissues.

The kidneys are the main organs regulating molybdenum levels in the body and promote its excretion through urine. Urinary excretion of molybdenum directly reflects dietary molybdenum intake. During low molybdenum intake, about 60% of consumed molybdenum gets excreted through urine and 90% is excreted when molybdenum intake is high. The average U.S. urinary molybdenum concentration is 69 mcg/L. In molybdenum cofactor deficiency and in that single case of molybdenum deficiency, urinary sulfate and serum uric acid were low, but urinary xanthine, hypoxanthine and plasma methionine increased. However, these indicators have not been associated with molybdenum intake in normal healthy people.

Molybdenum Food Sources

Foods high in molybdenum include legumes, beans, whole grains, nuts and liver. They are also the top sources of molybdenum in the U.S. diet. For teenagers and children, the top sources are milk and cheese. Molybdenum deficiency is quite rare because it can be found in a lot of different foods.

Molybdenum is absorbed at a rate of 40-100% from dietary sources in adults. Soy contains relatively high amounts of molybdenum but is a less bioavailable source (56.7% absorption rate), whereas foods like kale are as bioavailable as other foods (86.1%). Dietary tungsten reduces the amount of molybdenum in tissues and sodium tungsten is a competitive inhibitor of molybdenum.

Molybdenum and Sulfur Catabolism

  • The transsulfuration pathway is closely connected to the methylation pathway and represents the intersection between the methylation pathway and the antioxidant system by providing the amino acid cysteine for the synthesis of glutathione.
  • The pathway is activated by high methionine inputs, serving to get rid of the excess (e.g., after a high-protein meal), and by oxidative stress, serving to increase the synthesis of glutathione when it is most needed. If the sole need is to get rid of excess methionine, the cysteine is catabolized to taurine and sulfate. If the sole need is to increase glutathione synthesis, it is directed into that pathway.
  • Serine and vitamin B6 are needed for its production from homocysteine. The conversion always generates alpha-ketobutyrate as a byproduct, which is the major source of methylmalonic acid, which is a marker of vitamin B12 status. The methylmalonic acid requires biotin to be produced, and vitamin B12 to be eliminated. The synthesis of glutathione from cysteine requires glycine, magnesium, and ATP. On its way to sulfate, cysteine first generates sulfite. Sulfite is toxic and its accumulation can cause deficiencies of thiamin and vitamin B6. The conversion of sulfite to sulfate requires molybdenum.

Signs and Symptoms of Molybdenum Deficiency

  • Seizures, mental retardation, and dislocated lenses within the eye, all occurring in the newborn, and is unlikely to be informative for what moderate deficits in molybdenum might look like.
  • More moderate sulfite accumulation may impair thiamin and B6 status and cause the signs and symptoms discussed in those sections.
  • Presumably, molybdenum deficits could contribute to sulfite sensitivity as well, which results in allergy-like reactions (dermatitis, hives, flushing, low blood pressure, abdominal pain, diarrhea, anaphylaxis, asthma) to the sulfites used as food additives.

Risk Factors for Molybdenum Deficiency

  • Molybdenum is very rich in legumes. The need for molybdenum increases with high intakes of protein, especially of animal proteins, as a result of their high methionine content. Thus, a diet rich in animal proteins and low in legumes is likely to lead to significantly lower molybdenum status than the opposite pattern.
  • The need for molybdenum appears to also increase during pregnancy, where the production of hydrogen sulfide, essential to the growth of the placenta and embryo, provides an additional source of sulfite. The morning sickness of pregnancy may result from sulfite-induced B6 deficiency that occurs on the background of low molybdenum intakes.
  • Low soil concentrations of molybdenum, ranging from Iran to Northern China cause a dietary molybdenum deficiency, which is associated with an increased rate of esophageal cancer. There is no evidence that excess molybdenum causes cancer in humans or animals.

Molybdenum Excess

  • The upper limit is set at 30 micrograms per day per kilogram bodyweight, which in a 70-kilogram individual is 2100 micrograms per day. There is no reason to use doses higher than this, and supplements often contain as little as 150 micrograms and rarely contain more than one milligram.
  • Exposure to prolonged high intakes of molybdenum can raise uric acid levels because xanthine oxidase breaks down purines into uric acid.
  • Exposure to molybdenum in molybdenum-copper plants can raise serum bilirubin and decrease blood albumin/globulin ratios, which is interpreted to indicate liver dysfunction.

Testing for Molybdenum Status

  • Serum or Whole Blood Molybdenum: HDRI tests report an exact value within a normal range.
  • Uric Acid: In addition to converting sulfite to sulfate, molybdenum is also necessary to make uric acid. Uric acid is low in molybdenum deficiency.
  • Urinary Sulfite and Sulfate: High urinary sulfite and low urinary sulfate indicate a molybdenum deficiency.
  • Serum Sulfate and the Cysteine-to-Sulfate Ratio: Low serum sulfate and a high cysteine-to-sulfate ratio may indicate molybdenum deficiency.

Correcting a Molybdenum Deficiency

Increasing legumes and decreasing animal protein may help correct a molybdenum deficit, but animal protein is nutritionally important and some individuals do not tolerate legumes well (soak and sprout). If dietary measures are unfeasible or insufficient, 500-1000 micrograms per day of molybdenum supplementation should be more than adequate, and this can likely be dropped to 100-200 micrograms per day as a maintenance dose once markers and signs and symptoms resolve. If consuming legumes, be sure to sprout and/or soak effectively.

  • The RDA for molybdenum in adults 19 years of age and older is 45-50 mcg/d with a tolerable upper limit of 2,000 mcg/d. Infants should get 2-3 mcg/d, which can be easily obtained from 0.5-0.8 liters of breast milk.
  • The highest sources of molybdenum are beans, legumes and liver. Getting enough copper from these foods also prevents copper deficiency that may happen due to excess molybdenum intake. Other minerals needed for molybdenum to work are iron, sulfur and selenium.



Elemental sulfur is non-toxic and soluble sulfate salts come packaged in things like Epsom salts, which are typically used in baths for helping with muscle recovery and muscle soreness. Burning sulfur (power plants) creates sulfur dioxide (SO2), which can be harmful to the eyes and lungs in large concentrations. When SO2 reacts with atmospheric water and oxygen, it produces sulfuric acid (H2SO4) and sulfurous acid (H2SO3), which make up acid rain. Sulfuric acid is also a powerful dehydrant that can be used to dehydrate sugar or organic tissue. Sulfuric acid can also be produced in the body by eating sulfur-rich amino acids found in animal protein.

  • Sulfur (S) is the chemical element with an atomic number of 16 and a neutral charge.
  • Sulfate (SO42-) and sulfite (SO32-) are oxyanions (an oxygen-containing negative ion) of sulfur with a negative charge. Sulfate is a salt found in some foods as well as cleaning products, but sulfite is used for food preservation and processing.
  • Sulfur oxide is the smelly substance found in volcanoes and thermal springs, whereas organic sulfur is used by the body to carry out a wide range of processes, especially antioxidant defense.

Historically, sulfur has been used to treat skin conditions, dandruff, improve wound healing and protect against acute radiation. Today, organic sulfur has been seen to improve rosacea and psoriasis. Sulfur springs and water have been known to have therapeutic effects for centuries. Studies show that spa therapy with sulfur water improves osteoarthritis and inhaling aerosolized sulfur containing water improves respiratory conditions. Sulfur-containing foods like broccoli may protect against inflammatory conditions like vascular complications from diabetes and heart disease.

Sulfur exists in all cells and extracellular compartments as part of the amino acids – cysteine and methionine. Covalent bonds of sulfhydryl groups between molecules form disulfide bridges that are required for the structure of proteins that govern the function of enzymes, insulin and other proteins.

Sulfur is also a component of chondroitin in bones and cartilage, thiamine (vitamin B1), biotin (vitamin B7), pantothenic acid (vitamin B5) and S-adenosyl methionine (SAM-e), methionine, cysteine, homocysteine, cystathione (an intermediate in the formation of cysteine), coenzyme A, glutathione, chondroitin sulfate, glucosamine sulfate, fibrinogen, heparin, methallotheionein and inorganic sulfate.

With the exception of thiamine and biotin, all of these substances are synthesized utilizing methionine or cysteine. The vast majority of the sulfur demands of the body are met with methionine and cysteine consumption. Glutathione, taurine, Nacetylcysteine, MSM (methylsulfonylmethane) and inorganic sulfate can spare the dietary need for methionine and cysteine.

Early Sulfur Use and Glutathione

Next to hydrogen, CO2 (carbon dioxide) and nitrogen, sulfur was probably one of the first nutrients organisms used as a building block of life and for energy production. These organisms can be divided into sulfur reducing or sulfur oxidizing. Sulfur-reducing anaerobic bacteria are believed to trace back to 3.5 billion years ago, making them one of the oldest living microorganisms on Earth. They obtain energy through a process called sulfate respiration, during which the oxidation of organic compounds or molecular hydrogen gets coupled to the reduction of sulfate.

  • Sulfur-oxidizing microorganisms oxidize hydrogen sulfide (H2S) into elemental sulfur or sulfate to generate reducing power. Sulfur acts as a signaling nutrient for hydrogen sulfide, which is a colorless gas that has many therapeutic effects when generated in the body. Many invertebrates need sulfur to grow and to avoid some of the potential harmful effects of hydrogen sulfide. At low concentrations, hydrogen sulfide stimulates the electron transport chain to increase energy production.

One of the most important roles of sulfur is serving as a precursor in glutathione synthesis and promoting detoxification. The sulfur amino acids (SAA) methionine and cysteine promote protein synthesis as well as glutathione synthesis. Eating a sulfur-rich diet in humans increases glutathione levels and reduces oxidative stress.

  • Glutathione regulates prostaglandin biosynthesis and thus has anti-inflammatory effects. It also has detoxifying properties that support liver health. Sulfur baths and sulfur mineral water consumption have been shown to increase antioxidant defense status, lower oxidative stress and improve lipids. Most of the sulfur in our bodies is stored as glutathione in the liver and because inflammation depletes glutathione it will also deplete sulfur.
  • Cysteine is the rate-limiting factor in glutathione synthesis and a cysteine deficiency will result in low glutathione levels. Thus, suboptimal cysteine levels can lead to low glutathione and increased oxidative stress. The increased oxidative stress seen in aging is even thought to be the result of cysteine deficiency. Eating more sulfur in the diet can help save the losses of glutathione.

Defects in Fe-S cluster biogenesis cause numerous mitochondrial issues, anemia and problems with fatty acid and/or glucose metabolism. Mammalian target of rapamycin (mTOR), the body’s master growth pathway responsible for growth, regulates iron metabolism through iron-sulfur cluster assembly. Prolonged elevation of iron-sulfur cluster assembly enzyme (ISCU) protein levels enhanced by mTOR can inhibit iron-responsive element and iron-regulatory protein binding activities that are involved in iron uptake. Thus, sulfur is important for keeping iron levels in check and preventing iron overload. Protein and amino acids that contain sulfur (which also tend to contain the most leucine) are the most mTOR-stimulating food sources that promote growth.

  • Under low sulfur amino acid intake, protein synthesis is maintained at the expense of sulfate and glutathione synthesis. Low serum levels of cysteine and glutathione are associated with muscle wasting diseases and mitochondrial damage.

Sulfur and Alzheimer’s

Alzheimer’s disease patients have low levels of sulfur and selenium. These reductions are implicated in the lower glutathione levels seen in these patients and the increased oxidative stress and neuroinflammation, which promote neurodegeneration. Sulfur is also a potent aluminum antagonist that can reduce aluminum accumulation. Aluminum is a neurotoxin and considered a causative factor in Alzheimer’s disease. High amounts of aluminum in the brain tissue are associated with familial Alzheimer’s disease and other neurological disorders.

Sulfur and Connective Tissue

Connective tissue, the skin, ligaments and tendons require sulfur for proper cross-linking and extracellular matrix proteins like glycosaminoglycans (chondroitin sulfate, dermatan sulfate, keratan sulfate and heparan sulfate). Extracellular matrix proteins are highly sulfonated. They strengthen the bone structure and retain moisturization. Sulfur is needed to make bile acid for fat digestion and is a constituent of bone, teeth and collagen. The hair and nails are made of a sulfur-rich protein called keratin. Sulfur is also a component of insulin and hence is needed for blood glucose regulation.

Vitamin D Sulfate

Vitamin D3 sulfate is a water-soluble form of vitamin D3, unlike un-sulfated vitamin D3, and as a result of that, it can travel the bloodstream more freely without needing to be carried in LDL lipoproteins. Vitamin D3 sulfate has less than 5% of the ability of vitamin D to mobilize calcium from bones and about 1% of the ability to stimulate calcium transport, raise serum phosphorus or cause bone calcification. The form of vitamin D in human milk and raw cow’s milk is vitamin D3 sulfate but pasteurization destroys it.

  • The origins of vitamin D3 sulfate are not clear, but a sulphated precursor may be needed for its synthesis. Cholesterol sulfate is considered a potential precursor as it’s widely distributed throughout the body. Instead of being just a metabolic end-product, cholesterol sulfate is found in all cell membranes and epidermal barriers, but mostly in skin tissue. Sunlight hitting the skin also appears to be a source of vitamin D3 sulfate. Regardless, adequate sulfur status is required to make vitamin D3 sulfate.
  • Cholesterol sulfate helps to create a barrier against harmful bacteria and fungi in the skin as well as support platelet adhesion. It regulates the gene for a protein called profilaggrin, which is a precursor to filaggrin that protects the skin. By interacting with phospholipids, cholesterol sulfate can stabilize biological membranes. Perhaps it is plausible that for optimal protection against the UV radiation from the sun you need adequate cholesterol sulfate and sulfur from diet.
  • During sperm maturation, cholesterol sulfate stabilizes sperm cell membranes. In cultured skin fibroblasts, cholesterol sulfate inhibits sterol synthesis at the level of 3-hydroxy-3-methylglutaryl-CoA reductase, the rate-limiting step in cholesterol synthesis. This affects epidermal lipid metabolism. Atherosclerosis may develop because of cholesterol sulfate deficiency. Cholesterol sulfate is also a substrate for the synthesis of sulfonated steroid hormones, such as pregnenolone sulfate and DHEA sulfate. Vitamin D induces sulfotransferase enzyme SULT2B1b activity, which governs cholesterol sulfurylation.

Sunlight exposure triggering eNOS sulfate production increases sulfate availability for heparan sulfate proteoglycan (HSPG) synthesis, which buffers against glycation damage and coagulation. Hyperinsulinemia reduces cholesterol sulfurylation into cholesterol sulfate by lowering calcitriol bioavailability, thus contributing to thrombosis seen in COVID-19. Platelets will respond to cholesterol sulfate but no other forms of cholesterol or steroid sulfates under the same conditions. Like vitamin D3 sulfate, cholesterol sulfate is also water-soluble and doesn’t have to be packed in LDL particles to be delivered to tissues. It has been shown that cholesterol sulfate inhibits enzymes involved in blood clotting, such as thrombin and plasmin, which may prevent coagulation in the arteries. Additionally, sulfate promotes oxygen delivery to oxidative phosphorylation dependent cells. Thus, a lack of sulfur in the diet may worsen COVID-19 outcomes by increasing protein glycation and coagulation and reducing tissue oxygenation.

Fatty Acid Transportation

Sulfur is needed for transporting free fatty acids from chylomicrons/VLDL/LDL into the capillary endothelium. Lipoprotein lipase (LPL), which is an enzyme that governs the uptake of free fatty acids from lipoproteins into cells, works with heparan sulfate proteoglycans (HSPGs). Abnormal or dysfunctional LPL expression is associated with various conditions like atherosclerosis, hypertriglyceridemia, obesity, diabetes, heart disease, stroke, Alzheimer’s and chronic lymphocytic leukemia. A low sulfur intake could lead to a decrease of free fatty acids into tissues that express LPL, such as the heart, skeletal muscle and brown adipose tissue, leading to an increase in free fatty acids in the blood and reduced supply to these tissues for energy.

Advanced Glycation End Product (AGE) Reduction

Glucose can enter the cells through specific cholesterol-rich sites in the cell wall called lipid rafts that also control GLUT-4’s actions. GLUT4 is a receptor that sits on our cellular membranes to bring glucose into muscle cells. Cholesterol sulfate in the cell membrane reduces the risk of oxidation. Overconsuming refined glucose and fructose can promote the formation of advanced glycation end products (AGEs) that are associated with cardiovascular disease, diabetes and aging.

  • Hyperglycemia increases AGEs and the production of reactive oxygen species. The conversion of glucose into fat storage also glycates the fat cells and damages them. As a result of that, cholesterol can’t be transported to the membrane and it accumulates in the cell, leading to macrophage accumulation that contributes to atherosclerosis and thrombosis.
  • Sulfur can be in oxidation states ranging from -2 to +6. If glucose gets reduced by sulfur +6, it will prevent glycating the muscle cells and protect against AGEs.
  • Sulfate ions attached to oxidized cholesterol have been shown to be protective against atherosclerosis. Glutathione, the sulfur antioxidant, also eliminates AGEs and AGEs are more dangerous when glutathione levels are low.

Sulfur-Dependent Enzymes, Functions and Consequences of Deficient Sulfur Intake

Sulfur-Dependent Enzymes/Proteins: Function: Consequences of Deficit

  • Glutathione: Protects against oxidative stress and inflammation: Increased oxidative stress and reduced immunity
  • Nrf2/ARE: Promotes glutathione synthesis and other antioxidants: Increased oxidative stress and reduced immunity
  • Heparan Sulfate Proteoglycans (HSPGs): Anticoagulation and protection against glycation damage: Increased risk of thrombosis and atherosclerosis
  • Lipoprotein Lipase: Promotes the uptake of cholesterol and free fatty acids into tissues: Hyperlipidemia, atherosclerosis, and decreased skeletal, muscle/heart function
  • S-adenosylmethionine (SAMe): Methylation donor, wide enzymatic substrate: High homocysteine, inflammation and depression
  • Vitamin D3 Sulfate: Hormone production, immune system function, Anticoagulation: Increased risk of autoimmunity, weaker immune system, blood clots
  • Cholesterol Sulfate: Stabilizes cell membranes, protects the skin, promotes vitamin D3 sulfate synthesis, platelet adherence, anticoagulation: Increased risk of coagulation, thrombosis and platelet aggregation. Cell membranes are more vulnerable to oxidation.
  • Hydrogen Sulfide: Cell signaling, antioxidant defense, glutathione: Increased oxidative stress, cardiovascular complications, inflammation
  • Methylation: Moves methyl groups around, prevents high homocysteine: High homocysteine, neuronal complications and inflammation
  • Endothelial NO Synthase (eNOS): Promotes nitric oxide and endothelial function: Atherosclerosis and hypertension
  • Trans-sulfuration Pathway: Mediates glutathione pathways and hydrogen sulfide production: Increased oxidative stress and reduced glutathione

Effects of Sulfur Containing Compounds

  • Glucosamine Sulfate – Glucosamine sulfate is an amino-monosaccharide (a combination of glutamine and glucose). It is required for cartilage glycosaminoglycan (GAG) synthesis. Glucosamine has many trials showing efficacy for osteoarthritis. It has been found that glucosamine supplementation was associated with a 39% reduction in overall mortality among 16,686 U.S. subjects. Among 466,039 participants without cardiovascular disease in the UK, habitual glucosamine use was linked to a lower risk of cardiovascular disease events.
  • Chondroitin Sulfate – Chondroitin sulfate is found in human cartilage, bone, skin, cornea and the arterial wall. It is believed to increase water retention and elasticity in cartilage. Sulfur in the diet provides sulfates for glycosaminoglycan synthesis and glutathione in cartilage.
  • Glutathione – Glutathione is the main antioxidant that regulates free radicals, immunity and redox homeostasis. A low protein diet with inadequate sulfur amino acids can induce a glutathione deficiency. Cysteine and Nacetylcysteine are glutathione precursors.
  • Cysteine – Oral cysteine supplementation increases glutathione levels. It can also chelate certain trace minerals and alleviate potential heavy metal toxicity.
  • N – acetylcysteine (NAC) – Oral NAC increases intracellular cysteine and glutathione levels. Administration of the glutathione precursor Nacetylcysteine increases glutathione synthesis and improves hydrogen sulfide clearance. NAC can increase the release of histamine from mast cells and peripheral mononuclear blood cells and lower nitric oxide levels. In certain susceptible individuals this may increase the contraction of the pulmonary vascular bed leading to what’s commonly referred to as “wheezing in the lungs”. Thus, NAC is not for everyone, and supplementation may need to be cycled on and off or necessitate the administration of nitric oxide boosters (beetroot powder, dietary nitrates, citrulline/arginine) and/or antihistamines.
  • Taurine – Taurine regulates detoxification, bile acid conjugation, membrane stabilization and cellular calcium modulation. It is important for muscle contractions, energy production, hydrogen sulfide synthesis and more.
  • Alpha – Lipoic Acid (ALA) – ALA regulates antioxidant activity and oxidative stress. It has also been shown to increase CoQ10 and glutathione levels. ALA also activates Nrf2.
  • Dimethyl Sulfoxide (DMSO) – DMSO can scavenge free radicals and pass-through membranes easily. It can also protect against the breakdown of joint tissue in inflammatory arthritic conditions.
  • Methyl-sulfonyl-methane (MSM) – In humans, MSM is used to treat arthritic conditions, muscle pains, allergies and for immunomodulation, although its effectiveness is not considered clinically significant. MSM inhibits inflammation through suppressing NLRP3 inflammasome activation. It has been found to be safe and effective for hemorrhoids. In mice, MSM can be therapeutic against obesity-induced metabolic disorders, such as hyperglycemia, hyperinsulinemia and insulin resistance.
  • S-adenosylmethionine (SAMe) – SAMe is a metabolite of methionine and an important methyl donor that can lower homocysteine. The body can make all the SAMe it needs from methionine, but defective methylation or inadequate consumption of SAMe cofactors (methionine, choline, folate) would reduce SAMe production. SAMe also increases the production of hydrogen sulfide.
  • Methionine – Methionine is one of the main protein-creating amino acids needed for methylation and protein synthesis. As a methyl donor, it helps to prevent fatty liver. AIDS patients have low methionine, and it can be effective for treating Parkinson’s disease and acute pancreatitis.

Organosulfur Compounds

Eating half an onion or more per day may lower the incidence of stomach cancer. In Northeast China, consumption of fresh cabbage and onions is inversely associated with brain cancer risk. More than one serving of garlic per week is inversely associated with the risk of colon cancer in postmenopausal women. Onion and garlic also possess antidiabetic, antibiotic, cholesterol-lowering and fibrinolytic effects. Garlic can lower mild hypertension and blood lipids, potentially reducing the risk of cardiovascular disease. Allium-containing vegetables like garlic, shallots and onions can raise glutathione levels via their organosulfur compounds.

  • To activate the beneficial compounds of garlic, you have to first crush it and let it sit for a few minutes. Heat inactivates the enzyme alliinase (which catalyzes the synthesis of allicin), reducing the beneficial effects of garlic. An in vitro study found that heating or boiling inhibited the anti-platelet aggregation properties of crushed and uncrushed garlic, but the crushed garlic maintained more of its anti-aggregatory activity compared to uncrushed garlic. Microwaving uncrushed garlic for 60 seconds or for 45 minutes in a regular oven blocks the DNA damage protective effects against a carcinogen in rats. Some of garlic’s beneficial compounds can be retained if you crush it and leave it out in the open for 10 minutes before heating.


Sulforaphane (SFN) is another sulfur-containing compound that has a long record of health benefits. Research has shown sulforaphane to be beneficial in managing Type-2 diabetes, improving blood pressure, Alzheimer’s disease, liver detoxification, LDL cholesterol, the immune system, bacterial and fungal infections, inflammation, liver functioning, brain derived neurotrophic factor (BDNF) and may reduce cancer risk. A lot of these effects are mediated by increased glutathione production as SFN promotes glutathione synthesis through the activation of the Nrf2/ARE antioxidant defense system. Sulforaphane is produced when we eat cruciferous vegetables like broccoli, cauliflower, cabbage and Brussels sprouts. Eating cruciferous vegetables have been shown to raise glutathione S-transferase activity (a family of phase II detoxification enzymes), which binds glutathione to a wide variety of toxic compounds for their elimination.

  • Sulforaphane primarily inhibits Histone Deacetylase (HDAC), which is a group of enzymes that interact with DNA. HDAC deacetylases or unravels DNA proteins called histones that keep it compact. Sulforaphane inhibits HDAC enzymes, which increases the activity of another pathway called Nrf2. This stimulates the production of important antioxidants like glutathione, thioredoxin, and NQO-1. The same HDAC inhibition leads to the activation of autophagy as well. Sulforaphane promotes energetic stress, autophagy, and cell death. It will kill both cancerous cells but may scavenge some weaker healthy cells in the process.
  • SFN causes mild oxidative stress, lipid peroxidation, and generates ROS, which are considered to be a part of its chemo-protective properties by up-regulating glutathione and autophagy. Excessive sulforaphane can cause some genome instability and over-activation of white blood cells. In mice, sulforaphane increases the susceptibility to seizures and other symptoms of toxicity. However, that was done with a dose of 200 mg/kg, which is pretty hard to reach by eating just vegetables or broccoli. The optimal intake of sulforaphane is around 20-40 mg/day in humans.
  • When certain plants get damaged from either chewing or cutting, they produce myrosinase that transforms glucoraphanin into sulforaphane. After this process, SFN starts to degrade quite rapidly. Cooking at temperatures below 284˚F (140˚C) also produces sulforaphane but higher temperatures start to destroy it. Adding mustard seeds to cooked broccoli increases the bioavailability of sulforaphane.
  • Sprouting cruciferous vegetables increases their glucoraphanin content by 10-100 times. Broccoli sprouts are the highest in glucoraphanin and sulforaphane. Raw cruciferous vegetables, if overconsumed, can inhibit iodine absorption because of goitrogens. Uncooked Brussels sprout juice in rats causes DNA damage and apoptosis or programmed cell death. Thus, it is better to cook or steam your vegetables slightly to get the best benefits, but not overcook them.

A small amount of sulfur can be obtained from the organosulfur compounds found in foods like broccoli, garlic and onions. However, the actual content of sulfur in a food depends on the soil quality.

Whole foods appear to be a more bioavailable source of sulfur than supplements. A study found that sulfur-methyl-L-methionine (SMM) from kimchi was more bioavailable than SMM by itself and it led to better digestion. Fresh vegetables and plants also contain more organosulfur compounds than processed foods. Taurine, which spares cysteine and hence the utilization of sulfur in the body for other functions, is found in animal foods but not in plants.

Benefits of Hydrogen Sulfide (H2S)

Overproduction of H2S is implicated in cancer, whereas deficiency can cause vascular disease. Hydrogen sulfide is involved in multiple cell signaling processes, such as the regulation of reactive oxygen species, reactive nitrogen species, glutathione and nitric oxide.

Hydrogen sulfide has cardioprotective effects that prevent atherosclerosis and hypertension. Hydrogen sulfide has vasorelaxant effects and acts as an endogenous potassium-ATP channel opener. H2S stimulates endothelial cells to facilitate smooth muscle relaxation. Disrupted H2S production has been suggested to promote endothelial dysfunction.

  • Hydrogen sulfide enhances the effects of nitric oxide by increasing endothelial NO synthase (eNOS). H2S and nitric oxide are mutually dependent in regulating angiogenesis and endothelium-dependent vasorelaxation. Formation of NO and H2S creates a novel compound called nitrosothiol that has vasodilating effects. The cytoprotective effects of hydrogen sulfide are dependent on nitric oxide. Thus, you need sufficient NO and the minerals required for its synthesis to gain the benefits of H2S. Next to carbon monoxide and nitric oxide, hydrogen sulfide is thought to be the third biological gas. The benefits on vasoactivity of garlic are also mediated by H2S, which is a food relatively high in sulfur.
  • Hydrogen sulfide is an endogenous stimulator of angiogenesis or the growth of new blood vessels. Patients with coronary artery occlusion or multi-vessel lesions have lower H2S levels. In mice and human umbilical vein endothelial cells, H2S exerts antiatherogenic effects. It also protects against endoplasmic reticulum stress. Some of the cardioprotection is also mediated through Nrf2 signaling. Hydrogen sulfide alleviates myocardial ischemia-reperfusion injury by maintaining mitochondrial function.
  • Hydrogen sulfide plays a role in kidney homeostasis and may provide kidney protection. It affects glomerular filtration and sodium reabsorption. H₂S regulates blood pressure and vascular tone through activating the renin angiotensin aldosterone system (RAAS). During renal hypoxia, H₂S can help to restore oxygen balance by increasing blood flow to the medulla. Tubulointerstitial hypoxia has been recognized as the final pathway from chronic kidney disease (CKD) to end stage renal disease (ESRD). Sodium hydrogen sulfide (NaHS) has been shown to attenuate fibrosis and inflammation in obstructive kidney disease at doses starting at 5.6 mcg/kg/d and optimally at 56 mcg/kg/d.

H2S may have neuroprotective effects by increasing glutathione and suppressing oxidative stress. There is a high level of hydrogen sulfide in the brain and it may act as an endogenous neurotransmitter. H2S might be able to scavenge peroxynitrite and prevent oxidative stress, especially in the brain where there is low extracellular glutathione. Alzheimer’s patients have lower hydrogen sulfide levels in the brain.

Hydrogen sulfide is involved in cell-death and inflammatory signaling as an endogenous mediator. Elevation of H2S accompanies inflammation, infection and septic shock. Inhibiting H2S production contributes to the gastric injury caused by nonsteroidal anti-inflammatory drugs (NSAIDS).

  • Endogenous gases (CO, NO, H2S) regulate mitochondrial biogenesis during inflammation and oxidative stress. Hydrosulfide anions HS – (80% of H2S dissociates to HS – in the extracellular space but are essentially equal in the cell) are strong reducing agents of reactive oxygen species. In cardiomyocytes, hydrogen sulfide activates Mn-SOD and Cu,Zn-SOD and decreases ROS during ischemia/reperfusion. However, in the presence of oxygen, H2S can generate free radicals.
  • Nitric oxide and hydrogen sulfide protect gastrointestinal integrity and promote ulcer healing. However, H2S produced by gut microbes is associated with ulcerative colitis, Crohn’s disease and irritable bowel syndrome. Thus, having an overabundance of bacteria that produce H2S in the gut could be detrimental.

H2S Synthesis

Hydrogen sulfide gets synthesized by three enzymes: cystathionine γ-lyase (CSE), cystathionine β- synthetase (CBS) and 3-mercaptopyruvate sulfur-transferase (3-MST). CSE and CBS go through the transsulfuration pathway during which a sulfur atom gets transferred from methionine to serine, forming a cysteine molecule. Thus, dietary amino acids like methionine and cysteine are the main substrates in the production of hydrogen sulfide. They are also needed for glutathione and taurine synthesis.

After consumption, methionine reacts with adenosine triphosphate (ATP) with the help of methionine adenosyltransferase to produce S-adenosylmethionine (AdoMet), a universal transmethylation methyl donor. The transfer of AdoMet creates Sadenosylhomocysteine (AdoHcy), which gets rapidly hydrolyzed into adenosine and homocysteine by AdoHcy hydrolase. Homocysteine can be either methylated into methionine or used to synthesize cysteine and hydrogen sulfide. About 50% of the methionine taken up by hepatocytes gets regenerated. The remaining 50% is metabolized by the trans-sulfuration pathway.

  • In the first step of the transsulfuration pathway, homocysteine is condensed with serine to form cystathionine by cystathionine β-synthase (CBS). Then, cystathionine is cleaved into α-ketobutyrate, ammonia and cysteine by cystathionine γ-lyase (CSE). Cysteine cannot be converted back into methionine by mammals, making methionine an essential amino acid. However, cysteine can be created from methionine via the trans-sulfuration pathway.

The transsulfuration pathway is present in many tissues, such as the kidney, liver and pancreas. It does not appear to take place in the spleen, testes, heart and skeletal muscle. Inhibition of the transsulfuration pathway results in a 50% decrease in glutathione levels in cultured cells and tissues. Oxidative stress can activate the transsulfuration pathway and antioxidants downregulate it. The synthesis of glutathione from cysteine depends on ATP and thus magnesium.

Sulfates and Sulfites

Sulfites are food preservatives derived from sulfur added to packaged foods, hair colors, topical medications, eye drops, bleach and corticosteroids to prevent spoilage. They can also develop naturally during fermentation, such as in sauerkraut, kimchi, beer or wine. Thus, alcohol can be a significant source of sulfites, which in excess can promote inflammation and gastrointestinal problems. About 1% of people, and 3-10% of asthmatics, are sulfite sensitive and they experience swelling, rashes, nausea and possibly seizures or anaphylactic shock when consuming large amounts of sulfites. Some people are allergic to sulfur and sulfur-containing foods like garlic or eggs, causing them to experience swelling, rashes and low blood pressure.

Sulfate is a source of sulfur for amino acid synthesis. Sulfate-reducing bacteria in the gut can promote ulcerative colitis through hydrogen sulfide. Patients of ulcerative colitis have elevated levels of fecal sulfide and sulfate-reducing bacteria. Sodium sulfate supplementation has been shown to stimulate the growth of sulfate-reducing bacteria. Excess sulfide can overburden the detoxification systems, impairing butyrate oxidation and causing colonic epithelial inflammation.

Gastrointestinal absorption of sulfate happens in the stomach, small intestine and colon. The absorption process is sodium-dependent. Heat and cooking reduce the digestibility of cysteine because heating oxidizes cysteine into cystine, which is absorbed more poorly. More than 80% of oral sulfate taken as soluble sulfate salts like sodium sulfate or potassium sulfate gets absorbed. Insoluble sulfate salts like barium sulfate barley get absorbed. The sulfate that does not get absorbed in the upper gastrointestinal tract will be passed to the large intestine and colon where it is either excreted in the feces, reabsorbed or reduced to hydrogen sulfide.

Sulfur Support

One of the most important antiaging pathways in the body is that of the Nrf2 transcription factor, and one of the best ways to support Nrf2 is to eat foods rich in sulfur. Nrf2 is responsible for unzipping and exposing genes that encode for the expression of antioxidant proteins that protect against oxidative damage. Activating Nrf2 switches on a host of antioxidant pathways, increases glutathione production, and can even trigger the expression of an antiaging phenotype. Glutathione acts as a powerful antioxidant within the mitochondrial matrix, and other antioxidants that result from Nrf2-induced transcription also benefit mitochondria in a similar manner.

H2S causes the formation of a disulfide bond between two cysteine residues: cys-226 and cys- 613. The resulting compound deactivates what are called keap1 ubiquitin ligase substrate adaptors. When these adaptors are activated, they cause a chain of events that suppresses Nrf2. So, by deactivating these adaptors, H2S creates an environment in which Nrf2 can act freely and promote the transcription of powerful antioxidant genes.

One of the best ways to increase the activation of Nrf2 factors is to consume a lot of sulfur (hence HS2). So, fill your diet with plenty of sulfur-containing foods from the Brassica family, which includes bok choy, broccoli, cabbage, cauliflower, horseradish, kale, kohlrabi, mustard leaves, radishes, turnips, and watercress. These foods, along with sulfurous and stinky eggs, onions, and garlic, contain sulforaphane, an H2S-containing compound. Another Nrf2 activator is curcumin. Finally, hydrogen-rich water is also a good way to activate NrF2 pathways.


The minimal optimal intake of sulfur amino acids per day is roughly 3.0 grams, but this demand increases up to 5.0 grams during disease states and/or injury. Generally, you can obtain that amount from eating 0.6-1.0 grams of protein per pound of body weight every day. To prevent the negative side-effects of excess methionine, ensure an adequate intake of B vitamins and glycine (3-5 grams per meal) or get your protein from glycine-rich organ meats/tendons/ligaments.

Sulfur amino acids are not maintained in the body long term. They either get excreted through urine, oxidized into sulfate or stored as glutathione. Sulfur is excreted primarily as sulfate with urinary sulfate reflecting the overall intake of sulfur from inorganic sources or amino acids. The 24-hour urinary excretion of urea, the final end-product of protein metabolism, reflects the 24-hour urinary excretion of sulfate because methionine and cysteine are the primary sources of body sulfate stores. Urinary sulfate excretion is inversely associated with all-cause mortality in the general population with higher excretion rates linked with mortality.

Many drugs used in the treatment of joint diseases and pain like acetaminophen require a lot of sulfates for their excretion. Up to 35% of acetaminophen is excreted conjugated with sulfate and 3% is conjugated with cysteine. The rest is conjugated with glucuronic acid, which is a major component of glycosaminoglycans that is essential for the integrity of cartilage. Thus, acetaminophen depletes the body of sulfur. Added methionine or cysteine can overcome methionine deficiency induced by acetaminophen.

Food Sources

Glutathione status is compromised in various disease states and an increased supply of sulfur amino acids can reverse many of these changes. A restriction in dietary sulfur amino acids slows down the rate of glutathione synthesis and diminishes its turnover. Fruit and vegetables contribute up to 50% of dietary glutathione, whereas meat contributes 25% for an average diet. Direct food sources high in glutathione are freshly prepared meat, fruit and vegetables are moderate sources and dairy and cereal are low in glutathione. Freezing foods maintain relatively the same amount of glutathione as fresh food, but other preservation methods, such as fermentation or canning, lead to extensive losses. Whey protein is also a good source of cysteine and hence glutathione and has been shown to lower oxidative stress. Milk thistle can raise glutathione levels and has antioxidant properties. Turmeric and curcumin can also promote glutathione synthesis and inhibit inflammation.

  • Organosulfur compounds in allium vegetables like garlic and onions are also beneficial for the body’s antioxidant systems. They may have protective effects on cardiovascular disease and cancer. Eating only half of an onion per day and a single serving of garlic per week may be enough to provide the benefits.
  • Sulforaphane-containing vegetables like broccoli and cabbage give an additional boost in glutathione and anti-cancer defenses. To activate the beneficial compounds, you have to cut and slightly cook the vegetables at temperatures below 284˚F (140˚C). Eating cruciferous raw will begin to inhibit iodine absorption and promote hypothyroidism. How many vegetables you need to eat is hard to know but the general recommendation of 3-5 cups of vegetables a day should be more than enough. You also have to pay attention to how you individually react because sulforaphane may cause digestive problems for some people.

Excess Methionine

Excess methionine intake may lead to harmful side-effects, such as brain lesions and retinal degeneration, especially if not balanced with glycine intake. High dietary methionine intake (5-6 g/d compared to the 1-1,2 g RDA) can also raise homocysteine levels, even on top of adequate B-vitamin intake.

Methionine restriction (MR) is thought to increase lifespan and slow down aging. Additionally, it’s possible that those effects can happen without caloric restriction, which so far is the only known way of lengthening life in many species. Restricting methionine in Baker’s yeast extends their lifespan, which was accompanied by an increase in autophagy. However, when autophagy genes were deleted, the extension in lifespan was also prevented. It’s thought that restricting just protein can have the same effect on life-extension as caloric restriction without needing to restrict calories.

  • Compared to caloric restriction, protein restriction does not contribute to the benefits of caloric restriction. The benefits of reduced protein intake are caused primarily by decreased caloric consumption. Restricting protein and methionine may actually cause other problems related to poor detoxification, methylation and glutathione synthesis. Improper methylation is linked with autoimmune conditions.
  • Loss of methionine promotes the greying of hair. Methionine and cysteine are also important for alleviating oxidative stress.
  • Furthermore, glycine supplementation has been found to have the same effects on life-extension as methionine restriction. Glycine is found in organ meats, ligaments, drumsticks, skin and collagen supplements. Bone broth or chicken soup (especially ones that contain collagenous meats), rich in glycine, glucosamine and sulfur, has been found to lower inflammation, infections and reduce joint pain.

Antioxidant Vitamins and Minerals

Vitamin E

Signs and Symptoms of Deficiency

  • Vitamin E deficiency is best understood from malabsorption disorders impacting all fat-soluble vitamins and from a rare genetic disorder known as alpha-tocopherol transfer protein deficiency that causes a specific disruption of vitamin E supply to all tissues except the liver.
  • These result in ataxia (loss of full control over body movements), peripheral neuropathy (weakness, numbness, pain, or tingling in the hands and feet), retinopathy (damage to the eye’s retina). The ataxia of vitamin E is often mistaken for Friedrich’s ataxia, a genetic disorder in iron metabolism.

Risk Factors for Deficiency

Vitamin E’s only well-established role is to protect polyunsaturated fatty acids (PUFAs) from a process known as lipid peroxidation, which is a form of oxidative damage.

Moderate deficits of vitamin E are most likely to occur on diets that cause tissue concentrations of PUFA to increase without a proportionate increase in vitamin E. Most high-PUFA oils are rich in vitamin E. However, years of consuming them can cause tissue concentrations of PUFA to remain elevated for up to four years after one stop consuming them. By contrast, vitamin E levels drop very soon after discontinuing these oils. This may cause an extended period where dietary vitamin E is inadequate to protect tissue concentrations. As an example, someone who eats sunflower oil for years and then switches to coconut oil may spend up to four years in a moderate vitamin E deficit because coconut oil does not provide enough vitamin E to protect the fatty acids that came from the sunflower oil.

Excess Vitamin E

Excess vitamin E is broken down and excreted in the urine, so there is no toxicity syndrome associated with it. However, vitamins E and K share the same catabolic pathway, and excess vitamin E may cause a vitamin K deficiency and thin the blood.

Testing for Vitamin E

Plasma vitamin E is the best marker of vitamin E status. It is low in deficiency.

Testing Caveats

Since vitamin E is carried in lipoproteins, hypolipoproteinemias may cause vitamin E status to appear lower than it is and hyperlipoproteinemias may have the opposite effect.

Correcting Vitamin E Deficiency

Vitamin E deficiency only occurs with malabsorption disorders or defects in alpha-tocopherol transfer protein, and these must be managed with appropriate medical treatment.

Vitamin C


Vitamin C is an antioxidant that many animals produce, especially during stress. Humans have lost that ability to synthesize vitamin C and thus we need to get it from the diet. Vitamin C has been shown to increase glutathione levels. It also recycles oxidized vitamin E, providing cellular membranes protection against lipid peroxidation. It is also essential for collagen synthesis and collagen is what most organs, including the lungs and the endothelium, are made of.

There’s some evidence showing that the need for vitamin C increases only in diets of glucose-based metabolism. In fact, ascorbic acid and glucose compete for cellular transport. High levels of blood glucose inhibit the uptake of vitamin C because both of them use the same membrane transport chain and because glucose is a much more prioritized nutrient.

  • A systematic review of 23 clinical studies, encompassing 6,000 children, found that supplementing with 1-2 grams of vitamin C per day decreased the duration and/or severity of the common cold by 13-26%. In adults, 1-4.1 grams of vitamin C/day reduced the duration and/or severity of the common cold by 6.9-20%. Among military recruits, 1-2 grams of vitamin C/day reduced the duration of cold symptoms by up to 69%.
  • In elderly patients with acute respiratory infections, 200 mg of vitamin C/day has been shown to speed recovery and lower mortality. Many doctors also use intravenous vitamin C as a potential treatment for COVID-19, however, it is not yet a standard care. In organ failure and sepsis, intravenous vitamin C has not improved organ dysfunction or markers of inflammation, but it has lowered mortality rates.
  • Athletes who take vitamin C regularly are half as likely to catch a cold as athletes who do not. Supplementing 600 mg of vitamin C a day after an ultramarathon reduced the incidence of upper respiratory infections by over 50%.
  • A recent 2020 meta-analysis published in the Journal of Intensive Care showed that 1–6 grams of intravenous vitamin C per day shortened the ventilation time of patients needing intensive care by 25 %. 
  • Vitamin C may help with autoimmunity by controlling histamine levels and destroying excess histamine. Histamine is an organic compound involved in immune responses, especially inflammation, allergies and itching. In excess, it can cause autoimmunity and hypersensitivity. It has been found that 2 grams of vitamin C can decrease histamine levels by 38%.

Signs and Symptoms of Deficiency

  • Scurvy, defects in collagen synthesis that cause bleeding at or underneath the surface of the skin and oral cavity. The skin may appear to bruise without requiring any physical trauma. Hairs may become kinkier and appear in a “corkscrew” shape. Fatigue and shortness of breath on exertion also occur. Plausible signs of more moderate deficits include decreased immunity, faster aging skin, low bone mineral density and an increased risk of osteopenia and osteoporosis.
  • Vitamin C recycles vitamin E, and its deficiency lowers vitamin E status. It is also possible that moderate deficits might cause low noradrenaline production resulting in lethargy and trouble focusing, and low oxytocin, compromising the sense of affection and bonding in response to physical intimacy.
  • Lack of vitamin C may have a contributing role in insulin resistance. Supplemental antioxidants in type-2 diabetes could improve the condition and attenuate diabetic pathogenesis. An imbalance between the declining endogenous antioxidants and increasing production of reactive oxygen species can lead to a state of chronic systemic inflammation that onsets many pathologies. Taking 500 mg of vitamin C twice a day has potential to reduce proinflammatory markers like CRP and IL-6 in obese/diabetic patients. Oral vitamin C increases polymorphonuclear phagocytosis in diabetics and improves glucose tolerance in older subjects with diabetes. A daily dose of 1000 mg of vitamin C (500 mg twice daily) may be beneficial in lowering blood sugar and lipids in type-2 diabetics. Ascorbic acid supplementation improves skeletal muscle insulin sensitivity in type-2 diabetes.

Risk Factors for Deficiency

A diet low in fresh foods, especially fruits and vegetables, that does not contain vitamin C supplements or vitamin C-containing multivitamins is most likely to produce scurvy. Diets poor enough to cause scurvy can sometimes be found among chronic alcoholics.

There are opposed claims that carbohydrates increase and decrease the vitamin C requirement but at the present time neither high nor low carbohydrate intake should be considered a direct cause of vitamin C deficiency. High levels of physical activity, illness, and exposure to toxins including ethanol and cigarette smoke especially increase the need for vitamin C.

Vitamin C Excess

  • Vitamin C is not toxic, but when consumed above the rate of intestinal absorption it may cause diarrhea. Bowel tolerance occasionally occurs as low as 4 grams per day but often takes more than 10 grams per day.
  • Excess vitamin C may cause some problems in vulnerable individuals: it increases iron absorption and possibly iron-induced oxidative damage in individuals with hemochromatosis; it increases the risk of oxalate stones in individuals with kidney disease; it increases the risk of hemolysis in newborns with glucose 6-phosphate dehydrogenase deficiency, a genetic disorder.

Testing for Vitamin C

Fasting plasma ascorbate is the best marker of vitamin C status.

Correcting Vitamin C Deficiency

  • All citrus fruits, including orange, grapefruit, lime, and lemon are excellent sources of vitamin C. Papaya, strawberries, pineapples, kiwis, cantaloupes, and raspberries too. Even Swiss chard and cruciferous vegetables such as broccoli and cauliflower are also excellent sources, as is parsley, which provides over half of the recommended daily amount.
  • Athletes, smokers who cannot quit, and individuals with frequent illness or who otherwise appear to have a high need may raise this dose to two grams. 
  • Ascorbic acid is a synthetic form of vitamin C that is typically made from GMO corn, and lacks the beneficial bioflavonoids present in whole-food form of vitamin C. Look for an all-organic food-based supplement or a USP-grade vitamin C, produced in a GMP-certified facility. Whole Foods Market Food-Sourced Vitamin C, American Nutraceuticals Vitality C, and OrthoMolecular Buffered C Capsules. Take no more than 500mg at a time. At 100mg all the tissues are saturated, at 200mg the blood plasma is saturated, but at 500mg dose the absorption appears complete and rate of absorption will decrease.



Manganese (Mn) is an essential mineral involved in the function of many enzymes, the immune system, blood clotting, bone formation and metabolism. In nature, it is found in combination with iron. Deficiencies in manganese impair growth, lead to skeletal defects, reduce fertility and alter glucose tolerance. Manganese metalloenzymes include arginase, glutamine synthetase, phosphoenolpyruvate decarboxylase and MnSOD, all of which have an important role in antioxidant defense and metabolic reactions. Manganese superoxide dismutase deficiency triggers mitochondrial uncoupling and the Warburg effect, which may promote cancer and metastasis.

Manganese deficiency reduces bone mineral density, whereas supplementation improves bone health. Women with osteoporosis have been observed to have lower serum manganese levels than those without osteoporosis.

One of primary functions of manganese is that it makes up Mn superoxide dismutase (MnSOD), which scavenges free radicals and reactive oxygen species (ROS) in the mitochondria, endothelium and even in atherosclerotic plaque.

Atherosclerosis is a disease of chronic inflammation that damages the blood vessel wall and oxidizes LDL cholesterol. Superoxide dismutase protects against the oxidation of lipids. Manganese protects against heart mitochondria lipid peroxidation in rats through MnSOD. MnSOD can reduce oxLDL-induced cell death of macrophages, inhibit LDL oxidation and protect against endothelial dysfunction. There is an association between decreased MnSOD and atherogenesis.

Insulin resistance can be thought of as a cellular antioxidant defense mechanism against oxidative stress in the absence of other antioxidant defense systems, such as manganese superoxide dismutase or glutathione. In other words, a lack of manganese may be a direct cause of insulin resistance.

Manganese is required for creating oxaloacetate from pyruvate via pyruvate carboxylase. In mammals, oxaloacetate is needed for gluconeogenesis, the urea cycle, neurotransmitter synthesis, lipogenesis and insulin secretion.

Oxaloacetate also synthesizes aspartate, which then gets converted into other amino acids, asparagine, methionine, lysine and threonine. During gluconeogenesis, pyruvate is converted first into oxaloacetate by pyruvate carboxylase, which is then simultaneously decarboxylated and phosphorylated into phosphoenolpyruvate (PEP). This is the rate-limiting step in gluconeogenesis. Pyruvate carboxylase is expressed the most in gluconeogenic tissues, such as the liver, kidneys, pancreatic islets and lactating mammary glands.

Arginase is another manganese-containing enzyme and the final enzyme in the urea cycle, during which the body gets rid of ammonia. Arginase converts L-arginine into L-ornithine and urea. Manganese ions are required for stabilizing water and hydrolyzing L-arginine into L-ornithine and urea. Arginase is also involved with nitric oxide synthase. Disorders in arginase metabolism are implicated with neurological impairment, dementia and hyperammonemia. Excess ammonia is not acutely harmful to humans as it will either be converted into amino acids or excreted through urine. However, high ammonia is associated with upper gastrointestinal bleeding in cirrhosis and kidney damage. Urea cycle disorders cause delirium, lethargy and even strokes in adults.

Manganese is a co-factor for glutamine synthetase (GS), which is an enzyme that forms glutamine from ammonia and glutamate. Glutamine is used by activated immune cells. It supports lymphocyte proliferation and helps to produce cytokines by lymphocytes and macrophages. Additionally, glutamine may help people with food hypersensitivities by reducing inflammation on the gut surface. It can thus protect against and repair leaky gut, hence improving immunity. Getting enough glutamine from the diet or by using a supplement may help to protect intestinal epithelial cell tight junctions, which prevents intestinal permeability. Glutamine synthetase is most predominantly found in the brain, astrocytes, kidneys and liver. In the brain, glutamine synthetase regulates ammonia detoxification and glutamate – the excitatory neuro-transmitter. Manganese gets in the brain with the help of the iron-carrying protein transferrin, but manganese doesn’t seem to compete with iron absorption.

Manganese-Dependent Enzymes, Functions and Consequences of Deficient Manganese Intake

Manganese-Dependent Enzymes/Proteins: Function: Consequences of Deficit

  • Superoxide Dismutase: Removes superoxide anions: Increased tissue and mitochondrial damage and oxidative stress
  • Arginase: Participates in the urea cycle to remove harmful ammonia: Ammonia accumulation, kidney damage
  • Pyruvate Carboxylase: Converts glucose into oxaloacetate, gluconeogenesis, lipogenesis, neurotransmitter biosynthesis, insulin secretion: Impaired insulin production, low-carb intolerance, ammonia accumulation
  • Glutamine Synthetase: Glutamine formation, nitrogen metabolism, ammonia detoxification: Weaker immunity, intestinal permeability, ammonia accumulation, neurotoxicity
  • Divalent Metal Transporter 1 (DMT1): Transports ferrous iron, regulates iron homeostasis, absorption and transportation of manganese, binds to divalent metals: Poor iron homeostasis, manganese deficiency
  • Transferrin Receptor (TfR): Imports iron into the cell, manganese influx and efflux: Poor iron homeostasis, manganese overload or deficiency


There is no established RDA for manganese. The estimated safe and adequate daily intake for manganese has been set at 2-5 mg/d. Adequate intakes for adult males are 2.3 mg/d and 1.8 mg/d for females. Men on experimentally manganese-deficient diets (< 0.74 mg/d) have been shown to develop erythematous rashes. Women consuming < 1 mg of manganese per day experience altered mood and increased pain during their premenstrual phase of the estrous cycle. During pregnancy or lactation, the demand for manganese increases to 2.0-2.6 mg/d. Children that are 1-3 years old should get 1.2 mg/d, 4-8 years old 1.5 mg/d and boys 9-13 years old should get 1.9 mg/d and girls 1.6 mg/d. Newborns that are 6 months old or younger should get 0.003 mg/d and 7– 12-month-olds should obtain 0.6 mg/d. The tolerable upper intake levels for manganese have been set at 9-11 mg for adults and 2-9 mg for children 12 months of age or older.

Manganese absorption and influx is mostly mediated by the divalent metal transporter 1 (DMT1) and transferrin receptor (TfR) on the cell surface that also transport other divalent cations, such as iron and calcium. Iron deficiency can increase the risk of manganese poisoning because manganese absorption will increase under low iron states.

  • About 75% of the manganese in human milk is bound to lactoferrin. Excess ferric lactoferrin could inhibit the absorption of this manganese complex. The addition of calcium to human milk significantly decreases manganese absorption, while addition of phytates, phosphate and ascorbic acid to infant formulas, as well as iron and magnesium to wheat bread has no significant effect. High manganese intake leads to adaptive changes that include reduced gastrointestinal absorption of manganese, enhanced liver metabolism and increased manganese excretion.
  • In adults, 3-5% of manganese is absorbed through the gastrointestinal (GI) tract with women absorbing slightly more than men, possibly due to poorer iron status. After GI absorption, manganese enters the bloodstream and is distributed throughout different tissues. Intravenous administration of manganese bypasses GI regulation and results in 100% of absorption. Aging decreases manganese absorption and retention. Thus, we need more manganese as we get older.
  • The primary manganese excretion pathway is biliary secretion. More than 95% of manganese is excreted through bile so the threshold for dietary manganese toxicity is quite high.

Food Sources

Manganese is found in many foods, including grains, clams, oysters, legumes, vegetables, tea and spices. One of the most commonly consumed sources of dietary manganese are rice, nuts and tea. Dietary and non-experimental manganese deficiency is quite rare, and toxicity occurs mostly due to environmental exposure. Some supplements are also fortified with manganese, ranging from 5 to 20 mg. The amount of manganese in human breast milk ranges from 3-10 mcg/L. Cow’s milk-based infant formulas contain 30-100 mcg/L. Soy-based formulas have the highest concentration of manganese (200-300 mcg/L), which might lead to manganese accumulation. The absorption of manganese from human milk is the highest (8.2%) compared to soy formulas (0.7%) and cow’s milk formula (3.1%).

Signs and Symptoms of Manganese Deficiency

Miliaria crystallina, a form of dermatitis resulting from blocked sweat glands that appear as tiny clear bubbles on the skin. This can also result from excessive sweating, sunburn, or fever. It may also cause bone irregularities, low bone mineral density, low cholesterol, slow hair and nail growth, and reddening of beard hair. Moderate deficits of manganese may accelerate atherosclerosis.

Risk Factors for Deficiency

Manganese is particularly rich in whole grains, legumes, nuts, seeds, coffee, tea, spices, and mussels. Diets low in plant products are likely to be considerably lower in manganese than diets rich in plant products.

Manganese Toxicity

  • Acute manganese toxicity causes manganism, characterized by neurological symptoms, mood swings, compulsive behavior and decreased response speed. Manganese overexposure can also impair cardiovascular function and heartbeat. Chronic exposure leads to a more permanent dysfunction that resembles Parkinson’s disease. Unlike Parkinson’s, manganism does not appear to cause a loss of sense of smell and patients do not respond to LDOPA treatment. The neurotoxic effects appear to be caused by disturbed iron and aluminum metabolism and iron overload that cause oxidative stress. Oxidative stress is one of the main factors of manganese-induced neurotoxicity. It is important to note that a lack of copper in the body leads to iron overload, which can lead to manganese overload in tissues. Thus, a lack of one mineral, such as copper, can lead to the harmful accumulation and dysregulation of other minerals in the body.
  • Manganese accumulation in the mitochondria can also cause mitochondrial dysfunction by inhibiting complex I and II. The highest accumulation rate is observed in the mitochondria of astrocytes and neurons compared to other organelles after chronic manganese exposure. Excessive manganese gets excreted out of the mitochondrial lumen through sodium-independent mechanisms, but it gets imported mainly by the calcium uniporter. Manganese inhibits calcium efflux, which increases the probability of mitochondrial permeability transition associated with brain injury and stroke.
  • Manganese poisoning can occur due to drinking contaminated water or when exposed to the fuel additive methylcyclopentadienyl manganese tricarbonyl (MMT) and the pesticide manganese ethylene-bisdithiocarbamate (Maneb). Permanganate (Mn 7+) is much more toxic than Mn 2+ with potassium permanganate having a lethal dose of 10 grams. Mining and processing manganese causes air and water pollution, which threatens the health of workers and local residence, especially in South Africa, China and Australia where most of the world’s manganese is mined from.
  • The olfactory tract is the most direct pathway for manganese to get into the brain. By using two zinc transporters ZIP8 and ZIP14, it can bypass the blood-brain barrier. Infants have an immature blood-brain barrier, making them more vulnerable to manganese toxicity. MRI studies show that manganese accumulates predominantly in the globus pallidus located in the basal ganglia. Dopamine oxidation by manganese causes oxidative stress. Chronic manganese exposure has been seen to reduce choline levels in the hypothalamus and thalamus.
  • Intravenous absorption of manganese is close to 100%, which can cause manganese toxicity. Infants have a much higher absorption and retention of manganese than adults, making them more susceptible to manganism. They also have a higher total amount of manganese in the body than older children and adults. The amount of manganese in the hair of newborn babies increases from 0.19 mcg/g at birth to 0.965 mcg/g at 6 weeks of age and 0.685 mcg/g at 4 months when they’re fed infant formulas. Normal children at age 8 have a hair manganese concentration of 0.268 mcg/g and those with learning disability (hyperactive) have 0.434 mcg/g.
  • Liver damage impairs manganese excretion, causing high levels of manganese in the blood. Patients with portosystemic shunts (also known as liver shunts) and biliary atresia (narrowed or blocked bile ducts) exhibit hypermanganesemia, even without increasing dietary manganese intake.

Testing Manganese Status

Lymphocyte manganese is thought to be better than whole blood manganese for measuring manganese deficiency.

Most of blood manganese gets distributed in soft tissue (~60%), with the remainder being in the liver (30%), kidney (5%), pancreas (5%), colon (1%), bone (0.5.%), urinary system (0.2.%), brain (0.1.%) and erythrocytes (0.0.2%). Divalent Mn 2+ is the predominant form of blood manganese and it is complexed with different molecules, such as albumin (84% of total Mn 2+), hexahydrated ion (6%), bicarbonate (6%), citrate (2%), and transferrin (Tf) (1%), whereas almost all trivalent Mn 3+ is bound to transferrin. Mn 3+ is more reactive and gets reduced to Mn 2+ and Mn 2+ can be oxidized to Mn 3+ by ceruloplasmin the active form of copper. Mn 3+, typically coming in the form of manganese (III) fluoride, manganese (III) oxide and manganese (III) acetate, is more effective at inhibiting the mitochondrial complex I. The reduction of Mn 3+ to Mn2 + is mediated by ferrireductase, which helps to avoid oxidative stress.

Tissues with a high energy demand like the brain and liver as well as high pigment regions such as the retina and skin have the highest concentrations of manganese. Approximately 40% of total body manganese is stored in the bones (1 mg/kg). It has been found that the hand bone manganese levels of welders exposed to high manganese environments are significantly higher compared to non-occupationally exposed individuals.

Testing Caveats

The syringe used to draw the blood can contaminate the blood with manganese and the first draw should be discarded so the second draw can be used for the measurement. If heparin is used as an anticoagulant in the blood tube rather than EDTA, the heparin can provide manganese contamination. The water used for dilutions in the laboratory analysis must be properly purified because it also can be contaminated. Red blood cell or whole blood measurements are ideal because red blood cells contain 25 times as much manganese as plasma or serum. This brings the concentration far away from the limit of detection and makes the possibility of contamination less threatening to interpretation. It also eliminates the possibility that hemolysis could release manganese to contaminate the serum or plasma.

Correcting Manganese Deficiency

Increasing the amount and diversity of plant foods is the most likely thing to improve manganese status. Supplements often contain 8 milligrams or higher. Then reducing to 3-5 milligrams when levels stabilize. 



Zinc is another important nutrient needed for optimal immune cell functioning. It plays a key role in over 300 enzymatic reactions and cellular communications. A deficiency in zinc promotes proinflammatory cytokines and weaker immunity. Many studies since the 1970s have noted zinc deficiency is related to different autoimmune diseases such as type-1 diabetes, rheumatoid arthritis, multiple sclerosis, systemic lupus, autoimmune hepatitis, celiac disease and Hashimoto’s thyroiditis.

Zinc also plays an important role as a structural agent of proteins and cell membranes preventing oxidative stress. Zinc is important for hormone production and immunity. Low zinc status can cause gastrointestinal problems and increase the risk of pneumonia. However, high zinc supplementation can lead to toxicity and stomach pain.

Zinc acetate and zinc gluconate lozenges have been shown to inhibit cold viruses from latching onto cells and shorten flu duration. Lozenges are beneficial only in the early stages of infection. The optimal dose in adults according to clinical studies is around 80-200 mg/day divided into multiple doses taken 2–3 hours apart. Best results are achieved when starting within 24 hours of first symptoms. According to studies in children, regular use of zinc can prevent the flu. It has been shown to inhibit the replication of viruses like SARS and arterivirus. Do not exceed 200 mg of zinc per day for any longer than one to two weeks and copper should always be taken in conjunction with it. Avoid nasal sprays as they might cause a lingering loss of smell perception.

Zinc/copper – Typical ratios for general population is 15-20 mg/1 mg zinc/copper or (30-40 mg/2 mg copper), in elderly populations usually 40-80 mg of zinc with 1-2 mg of copper is used, respectively. In AREDs, 40 mg/1mg zinc/copper twice daily lowered mortality by 27%, which was driven by a reduction from deaths from respiratory causes. Copper is needed as a cofactor for lysyl oxidase which crosslinks collagen and elastin giving it tensile strength. Copper is important for elastin/collagen synthesis and both are important for healthy lung function.

Zinc helps to catalyze the calcification of bone. Zinc deficiency causes skeletal abnormalities by reducing parameters of calcium metabolism in the bone. Zinc is also needed for collagen synthesis and zinc deficiency can increase damage to the body’s soft tissue. Supplementation with arginine, glutamine, vitamin C and zinc has been shown to increase collagen synthesis during the first 2 days after inguinal hernia repair. Zinc also helps those with bed sores.

Zinc speeds up wound healing. Wounds do not heal as fast with zinc deficiency. Oral zinc sulfate improves foot and leg ulcers. Zinc deficiency exacerbates ulcers by increasing oxidative stress in the skin. Zinc sulfide nanoparticles improve skin regeneration. Healing of the aorta requires zinc. Think of zinc as a healing mineral. Zinc can be thought of as our adamantium and the source of our healing power.

Atherosclerosis Protection

  • Zinc, especially when taken with appropriate amounts of copper, prevents the oxidation of LDL cholesterol, which is one of the main mechanisms for atherosclerosis. Excess iron promotes LDL oxidation, whereas zinc protects against this. Zinc supplementation at doses over 50 mg/day can reduce HDL cholesterol, however, if copper status is maintained, this will likely not occur. Atherosclerosis develops in parallel with the decrease of zinc absorption, greater prevalence of zinc deficiency and increased inflammation that happens during aging.
  • The preventative effect of zinc on cardiomyopathy is mediated by metallothionine, the main protein zinc is bound to. Metallothionine has an antioxidant effect, including in the heart. It controls the amount of zinc in tissues. Zinc deficiency causes a deficiency in metallothionine, which results in increased reactive oxygen species in the cell, enhanced oxidative stress, inhibition of cytochrome c oxidase activity, impaired mitochondrial function and eventually cellular death, especially in the liver, kidney and connective/collagenous tissues. Metallothionine expression protects against the toxicity of cancer treatment drugs like doxorubicin. In other words, if you are zinc deficient you will likely experience worse chemotherapy side effects. Zinc has also been shown to protect metallothionine-deficient mice from alcohol-induced myocardial fibrosis. Selenium promotes the release of zinc from metallothionine and their combination improves immunity in the elderly after influenza vaccination. Inflammation also makes metallothionine use zinc, which explains why zinc levels are low in inflammatory conditions such as atherosclerosis. High homocysteine also impairs metallothionine and disrupts redox homeostasis.
  • Zinc supplementation may help heal unstable plaque by promoting calcification, which is less likely to rupture. Statins work by reducing inflammation and promote the calcification of unstable plaques. Statin drugs, however, also reduce zinc levels by 8%. Thus, their benefits are limited and are they are not without side effects. Elevated serum copper, with low zinc and magnesium, is associated with an increased risk of cardiovascular disease mortality. A low urinary zinc, which is indicative of zinc deficiency, is associated with atherosclerosis severity. In atherosclerosis, there is a significant decrease in plasma, aorta, liver, myocardium and pancreas zinc levels. Patients with myocardial infarctions have low plasma zinc levels, averaging just 67 mcg/dL, instead of the 75-125 mcg/dL that is considered normal.

Brain Development

Zinc is important for brain development, learning and plasticity. Zinc deficiencies are implicated in brain disorders. Zinc supplementation in malnourished schoolboys has been shown to increase cortical thickness significantly more than in those who have received all the essential amino acids, vitamins and minerals without zinc.

  • Zinc is needed for synthesizing many neurotransmitters, such as serotonin and melatonin. Taking zinc has been shown to improve sleep in humans.
  • Zinc homeostasis regulates the central nervous system. Dysregulated zinc homeostasis and excess synaptic zinc concentrations, typically induced by inflammation, can cause neurotoxicity and mitochondrial damage. Zinc also regulates the activity of the adrenal glands and cortisol levels.

Thyroid Hormone Production

Zinc and other trace minerals like copper and selenium are needed for the production of thyroid hormones. On the flip side, you need adequate amounts of thyroid hormones to absorb zinc, which is why hypothyroidism can cause an acquired zinc deficiency. Hypothyroidism reduces zinc absorption in the intestine. Zinc is required to activate the T3 receptor, hence zinc deficiency impairs T3 receptor action. Zinc deficiency is associated with hypothyroidism and severe alopecia, i.e., hair loss. Supplementing with zinc in those who are deficient improves thyroid function. Thus, it’s a vicious cycle of zinc deficiency impairing thyroid hormone function, which drives more zinc deficiency.

  • The overconsumption of sugar, especially in conjunction with copper deficiency, also drives zinc deficiency through the promotion of fatty liver disease. Indeed, since the liver produces the active thyroid hormone T3, and active thyroid hormones are required for the absorption of zinc, damage to the liver will reduce zinc status. Considering that millions of people have hypothyroidism, a zinc deficit may be more rampant than originally thought.

Blood Sugar Regulation

Zinc is important for glucose metabolism and insulin production. Zinc helps with the uptake of glucose into the cell and with insulin synthesis. A 2012 systematic meta-analysis that included 22 studies concluded that zinc supplementation has a beneficial effect on glycemic control and lipids in patients with type-2 diabetes. In type-1 diabetes, a combination of zinc and vitamin A (10 mg zinc a day and 25,000 IU vitamin A every other day) can improve apolipoprotein-B/A1 ratios (essentially LDL+VLDL/HDL ratios).

  • Zinc is required for pancreatic carboxypeptidase, which may be needed for insulin maturation and secretion. Furthermore, zinc supplementation has been shown to improve insulin resistance and metabolic syndrome in obese children.
  • Zinc deficiency may also lead to metabolic acidosis by reducing carbonic anhydrase activity. Carbonic anhydrases are a family of enzymes that catalyze the conversion of carbon dioxide and water to bicarbonate and protons. Most carbonic anhydrases contain a zinc ion at their active site and are thus classified as metalloenzymes. Without carbonic anhydrases, tissue oxygenation decreases, and lactic acidosis increases. Zinc losses increase in urine and sweat during exercise. Additionally, zinc needs increase during exercise to help working muscle, as well as after exercise to repair and build muscle. Thus, many athletes are at risk of zinc deficiency, which can impair performance and decrease the lactate threshold (i.e., when lactate accumulates faster than it can be removed). In zinc-deficient rats, lactic acid buffering agents like lactic dehydrogenase (LDH), malic dehydrogenase (MDH), alcohol dehydrogenase (ADH) and NADH diaphorase are lower.

Zinc and the Immune System

Even a modest zinc deficiency can impair the functions of macrophages, neutrophils, natural killer cells and the complement system, reducing their cytotoxicity. Zinc is needed for the production of T cells. People with zinc deficiency show reduced natural killer cell cytotoxicity, which can be fixed with zinc supplementation.

Zinc is an essential cofactor for thymulin, which is a thymic hormone. Without zinc, thymulin can’t bind to zinc and this impairs immunity. With the help of zinc, thymulin helps to differentiate immature T cells, preserving the balance between killer T cells and helper T cells. Autoimmune diseases with a T cell imbalance, such as rheumatoid arthritis, are associated with zinc deficiency. Thymulin also modulates the release of cytokines.

Zinc is needed for the interaction between the natural killer cell inhibitory receptor p58 and major histocompatibility complex (MHC) class I molecules. A deficiency in zinc impairs natural killer cell activity, phagocytosis of macrophages, cytotoxicity of neutrophils and generation of the oxidative burst needed to kill pathogens. Zinc ions have been shown to stimulate the production of lymphocytes, which attack invading pathogens. The addition of zinc releases interleukin-1, interleukin-6, tumor necrosis factor-α and interferon gamma in human peripheral blood mononuclear cells, which help us fight infections.

Low zinc status has been associated with an increased risk of pneumonia, respiratory tract infections, diarrhea and other infectious diseases.

Zinc administration helps patients with hepatitis C virus-induced chronic liver disease. It is also noted that zinc deficiency is related to different autoimmune diseases such as type-1 diabetes, rheumatoid arthritis, multiple sclerosis, systemic lupus, autoimmune hepatitis, celiac disease and Hashimoto’s thyroiditis. A significant number of COVID-19 patients are zinc deficient, which is associated with worse COVID-19 outcomes. Zinc has been shown to inhibit the replication of viruses like SARS and arterivirus.

Zinc enables the calcium-binding protein calprotectin to inhibit the reproduction of bacteria through neutrophil degradation. Prophylactic zinc intake before LPS treatment in a porcine sepsis model has been shown to reduce the inflammatory response. Thus, doses of zinc before an LPS infection may be protective.

Extremely large doses of zinc (up to 400 mg/day) have been shown to impair immune function. In vitro, doses 7-8 times the physiological level inhibit T cell function and reduce interferon-alpha production.

Typical ratios for the general population are 15-20 mg/1 mg zinc/copper or (30-40 mg/2 mg copper), in elderly populations usually 40 of zinc with 1 mg of copper is used once to twice daily. In the AREDs study, 40 mg/1mg of zinc/copper twice daily significantly lowered mortality by 27%, which was seemingly driven by a reduction from deaths from respiratory causes.


The human body contains about 2-4 grams of zinc, out of which about 0.1% gets depleted every day. Only 1/1000 of the total zinc pool gets renewed on a daily basis. Zinc’s biological half-life is 280 days. Up to 57% of zinc in the body is located in muscle and 29% in bone. There is no separate storage site for zinc in the body, which is why it needs to be obtained from dietary sources on a regular basis.

Supplementing 400 mcg of folic acid every other day for 4 weeks has been shown to reduce zinc excretion by 50%. However, polyphenols, such as resveratrol and quercetin, may enhance the uptake of zinc into certain cells via metallothionine.


Phytate, phosphate and other phytonutrients are able to chelate zinc, including other minerals. Phytate is a mineral chelator that affects zinc bioavailability. In Korean adults, lower zinc bioavailability because of phytates is related to a higher risk of atherosclerosis. Foods high in phytates like grains bind to zinc, iron and calcium and reduce their absorption, which is why diets high in phytates can cause zinc and iron deficiency.

Another inhibitor of zinc absorption is calcium, which enhances phytate’s ability to reduce zinc absorption. The ratios between phytate-zinc and phytate-zinc-calcium can predict the risk of zinc deficiency.

A high intake of other minerals like copper, magnesium, calcium, iron and nickel also reduces the absorption of zinc.

Ferrous iron (Fe 2+) supplements can reduce zinc absorption and lower plasma zinc levels. That is why experts recommend taking iron supplements away from food. However, when zinc and iron are consumed together in a meal, this effect does not seem to happen.

Certain antibiotics can inhibit the absorption of zinc. Taking these either 2 hours before, or 4-6 hours after zinc intake, can minimize this effect. Zinc reduces the absorption of penicillamine, which is used to treat rheumatoid arthritis. Diuretics like chlorthalidone and hydrochlorothiazide increase zinc excretion by as much as 60%. ACE inhibitors, like lisinopril and other blood pressure lowering medications in this class that end in “pril” deplete zinc. Omeprazole, a common antacid/heartburn medication, has been found to lower serum zinc levels. This is because proton pump inhibitors reduce zinc absorption from food due to a reduction in stomach acid.

Inflammation and certain disease states also promote zinc excretion. Picolinate complexes are more easily absorbed by the body. Zinc picolinate has been seen to improve zinc status in children with a genetic mutation that prevents them from absorbing zinc from cow’s milk.

Food Sources

Since zinc is a copper antagonist, too much dietary zinc can lead to copper deficiency. Accordingly, too much zinc in relation to copper is associated with hypercholesterolemia and increased coronary heart disease mortality. At the same time, excess iron supplementation inhibits zinc and copper absorption, which can weaken the immune system and cause copper-deficient anemia. Thus, it is necessary to balance these three minerals – iron, zinc and copper.

  • Consume copper-laden organ meats, such as liver, into your diet (0.5-1 oz. per day or 1-3 oz. two to three times per week). Oysters and mollusks are the highest sources of zinc and can be consumed perhaps 1-2 times per week. Other high copper foods include shellfish (lobster and crab), dark chocolate, certain seaweeds, nuts, lentils and beans.
  • Daily zinc and iron requirements can be met with appropriate intakes of red meat based on your body’s protein and iron/zinc requirements. The RDA for protein is 0.36 g/lb. of bodyweight or 0.8 g/kg, however, many experts consider this to be inadequate. In fact, a higher protein intake has been found to be superior in terms of weight loss, satiety, body composition, wound healing and bone density. Thus, a more appropriate intake for most people is at least 0.6-0.7 g of protein/lb. of body weight or 1.2-1.4 g/kg. The optimal daily protein intake for muscle growth and hypertrophy appears to be 0.8-1.0 g/lb or 1.6-2.2 g/kg of body weight.
  • If you are eating a vegetarian diet, a diet high in phytates, and/or are using zinc inhibitors such as certain medications and antacids, then your zinc demand increases. Thus, you may need up to 50- 100% more zinc every day.

Factors that Increase Zinc Demand

  • Intestinal malabsorption conditions and gut issues, like inflammatory bowel disease, Crohn’s, sickle cell anemia, cystic fibrosis as well as diabetes, can cause secondary zinc deficiency.
  • Chronic diarrhea can lead to an excessive loss of zinc, whereas supplementation can help to offset these effects.
  • Infections, like hookworms, can result in zinc deficiency, leading to physical and mental developmental problems in children. Hookworms can also promote iron deficiency.
  • Kidney diseases and liver diseases such as liver cirrhosis and non-alcoholic liver disease, alcoholism and chronic inflammation can increase the urinary excretion of zinc. Liver cirrhosis patients show abnormally high levels of zinc in the urine.
  • Mercury exposure and heavy metal toxicity can cause zinc deficiency
  • Zinc demand increases during pregnancy, nursing and growth periods. Pregnancy is hallmarked by an increased zinc retention and a lack of nutrition can lead to harm to the fetus that may have long lasting consequences.
  • Bariatric surgery causes impaired zinc absorption and promotes zinc deficiency
  • Obesity can increase zinc excretion due to kidney damage. In obese subjects, plasma zinc concentrations are significantly lower. Low serum zinc levels in obese patients have been correlated with higher urinary zinc excretion.
  • Athletes also have a lower serum zinc level than nonathletes due to increased zinc demands and losses during exercise

Supplemental doses of 80-150 mg/day of zinc can be immunosuppressive if not taken with copper. The lowest median effective dose of supplementary zinc is deemed to be 24 mg/day. Using zinc-containing nasal gels or sprays has been associated with a loss in the sense of smell.

Men taking over 100 mg/day of zinc experience a 2.9-fold increase in the risk for metastatic prostate cancer, which is likely due to copper deficiency.

Frequency of Deficiency

Red meat avoidance is thought to contribute to iron and zinc deficiency, especially in young premenopausal women. Vegetarian diets, as well as a preference of poultry, fish and dairy over red meat has been shown to increase the risk of zinc deficiency. The requirement of zinc for vegetarians is at least 50% higher than omnivores because zinc is not particularly bioavailable in plant-based foods. Thus, adult vegetarian males might need up to 16-20 mg/day and vegetarian females 12-14 mg/day of zinc.

Children in certain U.S. middle- and upper-income families, have been seen to have impaired taste acuity, low hair concentrations of zinc and poor growth. This is due to “picky eating”, but technically, it is due to not eating zinc-rich animal foods like red meat. When giving these children zinc at 2 mg/kg of body weight, their ability to taste, appetite and growth rate improves.

The demonization of all grains, especially in those who consume large amounts of muscle meat but not organ meats, may be a leading contributor of copper deficiency. On the flip side, a high intake of grains and low intake of animal protein can lead to dwarfism, as observed in Middle Eastern countries such as Turkey, Morocco, Tunisia, Iran and Egypt. The high phytate content of bread in some regions like Iran, where the diet is primarily made up of grains, contributes to zinc deficiency.

  • Phosphates in clay bind to zinc, which is why geophagia (clay eating) is known to cause Iranian dwarfism. Zinc deficiency has been observed in regions like Egypt and Iran, who typically consume adequate amounts of zinc in their diet, but this is on top of excessive amounts of phytate and fiber.

It has been observed that the rising CO2 levels in the atmosphere can reduce the amount of zinc and iron in common crops, such as rice, wheat, peas and soybeans, with projections that a 10% drop in these minerals will occur by the end of the century. These puts developing countries, which are particularly dependent on these crops, in greater danger of zinc/iron deficiencies.

The low level of HCl in the stomach is also a predisposing factor.

Zinc-Dependent Enzymes, Functions and Consequences of a Deficit

Zinc-Dependent Enzymes/Proteins: Function: Consequences of Deficit

  • Metallothionine: Protection against oxidative stress: Increased oxidative stress and tissue damage
  • Zinc, Copper Superoxide Dismutase: Protect against oxidative stress: Increased oxidative stress and tissue damage
  • p53: DNA damage repair: DNA damage and DNA mutations
  • Poly (ADP-ribose) Polymerase: DNA damage repair: DNA damage and DNA mutations
  • Glutathione Synthesis: Protect against oxidative stress: Increased oxidative stress and weaker immunity
  • Glutathione Peroxidase: Removes hydrogen peroxide: Increased oxidative stress and weaker immunity
  • Nitric Oxide Synthase: Cardiovascular function, antiviral effects: Oxidative stress, atherosclerosis, and hypertension
  • Thyroid Hormones: Regulate metabolic rate, body temperature and energy balance: Chronic fatigue, frailty, weight gain, metabolic syndrome and decreased immunity
  • Luteinizing Hormone: Precursor to testosterone Hypogonadism and low sex hormones
  • Growth Hormone: Physical repair, fat burning: Frailty, aging and muscle loss
  • Insulin Secretion: Shuttle nutrients into the cells: Insulin resistance and metabolic syndrome
  • Serotonin: Promotes melatonin production and relaxation: Chronic stress, insomnia and altered mood
  • Melatonin: Promotes sleep onset and antioxidant activity: Sleeping problems, poor metabolic health, increased oxidative stress and neurodegeneration
  • Dopamine Transporter: Feeling of reward and motivation: Depression and apathy
  • Glycolysis Oxidation of glucose and lactate: Lactic acidosis and glucose intolerance
  • Beta-Oxidation: Oxidation of lipids and triglycerides: Dyslipidemia and obesity
  • Autophagy: Removes cellular waste material and dysfunctional organelles: Mitochondrial dysfunction, excess inflammation and impaired immunity
  • Lysosomes: Engulf debris and mediates autophagy: Waste material accumulation
  • Carboxypeptidase: Digestive enzyme and digestion of protein: Digestion problems and nutrient deficiencies
  • Carbonic Anhydrase: Conversion of carbon dioxide and water to bicarbonate and protons: Anemia and reduced tissue oxygenation
  • Alkaline phosphatase: Helps to break down proteins: Liver dysfunction

Signs and Symptoms of Zinc Deficiency

  • The earliest sign of zinc deficiency is usually patches of dry skin, eczema, dermatitis, and psoriasis. These often progress to acne, blisters, or pustules. Infection risk increases, resulting in sore throat or diarrhea. Poor glucose tolerance, impaired wound healing, low or dysregulated sex hormones, and hair loss (alopecia) also may occur. Lower appetite and increased caloric needs often result in weight loss, especially of lean mass.
  • In children, zinc deficiency delays puberty.
  • Zinc deficiency may cause resistance to vitamin A, vitamin D, thyroid hormone, sex hormones, cortisol, and pharmaceutical glucocorticoids. Zinc is involved in virtually every aspect of vitamin A metabolism, and an apparent vitamin A deficiency that cannot be corrected with vitamin A should be seen as a major indicator of zinc deficiency. Zinc deficiency may also impair acid-base balance and increase the vulnerability to heavy metal toxicity.
  • A deficiency in zinc creates an imbalance between Th1 and Th2, regulatory and killer T cells and reduced NK cell function. 
  • Zinc deficiency promotes oxidative stress, DNA damage and undermines antioxidant defenses in rats. In humans, zinc deficiency causes DNA damage. Zinc is involved in hundreds of proteins, including DNA-binding proteins, copper/zinc superoxide dismutase (CuZnSOD), and DNA damage repair proteins like p53. Zinc is also needed for activating poly (ADP-ribose) polymerase that are involved in DNA repair at DNA damage sites.
  • Loss of taste and smell
  • Night blindness and vision impairment
  • Frequent diarrhea and enteropathy
  • Loss of cognition and impaired learning
  • Behavioral abnormalities, ADHD and depression
  • Schizophrenia and psychiatric disorders

Risk Factors for Zinc Deficiency

  • Zinc is most abundant in oysters, red meat, and cheese, and the principal inhibitor of absorption is phytate. Phytate is found in whole grains, nuts, seeds, and legumes, and is especially high if these foods have not been prepared through soaking, sprouting, or fermentation. The overwhelming risk factor for zinc deficiency is a diet low in animal products and high in phytate.
  • Chronic diarrhea, persistent vomiting of bile (giving the vomit a green color), malabsorption disorders, impaired methylation, and rare genetics in zinc transporters can all cause zinc deficiency as well.
  • A collection of disorders in the production of heme, known as porphyrias, can cause zinc deficiency. If this is the cause of zinc deficiency, zinc protoporphyrin should be elevated.

Zinc Excess and Toxicity

Acutely, zinc toxicity can cause gastric distress, such as nausea and vomiting, and dizziness. A high-dose zinc supplement of 50 mg or more on an empty stomach can cause mild nausea, but dangerous levels of toxicity are rare. One death has been attributed to an accidental intravenous infusion of seven grams of zinc over a 60-hour period. Chronically, excess zinc can impair immune function and lead to copper deficiency, and perhaps deficiencies of other poorly studied minerals like molybdenum and chromium. To prevent this, zinc supplements should not be used at doses higher than 45 milligrams per day unless there is strong justification to do so, and the ratio to copper should be kept between 2:1 and 15:1, preferably toward the middle of that range.

Testing Zinc Status

  • It is very important to measure it in plasma rather than serum, and if the order says “serum or plasma” explicit instructions should be put in the order to use plasma and not serum.
  • Most ranges are too broad, with the lower end at 50-60 micrograms per deciliter. Measured in micrograms per deciliter, plasma zinc should be at least 70 in females and 74 in males, and the sweet spot is likely between 100-120. Measured in parts per billion, as on the ION panel, zinc should be above 700 in females and 740 in females, with the sweet spot likely to be between 1000 and 1200.
  • Plasma and serum zinc levels are most commonly used to assess zinc deficiency, but they do not reflect cellular zinc status. Clinical symptoms of zinc deficiency can be seen even in the absence of low zinc indicators. What’s more, plasma and serum zinc values fluctuate diurnally and drop after meals and exercise.
  • The best way to measure zinc deficiency is neutrophil zinc levels.
  • Zinc concentrations in leukocytes or lymphocytes can be much more reflective of zinc status because they are associated with growth development and immunity. The ratio between CD4+ and CD8+ T cells has also been proposed as a test for zinc deficiency.
  • The levels of zinc in hair can reflect dietary intake of zinc, at least in animals. There is also a correlation between zinc concentrations in plasma and hair. The advantage of hair tests is that it can reflect intakes over several months, giving a more accurate measurement of the body’s zinc status.
  • Zinc-dependent enzyme activities such as superoxide dismutase, metallothionine and others in organs can be another way to measure zinc deficiency. In zinc-deficient animals, zinc-metalloenzymes and zinc itself are reduced.
  • The most accurate measurement of zinc deficiency is neutrophil zinc levels and possibly hair mineral analysis. Neutrophil zinc levels in healthy individuals tend to average around 108 ug of zinc/10 10 cells, whereas those who are deficient in zinc average 82 ug of zinc/10 10 cells. Normal zinc values range from 150-240 mcg/g of hair, whereas less than 70 mcg/g may indicate zinc deficiency. Zinc concentration in hair depends on the rate of hair growth and the delivery of zinc to the root, and hence, it is not 100% accurate. Environmental contamination can also affect copper and zinc levels in hair. Thus, hair mineral analysis, in addition to neutrophil or perhaps lymphocyte or red blood cell zinc levels, and leukocyte copper levels, should be implemented for assessing suspected zinc and copper deficiency more accurately.

Testing Caveats

  • Inflammation lowers plasma zinc, but this might simply reflect increased needs during inflammation.
  • Plasma zinc modestly declines during pregnancy, but this also might indicate increased needs during pregnancy.
  • Hemolysis can release zinc from red blood cells and cause falsely high zinc levels. Hemolysis can occur inside your body if you have certain medical disorders, but it can also occur during blood collection due to poor positioning of the needle or other technical difficulties.
  • Plasma zinc in significant excess of 130 micrograms per liter or 1300 parts per billion is implausible in the absence of outright zinc poisoning and the measurement should be repeated.

Correcting Zinc Deficiency

  • If the cause is a dietary pattern with a low zinc-to-phytate ratio, the ideal strategy is to alter the dietary pattern to one with a higher zinc-to-phytate ratio. If the cause is malabsorption, the malabsorption should be addressed as the root cause. 
  • Zinc supplementation is not needed when you are getting enough of it from diet. Zinc supplementation is mostly beneficial for fixing deficiencies quickly or trying to help with an acute infection. Chronic intakes of zinc over 80-100 mg/day can promote copper depletion, especially if dietary copper intake is not concomitantly increased. The idea is to try and obtain anywhere from 20-80 mg of zinc, 8-18 mg of iron and 3 mg of copper each day. This will of course depend on the person.
  • Zinc acetate, gluconate, sulfate, citrate, or methionine should be used, and not zinc oxide or zinc picolinate. Ideally, the zinc should be taken on an empty stomach, but if this causes nausea it should be taken with some food and should at least be taken far away from phytate-rich meals. The zinc should be spread out as much as possible to ensure better absorption. For example, 15 milligrams three times per day five hours apart is much better than taking 45 milligrams once per day.
  • The goal should be correction of the plasma zinc and any signs and symptoms of deficiency. It is important to realize, however, that normalizing the plasma zinc means the deficiency is being fixed, not that it has been fixed. A zinc deficiency that has been sustained over months may take months to correct. Resolution of signs and symptoms is an important benchmark, and being able to cut down the dose of the supplement without plasma zinc falling back into the deficient range is the other key benchmark to reach before considering the deficiency fixed.
  • Zinc modulates cell-mediated immunity, has antioxidant, and anti-inflammatory properties that can provide a potent cure for the common cold. Zinc lozenges are best for staving off a cold. It begins to release ionic zinc, which is the key to its antiviral activity. Dissolving a lozenge slowly in the mouth provides a steady release of free ions into the pharyngeal region in the nasal cavity, which can have a greater effect on reducing respiratory and nasal symptoms associated with sickness. Make sure it doesn’t have any additives or citric acid, as this commonly added compound can bind tightly to zinc ions, preventing them from being released. Zinc acetate. Avoid effervescent lozenges, which can reduce the production of ionic zinc.

Correcting Zinc Excess

  • In acute zinc poisoning, medical treatment is required.
  • Cases of zinc-induced copper deficiency should be corrected by removing the supplemental zinc and following the instructions for correcting a copper deficiency in that section.
  • Screening for other mineral deficiencies is highly advised in this context because the ability of zinc to induce deficiencies in other positively charged minerals is very plausible and has not been well studied.


Copper Deficiency Anemia

Anemia is defined as a decrease in the oxygen carrying capacity of the blood. Anemia is suggested when levels are slightly below a normal hemoglobin level of around 13.8-17.2 g/dL in adult men and 12.1-15.1 g/dL in adult women.

As a result, you can experience chronic fatigue, shortness of breath, weakness, pale skin, lightheadedness and other problems. Both too much, as well as too little iron, can make people more susceptible to infections. Some amounts of iron are needed for fighting harmful bacteria; however, excess iron also promotes the growth of these pathogens.

Copper improves the ability of red blood cells to transport oxygen and nutrients, creating a ‘hypernutritive state’. Clinicians nowadays acknowledge that copper sulfate can increase the number of red blood cells. Copper can also protect against the oxidation of red blood cells, making them more resilient.

Copper stimulates the release of stored iron in tissues during the creation of red blood cells. Thus, copper mobilizes iron, helping to shift iron storage into hemoglobin.

Iron and copper are absorbed in the upper small intestine and hepcidin controls the absorption of iron, by inhibiting iron export in the intestine. Hepcidin expression is decreased on a copper deficient diet, potentially leading to iron deficiency. In other words, a low copper diet can lead to low iron absorption and iron deficiency anemia.

Hephaestin and its homologue ceruloplasmin, the latter being the major copper-carrying protein in blood, are required for efficient iron transformation into transferrin. Their synthesis and activity are positively correlated with copper levels in the cell. Thus, a copper deficiency can lead to a reduction in hepcidin, hephaestin and ceruloplasmin, jeopardizing iron metabolism and restricting its movement out of the gut and liver to areas where it may be needed in the body. Additionally, copper is also needed for the synthesis of heme, which is a constituent of hemoglobin. Thus, in order to get iron where it needs to go in the body, it must be placed onto transferrin, which requires copper.

  • To sum it up, the absorption, export and transport of iron requires copper. All things regarding iron require adequate amounts of copper and many issues that are thought to be caused by “iron deficiency” may actually be caused by copper deficiency.

A copper deficiency can decrease iron levels and cause iron deficiency anemia in some tissues while resulting in iron overload in other tissues, such as the liver and intestine. An absence or dysfunction of ceruloplasmin leads to the accumulation of iron in the brain, liver, intestine, pancreas and retina. Tissue iron overload and very high serum ferritin levels have been seen in those with familial ceruloplasmin deficiency. Deficiencies in ceruloplasmin also cause iron to accumulate in the spleen, which leads to microcytic, hypochromic anemia, dementia, cerebellar ataxia and diabetes.

Cardiovascular Disease

Copper deficiencies are seen in animals and humans with a wide range of heart disease outcomes, such as aortic rupture, fissures, cardiac enlargement, abnormal lipid metabolism, and ischemic heart disease. Copper deficiency is one of the few nutrient shortages that elevates cholesterol, blood pressure, homocysteine, adversely affects the arteries, impairs glucose tolerance, and promotes thrombosis. People with hypertension tend to have lower copper than those with normal blood pressure. In men, copper deficiency can cause irregular heartbeat.

  • According to a 1965 autopsy study, people who died from a myocardial infarction, had lower amounts of copper in their myocardium. 
  • Atherosclerotic arteries have been shown to have lower copper and reduced cytochrome c oxidase activity than those without atherosclerosis. Cytochrome c oxidase is a copper-dependent enzyme. A shutdown of the copper-dependent cytochrome c oxidase is how cyanide leads to death, by inhibiting the production of ATP. Decreased cytochrome c oxidase in heart muscle has been noted after myocardial infarction. There is an increase of copper levels in patients with myocardial infarction, which may lead to copper depletion due to an increase in copper need.
  • A decline in the copper content of the aorta has been seen alongside increased atherosclerosis. Among Nigerians, in both older men and women, significant reductions of arterial copper are observed. Similar observations have been made in African Americans and Minnesota Caucasians, although their copper levels are higher.
  • Copper deficiency and low ceruloplasmin raises iron levels and can cause iron overload. High iron is a risk factor for heart disease and is associated with cardiovascular events. Elevated iron raises the demand for copper by inducing a mild copper deficiency. 
  • Copper is needed to strengthen collagen, and hence, a lack of copper may reduce the health of the arteries and the heart. Copper is needed as a cofactor for lysyl oxidase which cross-links collagen and elastin giving it tensile strength. High homocysteine increases homocysteine thiolactone, which inhibits lysyl oxidase. As a result, your arteries can get damaged and become more susceptible to atherosclerosis. Aneurysms and blood vessels are more likely to rupture/tear with high blood pressure on a diet deficient in copper due to decreased collagen/elastin strength. Low lysyl oxidase, a marker of reduced copper status, is associated with ischemic heart disease. Homocysteine alone is a risk factor for cardiovascular disease, stroke, and ischemic heart disease. Homocysteine can bind copper and induce copper deficiency.
  • Copper is important for neovascularization or angiogenesis (the process of growing new blood vessels). Thus, copper is also important in wound healing, whether that be ulcers, cuts, bruises or organ damage. The repair of collaterals, which are new blood vessels that supply the heart when larger arteries become blocked due to atherosclerosis, may not occur if the diet is low in copper. Copper ions also activate endothelial nitric oxide synthase (eNOS), which explains its importance in vasodilation and better endothelial function.

Inflammatory Conditions

Elevated copper levels in the blood can indicate inflammation, which itself is a cardiovascular disease risk factor. That’s why it is more accurate to look at enzyme activity or leukocyte copper levels than just blood copper levels.

  • Diabetics have a reduction in liver copper content. In fact, diabetes itself can cause an imbalance of copper and a loss in copper utilization in the heart. That can contribute to the pathogenesis of diabetic arteriopathy. Inflammation is also raised during hyperglycemia, hyperinsulinemia, glucose intolerance and diabetes. Patients with peripheral arterial disease show higher blood pressure, high triglycerides, lipids and elevated serum copper because inflammation raises copper. Thus, diabetes can cause copper dysregulation and lead to cardiovascular disease development.
  • Other inflammatory conditions like rheumatoid arthritis or infections exhibit elevated copper levels. It is also known that diets low in copper can cause osteoporosis. Copper deficiency reduces bone integrity, leading to brittle bones and fractures by decreasing lysyl oxidase. Low serum copper, iron and zinc are risk factors for osteoporosis. Excessive intake of milk, high in calcium and low in copper, may exacerbate this problem instead of mitigating it.
  • There is an epidemiologic association between osteoporosis, ischemic heart disease and a diet low in copper. Osteoblast activity, osteoblasts are the cells that build our bone, decreased in copper deficiency and human osteoporosis. A supplementation trial with trace minerals that included copper, zinc, manganese and calcium improved bone density compared to either calcium only or trace minerals only. Decreased copper has been found in people with bone spurs, ischemic necrosis of the arteries, fractures and decreased lumbar bone density.

Oxidative Stress

Copper inhibits oxidative stress and reactive oxygen species (ROS) via superoxide dismutase (SOD). Superoxide anions cause lipid peroxidation in addition to other problems, which can be neutralized primarily by copper-zinc superoxide dismutase (Cu,Zn SOD). Excessive oxidative stress is a key contributor to the pathogenesis of many diseases, primarily by raising inflammation.

  • Endothelial dysfunction, which is when the lining of the arteries is damaged and there is decreased arterial relaxation, precedes cardiovascular disease and is caused by reduced nitric oxide availability. A low copper intake can be a major contributor to reduced nitric oxide status. This is because copper is a cofactor for the function of superoxide dismutase, which inhibits the free radical superoxide anion, which sequesters nitric oxide to form the toxic peroxynitrite. Thus, a copper deficiency can result in a “nitric oxide steal”, transforming it into a damaging and inflammatory molecule. Polyphenol-rich blackcurrant powder/juice may improve nitric-oxide mediated relaxation of coronary arteries via a copper- and iron-dependent antioxidant effect.
  • Low dietary copper intake increases free radical production in healthy men, which may increase the risk of colon cancer. Elevated reactive oxygen species cause death of endothelial cells, which also leads to cardiovascular disease. Reperfusion injury, which occurs after a blocked artery is re-opened, is also driven by ROS. Maintaining adequate copper intake helps to reduce the amount of ROS by regulating extracellular SOD.
  • Copper seems to increase the activity of glutathione peroxidase, which is needed for handling hydrogen peroxide. In fact, copper deficiency has been shown to decrease glutathione peroxidase. Through an overall reduction in oxidative stress, ensuring adequate levels of copper can boost glutathione levels, which is the main antioxidant in the body that protects against oxidative stress. Thus, copper acts as an antioxidant mineral. In fact, a lack of glutathione may reduce the ability of the body to store copper as a complex with metallothionein. Hence, a low copper status can increase oxidative stress, resulting in a reduction in glutathione, which leads to further loss of copper and dysfunctional copper utilization. In other words, a low intake of copper can lead to an increased loss of copper.

Mitochondrial Function 

Copper is a co-factor for respiratory complex IV in the mitochondria. A copper deficiency impairs immature red blood cell bioenergetics, which alters the metabolic pathways, turning off the mitochondria and switching over to more glycolysis (sugar burning). As a result, there is a reduction in energy production and excessive lactate production from glycolysis. Lactic acidosis or the buildup of lactic acid is associated with several cancers and inflammatory diseases. During oxygen shortage, which can accompany copper deficiency anemia, lactic acid can begin to accumulate.

  • Copper also plays a role in burning fat. Obese patients require more copper than the RDA (typically exceeding 1.23 mg/day). Norepinephrine, the hormone that promotes fat burning and alertness, requires copper for its synthesis. The transcription factor in the hypothalamus called HIF-1 alpha, is also copper-dependent, and it has a role in preventing obesity.

Metabolic Syndrome

Copper deficiency has a detrimental role in your metabolic health and condition. Metabolic syndrome is a condition in which at least three or more of the five are present: high blood pressure, central obesity, high fasting triglycerides, high blood sugar and low serum HDL cholesterol. It is associated with cardiovascular disease and type 2 diabetes by causing inflammation. Metabolic syndrome doubles the risk of cardiovascular disease and increases all-cause mortality by 1.5-fold.

  • Copper deficiency, induced by high fructose intakes, impairs insulin binding and reduces insulin sensitivity. Diabetes can disrupt copper metabolism and copper deficiency can alter glucose metabolism. Accumulation of iron ions in the pancreas, due to copper deficiency and a lack of ferroxidase activity, is thought to cause diabetes.
  • Low copper intake also raises cholesterol and triglycerides and copper supplementation can lower their levels in the blood. Copper deficiency increases the activity of hydroxymethylglutaryl-coenzyme A reductase (HMGA-CoA reductase), which is the rate-controlling enzyme for cholesterol synthesis, and hence increases cholesterol levels. 
  • Copper deficiency also impairs thyroid hormone production. The thyroid is central to regulating metabolic rate and energy balance. There is a positive correlation between serum copper and thyroid hormones in children with congenital hypothyroidism. The ratio of copper and selenium influences thyroid functioning in patients with hypothyroidism. In thyroid disease, the metabolism of zinc, copper, manganese and selenium is abnormal. Low copper status also reduces the conversion of T4 into T3. Serum copper is also regulated by thyroid hormones, which stimulates the synthesis and the export of ceruloplasmin. Less thyroid hormones (hypothyroidism) = decreased ceruloplasmin = copper deficit. In fact, thyroid hormones are known to be needed for kidney sodium reabsorption. Ironically, sodium is needed to bring iodine into the thyroid gland (as well as other tissues such as lactating breast, salivary glands, stomach and intestines) to make thyroid hormones. Indeed, two sodium ions are needed to transport one iodide molecule into these tissues. Thus, thyroid hormone production and sodium status are interdependent on one another.

Kidney Health

Ceruloplasmin protects the kidneys as it acts as an antioxidant. The development of kidney dysfunction may occur in part due to a lack of copper, with kidney function improving upon copper supplementation. One group of authors concluded, “Copper deficiency can worsen nephrotic syndrome by decreasing the ceruloplasmin activity, which protects the glomeruli.” Additionally, kidney damage can increase the loss of copper in the urine. Patients with kidney damage tend to develop moderate copper deficiency. An easy indication of copper loss is spillage of albumin into the urine. This is because most copper in the blood is bound to the protein ceruloplasmin. The urinary losses of copper can be 8-32 times higher than normal in those with kidney damage.

Reproductive Health

Both copper transport as well as ceruloplasmin’s ferroxidase activity are exhibited in the testicles, primarily helping in the processes of spermatogenesis. Thus, copper is important for male reproductive systems. Additionally, the copper-dependent cytochrome c oxidase has an integral role in energy metabolism in the testes, enabling the production of ATP needed for sperm motility. Essentially, if a man is deficient in copper, their sperm does not swim as well. On top of that, a copper deficiency can also make the sperm more vulnerable to oxidative stress and DNA damage. When couples are having difficulties getting pregnant, it might be due to inadequate copper status. Foods high in copper like liver, oysters and clams are also considered fertility-boosting foods.

Immune System

Micronutrients, including copper and iron, are needed for modulating immune function and reducing the severity of infections. A copper deficiency has been shown to cause thymus (one of the main organs that produces immune cells) atrophy, reducing the amount of circulating neutrophils and decreasing the ability of macrophages to kill pathogens. Repletion of copper appears to be able to reverse this. By causing iron deficiency, a copper deficiency can also reduce phagocytosis and lymphocyte proliferation. In fact, infants with copper deficiency have been documented to have recovery in their immune health with copper supplementation. Copper is also essential for the production of interleukin-2, which is a cytokine that helps us fight infections.

The Functions of Copper

  1. Energy production (cytochrome c oxidase, composed of copper and iron)
  2. Detoxification of superoxide anions (superoxide dismutase converts superoxide to oxygen and hydrogen peroxide)
  3. Synthesis of collagen and elastin (copper makes up lysyl oxidase)
  4. Production of hemoglobin (ceruloplasmin catalyzes the oxidation of iron, which is necessary for iron to bind to its transport protein, transferrin)
  5. Melanin production (tyrosinase converts tyrosine to melanin and is a copper containing enzyme)
  6. Myelin production (the synthesis of phospholipids in myelin sheaths in peripheral nerves are dependent on copper)
  7. Fat burning and beta oxidation
  8. Inhibition of inflammation through antioxidants
  9. Synthesis of thyroid hormones (thyroxine)

“Copper metabolism is altered in inflammation, infection, and cancer. In contrast to iron levels, which decline in serum during infection and inflammation, copper and ceruloplasmin levels rise.” This is why so many doctors fear “copper overload” and don’t take copper deficiency seriously, i.e., because they rarely see low copper levels on a blood draw.


Balance studies suggest that a daily intake of 0.8 mg leads to net copper loss whereas net gains are seen with 2.4 mg/day.

Men and women fed diets low in copper, around 1 mg/day, develop increases in blood pressure, cholesterol, glucose intolerance, and abnormal electrocardiograms.

There is around 50-120 mg of copper in the human body. Copper is mainly stored in the liver, but it is also found in the heart, brain, kidneys and muscle. About 1/3rd of the total body copper is in the liver. However, copper is present in almost every tissue of the body. The daily copper turnover is estimated to be around 1 mg through fecal loss. Thus, total body copper stores can be depleted in a few months if daily intake is not near this level of intake. More importantly, this does not take into account copper losses in sweat, which can be quite significant. Overweight people appear to require more copper than normal weight ones, generally needing more than 1.23 mg/day. In obese children, copper levels in the blood are lower, but slightly higher in the plasma, than in controls. They also have lower iron levels, which may be due to inflammation caused by excess body fat. It is inflammation that raises copper and lowers iron in the blood.

The upper safe threshold is deemed to be 10 mg/day for adults. Taking 10 mg/day of copper for 12 weeks has not been seen to cause liver damage, but one case reports that a long-term intake of 60 mg/day resulted in acute liver failure. Intakes of 7-7.8 mg/day for 4-5 months in healthy male volunteers between the ages of 27-48 may cause some negative side effects, such as decreased antioxidant defense, suppressed immunity and increased excretion of copper. However, it seems that the body’s own homeostatic regulation of copper absorption is being automatically regulated to minimize the amount of excess copper retention.

Copper and Iron in Food

The RDA for iron is 8 mg for adult men and 18 mg for adult women. During pregnancy, the RDA increases to 27 mg. Normal ranges for serum ferritin are 20-250 ng/ml for adult males and 10-120 ng/ml for women. A serum ferritin below 30 suggests iron deficiency. Numbers above the reference range may indicate oxidative stress or just iron overload. People, especially children, who take supplements may overdose on iron. You can get iron poisoning from doses as low as 10-20 mg/kg.

Our bodies have a hard time eliminating iron. Losses only occur, at least in a significant amount, during bleeding, blood donation, menstruation in women or through chelation. That is why females are more susceptible to anemia and iron deficiency, whereas men are more prone to iron overload. Common iron chelators include coffee, spirulina, chlorella, green tea, beans, whole grains and vegetables. That is why, although things like spinach and beans contain high amounts of iron, it is harder to reach iron overload eating them because a large proportion of the iron gets chelated and/or not absorbed.

Iron and zinc are copper antagonists. Foods are not fortified with copper, which contributes to this epidemic of copper deficiency. Unsaturated fats (omega-6 seed oils) are also lacking copper because transition metals are removed by chelation to increase shelf-life. At the same time, foods high in copper, such as liver, oysters, lobster and crab are eaten less frequently

Muscle meat is extremely low in copper but high in zinc and iron. Heme iron, as found in meat, is particularly well absorbed compared to non-heme iron. The highly bioavailable iron in cooked meat may also reduce the absorption of copper. Excess cystine and cysteine consumption enhances copper deficiency in rats. Foods high in cystine/cysteine are animal proteins like poultry, beef, pork, eggs, fish, etc., and in smaller amounts in lentils and oatmeal. These foods are also highest in iron. Zinc absorption is also greater when eating animal protein compared to plant foods, which inhibits copper absorption. This might be why vegetarians or vegans may need more zinc than omnivores but less copper.

  • Total copper absorption is higher with a lacto-ovovegetarian (dairy, eggs, and vegetarian) diet (0.48 mg/day) compared to a non-vegetarian diet (0.40 mg/day) because of its higher copper content. Moreover, the “antinutrients” in plants (phytic acid and phytates) can increase copper absorption by antagonizing zinc.
  • Increasing the intake of plants and reducing the intake of muscle meat can help to improve copper status; or simply eat other animal foods, such as liver and shellfish, which contain copper. Importantly, when you accumulate iron, your copper requirements increase.
  • A higher copper intake may explain why some studies show that vegans live longer than those eating a Standard American Diet. Indeed, the daily copper intake is 27% higher in vegetarians compared to omnivorous adolescent females. These studies however are including people who do not frequently incorporate copper-rich organ meats like liver and rely mainly on high iron muscle meat, which is the issue. Despite the reduced bioavailability, the higher copper content of plant-based diets seems to at least provide an adequate amount of copper.
  • Foods rich in fructo-oligosaccharides like chicory root, blue agave, artichoke, asparagus, Yacon root, garlic, and green bananas, have also been shown to enhance the absorption of copper, zinc and selenium. Soybean protein, however, seems to reduce copper absorption. A high fiber diet improves copper absorption because of fructo-oligosaccharides and inulin.

Zinc/Copper Ratio

Zinc is a copper antagonist, which is why ingesting large doses of zinc can lead to copper deficiency by inhibiting its absorption and increasing its secretion. A high concentration of zinc in the small intestine triggers the expression of metallothionines, which bind to copper.

The golden rule when supplementing with zinc, is that at a minimum, for every 40mg of zinc, 1 mg of copper should be employed.

High copper and phytate intake may be a protective factor against the Standard American Diet high in zinc and iron (phytate can also bind free iron). Phytic acid decreases the ratio of zinc to copper that gets absorbed in the intestinal tract. This is not to say that you need to eat fiber or phytic acid, but it’s important to balance the zinc/copper ratio, and that means sourcing more than just muscle meat and eggs.

Organ meats like liver have a much more appropriate iron-zinc to copper ratio than muscle meat. Per ounce of beef liver, you get 4.1 mg of copper or 4.5 times the RDA for copper of 0.9 mg. However, it is not recommended to consume more than 1 oz. of beef liver per day as total intakes of copper at or over 10 mg for several months could cause unwanted side-effects. Although the liver is high in cholesterol, it may be an antidote to the hypercholesterolemic effects of meat, which may actually be due to the low copper content of muscle meat. Liver, heart, kidney, suet, etc. have fat-soluble vitamins like K2, A, D as well as CoQ10. Per calorie, liver is one of the most nutrient dense foods in the world. It is also relatively low in calories compared to muscle meat (~130-150 vs ~150-200 calories/3.5 oz).

  • You can cover nearly all your needs for most vitamins and minerals by eating a single ounce of liver. Unfortunately, most people find organ meats disgusting but a simple way around this is to eat a blend of ground muscle meat with liver/heart (75% muscle meat/25% liver and heart). Organ meats and offal have been completely neglected in the modern industrialized diet landscape, whereas they are relatively common in France and other Mediterranean countries.
  • Oysters are another example of this as they’re high in copper, which seems more than sufficient to counteract the inhibitory effects of their high zinc content.

The zinc to copper ratio of cow’s milk is 38, whereas that of human milk is between 4 and 6, this might explain the health benefits of populations that breast feed for several years versus in the United States, where children are typically switched over to cow’s milk at 9-12 months of age. A zinc/copper ratio of 38 leads to copper deficit in infants and is clearly not healthy for infants or adult humans. Additionally, a higher zinc to copper ratio (as found in cow’s milk) positively correlates with mortality due to coronary heart disease in 47 cities in the United States.

Thus, an optimal intake of zinc in an adult can range anywhere from 20-80 mg/day, depending on the person and the situation. The optimal intake of copper, however, seems to sit at around 3 mg/day, providing an optimal Zn/Cu ratio of anywhere from 4-20:1.

Foods with a high Zinc:Copper Ratio (these foods must be balanced with appropriate amounts of copper from other food sources):

  • Oysters
  • Muscle meat
  • Breakfast cereal
  • Cow’s milk
  • Prepackaged meat
  • Mollusks/shellfish

Foods with a low Zinc:Copper Ratio (these will need to be paired with foods higher in zinc):

  • Organ meats/liver
  • Seaweed/spirulina
  • Lentils/beans/chickpeas
  • Dark chocolate/cacao
  • Vegetables

The takeaway is that you shouldn’t make these high zinc:copper ratio foods are the only ones that you eat in your diet. Additionally, you should not overconsume high copper containing foods either, like eating 3 oz. of liver every day. As a rule of thumb, eat around 0.5 to 1 oz. of liver/day for copper and at least 12 oz. of red meat for zinc, iron, B12 and protein.

Exercise and Zinc:Copper

Exercise stimulates the growth of muscle and bone, which are made-up of larger amounts of zinc compared to copper (zinc/copper ratios 56 and 120, respectively) and thus exercise tends to protect against a diet higher in zinc to copper (i.e., more zinc gets directed towards muscle and bone growth). This may be why weightlifters are somewhat protected from their high intake of meat, as zinc is needed for muscle and bone growth. This also suggests that weightlifters need more zinc, in order to develop larger muscles and stronger bones. Thus, zinc requirements go up when building muscle, and this is likely why many weightlifters crave muscle meat (for the high zinc content).

Copper and Molybdenum

Another copper inhibitor is molybdenum (Mo). It is a mineral found in foods like pork, lamb, beef, beans, eggs and cereal grains in small amounts. Molybdenum and copper have been found to have antagonistic roles with each other. Indeed, a Mo/Cu ratio of 2.5/1 in animals can lead to copper deficiency and altered immune responses during infection.

Patients with type-2 diabetes have been shown to have higher serum and urine copper levels due to molybdenum removing it from tissues and eliminating it through urine. Those with severe nephropathy have a higher urine level of Cu/Mo. Thus, excess molybdenum, when combined with sulfur, may promote the excretion of copper through urine or bile via binding with protein-bound and free copper.

Copper Absorption

Copper is absorbed in the gastrointestinal tract and is transported to the liver.

Liver damage, cirrhosis or fibrosis increase the demand for copper and decrease its absorption. Fibrate medications (such as bezafibrate, fenofibrate, gemfibrozil) may be able to restore low copper levels in NAFLD disease and increase concentrations of hepatic Cu-Zn SOD. Malabsorption diseases like celiac disease, short bowel syndrome and IBS also reduce copper absorption. Copper deficiency has been seen in patients with celiac disease and it can cause anemia and thrombocytopenia. Gastric bypass surgery or colon removal can cause copper deficiency.

The oral bioavailability of copper can range from 12-75%, depending on the amount of copper in the diet. The average bioavailability of most normal diets is between 30-40% on the typical Western diet. That number can be lower in the presence of excess zinc, molybdenum, iron or fructose/added sugars. The refining of grains and cereals can reduce the copper content by up to 45%.

Indiscriminate use of multivitamins that often contain zinc and iron can be problematic for people low in copper.

Copper absorption occurs in the stomach and the small intestine, but the most efficient absorption takes place in the ileum and duodenum. For optimal absorption, copper needs acid from the stomach to be liberated from food. During absorption, excess copper is transiently stored in the enterocytes by binding to metallothionine. Once inside the enterocyte, cuprous ions bind to different copper chaperones to be distributed to various organelles and cell compartments. Thus, damage to the microvilli of enterocytes, which contain micronutrient absorption transporters, will decrease copper absorption. It has been shown that the overconsumption of refined sugar and fructose damages the enterocytes, which will likely reduce copper absorption.

  • Iron can compete with copper for absorption via the DMT1 (divalent metal transporter 1) transporter. Iron deprivation or iron deficiency due to chronic disease or malnutrition, can lead to copper overload, possibly due to absorption increases in ATP7A, which brings copper into the portal circulation. Zinc also competes with copper absorption via DMT1.
  • Sodium may enhance copper absorption or retention and people on amiloride may need more copper as it appears to reduce copper and sodium absorption in the intestine. Thus, low salt diets may reduce, whereas normal salt diets may improve copper absorption.
  • In the presence of excess copper, CTR1 reduces copper absorption by enterocytes. However, when enterocytes are damaged because of intestinal tract injuries, copper deficiency may occur.
  • Fructose increases the requirements for copper and exacerbates the effects of copper deficiency. Thus, added sugars are a tax on copper status.

Approximately 0.5-2.5 mg of copper is excreted via feces every day. Biliary copper secretion cannot be reabsorbed, as it is prevented by binding to bile salts and comes out in the feces. Thus, the body has the ability to get rid of copper excess through bile excretion, which is regulated by the liver (liver cells excrete excess copper into bile). Low blood copper levels, or low ferritin levels, leads to copper being released into the blood circulation. To prevent copper overload, surplus copper can be excreted through the natural shedding of the intestinal epithelial cells.

Copper absorption in the stomach is stimulated by an acidic pH and is inhibited by zinc and cadmium. Stomach acid frees up copper bound to food and facilitates peptic digestion, which releases copper from natural organic complexes. That is why proton pump inhibitors or other acid suppressing over the counter therapies or medications can reduce copper absorption as it reduces the release of copper from natural organic complexes in food.

Cadmium is a common toxic heavy metal that has accumulated in the environment due to pollution. Ironically, zinc helps to reduce the absorption of cadmium.

Vitamin C can enhance, or inhibit, copper absorption. If taken prior to (around 75 minutes before) or with copper, vitamin C reduces copper absorption by blocking the binding of copper to metallothionein. However, if vitamin C is taken after copper ingestion (75 minutes after) it increases ceruloplasmin and lysyl oxidase activity. Vitamin C also seems to help facilitate the transfer of copper ions into cells, reacting with the copper carrying protein ceruloplasmin, reducing cupric copper (CuII+) to cuprous copper (CuI+) making the bound copper atoms more freely available and facilitating their cross-membrane transport. Moreover, histidine may aid the transport of copper from albumin into certain cells. Additionally, glutathione appears to help facilitate the transfer of copper to metallothionine and superoxide dismutase. Thus, cysteine and glycine, which help to increase glutathione levels, may also help with copper transport in the body.

In large doses, vitamin C may decrease copper status by increasing iron and zinc absorption. However, there may not be enough vitamin C in whole foods like fruit and vegetables to inhibit copper absorption or deplete it.

  • That is why it is better to focus on getting vitamin C and potassium from whole foods and use supplemental doses only acutely during sickness or an infection. On the flip side, Vitamin C + E can also combat copper toxicity-induced lipid peroxidation and liver damage. They have also been shown to reduce the oxidation of HDL cholesterol caused by excess copper.

Copper homeostasis is maintained in the liver. Importantly, the thyroid gland regulates more than 5% of all the genes expressed in the liver, including copper metabolism.

  • Thyroid hormones stimulate the synthesis and export of ceruloplasmin from the liver into the serum. Thus, being hypothyroid may hinder copper homeostasis and utilization in the body.

One of the biggest chelators of copper is glyphosate. Deficiencies in trace minerals like iron, molybdenum, copper and others are associated with celiac disease and it can also be attributed to glyphosate’s ability to chelate these metals. Glyphosate is one of the most common pesticides in the U.S. used on almost all types of fruit and vegetables. Not only does it reduce the mineral content of the vegetation, but it also disrupts the microbiome potentially promoting malabsorption diseases.

  • Glyphosate is a strong chelator thanks to its ability to form strong complexes with transition metals. Glyphosate has also been shown to decrease iron, magnesium, manganese and calcium levels in non-GMO soybeans.

Copper-Dependent Enzymes and Functions and the Consequences of a Deficit

Copper-Dependent Enzymes/Proteins: Function: Consequences of Deficit

  • Cytochrome c oxidase: Cellular respiration: Decreased energy production
  • Superoxide dismutase: Dismutation of superoxide anion radical: Increased oxidative stress
  • Catalase: Catalyze the conversion of hydrogen peroxide into water: Increased oxidative stress and lipid peroxidation in the heart
  • Glutathione: Scavenge free radicals: Increased oxidative stress
  • Glutathione peroxidase: Eliminates hydrogen peroxide: Increased oxidative stress
  • NADPH: Free radical protection and increase nitric oxide: Reduction in glutathione and increased oxidative stress
  • Tyrosinase: Converts tyrosine to dopamine: Depression
  • Dopamine-B-hydroxylase: Converts dopamine to norepinephrine: Depression, decreased “fight or flight response”, potentially decreased ability to survive stressful events, obesity
  • Peptidylglycine alpha-amidating monooxygenase: Neuropeptide synthesis and peptide hormone processing: Brain processing problems
  • Lysyl oxidase: Conversion of procollagen to tropocollagen and of pro-elastin to elastin in the connective tissues: Decreased strength of blood vessels, cartilage, heart, bones, enamel, ligaments and damage to these tissues
  • Cartilage matrix glycoprotein: Formation of extracellular matrix and copper transport in cartilage cells: Decreased tendon strength, loss of cartilage tissue and osteoarthritis
  • Soluble pyridoxal-dependent monoamine oxidase: Oxidation of catecholamines to aldehydes: Reduced glucose uptake in fat cells and reduced leukocyte transmigration into endothelium decreasing pathogen killing
  • Ceramide galactosyl transferase: Myelinogenesis: Myelopathies and neurological disorders
  • Prostaglandin GG2 or GH2 reductase: Synthesis of prostaglandin F2- alpha: Inflammation, growth deficiency
  • Beta-oxidation: Governs fat burning: Metabolic syndrome, obesity & insulin resistance
  • Ceruloplasmin: Copper and iron transportation: Anemia, fatigue, iron overload
  • Hemoglobin: Tissue oxygenation and energy production: Anemia, fatigue, poor energy production
  • Hepcidin/Hephaestin: Intestinal iron absorption/oxidation of ferrous to ferric iron: Anemia

In humans, copper levels are high in the organs during childhood and start declining throughout later stages of life. During old age, hepatic and aortic copper decreases substantially, which is inversely associated with the concentration of calcium in the arteries.

Signs and Symptoms of Copper Deficiency

Anemia that may mimic iron deficiency or B12/folate deficiency, malabsorption of iron causing actual iron deficiency, leukopenia, neutropenia, high cholesterol, osteoporosis, histamine intolerance, hypopigmentation of skin and hair, neurotransmitter imbalances such as low adrenaline or high serotonin.

Patients with an acquired copper deficiency and lack of ceruloplasmin can get liver iron overload, diabetes, neurological issues and retinal degeneration. People with non-alcoholic fatty liver disease (NAFLD) have significantly lower copper levels in the liver, which suggests that copper deficiency likely contributes to the iron accumulation in the liver of those with NAFLD. Iron overload is associated with many diseases like arthritis, cancer, tumor growth, diabetes, heart failure and liver damage. Studies link excess heme iron with colon cancer. By reducing iron overload, copper may slow down the aging process. Furthermore, iron overload can induce copper deficiency. 

  • Anemia
  • Defective keratinization of the oral cavity
  • Neutropenia
  • Hypopigmentation of hair and skin
  • Abnormal bone formation/bone fragility
  • Cartilage damage, joint pain and arthritis
  • Reduced immunity
  • Vascular/blood vessel issues
  • Cardiac hypertrophy
  • Heart murmurs and valvular regurgitation
  • Fragile collagen/elastin (fragile organs/tissues) – tendon/tissue ruptures/tears
  • Aneurysms of blood vessels (rupture of heart/blood vessels)
  • Increased lipid accumulation in the heart
  • Abnormal EKG – changes in ST segments, prolonged PR intervals and R wave duration and amplitude
  • His Bundle electrical abnormalities
  • Increased QT intervals, inversion of the T wave and increased QRS amplitudes and notching
  • Decrease in ATP levels and energy
  • Increased lactic acid
  • Decreased ventricular contractility in the heart

Risk Factors for Copper Deficiency

  • The best food sources of copper are liver, oysters, shiitake mushrooms, pure chocolate, and spirulina. Other good sources are shellfish, whole grains, legumes, and potatoes. Diets low in these foods will predispose an individual toward copper deficiency.
  • Soil variation is large, and low soil copper is another major factor predisposing toward deficiency.
  • Improperly formulated infant formula and total parenteral nutrition have resulted in copper deficiency.
  • Zinc supplementation can cause copper deficiency, especially if the dose is over 45 milligrams or if the ratio of zinc to copper is greater than 15.
  • Impaired methylation, antacids, proton pump inhibitors, gastric bypass surgery, and any digestive problems affecting the stomach or upper intestine can cause copper malabsorption.
  • High doses of vitamin C may impair copper metabolism but evidence for this is limited.
  • Menkes disease is a very rare defect in copper metabolism that causes copper accumulation in some tissues but overall presents as systemic copper deficiency.
  • Copper deficiency can reduce the function of superoxide dismutase (SOD) increasing oxidative stress and oxidized lipids in the body. Furthermore, copper is needed to strengthen collagen and hence a lack of copper may reduce the health of the arteries and the heart. A lack of copper also reduces the body’s ability to use iron and can lead to anemias commonly thought to be due to iron deficiency.
  • Copper deficient diets can reduce cytochrome c oxidase activity and heme synthesis from iron and protoporphyrin. This reduction in cytochrome c oxidase limits the reduction of Fe3+ iron to Fe2+ iron to form heme. Thus, copper deficiency reduces iron utilization by the mitochondria.

Copper Toxicity

  • In theory, excess copper may cause oxidative stress and contribute to Alzheimer’s disease and other neurodegenerative diseases. However, the only well-established syndrome of copper toxicity is Wilson’s disease, which is a genetic defect in the ability to excrete copper into the bile. This results in unregulated copper absorption, impaired transport into some tissues causing local deficiency, but net copper overload and deposition of excess copper in the liver, brain, and cornea, where it causes oxidative damage. 
  • Copper-rich diets are unlikely to meet the upper limit, and they are also rich in zinc, which protects against copper toxicity. Supplemental copper should be kept under 10 milligrams per day, and ideally should be kept under 3 milligrams per day unless higher doses are needed to correct a deficiency or to prevent the zinc-to-copper ratio from exceeding 15. Copper may contaminate water at doses that exceed the upper limit, but this will make you nauseated and turn your laundry, sinks, toilets, and bathtubs light blue or green.
  • Filtering the water or running it for a minute before consumption will eliminate a large amount of contaminating copper. Infants cannot regulate their copper absorption and should not be given copper supplements.

Testing Copper Status

C-reactive protein has been associated with an elevation of copper. Usual plasma copper tests are insensitive and not entirely accurate. Low copper levels in the liver would likely be a better determinant but a more practical strategy would be to measure leukocyte copper levels, which are more reflective of total body copper status and are depleted in those with significant atherosclerosis or coronary artery disease.

Unfortunately, measuring copper levels in the liver requires a biopsy and hence it is not very practical. Hair mineral analysis is a potential option to add to other measurements for an overall assessment of trace mineral status. Scalp hair remains isolated from other metabolic activities and is a unique indicator of elements concentrated in an individual at a given time point. Hair analysis has been used for successful assessment of heavy metal toxicity. Red blood cell copper may also be a better indicator of copper status versus serum levels and may reveal an undiagnosed pandemic of copper deficiency.

Best to Worst Ways to Diagnose Copper Deficiency:

  1. Liver copper levels
  2. Leukocyte copper levels
  3. Red blood cell copper levels
  4. Blood copper levels and ceruloplasmin

Testing Caveats

  • Ceruloplasmin is increased by inflammation and estrogen. Since most copper within serum is bound to ceruloplasmin, this tends to elevate serum copper as well, but to a lesser degree.
  • Pregnancy nearly doubles the levels of these markers. Lactation has a significant but weaker effect.
  • Supplemental estrogen increases copper by 30 to 90%.
  • Whether these markers remain suitable for assessing copper deficiency during these conditions and how the ranges should be altered has not been studied.

Correcting Copper Deficiencies

  • 7 milligrams of supplemental copper per day for two months have been shown to fully correct anemia and neutropenia associated with celiac-induced copper deficiency.
  • Ideally copper-rich foods should be emphasized, but this can serve as a general strategy for supplementation. The aim should be to normalize blood markers and resolve any related signs and symptoms.
  • If the cause is zinc supplementation, the zinc should be removed until the deficiency is fixed, and the dose should be lowered or its ratio to copper should be improved if the supplement is reintroduced. If the cause is antacids or proton pump inhibitors, alternative strategies for improving these symptoms should be sought if possible. Malabsorption disorders require medical treatment.

Correcting Copper Toxicity

Wilson’s disease requires chelation therapy. However, chelation therapy may cause deficiencies of other minerals, so screening for other deficiencies is advised. The rare cases of outright copper poisoning require close medical attention. Other potential harms of excess copper are speculative and if suspicions are raised, improving zinc status is likely the best protection.



Selenium is an essential mineral important for hormonal production, antioxidant defense and redox homeostasis (balancing oxidative stress). It’s also a cofactor for the antioxidant glutathione peroxidase – boosting its expression and activity. Viral infections can increase the need for selenium due to increased production of reactive oxygen species.

Selenium is involved in repairing oxidized methionine residues, thus playing a role in oxidized protein repair systems. Cooking protein-rich food like meat at high temperatures creates carcinogenic compounds called heterocyclic amines and polycyclic aromatic hydrocarbons, which might be mitigated in the presence of adequate selenium.

Selenium deficiency is linked to pathogenicity of multiple viruses. Deficient selenium enhances the pathology of influenza infection. Sufficient selenium improves survival from influenza-induced pneumonia. Getting more dietary selenium protects against influenza. The host’s selenium status is a determining factor in influenza virus mutations. Supplementing 200 mcg of selenium for 8 weeks in selenium-deficient people increased cytotoxic lymphocyte-mediated tumor cytotoxicity by 118% and natural killer cell activity by 82.3% compared to baseline. The best source of selenium appears to be yeast.

Selenium is contained in over two dozen selenoproteins in the body, many of which have roles in cell redox homeostasis and antioxidant defense. Selenium has two forms: inorganic (selenate and selenite) and organic (selenomethionine and selenocysteine) both of which are good dietary sources of selenium.

Sodium-Selenium-Iodine (SSI) Connection

Selenoproteins are involved with thyroid hormone metabolism and antioxidant defense. Selenium is present in selenoproteins as selenocysteine, which is essential for enzymatic activities. In addition to iodine, the thyroid gland is also the highest concentrated source of selenium per gram of tissue in the body due to a high number of selenoproteins.

The main selenoproteins, namely glutathione peroxidase, thioredoxin reductase and deiodinases are expressed in the thyroid gland in large quantities.

How Selenoproteins Affect Thyroid Function

  • Glutathione peroxidases (GPx) are selenoenzymes that regulate thyroid hormone synthesis, contributing to the high content of selenium in the thyroid. They also protect thyroid cells against hydrogen peroxide and other free radicals, which would otherwise inhibit thyroid function. Selenium deficiency reduces glutathione peroxidase levels. A study noted that there was an association between higher TSH and decreased selenium/glutathione peroxidase activity.
  • Thioredoxin reductases (TrxR) are essential for antioxidant defense and regulation of certain transcription factors. So far, there have been three selenoenzymes in the thioredoxin reductase family identified – TrxR1, TrxR2 and TrxR3. They help protect the thyroid against oxidative damage.
  • Deiodinases (DIO) scavenge iodide from iodinated tyrosine inside the thyroid gland during thyroid hormone biosynthesis and are a family of thioredoxin proteins. The breakdown of thyroglobulin (Tg) during thyroid hormone biosynthesis produces 6-7 times more iodinated tyrosine than thyroid hormones; deiodinases are then available to salvage iodide from iodinated tyrosine. Without deiodinase, iodide and left-over iodinated tyrosine would be excreted through urine, reducing thyroid hormone biosynthesis. In fact, mutations in deiodinases cause iodine deficiency and selenium directly controls deiodinase activity. TSH stimulates the conversion of T4 into T3 via deiodinases.

Thus, selenium is important for not only activating thyroid hormones, but also recycling them. In other words, iodine does not work without selenium and sodium and a lack of any of these essential nutrients will worsen thyroid function.

Chronic lymphocytic thyroiditis (CLT) can be improved with selenium at a dose of 200 mcg/day given for 3-12 months by decreasing anti-thyroperoxidase (TPO) antibodies. The suppression of antibodies appears to require doses above 100 mcg/day to maximize glutathione peroxidase. CLT is the most common autoimmune thyroid disease in which iodine status is adequate and where genetic factors of selenium deficiency are present. Giving 200 mcg of selenium/day as selenomethionine might help to reduce postpartum thyroiditis by reducing thyroid antibodies. Selenium given at 80 mcg/day for 12 months has also been observed to significantly lower anti-TPO antibodies in patients with Hashimoto’s thyroiditis with normal T4 and TSH levels.

  • Anti-TPO antibodies promote the production of inflammatory cytokines by thyroid lymphocytes, making the effects of selenium more pronounced during episodes of inflammation.

Graves’ disease is also correlated with lower selenium levels and selenium is necessary for protecting against the increased oxidative stress that occurs during this condition. Selenium supplementation has also been shown to improve the quality of life in patients with Graves’ orbitopathy.

Selenium supplementation in those who have a baseline deficiency likely provides significant benefits, whereas consuming over 300 mcg/day of selenium may potentially lead to negative consequences:

  • Generally, the majority of observational studies and meta-analyses see an inverse relationship between selenium/selenoprotein status and cardiovascular disease risk. The main mechanism appears to be due to selenoproteins’ ability to inhibit oxidative stress, lower inflammation and protecting vascular cells against apoptosis or calcification. Selenoproteins regulate redox and calcium homeostasis. Selenoproteins increase resistance to oxidative stress, whereas selenium deficiency increases damage from oxidative stress.
  • Selenoproteins can prevent the oxidation of lipids, which reduces the potential for atherosclerosis. The oxidation of LDL is a bigger risk factor for atherosclerosis and heart disease than total or LDL cholesterol levels alone. Furthermore, lipoproteins become oxidized when oxidative stress exceeds the body’s antioxidant capacity. Supplemental selenium at doses of 100-300 mcg/day has been shown to lower total cholesterol and raise HDL cholesterol, which may help clear the blood from potentially oxidizable lipids. 
  • Glutathione peroxidase-3 (GPx3) deficiency, which is a selenium-dependent enzyme, promotes platelet thrombosis and vascular dysfunction. GPx3 can also inhibit the oxidation of LDL cholesterol by eliminating hydroperoxides, thus preventing vascular inflammation and atherogenesis. GPx4 has similar effects. Selenium levels are directly correlated with GPx activity.
  • Impairment of selenoproteins during selenium deficiency may be a contributing factor in congestive heart failure and cardiomyopathy. Low selenium status is associated with future cardiovascular death in patients with acute coronary syndrome (someone who has had a heart attack). Selenium deficiency in heart failure patients is independently associated with impaired exercise tolerance and a 50% higher mortality rate.
  • Thioredoxins also regulate cardiac function and cardiovascular disease risk. They also affect cardiac remodeling. Trx-1 has been shown to reduce oxidative stress and cardiac hypertrophy in response to oxidative stress.

People with lower selenium status are more likely to experience cognitive decline and neurodegeneration because of increased oxidative stress. Low selenium in the elderly also correlates with worse memory. In France, supplementation with antioxidants, including selenium, has been shown to improve episodic memory and semantic fluency in subjects aged 45-60.

Heavy Metals

Selenium has detoxifying effects on several heavy metals, such as cadmium, mercury and lead. The mechanisms are mediated by glutathione peroxidases and other antioxidants that help to eliminate these toxic compounds. Mercury toxicity can inhibit selenoenzymes that are needed to combat oxidative stress. Thus, selenium might be a cornerstone mineral for preventing the damage that occurs from heavy metal toxicity.

  • This is also one of the reasons why seafood that has higher levels of selenium poses a lower risk for mercury toxicity. Tuna actually contains selenoneine, which is a potent antioxidant. The ratio of selenium to mercury matters more as selenium counteracts the harms from mercury. The consumption of fish can contribute up to 16.7% of the dietary protein intake for humans worldwide.
  • The addition of selenium fertilizers has been shown to reduce the accumulation of cadmium and lead into crops like lettuce. Fruit stays firm and ripe longer if sprayed with foliar selenium, possibly due to an increased protection against oxidation. Selenium also protects plants against environmental stressors like UV-B radiation and extreme temperatures.
  • However, in large amounts, selenium can act as an environmental pollutant, killing fish. In most cases, high selenium in the environment is the result of activities like coal burning and mining.


The RDA for selenium is 15 mcg for infants, 20-40 mcg for children and 55 mcg for adults. During pregnancy and lactation, the RDA for selenium increases to 60-70 mcg/day, respectively. Selenium toxicity or selenosis generally occurs if you exceed 400 mcg/day (although the actual level that induces toxicity is likely at 800mcg/day or higher).

Large doses of selenium in individuals without selenium deficiency may promote hyperglycemia and insulin resistance. Symptoms of too much selenium consumption include a metallic taste in the mouth, garlic odor, hair and nail loss and brittleness. Diarrhea, nausea, fatigue and skin lesions are also common.

The low selenium content of New Zealand’s diet was fixed by increasing the import of high-selenium wheat. Selenium levels are well known to be lower in smokers and the elderly.

Things that Raise the Requirement for Selenium

  • Hemodialysis removes selenium from blood
  • HIV patients have lower levels of selenium because of malabsorption
  • Certain medications like cisplatin lower selenium in hair and serum
  • Malabsorption conditions like IBS, intestinal permeability, etc.
  • Aging
  • Heavy metal toxicity and pollution
  • Living in a low selenium soil environment
  • Hypothyroidism
  • Chronic inflammatory conditions like diabetes and cardiovascular disease

General Note on Selenium

Due to the extremely wide variation of soil selenium and the fact that hardly anyone knows exactly where all of their food comes from, it’s assumed that everyone is at approximately equal risk of having too much or too little selenium, and believe everyone should measure their plasma selenium to confirm their actual selenium status. Deficiency and toxicity look very similar to one another, underscoring the need to measure selenium status even further.

Availability from Food

Brazil nuts, wild salmon, kidneys, mutton, egg yolk. 

How much selenium is in food depends on the amount of selenium in the soil. The soil consists of inorganic selenium that the plants obtain and convert into the organic form. Selenocysteine and selenite promote selenoprotein biosynthesis by getting reduced to hydrogen selenite, which is then converted to selenophosphate which supports selenoprotein biosynthesis. In animal and human tissues, selenium is in the form of selenomethionine and selenocysteine.

Ocean waters and rivers also contain quite a lot of selenium, which is why meat, fish and seafood are generally much higher in selenium than plants.

2-3 Brazil nuts per day will achieve daily requirements. Other options for daily selenium consumption are consuming seafood 2-3 times per week since that will also provide iodine, omega-3s and protein. The majority of selenium is absorbed in the small intestine (50-80%) and excreted by kidneys (60%). Thus, your selenium status is also determined by the state of your digestive and excretory organs.

Frequency of Deficiency

Mild deficiency is common

Selenium-Dependent Enzymes, Functions and Consequences of a Deficit

Selenium-Dependent Enzymes/Proteins: Function: Consequences of Deficit

  • Glutathione Peroxidase: Removes hydrogen peroxide: Increased oxidative stress and weaker immunity
  • Thioredoxin reductase: Antioxidant defense, peroxynitrite protection, convert T4: Oxidative stress, atherosclerosis and lipid peroxidation
  • Deiodinases: Convert T4 into T3 and iodine transport in thyroid cells: Hypothyroidism
  • Thyroid Hormones: Regulate metabolic rate, body temperature and energy balance: Chronic fatigue, frailty, weight gain, metabolic syndrome and decreased immunity
  • Glutathione: Scavenge free radicals: Increased oxidative stress

Signs and Symptoms of Selenium Deficiency

  • Keshan disease is a classical deficiency disorder. It includes hepatic cirrhosis, white nail beds and fingernails falling out, and cardiac insufficiency with fibrosis and necrosis.
  • Generally, selenium deficiency increases the vulnerability to infections, toxins, and other nutrient imbalances, especially to those that cause oxidative stress, such as vitamin E deficiency and iron overload.
  • Less well established but plausible signs of selenium deficiency include the following: poor production of T3, the active thyroid hormone, from its precursor, T4; Hashimoto’s thyroiditis; and cancer, especially prostate, colorectal, and lung cancers. While not clearly documented, white spots and streaks in the fingernails might occur in deficiency; however, these are more clearly documented in toxicity.
  • Selenium deficiency increases thyroid size and risk for goiter. Lower selenium levels are associated with increased thyroid volume and nodule formation. Thus, adequate selenium may protect against goiter as well as thyroid disease. The incidence of goiter in children is associated with the amount of selenium in the local soil – i.e., low selenium in soil, low selenium in food, selenium and iodine deficiency, hypothyroidism and goiter. Fixing iodine deficiency in children with goiter and selenium deficiency does not reduce the volume of goiter or improve thyroid function.
  • Selenium deficiency leads to the activation of oncogenes (cancer causing genes) due to an increased formation of reactive oxygen species. Thus, selenium might have a role in the prevention of cancer due to its antioxidant and immunomodulatory properties.

Risk Factors for Selenium Deficiency

  • Selenium content is richest in organ meats and seafoods. Brazil nuts are rich in selenium but more variable than animal foods. Diets lower in these foods are more likely to produce selenium deficiency than diets high in them.
  • However, the overwhelming risk factor for selenium deficiency is deficient levels of selenium within the soils where most of the foods are grown. Deficient methylation should not lower blood levels of selenium but might impair the utilization of selenium for biological functions.

Signs and Symptoms of Selenium Toxicity

  • High soil content: Hepatic cirrhosis, hair loss (alopecia), and nails that are brittle with white spots and streaks and may fall out.
  • In cases of acute poisoning due to errors in formulating supplements: muscle cramps, nausea, diarrhea, irritability, fatigue, loss of the hair and nails, and peripheral neuropathy (weakness, numbness, pain, or tingling in the hands and feet).
  • More moderate excesses of selenium may increase the risk of diabetes.

Risk Factors for Selenium Toxicity

High soil levels are the main cause of toxicity, but in the past, poisoning has occurred from mistakes in the formulation of supplements. Deficient methylation may impair the ability to excrete excess selenium.

Testing for Selenium Status

Plasma selenium is the ideal marker of selenium status. Serum and whole blood are likely to be equivalent, but plasma selenium is better studied and preferred. Plasma selenium should be kept between 90 and 140 μg/L, with the possible sweet spot being 120. For units, μg/L and ng/mL are interchangeable.

Correcting a Selenium Deficiency

  • Organ meats, seafood, and Brazil nuts can be used in the diet to increase selenium intakes, but it must be kept in mind that Brazil nuts are extremely variable in their selenium content. Some sources may advocate using mushrooms, but selenium is poorly bioavailable from mushrooms.
  • For supplements, selenomethionine should be used. Selenite and selenate are acceptable but not preferable. Methylselenocysteine should be avoided. 100 micrograms per day is fully adequate to correct a deficiency, but 200 micrograms per day could be used for 3-4 weeks if faster progress is desired. Regardless, five months should be given to see the full effect.
  • If plasma levels cannot be sustained in the optimal range with diet alone, the long-term maintenance dose of a supplement should be 100 micrograms per day for adults, or 1-1.5 micrograms per kilogram body weight per day for children. It is important to follow up plasma selenium to ensure the target range has been reached and not exceeded.
  • Selenium – 50-200 mcg daily improves glutathione peroxidase and immune cell proliferation.
  • Taking 200 mcg of selenium has been shown to increase glutathione peroxidase in patients with chronic kidney failure. Over 400 mcg/day of selenium, however, can be toxic and cause nausea.
  • Selenium supplementation without prior iodine replenishment may exacerbate hypothyroidism because there isn’t enough glutathione peroxidase to clean up the hydrogen peroxide that gets created during iodine-deficient hypothyroidism. Those unleashed free radicals will then begin to damage thyroid cells and interfere with thyroid health. Thyroid function has not been shown to change in healthy subjects receiving additional supplemental selenium if they have no parameters of hypothyroidism.

Note on Selenium Supplementation

Selenium supplements mostly come in the form of selenomethionine, selenium-enriched yeast, sodium selenite or sodium selenate. The human body can absorb up to 70-90% of selenomethionine but only 50% of selenium from selenite. Thus, selenomethionine is the best organic selenocompound for improving selenium status because it is incorporated into proteins in a non-specific way. However, selenomethionine needs to be reduced to hydrogen selenide (H2Se) by selenocysteine beforehand, making it less efficient metabolically. Nevertheless, organic selenocompounds like selenomethionine cause less acute toxicity, which is why they are more preferred in short-term therapy.

Plasma or serum selenium levels at 8 mcg/dL or above are enough to meet the requirements for selenoprotein biosynthesis. The average serum selenium concentration in U.S. adults over 40 years old is 13.67 mcg/dL. Males tend to have higher selenium levels than females and whites more than African Americans. Blood and urine selenium reflect only recently consumed selenium. Measuring glutathione peroxidase can be an indirect measurement of selenium status. Selenoprotein P may be one of the best markers for measuring total body selenium status.

Correcting Selenium Toxicity

  • In the case of toxicity, liver damage and other complications will require close medical care.
  • For less severe excesses of selenium, the source of excess selenium, whether supplements or foods, should be removed. Since excess selenium causes oxidative stress, the other nutrients in the antioxidant section should be examined and optimized.


It forms hemoglobin, comprises proteins throughout the body, and regulates cell growth and differentiation. It even helps maintain brain function, metabolism, endocrine function, and immune function and plays a role in the production of ATP. However, if you consume too much, you can develop hemochromatosis (particularly dangerous for men who don’t get rid of excess, via menstruation, and sedentary individuals who don’t turn over as many RBCs). As your cells create energy, they create low, manageable levels of superoxide, which enzymes convert into hydrogen peroxide to be converted to water and oxygen. When iron interacts with superoxide or hydrogen peroxide it leads to a chemical reaction that produces a free radical known as hydroxyl radical. Too many of these can lead to age-related chronic conditions like Alzheimer’s, Parkinson’s, cancer, heart disease, and diabetes.

Iron is a cofactor to many DNA repair and replication proteins like Pol #, Rad 3/XPD and Dna2. Mutations of iron-requiring proteins are associated with diseases of DNA repair defects in mammals. Base excision repair glycosylases that remove damaged bases contain the iron-sulfur cluster protein cofactor. Hence, good iron (and thus by default copper) and sulfur status are important for DNA repair.

Frequency of Deficiency

Developing countries and some vegans. Celiac disease, Crohn’s disease and pregnancy are predisposing factors

Availability from Food

Blood, bovine liver, oysters, mussels, beef, sardines, dark green vegetables. Vitamin C promotes the absorption of iron.

Signs and Symptoms of Iron Deficiency

  • Iron deficiency leads to anemia, which may be asymptomatic early on, but which can cause declining work performance, fatigue, weakness, pale skin, arrhythmia, palpitations, dizziness or lightheadedness, and muscle cramps. During anemia, blood is rerouted to supply the brain and heart at the expense of most other tissues, which causes a decline in many other bodily functions, such as digestion and skin health. Iron deficiency also causes hypothyroidism, leading to signs such as cold hands and feet, increased sensitivity to cold in general, hair loss, and swelling (edema) in the face.
  • In children, iron deficiency causes short stature and permanent decrements in brain function manifesting as low IQ, and it is especially critical to catch it and correct it early. Iron deficiency also delays puberty.

Risk Factors for Iron Deficiency

  • Loss of blood during menstruation and increased needs during childhood and pregnancy are the major risk factors for iron deficiency. Additionally, the absorption of iron is more reliable from animal foods than from plant foods, and the phytate found in whole grains, nuts, seeds, and legumes (especially abundant when these foods are not processed by fermentation, soaking, or sprouting) is a major inhibitor of iron absorption.
  • Polyphenols, found generally in plants, and especially rich in fruits and vegetables, are also inhibitors of iron absorption. Thus, a dietary pattern low in animal foods and rich in plant foods is an additional risk factor for iron deficiency, especially when iron-containing supplements and iron-fortified foods such as enriched flour are not used.

Signs and Symptoms of Iron Overload

  • Clinical iron overload is known as hemochromatosis. Classically, it is understood as causing four manifestations, known as a tetrad: hepatic cirrhosis, diabetes, hyperpigmentation of the skin, and cardiac failure. The hyperpigmentation increases in response to sun exposure and generally consists of brown, bronze, or gray coloring. It can be driven by iron deposits or increased melanin; however, iron overload is a major risk factor for a collection of disorders known as porphyrias, where intermediates in heme synthesis known as porphyrins may also accumulate in skin and generate brown or red coloration in response to sun exposure. Hyperpigmentation may also affect the teeth and be accompanied by enamel loss. Patients also report fatigue, joint pain, depression and mood swings, hair loss, chest pain, dizziness, impaired sexual function, menstrual problems, and abdominal pain. Iron overload appears to raise blood cholesterol and to contribute to Alzheimer’s, and possibly Parkinson’s. Iron overload causes oxidative stress, so general wear and tear on the tissues, problems associated with the deficiencies of other antioxidant nutrients, and aggravation of most chronic disease risk, should be expected.
  • Production of reactive oxygen species during iron metabolism causes lipid peroxidation. High iron levels in the body increases the susceptibility to having greater levels of oxidized lipids. Iron overaccumulation promotes oxidative stress and is associated with many diseases like arthritis, cancer, tumors, diabetes, heart failure and liver damage. Too much ferritin also supports lipofuscin formation, which is one of the main age-related pigments that accelerates aging.

Risk Factors for Iron Overload

  • In the HFE gene, there are two notable variants, C282Y and H63D. Globally, for C282Y, 7.5% are heterozygous and 0.5% are homozygous; for H63D, 17% are heterozygous and 2% are homozygous. Conventionally, homozygosity for C282Y is considered the major risk factor for hemochromatosis. However, clinical hemochromatosis does occur in patients homozygous for H63D.
  • If one considers the oxidative stress of more moderate iron overload, then having any of these genotypes is a very significant risk factor. Although most hemochromatosis results from these mutations in the HFE gene, there are at least six other rarer genes in which mutations can be the cause, and tests for these genes are not accessible. It is therefore imperative to use blood tests as the major means of assessing iron status and to only use genetic tests as a means of explaining the results and determining what to do about them.
  • Blood transfusions, hemodialysis, and liver diseases may also contribute to iron overload. Iron-rich diets, iron-containing supplements, and foods fortified with iron such as enriched flour, may make a contribution to iron overload but are unlikely to cause even moderate iron overload if there are not additional risk factors present.

Testing for Iron Status

  • On a complete blood count (CBC) low hemoglobin, low mean corpuscular hemoglobin (MCH), and high red blood cell distribution width (RDW) are indicators of iron deficiency anemia. Mean corpuscular volume (MCV) is likely to be low (making the anemia microcytic), unless a deficiency of vitamin B12 or folate also exists.
  • Reticulocyte hemoglobin (CHr) may decrease earlier than the other markers and may be particularly useful in children, where catching anemia early is critical to preserving the brain from irreversible decreases in function.
  • Iron saturation can be found on an iron panel and is an estimate of transferrin saturation. Transferrin saturation can be calculated directly by getting the iron panel and serum transferrin at the same time. To calculate it, divide the serum iron from the iron panel by the serum transferrin and multiply by 70.9%. It is always preferable to use transferrin saturation over iron saturation because iron saturation often underestimates transferrin saturation and sometimes the gap is large. At a minimum, test both one or two times to determine whether iron saturation is a good proxy for transferrin saturation in your specific case and only substitute the former if it appears reliable for you. Ideally your transferrin saturation is between 30 and 40%. Consistent deviations from these percentages, even in the normal range, should be considered potential early signs of deficiency (under 30%) or overload (over 40%). Deviations out of the normal range should be considered very clear indicators of a current problem.
  • Ferritin: Ferritin is a good indicator of long-term iron stores when oxidative stress and inflammation are not present. However, oxidative stress and inflammation both increase ferritin levels independently of iron status and can create a false impression of iron overload. Oxidative stress and inflammation may also keep ferritin normal when it would otherwise drop, masking cases of iron deficiency. When ferritin is normal or high and all other signs suggest iron deficiency anemia, this indicates anemia of chronic disease. It is harmful and potentially fatal to treat this as a case of iron deficiency and requires medical care. When there are no signs of oxidative stress or inflammation, low ferritin should be taken as a sign of iron deficiency and high ferritin as a sign of iron overload, especially when corroborated by transferrin saturation.
  • High-Sensitivity C-Reactive Protein: hs-CRP is a marker of systemic inflammation. Inflammation may drive up ferritin but make all other markers look like iron deficiency. When ferritin is critical to the interpretation, hs-CRP should be measured to rule out a contribution of inflammation to the ferritin measurement. If hs-CRP is high, ferritin is normal or high, and all other markers look like iron deficiency, anemia of chronic disease should be considered and any nutritional treatment should pend proper medical diagnosis and care.

Testing Caveats

  • The anemia of other nutrient deficiencies, especially copper but possibly vitamin B6, may cause similar alterations to hemoglobin levels. Riboflavin and copper deficiencies may contribute to iron deficiency directly by impairing its absorption. Macrocytic anemia caused by vitamin B12 or folate deficiencies could coexist with iron deficiency and make the red blood cell measurements more difficult to interpret, especially the MCV. Anemia can have other causes such as kidney disease, bone marrow disease, thalassemia minor, sickle cell anemia, autoimmune disorders and exposure to certain toxic chemicals.
  • Friedrich’s ataxia is a genetic disorder of iron distribution that causes some manifestations of deficiency and others of iron overload, but with normal iron markers. The ataxia (loss of full control over body movements) resembles that seen in vitamin E deficiency and the latter is often mistaken for the former.

Correcting an Iron Deficiency

  • Temporarily reduce plant foods and use iron-rich foods such as clams, liver, and red meat multiple times a day. For vegetarians, sprouted legumes, greens, seaweed, and potatoes are the best food sources, and the iron will be best absorbed if accompanied by 500-1000 mg of vitamin C per meal. 
  • Supplements that promote detoxification, such as sulforaphane or milk thistle, should be avoided until the deficiency is corrected.
  • Iron supplements may often be needed. Ferrous sulfate is the most common, but it contributes to oxidative stress and bacterial dysbiosis in the intestines and causes constipation and other undesirable side effects. The recommended supplements (Testing Nutritional Status) to avoid the risk of these side effects are Iron Smart liposomal iron and Proferrin ES heme iron. A meal of clams can provide 10-20 milligrams of iron per meal. This alone meets the RDA for everyone except pregnant women, who require 27 milligrams per day. Retest monthly until markers are in range and then reduce the dose. Except for pregnant women the appropriate maintenance dose is twice a day. Iron supplements should not be given to infants under the age of six months.
  • Iron deficiency that does not improve with iron supplementation may reflect a need to address copper or riboflavin deficiencies.
  • The goals for correcting the deficiency, whether with foods or supplements, are to bring all anemia markers into the normal range, bring transferrin saturation between 30 and 40%, and bring ferritin up to at least 60 ng/mL and preferably 100-150 ng/mL.

Correcting Iron Overload

  • Clinical hemochromatosis can cause organ failure and it is imperative to achieve a proper diagnosis and medical treatment, which may involve chelation or phlebotomy.
  • When correcting more moderate iron overload, blood donation is a good option. This removes iron with little risk of causing deficiencies in other nutrients.
  • Donate once every two months two or three times, and then recheck the iron markers four weeks after the last blood donation.
  • The primary goal is to bring transferrin saturation under 40%, but not lower than the bottom of the reference range and not consistently under 30%. The secondary goal is to bring ferritin below 60 ng/mL, and as l ow as 20 mg/mL if it improves signs, symptoms, oxidative stress markers, or the individual’s subjective sense of wellbeing.
  • Consuming 300 milligrams of calcium per meal and including sources of phytate such as whole grains, legumes, nuts, and seeds can help reduce iron absorption from food. If taking this approach, or if using chelation treatment, it is important to assess the status of zinc and other nutrients, since their absorption may suffer too.
  • Additionally, detoxification-promoting supplements such as milk thistle or sulforaphane will help shuttle iron into ferritin, which is protective.

Glutathione (GSH)


Glutathione (GSH) is the body’s main antioxidant produced in the liver. It protects against free radicals, heavy metals and helps to eliminate lipid peroxides as well as toxins through Nrf2-mediated M1-like macrophage polarization. Immune cells work best with optimal glutathione levels that balance redox status. GSH is more powerful and practical than regular antioxidant supplements because the body self-regulates it in conjunction with the immune system. Glutathione will either stimulate or inhibit immune response to control inflammation, thus protecting against autoimmunity as well, by priming T cells for inflammation. However, endogenous glutathione not only limits inflammatory reactions but fine-tunes the innate immune response towards antiviral pathways in response to an infection independent of GSH’s antioxidant properties.

GSH shields cells and cellular molecules from damaging oxidants and facilitates the excretion of toxins from cells. You need adequate protein intake to form it (0.5-0.8g per pound of bodyweight). Consume foods with GSH precursors, including milk thistle, quality whey protein, arugula, broccoli, cauliflower, and kale, and foods that support methylation, such as avocado, lentils, liver, garbanzo beans, Brazil nuts, grass-fed beef, and spinach.

Glutathione promotes the regulation of nitric oxide by enhancing citrulline function. Without enough NADPH, your body can’t recharge glutathione after it becomes oxidized. This will put breaks on all the detoxification systems. Glutathione is extremely important for protecting red blood cells from oxidative stress and its levels are highly dependent on magnesium.

  • Additionally, magnesium helps to provide the ATP required for glutathione synthesis and two ATP molecules are used for the biosynthesis of one glutathione molecule.
  • Selenium is a cofactor for the antioxidant glutathione peroxidase, boosting its expression and activity, this is important for reducing inflammation during viral infections. Supplementing selenium replete humans with 200 mcg/day of selenium can improve T-lymphocyte mediated immune responses, increase cytotoxic lymphocyte-mediated tumor cytotoxicity and natural killer cell activity compared to baseline.
  • Furthermore, taking 297 mcg/day vs. 13 mcg/day of selenium improves the activation and proliferation of B lymphocytes, enhances cytotoxic T lymphocytes and improves activated T cell function.
  • Another antioxidant defense mechanism against free radicals is metallothioneins (MTs), which are small, cysteine-rich, heavy metal-binding proteins. They are mostly known for detoxifying heavy metals, in particular cadmium and maintaining metal ion homeostasis. Human cells with excessive MTs are resistant to cadmium poisoning. In mammals, MTs bind zinc but if there’s excess cadmium, MTs will bind cadmium instead of zinc. During stress, MTs release zinc when nitric oxide and ROS levels increase. Although zinc itself raises the zinc-binding activity of metallothionein, zinc is needed to upregulate MTs through metal regulatory transcription factor 1 (MTF-1). Thus, the antioxidant effects of MTs are dependent on zinc. Zinc is also needed for glutathione production, as revealed by studies wherein zinc deficiency is accompanied by a deficiency of glutathione and increased oxidative stress. Zinc also protects endothelial cells from hydrogen peroxide via Nrf2-dependent stimulation of glutathione biosynthesis.

Benefits of Glutathione

  • Glutathione is a master antioxidant that neutralizes free radicals and keeps other antioxidants like vitamin C and E in their active form.
  • Glutathione reduces oxidative stress, which in high amounts can lead to many diseases and cancers.
  • Glutathione supports liver health and helps fight fatty liver disease. The liver being the most important detox organ, it greatly benefits from glutathione.
  • Glutathione aids the immune system by controlling inflammation and regulating autoimmune responses.
  • Glutathione promotes the regulation of nitric oxide by enhancing citrulline function. This improves blood flow and supports heart health. Citrulline levels typically plummet with acute respiratory distress, especially during sepsis, which can be an end-stage complication of viral infections. Improving citrulline levels can help with endothelial health due to increased nitric oxide levels and nitric oxide itself has numerous antiviral effects. Thus, maintaining good glutathione and citrulline levels should help to ensure sufficient nitric oxide and improved immune function.
  • Glutathione regulates cell death and cell cycle. A deficiency of glutathione can result in apoptosis or cellular death.
  • Glutathione is used for DNA repair, protein synthesis, amino acid transportation and enzyme activation. All of the body’s systems are affected by glutathione.

Food Sources

Fruit and vegetables contribute up to 50% of dietary glutathione, whereas meat contributes 25% for an average diet. Direct food sources high in glutathione are freshly prepared meat, fruit and vegetables are moderate sources and dairy and cereal are low in glutathione. Freezing foods maintain relatively the same amount of glutathione as fresh food, but other preservation methods, such as fermentation or canning, lead to extensive losses. Whey protein is also a good source of cysteine and hence glutathione and has been shown to lower oxidative stress. Milk thistle can raise glutathione levels and has antioxidant properties. Turmeric and curcumin can also promote glutathione synthesis and inhibit inflammation.

Supplements that promote glutathione production are N-acetyl cysteine (NAC), alpha-lipoic acid and liposomal glutathione. Magnesium and vitamin C can also increase glutathione levels. Most glutathione supplements are destroyed by the digestive tract and they’re poorly absorbed when taken orally. To circumvent this, many advocate for liposomal glutathione. 

Signs and Symptoms of Poor Glutathione Status

Poor immune function, asthma, respiratory congestion, and in severe cases liver failure.

There are many things that deplete your body’s glutathione levels, such as environmental toxins, poor lifestyle habits, sleep deprivation, excessive alcohol, chronic stress, getting older, inflammatory foods and nutrient deficiencies.

Risk Factors for Poor Glutathione Status

  • Acetaminophen (Tylenol) depletes glutathione, which is the mechanism by which it causes liver failure when overdosed.
  • Glutathione levels decrease during fasting, and diets that are low in protein or carbohydrate decrease its synthesis.
  • Glutathione is made from glutamate, cysteine, and glycine. Glutamate is rarely limiting except in disease states that consume it, such as cancer. Cysteine is often limiting, especially in the fasting state. Glycine is often limiting, especially after a meal rich in animal protein.
  • Magnesium deficiency or metabolic disruptions that affect ATP production or insulin sensitivity such as hypothyroidism, diabetes, and insulin resistance decrease the synthesis of glutathione.
  • Diets low in plant polyphenols also decrease the synthesis of glutathione. Deficiencies of glucose 6-phosphate dehydrogenase, thiamin, niacin, and riboflavin compromise the recycling of glutathione.
  • Diets low in meat and in low-calorie fruits and vegetables provide less exogenous glutathione than diets high in these foods.
  • Rare genetic defects can impair glutathione synthesis.

Testing for Glutathione Status

  • Total Glutathione: If low, this test suggests low glutathione synthesis or loss of glutathione from the body due to detoxification processes. This test may miss having an oxidized glutathione pool due to oxidative stress or a poor rate of recycling.
  • Oxidized and Reduced Glutathione: If the reduced glutathione is low, the oxidized glutathione is high, or both, this indicates that the glutathione pool is being oxidized faster than it can be recycled. The causes could be excess oxidative stress, poor recycling, or both. A low rate of synthesis also makes the glutathione pool become oxidized more easily, so this should also be considered. 
  • Pyroglutamate (oxoproline): When elevated, pyroglutamate indicates that glycine is limiting for glutathione synthesis. When normal or low, and the other tests suggest a low rate of glutathione synthesis, cysteine is more likely to be limiting.

Further Testing

If glutathione synthesis is compromised and pyroglutamate is not elevated, then the following possibilities should be considered:

  • Low total protein intake. Conduct a dietary analysis and ensure that daily protein meets at least one gram per kilogram body weight.
  • Low conversion of methionine to cysteine. Consult the methylation, sulfur catabolism, and vitamin B6 sections. The combination of high methionine and low homocysteine supports this, as does the combination of high homocysteine and signs of vitamin B6 deficiency.
  • Low insulin signaling. Fasting insulin is optimally 2-6 uIU/mL. If elevated above this range, insulin resistance could be compromising glutathione synthesis. 
  • Magnesium deficiency.
  • Low ATP. Insulin resistance, hypothyroidism, or diabetes could compromise the supply of ATP.
  • Low intake of fruits and vegetables. A dietary analysis can be conducted to examine fruit and vegetable intake. If lower than five to nine servings per day, there may be inadequate polyphenol stimulation of glutathione synthesis.
  • Glycine: If the previous tests suggest glutathione synthesis is compromised and pyroglutamate is elevated.

If the glutathione pool is oxidized (low reduced glutathione, elevated oxidized glutathione, or both), then the following possibilities should be considered:

  • Glucose 6-phosphate dehydrogenase (G6PD) deficiency. This is the most common genetic defect in the world and compromises glutathione recycling.
  • Thiamin
  • Riboflavin
  • Niacin

Testing Caveat

Many infections and serious illnesses requiring medical care may deplete glutathione.

Correcting Poor Glutathione Status

  • Consuming at least one gram per kilogram body weight of protein, consuming >200 grams of carbohydrate per day (for someone without digestive or blood sugar issues prohibiting this), supplementing with one or two servings of hydrolyzed collagen, eating a diet rich in fruits and vegetables, implementing a good physical activity routine, and optimizing body composition are all good strategies to improve glutathione status.
  • N-acetyl-cysteine at up to 1600 milligrams per day in divided doses has been used to increase glutathione status. This is most likely to be effective when glycine is not limiting, as in the fasting state or after a collagen-supplemented meal, and in individuals who do not show elevated pyroglutamate.
  • Unpasteurized milk, raw egg white, and whey protein supplements all contain glutamylcysteine bonds that overcome the first step of glutathione synthesis. Consuming these foods to provide 30 grams or more of protein per day may be particularly advantageous if low insulin signaling, low polyphenol stimulation of glutathione synthesis, or genetic impairments in the first step of glutathione synthesis are at issue. Unpasteurized milk is considered a foodborne illness risk by the CDC and FDA, though all available data indicates that it is much safer than other foods commonly consumed, such as deli meats and hot dogs. Raw egg whites will cause a biotin deficiency if not accompanied by supplemental biotin and their protein is less bioavailable than from cooked egg white.
  • Supplements designed to upregulate detoxification, such as milk thistle or sulforaphane, increase glutathione synthesis. These may be especially helpful if a diet rich in fruits and vegetables is infeasible, or to compensate for low insulin signaling.
  • Glutathione supplements at 500-1000 milligrams per day overcome all possible problems in glutathione synthesis and may compensate to some degree for poor glutathione recycling. Non-liposomal glutathione is less expensive than liposomal. If cost is an issue, try non-liposomal first, and only using liposomal glutathione if markers of glutathione status, or certain signs and symptoms that you suspect are related to glutathione status, fail to improve. If speed of results is more important, start with liposomal glutathione since there is a chance it will be more effective than regular glutathione.



It is the only mineral that becomes part of thyroid hormone. The thyroid gland has the highest need for antioxidant protection in the body, however. Thyroid hormone also regulates the rate of ATP production, and ATP is needed to support the antioxidant system through the synthesis of glutathione.

The thyroid gland absorbs iodine from the blood to make thyroid hormones, so about 15-20mg of iodine is concentrated in thyroid tissue and hormones. Hypothyroidism can lead to low free-testosterone. One proposed explanation for the high occurrence of hypothyroidism and hypogonadism in men today compared to decades ago is the increase in environmental toxic halogens, such as fluoride, chlorine, and bromine. When concentrated in the body’s tissue in high amounts, these can replace iodine’s locations inside the cells (most notably thyroid and Leydig cells in the testes).

RDA is 150 mcg-s but a lot of people are still deficient. If you’re not eating a lot of seafood, like oysters, salmon, algae, sea kelp, and lobster, then you may want to supplement iodine. Taking about 300-400 mcg-s can be good for fixing symptoms of low thyroid. Raw vegetables will also inhibit iodine absorption so if you don’t feel like having hypothyroidism, then make sure you cook your veggies or replace them with starchy tubers.

Iodine, Hypothyroidism, and Goiter

Thyroid hormone levels are regulated by thyroid-stimulating hormone (TSH), also known as thyrotropin. TSH promotes the uptake of iodine by the thyroid and stimulates the synthesis and release of T4 and T3. Thyroid hormone production works in a negative feedback loop with TSH. This is why people with hypothyroidism have high TSH levels because their body is trying to make more thyroid hormones.

In the presence of iodine, T4 gets synthesized and is transformed into T3 based on needs. The formation of thyroid hormones is initiated by thyroglobulin (Tg), which gets synthesized by TSH when thyroid hormones are low. If iodine is overconsumed, the activity of sodium-iodide symporter (NIS) decreases in order to slow down the synthesis of thyroid hormones.

Iodine is an essential trace mineral needed for thyroid functioning, thyroid hormone synthesis, physical and mental development and metabolism. It can only be obtained from diet or supplements. Low iodine status is one of the biggest risk factors for hypothyroidism. Iodine is the heaviest, yet least abundant, element that occurs in several oxidation states, such as iodide (I −) and iodate (IO −3).

Iodide combined to DHA and arachidonic acid in cell membranes protects them from oxidative damage. Iodide acts as an electron donor in the presence of hydrogen peroxide and peroxidases. Thus, iodine/iodide is important for protecting against lipid peroxidation and oxidative stress. In fact, it is thought that the high levels of iodine in algae played an important antioxidant role when they first started to produce oxygen 3 billion years ago.

  • T4 and T3 have been shown to be more potent at inhibiting lipid peroxidation compared to vitamin E, glutathione or vitamin C. Thus, iodide and thyroid hormones act as antioxidants.

Iodine contributes to 65% of the molecular weight of T4 and 59% of T3. Only about 10-20% of T3 is secreted by the thyroid gland itself, whereas most of it is produced from T4. Up to 80% of T3 gets created outside of the thyroid gland through deiodination of T4 with the help of type I deiodinase in the liver and kidneys. Skeletal muscle can also initiate the conversion of T4 into T3.

An iodine-replete adult contains about 25-50 mg of iodine out of which 20-50% is stored in the thyroid. The iodine gets transported into the thyroid as iodide by the sodium-iodide symporter (NIS). This NIS-mediated delivery of iodide into the follicular cells of the thyroid gland is the first step in the synthesis of thyroid hormones. That is why the concentration of iodine in the thyroid gland is 20-50 times greater than in the plasma. The remaining iodine that is left in the bloodstream will be excreted through urine.

The size of the thyroid gland is dependent on iodine intake, whereby an excessive or deficient intake of iodine can lead to goiter. Iodine-induced goiter was first described in the 19th century and it has also been documented in children. Excessive iodine intake is thought to contribute to goiter in Sudan, Ethiopia, Algeria and China. It can also lead to reversible hypothyroidism.

Hypothyroidism from excess iodine intake may happen because of thyroid autoimmunity, characterized by elevated anti-thyroid antibodies. Excess iodine is considered a risk factor for the development of thyroid autoimmune disease. Autoimmune thyroiditis and hypothyroidism are more common the older you get with antibodies peaking at 45-55 years of age. Urinary iodine levels > 300 μg/L are considered excessive in children and adults and levels > 500 μg/L are considered excessive in pregnant women.

  • The relationship between iodine intake and thyroid disorders is U-shaped. Both too low, as well as excessive iodine intake, results in hypothyroidism, hyperthyroidism and potentially autoimmune thyroiditis.

Excess iodine can also cause hyperthyroidism, which happens after the iodine-deficient thyroid gland nodules escape control of TSH and start overproducing thyroid hormones. Graves’ disease is the most common form of hyperthyroidism. Other autoimmune thyroid disorders include Hashimoto’s thyroiditis, post-partum thyroiditis and autoimmune arthritis. Hashimoto’s thyroiditis is associated with a significantly higher risk of papillary thyroid carcinoma. Thyroiditis refers to inflammation of the thyroid gland. Inflammation also promotes hypothyroidism by blocking T4 conversion to T3. Low thyroid individuals have a higher risk of hip fractures and non-spine fractures.


A meta-analysis discovered that consumption of iodine-rich seafood (>300 mcg/day of iodine) decreased the risk of thyroid cancer. Molecular iodine (I 2) at 3 mg/day has been proposed to be able to suppress benign and cancerous neoplasia due to its antioxidative effects. Radioactive iodine can increase the risk of thyroid cancer and its uptake is higher in iodine-deficient people. Thus, iodine-deficient people are at a higher risk of developing thyroid cancer.


There’s an interrelationship between thyroid dysfunction and hypogonadism or low testosterone in men. Free testosterone levels are reduced in subjects with hypothyroidism and thyroid hormone treatment normalizes that. Testosterone has protective effects on thyroid autoimmunity by reducing titers of thyroid peroxidase and thyroglobulin antibodies. There is an association between erectile dysfunction and hypothyroidism. Hypothyroidism increases the risk of gaining weight and developing obesity, which can promote metabolic syndrome and other chronic diseases.


Hypothyroid patients have elevated lipoprotein(a) [Lp(a)], which is a risk factor for cardiovascular disease. Lp(a) attracts oxidized lipids and can cause inflammation. Those with hypothyroidism also have higher phospholipase A2 (Lp-PLA2), which is a pro-inflammatory enzyme that moves with LDL particles. C-reactive protein (CRP), one of the primary markers of inflammation, has been found to be elevated in patients with subclinical hypothyroidism, which increases cardiovascular disease risk.

The body needs thyroid hormones to use cholesterol and cholesterol is a precursor to testosterone and other steroid hormones like DHEA, pregnenolone and progesterone. Thyroid hormones influence cholesterol synthesis, catabolism, absorption and excretion by regulating cholesterol 7alpha-hydroxylase (CYP7A), the rate-limiting enzyme in the synthesis of bile acids. T3 stimulates lipoprotein lipase (LPL) to increase the breakdown of VLDL cholesterol. Furthermore, T3 increases the expression of LDL cholesterol receptors that enable LDL to enter cells to be used for its essential functions instead of staying in the bloodstream. T3 can protect LDL from becoming oxidized by mopping up free radicals.

Hyperthyroidism, or an over-active thyroid, has the opposite effect to hypothyroidism and is associated with low HDL and LDL levels. This is not ideal as very low cholesterol is associated with depression, memory loss and increased mortality.

Heart Health

Thyroid hormones are important for the development of a healthy heart and abnormal thyroid hormone function can cause issues like cardiac hypertrophy and irregular heartbeat. Heart, endothelial and other cells have thyroid hormone receptors which regulate thyroid hormone function. Thyroid dysfunction can affect cardiac output, blood pressure, vascular resistance and heart rhythm.

Administration of iodide, the reduced form of iodine, has been shown to protect the heart tissue from myocardial ischemia reperfusion injury in mice. Smoking increases the risk of atherosclerosis, cardiovascular disease and autoimmune conditions like Graves’ disease. Importantly, smokers appear to have lower levels of thyroid stimulating hormone activity than non-smokers. Smoking is also associated with an increased risk of thyroid disease.


East-Asian countries like Japan and Korea include a lot of seaweeds into their diet. The average iodine intake in Japan is 1.2 mg/day from eating seaweeds like kelp, nori and kombu.

According to the World Health Organization, based on estimates from 2002, the proportion of the population with insufficient iodine intake (measured as urinary iodine < 100 mcg/L) is as follows, Americas (9.8%), Western Pacific (24.0%), South-East Asia (39.8%), Africa (42.6%), Eastern Mediterranean (54.1%) and Europe (56.9%).

The Standard American Diet is typically low in iodine unless it includes things like pastured eggs, cranberries, milk, yogurt, shrimp, oysters, tuna/cod or seaweed.

Iodine is especially important during the first 1000 days of life, as infants in that timeframe are more vulnerable to hypothyroidism and developmental issues. Thyroid hormones are needed for the brain’s myelination and neuronal migration. An iodine deficiency during infancy can impair physical and neuromotor development. It also increases the risk of stillbirths, abortions and developmental abnormalities. Impaired thyroid function in iodine-deficient children is correlated with reduced insulin-like growth factor-1 (IGF-1) and IGF-binding protein-3 (IGFBP-3) and stunted growth.

  • A severe iodine deficiency in utero may lead to cretinism, which causes mental retardation, deaf-mutism (a person who is both deaf and unable to speak) and spasticity.
  • Selenium deficiency is also thought to contribute to cretinism and lower intelligence as iodine and selenium work together in the formation of thyroid hormones.

Women in regions with high dietary iodine intake have higher amounts of iodine in their breast milk. In Korean preterm infants, subclinical hypothyroidism is associated with high iodine levels in breast milk. Expression of the sodium-iodide symporter (NIS) in mammary glands regulates iodine absorption and contributes to the presence of iodine in breast milk. In the thyroid, NIS is regulated by thyroid stimulating hormone, whereas in breast tissue prolactin, oxytocin and β-estradiol regulate its expression. Some environmental chemicals like perchlorate, pertechnetate, nitrate and thiocyanate can compete with iodine absorption by hijacking the sodium-iodide cotransporter.

To get the right amount of iodine, you would want to consume a diet that provides anywhere from 150-300 mcg/day of iodine. That ensures there is circulating iodine in your system in adequate quantities to fuel thyroid hormones.

Food and Other Sources of Iodine

Brown algae seaweed accumulates more than 30,000 times more iodine in seawater.

Dairy and milk can also be a reliable source of iodine in many diets, including camel milk and goat milk. Vegan diets that lack seafood and dairy dramatically increase the risk of iodine deficiency unless seaweed or two and a half medium sized potatoes are eaten on a daily basis.

Most commercial bread has extraordinarily little iodine, but it can be fortified with potassium iodate or calcium iodate. Pasta can contain iodine only when cooked in water with iodized salt or when made out of iodized dough. Most fruits and vegetables are a poor source of iodine.


Raw cruciferous vegetables contain goitrogenic compounds called glucosinolates that if overconsumed may inhibit iodine absorption and cause low thyroid function. Cruciferous vegetables include collard greens, broccoli, kale, cauliflower, cabbage and arugula. Soy, cassava, peanuts, corn, certain beans, millet, pine nuts and strawberries also contain goitrogens. Cooking lowers the amount of goitrogenic compounds, thus, if you consume these foods cooked, then it’s much less likely that there will be any issues.

  • Most goitrogenic foods do not have a clinical effect in people who are getting adequate amounts of iodine from their food. It will have a bigger impact on those who are already iodine deficient or are consuming a diet low in iodine. If you have thyroid problems, then it’s not a good idea to eat raw cruciferous vegetables. Nevertheless, the intake of cruciferous vegetables is associated with a reduced risk for cancer and cardiovascular disease. The breakdown products of glucosinolates activate anti-cancer pathways.

Some amino acids can partially inhibit thyroid hormone transport by competing with the receptors. Leucine has also been found to have inhibitory effects on T3 and T4 uptake by pituitary cells. Large doses of amino acids in isolation, like a tryptophan supplement or a branched chain/essential amino acid supplement, may have a competitive effect, but this may only be an issue for an hour after consumption.

Certain medications can inhibit thyroid hormone uptake into certain tissues by competing with them due to structural similarities. These include certain antiarrhythmic drugs, calcium channel blockers (like nifedipine, verapamil and diltiazem), calmodulin antagonists and benzodiazepines. Some anti-inflammatory drugs like diphenylhydantoin, meclofenamic acid, mefenamic acid, fenclofenac, flufenamic acid and diclofenac inhibit T3 uptake. Medications that have goitrogenic effects include antibiotics like ciprofloxacin and rifampin, steroids, statins and others. However, diabetic drugs like metformin may reduce the goitrogenic effects of type-2 diabetes and obesity. ACE inhibitors such as benazepril, lisinopril and fosinopril are blood pressure medications that can elevate potassium levels when taken together with potassium iodide. Taking potassium iodide with potassium-sparing diuretics can also cause hyperkalemia (high potassium). Certain food chemicals and flavor-enhancers like perchlorate block the thyroid’s ability to absorb and use dietary iodine. 

Prolonged fasting for 72 hours has been shown to decrease serum T3 by 30% and thyroid-stimulating hormone by 70% in healthy men. Similar results have been noted with 4-day fasts. Men typically see greater changes than women. However, T3 and reverse T3 return to prefasting levels after refeeding and returning to eating a normal diet. Thus, alterations in thyroid hormones are an acute adaptive mechanism to food scarcity to preserve energy. Having a lower metabolic rate also protects against muscle loss during fasting.

  • Shorter intermittent fasting isn’t nearly as big of a stressor as extended fasting, and it also has less of an effect on thyroid functioning.
  • People with hypothyroidism don’t typically need to change their thyroid medication dosage and can safely practice intermittent fasting. Serum T3 and T4 have dropped in some studies but the data is inconsistent. A decline in thyroid hormone levels with fasting is thought to be caused by alterations in protein binding because free thyroid indices stay the same.
  • Refeeding with a predominantly carbohydrate-rich diet has been shown to reverse changes in serum T3 and rT3 caused by fasting even when hypocaloric. Carbohydrates, and the glucose they are converted into, are the main fuel for the thyroid and brain, which can raise metabolic rate if insulin/leptin resistance is not induced. In fact, insulin is needed for converting T4 into T3 and raising metabolic rate. This can make exogenous carbohydrates important for certain people, especially those whose thyroid functioning does down on a low-carb diet. Acutely raising leptin by eating some whole food carbs and spiking insulin can improve insulin sensitivity and weight loss. Restoring normal leptin levels has been shown to normalize blood sugar and insulin resistance. Some ketogenic diets may reduce T3 and raise reverse T3. That is why chronic ketosis may not be optimal for thyroid function and insulin sensitivity because it can also induce mild short-term carbohydrate intolerance. Instead, cyclical keto can help to bypass this negative side-effect while still providing the other benefits of ketosis, such as an improved lipid profile and lower blood sugar.

Iodine-Dependent Enzymes, Functions and Consequences of a Deficit in Iodine

Iodine-Dependent Enzymes/Proteins: Function: Consequences of Deficit

  • Thyroid Hormones: Regulates metabolic rate, body temperature and energy balance: Chronic fatigue, frailty, weight gain, metabolic syndrome and decreased immunity
  • Thyroglobulin: Initiates thyroid hormone synthesis: Low thyroid function
  • Sodium-Iodine Symporter: Transports iodine into thyroid cells: Iodine deficiency and impaired thyroid function
  • Apoptosis: Programmed cell death and elimination of premalignancies: Accumulation of dysfunctional cells
  • Mucinase: Breaks down mucus and bacteria: Increased risk of infection
  • Brain Receptor Formation: Proper cognitive and mental development: Increased risk of cretinism and mental retardation

Hypothyroidism is about 10 times more prevalent in women than in men because they have higher iodine requirements during lactation and pregnancy.

Risk Factors for Developing Hypothyroidism or Hyperthyroidism

  • Pregnancy or lactation
  • Iodine deficiency
  • Iodine excess
  • Rapid transition from iodine deficiency to sufficiency
  • Autoimmune conditions
  • Genetic risk factors
  • Smoking
  • Selenium deficiency
  • Drugs and pharmaceuticals
  • Infections
  • Fluoride in drinking water may also inhibit sodium-iodide symporter activity, causing iodine deficiency.

Infant formulas have to be fortified with iodine to mimic breast milk nutrition. The infant formulas in the U.S. are regulated to contain 5-76 mcg/100 kcal of iodine, whereas in the EU it is 15−29 mcg/100 kcal. If the mother is iodine deficient, their whole-body iodine stores will be more concentrated in their breast milk to safeguard infant dietary requirements. Prenatal supplements containing iodine are recommended during pregnancy and lactation, but if the mother is already consuming too much iodine it may cause fetal complications.

Chronic low-calorie dieting can cause irreversible damage to the thyroid. A 2016 study on the Biggest Loser competitors discovered that 6 years after the show the participants had regained 70% of the weight they initially lost and were burning 700 fewer calories per day compared to when they started the show. Despite gaining some lean muscle during the show, their metabolic rate didn’t increase due to the severe calorie restriction they experienced, which mimicked starvation. This is the result of crash dieting and yo-yo dieting, which inevitably disrupts thyroid function.

Frequency of Deficiency

Approximately 40% of the world.

Availability from Food

Seaweed (particularly kelp/kombu), seafood and egg yolk. Impoverished soil is a predisposing factor.

Signs and Symptoms of Iodine Deficiency

  • When iodine deficiency occurs during pregnancy and the first year of life, it results in cretinism. This causes a general stunting of physical and neurological development with a lifelong decrease in IQ.
  • Hypothyroidism at any age during development will slow growth, and will prevent the development or maintenance of fertility. More generally, hypothyroidism causes signs such as fatigue, brain fog, cold hands and feet, increased sensitivity to cold in general, hair loss, and swelling (edema), especially in the face.
  • Iodine deficiency hypothyroidism may be accompanied by goiter, which manifests as a swelling in the neck due to an enlargement of the thyroid gland, and may feel like a lump in the throat.
  • Hypothyroidism compromises immune function, and iodine itself is antimicrobial; either of these may account for increased vulnerability to infections. Poor digestive function, including constipation, small intestinal bacterial overgrowth (SIBO), and fat malabsorption may be considered plausible results of hypothyroidism due to a slowing of gastric motility.
  • Fibrocystic breast disease may also be a manifestation of iodine deficiency.

Risk Factors for Iodine Deficiency

  • Consuming foods grown in low-iodine soil, not consuming many seafoods, not using iodized salt, and not using iodine supplements or iodine-containing multivitamins.
  • Women who are pregnant or lactating, and probably women with large breasts, have increased iodine needs.
  • High exposure to thiocyanate, a compound that inhibits the transport of iodine into the thyroid and mammary glands. Thiocyanate is produced during the detoxification of cyanide from cigarette smoke or from the cyanogenic glycosides in many plant foods, and is produced from glucosinolates found in cruciferous vegetables. The most important sources of cyanogenic glycosides are cassava, lima beans, sorghum sprouts, flax, the seeds of apples and pears, and the leaves, fruit and seeds of black cherries, cherries, almonds, plums, peaches and apricots. The most widely used cruciferous vegetables include broccoli, Brussels sprouts, cabbage, cauliflower, collard greens, kale, kohlrabi, mustard, rutabaga, turnip, and bok choy. Other crucifers include arugula, horseradish, radish, wasabi, watercress, and maca. Sulforaphane, used as a supplement to promote detoxification, generates isothiocyanate.
  • Isoflavones derived from soy also bind to iodine and prevent its utilization for the production of thyroid hormone. Fluoride and bromine compete with iodine for transport and utilization. Fluoride is found mainly in toothpaste and fluoridated water. Bromine is put to a multitude of uses, such as flame retardants, dyes, insecticides, furniture foam, gasoline, and the casings of electronics, and is thus ubiquitous in the modern environment.
  • Low ATP/magnesium
  • Chronic calorie restriction
  • Prolonged starvation
  • Extended fasting
  • Severe illness
  • Kidney damage
  • Liver damage
  • Chronic stress
  • Excess fructose consumption
  • Chronic sleep deprivation

Signs and Symptoms of Iodine Excess

  • Acute administration of iodine to individuals with underlying thyroid diseases, especially those resulting from iodine deficiency, may cause transient hyperthyroidism. Iodine supplementation above 1 milligram per day increases TSH over the course of two weeks, with no established clinical consequences. While a theoretical risk, prolonged elevation of TSH could contribute to goiter or thyroid cancer. Exposure to grams of iodine at once causes acute poisoning. This is extremely rare, but results in abdominal pain, fever, nausea, vomiting, and possibly coma. Allergies to iodine are possible, but very rare.
  • Iodermia is a rare reaction to iodine that causes skin eruptions that appear as acne, itching (pruritis), and hives (urticaria).

Risk Factors for Iodine Excess

Consumption of very iodine-rich seaweeds in their raw state (mainly kelp, which is also known as kombu, haidai, or by various scientific names beginning with Laminariales) could lead to iodine excess. Boiling for 15-30 minutes removes the iodine risk. Consuming one gram per day of raw kelp provides more than 1 milligram per day of iodine, and consuming 8 grams per day provides more than 20 milligrams. Use of iodine supplements or topical use of iodine could also provide excess.

Testing for Iodine Status

Under normal circumstances, only 10% or less of circulating iodine gets taken up by the thyroid but during chronic deficiency it can be more than 80%. The half-life of plasma iodine is about 10 hours, but this is reduced in iodine deficiency. Over 90% of iodine is absorbed in the small intestine and 90% of it is excreted within the first 24-48 hours. The half-life of T4 is 5 days and for T3 it is roughly 1.5-3 days. Urinary iodine concentration (UIC) is the most commonly used biomarker for measuring iodine status within a population. Intradiurnal rhythms will offset individual spot urine samples, which is why spot urinary iodine is not recommended for individual assessment.

Thyroid-stimulating hormone (TSH) is often used to assess hypothyroidism, but it is not fully accurate due to individual differences and diurnal variations. Generally, TSH levels start to rise when iodine intake drops below 100 mcg/day. The normal range for TSH is between 0.45-4.5 mU/L and 95% of the disease-free population in the U.S. has their TSH at 0.45 and 4.12 mU/L. T4 and T3 measure hormone levels but not necessarily thyroid hormone function (receptor activation and subsequent effects thereafter). TSH is not accurate for assessing iodine status in adults but it may be accurate for assessing iodine status in newborns because they have a higher rate of iodine turnover than adults.

Testing Caveats

Urinary iodine assesses iodine intake, but it cannot assess whether iodine intake is sufficient to overcome iodine antagonists. If these antagonists stop iodine from getting into the thyroid gland, this does not necessarily stop it from being excreted in the urine.

Correcting Iodine Deficiency

Abrupt intake of iodine after a period of deficiency, such as seen with salt iodization, can cause hyperthyroidism and raise thyroid antibodies, especially in young women. Thus, introducing too much iodine when you have been deficient beforehand might trigger autoimmunity against the thyroid. Thus, a more gradual re-introduction of iodine, and from more natural sources (salts or foods naturally containing iodine), may be optimal.

Take a kelp supplement providing 2-300 micrograms per day. Maine Coast Sea Seasonings also sells shakers of kelp granules or of salt and spices with added seaweed that can be used in foods to ensure adequate iodine. Also, avoid goitrogens and other iodine antagonists.

Correcting Iodine Excess

Excess iodine is more toxic in the presence of selenium deficiency, which can lead to damage and oxidation of proteins. In fact, supplemental selenium alleviates the toxic effects of excess iodine, such as thyroid damage and thyroid hormone dysfunction. Acute symptoms of iodine poisoning include burning of the mouth, vomiting, diarrhea, coma and pain in the stomach and throat. Some people are also hypersensitive towards iodine-containing foods and products, which makes them experience rashes and allergies. However, there are no confirmed reports of actual iodine allergy.

If adverse effects on thyroid health accompany the use of high-dose iodine, the main nutritional strategy is to remove the source of iodine. Since the thyroid gland has the highest antioxidant needs in the body, optimizing the nutrients in the antioxidant section can be used to augment this strategy.

Electrolytes: Sodium, Potassium, and Chloride


The main electrolytes are sodium, potassium, magnesium, phosphate, calcium, chloride and bicarbonate. There are others like zinc, copper, iron, manganese, molybdenum and chromium. You obtain these minerals from food, water and supplements.

Electrolytes, especially sodium, help your body to maintain normal fluid levels in the blood, within cells and outside of cells. How much fluid each of these compartments holds depends on the amount and concentration of electrolytes in it.

  • If the electrolyte concentration is too low, fluid will leave that particular compartment (blood or intra-, extracellular space)
  • If the electrolyte concentration is too high, fluid will move into that particular compartment (osmosis).

Sodium is essential for carrying nerve impulses, maintaining muscle function, and regulating fluid balance and blood pressure. Chloride is needed for digestion and respiration.

The Sodium-Potassium Pump moves sodium ions out and potassium ions into the cell. This is powered by magnesium and ATP. For every ATP that gets broken down, 3 sodium ions move out and 2 potassium ions move in.

Electrolyte imbalances can have many negative health consequences such as heart failure, arrythmias, oxidative stress or even death.

  • Fluid and electrolyte imbalances are most often caused by dehydration, excessive sweating, vomiting, diarrhea and nutrient deficiencies. Certain conditions like kidney disease, anorexia nervosa, and medical burns can also cause this.
  • Symptoms of electrolyte imbalances include chronic fatigue, irregular heartbeat, high blood pressure, brain fog, sleeping problems, muscle weakness, cramping, headaches and numbness.

Blood Reference Ranges

  • Calcium: 5–5.5 mEq/L
  • Chloride: 97–107 mEq/L
  • Potassium: 5–5.3 mEq/L
  • Magnesium: 1.5-2.5 mEq/L
  • Sodium: 136–145 mEq/L

To avoid electrolyte imbalances, you have to obtain enough minerals from food and liquids. You also need to avoid damage to your organs like your intestines, liver and kidneys so you don’t lose the ability to absorb, reabsorb and/or utilize these minerals.

Magnesium is what primarily regulates the sodium potassium pump. However, a lack of sodium can lead to magnesium deficiency, as can a lack of vitamin B6 or selenium. Thus, salt, vitamin B6 and selenium also control the sodium potassium pump indirectly because they control magnesium status in the body. When in a magnesium deficient state, calcium and sodium accumulate in the cell, promoting hypertension and cardiomyopathy. Magnesium protects against potassium loss and muscle potassium levels won’t normalize unless magnesium status is restored even when serum potassium rises.

The quality of the salt depends on the cleanliness of the sea and the area in which the salt was handled. Favor coarse sea salt and grind it yourself. Some countries add iodine to salt but it isn’t the best source. Instead, take one tsp of kelp to get the same amount of iodine as one pound of iodine-enriched sea salt.

Mix together different types of salts and dried herbs to maximize nutritional density. Sea salt, rose salt, and black salt with rosemary, basil, and mint.


  • Purity tested, unrefined sea salts
  • Mineral salts
  • Pink salts sold under various names (Himalayan salt, rose salt, rock salt, halite)
  • Black salts
  • Herbamare seasoning
  • Rare specialty salts (with monosodium glutamate, MSG)


  • Common refined salts and table salt
  • Seasoned salt (with monosodium glutamate, MSG)

Potassium Summary

Potassium is the most abundant intracellular cation (an ion with a positive charge) that helps to maintain intracellular fluid volume. The adult human body contains around 1,755 mg of potassium per kg of body weight. Out of that amount, only 2% is located in the extracellular fluid with most of it being found in skeletal muscle. The concentration of potassium in the cell is 30 times higher than outside the cell. This difference creates a transmembrane electrochemical gradient that is regulated by the sodium-potassium ATPase pump (Na + -K + ATPase). The gradient of potassium across cell membranes determines the cells’ membrane potential. The resting membrane potential and the electro-chemical differences across cell membranes are critical for normal cellular function and biology. Transfer of potassium ions across nerve membranes is essential for nerve function and transmission.

Once activated, the sodium-potassium pump exchanges 2 extracellular potassium ions for 3 intracellular sodium ions. Other channels responsible for maintaining differences in cell membrane potential are the sodium-potassium chloride (Cl) symporter and sodium-calcium (Ca) exchanger. The ATPase is also stimulated by activation of β-adrenergic and insulin receptors, which are stimulated by epinephrine/norepinephrine and insulin, respectively. Consequently, simultaneous stimulation of both the β-adrenergic and insulin receptors increases the influx of potassium into the cell but causes sodium to leave the cell via the Na + -K + ATPase.

Thyroid Hormone Transport

Triiodothyronine (T3) and thyroxine (T4) increase Na-KATPase subunits by increasing gene expression (although the effect is the opposite in the thyroid gland, as thyroid hormones will have a negative feedback effect on the Na-K-ATPase). The Na-K-ATPase provides the sodium gradient to absorb iodide via the sodium-iodide symporter, thus reducing its activity will reduce iodine transport into the thyroid gland, thus reducing thyroid hormone synthesis.

GLUT4 and IRS1 Relationship

Insulin substrate receptor-1 (IRS1) and intracellular glucose transport proteins (GLUT4) facilitate the influx of glucose into the cell. Downstream signaling events to that, involving cyclic adenosine-monophosphate (cAMP), protein kinase A (Akt), and IRS1-phosphatidylinositide-3-kinase (PI3-K) regulated pathways also mediate the influx of glucose as well as potassium into the cell. The fastest potassium exchange occurs in the kidneys and the slowest in muscles and the brain.

Metabolic Acidosis

Metabolic acidosis, or a drop in extracellular pH, increases the loss of intracellular potassium into the extracellular space via transporters that regulate pH in skeletal muscle. Organic acidosis, caused by an accumulation of lactic acid or uric acid, lowers intracellular pH, which stimulates the movement of hydrogen out of the cell via the sodium-hydrogen transporter and bicarbonate into the cell via the sodium-bicarbonate transporter. As a result, intracellular sodium increases, which maintains Na+-K+ ATPase activity limiting the loss of potassium from the cell. Thus, organic acidosis, say from lactic acid build up from excessive exercise, causes a much smaller loss of intracellular potassium than does metabolic acidosis.

  • Metabolic acidosis promotes a net efflux of calcium from bone by increasing osteoclastic resorption and decreasing osteoblast formation. Neutralization of acidosis with potassium bicarbonate (KHCO3), but not sodium bicarbonate, improves calcium and phosphorus balance, reduce bone resorption, reduces calcium excretion through urine and reduce the age-related decrease in growth hormone secretion without salt restriction.
  • Potassium citrate has been shown to have beneficial calcium-retaining effects in bone. Increasing potassium consumption improves bone density in elderly women and may prevent osteoporosis. Greater potassium intake from fruits and vegetables is associated with higher bone mineral density thanks to potassium citrate’s (and the bicarbonate that is formed from it) ability to balance acid.

Fixing low grade metabolic acidosis with potassium bicarbonate has been shown to increase 24-hour mean growth hormone secretion as well as provide a nitrogen sparing effect that helps to prevent muscle loss in postmenopausal women. In patients on bed rest, potassium bicarbonate (3,510 mg/day) and whey protein supplementation (0.6 g/kg of body mass per day) for 19 days has been noted to mitigate the loss of muscle function due to inactivity.

  • Prolonged periods of inactivity, like hospitalization or spaceflight, can cause muscle wasting and weakness, which increases the risk of fractures. Higher protein intake has been shown to mitigate muscle loss and catabolism. Taking whey protein alone, without balancing it with some form of base, might create a net acidic environment promoting bone demineralization. Thus, increased protein consumption, particularly from protein powders, would likely warrant increased intake of alkaline foods or beverages.
  • To be clear, the body tries to maintain a normal pH in the blood, even with a surplus of acid. Thus, measuring blood pH levels is not the best way to determine acid-base balance. Typically, levels of bicarbonate in the blood will drop faster than blood pH and are a better marker of overall acid-base balance, as is urinary pH levels. You can have an acidic urine (indicating acid surplus) but a normal blood pH.

The alkaline theory has already been tested in several studies of patients with kidney disease showing that consuming an alkaline diet (either via fruits/vegetables or sodium bicarbonate supplementation) over several months can improve metabolic acidosis and kidney function. In postmenopausal women, an alkaline treatment (potassium bicarbonate supplementation) improved calcium and phosphorus balance, reduced bone resorption and increased bone formation and reduces their urinary nitrogen (i.e., muscle) loss. These findings have been confirmed in middle-aged and elderly men, whereby alkaline therapy (potassium bicarbonate) has a muscle protein-sparing effect.

Animal proteins, when broken down, release their sulfur-containing amino acids that provide an acidic load (sulfuric acid), which cannot simply be breathed out of the body.

Added sugars and grains also contribute to the dietary acid load and are typically overconsumed in the Western world. The lack of potassium/bicarbonate-forming foods in the western diet exacerbates the metabolic acidosis caused by eating processed, industrialized foods, promoting osteoporosis, inflammation and kidney stones.

Bicarbonate-forming and potassium-rich foods are thought to improve bone health, thanks to regulating acid-base homeostasis as well as their antioxidant content. Fruits and vegetables are the only foods that contain both potassium and bicarbonate-forming substances, giving them a negative potential renal acid load (PRAL). Eating acidic foods isn’t necessarily harmful as long as other variables like potassium/calcium/magnesium intake, bicarbonate-forming foods, metabolic and kidney health are taken into account.

Potassium, Sodium, and Blood Pressure

The low salt guidelines are not really warranted for most people and may actually cause other problems, such as insulin resistance, hypothyroidism, increased heart rate, heart failure, kidney damage, high triglycerides and cholesterol.

Chronic salt restriction may cause “internal starvation”, making the body raise insulin levels because insulin helps the kidneys retain sodium. That is why a high salt intake can be more dangerous if you are diabetic or have insulin resistance because your body is holding onto more sodium. On the flip side, healthy kidneys can handle excess sodium with ease. Salt sensitivity is primarily driven by insulin resistance and sympathetic overdrive.

The body needs sodium for nerve function, muscle contraction and cell metabolism. You would be fine without ever eating another gram of sugar, but you wouldn’t survive very long without salt.

Regular table salt (sodium chloride) can raise blood pressure significantly more than sodium bicarbonate or sodium acetate. Table salt is 100% sodium chloride, whereas many unrefined salts are anywhere from 92-97% sodium chloride, where the other 2-8% are composed of other minerals like calcium, magnesium and iodine. Sodium bicarbonate has actually been shown to lower blood pressure slightly in hypertensive individuals.

Modern diets that are high in salt wouldn’t be such a big issue if they also didn’t lack bicarbonate and potassium. Thus, it isn’t the dietary salt that’s the problem, it is the lack of the other alkaline minerals (calcium, magnesium and potassium) and base-forming substances/bicarbonate. Fruit and vegetables contain potassium phosphate, sulfate, citrate, bicarbonate and others, but not chloride, which can be added to salt substitutes and supplements (think magnesium chloride). Potassium bicarbonate has a natural sodium-excreting effect, reversing sodium chloride-induced increases in blood pressure.

Low potassium levels in the blood usually occur alongside low magnesium levels, both of which can promote cardiovascular complications. This is because low potassium levels can be caused by magnesium deficiency.

Ways Potassium can Help with Hypertension and Cardiovascular Disease

  • Inhibits free radical production in vascular endothelial cells and macrophages
  • Inhibits proliferation of vascular smooth muscle cells
  • Inhibits platelet aggregation and arterial thrombosis
  • Reduces renal vascular resistance
  • Reduces atherosclerotic lesion formation
  • Lower blood pressure and water retention
  • Increases endothelial vasodilation
  • Reduces inflammation and oxidative stress
  • Improves insulin sensitivity
  • Reduces catecholamine related vasoconstriction

Blood Sugar Management

Potassium also has a beneficial effect on blood sugar management and insulin resistance. These problems may become a bigger issue for hypertensive people who are prescribed potassium excreting thiazide diuretics. Thiazide diuretics are the preferred pharmacological treatment for hypertension but have a tendency to reduce glucose tolerance and increase the risk of type 2 diabetes. Thiazide diuretics lower serum potassium, which may actually be caused by an increased urinary loss of magnesium, and diuretic-induced hypokalemia has been shown to reduce glucose tolerance by reducing insulin secretion.

  • Potassium-sparing diuretics, such as amiloride and spironolactone, however, reduce potassium and magnesium excretion and in some instances can even cause hyperkalemia (too high potassium), particularly in those with kidney issues.

Potassium is an essential activator of pyruvate kinase, which is the enzyme involved with the last step of glycolysis, whereby energy is produced from glucose. One of the binding sites of pyruvate is dependent on potassium ions.

Kidney Health and Functioning Methods

  • Blood Pressure – hypertension damages small blood vessels in the kidneys. Most people are below 140/90. If you have kidney failure, most doctors will say that blood pressure should be lower than 130/80 but 120/80 is considered normal.
  • Protein in Urine – traces of albumin protein in urine are an early sign of kidney disease. Optimally, you want to have less than 30 mg of albumin per gram of urinary creatinine.
  • Serum Creatinine – poor kidney functioning leads to the accumulation of creatinine in the blood, typically a waste product. A normal serum creatinine is 0.7-1.3 mg/dL for men and 0.6-1.1 mg/dL for women. However, it can vary, depending on other variables, as having more muscle can increase serum creatinine.
  • Glomerular Filtration Rate (GFR) – this is a calculation of kidney functioning based on creatinine levels, age, race, gender, etc. A score over 90 is good, 60-89 should be monitored, and less than 60 for three months indicates kidney damage.
  • Cystatin C – is one of the best ways to estimate kidney function as muscle mass, exercise and creatinine levels will not affect the results, unlike GFR. A normal cystatin C is 0.6-1 mg/L.

To improve kidney health, you want to eat a healthy diet, maintain an active lifestyle, consume an adequate amount of salt, potassium and magnesium, consume bicarbonate or fruits/vegetables, stay hydrated and avoid refined carbs/sugars/omega-6 seed oils. You should also avoid smoking and excessive alcohol intake.

Because low potassium impairs calcium reabsorption by the kidneys, it can increase urinary calcium, which can cause kidney stones. Potassium citrate may prevent kidney stones from forming and it also helps to break down kidney stones. However, it is primarily citrate that seems to be responsible for this effect. Nevertheless, a low potassium intake is still a potential contributor to kidney stone formation.

Potassium Food Sources

In Nordic countries, fruit and vegetables contribute 17.5% of overall potassium intake, whereas in Greece they provide 39%. Vegetables and potatoes typically provide about 24.5% of the total potassium intake in the UK. In the U.S., potatoes contribute up to 19-20% of the total daily potassium intake. There is an inverse relationship between both raw, as well as cooked, vegetables and blood pressure, although the relationship is slightly greater with raw vegetables. Monocropping, and other non-regenerative farming methods, depletes the soil of potassium, reducing the potassium content of the food that is grown on it.

For primary prevention of hypertension, it has been recommended to get over 3,500 mg/day of potassium, which is above the adequate intake for men and women.

Many “salt sensitive” people simply need more potassium, magnesium or calcium instead of sodium restriction. It’s very likely that the higher the magnesium intake, the less potassium is needed, as the former helps prevent potassium loss from the cell.

Hunter-gatherer tribes that eat only whole foods have been estimated to consume anywhere from 5,850-11,310 mg/day of potassium. Sodium intake was estimated at 1,131-2,500 mg/day but this did not take into account sodium consumed from blood, interstitial fluids, salt licks and salty/brackish water. Thus, sodium intake is an underestimation. To be fair, the potassium to sodium ratio of our ancestors likely sits somewhere between 2-3:1. On the other hand, industrialized societies that consume a lot of processed foods get about 2,100-2,730 mg/day of potassium and about 3,400 mg/day of sodium or a K/Na ratio of 0.7:1. Potentially up to 10 in foragers.

  • Estimates for ancestral sodium intake did not take into account the sodium content of aquatic vegetation/seafood, organs, blood, interstitial fluids, salt licks and salt/brackish water, which would have increased the estimated sodium intake that would have occurred during Paleolithic times. Indeed, blood contains 3,200 mg of sodium per liter and interstitial fluids can be even higher in salt.

Even fairly large daily doses of potassium do not seem to be an issue for those with normal kidney function. The ratio of dietary potassium to sodium also affects potassium concentrations.

Potatoes have even been shown to have a beneficial effect on blood pressure, lipid profiles and glycemic control. This may have something to do with their high potassium content. Consider eating lightly cooked and cooled potatoes. Lightly cooking and cooling potatoes maintains the resistant starch, helping to reduce the spike in glucose and insulin that occurs after you eat it. Perhaps more importantly, eating a steak with your potato will also reduce the glucose/insulin spike.

Potassium Absorption and Excretion

Approximately 90% of the consumed potassium is lost in the urine and 10% of it is excreted in the stool. A small amount of potassium is lost through sweat. With zero potassium intake, serum potassium can reach deficient levels of 3.0-3.5 mmol/L in about a week. Potassium excretion is regulated by the kidneys in response to dietary potassium intake. Unless you are potassium deficient, excretion of potassium increases rapidly after consuming potassium.

The glomerulus of the kidneys freely filters potassium and 70-80% of it is reabsorbed in the proximal tubule and loop of Henle. The two major factors that contribute to potassium loss are the renal handling of sodium and mineralocorticoid activity. Reabsorption of potassium in the proximal tubule is mostly passive and happens in proportion to the reabsorption of solute and water. In the Henle’s loop of the kidney, a small amount of potassium is excreted in the descending limb, whereas reabsorption of potassium and sodium occurs in the thick ascending limb. A lot of the potassium excretion/regulation happens in the late distal convoluted tubule (DCT) and the early connecting tubule of the kidney. Dietary potassium intake inhibits the sodium-chloride transporter in the distal convoluted tubule, reducing the absorption of salt by the kidneys. In other words, potassium consumption promotes salt excretion and helps people handle higher salt loads. Low potassium, however, causes salt retention and contributes to hypertension through activation of the sympathetic nervous system.

Aldosterone is a major mineralocorticoid that increases the excretion of potassium out in the urine by increasing sodium reabsorption in the lumen. It stimulates epithelial sodium channels and Na + -K + ATPase activity. Primary aldosteronism is associated with an increased risk of cardiovascular disease. The diurnal rhythm of aldosterone expression can affect renal potassium excretion, which should be kept in mind when taking urine samples. Aldosterone tends to be highest in the morning between 6-9 AM together with cortisol and drops down in the afternoon. Salt restriction increases aldosterone, which promotes sodium reabsorption and potassium/magnesium excretion, creating the opposite desired effect. Normal or even excess sodium intake results in suppressed or delayed aldosterone activity. Thus, reducing sodium intake may not be the most effective long-term strategy for lowering blood pressure.

A normal serum potassium concentration is 3.6-5.0 mmol/L. Hypokalemia or low potassium levels occur below 3.6 mmol/L and hyperkalemia (elevated potassium) is above 5.0 mmol/L.

Hypokalemia and hyperkalemia are rare in healthy people with normal kidney function, but it can occur due to diarrhea, kidney failure or vomiting. Hypokalemia affects up to 1/5th of hospitalized patients because of the use of diuretics and other pharmaceuticals. Mild hypokalemia can cause constipation, muscle cramps, weakness and malaise. Moderate hypokalemia causes encephalopathy, glucose intolerance, paralysis, arrhythmias and dilute urine. Severe hypokalemia can be fatal due to the induction of arrythmias. Magnesium deficiency can promote hypokalemia by increasing excretion of potassium. Hypokalemia and magnesium deficiency are associated with each other. Thus, fixing potassium deficiency would also require improving magnesium deficiency. Hyperkalemia can result from the use of ACE inhibitors, such as benazepril, and ARBs, such as losartan because they reduce potassium excretion. Potassium-sparing diuretics can also increase the risk of hyperkalemia. The side-effects of hyperkalemia include arrhythmias, palpitations, muscle pain and weakness. In severe cases hyperkalemia can cause cardiac arrest and death.

Things that Increase Potassium Demand or Excretion

  • Sodium overload
  • Magnesium deficiency
  • Metabolic acidosis
  • Diabetes, insulin resistance
  • A drop in extracellular pH levels
  • A drop in extracellular bicarbonate
  • Diarrhea, vomiting or extreme sweating
  • Inflammatory bowel disease
  • Diuretics or proton pump inhibitors (PPIs)
  • Kidney damage or kidney injury

Things that Improve Potassium Status

  • Sodium
  • Magnesium
  • Insulin
  • Bicarbonate
  • Citrate
  • Potassium-sparing diuretics

Ways to Optimize Potassium Intake without Causing Hyperkalemia

  • Assess your blood pressure and kidney health
  • Include 4-5 cups of fruit and vegetables into your daily diet or consume land animal meat plus fish
  • Include more high-potassium foods (Fish, greens, potatoes, tomatoes and beans) in the diet if tolerated
  • Aim for a daily potassium intake of at least 4,000 mg and optimally 4,500 mg
  • Aim for a daily sodium intake of 3,500-4,000 mg
  • Increase sodium intake if you are sweating a lot and potassium intake if you have diarrhea or are suffering from some malabsorption diseases
  • Minimize packaged foods and processed foods
  • Salt to taste with natural salt sources like sea salt or rock salt
  • Be careful with using salt substitutes. Especially if they’re the only source of sodium in your diet.
  • Add potassium or sodium bicarbonate if you suffer from metabolic acidosis
  • Add potassium citrate if you suffer from kidney stones or kidney damage
  • Drinking alkaline mineral waters can help to keep you hydrated and reduce chronic latent metabolic acidosis
  • Before potassium supplementation, assess your potassium status
  • Check potassium levels 1 week after increasing potassium intake to see if there is a baseline risk for hyperkalemia.
  • Always work with your doctor before implementing any dietary change or adding a supplement.

Potassium-Dependent Enzymes, Functions and Consequences of Deficient Potassium

Potassium-Dependent Enzymes/Proteins: Function: Consequences of Deficit

  • Sodium-Potassium ATPase: Regulates transmembrane electrochemical gradient, nerve function and fluid volume: Sodium/calcium overload, hypertension, arterial calcification and nerve dysfunction
  • Pyruvate: The end-product of glycolysis and glucose metabolism: Hyperglycemia, diabetes, and loss of ATP
  • Pyruvate Kinase: Glycolysis/glucose metabolism: Hyperglycemia, diabetes and loss of ATP
  • Pyruvate Dehydrogenase Kinase: Inactivate pyruvate dehydrogenase during glycolysis: Impaired energy production and loss of ATP
  • Ribokinase: Production of ATP and D-ribose, glucose metabolism: Impaired energy production and glucose intolerance
  • Branched-chain α-ketoacid dehydrogenase kinase: Catalyzation of the oxidative decarboxylation of branched, shortchain alphaketoacids: Iodine deficiency and impaired thyroid function
  • Fructose 1,6-bisphosphatase: Converts fructose- 1,6-bisphosphate to fructose 6- phosphate in gluconeogenesis: Inadequate glucose production and energy shortage in certain glucose dependent organs
  • Diol Dehydratase: Catalyze the B12- dependent conversion of 1,2-diols to the corresponding aldehydes, glycerol-lipid metabolism: Impaired alcohol and fatty acid metabolism
  • Heat Shock Cognate Protein (Hsc70): Regulate proper protein folding, autophagy, apoptosis and cell stability: Cell senescence, DNA damage, carcinogenesis and neurodegeneration
  • Pyridoxal Kinase: Vitamin B6 metabolism: Impaired serotonin, melatonin and dopamine production: Nerve dysfunction
  • Histone Deacetylase (HDAC) Inhibition: DNA binding and DNA expression: Accelerated aging, cardiac defects and neurodegeneration
  • IMP dehydrogenase or Inosine-5- monophosphate dehydrogenase (IMPDH): Guanine de novo biosynthesis, DNA/RNA synthesis, and energy transfer: Impaired cellular function and weaker immunity
  • Serine Dehydratase (SDH): Gluconeogenesis, pyruvate production and release of ammonia: Hyperglycemia and impaired glucose tolerance
  • Tryptophanase: Tryptophan and nitrogen metabolism and neurotransmitter production: Ammonia build-up and low melatonin and serotonin
  • Tyrosine Phenol-Lyase: Tyrosine and nitrogen metabolism, protein synthesis, thyroid hormone production: Impaired neurotransmitter production, low thyroid

Signs and Symptoms of Potassium Deficiency

  • Estimated daily minimum for potassium is 2000 mg/day and the RDA 4700 mg/day. You shouldn’t worry about eating too much potassium unless you’re taking supplements. If you’re not eating a lot of green leafy vegetables and avocados, then you may not be getting enough. Using potassium chloride salts with reduced sodium like NuSalt or taking potassium gluconate can be useful.
  • Inadequate potassium elevates the salt-to-potassium ratio. A high ratio contributes to high blood pressure, edema (swelling), and chronic acid burden (leading to increased risk of osteopenia, osteoporosis, and kidney stones). Potassium stimulates insulin, and it is plausible to suggest a high-carbohydrate meal would destabilize blood sugar more when it is also low in potassium.
  • Low-potassium diets can contribute to hypokalemia, but are rarely the cause all on their own. Hypokalemia leads to a slower heart rate (bradycardia); cardiac arrhythmia or palpitations; reduced intestinal motility (which could lead to constipation and theoretically to small intestinal bacterial overgrowth, SIBO); muscle spasms and twitches; lower levels of insulin secretion, leading to hyperglycemia; low blood pressure (hypotension) and in severe cases, hypokalemia can result in skeletal muscle necrosis (cell death), rhabdomyolysis (damaged muscles spilling their contents into the blood), and life-threatening changes in heart function. 

Risk Factors for Potassium Deficiency

  • The primary dietary risk factors are a low intake of fruits and vegetables, high intake of added fats and oils and refined carbohydrates, and discarding the juices of meat and the cooking water used for plant foods. Additionally, foods prepared in brines reduce the potassium content of the diet because brines exchange sodium for potassium.
  • Malabsorption conditions, such as bariatric surgery, IBS and inflammatory bowel disease (ulcerative colitis and Crohn’s) can reduce potassium absorption.
  • Refeeding syndrome is a major cause of hypokalemia. During starvation or chronic malnutrition (as might occur in alcoholism, eating disorders, or illnesses that impact food intake), catabolism releases intracellular potassium stores and causes loss of potassium from the body. During refeeding, insulin brings potassium into cells, lowering its concentration in the serum, causing hypokalemia. The high rate of cellular repair and need to rebuild intracellular potassium stores aggravates hypokalemia. Low levels of magnesium (hypomagnesemia) and phosphorus (hypophosphatemia) are also found in refeeding syndrome.
  • Diarrhea and vomiting both cause direct loss of potassium. Vomiting also causes alkalosis from the loss of stomach acid, and alkalosis drives potassium into cells and increases its excretion in the urine, both of which lower its concentration in the serum. During illnesses that cause vomiting and diarrhea, dietary potassium is usually low, making it difficult to replenish serum levels. 

Signs and Symptoms of Excess Potassium

Supplemental potassium on an empty stomach could stimulate insulin secretion and lower blood sugar, contributing to hypoglycemia. Symptoms of hypoglycemia include hunger, fatigue, shakiness, irritability, anxiety, sweating, and in extreme cases confusion, visual disturbances, seizures, and loss of consciousness. Extreme hypoglycemia causing seizures has not been documented from potassium supplementation, however.

Hyperkalemia can cause fast heart rate (tachycardia) and cardiac arrhythmia, and palpitations. Confusion, paresthesia (tingling, numbness, or a feeling of something crawling on the skin) may also occur. In severe cases, hyperkalemia causes weakness, paralysis, and cardiac arrest, and can be fatal.

Risk Factors for Excess Potassium

  • Potassium supplements are generally safe for healthy adults. Potassium chloride supplements have caused gastrointestinal distress when provided in a wax matrix or microencapsulated gelatin capsule, but not as a powder mixed with water. Supplemental potassium has been used in amounts as high as 15.6 grams per day in healthy adults without causing any instances of hyperkalemia.
  • Dietary potassium may contribute to hyperkalemia in diabetes or insulin resistance, where the insulin response to potassium is inadequate. It may also contribute to hyperkalemia in cases of drugs or medical conditions that impair the excretion of potassium into the urine, which include Addison’s disease, a selective deficiency in adrenal production of aldosterone, and therapy with heparin, ACE inhibitors, beta-blockers, and nonsteroidal anti-inflammatory drugs (NSAIDs). In these cases, supplemental potassium is more dangerous than food potassium because it raises blood levels of potassium faster. Acidosis, cellular damage, low ATP production from hypothyroidism or diabetes, and digitalis overdose can all shift potassium from the cells into the blood, causing hyperkalemia.
  • Potassium supplements can be taken in multiple servings, and bulk powders can make it easy to do so. 15 grams per day have been used safely in trials, potassium-rich foods may provide 5 to 15 grams per day, and a healthy adult has the capacity to excrete up to 33 grams of potassium per day. On an empty stomach, high-dose potassium supplements may cause hypoglycemia. Taken with a meal and spread evenly through the day, however, they are safe for healthy individuals. Nevertheless, the conditions that impair potassium excretion are numerous, and some of them — insulin resistance and NSAID usage — are common. If you are using potassium supplements that provide more than a gram per day spread evenly across meals, he recommends consulting your physician to ensure healthy insulin secretion and sensitivity, healthy kidney function, and that you are not taking drugs that contraindicate the use of potassium supplements.

Testing Caveats

  • Maintaining healthy blood pressure also requires maintaining healthy body composition, a good physical activity routine, avoiding excess alcohol, proper stress management, and adequate intake of other minerals, such as calcium and magnesium. Blood pressure elevations are not specific indications of the salt-to-potassium ratio and are not necessarily related to diet or lifestyle.
  • Edema may have many other causes, most notably hypothyroidism (especially when affecting the face) or diabetes (especially when affecting the lower legs).
  • Toxic levels of barium and thallium may mimic potassium deficiency.
  • Assessing potassium status is difficult because most of the body’s potassium is located in the cell. Blood potassium levels do not correlate accurately with tissue potassium stores. Muscle biopsies can be used to look at tissue potassium status but measuring net potassium retention and excretion can also be an indicator.

Signs and Symptoms of Sodium and Chloride Deficiency

  • Insulin resistance and elevated total cholesterol, LDL cholesterol, and triglycerides.
  • Overactivation of the sympathetic nervous system and increased vulnerability to developing anxiety, dehydration and weakness, and poor intestinal absorption of many nutrients.
  • The nutrients most likely to be affected are glucose, vitamin C, biotin, pantothenic acid, phosphorus, magnesium, and iodine. Calcium, niacin, and thiamin could also be affected.
  • Chloride is required for the secretion of stomach acid (which is hydrochloric acid, made from hydrogen and chloride) and low chloride intakes presumably compromise digestion by causing hypochloridia (low stomach acid).
  • Hyponatremia refers to low blood levels of sodium and should be seen as distinct from inadequate dietary sodium. Signs and symptoms include nausea, vomiting, headache, confusion, weakness and fatigue, cramping, muscle spasms, ataxia (loss of full control over body movements), restlessness, irritability, and in extreme cases seizures or coma.
  • Hypochloremia refers to low blood levels of chloride. It is far rarer than hyponatremia and very rarely occurs to a clinically important extent on its own. It causes metabolic alkalosis, especially if produced from loss of stomach acid during extended vomiting. This can mimic the symptoms of hypocalcemia by decreasing the concentration of ionized calcium in the blood and can cause hypokalemia by driving potassium from the serum into cells. Possible signs and symptoms of hypocalcemia and hypokalemia include muscle spasms, twitching, tremors, cardiac arrhythmia, palpitations, bradycardia (slow heart rate), and confusion. In severe cases seizures, coma, and death could result but this has never been documented from isolated hypochloremia. Isolated chloride deficiency has only been produced from errors in the production of infant formula, where it produced growth failure, irritability, anorexia, gastrointestinal distress, and weakness, and in some cases metabolic alkalosis and hypokalemia. None of the infants died and the only sign that persisted after correction of the diet was delayed speech development and language skills.

Common Causes of Low Sodium Levels

  • Rapid loss of electrolytes from the body like diarrhea, vomiting or excessive sweating
  • Intestinal damage such as bariatric surgery, celiac’s, IBS, Crohn’s and ulcerative colitis
  • Medications, particularly diuretics
  • Prolonged exercise for several hours.
  • Exercising in the heat or intense exercising causing significant sweating.
  • Sauna sessions.
  • Overhydration, i.e., drinking too much plain water without enough salt
  • States of water retention such as congestive heart failure, cirrhosis and kidney failure
  • Medications that cause water retention, such as selective serotonin reuptake inhibitors (SSRIs)
  • Syndrome of inappropriate antidiuretic hormone production (SIADH). Anti-diuretic hormone is produced by the hypothalamus and it regulates water retention by the kidneys. When antidiuretic hormone is produced in excess, it causes a drop in blood sodium levels.
  • Hormonal imbalances affecting levels of aldosterone, thyroid hormones and cortisol

Risk Factors for Sodium and Chloride Deficiency

  • Sodium and chloride are also found in fresh foods in roughly equal proportions, although meat, fish, and eggs are somewhat richer in sodium, while nuts, vegetables, fruits, and grains are somewhat richer in chloride. A mix of natural foods that is diversified among plant and animal foods and among land and sea foods may provide sufficient sodium and chloride for many individuals, but it is also possible that chronic stress increases the need for salt beyond what natural, unprocessed foods can provide.
  • The amount of salt recommended as sufficient for adults by the Institute of Medicine translates to two thirds of a teaspoon of regular table salt per day. 
  • Unless you suffer from high blood pressure or a high risk of kidney stones or osteoporosis you should be liberal with salt and salt your food to taste, while also trying to eat a potassium-rich diet for balance.
  • All electrolytes, especially sodium, chloride, and potassium, are lost in vomit, diarrhea, sweat, and urine. Common causes of fluid loss are foodborne illnesses, gastrointestinal infections, diuretics, diabetes, sauna use, and intense physical activity. Persistent vomiting will disproportionately cause alkalosis and loss of chloride because of the expulsion of stomach acid. Untrained individuals will lose large amounts of sodium when engaging in exercise that causes intense sweating. As individuals train, especially in hyperthermic conditions, they adapt by excreting less sodium into sweat.
  • Mixing some electrolytes into water as a workout fuel, such as 1/16 teaspoon of salt and the juice of one quarter lemon per bottle of water, and consuming a diet that is salted to taste, should protect against this.

Signs and Symptoms of Excess Sodium and Chloride

A high salt-to-potassium ratio increases blood pressure and may also increase extracellular fluid in general, contributing to edema (swelling). It also contributes to a chronic acid burden, which lowers bone mineral density and increases the risk of osteopenia, osteoporosis, and kidney stones.

Hypernatremia is sometimes caused by a defect in the sense of thirst. Weakness, nausea, and loss of appetite are other early symptoms. In severe cases, it may lead to cerebral edema and shrinkage of brain cell volume, muscle twitching or spasming, confusion, seizures, coma, and death.

Risk Factors for Excess Sodium and Chloride

The Institute of Medicine set the tolerable upper intake limit at one teaspoon of salt as well, though acknowledging that increased sweating may increase needs. The value of salt restriction is hotly contested in the scientific literature, however, and both known physiology and clinical evidence suggest that consuming adequate potassium is far more important than restricting salt for blood pressure.

Suggestions for Increasing Salt

For individuals with high blood pressure, a high risk of kidney stones (having had a kidney stone in the past, or signs of high risk discovered on a urinalysis, such as a high presence of calcium oxalate crystals), or a high risk of osteoporosis (postmenopausal women, anyone with low bone mineral density), construct a potassium-rich diet. If blood pressure is normal, salt your food to taste as you’re unlikely to salt your food beyond your actual needs.

Suggestions for Increasing Potassium and Decreasing Salt

  • In the case of high blood pressure or edema, the first nutritional effort should be to raise dietary potassium. This interpretation is especially strong if dietary potassium is under 4.7 grams, but could be plausible at almost any level. Salt should be restricted gradually if raising dietary potassium does not work.
  • Three options for constructing a potassium-rich diet: 1) a diet very rich in fruits and vegetables, 2) a low-fat diet that is low in grains and free of refined carbohydrates, and 3) a low-carbohydrate, high-fat diet that emphasizes vegetables with high ratios of potassium to net carbs.

In Summary

Potassium and sodium are important minerals for cardiovascular health and the prevention of hypertension and insulin resistance. Traditionally, all the blame has been put on sodium when really it is sugar that’s the problem. Insulin resistance and diabetes can cause sodium retention and accumulation and raise blood pressure. At the same time, salt restriction comes with an array of negative side-effects that perpetuate insulin resistance and cardiac complications. Thus, it is more important to fix the underlying cause of hypertension, i.e., metabolic syndrome and obesity, which is due to an overconsumption of refined carbohydrates and sugars. Keeping potassium intake high by eating more muscle meat, fish, potatoes, fruit and green leafy vegetables alongside other mineral-dense foods is a great way to prevent glucose intolerance and ensure a healthy sodium to potassium ratio. Reaching an intake of potassium of 4,000-4,500 mg/day may seem like a daunting task but it is possible if you replace the processed foods with whole animal foods and fresh produce.

  • Consuming foods raw or consuming the cooking water and juices always helps improve potassium intake.
  • Avoiding refined carbohydrates always helps improve potassium intake.
  • The lean portions of meat, eggs, and dairy always make a significant contribution to potassium intake.
  • If you are focusing on cutting calories, a high volume of fruits and especially vegetables are the best way to improve potassium intake.
  • If you have difficulty eating high volumes of low-calorie foods due to time constraints, digestive difficulties, or difficulty meeting caloric requirements, then a diet with moderate amounts of whole grains and larger amounts of potatoes and legumes is the best way to improve potassium intake.
  • If you have trouble digesting or metabolizing fats, or need to temporarily reduce fat to extreme levels for body composition goals, then consuming fat-free dairy products, lean cuts of meat, and egg whites supplemented with biotin and alternative sources of choline is the best way to improve potassium intake.
  • If you are eating a low-carbohydrate, high-fat diet, selecting the foods with the highest potassium-to-net carb ratios and eating them in large volumes is the best way to improve potassium intake.
  • Depending on your goals, any of the above strategies can be mixed and matched.

Potassium Supplements

If all of the above strategies prove infeasible or unsustainable, you can obtain a portion of the potassium requirement from supplements. In such cases, he recommends mixing potassium citrate powder in water for the least risk of gastrointestinal distress. Potassium should always be taken with a full meal and the dose should be spread out across the day. Potassium supplements should not be used by anyone with diabetes, insulin resistance, impaired kidney function, or who is using ACE inhibitors, beta-blockers, and nonsteroidal anti-inflammatory drugs (NSAIDs), unless prescribed by a physician.

Other Minerals



Boron appears to support executive brain function, to improve testosterone in men, and to protect against prostate cancer in men and lung cancer and cervical dysplasia in women.

Food selection is an unlikely cause of inadequate boron, but low plant food intake could contribute. Low accumulation in the food chain can be caused by low soil boron, low soil organic matter, or soil pH below 5.0 or above 6.5. Taking boron supplements does not eliminate the harm of eating low-boron foods, because low boron uptake into plant tissues also compromises their content of chlorophyll and fat-soluble vitamins. Nevertheless, supplemental boron at 3 milligrams per day has shown some promise for increasing testosterone levels in men.

Urine, blood and other bodily fluids primarily contain boric acid. The absorption of boron occurs in the intestine but not through the skin. Boron homeostasis is regulated primarily by the kidneys and urinary excretion similar to sodium. The excretion of boron happens mostly through urine, feces, bile or sweat. Up to 92-94% of boron gets excreted in the urine after 96 hours of consumption. If dietary intake of boron is high, excretion is also higher and vice versa.

Boron’s Effect on Health and Vitality

More than 90% of boron consumed is absorbed and distributed as boric acid with 98% getting excreted through urine within 120 hours. Nearly 96% of the boron in an organism is uncharged boric acid [B(OH)3] and a small amount of it is the borate anion [B(OH)4 -]. Boric acid or borate forms ester complexes with many important sugars in energy production and stabilizes them, such as ribose, helping to produce energy and combat fatigue. Because of that, boron can regulate ribose-containing enzymes and catalysts, such as S-adenosylmethionine (SAMe), diadenosine phosphate, NAD+, and the NAD+ metabolite cyclic ADP ribose (cADPR).

These enzymes are involved with energy production, neurological function, cardiovascular health and bone formation. S-adenosylmethionine (SAMe) and diadenosine phosphates have a high affinity for boron. S-adenosylmethionine is one of the most common enzymatic substrates in the body, used primarily in methylation reactions. Boron also binds to oxidized NAD+ and cyclic ADP ribose, which can prevent the release of intracellular calcium.

Prostate Cancer

Turkish men with a boron intake of 6 mg/day have significantly smaller prostate glands than men who consume 0.64–0.88 mg/day. Physiological concentrations of boric acid have been shown to inhibit prostate cancer cell growth in a dose-dependent manner through controlled apoptosis. Tumor suppressor p53 function requires the activation of activating transcription factor 4 (ATF4) and binding immunoglobulin protein (BiP) also known as glucose regulated protein (GRP-78) or heat shock 70 kDa protein 5 (HSPA5), which get increased by physiological doses of boric acid. Boric acid inhibits cADPR, reducing endoplasmic reticulum Ca2+. This reduction in endoplasmic reticulum Ca2+ activates ATF4 and nuclear factor erythroid 2 like 2 (Nrf2), which increases antioxidant response element genes.

Oxidative Stress Defense

Supplemental doses of boron are likely to act as an Nrf2 booster, which activates our body’s overall antioxidant defense enzymes. This is why boron has been suggested to protect against oxidative stress and DNA damage. Boron compounds (such as boric acid and borax) can increase total glutathione levels, total antioxidant capacity and numerous antioxidant enzyme activities in red blood cells, such as superoxide dismutase, catalase, glutathione peroxidase, glutathione-S-transferase (GST) and glucose-6-phosphate dehydrogenase (G-6-PDH).

  • Superoxide dismutase prevents tissue damage from superoxide anions and catalase can prevent lipid and protein oxidation in red blood cell membranes against peroxide radicals. G-6-PDH provides the NADPH for increasing reduced glutathione, which prevents hemoglobin denaturation, preserves red blood cell membrane sulfhydryl group integrity and detoxifies oxidants in red blood cells. Thus, maintaining adequate boron intake may help to preserve the integrity of red blood cells and increase oxygenation throughout the body.


Boron might be useful for reducing symptoms of osteoarthritis by reducing inflammation. By binding to 6-phosphogluconate, boron inhibits the 6-phosphogluconate dehydrogenase enzyme and reduces the inflammatory response and reactive oxygen species. Boron also inhibits other inflammatory enzymes like lipoxygenase that triggers the inflammatory responses of prostaglandins, leukotrienes and thromboxanes. Supplementing with calcium fructoborate at 112 mg/day reduces LDL, triglycerides, total cholesterol, interleukin-6, monocyte chemoattractant protein-1, c-reactive protein and the pro-inflammatory cytokine IL-1beta. Boron intake helps to regulate osteoblast and osteoclast proteins. Boron deprivation inhibits protein synthesis, which can result in delayed wound healing and soft tissue repair.

Bone Health

Boron also controls calcium and magnesium metabolism, which are vital for bone health. Boron supplementation reduces calcium excretion. In postmenopausal women, a low boron diet (0.25 mg boron/2,000 kcal) can raise urinary calcium and magnesium excretion. At the same time, a low boron diet promotes hyperabsorption of calcium for compensation. That can cause cardiovascular and bone health complications. Supplementing with 3 mg of boron a day for 10 months in sedentary female college students reduces serum phosphorus, increases serum magnesium and may slow the loss in bone mineral density.

Sex Hormones and Vitamin D

Boron affects the function of many hormones, including vitamin D. Supplementing 3 mg/day of boron after 63 days of boron deprivation (0.25 mg/day) raises 25-OH-vitamin D (calcidiol) levels in older men and women. Boron also increases the half-life of active vitamin D likely through inhibition of 24-hydroxylase, which is the primary enzyme that inactivates calcitriol.

Boron affects sex hormones like estrogen and testosterone. By inhibiting sex hormone binding globulin (SHBG), boron prevents testosterone from being bound up, resulting in higher free testosterone. Instead of increasing estrogen directly, boron inhibits its breakdown and enhances estrogen receptor beta activity. Both estrogen and testosterone levels have been shown to double in women and men, respectively, after an increase in boron intake in individuals who were previously on a low boron diet. In healthy men, supplementing with boron at 10 mg/d for only a week can raise free testosterone from 11.83 pg/mL to 15.18 pg/mL and decrease estrogen from 42.33 pg/mL to 25.81 pg/mL (although in some studies boron increases both testosterone and estradiol levels in men).

  • All inflammatory markers (high-sensitivity c-reactive protein, IL-6 and TNF-alpha) decreased. The increase in testosterone with boron supplementation may also be due to improved vitamin D status, which does have an effect on sex hormones.

Boron Food Sources

Boron is found the most in plant foods, such as legumes, vegetables, tubers and fruit. Alcoholic beverages like wine, beer and cider also have some boron. Prunes are an excellent source of boron, providing 1.5 to 3.0 mg of boron per 3 oz serving. A study found that eating 3 ounces of prunes a day for a year improved bone mineral density in postmenopausal women, but dried apples did not. Boron does not accumulate in fish or land animals, but it does in algae, seaweed and plants. Many people following an animal-based diet like to eat avocadoes to boost their boron intake (8 oz. provides ~ 2 mg of boron).

Boron-Dependent Enzymes, Functions and Consequences of Deficient Boron Intake

Boron-Dependent Enzymes/Proteins: Function: Consequences of Deficit

  • Superoxide Dismutase: Removes superoxide anions: Increased tissue damage and oxidative stress
  • Catalase: Removes hydrogen peroxide: Increased tissue damage and oxidative stress
  • NAD+ (Nicotinamide Dinucleotide): Energy production and governs most enzymatic reactions: Accelerated aging and onset of disease
  • D-Ribose: Component of ribonucleotides in RNA, energy production: Chronic fatigue and impaired gene expression
  • S-adenosylmethionine (SAMe): Methylation donor, wide enzymatic substrate: High homocysteine, inflammation and depression
  • Vitamin D: Hormone production, immune system function, bone density, physical growth: Increased risk of autoimmunity, weaker immune system, loss of bone density and mood disorders
  • Cyclic ADP Ribose (cADPR): Calcium signaling, functions of ribose: Low blood calcium levels, intracellular calcium accumulation
  • 6-Phosphogluconate: Regulates respiratory burst mechanisms and inflammation: Excess inflammation and reactive oxygen species
  • Collagenase: Degrades calcified collagen barriers: Bed sores, arthritis and tissue calcifications
  • Calcitonin: Reduces calcium levels and inhibits osteoclast activity: Excess calcification and reduced bone health
  • Estradiol: Female reproduction and fertility, neuroprotection: Infertility, neurodegeneration and impaired cognition
  • Gcn4: Transcription factor for gene expression and protein synthesis: Muscle mass and soft tissue deterioration
  • Delta-aminolevulinic acid dehydratase (ALA-D): Heme synthesis, precursor to hemoproteins and cytochromes: Anemia, low heme and poor tissue oxygenation

Soil and Environmental Content

Brazil, Japan and most of the U.S. have low boron in the soil because of high rainfall. California, Chile, Russia, China, Argentina, Turkey and Peru, however, have higher boron levels. Excessive levels of boron in the soil also reduce crop yields. One estimate suggested that up to 17% of the barley loss in Southern Australia was caused by boron toxicity. Borate deposits form into the ground when boric acid reacts with steam, which is why areas with hot springs and geysers tend to have more boron.


Environmental boron exposure is not a threat to human health. However, accidental consumption of borax found in household chemicals and pesticides (at doses of 18 to 9,713 mg) causes nausea, gastrointestinal distress, vomiting, convulsions, diarrhea, rashes and vascular collapse. Oral doses of 88 grams of boric acid were not shown to be toxic. However, taking over 84 mg/kg of boron has caused gastrointestinal, cardiovascular and renal adverse effects, dermatitis and death.

In excess amounts, boron can also contribute to the development of goiter by competing with iodine absorption. High concentrations of boron are used to eliminate bacterial and fungal infections by causing mitochondrial dysfunction.


Supplemental boron usually comes in the form of sodium borate, sodium tetraborate, boron amino acid chelate, boron gluconate, boron glycinate, boron picolinate, boron ascorbate, boron aspartate, boron citrate and calcium fructoborate. Taking 10 mg of boron as sodium tetraborate for 7 days can reduce sex hormone binding globulin (SHBG), resulting in higher testosterone, lower high sensitivity CRP (hsCRP) and TNF-alpha 6 hours after supplementation. Boron supplementation does not seem to affect lean body mass or strength in young male bodybuilders already engaged in resistance training. Calcium fructoborate has been shown to reduce inflammation in osteoarthritis and cardiovascular disease.

When taking boron supplements, it might be worthwhile to consume away from foods that contain B-vitamins and/or consume more foods with B-vitamins like beef, fish, eggs, vegetables and beans. Boron has a high affinity for riboflavin and ingesting high doses of boron may lead to side effects due to riboflavin deficiency (dry skin, photosensitivity and inflammation of the mouth and tongue).



Chromium appears to support glucose tolerance, insulin sensitivity, and to raise HDL-cholesterol.

Lack of chromium can cause poor glucose metabolism and reduced insulin sensitivity. Chromium has been shown to alleviate high glucose and insulin resistance in L6 skeletal muscle by regulating pathways of glucose uptake and insulin sensitivity. Chromium is important for regulating blood sugar. Vanadium deficiency may also be a factor, although more research about the risks vs benefits is needed.

Chromium is found in the highest concentrations in whole grains, unrefined sugars, and brewer’s yeast (but not other edible yeasts), and in lesser amounts in fruits and vegetables. Needs for chromium are probably proportional to carbohydrate intake. The refining of grains and sugars removes chromium and this may contribute to poor glucose tolerance on diets high in refined carbohydrates. It may be that choosing unrefined grains and unrefined sugars over their refined counterparts is adequate. Nevertheless, soil chromium varies and this influences the chromium stores of plants. Supplementation of 200 micrograms per day of chromium has shown some promise for improving glucose metabolism.

Chromium picolinate, specifically, has been shown to reduce insulin resistance and may even reduce the risk of cardiovascular disease and type-2 diabetes. A report on four meta-analyses of human studies saw a significant reduction in fasting plasma glucose levels from chromium supplementation. A 2016 review covering six meta-analyses concluded that chromium decreases fasting blood glucose and HbA1C. Thus, you do not want to be deficient in chromium because that is associated with diabetes and hyperglycemia.

  • A reported benefit of chromium is that it has also been found to be protective against atherosclerotic lesions (so it protects blood vessels), but to date, this has only been observed in experimental animals. Chromium picolinate has been shown to significantly decrease triglycerides, insulin, HOMA-IR, inflammation, and insulin resistance in patients with nonalcoholic fatty liver disease.
  • Although a number of researchers have demonstrated this inverse association between cardiovascular disease and the chromium content of drinking water, it is important to add that the causal relationship is not proven. It remains an area worthy of further investigation, but certainly suggests that chromium can be significant as a nutritional source when it is present in your drinking water.

Chromium Benefits

Chromium 3+, or trivalent chromium, was found to be the main active component of the ‘glucose tolerance factor’ in rats that alleviated their glucose intolerance caused by high sucrose consumption. In diabetic patients, chromium-enriched yeast can decrease fasting blood glucose and insulin. Chromium is required for the binding of insulin to the cell surface so it can exert its effects. However, chromium appears to require synergy with nicotinic acid to work in lowering blood sugar through the glucose tolerance factor. GTF enhances the activity of insulin.

Chromium supplementation does not appear to improve insulin sensitivity in healthy non-obese people.

The current understanding is that chromium binds to an oligopeptide to form chromodulin that activates the insulin receptor to mediate the actions of insulin. Chromodulin stimulates insulin-dependent tyrosine kinase activity that activates the insulin receptor. Thus, chromodulin functions as an amplifier of insulin signaling. Another oligopeptide called low-molecular-weight chromium-binding substance (LMWCr) carries chromium around the body as a second messenger for insulin signaling.

Because of its effects on insulin and glucose metabolism, chromium is thought to help with polycystic ovary syndrome (PCOS), which is characterized by insulin resistance and dyslipidemia. Chromium supplementation of 200-1,000 mcg/d for 8-24 weeks has not been found to have a significant effect on fasting glucose, but it did lower fasting insulin and bodyweight. Among diabetic PCOS patients, chromium supplementation improved HOMA-IR scores (a marker of insulin resistance). However, due to mixed results, more studies are needed.

By increasing insulin sensitivity, chromium supplementation has also been promoted as a way to increase muscle mass and athletic performance. With higher insulin action, nutrients would be stored and utilized faster, which is why bodybuilders use injectable insulin. The potential benefits of chromium on muscle anabolism are thought to be marginal, however, many athletes are thought to be deficient in this nutrient. If not deficient, the effects appear negligible.

Athletes who train at an intense level and sweat for around 60 minutes per training session, should consider supplementing with an extra 600 mcg of chromium picolinate (which has a 1.2% bioavailability, providing 7.2 mcg of chromium) or another chromium supplement with a similar bioavailability (such as Brewer’s yeast chromium) on exercise days.

  • Diets high in simple sugars increase urinary chromium excretion by 300%. Athletes tend to consume more simple sugars to fuel their workouts and for post-exercise glycogen replacement. This would lead to further chromium losses out of the urine and increase the risk of chromium deficiency.
  • Caffeine or coffee may increase urinary chromium losses. Thus, it may not be a bad idea for those consuming caffeine/coffee to get extra chromium in their diet.

A prospective study involving 3,648 subjects found an inverse association between the occurrence of metabolic syndrome and toenail chromium concentrations. Low toenail chromium concentration has also been associated with an increased risk of a heart attack. In Korean males, insulin resistance is associated with lower chromium hair concentrations and higher Ca/Mg ratio. Type 1 and Type 2 diabetes are correlated with blood chromium deficiency.


The most recent adequate intake (AI) for chromium in the U.S. has been set at 25-35 mcg/d for adults. To reach the 1 mcg/d recommendation you would have to ingest about 33-100 mcg/d. In 1980, the Estimated Safe and Adequate Daily Dietary Intake (ESADDI) for chromium was set at 50-200 mcg/d for adults. According to the World Health Organization, an approximate chromium intake of 33 mcg/d is likely to meet normal requirements. In Australia and New Zealand, the AI for chromium is 35 mcg/d for men, 25 mcg/d for women, 30 mcg/d for pregnant women and 45 mcg/d for lactating women.

Chromium-Dependent Enzymes, Functions and Consequences of Deficient Chromium Intake

Chromium-Dependent Enzymes/Proteins: Function: Consequences of Deficit

  • Glucose Tolerance Factor (GTF): Enhances insulin activity: High blood sugar, reduced muscle gains
  • Chromodulin: Activates the insulin receptor: High blood sugar, insulin resistance & reduced muscle gains
  • Tyrosine Kinase: Activates the insulin receptor: High blood sugar, insulin resistance & reduced muscle gains
  • Low-Molecular-Weight Chromium- Binding Substance (LMWCr): Carry chromium around the blood, mediate insulin signaling: Elevated blood sugar, insulin resistance and reduced muscle gains
  • Glycolytic Flux: Conversion of glucose into pyruvate and ATP: Glucose intolerance, metabolic inflexibility, lactic acid accumulation and lack of energy
  • Superoxide Dismutase: Removes superoxide anions: Increased tissue damage & oxidative stress
  • Glutathione Peroxidase: Removes hydrogen peroxide: Increased oxidative stress and weaker immunity
  • DNAzymes: RNA cleavage, catalyst of enzymes: Inadequate enzymatic reactions

Symptoms of Deficiency

In deficiency the body tends to shut down urinary/fecal losses and increase mineral absorption. Thus, it may appear that someone is in positive mineral balance (less urinary/fecal losses than what is being absorbed) but this may actually indicate mineral deficiency. This is why you typically need to give an oral or IV loading dose of a mineral to see how much gets excreted out in the urine (at least for minerals that are regulated by the kidney) to determine deficiency. This is because if the body does not excrete much of a high loading dose of a mineral, this suggests a deficiency, as the body is trying to hold onto the mineral.

Chromium Foods

Chromium is found in many foods, such as meat and vegetables. Many medicinal plants like sand immortelle, foxglove, Alexandrian laurel, Greek valerian, marsh cudweed, adenostilis and lobelia have high amounts of chromium. However, not all chromium in foods has glucose tolerance factor (GTF) and thus total chromium content may not be a valid indicator of the insulin sensitizing benefits of a given food.

Foods with the highest amount of chromium as GTF are brewer’s yeast, black pepper, liver, cheese, bread and beef, whereas the lowest ones are skim milk, chicken breast, flour and haddock. Supplementation with 9 grams of Brewer’s yeast per day for 8 weeks can improve impaired glucose tolerance, reduce serum cholesterol and lower the insulin response to a glucose load in humans. Polyphenolic herbs and spices like cinnamon have also been shown to improve insulin sensitivity together with chromium.

The richest sources of chromium are mussels and oysters, probably because of environmental contact. Fresh water fish living in areas of stainless-steel manufacturing, chrome plating or rubber processing have nearly 5 times more chromium than normal. They also get more of the toxic hexavalent chromium, which causes mutagenic gene damage.

Refining grains and wheat reduces the amount of chromium by up to 8-fold. Peeling apples and eating them without the skin reduces their chromium content by 70% (from 1.4 mcg to 0.4 mcg per apple).

Human milk also contains small amounts of chromium, which ranges from 0.25-60 mcg/L, depending on the nutrient and lactation status of the mother. Infants of less than 6 months of age need less than 0.5 mcg/d of chromium. Finnish infants who are exclusively breast-fed and get 0.27 mcg/d of chromium do not show any abnormalities. Exposure to excess environmental chromium during pregnancy increases the risk of delivering low birth weight babies. Chromium levels in the body are higher at birth than later in life, which might explain why infants need much less chromium.

Chromium can also be obtained from the use of stainless-steel cookware during cooking. Cooking acidic foods like tomato sauce for several hours promotes the leaching of nickel and chromium from the cookware into the food. Preparing fresh meat in a food processor equipped with stainless-steel blades nearly doubles its chromium content and it does so 10-fold for liver after 3 minutes of blending. Canned and processed foods may be higher in chromium than fresh foodstuff because of this reason. The exception is refined white sugar that is incredibly low in chromium, whereas brown sugar and molasses are high in chromium. Consuming refined sugar as it comes in candies, pastries or other processed foods will thus contribute to excretion of chromium, especially if it is not being replaced.

Factors that may Affect Chromium Levels

Vitamin C (ascorbic acid) and prostaglandin inhibitors, such as aspirin, increase chromium absorption, whereas antacids and oxalates decrease it. Taking 100 mg of vitamin C together with 1,000 mcg of chromium raises plasma chromium levels more than taking 1,000 mcg of chromium alone. High sugar and fructose intake increases chromium excretion. Simple sugars excrete more chromium than complex carbohydrates. Thus, hyperglycemia and insulin resistance will also promote chromium elevation in blood and its excretion. Diabetics show a 3-fold increase in urinary chromium excretion. Physical exercise, sweating and injury will also promote chromium losses. Infections such as viruses promote the excretion of chromium.

Taking chromium together with insulin can trigger hypoglycemia because of the increased insulin sensitivity. The same applies to metformin or other blood sugar lowering medication.

It is recommended to not take levothyroxine or other thyroid medications with food or together with a chromium supplement. Instead, it would be best to take levothyroxine before eating and chromium at least 2 hours after levothyroxine. Chromium supplementation has been shown to reverse corticosteroid-induced diabetes.


In conclusion, chromium is considered an essential nutrient, especially because of its effects on insulin, glucose and lipid metabolism. However, healthy individuals do not need to deliberately be eating a high chromium diet to prevent metabolic syndrome as there are other more important variables, such as overall energy intake and body composition. Chromium has a more beneficial effect in people who have diabetes, insulin resistance or prediabetes. For them, chromium picolinate supplementation of 200-1,000 mcg/d may improve glycemic control and fasting insulin levels. An adequate consumption of 25-35 mcg/d from whole foods would probably be enough to prevent prediabetes in already healthy subjects but optimally most people would benefit from 33-100 mcg/d. To obtain that amount, you can get the most chromium from animal foods, especially mussels, oysters and lobster, but nutritional yeast and potatoes also have quite a lot. The demand for chromium increases with diabetic comorbidities, exercise and sweating.



Many authorities around the world add fluoride to the water supply, usually citing studies which have shown how this measure can reduce the prevalence of tooth decay. Untreated dental caries can lead to weight gain, impair growth, increase the risk of infections, affect school performance and possibly lead to death. Adequate fluoride intake inhibits demineralization and bacterial activity in dental plaque.

Fluoride is the ionic form of fluorine, which promotes bone formation and fights tooth decay. Teeth and bones store 99% of the fluoride in the human body. In adults, 50% of absorbed fluoride gets retained and 50% is excreted through urine. In children the absorption rate is up to 80% because their bones and teeth are in the growth stage.

A 2015 review of 20 observational studies discovered that water fluoridation reduces the risk of tooth decay and fillings by 35% and permanent loss of adult teeth by 26% in children receiving fluoridated water compared to children receiving unfluoridated water. A 2018 cross-sectional study in the U.S. found that living in a county where 75% or more of the drinking water is fluoridated with at least 0.7 mg/L of fluoride was associated with a 30% reduction in the rate of primary teeth caries and a 12% reduction in the rate of caries in primary teeth. In Australian adults, exposure to fluoridated municipal water for at least 14 years associates with an 11-12% lower rate of decayed, missing or filled teeth than those whose water had negligible amounts of fluoride. The average rate of decayed, missing or filled teeth in Australian Defense Force members aged 17-56 is 24% lower in those whose water that contained 0.5- 1.0 mg/L of fluoride for at least half of their lifetime compared to those exposed for less than 10% of their lifetime. However, the benefit of fluoride is from its topical use, not its oral ingestion, and there are potential side effects from consuming fluoridated water. One group of authors concluded, “Fluoride has modest benefit in terms of reduction of dental caries but significant costs in relation to cognitive impairment, hypothyroidism, dental and skeletal fluorosis, enzyme and electrolyte derangement, and uterine cancer. Given that most of the toxic effects of fluoride are due to ingestion, whereas its predominant beneficial effect is obtained via topical application, ingestion or inhalation of fluoride predominantly in any form constitutes an unacceptable risk with virtually no proven benefit.”


The daily adequate intake (AI) for fluoride in adults is 3-4 mg, 3 mg in teens aged 14-18, 1-2 mg in children aged 4-13, 0.7 mg in 1-3-year-olds, 0.5 mg in 7-12- month-olds and 0.01 mg in newborns less than 6 months of age. The U.S. Public Health Service recommends a fluoride concentration of 0.7 mg/L in drinking water for prevention of dental caries. The maximum allowable concentration established by the EPA is 4.0 mg/L and maximum recommended concentration is 2.0 mg/L. Average fluoride intakes in the U.S. from both foods and fluorinated drinking water is 1.2-1.6 mg for infants less than 4 years old, 2.0-2.2 mg for 4-11-year-olds, 2.4 mg for 11- 14-year-olds and 2.9 mg for adults.

Food Sources

Brewed tea is one of the highest sources of dietary fluoride because the tea plants absorb fluoride from the soil. Fluoride levels in tea brewed with distilled water can range from 0.3 to 6.5 mg/L (0.07 to 1.5 mg/cup). One cup of coffee contains 0.22 mg of fluoride. Other foods like shrimp, pork, beef and tuna have 0.02-0.17 mg of fluoride per 3 oz. serving, while a medium baked potato has 0.08 mg. The amount of fluoride in breast milk and cow’s milk is almost undetectable. Thus, most food sources are relatively low in fluoride and unless you are regularly drinking tea, it would be difficult to reach the adequate intake of 3-4 mg/d. Fluorinated municipal drinking water accounts for 60% of the fluoride intake in the U.S.

Dental Hygiene Sources

Most toothpaste in the U.S. contains sodium fluoride or monofluorophosphate, usually at a concentration of 1,000-1,100 mg/L (about 1.3 mg per quarter of a teaspoon used for one brushing). How much fluoride is absorbed from toothpaste depends on the amount used and how much a person swallows it. It is estimated that adults ingest 0.1 mg/d from toothpaste, children aged 6-12 ingest 0.2-0.3 mg/d and children less than 5 years old 0.1-0.25 mg/d. Other dental products that contain fluoride are mouth washes, orthodontic bracket adhesives and cavity liners. Oral antifungal medicine like voriconazole provides 65 mg/d of fluoride, which in the long-term can cause high serum fluoride levels.


Serious systemic fluoride toxicity can be caused by doses of 5 mg/kg (about 375 mg for a 165 lb. person). That threshold is almost impossible to reach by being exposed to drinking water or dental care products. Excess fluoride intake causes gastrointestinal distress, nausea, abdominal pain and diarrhea. Ingestion of large doses of sodium fluoride (60 mg) can promote skeletal fluorosis, causing osteoporosis and bone fractures.

Excess fluoride intake above the recommended intake, especially in childhood, can lead to dental fluorosis, characterized by white or brown lines or flecks on the teeth. NHANES data has discovered that the rates of dental fluorosis have increased from 29.7% in 2001-2002 to 61.3% in 2011-2012. High fluoride intake in children may also be associated with lower IQ and impaired cognition.

A meta-analysis of all available studies on the topic from 2018 indicated that exposure to high levels of fluoride in water was strongly associated with reduced levels of intelligence in children. This was further endorsed by research published in 2019, focused on mother-child pairs from six Canadian cities which found that high fluoride exposure during pregnancy was correlated with lower IQ scores among young children, especially boys. It led to the author’s recommendation for pregnant mothers to reduce their fluoride intake during pregnancy, but the topic is controversial. It even led to the editor of the JAMA Pediatrics who published the findings, writing something of a disclaimer and reminding us that “scientific inquiry is an iterative process”. With the benefit of hindsight however, on the topic of fluoride and its various compounds, the jump to mandatory addition to the water supply in certain areas may have been taken too hastily.


Overall, drinking only tap water might be problematic for infants and children in developing years but complete avoidance may lead to fluoride deficiencies. Even supplementing fluoride 0.25-1 mg/d for 24-55 months in children living in communities without fluorinated drinking water has resulted in a 24% reduced rate of decayed, missing and filled tooth surfaces. In areas where water fluoridation rates are lower than 0.6 mg/L, fluoride supplementation of 0.25-1 mg/d may reduce the rate of caries in primary teeth by 48-72% in children aged 6-10. Thus, a moderate consumption of fluorinated water (1-1.5 liters a day) should be acceptable and may even be beneficial. Cooking your food and vegetables with fluorinated water may also be recommended if you have a low intake of fluoride.


Lithium is the lightest solid element in the periodic table, and it is an essential trace mineral with many recommending an intake of 1 mg/day to meet requirements. In miniscule doses, lithium has been shown to have a number of health-related benefits. Observational studies in Japan have noted that low-dose lithium in drinking water is associated with better longevity.

  • Lithium has been associated with the low prevalence of both coronary heart disease and of gastroduodenal ulcers among the Pima Indians of Arizona, where levels in their water supplies can exceed 100 ug/l. That’s over fifty times the U.S. average. Other teams of researchers found a negative correlation between lithium levels in drinking water and cardiovascular death rates in the U.S. and given that lithium has for years been prescribed as a mood stabilizer, associations with less aggressive behavior among the populations using the water could lie behind a lower incidence of mental disorders, violence and also of heart attacks.
  • More recently in Denmark, higher levels of lithium in the local water supply have been linked to lower levels of dementia. Higher lithium levels in drinking water have also been shown to have a protective effect on the risk of suicide in countries across the entire world. Therapeutic doses of lithium (600-1800 mg/day) are commonly used to treat mania and depression in patients of bipolar disorder.
  • Lithium administration has been shown to protect against hyponatremia or low sodium levels in the blood. The mechanisms for that are proposed to be lithium’s ability to reduce water retention in diabetes insipidus. Lithium toxicity, however, can cause hypotension and cardiovascular complications, which is why its serum levels have to be monitored carefully. Maternal use of lithium during the first trimester has been found to increase the risk of cardiac malformations.
  • There are observational studies associating low-dose lithium in drinking water with benefits such as lower risks of dementia, homicide, and suicide, but also studies associating it with harms, such as impaired calcium metabolism. 


Silicon is best known to most of us as the base material for semiconductor manufacturing and the creation of the computer chip beginning with silica sand, which is made up of silicon dioxide. As the eighth most common element in the universe, making up more than 90% of the earth’s crust, it should be no surprise that trace elements (mostly silicon dioxides) are found in our drinking water. 

  • We have already read that hard water is associated with lower death rates from coronary heart disease, but across the U.S., where the water contains above average levels of silicon – 15mg per liter vs. 8 mg per liter – that association becomes even more positive. This can be related to the silica content in natural water supplies which is commonly in the 5 to 25 mg/L range. The association is further supported by the situation in Eastern Finland, where lower silicon concentration levels in the water are associated with more heart disease than found in the west of the country.
  • There are further benefits associated with silicon. Researchers at UK’s Keele University found that drinking around a liter of silicon-rich mineral water every day can speed up the removal of toxic aluminum from the body via the kidneys and ultimately urine. They even recommend selecting your bottled water according to its silicon content.
  • Silicon might support bone health and nickel might support reproductive function and liver health, but the evidence for this is limited to animal experiments and there is no evidence supporting these roles in humans. 


Evidence for beneficial effects of other trace elements is not great:

Strontium has shown benefits to bone mineral density in osteoporotic women when supplemented as 2 grams per day of strontium ranelate, which provides about 340 milligrams of elemental strontium. There is no evidence on which to consider this a nutritional effect rather than a pharmacological effect, however, and it is not clear that strontium has an essential role in human biology.

Vanadium supplementation has improved insulin sensitivity in people with diabetes, but it is not clear that it has any role as an essential nutrient and animal experiments suggest that it has a very narrow therapeutic window, causing harms at doses that are not much higher than the doses that cause benefits.

  • Cell studies show that vanadium has insulin-mimetic properties and anti-diabetic effects in animals. Because of this potent insulin mimicry, excessive intakes of vanadium can cause hypertension and death. However, oral vanadyl sulfate at 100 mg/day for 3 weeks improves liver and peripheral insulin sensitivity in type 2 diabetic patients. Supplemental vanadyl sulfate (l00 mg/d) or sodium metavanadate (125 mg/d) has not been shown to improve glycemic control in type 1 diabetics but their daily insulin requirements did decrease.
  • The threshold for vanadium toxicity in humans is around 10-20 mg/d or only 1/5th of the observed beneficial dosage for insulin reduction, causing mild gastrointestinal disturbance and green tongue. In mice, the lethal dose has been estimated to be 1000 mg/kg body weight. Vanadium deficiency is not considered common in humans and most diets provide 15-30 mcg/day. Foods with vanadium include shellfish, mushrooms, herbs and some seeds. Fruit and vegetables contain little vanadium.

While there is some evidence that arsenic deprivation in animals can produce deficiency signs, there is no evidence of this in humans, no known essential roles of arsenic in animal biology, and clear evidence of its toxicity.

Nickel is circumstantially essential for growth, reproduction and glucose regulation in animals. It also influences iron metabolism, increasing its concentrations in the liver. Vitamin B12 and folic acid are also connected to nickel status. These vitamins are important for regulating homocysteine and thus affecting cardiovascular disease risk.

  • Estimated daily requirements for nickel have been thought to be 25-35 mcg/d. Doses of 0.6 mg from water can cause skin irritation and rashes. Food sources of nickel include chocolate, nuts, beans, peas and grains. Most diets provide less than 150 mcg/d.

Cobalt – It is a key component of cobalamin or vitamin B12, which is an essential vitamin. Vitamin B12 deficiency can cause hyper-homocysteinemia, which is associated with cardiovascular disease and Alzheimer’s. Ruminants convert cobalt into vitamin B12 in their stomachs.

  • Grazing animals in areas with low cobalt in the soil experience “bush sickness” and other wasting diseases. Cobalamin neuropathy causes nervous system abnormalities. In experimental acrylamide neuropathy, ultra-high doses of vitamin B12 (500 mcg/kg of body weight, intraperitoneally) promote nerve regeneration in rats.
  • Cobalt deficiency can lead to pernicious anemia, which is a disease wherein not enough red blood cells are produced due to a vitamin B12 deficiency. It can be treated with oral B12 replacement at doses of 1,000 mcg/d or with injections.
  • There is no established RDA for cobalt, but adults are suggested to get 10-20 mcg/d. The upper limit is 250 mcg and therapeutic range 50-100 mcg/d. You can get cobalt from liver, buckwheat, cereal grains, meat, seafood and vegetables.
  • The RDA for vitamin B12 is 2.4 mcg. You can get vitamin B12 only from animal foods. Clams and liver are the richest sources of vitamin B12 with a dose of 70-84 mcg/3oz serving. Fish like salmon and trout provide 4.8-5.4 mcg/3oz. Nutritional yeast provides around 2.4 mcg of B12 per serving.
  • The median lethal dose for soluble cobalt salts is estimated to be 150-500 mg/kg. Soluble cobalt salts are considered possibly carcinogenic to humans. Addition of cobalt compounds to stabilize beer foam in 1966 Canada caused a type of cardiomyopathy called drinker’s cardiomyopathy.

Zinc promotes the production of the endogenous metal chelator, metallothionein, even when provided over and above the levels needed to support all other aspects of zinc nutritional status. If hair mineral analysis shows elevated levels of heavy metals, zinc supplementation, along with careful evaluation of the status of zinc, copper, and the other positively charged minerals, may help promote detoxification. Arsenic is specifically detoxified using methylation, and if arsenic is elevated, nutritional support for the methylation process may promote its clearance. Barium is most effectively detoxified with sulfate, so support for sulfur amino acids, vitamin B6, and molybdenum may help promote its clearance.

Essential Fatty Acids


The plant-based omega-6 fatty acid we tend to consume is linoleic acid (LA), whereas the omega-6 our bodies use is animal based arachidonic acid (AA). The omega-3s from plants are alpha-linoleic acid (ALA), but the animal-based omega-3s are EPA and DHA. The experiments that have dictated the omega-6 to omega-3 ratio are mostly on animals fed on plant-based oils. The enzymes that convert linoleic acid into arachidonic acid and alpha-linoleic into EPA and DHA are the same. So, too much intake of one fat may use up the enzymes and hurt the conversion of the other, resulting in greater imbalance. Although, unless you are a vegan, this doesn’t matter because the fatty acids you get from animals (eggs, liver, fish, and even algae) do not compete for the same enzymes. Obsessively swearing off of omega-6s can hurt the mitochondrial membrane so don’t worry unless you’re a vegan.

LA and ALA are defined conventionally as “essential fatty acids” because we cannot synthesize them. By contrast, we synthesize AA from LA, and we synthesize EPA and DHA from ALA, so AA, EPA, and DHA are not considered essential. Nevertheless, there is no clear evidence that we require LA or ALA to be present in our bodies to support our health, and there is clear evidence that we require AA and DHA.

Both EPA and DHA are precursors of various eicosanoids that are responsible for reducing inflammation. It has been shown to downregulate 41 genes that are involved in aging and decrease the rate at which telomeres shorten. Because fish oil inhibits inflammatory eicosanoids and cytokines, it has been shown to be a beneficial replacement for NSAIDs in the treatment of rheumatoid arthritis. Omega-3 fatty acids are known to improve dyslipidemia and inflammation in the context of cardiovascular disease. In patients with metabolic syndrome, omega-3 supplementation improves body weight, blood pressure, lipids and inflammatory markers.

Higher proportions of omega-6 can predict earlier death and physical and cognitive decline. This is because linoleic acid can make RBCs more susceptible to oxidative damage. Low omega-3 fatty acids predict smaller brain volume and cognitive decline. Also, high omega-3 fatty acids in the RBCs lower your risk for colon cancer. The ideal dietary ratio omega-6 to omega-3 is 4:1.

The Difference Between Essential Omega Fats

Omega-3 Fatty Acids are an indispensable part of the cell membrane and they have anti-inflammatory benefits that may protect against heart disease, eczema, arthritis and cancer. Dietary omega-3s help with regulating inflammation and the immune system. Food sources of omega-3s include salmon, salmon eggs, grass-fed beef, sardines, krill oil, algae and some nuts. There are 3 main types of omega-3s:

  • EicosaPentaenoic Acid (EPA) and DocosaHexaenoic Acid (DHA) are animal-sourced long-chain omega-3 fats mostly found in seafood. They are essential for the nervous system as well as brain and general health. Sidenote: DPA (docosapentaenoic acid) is another long-chain omega-3 found in grass-fed meat and ~ 30% of DPA converts to DHA in the body. In other words, DPA is another source for DHA when consuming grass-fed meat.
  • Alpha-Linolenic Acid (ALA) is a plant-based shorter-chain omega-3 fatty acid. Only small amounts of ALA get converted into EPA and even less into DHA. Most humans convert only 5% of ALA to EPA and 0.5% to DHA, although women of reproductive age may convert up to 21% ALA to EPA and 9% to DHA. Thus, seafood, which contains preformed EPA/DHA, is a more bioavailable source of long-chain omega-3s.

Omega-6 Fatty Acids are essential polyunsaturated fats (PUFAs) like omega-3s. They have six carbon atoms at the last double bond instead of three. Omega-6s are mostly used for energy and mediating the inflammatory response. Unfortunately, most people consume too much omega-6 fat. The most common omega-6 fats are linoleic acid (LA) and conjugated linoleic acid (CLA). You get omega-6 polyunsaturated fats from mostly vegetable oils, processed foods, salad dressing, TV dinners, etc., but also from nuts and seeds.

Omega-9 Fatty acids are monounsaturated fats (MUFAs) with a single double bond. These fats aren’t inherently essential because the body can produce them on its own but they’ve been found to lower triglycerides and VLDL and can improve insulin sensitivity. Omega-9s are the most abundant fats in the cell. You can get them by consuming olive oil and certain nuts.

The amount of linoleic acid in adipose tissue and platelets is positively associated with coronary artery disease, whereas long-chain omega-3 fats (EPA and DHA) have an inverse correlation. A higher amount of linoleic acid in adipose tissue has also paralleled the rise in diabetes, obesity, allergies and asthma. The reason has to do with how excess omega-6 consumption offsets the body’s fatty acid balance, causing inflammation, which leads to an overactive immune system and disease.

Immune Health

Many human clinical studies have found that oxidized linoleic acid metabolites activate NF-kB, which produces pro-inflammatory cytokines, whereas supplementing with EPA/DHA lowers inflammation. This can be an important strategy for potentially alleviating the cytokine storm and lung injury from coronaviruses, which result from excessive inflammation and NF-kB activation.

Excess linoleic acid, and a lack of EPA/DHA, has been proposed to create a proinflammatory and pro-thrombotic state. Thrombosis, or blood clotting, is one of the contributing factors to COVID-19 mortality. Furthermore, studies have suggested that omega-3s may improve survival in acute respiratory distress syndrome (ARDS) and sepsis.

Fish oil rich in DHA has been shown to increase neutrophil and monocyte phagocytosis by 62% and 145%, respectively, but not EPA-rich fish oil.

DHA (docosahexaenoic acid) supplementation can prevent the accumulation of macrophages in LPS exposure and hyperoxia. It also lowers HMGB1. Long-chain fatty acids like DHA and EPA may function as ACE enzyme inhibitors with anti-inflammatory properties. Dietary omega-3s also inhibit TLR4 receptor recruitment, which lowers pro-inflammatory pathways.

Omega-3s may also Reduce the Cytokine Storm in the Lungs through these Mechanisms

  • Lower omega-6-to-3 ratio in immune cells
  • Inhibition of inflammatory NF-kB activation
  • Anti-inflammatory and pro-resolving effects of long-chain omega-3s
  • Improving survival in sepsis and acute respiratory distress syndrome
  • Decreased arachidonic acid-mediated inflammation
  • Increased neutrophil and monocyte phagocytic activity

Fat Oxidation Dangers

All polyunsaturated fats are easily oxidized when exposed to heat, light, oxygen and pressure. This process is called lipid peroxidation, which can cause DNA damage, mutagenesis and carcinogenesis. Lipid peroxidation damages the skin and can cause inflammatory acne.

If you eat oxidized fats, they will get stored in your cell membranes and begin to cause chronic low-grade inflammation. Oxidized fats essentially become signaling molecules, contributing to cellular malfunctioning:

  • Oxidized linoleic acid and its by-products have been shown to damage the mitochondria and impair healthy cellular functioning.
  • People eating a high omega-6 diet may be more susceptible to sunburns because their cell membranes go through lipid peroxidation when exposed to the sun’s UV light.
  • A higher omega-6-to-3 ratio is associated with lower immune cell function, which can cause lower immunity. Both dietary and supplemental omega-3s can incorporate into the cellular membranes of all immune cells.
  • In animals, high omega-6 corn oil promotes lung adenocarcinoma and cancer growth, whereas omega-3 fats inhibit this. One Japanese researcher said that EPA and DHA impede carcinogenesis, whereas LA and inflammatory fats speed it up.
  • Patients with peripheral vascular disease have inflamed fat stores with deficient DHA-derived compounds. Restoring omega-3 fat status in obese animals has been shown to shift the adipose tissue to an anti-inflammatory state.
  • In mice, long-chain omega-3s promote fat burning and inhibit fat cell proliferation. Rats fed fish oil have less visceral fat and lower insulin resistance compared to those fed corn oil or lard.

Instead of increasing your linoleic acid consumption, it is better to focus on lowering inflammation, which is oxidizing your current linoleic acid stores.

How to Balance Omega-3 and Omega-6 Fats

It is thought that during the Paleolithic era total linoleic acid intake was around 7.5-14 grams, which is half as much as humans consume today. Not to mention that all that linoleic acid came from real foods, whereas nowadays it primarily comes from oxidized omega-6 seed oils. At the same time, ALA consumption is ten times less (1.5 grams today vs. 15 grams in Paleolithic times) and EPA/DHA is 143 times less (100-200 mg today vs 660-14,250 mg in Paleolithic humans).

During Paleolithic times, humans consumed around ten times more ALA than we do today (15 grams versus 1.4 grams), which would have provided a considerable amount of EPA (~ 750 mg of EPA for men and 3.15 grams of EPA for women of child-bearing age). Such high ALA intake may partially explain why our bodies only convert small amounts of ALA into long-chain omega-3s, or that we used to consume more preformed EPA/DHA/DPA that the body didn’t need to convert much ALA to the longer chain omega-3s. Indeed, it is estimated that early humans consumed a lot of EPA and DHA – approximately 2000-4000 mg a day (but up to 14,250 mg). On top of that, the omega-6 fats they did obtain from nuts and seeds came in their unoxidized form, whereas virtually all omega-6s people eat nowadays are oxidized. The omega-3 content from ALA in plants is generally about three times higher than the omega-6.

Muscle meat of wild animals has 2-5 times more omega-6 than omega-3, but the fat is closer to a ratio of 1:1. So, ancestral humans ate both plants and animals, achieving the desired 1:1 omega-6-to-3 ratio. However, the grain-fed cattle have an omega-6-to-3 ratio twice that of grass-fed animals.

Conjugated linoleic acid (CLA) is a trans-fat obtained from grass-fed animals that may have some cancer-fighting properties. Vaccenic acid is a trans-fat found in human milk and it has been studied for its ability to lower cholesterol. Thus, the small amount of natural fats found in whole foods are not inherently harmful as long as they’re not consumed to excess.

According to research, the optimal dietary fat ratio of monounsaturated (MUFA) to polyunsaturated (PUFA) to saturated fats (SFA), should be 6:1:1, respectively. Within that framework, the ideal PUFA ratio is 1:1 between omega-6 and omega-3s.

People who eat fish once or twice a week have been shown to have 50% fewer strokes, 50% lower CVD risk and 34% lower CVD mortality risk compared to those eating no fish. Supplemental fish oil reduces risk factors for cardiovascular disease but hasn’t been definitively shown to prevent it. Omega-3 supplements may reduce cardiovascular disease mortality.

Unfortunately, rancid or oxidized fish oil can still cause lipid peroxidation if it has been exposed to heat or sunlight. The amount of spoilage depends on extraction, processing and containment practices. High humidity increases the likelihood of oxidation as well. If it smells bad and tastes awful, then it’s probably oxidized in some way. A lot of companies also use flavorings like lemon or strawberry to mask the smell.

Correcting Essential Fatty Acid Imbalances

  • If AA is low, increase AA intake by consuming one 100 gram serving of liver per week and up to 3-4 whole eggs or egg yolks per day. If this is not feasible, an arachidonic acid supplement can be used at 250 milligrams per day with a meal.
  • If the AA/EPA ratio is low as a result of high or high-normal EPA, first reduce or remove EPA supplements. If the EPA is needed for pharmacological management of high triglycerides, or if it is proving useful for management of a psychiatric condition, then work with a health care practitioner to find the minimum effective dose, and utilizing the strategies described above for boosting AA intake to see if the ratio can be normalized.
  • If DHA is low, increase the intake from natural foods by using 3-4 whole eggs or egg yolks per day from chickens raised on pasture, consuming 2-3 100-gram servings of fatty fish per week, or using ½ teaspoon of cod liver oil per day. There is some evidence supporting the use of krill oil to improve the brain content of DHA more rapidly, which may be helpful for psychiatric conditions.

Arachidonic Acid (AA)

Signs and Symptoms of Arachidonic Acid Deficiency

The only well-established deficiency sign for arachidonic acid in humans is eczema. Mechanistic evidence suggests that arachidonic acid deficiency also increases the risk of food intolerances, infectious diseases, autoimmune disorders, and chronic, low-grade inflammation. Drugs that interfere with AA metabolism cause gastrointestinal distress. The blood thinning effect of fish oil results from EPA interfering with AA metabolism.

Risk Factors for AA Deficiency

AA is abundant in egg yolks and liver. It can be made from LA, which is found in small amounts in animal products and olive oil, and in larger amounts in vegetable oils, but the conversion depends on genetics, insulin sensitivity, protein, calories, calcium, zinc, biotin, and vitamin B6. Thus, a diet that lacks egg yolks and liver does not necessarily lead to AA deficiency but increases its risk due to the many difficulties synthesizing AA from LA. Oxidative stress and chronic inflammation deplete AA. Nonsteroidal anti-inflammatory drugs (NSAIDs) interfere AA metabolism and may contribute to deficiency signs regardless of AA levels. High-dose EPA, as would be found in high-dose fish oil or used pharmacologically to lower triglycerides, causes a similar effect as NSAIDs. AA needs are highest during childhood growth, bodybuilding, pregnancy, lactation, and recovery from injury.

Alpha-Linolenic Acid (ALA)

Alpha-linolenic acid is a plant-based omega-3 fatty acid that cannot be synthesized in the human body. ALA increases BDNF. It can be found in olives, extra-virgin olive oil, avocados, and walnuts. Olive oil primarily consists of a monosaturated omega-9 fatty acid called oleic acid. Oleic acid possesses antioxidant properties that protect omega-3s from oxidation and is also a primary component of the myelin sheath.

ALA is an essential fatty acid, because it can’t be made by the body, and is popular amongst vegans and vegetarians because plant sources can be converted into DHA and EPA. However, only 2-10% of all ALA consumed is converted into DHA or EPA. Also, the ALA-converting genes, FADS, can vary widely. One variant of the FADS gene increases conversion, while another decreases it.

The FADS variant that increases it is mostly found in African, Indian, Pakistani, Bangladeshi, and Sri Lankan populations. It is least common in Native Americans and indigenous Arctic populations. Likely due to availability of plant sourced ALA omega-3 fatty acids. The more an ancestral population relied on plant sources of fatty acids, the more the population adapted to convert ALA into usable DHA and EPA and vice versa for the decreasing conversion gene variant.

Eicosapentaenoic Acid (EPA)

Eicosapentaenoic acid is an omega-3 fatty acid that’s highly available in algae and oily fish, as well as in fish oil. EPA levels in the brain are typically 250-300 times lower than DHA levels. So, it is not critical for neuronal health, but still plays a role. EPA helps to improve the strength of cell membranes and influences behavior and mood. It also acts as a precursor to eicosanoids, which are signaling and inhibiting molecules crucial in inflammatory and allergic reactions. ALA to EPA conversion is quite low (2-8%).

Docosahexaenoic acid (DHA)

Docosahexaenoic acid is an omega-3 fatty acid that’s critical for brain growth in infants and proper brain function in adults. DHA deficiency is associated with fetal alcohol syndrome, ADHD, cystic fibrosis, phenylketonuria, depression, aggressive hostility, and adrenoleukodystrophy.

A study found that DHA improved the episodic memory of women and the working memory of men. Another study found that it prevented aggression in students during times of mental stress. DHA has been shown to improve memory and reaction time in adults, slow down aging of the brain, may prevent dementia, and improve learning. Omega-3 fatty acids lower blood pressure and DHA improves blood lipid levels. In women omega-3 use appears to reduce risk of stroke.

Shellfish, fish, such as shrimp, lobster, Dungeness crab, king crab, anchovies, salmon, herring, mackerel, tuna, and halibut. Or consume 10-15g of krill (lower in the food chain) oil on the days you don’t eat fish. DHA is also available in grass-fed eggs and beef. If vegan/vegetarian, take spirulina and chlorella.

  • Fish create an enzyme that converts the plants (particularly algae) they consume into EPA and DHA. It has been shown that people who consume these enzymes or precursors to them, along with omega-5, 7, 9, 11, gamma-lipoic acid, and conjugated linoleic acid, and supportive minerals such as zinc and magnesium, can upregulate their conversion of plant-based oils into EPA and DHA.
  • A properly structured diet should include saturated, monosaturated, and polyunsaturated fatty acids along with phytochemicals, antioxidants, and minerals. This includes fish and roe, olive oil, grass-fed meats, seeds, nuts, organic vegetables, roots and tubers, and whole fruits. Curcuminoids in turmeric and curcumin may assist with the body’s own formation of EPA and DHA.


Fish oil and fish liver oil are recommended for those that don’t eat enough fatty fish (2 x a week). Fish and other seafood contain long-chain omega-3 fatty acids (EPA and DHA). Omega-3s can be found in vegetable oils, but they mostly contain short-chain alpha-linoleic acid (ALA), which is poorly absorbed in men. If taking fish oils, don’t let them be exposed to air or light or else they will oxidize.

Omega-3s can increase muscle protein synthesis and support healthy circulatory and brain function. Fish oils generally have more EPAs than DHA (usually 2:3 ratio), but higher DHA are optimal for recovery, neuronal health, and anti-inflammation. Make sure it is 1:1 and natural triglyceride form and not cheaper ethyl-ester form. It should be packaged with antioxidants, such as astaxanthin and vitamin E, to keep them from becoming rancid. Unlikely to happen, but if you eliminate all omega 6s and take excessive omega 3s you can deleteriously affect cardiolipin, a critical component of your mitochondrial membranes. Living Fuel SuperEssentials fish oil.

Compared to fish oil, krill oil is more sustainable but it contains much less EPA/DHA. However, a 2011 study found that the two have essentially the same metabolic effects despite krill oil containing less EPA and DHA. This may be because krill oil is absorbed better than fish oil, especially when taken on an empty stomach. Another benefit of krill oil is that the omega-3s are bound to phospholipids, which don’t get destroyed in the gut and more of them cross the blood-brain barrier. They’re also a more sustainable food source.

Signs and Symptoms of DHA Deficiency

DHA deficiency predisposes to low-grade, chronic inflammation, poor visual acuity, slower mental processing, learning deficits, and possibly Alzheimer’s disease and psychiatric conditions such as depression, anxiety, and attention deficit and hyperactivity disorder (ADHD).

Risk Factors for DHA Deficiency

DHA is found in large amounts in seafoods and in smaller amounts in egg yolks when chickens are raised on pasture. A diet low in seafood and based on grain-fed animal products is the major risk factor for low DHA levels. DHA can be made from EPA in fish oil and from ALA in plant oils but the conversion depends on genetics, insulin sensitivity, protein, calories, calcium, zinc, biotin, and vitamin B6. Oxidative stress and chronic inflammation deplete DHA. High intakes of LA from vegetable oils aggravate the effect of low DHA intakes by replacing DHA in tissues with a different fatty acid, docosapentaenoic acid (DPA).

Vitamin & Mineral Summary (The Mineral Fix)

Optimal Daily Intake of Minerals

Both EPA and DHA can be created by the body by converting the essential omega-3 fatty acid alpha-linoleic acid (ALA) into EPA and DHA. So technically, EPA and DHA are not essential nutrients. However, the conversion of ALA to EPA and DHA in the body is low and taking preformed EPA and DHA has numerous health benefits. Hence, despite the fact that EPA and DHA are not considered ‘essential’, a lack of these nutrients in the diet can lead to poor health, especially during pregnancy, malnourishment, childhood growth and during some diseases. And this is likely to be the case for numerous ‘non-essential’ minerals. In fact, the situation is likely grimmer as there isn’t a mechanism in the body to produce non-essential minerals. Thus, both essential and non-essential minerals must be obtained through diet on a regular basis to maintain optimal nutrient status and health.

7 Macrominerals

Mineral: Health Function: Risk of Deficiency/Excess

  • Calcium: Improves bone mineral density. Promotes fat breakdown: Deficiency: osteoporosis, weight gain. Excess: calcification, atherosclerosis
  • Chloride: Creates stomach acid, fights infections, maintains electrolyte balance: Deficiency: lack of nutrient absorption, illness. Excess: hypertension, vascular damage, and metabolic acidosis.
  • Magnesium: Improves bone mineral density, regulates blood pressure, maintains insulin sensitivity: Deficiency: atherosclerosis, hypertension, insulin resistance, osteoporosis. Excess: diarrhea
  • Phosphorus: Improves bone mineral density, glycolysis, gluconeogenesis: Deficiency: osteoporosis, anorexia, rickets. Excess: atherosclerosis, cardiovascular disease
  • Potassium: Regulates blood pressure, maintains insulin sensitivity, reduces atherosclerotic lesions: Deficiency: hypertension, atherosclerosis, insulin resistance. Excess: Impaired kidney function, electrolyte imbalance, arrhythmia
  • Sodium: Regulates blood pressure, electrolyte balance, transports iodine into the thyroid, transports nutrients into the cell: Deficiency: hypotension, insulin resistance, cramping, hypothyroidism. Excess: hypertension
  • Sulfur: Promotes antioxidant systems, cholesterol and vitamin D sulfate, manages inflammation, detoxification, methylation: Deficiency: low glutathione, low protein synthesis, weaker immunity, hypercholesterolemia, atherosclerosis, vascular damage. Excess: gut disturbance, rashes, inflammation, high methionine levels

10 Trace Minerals

Mineral: Health Function: Risk of Deficiency/Excess

  • Chromium: Enhances insulin action, improves glycemic control, supports lipid metabolism, lowers blood sugar, supports antioxidant defense: Deficiency: insulin resistance, hyperglycemia, hyperlipidemia, hyperinsulinemia, diabetes. Excess: hypoglycemia, low birth weight in infants, anemia, iron deficiency
  • Cobalt: Vitamin B12 function, nerve function and regeneration, myelination and cognition: Deficiency: neuropathy, anemia, muscle wasting, cognitive impairment: Excess: cardiomyopathy, lethal toxicity
  • Copper: Regulates iron status, improves lipid profile, maintains glycemic control, supports antioxidant defense, helps with energy production, collagen and soft tissue synthesis, thyroid function, immune system function, reproductive system, kidney health: Deficiency: anemia, cardiovascular disease, atherosclerosis, vascular damage, hyperglycemia, hypothyroidism, iron overload, collagen damage. Excess: Angiogenesis/survival of malignant cells and tumors, inflammation
  • Fluoride: Prevents tooth decay, dental mineralization, fights infections: Deficiency: tooth decay, bacterial infections, bone demineralization, weight gain, impaired growth. Excess: cognitive impairment, nausea, abdominal pain, gastrointestinal distress, dental fluorosis
  • Iodine: Maintains thyroid function, produces thyroid hormones, supports metabolic health, mental development, immune system function, protects against lipid peroxidation: Deficiency: hypothyroidism, hypogonadism, low energy, frailty, osteoporosis, goiter, hypercholesterolemia, obesity. Excess: autoimmunity, thyroiditis, muscle wasting
  • Iron: Tissue oxygenation, regulates oxidative stress, nitrogen fixation, electron transfer: Deficiency: anemia, fatigue, low energy, infection risk, physical deterioration. Excess: atherosclerosis, inflammation, infection risk, organ damage, oxidative stress
  • Manganese: Antioxidant defense, MnSOD activity, immune system function, glycolysis, gluconeogenesis, nitrogen metabolism, removes excess ammonia, bone mineral density: Deficiency: atherosclerosis, endothelial dysfunction, insulin resistance, diabetes, kidney damage, cirrhosis. Excess: neurological complications, mitochondrial dysfunction, metabolic syndrome, atherosclerosis
  • Molybdenum: Nitrogen fixation, removes excess sulfites, metabolizes toxins and alcohol, metabolizes purines and sulfur: Deficiency: neurological damage, poor physical development, toxin accumulation. Excess: reduces copper absorption, increases urea levels, promotes gout, liver dysfunction
  • Selenium: Supports thyroid function, produces thyroid hormones, immune system function, protects against oxidative stress, prevents lipid peroxidation, detoxifies heavy metals: Deficiency: hypothyroidism, weaker immune system, atherosclerosis, oncogenesis, low glutathione, hyperlipidemia. Excess: hyperglycemia insulin resistance, nausea
  • Zinc: Immune system function, antioxidant defense, calcification of bone, wound healing, produces thyroid hormones, insulin production glucose metabolism, brain development and plasticity, sex hormone production, melatonin/serotonin production, glutathione synthesis, DNA damage repair: Deficiency: hypothyroidism, hypogonadism, hyperglycemia, atherosclerosis, osteoporosis, mental impairment, weak immunity. Excess: decreased HDL cholesterol, reduced immunity, altered iron metabolism, nausea, diarrhea, cramping

5 Possibly Essential Trace Minerals

Mineral: Health Function: Risk of Deficiency/Excess

  • Boron: Brain function, tumor suppression, antioxidant defense, improves vitamin D status, better testosterone/estrogen status, elastase/collagenase activity, anti-osteoarthritic effects: Deficiency: vitamin D deficiency, osteoarthritis, hypogonadism, inflammation, impaired brain function. Excess: gastrointestinal distress, kidney damage, goiter, reduced iodine absorption
  • Lithium: Neurotransmitter balance, brain function, mimics the effects of insulin, improves glucose metabolism: Deficiency: depression, increased suicide rate, mental impairment, aggression. Excess: inhibits iodine absorption, gastrointestinal stress, nausea, convulsions, coma, death
  • Nickel: Regulates glucose metabolism, regulates homocysteine metabolism, supports reproduction and growth: Deficiency: hyperglycemia, hyper-homocysteinemia, impaired growth, infertility. Excess: rashes and skin irritation
  • Silicon: Support connective tissue, blood vessels and arteries, reduce plaque formation, protect against atherosclerosis: Deficiency: atherosclerosis, osteoarthritis, plaque formation, hypertension. Excess: calcification, impaired tissue mobility
  • Vanadium: Mimics the effects of insulin, improves glucose metabolism, supports metabolic health: Deficiency: hypothyroidism, depressed fertility and growth, hyperglycemia, insulin resistance. Excess: hypertension, gastrointestinal stress, death
Here is an overview of these same minerals, their recommended dietary sources and recommended daily intakes for adults

7 Macrominerals

Mineral: Recommended Dietary Sources: Optimal/Deficiency/Excess Intake

  • Calcium: Milk, cottage cheese, curd, cheese, yogurt, pumpkin seeds, nuts, spinach, sardines with bones, salmon, cartilage, soft ribs: Optimal: 1,000-1,200 mg/d. Deficiency:< 550 mg/d. Excess Intake: >1,500-2,000 mg/d
  • Chloride: Sea salt, rock salt, mineral waters, celery, tomatoes, lettuce, meat, olives, fish, seaweeds, kelp, whole grains, beans, legumes: Optimal: 5,200 mg/d. Deficiency: < 1,000 mg/d. Excess Intake: > 7,500 mg/d
  • Magnesium: Pumpkin seeds, nuts, legumes, beans, lentils, spinach, chia seeds, salmon, halibut, avocado, dark chocolate, coffee: Optimal: 400-600 mg/d. Deficiency: < 180 mg/d. Excess Intake: > 1,000 mg/d (however some people may benefit from high amounts, i.e., 1,800 mg/day for high blood pressure for example)
  • Phosphorus: Sardines with bones, salmon with bones, liver, yogurt, fish, meat, cheese, seafood, beans: Optimal: 750-1,250 mg/d. Deficiency: < 580 mg/d. Excess Intake: > 2,000 mg/d
  • Potassium: Potatoes, carrots, apricots, Swiss chard, bok choy, broccoli, cauliflower, collard greens, squash, beans, legumes, strawberries, cherries, blueberries, oranges, apples, seafood, fish: Optimal: 4,000-6,000 mg/d. Deficiency: < 2,400 mg/d. Excess Intake: > 15,000 mg/d
  • Sodium: Sea salt, rock salt, mineral waters, celery, tomatoes, lettuce, meat, olives, fish, seaweeds, kelp, whole grains, beans, legumes: Optimal: 3,500 mg/d. Deficiency: < 1,000 mg/d. Excess Intake: > 5-6,000 mg/d (intake will depend on needs and losses, some people will need more than 5,000 mg/d)
  • Sulfur: Seafood, fish, eggs, meat, cruciferous vegetables, garlic, shallots, leaks, onions, organ meats: Sulfur-containing amino acids RDA: 13-15 mg/kg body weight. Optimal: 3-4X higher than the RDA. Taking 1 gram of MSM 3X/d for extra sulfur has shown numerous benefits on joint health and allergies

10 Trace Minerals

Mineral: Recommended Dietary Sources: RDA/Deficiency/Excess Intake

  • Chromium: Mussels, clams, oysters, brewer’s yeast, broccoli, meat, fish, shrimp, oats, barley, maple syrup, apples with the skin: RDA: 33-50 mcg/d. Optimal: 200-1,000 mcg/d. Deficiency: < 24 mcg/d. Excess Intake: > 1,000 mcg/d
  • Cobalt: Liver, seafood, clams, oysters, buckwheat, meat, beef, vegetables: Optimal: 10-20mcg/d. Deficiency: <2.4 mcg/d. Excess Intake: >1g/d
  • Copper: Liver, kidneys, mollusks, oysters, beans, lentils, seaweeds, buckwheat, dark chocolate, cocoa powder, potatoes: Optimal: 2.6-3.0 mg/d. Deficiency: < 0.8 mg/d Excess Intake: > 10 mg/d
  • Fluoride: Toothpaste, fluorinated drinking water, bottled water, tea, coffee, shrimp, seafood: Optimal: 3-4 mg/d. Deficiency: < 2 mg/d. Excess Intake: > 5 mg/d
  • Iodine: Seaweeds, kelp, nori, spirulina, salmon, fish, oysters, clams, whole milk, cheese, yogurt, iodized salt, fortified bread, eggs: Optimal: 150-200 mcg/d. Deficiency: <100 mcg/d. Excess Intake: > 300-1,000 mcg/d
  • Iron: Red meat, beef, pork, oysters, clams, dark chocolate, beans, lentils, beetroot, spinach: Optimal: 8-18 mg/d. Deficiency: < 8 mg/d. Excess Intake: > 45 mg/d
  • Manganese: Mussels, oysters, hazelnuts, pecans, rice, beans, legumes, chickpeas, clams, spinach, pineapple: Optimal: 2-5 mg/d. Deficiency: < 2 mg/d. Excess Intake: > 11 mg/d
  • Molybdenum: Beans, liver, peas, legumes, yogurt, chickpeas, eggs, potatoes: Optimal: 45-50 mcg/d. Deficiency: < 22 mcg/d. Excess Intake: > 2,000 mcg/d
  • Selenium: Brazil nuts, kidney, clams, oysters, sardines, shrimp, salmon, beef, eggs, liver, beans: Optimal: 300-400 mcg/d. Deficiency: < 50 mcg/d. Excess Intake: > 800 mg/d
  • Zinc: Oysters, mollusks, clams, eggs, meat, beef, lamb, mutton, pork, wheat, germ, buckwheat: Optimal: 20-80 mg/d. Deficiency: <8 mg/d. Excess Intake: > 80 mg/d (technically safe upper limit is set at 40 mg based on 60 mg/day causing some side effects but this also included supplemental zinc)

5 Possibly Essential Trace Minerals

Mineral: Recommended Dietary Sources: RDA/Deficiency/Excess Intake

  • Boron: Legumes, beans, lentils, vegetables, dried prunes, raisins, avocado, black currants, plums, almonds: Optimal: 3-11 mg/d. Deficiency: < 1 mg/d. Excess Intake: > 28 mg/d
  • Lithium: Mineral water, grains, vegetables, mustard, kelp, pistachios, dairy, fish and meat: Optimal: 1 mg/d. Deficiency: <100 mcg/d. Excess Intake: >2 mg/d
  • Nickel: Black tea, nuts and seeds, cacao, chocolate, meat, fish and grains: Optimal: 25-150 mcg/d. Deficiency: < 25 mcg/d. Excess Intake: 500mcg/d or higher
  • Silicon: Whole grains, fruits, vegetables: Optimal: 5-35 mg/d. Deficiency: <5 mg/d. Excess Intake: > 35 mg/d
  • Vanadium: Mushrooms, shellfish, black pepper, beer, wine, grains and certain unrefined salts: Optimal: 10-15 mcg/d. Deficiency: <10 mcg/d. Excess Intake: > 10-20 mg/d

Guidelines for Eating Superfoods

Not all foods are created equal in terms of their nutrient values, especially their mineral content. Some of them, like beef liver and pastured eggs, contain virtually all the nutrients your body needs while others, like prunes, are an excellent source of boron. Then there are a bunch of foods that are moderately good for getting a wide range of minerals, such as beans or potatoes. Regardless, there are specific “superfoods” that you may want to keep in your diet on a regular basis to cover your bases for some of the more common deficiencies. However, you shouldn’t be eating things like liver, cruciferous vegetables, dairy or legumes in excess either because they can cause imbalances with other minerals or reduce their absorption.

Here is a list of the more frequently referred to superfoods that you should know in what amounts and how often to eat:

Liver – Arguably the most nutrient-dense food on the planet is liver, whether from beef, lamb, pork, chicken or game. It is an excellent source of commonly deficient minerals, especially copper, iron, chromium, molybdenum, selenium and zinc. However, because liver is so packed with vitamins and minerals, eating it in excess will lead to increased urinary excretion and overload of certain nutrients.

  • You can either eat 0.5-1 oz. per day or 1-3 oz. two to three times per week. Theoretically, more frequent smaller intakes throughout the week are more beneficial and will result in greater absorption compared to large boluses in a single sitting.
  • There is concern that the liver of conventionally raised animals is full of toxins and chemicals. Liver can store dioxins and kidneys tend to store cadmium. However, if you source quality organs from reputable companies consuming organs in the above amounts should not pose any problems. In fact, the fat tissue can have more toxins because the adipose tissue is the primary storage site for calories as well as toxins. So, eating liver, even from conventionally raised animals, should have less toxins, unlike fatty marbled meat. Kidneys do taste funny because of their filtration role. You can soak both the liver and kidneys in water or milk to draw out their gnarly taste. Buying ground blends of meat that contain muscle meat, liver, heart and kidney will help mask the taste. You can cook the ground meat on the stove top and add taco spices to further mask the taste.

Heart – Although not as nutrient-dense as liver, the heart is still packed with a lot vitamins and minerals, in comparison to regular muscle meat. The most noticeable nutrient in the heart is CoQ10, which is a coenzyme involved with many mitochondrial processes as well as participating in the electron transport chain and ATP generation. It also has antioxidant properties and is has been used in cardiovascular diseases including those with heart failure. Heart also contains high amounts of protein and amino acids, zinc, selenium and elastin. However, it is slightly higher in iron than regular red meat. Consuming about 0.5-1 oz. of heart daily or 2-3 oz. of heart two to three times per week would suffice.

Oysters/Clams/Mollusks – Just a single 3 oz. serving of oysters or mollusks can cover your entire weekly zinc demand (75-150 mg vs the 8-11 mg RDA). However, it is likely your body doesn’t absorb all of it in a single sitting and responds by increasing urinary excretion. Regardless, eating oysters/clams/mollusks every day is probably not a good idea as it could lead to zinc overload, which reduces copper absorption. Thus, eating seafood like oysters once a week is sufficient enough to help boost your zinc RDA.

  • Remember, it is beneficial to include 1 mg of copper for every 20-40 mg of zinc. So, if you do eat large amounts of zinc in a given meal, have more copper-rich foods, like liver.

Red Meat/Beef/Pork/Chicken/Game – Meat is also an excellent source of many minerals, especially zinc, iron and sulfur. It is the best way to get all the sulfur amino acids, like methionine and cysteine, but because of that same reason can lead to a high methionine to glycine ratio.

  • Too much zinc and iron can inhibit copper absorption, elevating cholesterol levels and causing symptoms of anemia. That is why a diet high in muscle meat should be balanced with liver or other sources of copper such as Ezekiel bread.
  • Eating excessive amounts of processed meat has been linked with an increased risk of colon cancer but the evidence isn’t definitive and does not apply to pastured meat. Cooking meat and protein at high temperatures does create carcinogenic compounds like heterocyclic amines and polycyclic aromatic hydrocarbons. Consuming cooked meat with certain spices, coffee and other plant compounds seems to offset these harms. In fact, drinking coffee is associated with a lower risk of numerous cancers including liver cancer.
  • The tendons, ligaments and cartilage from ribs, drumsticks and wings is also a better way to get some glycine, which would balance the methionine, while still getting a high amount of sulfur amino acids. Eating pastured meat every day is actually important for optimal health, however you want to make sure that overall dietary acid load is balanced. This means that the diet should include some berries, dates, dark greens and/or bicarbonate-containing mineral waters.

Beans/Legumes/Lentils – Beans, legumes and lentils are one of the top nutrient-dense foods in developing countries that don’t have as much access to meat. They are the highest sources of plant-based protein, making them essential for any vegetarian/vegan diet.

  • Beans and lentils are also relatively high in copper, boron, molybdenum, magnesium and potassium. However, because of their phytate content, they will also chelate things like zinc, iron and calcium. That can either be a good or bad thing, depending on the person’s nutritional status. Excess iron, zinc and calcium can all be harmful to your health by causing calcification, oxidative stress and by inhibiting copper absorption. In that case, the phytates in beans and legumes will improve your health. On the other hand, if you are deficient in zinc (hypothyroid, hypogonadism) or deficient in calcium (osteoporosis), the antinutrients are exacerbating the deficiency of these minerals. Regardless, if you tolerate them, adding some beans and legumes to your iron/zinc-rich meals is an excellent way to prevent their excess intake.
  • You will likely realize whether or not you are eating too many beans and legumes by paying attention to your digestion and gastrointestinal condition. Cooking, soaking and sprouting beans/legumes/lentils greatly reduces their antinutrient content.

Broccoli/Cauliflower/Cabbage – Cruciferous vegetables are great for increasing glutathione through sulforaphane and Nrf2. They are also good for getting more potassium, boron, chromium, calcium and magnesium. Compared to beans, broccoli and cauliflower do not contain phytates or phytonutrients that chelate iron or zinc. However, their goitrogenic content does reduce iodine absorption if high amounts are consumed raw, which may cause goiter and hypothyroidism. To prevent that, you should not eat a high amount of these vegetables raw or in smoothies. Instead, cooking, heating, frying and steaming them reduces their goitrogenic properties without losing a lot of micronutrients.

Kale/Spinach/Collard Greens – All kinds of greens like kale and spinach can have some health properties, especially in terms of their magnesium, potassium and calcium content. However, they can also harm the thyroid when eaten raw. That is why you should cook them beforehand. They are also high in oxalates that can promote kidney stones and gastrointestinal distress in those who are susceptible, however, their high calcium content tends to make them fairly low in bioavailable oxalates. Citric acid (lemon juice) and increased calcium intake help to break down oxalates. So, if you are making a salad, adding some lemon juice, vinegar and eating it with some dairy can prevent potential negative effects.

Eggs – Similar to liver, eggs contain nearly all the vitamins and minerals your body needs. Eggs have all the amino acids both essential and non-essential. Because of that, eating 2-4 pastured eggs a day is an easy way to meet your daily sulfur requirements, while simultaneously hitting a lot of the other minerals, such as iodine, magnesium, molybdenum, selenium, zinc and phosphorus. You should avoid eating conventional eggs as they will have less omega-3s and other health promoting nutrients. To avoid a high methionine/glycine ratio, either stick to eating around 4 eggs a day or ensure you are consuming additional sources of glycine such as hydrolyzed collagen peptides.

  • The egg itself doesn’t contain calcium but the eggshells do. Eating eggshells isn’t necessary, but they can be a more natural and moderate-dose calcium supplement for those at a higher risk of osteoporosis or when overall calcium intake is low. You can wash the eggshells carefully, dry them and then grind them up into a powder and take around 1 tsp/d. However, it may be easier to consume calcium from natural mineral waters, which will also have a better bioavailability versus eggshells.

Dairy/Cheese/Milk – One of the most bioavailable and common sources of calcium is dairy. Milk is probably more bioavailable than cheese and curds because it’s a liquid and, similar to mineral waters, minerals get absorbed better when consumed in a liquid form. It is hard to get excess calcium (>1,500 mg/d) by eating dietary calcium. Regardless, you may want to add a little bit of dairy/calcium to your larger meals because it also reduces the total absorption of fat, helping with body composition. Consuming more calcium from sardines (with the bones) or a glass of pastured milk with salads will also protect against oxalates. On a daily basis, you can meet your calcium requirements by drinking either 1 glass of milk per meal or having 3 oz of fish with the bones next to 1.5-3 oz of cheese. Many people do not tolerate dairy, thus dairy consumption should be individualized.

Fish/Salmon/Sardines – Omega-3s are greatly beneficial for reducing inflammation and improving lipid profile. Fish itself is also a great source of other minerals, such as magnesium, iodine, selenium, zinc, manganese and potassium. You can also get calcium from the bones of small fish, like sardines or sprats.

  • Wild fish are more exposed to heavy metals and environmental pollution than farmed fish. However, they also have a higher selenium content that detoxifies some of these toxins. So, unless you are eating high-mercury fish like tuna or swordfish every day, you don’t have a lot to worry about in terms of heavy metal toxicity. The increased iodine content in open water fish also protects against lipid peroxidation, which can occur during cooking and damage healthy fats.
  • Overheating farmed fish turns the omega-3s inflammatory and more harmful than good because it has fewer protective minerals and antioxidants. Getting enough copper will also provide enough protection through superoxide dismutase. Both caffeine and coffee melanoidins inhibit lipid peroxidation and reduce the absorption of secondary lipoxidation products.
  • Fish consumption has been linked with reduced risk of cardiovascular disease and better metabolic health for a long time. People who eat fish once or twice a week have 50% fewer strokes, 50% lower cardiovascular (CVD) risk and a 34% lower CVD mortality risk compared to those eating no fish. Wild salmon is an excellent source of omega-3s and the antioxidant astaxanthin.

Coffee/Tea – The most consumed beverages in the world after water are coffee and tea. They have a long history of culinary and recreational use. However, research also finds these drinks have some health benefits. There’s evidence that habitual tea drinking has positive effects on brain efficiency and slows down neurodegeneration. The polyphenols in coffee have also been shown to reduce the risk of diabetes, Alzheimer’s, dementia, and even liver cancer.

  • There is not a high amount of minerals in teas but there can be a fair amount of manganese in tea and some potassium and chromium in coffee. However, coffee, and teas, are potent chelators of other minerals, such as calcium, iron and zinc. Thus, their intake must be individualized.
  • Chelation of iron and zinc can be a good thing, depending on the context. For example, chelating iron can protect against the oxidation of fats when we eat cooked meat. If you are eating a low calcium diet, you may want to consume some calcium, like cheese or milk, with coffee to prevent calcium deficiency or better yet natural mineral waters that contain calcium.
  • Contrary to popular belief, coffee does not make you lose magnesium directly, unless you overdose and induce diarrhea or over-activate the sympathetic nervous system, both of which can promote magnesium excretion.
  • The biggest minerals that get excreted due to coffee and caffeine are sodium and chloride. So, drinking mineral waters or consuming a bit more salt while drinking coffee can help prevent sodium and chloride deficiency.
  • On a daily basis, 1-2 cups of coffee or tea a day is a good moderate dose. It should prevent caffeine dependency and anxiety a lot of people are suffering from. The upper limit should be 3 cups a day. Any more than that may start to interfere with sleep quality. If you feel like you need caffeine to wake up and start the day, you should look into improving the quality of your sleep. Learning to function on less caffeine, such as ½ cup of coffee twice daily, is a great option for preventing the caffeine blues and other side effects.

Chocolate/Cacao – One of the best-known superfoods of South America is cacao found in chocolate. It is true that chocolate actually has a significant amount of minerals, such as magnesium, copper, iron and chromium.

  • Chocolate and cacao do contain some oxalates, but they do not contain phytates that chelate minerals. However, most conventional chocolates are high in sugars and fats that actually promote the excretion of minerals, especially magnesium. If you become insulin resistant or obese because of overindulging in chocolate and candy, then you will also increase the overall demand for these minerals. Thus, you should stick to dark chocolate (>70%) and/or raw cacao powders. Eating 1 oz. of 80% cacao dark chocolate can be a great savory treat for dessert.

Fruit/Berries/Juices – Fruits and berries are naturally high in potassium, which is hard to come by in other foods. You can also get citrate, which helps to buffer against the dietary acid load from meat and eggs. However, added fructose as a sweetener tends to promote the excretion of minerals. Added fructose can also induce insulin resistance, which places an additional demand for certain minerals, such as magnesium and chromium.

  • Fructose-sweetened beverages are linked with insulin resistance. Drinking juices from natural fruit is also not the best idea because you are getting a very large dose of fructose in one sitting, which overburdens the liver. Thus, it is best to stick to whole food sources of fructose from lower sugar fruit and berries, such as strawberries, blueberries and raspberries.
  • Vitamin C enhances the absorption of iron and chromium from the diet.

Shilajit (mumie, moomiyo or mummiyo) also called mineral pitch is a black-colored substance, consisting of paleohumus and vegetation fossils, that’s high in fulvic acid and has been used in Ayurvedic medicine for thousands of years. It is collected from steep rock faces at altitudes 1000- 5000 meters. Shilajit is not an actual food per se but instead an herb that can be taken as a supplement. Typical doses range from 200-2,000 mg/d.

  • Research has shown that shilajit improves mitochondrial respiration and oxidative phosphorylation, which promotes ATP production. Animal and human studies show it enhances spermatogenesis, testosterone levels and physical performance. It also has a beneficial effect on lipid profile, cholesterol levels, cognition and antioxidant status.
  • Shilajit has anti-inflammatory and antiulcerogenic properties. In obese patients, shilajit improves the function and regeneration of skeletal muscle.
  • Shilajit has been shown to have anti-addictive effects with fewer side-effects than alpha2- adrenergic or opioid agonists. By interacting with GABA levels in the brain, shilajit can also reduce the sensation of pain. In mice, ashwagandha and shilajit prevent ethanol withdrawal and alcohol addiction.
  • Shilajit powder contains some iron, calcium, magnesium, selenium, zinc and other minerals. The predominant fulvic acid makes the minerals more bioavailable. Humic acids in shilajit also act as a heavy metal chelator.

Generally, cooking and overheating destroys some nutrients, which for goitrogens, lectins or phytates may actually be a good thing.

  • Lightly cooking broccoli and cabbage triples their sulforaphane content vs. fully cooked. Steaming cruciferous vegetables leads to the highest nutrient content versus other cooking methods.
  • Other foods like meat can become more hazardous from high heat cooking through the formation of carcinogens and oxidized lipids/cholesterol. For that, vinegars, plant polyphenols and spices and chelators like phytate can help offset any harm. Fortunately, marinating meat before cooking reduces the formation of these carcinogens by up to 90%. Regardless, animal foods are more adversely affected by cooking than plant foods.
  • Vegetables and legumes actually need to be cooked to a reasonable degree to make them safer to eat, while the fats and protein in meat or fish can become oxidized.
  • As a rule of thumb, cook your animal foods on light to moderate or sear them shortly and boil/roast the plants for longer. The other alternative to make meat healthier is to cut off the char.

Lightly cooking and cooling starch like potatoes and rice also increases their resistant starch content. There are many studies showing that resistant starch can improve insulin sensitivity, lower blood sugar, reduce appetite and help with digestion. Resistant starch also stimulates the bacteria in your gut to produce short-chain fatty acids (SCFAs) like acetic acid, propionic acid, and butyric acid. The SCFAs can feed the cells that line the colon and help with nutrient absorption. Some studies show that 15-30 grams of resistant starch/day for 4 weeks can improve insulin sensitivity by 33-50%.

  • One medium cooked and cooled potato contains about 3 grams of resistant starch while 100 grams of cooked and cooled rice has 5 grams. To keep the resistant starch intact, you can reheat the food at low temperatures under less than 130 degrees. You don’t have to eat them cold but too high heat will convert it into regular starch.

Fresh foods tend to have more nutrients as storage can reduce nutrient content. Freezing, however, can help reduce the loss of the nutrients if the food is frozen right after harvest. Unfortunately, frozen veggies deactivate myrosinase, which is an enzyme that creates sulforaphane. Regardless, you would still get plenty of potassium, vitamin C and sulfur from vegetables. Organic foods also have more bioavailable nutrients, as pesticides and glyphosate can bind to minerals reducing their presence in the food and their bioavailability once consumed.

The US Department of Agriculture’s Pesticide Data Program publishes an annual report on the most pesticide-rich foods. They divide it into The Dirty Dozen and The Clean 15. Here’s a list for the year 2018:

  • The Dirty Dozen (Buy Organic and avoid conventional) – strawberries, spinach, nectarines, apples, grapes, peaches, cherries, pears, tomatoes, celery, potatoes, sweet bell peppers.
  • The Clean 15 (Safer to buy but still aim for organic) – avocados, sweet corn, pineapples, cabbages, onions, sweet peas, papayas, asparagus, mangoes, eggplants, honeydews, kiwis, cantaloupes, cauliflower and broccoli.

Fixing Mineral Deficiencies

About a third of the U.S. population is likely to be deficient in the below 10 minerals (estimated % not hitting RDA/AI or estimated % deficient):

  1. Boron (> 75%)
  2. Manganese (~ 75%)
  3. Magnesium (52.2-68%)
  4. Chromium (56%)
  5. Calcium (44.1-73%)
  6. Zinc (42-47%)
  7. Iron (25-34%)
  8. Copper (25-31%)
  9. Selenium (15-40%)
  10. Molybdenum (15%)

Here is how to prevent your body from becoming deficient of essential minerals by protecting against their excretion or improving their absorption:

Limit Added Sugar and Refined Food Intake – Hyperglycemia and high sugar consumption places an additional burden on the liver and kidneys, which also makes the body increase excretion of certain minerals, namely magnesium, chromium and copper.

  • Added sugars drive coronary heart disease by inducing insulin resistance and hyperinsulinemia. Sugar, especially fructose, is worse than starch or other whole foods carbohydrate sources. The overconsumption of fructose-sweetened beverages is linked with insulin resistance.
  • Animal and human studies have shown that replacing starch and glucose with sucrose or fructose, despite isocaloric eating, raises fasting insulin, reduces insulin sensitivity and increases fasting blood sugar. Compared to a diet containing less than 10% of calories from added sugars, a diet that consists of 25% calories or more from added sugars triples the risk of cardiovascular disease mortality.
  • Overconsuming added sugars can promote copper deficiency, which contributes to fatty liver and insulin resistance. Most refined foods are also virtually non-existent of vitamins and minerals because the processing methods remove them. The more refined foods and sugar you consume the more minerals you need, especially magnesium, chromium and copper.

Fix Insulin Resistance and Improve Glycemic Control – During insulin resistance, the body either is not producing enough insulin (like in type-1 diabetes), keeping the blood sugar elevated for longer, or the cells are not responsive to the actions of insulin and don’t allow the entry of nutrients into the cell. In either case, hyperglycemia ensues that makes you burn through minerals while increasing their excretion.

  • Abdominal visceral fat is strongly correlated with insulin resistance and type 2 diabetes. Thus, reducing the intake of added fructose, especially when combined with fat bombs such as heavy cream and butter, which can lead to visceral fat accumulation, is advised. Reducing the intake of calories shouldn’t happen at the expense of decreased nutrient intake, which means you have to focus more on eating nutrient dense foods as mentioned earlier.
  • Physical activity is one of the biggest predictors of overall insulin sensitivity and glucose tolerance. Resistance training and having more muscle mass are the best things for improving glucose tolerance. Skeletal muscle acts like a sponge for glucose and the more muscle you have the higher your carbohydrate tolerance is.
  • A lack of sleep impairs glucose tolerance, raises blood sugar and cortisol and promotes insulin resistance. Even one single night of bad sleep has been shown to induce the biomarkers of a pre-diabetic in the short term.
  • Trans fats and vegetable oils like margarine, corn, soybean, safflower, cottonseed and canola oil promote oxidative stress, inflammation and insulin resistance. People who consume high amounts of omega-6 seed oils have a worse lipid profile and markers of insulin resistance. Chronic inflammation also promotes insulin resistance.
  • Minerals that support glycemic control and insulin production are chromium, magnesium, potassium, sodium, copper and zinc. Insulin mimetics are lithium, nickel and vanadium although their supplementation requires consultation with your medical professional.

Improve Gut Health and Fix Malabsorption Conditions – Your gut is where most of the absorption of minerals from food occurs. Having a healthy gut is vital for assimilating and retaining nutrients. Many malabsorption conditions, such as intestinal permeability (leaky gut), IBS, Crohn’s and ulcerative colitis can reduce the absorption of certain minerals. If you have any gut condition, you will need to hit at least the RDA for magnesium, potassium, zinc, copper and selenium. If you already show signs of deficiencies in these minerals, you may need to increase your intake further in the short term.

  • Chloride is used by our body to make hydrochloric acid, helping to form stomach acid for killing pathogens and absorbing nutrients. Acid-suppressing drugs decrease how much stomach acid gets produced and, as a result, fewer minerals are absorbed. Thus, a low salt intake can reduce stomach acid production and inhibit the absorption of nutrients from food because of inadequate digestion.
  • Drinking mineral waters improves mineral absorption by 40-50% compared to food.
  • Zinc supplementation improves intestinal barrier function and may even help to resolve intestinal permeability in patients with Crohn’s disease. Sufficient amino acid intake from protein is also required for repairing the gut lining. Certain allergenic foods like gluten or eggs may damage the intestinal lining and lead to intestinal permeability.

Improve Liver and Kidney Health – Most of the metabolic processes are regulated by the liver and kidneys. They also determine the homeostatic balance and excretion of all minerals. Poor kidney function tends to promote the urinary loss of magnesium, chromium, manganese, zinc, copper and many others.

  • Excess iron damages the liver through oxidative stress and promotes fatty liver (visceral fat). Production of ROS during iron metabolism causes lipid peroxidation. Too much ferritin also supports lipofuscin formation, which is an age-related pigment that slows down cellular processes and promotes fatty liver. Replacing some of your muscle meat with organ meats or beans/legumes will help to lower iron overload and prevent liver damage.
  • Studies find that coffee can reduce risk of liver cirhhosis by 25-70%. It can also reduce risk of non-alcoholic fatty liver disease (NAFLD) by 30-60%. NAFLD results primarily from metabolic syndrome. Losing some weight and improving insulin resistance can help improve NAFLD.
  • Liver detoxification pathways require zinc, selenium, magnesium and molybdenum. Sulfur- and glutathione-rich foods like cruciferous vegetables, garlic, onions, eggs, and leeks support phase 2 detoxification.
  • The kidneys affect electrolyte balance the most. Kidney damage increases the demand for potassium, copper, zinc and chromium. Excess ammonia, resulting from deficient manganese and potassium, can overburden the kidneys. Proper hydration and drinking adequate amounts of water are also important for filtrating out waste products that would otherwise accumulate in the body.

Avoid Heavy Metal Exposure – Environmental pollutants, especially heavy metals, also increase the excretion of some minerals and compete with their absorption. What’s more, mineral deficiencies like iron deficiencies can increase the absorption of heavy metals, such as cadmium, lead and aluminum.

  • Zinc deficiency has been shown to promote the accumulation of cadmium in the liver whereas iron and copper deficiency raise cadmium intake by the kidneys. Cadmium is a toxic metal with a half-life of 10-30 years that antagonizes zinc. Animal studies show that cadmium promotes the urinary excretion of copper, zinc and iron. Supplementation with copper and zinc has helped to prevent the adverse effects of cadmium.
  • Sauna therapy also helps to eliminate heavy metals like arsenic, cadmium, lead and mercury as well as persistent organic pollutants (POPs). Sauna use in combination with niacin and exercise can result in a 25-30% decrease in POP levels in fat tissue and blood by heat-induced sweating. Sweating alone has actually been used to improve uremia, or the accumulation of toxins in the blood of patients with kidney disease. You can’t avoid all heavy metal exposure in an industrialized world. However, you can support your body with additional detoxification methods, such as exercise and sauna. Getting enough selenium, zinc and copper are also important for the body’s antioxidant defense systems.

Avoid Drugs/Medications That Promote Mineral Loss – Pharmaceuticals tend to reduce the absorption of minerals and promote their excretion. Antacids and diuretics affect magnesium and potassium the most. When taking a prescription drug for a certain medical condition that cannot be avoided, look up to see what nutrients they may deplete and make sure you obtain enough of them in the diet or through supplementation.

Eat Mineral-Dense Foods Regularly – You should be eating things like liver, oysters and/or clams on a fairly regular basis, at least once a week. This way your requirement for supplements will greatly reduce as you’ll be getting the nutrients from your food. It is not necessary to be eating “superfoods” daily with every meal. However, you could also “microdose” (1 oz/d) foods like liver to spread your intake across the entire week. Large acute doses of minerals tend to make the body increase urinary excretion or reduce their absorption. It is also harder to catch up on deficiencies compared to having a consistent intake of minerals from foods.

Add Some Mineral Waters to Your Diet – One of the best ways to get more magnesium and calcium into your diet is to drink mineral waters. Mineral waters have a better bioavailability while providing other health benefits. Because they lack calories, mineral water is one of the healthiest ways to simultaneously improve your mineral status and metabolic health. Consuming about 1/3-2/3rds of your daily water intake as mineral water would contribute greatly to your daily mineral requirements.

Supplement Your Deficiencies – Taking supplements is a quick way to overcome severe nutrient deficiencies that are causing health problems. However, they may also have negative side-effects. For example, taking an iron or zinc supplement will impair copper absorption. Likewise, a chromium supplement for someone who is already metabolically healthy may be just a waste of money. Thus, you should supplement only those minerals you are deficient or suboptimal in. First, test your mineral status and then consult with a medical professional about the appropriate course of action in terms of supplementation. Minor deficiencies can easily be fixed by improving diet or metabolic health.

People who exercise or sweat a lot due to either being physically more active, sunbathing, or taking saunas frequently are more prone to electrolyte imbalances. When you sweat you lose water, sodium, chloride, copper, chromium, selenium and iodine. Because sweating is an essential way for humans to regulate their body temperature, we can’t avoid it and thus may be prone to becoming deficient or at least suboptimal in different minerals.

  • It’s estimated that sweat contains on average 920-1,380 mg of sodium per liter. However, that would depend on your own electrolyte status and how hydrated you are. The RDA for sodium is 2300 mg, which is 6 grams or 1 teaspoon of salt. Vigorous exercise in hot weather for a prolonged period of time such as an endurance race or marathon may make you lose up to 4-10 liters and 3500-7000 mg of sodium through sweat.
  • If you are going for a long run, you do burn calories and fat, but you also lose sodium and other minerals through sweat. To keep the weight off, maintain insulin sensitivity and ensure optimal nutrient intakes. If you’re vigorously exercising or sweating without replacing minerals you may find yourself in a vicious cycle of nutrient deficiencies, mild insulin resistance, increased stress and enhanced cravings for salty/sugary junk foods.
  • Compared to oral rehydration fluids known to be effective in cholera, coconut water was found to have adequate potassium and glucose content, however, was relatively deficient in sodium, chloride and bicarbonate. The addition of salt to the coconut water is suggested to compensate for the sodium and chloride deficiency.

Index of Signs and Symptoms (Testing Nutritional Status)

This section is for finding associations and speculation for cause, effect, and symptom management. Use these suggestions to research deeper and then speak with a medical professional before jumping to conclusions and stating certainty.

  • Abdominal pain: iron overload, iodine deficiency, acute iodine poisoning
  • Acid-base imbalance: zinc deficiency, electrolyte imbalances
  • Acne: zinc deficiency, vitamin A deficiency, rare reactions to iodine
    • mTOR may promote intestinal inflammation and skin acne, which is more proof of how high mTOR all the time accelerates aging. However, this effect is probably due to a poor microbiome and other inflammatory lifestyle factors, not necessarily mTOR itself. mTOR makes things worse in some cases because of its anabolic effects.
  • Adrenal hormones, resistance to: zinc deficiency
  • Adrenaline, low: copper deficiency, vitamin C deficiency
  • Allergies: risk is increased by vitamin A deficiency and deficiencies or excesses of vitamin D and calcium; may occur in response to iodine; allergy-like reactions to sulfites that result from molybdenum deficiency
  • Alopecia: deficiencies of riboflavin, biotin, zinc, iron, or iodine; iron overload, selenium toxicity or vitamin A toxicity
  • Alzheimer’s disease: DHA deficiency, copper toxicity, or iron overload
    • Drinking rosemary-infused water can improve cognition and cerebrovascular health. Mineral water consumption can increase the excretion of silicic acid and aluminum in Alzheimer’s disease.
  • Androgens in women, high: deficiencies of vitamin D and calcium or vitamin K
  • Anemia, megaloblastic, macrocytic: deficiencies of folate, B12, or copper
  • Anemia, microcytic: deficiencies of iron, copper or riboflavin
  • Anemia, normocytic, normochromic: Riboflavin deficiency, vitamin B6 deficiency
  • Anemia, sideroblastic: “”
  • Anxiety: deficiency of methylation, vitamin B6, molybdenum, DHA, or salt; acute hypoglycemia in response to potassium on an empty stomach
  • Arsenic, slow rate of detoxification: deficient methylation
  • Asthma: deficiencies of glutathione or vitamin A; deficiencies or excesses of calcium and vitamin D; allergy-like reactions to sulfites that result from molybdenum deficiency
    • Sulfites are inorganic salts used for food preservation and in medications. You can get sulfites mostly from processed foods, wine and processed meat. They can also inhibit the browning of fruit and vegetables. Some people, especially asthmatics, are overly sensitive to sulfites, which cause gastrointestinal, cardiovascular, pulmonary and dermatological problems. Nausea, abdominal cramps, diarrhea, and urticaria are commonly reported.
  • Ataxia (loss of full control over body movements): deficiencies of magnesium, thiamin, biotin, vitamin B12, or vitamin E; hyponatremia; vitamin B6 toxicity; Friedrich’s ataxia, a genetic disorder in iron distribution
  • Atherosclerosis: See cardiovascular disease
  • Attention deficit: See distractibility.
  • Autoimmune disorders: deficiencies of vitamin A, vitamin D and calcium, or arachidonic acid, excess EPA from fish oil
  • Beard hair, reddened: manganese deficiency
  • Bitot’s spots: vitamin A deficiency
  • Bleeding disorders: Deficiencies of vitamin C, vitamin K, or arachidonic acid, excess vitamin E or EPA from fish oil
  • Blisters: zinc deficiency, flushing reaction to niacin
  • Blood pressure, high (hypertension): a high salt-to-potassium ratio, deficiencies of vitamin D and calcium, magnesium or riboflavin
  • Blood pressure, low (hypotension): Excess choline or magnesium; orthostatic hypotension from vitamin B12 deficiency; allergy-like reactions to sulfites that result from molybdenum deficiency; hyponatremia; hypokalemia
  • Blood sugar problems: deficiency or excess of vitamin K; oxidative stress and imbalances of antioxidant nutrients, especially zinc; chronic potassium deficiency or high-carbohydrate, low-potassium meals; acute hypoglycemia in response to potassium on an empty stomach; phosphorus deficiency; see also diabetes.
  • Bone mineral content, low: deficiencies of manganese, vitamin C, glycine, calcium and vitamin D, and vitamin K; excess phosphorus and vitamin A; a high salt-to-potassium ratio
  • Bone mineral content, high: Excess calcium
  • Bone pain: In rickets and osteomalacia, deficient vitamin D, calcium, phosphorus, or magnesium
  • Bradycardia (slow heart rate): hypercalcemia, hypermagnesemia, hypokalemia, hypochloremia,
  • Brain fog: hypothyroidism due to iodine or iron deficiency (see also selenium); anemia due to deficiencies of iron, copper, B 6, B 12, or folate; methylation imbalances
  • Breast, fibrocystic disease: Iodine deficiency
  • Bruising: deficiencies of vitamin C or vitamin K
  • Burning in the feet: pantothenic acid deficiency
  • Cancer: Oxidative stress, deficient or excess calcium and vitamin D, deficient or excess methylation, selenium deficiency. vitamin K deficiency; niacin deficiency
  • Cardiac arrhythmia or palpitations: hypercalcemia, hypochloremia, hypokalemia and hyperkalemia, magnesium deficiency, anemia due to deficiencies of iron, copper, B6, B12, or folate; methylation imbalances
  • Cardiovascular disease: atherosclerosis and heart disease risk: oxidative stress, deficient or excess calcium and vitamin D, excess phosphorus, and deficiencies of methylation, magnesium, molybdenum, vitamin B6, or manganese; enlarged heart and elevated cardiac output in thiamin deficiency; cardiac insufficiency in selenium deficiency; cardiac failure in iron overload
  • Cataracts: riboflavin deficiency
  • Cheilosis: deficiencies of riboflavin or vitamin B6
  • Chest pain: iron overload
  • Cholesterol, high: deficiency of copper or salt, iron overload
  • Cholesterol, low: manganese deficiency
  • Circadian rhythm, disrupted: vitamin A deficiency
  • Confusion: deficiencies of thiamin or vitamin B6; the delirium of B 12 deficiency; hypocalcemia or hypercalcemia, hyponatremia or hypernatremia, acute hypoglycemia in response to potassium on an empty stomach
  • Conjunctivitis: deficiencies of biotin or riboflavin; increased risk of eye infections more generally in vitamin A deficiency
  • Constipation: iodine deficiency, hypokalemia
  • Cramping: Hyponatremia, selenium poisoning, magnesium deficiency
  • Dehydration: sodium and chloride deficiency
  • Depression: deficiencies of niacin, vitamin B6, biotin, methylation, DHA; iron overload, hypercalcemia
  • Dermatitis: deficiencies of riboflavin, niacin, biotin, manganese, arachidonic acid, or molybdenum
  • Diabetes: oxidative stress, iron overload, selenium toxicity, niacin toxicity; as an autoimmune disease, type 1 diabetes risk may be increased by deficiencies of vitamin A, vitamin D, or arachidonic acid
    • Chromium, vanadium and magnesium are some of the most common deficiencies associated with diabetes.
    • Diabetics have a reduction in liver copper content. In fact, diabetes itself can cause an imbalance of copper and a loss in copper utilization in the heart. That can contribute to the pathogenesis of diabetic arteriopathy. Inflammation is also raised during hyperglycemia, hyperinsulinemia, glucose intolerance and diabetes. Patients with peripheral arterial disease show higher blood pressure, high triglycerides, lipids and elevated serum copper because inflammation raises copper. Thus, diabetes can cause copper dysregulation and lead to cardiovascular disease development.
  • Diarrhea: deficiency of zinc or niacin, excess magnesium or vitamin C, allergy-like reactions to sulfites that result from molybdenum deficiency
  • Distractibility: excess methylation
  • Dizziness or lightheadedness: Niacin deficiency; anemia due to deficiencies of iron, copper, B6, B12, or folate; upon standing, due to autonomic dysfunction in B12 deficiency; iron overload, zinc toxicity
  • Eclampsia: magnesium deficiency
  • Eczema: See dermatitis.
  • Edema: hypothyroidism from deficiencies of iodine, selenium, or iron; high salt-to-potassium ratio; edema of the oral cavity, deficiencies of riboflavin or vitamin B6; cerebral edema, hypernatremia
  • Enamel loss: iron overload
  • Encephalopathy: Niacin toxicity
  • Excessive sweating: manganese deficiency, acute hypoglycemia in response to potassium on an empty stomach
  • Exercise, poor performance or intolerance: deficient methylation; deficient riboflavin or niacin; deficient or excess vitamin K; autonomic dysfunction from vitamin B12 deficiency; shortness of breath on exertion due to vitamin C deficiency, or to anemia resulting from deficiencies of iron, copper, B 6, B 12, or folate
  • Eyes, dry: vitamin A deficiency
  • Fatigue and weakness: deficient methylation, deficient riboflavin, folate and B12 deficiency, hypochloremia, hyperkalemia, hypernatremia, iodine deficiency, iron deficiency and overload, magnesium deficiency, pantothenic acid deficiency, biotin deficiency, phosphorus deficiency, selenium toxicity, sodium and chloride deficiency
  • Fatty liver disease: deficient methylation, oxidative stress
  • Fertility and Sex Hormones: deficiencies of vitamin A, vitamin D and calcium, vitamin K, zinc, vitamin E, iodine, or arachidonic acid; iron deficiency and overload
  • Fibrocystic breast disease: See breast, fibrocystic disease.
  • Fibromyalgia:
    • Magnesium citrate appears to be effective on pain and clinical parameters in people with fibromyalgia. Magnesium citrate is also more available and easily absorbable compared to magnesium oxide. Magnesium-rich mineral water can be as easily absorbed as magnesium supplements, perhaps slightly better. With age, magnesium absorption decreases, and magnesium mineral water might be able to compensate for that.
  • Fingernails, white spots, streaks, brittle, falling out: selenium deficiency or toxicity
  • Food intolerances: deficiencies of vitamin A or arachidonic acid
  • Gait abnormalities (difficulty walking correctly): See ataxia.
  • Glossitis: Deficiencies of riboflavin or vitamin B6.
  • Goiter: deficient or excess iodine
  • Graves’ disease: excess iodine
  • Hair and nail growth, slow: manganese deficiency
  • Hair loss: See alopecia.
  • Hair, corkscrew-shaped: vitamin C deficiency
  • Hands and feet, cold: hypothyroidism due to deficiencies of iron or iodine (see also selenium)
  • Hashimoto’s thyroiditis: selenium deficiency or excess iodine
  • Headache: deficiencies of magnesium or riboflavin; deficiency or toxicity of niacin; toxicities of vitamin A or manganese, hyponatremia, histamine intolerance from deficient methylation or copper
  • Heart palpitations: See cardiac arrhythmia or palpitations.
  • Heavy metal toxicity, vulnerability to: zinc deficiency
  • Heart rate, slow: See bradycardia.
  • Heart rate, fast: See tachycardia.
  • Hepatitis: Niacin toxicity
  • Hepatic cirrhosis: iron overload, selenium deficiency and toxicity
  • Histamine intolerance: copper deficiency, deficient methylation
  • Hives (urticaria): See itching (pruritis) and hives (urticaria)
  • Homocysteine, elevated: deficiencies of methylation, vitamin B6, thiamin, or riboflavin, deficient or excess niacin; see methylation testing for a full explanation
  • Hypercalcemia:
    • High levels of ionized calcium in the blood can be caused by excess calcium or vitamin D, but not phosphorus. They are usually driven by a high amount of total calcium, but acidosis or low albumin may increase ionized calcium even when total calcium is normal.
    • Chronic excess of vitamin D will cause more persistent hypercalcemia than chronic excess of calcium when either are present on their own. However, excess calcium can cause persistent hypercalcemia in the presence of alkalosis and impaired kidney function.
    • In addition to soft tissue calcification, hypercalcemia can lead to frequent thirst and urination, confusion, lethargy, fatigue, depression, bradycardia (slow heart rate), arrhythmia, palpitations, or fainting.
    • Hypercalcemia may be driven in part by calcium moving from bone to blood, especially in response to vitamin D toxicity, in which case it will be accompanied by lower bone mineral density.
  • Hyperphosphatemia:
    • Phosphate binds to calcium, causing the calcium phosphate to leave the blood as it deposits in other tissues, both in healthy ways (e.g., bone) and unhealthy ways (e.g., kidney stones). Thus, hyperphosphatemia can cause tetany (deficient calcium available to the nervous and muscular systems) and soft tissue calcification (excess calcium phosphate deposited in soft tissues) but not osteomalacia (deficient calcium phosphate available to bone). Symptoms will primarily be those associated with tetany.
  • Hypochloridia (low stomach acid): deficient salt
  • Hypoglycemia: See blood sugar problems.
  • Hypothyroidism: deficiencies of iron or iodine (see also selenium)
  • Immunity to infection, poor: Deficiencies of vitamin A, vitamin D and calcium, vitamin B6, zinc, selenium, iodine, or vitamin C; oxidative stress
  • Impulsivity: Excess methylation
  • Inflammation, chronic systemic: Deficiencies of arachidonic acid, DHA, vitamin A, vitamin D and calcium, and vitamin B6
  • Insomnia and related sleep problems: Methylation imbalances; deficiencies of vitamin A, vitamin D and calcium, niacin, vitamin B5, vitamin B6.
  • Insulin: See blood sugar problems and diabetes.
  • Itching (pruritis) and hives (urticaria): flushing reactions to niacin, rare reactions to iodine, allergy-like reactions to sulfites that result from molybdenum deficiency; histamine intolerance from deficient copper or methylation
  • IQ, low: deficiencies of iron or iodine during childhood
  • Irritability and restlessness: Deficiencies of vitamin B5 or vitamin B6, selenium poisoning, hypochloremia, hyponatremia, acute hypoglycemia in response to potassium on an empty stomach
  • Jaundice: Niacin toxicity
  • Joint pain: iron overload
  • Kidney stones: a high salt-to-potassium ratio; deficiencies of vitamin A, vitamin B6, or magnesium; both deficiencies and excesses of calcium; excess vitamin D and phosphorus; excess collagen supplementation and vitamin C
    • Drinking mineral water can help with kidney stones. Calcium can bind to oxalates, which are what the majority of kidney stones are made of. Indeed, about 80% of kidney stones are made of oxalates and 20% calcium phosphate. Oxalate, or oxalic acid, is an organic acid found in certain plants, such as leafy green vegetables, spinach, some fruit, nuts and seeds. Too many oxalates can prevent calcium from being absorbed into the body and they may also lead to kidney stones and chronic systemic pain. Eating calcium-rich foods like cheese, dairy, fish, and broccoli can actually reduce the oxalate load in your body by providing calcium that can bind with oxalates in the gut. Drinking calcium and magnesium rich mineral water can reduce calcium oxalate stone formation.
  • Kidney Disease:
    • Drinking magnesium-calcium carbonate mineral water can benefit those with kidney disease. Consuming sulfate-bicarbonate, calcium-magnesium mineral water has also shown efficacy in patients with chronic pyelonephritis, which is renal disorders characterized by chronic inflammation. Drinking water rich in sodium-bicarbonate is also used to help with gastrointestinal issues, metabolism, kidneys and the urinary pathways.
  • Lazy eye: Niacin toxicity
  • Lethargy: See fatigue and weakness.
  • Leukopenia: copper deficiency
  • Lightheadedness: See dizziness and lightheadedness
  • Light therapy, inability to benefit from: vitamin A deficiency
  • Lips, lesions on the outside of (cheilosis): deficiencies of riboflavin or vitamin B6
  • Liver failure: glutathione depletion, niacin toxicity
  • Low-Fat and Low-Carb: Improved health on low-fat diets, deficiencies of riboflavin or pantothenic acid; improved health on low-carbohydrate diets, thiamin deficiency
  • Malabsorption: from an autoimmune condition, deficient vitamin A or arachidonic acid; generalized, from pellagra, niacin deficiency; of many water-soluble nutrients with no intestinal damage, deficient salt
  • Menstrual problems: See fertility and sex hormones.
  • Mental and cognitive health: imbalances of methylation and deficiencies of related nutrients, electrolyte imbalances, hypocalcemia and hypercalcemia, deficiencies of thiamin, niacin, and vitamin B6
  • Migraine: riboflavin deficiency
  • Miliaria crystallina (a form of dermatitis resulting from blocked sweat glands that appear as tiny clear bubbles on the skin): manganese deficiency
  • Mouth, lesions in and around: deficiencies of riboflavin or vitamin B6 in cases of cheilosis (lips), angular stomatitis (corners of mouth), glossitis (inflamed tongue), hyperemia and edema of the oral cavity (red, swollen, and bloody inside the mouth); biotin for dermatitis around the mouth; vitamin C deficiency for bleeding gums and other bleeding inside the mouth
  • Muscle spasms and twitching: Magnesium deficiency, hypocalcemia, hypokalemia, hyponatremia and hypernatremia
  • Nails: See fingernails, white spots, streaks, brittle, falling out.
  • Nausea: vitamin A toxicity, niacin toxicity too much zinc on an empty stomach, excess copper in drinking water, hyponatremia and hypernatremia, poisoning with iodine or selenium
  • Neural tube birth defects: deficient methylation
  • Neutropenia: copper deficiency
  • Night vision, poor: vitamin A deficiency
  • Numbness: pantothenic acid deficiency
  • Nutrient imbalances, vulnerability to: selenium deficiency
  • Obsessive compulsive disorder: deficient methylation
  • Optic neuritis: deficiency of thiamin or vitamin B12
  • Osteomalacia: deficiencies of calcium, phosphorus, vitamin D, or magnesium
  • Osteopenia: See bone mineral content, low.
    • Osteopenia and osteoporosis can be worsened by vitamin A at non-toxic levels when vitamin D and calcium are deficient.
    • Elevated parathyroid hormone (PTH) is a major factor in these conditions, and it is raised by deficiencies of vitamin D or calcium, or by excess phosphorus.
    • These disorders are caused by deficiencies of calcium or vitamin D, or an excess of phosphorus.
  • Osteopetrosis: See bone mineral content, high.
  • Osteoporosis: See bone mineral content, low.
    • Elevated parathyroid hormone (PTH) is a major factor in these conditions, and it is raised by deficiencies of vitamin D or calcium, or by excess phosphorus.
    • These disorders are caused by deficiencies of calcium or vitamin D, or an excess of phosphorus.
  • Oxytocin, low: vitamin C deficiency
  • Paleness: anemia due to deficiencies of iron, copper, B6, B12, or folate
  • Palpitations: See cardiac arrhythmia or palpitations.
  • Paralysis: thiamin deficiency or hyperkalemia
  • Paresthesia (tingling, numbness, or a feeling of something crawling on the skin): biotin deficiency, vitamin B12 deficiency, hyperkalemia
  • Parkinson-like symptoms: manganese toxicity
  • Parkinson’s disease: iron overload
  • Peripheral neuropathy: deficiencies of thiamin, riboflavin, and vitamin E; toxicity of selenium and vitamin B6
  • Preeclampsia: magnesium deficiency
  • Pregnancy, morning sickness: molybdenum deficiency, vitamin B6 deficiency
  • Pruritis: See itching (pruritis) and hives (urticaria).
  • Psychological conditioning, difficulty breaking free from: Excess methylation
  • Puberty, delayed: deficiencies of vitamin A, iron, and zinc
  • Psychosis: deficiencies of thiamin, niacin, and B12, hypocalcemia and hypercalcemia, hyponatremia
  • Pustules: zinc deficiency
  • Respiratory congestion: deficient glutathione
  • Restlessness: See irritability and restlessness
  • Retinopathy (damage to the eye’s retina): vitamin E deficiency
  • Rhabdomyolysis (damaged muscles spilling their contents into the blood): hypokalemia
  • Rheumatoid arthritis: pain pantothenic acid deficiency
    • Rheumatoid arthritis and other inflammatory disorders can cause levels of iron, zinc and selenium to drop in the blood and hence in the hair. High amounts of inflammation can increase copper levels in the blood and in the hair even when there is copper deficiency.
  • Rickets: deficiencies of calcium, phosphorus, vitamin D, or magnesium
  • Scurvy: vitamin C deficiency
  • Seizures: deficiencies of vitamin B1 or B6, hypocalcemia, hyponatremia and hypernatremia, hypochloremia, thiamin deficiency, hypoglycemia
  • Sense of position and vibration, lost: vitamin B12 deficiency
  • Sensitivity to cold in general, increased: Hypothyroidism from deficiencies of iron or iodine (see also selenium)
  • Serotonin, high: copper deficiency
  • Shortness of breath on exertion: vitamin C deficiency, or anemia due to deficiencies of iron, copper, B6, B12, or folate
  • Skin aging, faster: Deficient vitamin C, glycine, or niacin; oxidative stress
  • Skin and hair, hypopigmentation: copper deficiency
  • Skin, dermatitis: See dermatitis.
  • Skin, itching or hives: See itching (pruritis) and hives (urticaria).
  • Skin, dry patches: zinc deficiency
  • Skin, hyperpigmentation: iron overload
  • Skin, scaling: vitamin A toxicity, arachidonic acid deficiency
  • Sleeping problems: See insomnia and circadian rhythm
  • Small intestinal bacterial overgrowth (SIBO): Hypothyroidism from deficiencies of iodine or iron (see also selenium), hypokalemia
  • Soft tissue calcification: Deficiencies of magnesium, vitamin A, and vitamin K, deficient or excess calcium, excess phosphorus or vitamin D
  • Sore throat: zinc deficiency
  • Spasticity (constant muscle contraction): vitamin B12 deficiency
  • Spasms: See muscle spasms and twitching.
  • Substance abuse: Excess methylation
  • Swelling in the face: Hypothyroidism from iron or iodine deficiency (see also selenium)
  • Tachycardia (fast heart rate): thiamin deficiency, hypermagnesemia, hyperkalemia
  • Tetany: Deficiency of calcium and vitamin D, or magnesium; excess phosphorus
    • Since tetany is driven by hypocalcemia, deficiencies of vitamin D or calcium cause it. A large excess of phosphorus may also contribute to tetany by depleting blood levels of calcium. It is low ionized calcium rather than low total calcium that drives the condition, and alkalosis or high albumin may decrease ionized calcium even when total calcium is normal.
  • Thirst high: salt-to-potassium ratio, hypernatremia
  • Thyroid hormone, resistance to: zinc deficiency
  • Toxins, vulnerability to: Vulnerability to tissue damage from a wide variety of toxins, selenium deficiency; vulnerability to toxic metal accumulation, zinc deficiency
  • Tongue, inflammation: See glossitis.
  • Tremors: hypocalcemia
  • Triglycerides, elevated: deficient salt
  • Twitching: See muscle spasms and twitching.
  • Urticaria: See itching (pruritis) and hives (urticaria).
  • Visual disturbances: vitamin B12 deficiency, vitamin A toxicity, niacin, toxicity
  • Wound healing, impaired: zinc deficiency
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