Minerals are elements that originate in the Earth and cannot be made by living organisms. Plants obtain minerals from the soil, and most of the minerals in our diets come directly from plants or indirectly from animal sources. Minerals may also be present in the water we drink, but this varies with geographic locale. Minerals from plant sources may also vary from place to place, because soil mineral content varies geographically.

The information from the Linus Pauling Institute's Micronutrient Information Center on vitamins and minerals is now available in a book titled, An Evidence-based Approach to Vitamins and Minerals: Health Benefits and Intake Recommendations. The book can be purchased from the Linus Pauling Institute or Thieme Medical Publishers.

Select a mineral from the list for more information.


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  • Calcium is a major constituent of bones and teeth and also plays an essential role as second messenger in cell-signaling pathways. Circulating calcium concentrations are tightly controlled by the parathyroid hormone (PTH) and vitamin D at the expense of the skeleton when dietary calcium intakes are inadequate. (More information)
  • The recommended dietary allowance (RDA) for calcium is 1,000 mg/day-1,200 mg/day for adults. (More information)
  • The skeleton is a reserve of calcium drawn upon to maintain normal serum calcium in case of inadequate dietary calcium. Thus, calcium sufficiency is required to maximize the attainment of peak bone mass during growth and to limit the progressive demineralization of bones later in life, which leads to osteoporosis, bone fragility, and an increased risk of fractures(More information)
  • High concentrations of calcium and oxalate in the urine are major risk factors for the formation of calcium oxalate stones in the kidneys. Because dietary calcium intake has been inversely associated with stone occurrence, it is thought that adequate calcium consumption may reduce the absorption of dietary oxalate, thus reducing urinary oxalate and kidney stone formation. (More information)
  • Data from observational studies and randomized controlled trials support calcium supplementation in reducing the risk of high blood pressure and preeclampsia in pregnant women. The World Health Organization advises that all pregnant women in areas of low calcium intake (i.e., low-income countries with intakes around 300 to 600 mg/day) be given supplemental calcium starting in the 20th week of pregnancy. (More information)
  • Prospective cohort studies have reported an association between higher calcium intakes and lower risk of developing colorectal cancer; however, large clinical trials of calcium supplementation are needed. (More information)
  • Current available data suggest that adequate calcium intakes may play a role in body weight regulation and have therapeutic benefits in the management of moderate-to-severe premenstrual symptoms. (More information)
  • Adequate calcium intake is critical for maintaining a healthy skeleton. Calcium is found in a variety of foods, including dairy products, beans, and vegetables of the kale family. Yet, content and bioavailability vary among foods, and certain drugs are known to adversely affect calcium absorption. (More information)
  • Hypercalcemia, a condition of abnormally high concentrations of calcium in blood, is usually due to malignancy or primary hyperparathyroidism. However, the use of large doses of supplemental calcium, together with absorbable alkali, increases the risk of hypercalcemia, especially in postmenopausal women. Often associated with gastrointestinal disturbances, hypercalcemia can be fatal if left untreated. (More information)
  • High calcium intakes — either from dairy foods or from supplements — have been associated with increased risks of prostate cancer and cardiovascular events in some, but not all, observational and intervention studies. However, there is currently no evidence of such detrimental effects when people consume a total of 1,000 to 1,200 mg/day of calcium (diet and supplements combined), as recommended by the Food and Nutrition Board of the Institute of Medicine. (More information)

Calcium is the most abundant mineral in the human body. About 99% of the calcium in the body is found in bones and teeth, while the other 1% is found in the blood and soft tissue. Calcium concentrations in the blood and fluid surrounding the cells (extracellular fluid) must be maintained within a narrow concentration range for normal physiological functioning. The physiological functions of calcium are so vital to survival that the body will stimulate bone resorption (demineralization) to maintain normal blood calcium concentrations when calcium intake is inadequate. Thus, adequate intake of calcium is a critical factor in maintaining a healthy skeleton (1).



Calcium is a major structural element in bones and teeth. The mineral component of bone consists mainly of hydroxyapatite [Ca10(PO4)6(OH)2] crystals, which contain large amounts of calcium, phosphorus, and oxygen. Bone is a dynamic tissue that is remodeled throughout life. Bone cells called osteoclasts begin the process of remodeling by dissolving or resorbing bone. Bone-forming cells called osteoblasts then synthesize new bone to replace the bone that was resorbed. During normal growth, bone formation exceeds bone resorption. Osteoporosis may result when bone resorption chronically exceeds formation (1).

Calcium homeostasis

Calcium concentrations in the blood and fluid that surround cells are tightly controlled in order to preserve normal physiological function. A slight drop in blood calcium concentration (e.g., in the case of inadequate calcium intake) is sensed by the parathyroid glands, resulting in their increased secretion of parathyroid hormone (PTH). In the kidneys, PTH stimulates the conversion of vitamin D into its active form (1,25-dihydroxyvitamin D; calcitriol), which rapidly decreases urinary excretion of calcium but increases urinary excretion of phosphorus. Elevations in PTH also stimulates bone resorption, resulting in the release of bone mineral (calcium and phosphate) — actions that also contribute to restoring serum calcium concentrations. Increased circulating 1,25-dihydroxyvitamin D also triggers intestinal absorption of both calcium and phosphorus. Like PTH, 1,25-dihydroxyvitamin D stimulates the release of calcium from bone by activating osteoclasts (bone-resorbing cells). When blood calcium rises to normal levels, the parathyroid glands stop secreting PTH. A slight increase in blood calcium concentration stimulates the production and secretion of the peptide hormone, calcitonin, by the thyroid gland. Calcitonin inhibits PTH secretion, decreases both bone resorption and intestinal calcium absorption, and increases urinary calcium excretion (Figure 1). Finally, acute changes in blood calcium concentrations do not seem to elicit the secretion of the phosphaturic hormone fibroblast growth factor 23 (FGF-23), which is produced by bone-forming cells (osteoblasts/osteocytes) in response to increases in phosphorus intake (see the article on Phosphorus) (2). While this complex system allows for rapid and tight control of blood calcium concentrations, it does so at the expense of the skeleton (1).

Figure 1. Calcium Homeostasis. Calcium concentrations in the blood and fluid that surround cells are tightly controlled in order to preserve normal physiological function. A slight drop in blood calcium concentration (e.g., in the case of inadequate calcium intake) is sensed by the parathyroid glands, resulting in their increased secretion of parathyroid hormone (PTH). In the kidneys, PTH stimulates the conversion of vitamin D into its active form (1,25-dihydroxyvitamin D; calcitriol), which rapidly decreases urinary excretion of calcium but increases urinary excretion of phosphorus. Elevations in PTH also stimulates bone resorption, resulting in the release of bone mineral (calcium and phosphate) — actions that also contribute to restoring serum calcium concentrations. Increased circulating 1,25-dihydroxyvitamin D also triggers intestinal absorption of both calcium and phosphorus. Like PTH, 1,25-dihydroxyvitamin D stimulates the release of calcium from bone by activating osteoclasts (bone-resorbing cells). When blood calcium rises to normal levels, the parathyroid glands stop secreting PTH. A slight increase in blood calcium concentration stimulates the production and secretion of the peptide hormone, calcitonin, by the thyroid gland. Calcitonin inhibits PTH secretion, decreases both bone resorption and intestinal calcium absorption, and increases urinary calcium excretion.

[Figure 1 - Click to Enlarge]

Cell signaling

Calcium plays a role in mediating the constriction and relaxation of blood vessels (vasoconstriction and vasodilation), nerve impulse transmission, muscle contraction, and the secretion of hormones like insulin (1). Excitable cells, such as skeletal muscle and nerve cells, contain voltage-dependent calcium channels in their cell membranes that allow for rapid changes in calcium concentrations. For example, when a nerve impulse stimulates a muscle fiber to contract, calcium channels in the cell membrane open to allow calcium ions into the muscle cell. Within the cell, these calcium ions bind to activator proteins, which help release a flood of calcium ions from storage vesicles of the endoplasmic reticulum (ER) inside the cell. The binding of calcium to the protein troponin-c initiates a series of steps that lead to muscle contraction. The binding of calcium to the protein calmodulin activates enzymes that break down muscle glycogen to provide energy for muscle contraction. Upon completion of the action, calcium is pumped outside the cell or into the ER until the next activation (reviewed in 3).

Regulation of protein function

Calcium is necessary to stabilize a number of proteins, including enzymes, optimizing their activities. The binding of calcium ions is required for the activation of the seven "vitamin K-dependent" clotting factors in the coagulation cascade. The term, "coagulation cascade," refers to a series of events, each dependent on the other that stops bleeding through clot formation (see the article on Vitamin K).

Nutrient interactions

Vitamin D

Vitamin D is required for optimal calcium absorption (see Function or the article on Vitamin D). Several other nutrients (and non-nutrients) influence the retention of calcium by the body and may affect calcium nutritional status.


Dietary sodium is a major determinant of urinary calcium loss (1). High-sodium intake results in increased loss of calcium in the urine, possibly due to competition between sodium and calcium for reabsorption in the kidneys or by an effect of sodium on parathyroid hormone (PTH) secretion. Every 1-gram (g) increment in sodium (2.5 g of sodium chloride; NaCl salt) excreted by the kidneys has been found to draw about 26.3 milligrams (mg) of calcium into the urine (1). A study conducted in adolescent girls reported that a high-salt diet had a greater effect on urinary sodium and calcium excretion in White compared to Black girls, suggesting differences among ethnic groups (4). In adult women, each extra gram of sodium consumed per day is projected to produce an additional rate of bone loss of 1% per year if all of the calcium loss comes from the skeleton.

A number of cross-sectional and intervention studies have suggested that high-sodium intakes are deleterious to bone health, especially in older women (5). A two-year longitudinal study in postmenopausal women found increased urinary sodium excretion (an indicator of increased sodium intake) to be associated with decreased bone mineral density (BMD) at the hip (6). Another study in 40 postmenopausal women found that adherence to a low-sodium diet (2 g/day) for six months was associated with significant reductions in sodium excretion, calcium excretion, and amino-terminal propeptide of type I collagen, a biomarker of bone resorption. Yet, these associations were only observed in women with elevated baseline urinary sodium excretions (7). Finally, in a randomized, placebo-controlled study in 60 postmenopausal women, potassium citrate supplementation has been found to prevent an increase in calcium excretion induced by the consumption of a high-sodium diet (≥5,000 mg/day of elemental sodium) for four weeks (8)


Increasing dietary protein intake enhances intestinal calcium absorption, as well as urinary calcium excretion (9). The RDA for protein is 46 grams (g)/day for adult women and 56 g/day for adult men; however, the average intake of protein in the US tends to be higher (about 70 g/day in adult women and over 100 g per day in adult men) (10). It was initially thought that high-protein diets may result in a negative calcium balance (when the sum of urinary and fecal calcium excretion becomes greater than calcium intake) and thus increase bone loss (11). However, most observational studies have reported either no association or positive associations between protein intake and bone mineral density in children, adults, and elderly subjects (reviewed in 12). The overall calcium balance appears to be unchanged by high dietary protein intake in healthy individuals (13), and current evidence suggests that increased protein intakes in those with adequate supplies of protein, calcium, and vitamin D do not adversely affect BMD or fracture risk (14).


Phosphorus, which is typically found in protein-rich food, tends to increase the excretion of calcium in the urine. Diets with low calcium-to-phosphorus ratios (Ca:P ≤0.5) have been found to increase parathyroid hormone (PTH) secretion and urinary calcium excretion (15, 16). Also, the intestinal absorption and fecal excretion of calcium and phosphorus are influenced by calcium-to-phosphorus ratios of ingested food. Indeed, in the intestinal lumen, calcium salts can bind to phosphorus to form complexes that are excreted in the feces. This forms the basis for using calcium salts as phosphorus binders to lower phosphorus absorption in individuals with kidney insufficiency (17). Increasing phosphorus intakes from cola soft drinks (high in phosphoric acid) and food additives (high in phosphates) may have adverse effects on bone health (18). At present, there is no convincing evidence that the dietary phosphorus levels experienced in the US adversely affect bone health. Yet, the substitution of large quantities of phosphorus-containing soft drinks for milk or other sources of dietary calcium may represent a serious risk to bone health in adolescents and adults (see the article on Phosphorus).


Exposure to caffeine concentrations ≤400 mg/day have led to increased urinary calcium content in two randomized controlled trials (19, 20). However, caffeine intakes of 400 mg/day did not significantly change urinary calcium excretion over 24 hours in premenopausal women when compared to a placebo (21). A systematic review of 14 studies recently concluded that daily intake of ≤400 mg of caffeine was unlikely to interfere with calcium homeostasis, impact negatively bone mineral density, or increase the risks of osteoporosis and fracture in individuals with adequate calcium intakes (22).


A low blood calcium level (hypocalcemia) usually implies abnormal parathyroid function since the skeleton provides a large reserve of calcium for maintaining normal blood levels, especially in the case of low dietary calcium intake. Other causes of abnormally low blood calcium concentrations include chronic kidney failure, vitamin D deficiency, and low blood magnesium levels often observed in cases of severe alcoholism. Magnesium deficiency can impair parathyroid hormone (PTH) secretion by the parathyroid glands and lower the responsiveness of osteoclasts to PTH. Thus, magnesium supplementation is required to correct hypocalcemia in people with low serum magnesium concentrations (see the article on Magnesium). Chronically low calcium intakes in growing individuals may prevent the attainment of optimal peak bone mass. Once peak bone mass is achieved, inadequate calcium intake may contribute to accelerated bone loss and ultimately to the development of osteoporosis (see Disease Prevention) (1).

The Recommended Dietary Allowance (RDA)

Updated recommendations for calcium intake based on the optimization of bone health were released by the Food and Nutrition Board (FNB) of the Institute of Medicine in 2011 (9). The Recommended Dietary Allowance (RDA) for calcium is listed in Table 1 by life stage and gender.

Table 1. Recommended Dietary Allowance (RDA) for Calcium
Life Stage Age Males
Infants  0-6 months 200 (AI 200 (AI) 
Infants  6-12 months  260 (AI)  260 (AI) 
Children  1-3 years  700  700 
Children 4-8 years  1,000  1,000 
Children  9-13 years  1,300  1,300 
Adolescents  14-18 years  1,300  1,300 
Adults  19-50 years  1,000  1,000 
Adults  51-70 years  1,000  1,200 
Adults  >70 years 1,200  1,200 
Pregnancy  14-18 years 1,300 
Pregnancy  19-50 years 1,000 
Breast-feeding  14-18 years 1,300 
Breast-feeding  19-50 years 1,000

Disease Prevention


Osteoporosis is a skeletal disorder in which bone mass and strength are compromised, resulting in an increased risk of fracture. Sustaining a hip fracture is one of the most serious consequences of osteoporosis. Nearly one-third of those who sustain osteoporotic hip fractures enter nursing homes within a year following the fracture, and one person in four dies within one year of experiencing an osteoporotic hip fracture (23). Despite being a common diagnosis in postmenopausal women, osteoporosis also affects 4%-6% of men over the age of 50 years (24).

Osteoporosis is a multifactorial disorder, and nutrition is only one factor contributing to its development and progression (25). Other factors that increase the risk of developing osteoporosis include, but are not limited to, increased age, female gender, estrogen deficiency, smoking, high alcohol intake (three or more drinks/day), metabolic disease (e.g., hyperthyroidism), and the use of certain medications (e.g., corticosteroids and anticonvulsants) (26). A predisposition to osteoporotic fracture is related to one's peak bone mass and to the rate of bone loss after peak bone mass has been attained. After adult height has been reached, the skeleton continues to accumulate bone until the third decade of life. Genetic factors exert a strong influence on peak bone mass, but lifestyle factors can also play a significant role. Strategies for reducing the risk of osteoporotic fracture include the attainment of maximal peak bone mass and the reduction of bone loss later in life. A number of lifestyle factors, including diet (especially calcium and protein intake) and physical activity, are amenable to interventions aimed at maximizing peak bone mass and limiting osteoporotic fracture risk (27).

Physical exercise is a lifestyle factor that has been associated with numerous health benefits and is likely to contribute to the prevention of osteoporosis and osteoporotic fracture. There is evidence to suggest that physical activity early in life contributes to the attainment of higher peak bone mass (27). Moreover, lifelong participation in physical activities in the presence of adequate calcium and vitamin D supply (from dietary sources and/or sunlight exposure) may have a modest effect on slowing the rate of bone loss later in life (28). Current National Osteoporosis Foundation guidelines include recommendations of regular muscle-strengthening and weight-bearing exercise to all postmenopausal women and men ages 50 and older (29). Although benefits in reducing bone loss might be limited, muscle-strengthening exercise, including weight training and other resistive exercises (e.g., yoga and Pilates) and weight-bearing exercise (e.g., walking, jogging, and stair climbing), may improve strength, posture, balance, and coordination, thus contributing to reduced risk of falls (29). One compilation of published calcium trials indicated that the beneficial skeletal effect of increased physical activity was achievable only at calcium intakes above 1,000 mg/day in women in late menopause (reviewed in 28).

The progressive loss of bone mineral density (BMD) leading to osteopenia (pre-osteoporosis) and osteoporosis is usually assessed by dual-energy x-ray absorptiometry (DEXA) at the hip and lumbar spine (30). Several randomized, placebo-controlled clinical trials have evaluated the effect of supplemental calcium in the preservation of BMD and the prevention of fracture risk in men and women aged 50 years and older. A meta-analysis of 15 randomized controlled trials, including 1,533 men and women >50 years of age, found that increasing calcium intake from dietary sources (i.e., milk, milk powder, dairy products, or hydroxyapatite preparations) increased BMD by 0.6%-1% at the hip (+0.6%) and total body (+1.0%) after one year and by 0.7%-1.8% at the lumbar spine (+0.7%), femoral neck (+1.8%), total hip (+1.5%), and total body (+0.9%) sites after two years (31). A meta-analysis of 51 randomized controlled trials in 12,257 adults (>50 years) found that BMD at all bone sites (lumbar spine, femoral neck, total hip, forearm) increased by 0.7%-1.4% after one year and 0.8%-1.5% after two years of supplemental calcium, alone or in combination with vitamin D (31). Such modest increases may help limit the average rate of BMD loss after menopause but are unlikely to translate into meaningful fracture risk reductions. A meta-analysis of 20 randomized controlled trials that reported on total fracture risk found an 11% risk reduction associated with supplemental calcium with or without vitamin D (32). However, there was no effect when the analysis was restricted to the largest trials with the lowest risk of bias. Additionally, no reductions were found in risks of hip, vertebral and forearm fractures with calcium supplementation (32). Because estrogen withdrawal significantly impairs intestinal absorption and renal reabsorption of calcium, the level of calcium requirement might depend on whether postmenopausal women receive hormone replacement therapy (28).

The US Preventive Services Task Force conducted a meta-analysis of 11 randomized placebo-controlled trials that included 52,915 older people (of whom 69% were postmenopausal women) and reported that the supplementation of vitamin D (300-1,000 IU/day) and calcium (500-1,200 mg/day) for up to seven years resulted in a 12% reduction in the risk of any new fracture (33). There was no significant effect of vitamin D without calcium (33). A recently updated meta-analysis of randomized, placebo-controlled trials commissioned by the National Osteoporosis Foundation found a 15% reduction in risk of total fracture (8 studies) and a 30% reduction in risk of hip fractures (six studies) with calcium and vitamin D supplementation in older people (34). The National Osteoporosis Foundation advises that adequate intake of calcium (1,000-1,200 mg/day) and vitamin D (800-1,000 IU/day) be included in the diet of all middle-aged men and women (35).

The role and efficacy of vitamin D supplementation in strengthening bone and preventing fracture in older people remain controversial topics. The active form of vitamin D, 1,25-dihydroxyvitamin D, stimulates calcium absorption by promoting the synthesis of calcium-binding proteins in the intestine. While no amount of vitamin D can compensate inadequate total calcium intake, vitamin D insufficiency (defined as circulating concentrations of 25-hydroxyvitamin D below 20 ng/mL [50 nmol/L]) can lead to secondary hyperparathyroidism and an increased risk of osteoporosis (9, 36). Conversely, in postmenopausal women (ages 57-90 years) with adequate total calcium intakes (1,400 IU/day), serum 25-hydroxyvitamin D concentrations ranging from 20 ng/mL to 66 ng/mL had little effect on calcium absorption (only 6% increase over the range) (37). In a randomized, placebo-controlled trial, the supplementation of 1,000 IU/day of vitamin D to postmenopausal women (mean age, 77.2 years) for one year was found to significantly increase circulating 25-hydroxyvitamin D concentrations by 34% from baseline but failed to enhance calcium absorption in the presence of high total calcium intakes (dietary plus supplemental calcium corresponding to an average 2,100 mg/day) (38). This study also reported no significant difference in measures of BMD at the hip and total body between placebo- and vitamin D-treated women. In addition, the pooled analysis of seven randomized controlled trials, including 65,517 older individuals living in the community or in an institution, found that vitamin D (400-800 IU/day) could reduce the risk of any fracture only when combined with calcium (1,000 mg/day) (39). Interestingly, the results of a series of trials included in three recent meta-analyses (33, 40, 41) have suggested that supplemental vitamin D and calcium may have greater benefits in the prevention of fracture in institutionalized, older people who are also at increased risk of vitamin D deficiency and fractures compared to community dwellers (42, 43).

For more information about bone health and osteoporosis, see the article, Micronutrients and Bone Health, and visit the National Osteoporosis Foundation website.

Kidney stones

Approximately 6% of women and 15% of men in industrialized countries will have a kidney stone during their lifetime. Most kidney stones are composed of calcium oxalate or calcium phosphate. Subjects with an abnormally high level of calcium in the urine (hypercalciuria) are at higher risk of developing kidney stones (a process called nephrolithiasis) (44). High urinary oxalate level is another risk factor for calcium oxalate stone formation. Most subjects with a history of kidney stones and/or idiopathic hypercalciuria have increased intestinal calcium absorption (45). Although it was initially recommended to limit dietary calcium intake in these patients, a number of prospective cohort studies have reported associations between lower total dietary calcium intake and increased risk of incident kidney stones (46-48). The prospective analyses of three large cohorts, including a total of 30,762 men and 195,865 women followed for a combined 56 years, have indicated that the risk of kidney stones was significantly lower in individuals in the highest versus lowest quintile of dietary calcium intake from dairy or nondairy sources (49). Additionally, a five-year randomized intervention study that enrolled 120 men with idiopathic hypercalciuria (mean age, 45 years) reported that those assigned to a low-calcium diet (approximately 400 mg/day) had a 51% higher risk of kidney stone recurrence compared to those on a normal-to-high calcium (1,200 mg/day), low animal-protein, low-salt diet (50).

Mechanisms by which increased dietary calcium might reduce the risk of incident kidney stones are not fully understood. An inverse relationship was reported between total calcium intake and intestinal calcium absorption in the recent cross-sectional analysis of a cohort of 5,452 postmenopausal women (45). Moreover, women with higher supplemental calcium intake and lower calcium absorption were less likely to report a history of kidney stones (45). Adequate intake of calcium with food may reduce the absorption of dietary oxalate and lower urinary oxalate through formation of the insoluble calcium oxalate salt (51, 52). A recent small intervention study in 10 non-stone-forming young adults observed that the ingestion of large amounts of oxalate did not increase the risk of calcium oxalate stone occurrence in the presence of recommended level of dietary calcium (53).

However, a randomized, double-blind, placebo-controlled trial in 36,282 postmenopausal women reported that a combination of supplemental calcium (1,000 mg/day) and vitamin D (400 IU/day) was associated with a significantly increased incidence of self-reported kidney stones during a seven-year treatment period. More controlled trials may be necessary to determine whether supplemental calcium affects kidney stone risk (54). However, a systematic review of observational studies and randomized controlled trials that primarily reported on bone-related outcomes failed to find an effect of calcium supplementation on stone incidence (55). A potential kidney stone risk associated with calcium supplementation may likely depend on whether supplemental calcium is co-ingested with oxalate-containing foods or consumed separately. Further research is needed to verify whether osteoporosis treatment drugs (e.g., biphosphonates) rather than calcium supplements might influence the risk of stone occurrence (56).

Current data suggest that diets providing adequate dietary calcium and low levels of animal protein, oxalate, and sodium may benefit the prevention of stone recurrence in subjects with idiopathic hypercalciuria (57-59).

Hypertensive disorders of pregnancy

Pregnancy-induced hypertensive disorders, including gestational hypertension, preeclampsia, and eclampsia, complicate approximately 10% of pregnancies and are a major health risk for pregnant women and their offspring (60). Gestational hypertension is defined as an abnormally high blood pressure that usually develops after the 20th week of pregnancy. Preeclampsia is characterized by poor placental perfusion and a systemic inflammation that may involve several organ systems, including the cardiovascular system, kidneys, liver, and hematological system (61). In addition to gestational hypertension, preeclampsia is associated with the development of severe swelling (edema) and the presence of protein in the urine (proteinuria). Eclampsia is the occurrence of seizures in association with the syndrome of preeclampsia and is a significant cause of maternal and perinatal mortality.

Although cases of preeclampsia are at high risk of developing eclampsia, one-quarter of women with eclampsia do not initially exhibit preeclamptic symptoms. Risk factors for preeclampsia include genetic predisposition, advanced maternal age, first pregnancies, multiple pregnancies (e.g., twins or triplets), obesity, diabetes, and some autoimmune diseases (61). While the pathogenesis of preeclampsia is not entirely understood, nutrition and especially calcium metabolism appear to play a role. Data from epidemiological studies have suggested an inverse relationship between calcium intake during pregnancy and the incidence of preeclampsia (reviewed in 62). Impairment of calcium metabolism when circulating vitamin D concentration is low and/or when dietary calcium intake is inadequate may contribute to the risk of hypertension during pregnancy.

Secondary hyperparathyroidism (high PTH level) due to vitamin D deficiency in young pregnant women has been associated with high maternal blood pressure and increased risk of preeclampsia (63). The risk for elevated PTH concentration was also found to be increased in vitamin D-sufficient women with low-calcium intakes (<480 mg/day) during pregnancy when compared with adequate-to-high calcium intakes (≥1,000 mg/day) (64). In addition, vitamin D deficiency may trigger hypertension through the inappropriate activation of the renin-angiotensin system (see the article on Vitamin D).

Potential beneficial effects of calcium in the prevention of preeclampsia have been investigated in several randomized, placebo-controlled studies. The most recent meta-analysis of 13 trials in 15,730 pregnant women found that calcium supplementation with at least 1,000 mg/day (mostly 1,500-2,000 mg/day) from about 20 weeks of pregnancy (34 weeks of pregnancy at the latest) was associated with significant reductions in the risk of high blood pressure, preeclampsia, and preterm birth (62). Greater risk reductions were reported among pregnant women at high risk of preeclampsia (5 trials; 587 women) or with low dietary calcium intake (8 trials; 10,678 women). Another meta-analysis of nine randomized controlled trials in high-risk women indicated that lower doses of calcium supplementation (≤800 mg/day), alone or with a co-treatment (i.e., vitamin D, linoleic acid, or antioxidants), could also lower the risk of preeclampsia by 62% (65). Yet, based on the systematic review of high-quality randomized controlled trials, which used mostly high-dose calcium supplements, the World Health Organization (WHO) recently recommended that all pregnant women in areas of low-calcium intake (i.e., low-income countries with intakes around 300-600 mg/day) be given 1.5 to 2 g (1,500 to 2,000 mg)/day of elemental calcium from the 20th week of pregnancy (66).

Because excessive calcium supplementation may be harmful (see Safety), further research is required to verify whether calcium supplementation above the current IOM recommendation (1,000 mg/day for pregnant women, ages 19-50 years) would provide greater benefits to women at high risk of preeclampsia. Finally, the lack of effect of supplemental calcium on proteinuria (reported in two trials only) suggested that calcium supplementation from mid-pregnancy might be too late to oppose the genesis of preeclampsia (67, 68). A randomized, double-blind, placebo-controlled study — the WHO Calcium and Pre-eclampsia (CAP) trial — is ongoing to evaluate the effect of calcium supplementation with 500 mg/day, starting before pregnancy and until the 20th week of pregnancy, on the risk of preeclampsia in high-risk women (69, 70).

Colorectal cancer

Colorectal cancer (CRC) is the most common gastrointestinal cancer and the second leading cause of cancer death in the US (71). CRC is caused by a combination of genetic and environmental factors, but the degree to which these two types of factors influence CRC risk in individuals varies widely. In individuals with familial adenomatous polyposis (FAP) or hereditary nonpolyposis colorectal cancer (HNPCC), the cause of CRC is almost entirely genetic, while modifiable lifestyle factors, including dietary habits, tobacco use, and physical activities, greatly influence the risk of sporadic (non-hereditary) CRC.

Prospective cohort studies have consistently reported an inverse association between dairy food consumption and CRC risk. Experimental studies in cell culture and animal models have suggested plausible mechanisms underlying a role for calcium, a major nutrient in dairy products, in preventing CRC (72). In the multicenter European Prospective Investigation into Cancer and Nutrition (EPIC) prospective study of 477,122 individuals, followed for an average of 11 years, 4,513 CRC cases were documented (73). Intakes of milk, cheese, and yogurt, were inversely associated with CRC risk. The highest versus lowest quintile of total dairy intake (≥490 g/day vs. <134 g/day) was associated with a 23% lower risk of CRC. Similarly, CRC risk was 25% lower in those in the top versus bottom quintile of calcium intake from dairy food (≥839 mg/day vs. <308 mg/day). The 16-year follow-up of 41,403 women (ages 26-46 years at inclusion) from the prospective Nurses’ Health Study II (NHS II) documented 2,273 diagnoses of colorectal adenomas (precancerous polyps). The analysis of the prospective cohort found that women with total calcium intake of 1,001-1,250 mg/day had a 76% lower risk of developing advanced adenomas (i.e., adenomas more likely to become malignant) compared to those with intakes equal to and below 500 mg/day (74). In addition, a dose-response analysis using data from eight prospective studies (11,005 CRC cases) estimated that an increase of 300 mg/day in total calcium intake was associated with a 5% reduction in CRC risk (75). Total daily intake of calcium ranged from 333 to 2,229 mg in the examined studies. In addition, the dose-response analysis of six prospective studies (8,839 CRC cases among 920,837 participants) showed 11% lower odds of high-risk adenomas for each 300 mg/day increment in total calcium (75).

However, the meta-analysis of seven randomized, double-blind, placebo-controlled studies found no evidence of an effect of calcium supplementation (≥500 mg/day) for a median period of 45 months on total cancer risk and CRC risk (76). In addition, the re-analysis of the Women’s Health Initiative placebo-controlled trial failed to show a reduction in CRC risk in postmenopausal women supplemented with both vitamin D (400 IU/day) and calcium (1,000 mg/day) for seven years (77). Finally, the results of the meta-analysis of four randomized, placebo-controlled trials have suggested that calcium supplementation (1,200-2,000 mg/day) may reduce the risk of adenoma recurrence by 13% over three to five years in subjects with a history of adenomas (78). At present, it is not clear whether calcium supplementation is beneficial in CRC prevention. Larger trials designed to assess primarily the effect of long-term calcium supplementation on the incidence of adenomas and/or CRC are needed before conclusions can be drawn.

Lead toxicity

Children who are chronically exposed to lead, even in small amounts, are more likely to develop learning disabilities, behavioral problems, and to have low IQs. Deficits in growth and neurological development may occur in the infants of women exposed to lead during pregnancy and lactation. In adults, lead toxicity may result in kidney damage and high blood pressure. Although the use of lead in paint products, gasoline, and food cans has been discontinued in the US, lead toxicity continues to be a significant health problem, especially in children living in urban areas (79).

In 2012, the US Centers for Disease Control and Prevention set the reference value for blood lead concentration at 5 micrograms per deciliter (mg/dL) to identify children at risk (80). Yet, there is no known blood lead concentration below which children are 100% safe. An early study of over 300 children in an urban neighborhood found that 49% of children ages 1 to 8 years had blood lead levels above the threshold of 10 mg/dL, indicating excessive lead exposure. In this study, only 59% of children ages 1 to 3 years and 41% of children ages 4 to 8 years met the recommended levels for calcium intakes (81).

Adequate calcium intake could be protective against lead toxicity in at least two ways. Increased dietary intake of calcium is known to decrease the gastrointestinal absorption of lead. Once lead enters the body it tends to accumulate in the skeleton, where it may remain for more than 20 years. Adequate calcium intake also prevents lead mobilization from the skeleton during bone demineralization. A study of circulating concentrations of lead during pregnancy found that women with inadequate calcium intake during the second half of pregnancy were more likely to have elevated blood lead levels, probably because of increased bone demineralization, leading to the release of accumulated lead into the blood (82). Lead in the blood of a pregnant woman is readily transported across the placenta resulting in fetal lead exposure at a time when the developing nervous system is highly vulnerable. In a randomized, double-blind, placebo-controlled study in 670 pregnant women (≤14 weeks’ gestation) with average dietary calcium intakes of 900 mg/day, daily supplementation of 1,200 mg of calcium throughout the pregnancy period resulted in 8%-14% reductions in maternal blood lead concentrations (83). Similar reductions in maternal lead concentrations in the blood and breast milk of lactating mothers supplemented with calcium were reported in earlier trials (84, 85). In postmenopausal women, factors known to decrease bone demineralization, including estrogen replacement therapy and physical activity, have been inversely associated with blood lead levels (86).

Disease Treatment

Overweight and obesity

High dietary calcium intake, usually associated with dairy product consumption, has been inversely related to body weight and central obesity in a number of cross-sectional studies (reviewed in 87). Cross-sectional baseline data analyses of a number of prospective cohort studies that were not designed and powered to examine the effect of calcium intake or dairy consumption on obesity or body fat have given inconsistent results (87). Yet, a meta-analysis of 18 cross-sectional and prospective studies predicted a reduction in body mass index (a relative measure of body weight; BMI) of 1.1 kg/m2 with an increase in calcium intake from 400 mg/day to 1,200 mg/day (87). In a placebo-controlled intervention study, 32 obese subjects were randomized to energy restriction regimens (500 kCal/day deficit) for 24 weeks with (1) a standard diet providing 400 to 500 mg/day of dietary calcium and a placebo ("low calcium" diet), (2) a standard diet and 800 mg/day of supplemental calcium ("high calcium" diet), or (3) a high-dairy diet providing 1,200 mg/day of dietary calcium and a placebo (88). Energy-restricted diets resulted in significant body weight and fat loss in all three groups. Yet, body weight and fat loss were significantly more reduced with the high-calcium diet compared to the standard diet, and further reductions were measured with the high-dairy diet compared to both high-calcium and low-calcium diets. These results suggested that while calcium intake may play a role in body weight regulation, additional benefits might be attributable to other bioactive components of dairy products, such as proteins, fatty acids, and branched chain amino acids.

Yet, several mechanisms have been proposed to explain the potential impact of calcium on body weight (reviewed in 87). The most-cited mechanism is based on studies in the agouti mouse model showing that low-calcium intakes, through increasing circulating parathyroid hormone (PTH) and vitamin D, could stimulate the accumulation of fat (lipogenesis) in adipocytes (fat cells) (89). Conversely, higher intakes of calcium may reduce fat storage, stimulate the breakdown of lipids (lipolysis), and drive fat oxidation. A recent meta-analysis of randomized controlled trials estimated that high (1,300 mg/day) versus low (488 mg/day) calcium intake for a minimum of seven days increased fat oxidation by 11% (90). However, a double-blind, placebo-controlled, randomized, cross-over trial in 10 low-calcium consuming overweight or obese individuals reported that the supplementation with 800 mg/day of calcium for 5 weeks failed to modify the expression of key factors involved in fat metabolism (91). Moreover, while the model suggests a role for vitamin D in lipogenesis (fat storage), human studies have shown that vitamin D deficiency — rather than sufficiency — is often associated with obesity, and supplemental vitamin D might be effective in lowering body weight when caloric restriction is imposed (92, 93). Another mechanism suggests that high-calcium diets may limit dietary fat absorption in the intestine and increase fecal fat excretion. Indeed, in the gastrointestinal tract, calcium may trap dietary fat into insoluble calcium soaps of fatty acids that are then excreted (94). In addition, despite very limited evidence, it has also been proposed that calcium might be involved in regulating appetite and energy intake (95).

To date, there is no consensus regarding the effect of calcium on body weight changes. A meta-analysis of 29 randomized controlled trials in 2,441 participants (median age, 41.4 years) found that calcium supplementation was only associated with body weight and fat loss in short-term studies (<1 year) that used energy-restricted diets (96). Another meta-analysis of 41 randomized controlled trials (4,802 participants) found little-to-no effect of increased calcium intake from supplements or dairy foods for >12 weeks on body weight and body composition (97). Finally, a meta-analysis of 33 randomized controlled trials (4,733 participants) found no overall effect of calcium supplementation (from food or supplements) for >12 weeks on body weight changes. Yet, further subgroup analyses showed weight reductions in children and adolescents (mean, -0.26 kg), in adults (mean, -0.91 kg), and in those with normal BMI (mean, -0.53 kg). Supplemental calcium did not lead to weight loss in postmenopausal women or in overweight/obese individuals (98). At present, additional research is warranted to examine the effect of calcium intake on fat metabolism, as well as its potential benefits in the management of body weight with or without caloric restriction (99).

Premenstrual Syndrome (PMS)

PMS refers to a cluster of symptoms, including but not limited to fatigue, irritability, moodiness/depression, fluid retention, and breast tenderness, that begins sometime after ovulation (mid-cycle) and subsides with the onset of menstruation (the monthly period) (100). A severe form of PMS called premenstrual dysphoric disorder (PMDD) has been described in 3%-8% of women of childbearing age. PMDD interferes with normal functioning, affecting daily activities and relationships (101).

Low dietary calcium intakes have been linked to PMS in early reports, and supplemental calcium has been shown to decrease symptom severity (102). A nested case-control study within the Nurses' Health Study II (NHS II) found that women in the highest quintile of dietary (but not supplemental) calcium intake (median of 1,283 mg/day) had a 30% lower risk of developing PMS compared to those in the lowest quintile (median of 529 mg/day). Similarly, women in the highest versus lowest quintile of skim or low-fat milk intake (≥4 servings/day vs. ≤1 serving/week) had a 46% lower risk of PMS (103). In a randomized, double-blind, placebo-controlled clinical trial of 466 women with moderate-to-severe premenstrual symptoms, supplemental calcium (1,200 mg/day) for three menstrual cycles was associated with a 48% reduction in total symptom scores, compared to a 30% reduction observed in the placebo group (104). Similar positive effects were reported in earlier double-blind, placebo-controlled, cross-over trials that administered 1,000 mg of calcium daily (105, 106). Recent small randomized controlled trials also reported that supplemental calcium (400-500 mg/day) for three weeks to three months reduced severity and/or frequency of symptoms in women with mild-to-moderate PMS (107-110). Currently available data indicate that daily calcium intakes from food and/or supplements may have therapeutic benefits in women diagnosed with PMS or PMDD (111, 112).


The relationship between calcium intake and blood pressure has been investigated extensively over the past decades. A meta-analysis of 23 large observational studies conducted in different populations worldwide found a reduction in systolic blood pressure of 0.34 millimeters of mercury (mm Hg) per 100 mg of calcium consumed daily and a reduction in diastolic blood pressure of 0.15 mm Hg per 100 mg calcium (113). In the DASH (Dietary Approaches to Stop Hypertension) study, 549 people were randomized to one of three diets for eight weeks: (1) a control diet that was low in fruit, vegetables, and dairy products; (2) a diet rich in fruit (~5 servings/day) and vegetables (~3 servings/day); and (3) a combination diet rich in fruit and vegetables, as well as low-fat dairy products (~3 servings/day) (114). The combination diet represented an increase of about 800 mg of calcium/day over the control and fruit/vegetable-rich diets for a total of about 1,200 mg of calcium/day. Overall, the reduction in systolic blood pressure was greater with the combination diet than with the fruit/vegetable diet or the control diet. Among participants diagnosed with hypertension, the combination diet reduced systolic blood pressure by 11.4 mm Hg and diastolic pressure by 5.5 mm Hg more than the control diet, while the reduction for the fruit/vegetable diet was 7.2 mm Hg for systolic and 2.8 mm Hg for diastolic blood pressure compared to the control diet (115). This research suggested that calcium intake at the recommended level (1,000-1,200 mg/day) may be helpful in preventing and treating moderate hypertension (116).

Yet, two large systematic reviews and meta-analyses of randomized controlled trials have examined the effect of calcium supplementation on blood pressure compared to placebo in either normotensive or hypertensive individuals (117, 118). Neither of the analyses reported any significant effect of supplemental calcium on blood pressure in normotensive subjects. A small but significant reduction in systolic blood pressure, but not in diastolic blood pressure, was reported in participants with hypertension. Of note, calcium supplementation in these randomized controlled trials ranged from 400 to 2,200 mg/day, with 1,000 to 1,500 mg/day being the more common dosages. A more recent meta-analysis of 13 randomized controlled studies in 485 individuals with elevated blood pressure found a significant reduction of 2.5 mm Hg in systolic blood pressure but no change in diastolic blood pressure with calcium supplementation (119). The modest effect of calcium on blood pressure needs to be confirmed in larger, high-quality, well-controlled trials before any recommendation is made regarding the management of hypertension. Finally, a review of the literature on the effect of high-calcium intake (dietary and supplemental) in postmenopausal women found either no reduction or mild and transient reductions in blood pressure (120).

More information about the DASH diet is available from the National Institutes of Health (NIH).


Food sources

Data analysis of the US National Health and Nutrition Examination Surveys (NHANES) 2009-2010 and 2011-2012 found inadequate calcium intakes (defined as intakes below the Estimated Average Requirement [EAR]) in 37.7% of non-supplemented adults (ages, ≥19 years) and 19.6% of adults taking multivitamin/mineral supplements (121). Dairy foods provide 75% of the calcium in the American diet. However, it is typically during the most critical period for peak bone mass development that adolescents tend to replace milk with soft drinks (122). Dairy products represent rich and absorbable sources of calcium, but certain vegetables and grains also provide calcium.

However, the bioavailability of the calcium must be taken into consideration. The calcium content in calcium-rich plants in the kale family (broccoli, bok choy, cabbage, mustard, and turnip greens) is as bioavailable as that in milk; however, other plant-based foods contain components that inhibit the absorption of calcium. Oxalic acid, also known as oxalate, is the most potent inhibitor of calcium absorption and is found at high concentrations in spinach and rhubarb and somewhat lower concentrations in sweet potatoes and dried beans. Phytic acid (phytate) is a less potent inhibitor of calcium absorption than oxalate. Yeast possess an enzyme (phytase) that breaks down phytate in grains during fermentation, lowering the phytate content of breads and other fermented foods. Only concentrated sources of phytate, such as wheat bran or dried beans, substantially reduce calcium absorption (123).

Additional dietary constituents may affect calcium absorption (see Nutrient interactions). Table 2 lists a number of calcium-rich foods, along with their calcium content. For more information on the nutrient content of foods, search USDA's FoodData Central.

Table 2. Some Food Sources of Calcium
Food Serving Calcium (mg)
Tofu prepared with calcium sulfate (raw) ½ cup 434
Yogurt, plain, low-fat 8 ounces 415
Sardines, canned 3.75 ounces (1 can) 351
Cheddar cheese 1.5 ounces  303
Milk 8 ounces 300
White beans (cooked) ½ cup 81
Chinese cabbage (Bok choy/Pak choi, cooked) ½ cup 79
Figs (dried) ¼ cup 61
Orange 1 medium 60
Kale (cooked) ½ cup 47
Pinto beans (cooked) ½ cup 39
Broccoli (cooked) ½ cup 31
Red beans (cooked) ½ cup 25 


Most experts recommend obtaining as much calcium as possible from food because calcium in food is accompanied by other important nutrients that assist the body in utilizing calcium. However, calcium supplements may be necessary for those who have difficulty consuming enough calcium from food (124). No multivitamin/mineral tablet contains 100% of the recommended daily value (DV) for calcium because it is too bulky, and the resulting pill would be too large to swallow. The "Supplement Facts" label, required on all supplements marketed in the US, lists the calcium content of the supplement as elemental calcium. Calcium preparations used as supplements include calcium carbonate, calcium citrate, calcium citrate malate, calcium lactate, and calcium gluconate. To determine which calcium preparation is in your supplement, you may have to look at the ingredient list. Calcium carbonate is generally the most economical calcium supplement. To maximize absorption, take no more than 500 mg of elemental calcium at one time. Most calcium supplements should be taken with meals, although calcium citrate and calcium citrate malate can be taken anytime. Calcium citrate is the preferred calcium formulation for individuals who lack stomach acids (achlorhydria) or those treated with drugs that limit stomach acid production (H2 blockers and proton-pump inhibitors) (reviewed in 125).

Lead in calcium supplements

Several decades ago, concern was raised regarding lead concentrations in calcium supplements obtained from natural sources (oyster shell, bone meal, dolomite) (126). In 1993, investigators found measurable quantities of lead in most of the 70 different preparations they tested (127). Since then, manufacturers have reduced the amount of lead in calcium supplements to less than 0.5 micrograms (mg)/1,000 mg of elemental calcium (128). The US Food and Drug Administration (FDA) has developed provisional total tolerable intake levels (PTTI) for lead for specific age and sex groups (129). Because lead is so widespread and long lasting, no one can guarantee entirely lead-free food or supplements. A study found measurable lead in 8 out of 21 supplements, in amounts averaging 1 to 2 mg/1,000 mg of elemental calcium, which is below the tolerable limit of 7.5 mg/1,000 mg of elemental calcium (130). A more recent survey of 324 multivitamin/mineral supplements labeled for use in children or women found that most supplements would result in lead exposure ranging from 1%-4% of the PTTI (131).

Calcium inhibits intestinal absorption of lead, and adequate calcium intake is protective against lead toxicity, so trace amounts of lead in calcium supplementation may pose less of a risk of excessive lead exposure than inadequate calcium consumption. While most calcium sources today are relatively safe, look for supplements approved or certified by independent testing (e.g., US Pharmacopeia, ConsumerLab.com) (125), follow label instructions, and avoid large doses of supplemental calcium (≥1,500 mg/day).



Malignancy and primary hyperparathyroidism are the most common causes of elevated calcium concentrations in the blood (hypercalcemia) (132). Hypercalcemia has not been associated with the over consumption of calcium occurring naturally in food. Hypercalcemia has been initially reported with the consumption of large quantities of calcium supplements in combination with antacids, particularly in the days when peptic ulcers were treated with large quantities of milk, calcium carbonate (antacid), and sodium bicarbonate (absorbable alkali). This condition is termed calcium-alkali syndrome (formerly known as milk-alkali syndrome) and has been associated with calcium supplement levels from 1.5 to 16.5 g/day for 2 days to 30 years. Since the treatment for peptic ulcers has evolved and because of the widespread use of over-the-counter calcium supplements, the demographic of this syndrome has changed in that those at greater risk are now postmenopausal women, pregnant women, transplant recipients, patients with bulimia, and patients on dialysis, rather than men with peptic ulcers (reviewed in 133). Supplementation with calcium (0.6 g/day-2 g/day for two to five years) has been associated with a higher risk of adverse gastrointestinal events like constipation, cramping, bloating, pain, diarrhea (134). Mild hypercalcemia may be without symptoms or may result in loss of appetite, nausea, vomiting, constipation, abdominal pain, fatigue, frequent urination (polyuria), and hypertension (132). More severe hypercalcemia may result in confusion, delirium, coma, and if not treated, death (1).

In 2011, the Food and Nutrition Board of the Institute of Medicine updated the tolerable upper intake level (UL) for calcium (9). The UL is listed in Table 3 by age group.

Table 3. Tolerable Upper Intake Level (UL) for Calcium
Age Group UL (mg/day)
Infants 0-6 months 1,000
Infants 6-12 months 1,500
Children 1-8 years 2,500
Children 9-13 years 3,000
Adolescents 14-18 years 3,000
Adults 19-50 years 2,500
Adults 51 years and older 2,000

Although the risk of forming kidney stones is increased in individuals with abnormally elevated urinary calcium (hypercalciuria), this condition is not usually related to calcium intake, but rather to increased absorption of calcium in the intestine or increased excretion by the kidneys (9). Overall, increased dietary calcium intake has been associated with a decreased risk of kidney stones (see Kidney stones). Concerns have also been raised regarding the risks of prostate cancer and vascular disease with high intakes of calcium.

Do high calcium intakes increase the risk for prostate cancer?

Prostate cancer is the second most common cancer in men worldwide (135). Several observational studies have raised concern that high-dairy intakes are associated with increased risk of prostate cancer (136-138).

The analysis of a prospective cohort study (2,268 men followed for nearly 25 years) conducted in Iceland, a country with a high incidence of prostate cancer, found a positive association between the consumption of milk (at least once daily) during adolescence and developing prostate cancer later in life (139). Another large prospective cohort study in the US followed 21,660 male physicians for 28 years and found that men with daily skim or low-fat milk intake of at least 237 mL (8 oz) had a higher risk of developing prostate cancer compared to occasional consumers (140). The risk of low-grade, early-stage prostate cancer was associated with higher intake of skim milk, and the risk of developing fatal prostate cancer was linked to the regular consumption of whole milk (140). In a cohort of 3,918 male health professionals diagnosed with prostate cancer, 229 men died of prostate cancer and 69 developed metastasized prostate cancer during a median follow-up of 7.6 years (141). The risk of prostate cancer death was found to be increased in men with high (>4 servings/week) versus low (≤3 servings/month) intakes of whole milk. Yet, no increase in risk of prostate cancer-related mortality was associated with consumption of skim and low-fat milk, total milk, low-fat dairy products, full-fat dairy products, or total dairy products (141). A recent meta-analysis of 32 prospective cohort studies found high versus low intakes of total dairy product (15 studies), total milk (15 studies), whole milk (6 studies), low-fat milk (5 studies), cheese (11 studies), and dairy calcium (7 studies) to be associated with modest, yet significant, increases in the risk of developing prostate cancer (142). However, there was no increase in prostate cancer risk with nondairy calcium (4 studies) and calcium from supplements (8 studies). Moreover, high dairy intakes were not linked to fatal prostate cancer (142).

There is some evidence to suggest that milk consumption may result in higher circulating concentrations of insulin-like growth factor-I (IGF-I), a protein known to regulate cell proliferation (143). Circulating IGF-I concentrations have been positively correlated to the risk of developing prostate cancer in a recent meta-analysis of observational studies (144). Milk-borne IGF-I, as well as dairy proteins and calcium, may contribute to increasing circulating IGF-I in milk consumers (143). In the large EPIC study, which examined the consumption of dairy products in relation to cancer in 142,520 men, the risk of prostate cancer was found to be significantly higher in those in the top versusbottom quintile of both protein and calcium intakes from dairy foods (145). Another mechanism underlying the potential relationship between calcium intake and prostate cancer proposed that high levels of dietary calcium may lower circulating concentrations of 1,25-dihydroxyvitamin D, the active form of vitamin D, thereby suppressing vitamin D-mediated cell differentiation (146). However, studies to date have provided little evidence to suggest that vitamin D status can modify the association between dairy calcium and risk of prostate cancer development and progression (147-149)

In a multicenter, double-blind, placebo-controlled trial, 672 healthy men (mean age of 61.8 years) were randomized to daily calcium supplementation (1,200 mg) for four years. While no increase in the risk for prostate cancer has been reported during a 10.3-year follow-up, calcium supplementation resulted in a significant risk reduction in the period spanning from two years after treatment started to two years after treatment ended (150). In a review of the literature published in 2009, the US Agency for Healthcare Research and Quality indicated that not all epidemiological studies found an association between calcium intake and prostate cancer (151). The review reported that 6 out of 11 observational studies failed to find statistically significant positive associations between prostate cancer and calcium intake. Yet, in five studies, daily intakes of 921 to 2,000 mg of calcium were found to be associated with an increased risk of developing prostate cancer when compared to intakes ranging from 455 to 1,000 mg/day (151). Inconsistencies among studies suggest complex interactions between the risk factors for prostate cancer, as well as reflect the difficulties of assessing the effect of calcium intake in free-living individuals. For example, the fact that individuals with higher dairy and/or calcium intakes were found to be more likely to be engaged in healthy lifestyles or more likely to seek medical attention can mitigate the statistical significance of an association with prostate cancer risk (152). Until the relationship between calcium and prostate cancer is clarified, it is reasonable for men to consume a total of 1,000 to 1,200 mg/day of calcium (diet and supplements combined), which is recommended by the Food and Nutrition Board of the Institute of Medicine (see RDA) (9).

Do calcium supplements increase the risk for cardiovascular disease?

Several observational studies and randomized controlled trials have raised concerns regarding the potential adverse effects of calcium supplements on cardiovascular risk. The analysis of data from the Kuopio Osteoporosis Risk Factor and Prevention (OSTPRE) prospective study found that users of calcium supplements amongst 10,555 Finnish women (ages 52-62 years) had a 14% greater risk of developing coronary artery disease compared to non-supplement users during a mean follow-up of 6.75 years (153). The prospective study of 23,980 participants (35-64 years old) of the Heidelberg cohort of the European Prospective Investigation into Cancer and Nutrition cohort (EPIC-Heidelberg) observed that supplemental calcium intake was positively associated with the risk of myocardial infarction (heart attack) but not with the risk of stroke or cardiovascular disease (CVD)-related mortality after a mean follow-up of 11 years (154). Yet, the use of calcium supplements (≥400 mg/day vs. 0 mg/day) was associated with an increased risk of CVD-related mortality in 219,059 men, but not in 169,170 women, included in the National Institute of Health (NIH)-AARP Diet and Health study and followed for a mean period of 12 years. CVD mortality in men was also found to be significantly higher with total (dietary plus supplemental) calcium intakes of 1,500 mg/day and above (155).

In addition, the secondary analyses of two randomized placebo-controlled trials initially designed to assess the effect of calcium on bone health outcomes also suggested an increased risk of CVD in participants daily supplemented with 1,000 mg of calcium for five to seven years (156, 157). In the Auckland Calcium Study of 1,471 healthy postmenopausal women (ages ≥55 years), calcium supplementation resulted in increased risks of myocardial infarction and of a composite cardiovascular endpoint, including myocardial infarction, stroke, or sudden death (156). The analysis of data from 36,282 healthy postmenopausal women randomized to receive a combination of calcium (1,000 mg/day) and vitamin D (400 IU/day) or a placebo in the Women’s Health Initiative/Calcium-Vitamin D supplementation study (WHI/CaD study) initially reported no adverse effect on any cardiovascular endpoints with calcium (and vitamin D) compared to placebo (158). A re-analysis was performed with data from 16,718 women who did not take personal calcium supplements (outside protocol) during the five-year study (157). Although criticized on the approach taken (134, 159), the investigators estimated that women supplemented with calcium and vitamin D had a 16% increased risk of clinical myocardial infarction or stroke and a 21% increased risk of myocardial infarction compared to those who received a placebo (157). However, in another randomized, double-blind, placebo-controlled trial — the Calcium Intake Fracture Outcome (CAIFOS) study — in elderly women (median age, 75.1 years), the supplementation of 1,200 mg/day of calcium for five years was not found to increase the risk of vascular disease or related mortality (160). The WHI/CaD data re-analysis also failed to show an increased risk of mortality due to myocardial infarction or coronary artery disease with calcium therapy (156). Also, after an additional follow-up of 4.5 years at the end of the treatment period in the CAIFOS trial, the investigators reported fewer cases of heart failure-related deaths with supplemental calcium compared to placebo (160). In another randomized, placebo-controlled trial of calcium and/or vitamin D3 (RECORD trial), the evaluation of the effect of 1,000 mg/day of calcium (alone or with 800 IU/day of vitamin D) reported no significant increase in the rate of mortality due to vascular disease in 5,292 participants ages 70 years and older (161). A recent cross-sectional analysis of the Third National Health and Nutrition Examination Survey (NHANES III) evaluated the association between calcium intakes and cardiovascular mortality in 18,714 adults with no history of heart disease. No evidence of an association was observed between dietary calcium intake, supplemental calcium intake, or total calcium intake and cardiovascular mortality in either men or women (162).

A few prospective studies have reported positive correlations between high calcium concentrations in the blood and increased rates of cardiovascular events (163, 164). Because supplemental calcium may have a greater effect than dietary calcium on circulating calcium concentrations (see Toxicity), it has been speculated that the use of calcium supplements might promote vascular calcification — a surrogate marker of the burden of atherosclerosis and a major risk factor for cardiovascular events — by raising calcium serum concentrations. In 1,471 older women from the Auckland Calcium Study and 323 healthy older men from another randomized, placebo-controlled trial of daily calcium supplementation (600 mg or 1,200 mg) for two years, serum calcium concentrations were found to be positively correlated with abdominal aortic calcification or coronary artery calcification (165). However, there was no effect of calcium supplementation on measures of vascular calcification scores in men or women. Data from 1,201 participants of the Framingham Offspring study were also used to assess the relationship between calcium intake and vascular calcification. Again, no association was found between coronary calcium scores and total, dietary, or supplemental calcium intake in men or women (166). Nonetheless, in the Multi-Ethnic Study of Atherosclerosis (MESA), a US multicenter prospective study in 6,814 participants followed for a mean 10 years, the greatest risk of developing coronary artery calcification was found in supplement users with the lowest total calcium intake (~306 mg/day of dietary calcium and ~91 mg/day of supplemental calcium), when compared to supplement users with higher total calcium intakes and nonusers (167). Finally, an assessment of atherosclerotic lesions in the carotid artery wall of 1,103 participants in the CAIFOS trial was also conducted after three years of supplementation (168). When compared with placebo, calcium supplementation showed no effect on carotid artery intimal medial thickness (CIMT) and carotid atherosclerosis. Yet, carotid atherosclerosis (but not CIMT) was significantly reduced in women in the highest versus lowest tertile of total (diet and supplements) calcium intakes (≥1,795 mg/day vs. <1,010 mg/day) (168).

The most recent meta-analysis of 18 randomized clinical trials, including a total of 63,563 postmenopausal women, found no evidence of an increased risk for coronary artery disease and all-cause mortality with calcium (≥500 mg/day) supplementation for at least one year (169). Because these clinical trial data are limited to analyses of secondary endpoints, meta-analyses should be interpreted with caution. There is a need for studies designed to examine the effect of calcium supplements on CVD risk as a primary outcome before definite conclusions can be drawn. Based on an updated review of the literature that included four randomized controlled trials, one nested case-control study, and 26 prospective cohort studies (170), the National Osteoporosis Foundation (NOF) and the American Society for Preventive Cardiology (ASPC) concluded that the use of supplemental calcium for generally healthy individuals was safe from a cardiovascular health standpoint when total calcium intakes did not exceed the UL (171). NOF and ASPC support the use of calcium supplements to correct shortfalls in dietary calcium intake and meet current recommendations (171).

Drug interactions

Taking calcium supplements in combination with thiazide diuretics (e.g., hydrochlorothiazide) increases the risk of developing hypercalcemia due to increased reabsorption of calcium in the kidneys. High doses of supplemental calcium could increase the likelihood of abnormal heart rhythms in people taking digoxin (Lanoxin) for heart failure (172). Calcium, when provided intravenously, may decrease the efficacy of calcium channel blockers (173). However, dietary and oral supplemental calcium do not appear to affect the action of calcium channel blockers (174). Calcium may decrease the absorption of tetracycline, quinolone class antibiotics, bisphosphonates, sotalol (a β-blocker), and levothyroxine; therefore, it is advisable to separate doses of these medications and calcium-rich food or supplements by two hours before calcium or four-to-six hours after calcium (175). Supplemental calcium can decrease the concentration of dolutegravir (Tivicay), elvitegravir (Vitekta), and raltegravir (Isentress), three antiretroviral medications, in blood such that patients are advised to take them two hours before or after calcium supplements (175). Intravenous calcium should not be administrated within 48 hours following intravenous ceftriaxone (rocephine), a cephalosporin antibiotic, since a ceftriaxone-calcium salt precipitate can form in the lungs and kidneys and be a cause of death (175). Use of H2 blockers (e.g., cimetidine) and proton-pump inhibitors (e.g., omeprazole) may decrease the absorption of calcium carbonate and calcium phosphate (reviewed in 176, 177), whereas lithium may increase the risk of hypercalcemia in patients (175). The topical use of calcipotriene, a vitamin D analog, in the treatment of psoriasis places patients at risk of hypercalcemia if they take calcium supplements.

Calcium-nutrient interactions

The presence of calcium decreases iron absorption from nonheme sources (i.e., most supplements and food sources other than meat). However, calcium supplementation up to 12 weeks has not been found to change iron nutritional status, probably due to a compensatory increase in iron absorption (1). Individuals taking iron supplements should take them two hours apart from calcium-rich food or supplements to maximize iron absorption. Although high calcium intakes have not been associated with reduced zinc absorption or zinc nutritional status, an early study in 10 men and women found that 600 mg of calcium consumed with a meal halved the absorption of zinc from that meal (see the article on Zinc) (178). Supplemental calcium (500 mg calcium carbonate) has been found to prevent the absorption of lycopene (a nonprovitamin A carotenoid) from tomato paste in 10 healthy adults randomized into a cross-over study (179).

Linus Pauling Institute Recommendation

The Linus Pauling Institute supports the recommended dietary allowance (RDA) set by the Food and Nutrition Board of the Institute of Medicine. Following these recommendations should provide adequate calcium to promote skeletal health and may also decrease the risks of some chronic diseases.

Children and adolescents (9-18 years)

To promote the attainment of maximal peak bone mass, children and adolescents should consume a total (diet plus supplements) of 1,300 mg/day of calcium.

Adults (women: 19-50 years; men: 19-70 years)

After adult height has been reached, the skeleton continues to accumulate bone until the third decade of life when peak bone mass is attained. To promote the attainment of maximal peak bone mass and to minimize bone loss later in life, adult women (50 years of age and younger) and adult men (70 years of age and younger) should consume a total (diet plus supplements) of 1,000 mg/day of calcium. 

Older women (>50 years)

To minimize bone loss, postmenopausal women should consume a total (diet plus supplements) of 1,200 mg/day of calcium. Taking a multivitamin/mineral supplement containing at least 10 μg (400 IU)/day of vitamin D will help to ensure adequate calcium absorption (see the article on Vitamin D).

Older men (>70 years)

To minimize bone loss, older men should consume a total (diet plus supplements) of 1,200 mg/day of calcium. Taking a multivitamin/mineral supplement containing at least 10 μg (400 IU)/day of vitamin D will help to ensure adequate calcium absorption (see the article on Vitamin D). 

Pregnant and breast-feeding women

Pregnant and breast-feeding adolescents (<19 years) should consume a total of 1,300 mg/day of calcium, while pregnant and breast-feeding adults (≥19 years) should consume a total of 1,000 mg/day of calcium.

Authors and Reviewers

Originally written in 2001 by:
Jane Higdon, Ph.D.
Linus Pauling Institute
Oregon State University

Updated in April 2003 by:
Jane Higdon, Ph.D.
Linus Pauling Institute
Oregon State University

Updated in October 2007 by:
Victoria J. Drake, Ph.D.
Linus Pauling Institute
Oregon State University

Updated in August 2014 by:
Barbara Delage, Ph.D.
Linus Pauling Institute
Oregon State University

Updated in May 2017 by:
Barbara Delage, Ph.D.
Linus Pauling Institute
Oregon State University

Reviewed in September 2017 by:
Connie M. Weaver, Ph.D.
Distinguished Professor and Head of Foods and Nutrition
Purdue University

The 2017 update of this article was supported by a grant from Pfizer Inc.

Copyright 2001-2023  Linus Pauling Institute


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Chromium was first discovered in 1797. The most stable oxidation state of chromium in biological systems is trivalent chromium (Cr3+), which forms relatively inert complexes with proteins and nucleic acids (1). The essentiality of trivalent chromium is questioned, and its proposed function in the body remains poorly understood. In fact, in 2014 the European Food Safety Authority concluded that a dietary requirement — or even an Adequate Intake — cannot be set for trivalent chromium as no conclusive evidence exists that chromium is essential at any dietary intake (2). Trivalent chromium appears to have health effects only at pharmacological doses (reviewed in 3), and a dietary deficiency of the mineral has not been observed.

Another common and stable form of chromium in the environment is hexavalent chromium (Cr6+). Hexavalent chromium is derived from trivalent chromium by heating at alkaline pH and is used as a source of chromium for industrial purposes. Hexavalent chromium is highly toxic and is classified as a human carcinogen when inhaled (4). In the acidic environment of the stomach, hexavalent chromium can be readily reduced to trivalent chromium by reducing substances present in food, which limits the ingestion of hexavalent chromium (5-7).


Trivalent chromium has been proposed to be the cofactor for a biologically active molecule that could enhance the effects of insulin on target tissues. Insulin is secreted by specialized cells in the pancreas in response to increased blood glucose concentration, such as after a meal. Insulin binds to insulin receptors on the surface of cells, activating the receptors and stimulating glucose uptake by cells. Through its interaction with insulin receptors, insulin provides cells with glucose for energy and helps maintain blood glucose within a narrow range of concentrations. In addition to its effects on carbohydrate (glucose) metabolism, insulin also influences the metabolism of fat and protein (8). Together, a decreased response to insulin or decreased insulin sensitivity in peripheral tissues (adipose tissue, muscle, and liver) and a progressive defect in insulin secretion may result in impaired glucose tolerance, frequently leading to overt type 2 diabetes mellitus. The body initially increases the secretion of insulin by specialized pancreatic cells to overcome the decrease in insulin sensitivity. However, the pancreas eventually fails to produce enough insulin to maintain normal blood glucose concentrations. Individuals with type 2 diabetes are at increased risk for cardiovascular disease (9).

Possible mechanism of action

The precise composition and structure of the biologically active form of chromium is not known. One model postulates that trivalent chromium might be the cofactor of a low-molecular-weight chromium-binding substance known as LMWCr or chromodulin (10). Chromodulin has been shown to play a role in the transport of chromium from the tissues to the bloodstream for ultimate elimination in the urine (11). When chromium is consumed at high levels, such as from dietary supplements, levels of chromodulin in tissues rise. At these high levels, chromodulin is proposed to enhance the cascade of signaling events induced by the binding of insulin to extracellular α-subunit of the insulin receptor (IR) (12). Upon insulin binding, the tyrosine kinase domain of the intracellular β-subunit of the IR becomes activated and causes the phosphorylation of tyrosine residues in the β-subunit itself. Subsequently, IR activation triggers a series of rapid phosphorylation reactions that activate many downstream effectors, eventually resulting in an increase in glucose uptake and storage (10). While this model is supported by in vitro studies, this mode of action for chromodulin has not been confirmed to date by in vivo studies.

Some, but not all, studies conducted in cell-based and animal models of insulin resistance and diabetes mellitus have found that chromium inhibits the activity of protein tyrosine phosphatase-1B (PTP-1B) and other negative regulators of insulin signaling, suggesting that chromium might improve insulin sensitivity under insulin-resistant conditions (reviewed in 10). A study in diabetic mice also suggested that chromium may reduce insulin clearance and enhance insulin signaling by inhibiting the proteolysis (degradation) of insulin and some downstream effectors (13). Additional mechanisms that may underlie the effect of chromium on insulin sensitivity, such as the reduction of markers of oxidative stress and inflammation known to contribute to insulin resistance, are under investigation (reviewed in 10, 14).

Nutrient interactions


Chromium competes for one of the binding sites on the iron transport protein, transferrin. However, supplementation of older men with 925 μg/day of chromium for 12 weeks did not significantly affect measures of iron nutritional status (15). A study of younger men found an insignificant decrease in transferrin saturation with iron after supplementation of 200 μg/day of chromium for eight weeks, but no long-term studies have addressed this issue (16). In a 12-week, randomized controlled trial, supplementation with chromium picolinate (200 μg/day) did not affect iron nutritional status in premenopausal women when compared to picolinic acid or placebo (17). Iron overload in hereditary hemochromatosis may interfere with chromium transport by competing for transferrin binding. It has been hypothesized that decreased chromium transport might contribute to the pathogenesis of diabetes mellitus in patients with hereditary hemochromatosis (5).

Vitamin C

Chromium uptake is enhanced in animals when given at the same time as vitamin C (7). In a study of three women, administration of 100 mg of vitamin C together with 1 mg of chromium resulted in higher plasma levels of chromium than 1 mg of chromium without vitamin C (5).


Compared to diets rich in complex carbohydrates (e.g., whole grains), diets high in simple sugars (e.g., sucrose) result in increased urinary chromium excretion in adults. This effect may be related to increased insulin secretion in response to the consumption of simple sugars compared to complex carbohydrates (5).


Dietary chromium deficiency has not been observed in humans. Potential cases of chromium deficiency were thought to have been observed in a few patients on long-term intravenous feeding (parenteral nutrition) who did not receive supplemental chromium in their intravenous solutions. The subjects developed abnormal glucose utilization and increased insulin requirements that responded to chromium supplementation (18). However, because intravenous solutions provide chromium at doses well above dietary levels, it has been suggested that chromium might produce biological effects only at pharmacological doses (3, 14). However, the differences in symptoms among subjects, the range of doses of chromium utilized over varying windows of time, and the different reported outcomes are now realized to make interpretation of these results difficult, even in terms of any potential pharmacological effects from the chromium supplementation. Because chromium appeared to enhance the action of insulin and chromium deficiency has been proposed to result in impaired glucose tolerance, chromium insufficiency has been hypothesized to be a contributing factor to the development of type 2 diabetes mellitus (5, 19). However, evidence for this is ambiguous at best.

Urinary chromium loss was reportedly increased by endurance exercise in male runners, suggesting that chromium needs may be greater in individuals who exercise regularly (20). In one study, weightlifting (resistive exercise) was found to increase urinary excretion of chromium in older men. However, chromium absorption also increased, leading to little or no net loss of chromium as a result of resistive exercise (21).

The absence of animal models for chromium deficiency makes it difficult to study possible biochemical, physiological, and functional abnormalities associated with inadequate intakes of chromium (if chromium is nutritionally essential) (2).

The Adequate Intake (AI)

Because there was not enough information to set an estimated average requirement (EAR), the Food and Nutrition Board (FNB) of the US Institute of Medicine (now the National Academy of Medicine) established an adequate intake (AI) based on the chromium content in healthy diets (Table 1; 5).

Table 1. Adequate Intake (AI) for Chromium
Life Stage Age Males (μg/day) Females (μg/day)
Infants  0-6 months  0.2 0.2
Infants  7-12 months  5.5 5.5
Children  1-3 years  11 11
Children  4-8 years  15 15
Children  9-13 years  25 21
Adolescents  14-18 years  35 24
Adults  19-50 years  35 25
Adults  51 years and older  30 20
Pregnancy  18 years and younger  - 29
Pregnancy  19 years and older - 30
Breast-feeding  18 years and younger  - 44
Breast-feeding  19 years and older - 45

The case of trivalent chromium essentiality has been questioned in both animals and humans in the last decades, and in 2014 the European Food Safety Authority's Panel on Dietetic Products, Nutrition, and Allergies — which provides dietary guidelines for the EU community — concluded that requirements for chromium could not be established (2). The FNB, which sets dietary intake recommendations for the United States and Canada, is not currently reconsidering the AI level for chromium (22).

Disease Prevention

Impaired glucose tolerance and type 2 diabetes mellitus

Early controlled studies in subjects with impaired glucose tolerance reported that chromium supplementation improved some measure of glucose utilization or had beneficial effects on blood lipid profiles (23). Impaired glucose tolerance refers to a prediabetic state and is currently defined by the presence of impaired fasting glucose (fasting plasma glucose concentration of 100-125 mg/dL) and impaired glucose tolerance status (plasma glucose concentration of 140-199 mg/dL during a two-hour challenge test with a 75-g oral glucose load) (24). Impaired glucose tolerance is associated with modest increases in risk of cardiovascular disease, as well as other traditional microvascular complications of diabetes mellitus (25). Current estimates suggest that up to 70% of individuals with impaired glucose tolerance eventually develop type 2 diabetes (26).

In a randomized, double-blind, placebo-controlled study in 56 subjects at risk of developing type 2 diabetes, six months of daily chromium picolinate supplementation (500 μg or 1,000 μg) had no effect on glucose and insulin concentrations, insulin sensitivity, and blood lipid profiles (27). Another randomized, placebo-controlled trial in 31 individuals without diabetes reported a great variability in serum and urinary chromium concentrations in response to a daily supplementation with 1,000 μg of chromium picolinate for 16 weeks. Also, in the chromium-supplemented group, participants with higher vs. lower serum chromium concentrations (>3.1 μg/L vs. ≤3.1 μg/L) exhibited a decline in insulin sensitivity that could not be explained by expression changes in the genes involved in insulin signaling (28). Additionally, a meta-analysis of nine randomized clinical trials published between 1992 and 2010 reported that chromium at doses of 200-1,000 μg/day for 8-16 weeks had no effect on fasting glucose concentrations in 309 individuals without diabetes (29).

Cardiovascular disease

Impaired glucose tolerance and type 2 diabetes mellitus are associated with adverse changes in lipid profiles and increased risk of cardiovascular disease. Studies examining the effects of chromium supplementation on lipid profiles have given inconsistent results. While some studies have observed reductions in serum total cholesterol, LDL-cholesterol, and triglyceride levels or increases in HDL-cholesterol levels, others have observed no effect. Such mixed responses of lipid and lipoprotein levels to chromium supplementation may reflect differences in chromium nutritional status. It is possible that only individuals with insufficient dietary intake of chromium will experience beneficial effects on lipid profiles after chromium supplementation (6, 7, 30).

Moreover, a recent meta-analysis of 10 randomized controlled trials, mostly in patients with type 2 diabetes mellitus or metabolic syndrome, found chromium supplementation had no effect on either systolic or diastolic blood pressure (31). Yet, another meta-analysis of randomized controlled trials found chromium supplementation decreased circulating levels of two proinflammatory biomarkers associated with increased cardiovascular risk, hs-CRP and TNF-α, but not blood levels of IL-6 (32).

Health claims

Increases muscle mass

Claims that chromium supplementation increases lean body mass and decreases body fat are based on the relationship between chromium and insulin action (see Function). In addition to regulating glucose metabolism, insulin is known to affect fat and protein metabolism (8). At least 12 placebo-controlled studies have compared the effect of chromium supplementation (172-1,000 μg/day of chromium as chromium picolinate) with or without an exercise program on lean body mass and measures of body fat (reviewed in 33). In general, the studies that used the most sensitive and accurate methods of measuring body fat and lean mass (dual energy x-ray absorbtiometry or DEXA and hydrodensitometry or underwater weighing) did not find a beneficial effect of chromium supplementation on body composition (6, 30). In the US, the claim that chromium picolinate increases lean body mass is not allowed on supplement labels because it is not substantiated by the available research (34, 35).  

Promotes weight loss

Controlled studies of chromium supplementation have demonstrated little if any beneficial effect on weight or fat loss, and claims of weight loss in humans appear to be exaggerated. In 1996, the US Federal Trade Commission (FTC) ruled that there was no scientific basis for claims that chromium picolinate could promote weight loss and fat loss in humans (36). A 2013 meta-analysis of 11 randomized, double-blind, placebo-controlled trials in 866 overweight or obese subjects found a significant 0.50-kilogram (1.10-pound) reduction in body weight with supplemental chromium (most exclusively in the form of chromium picolinate) at doses between 137 μg/day and 1,000 μg/day for 8 to 24 weeks (37). However, such a small change did not reach a clinically significant weight loss of ≥5% of the initial body weight (38). A 2019 meta-analysis of 19 clinical trials found similar results: chromium supplementation at doses between 20 μg/day and 1,000 μg/day for 4 to 24 weeks decreased body weight in overweight or obese subjects by only 0.75 kg, a clinically insignificant amount (39). Some reports have suggested that supplemental chromium may reduce food craving and intake in overweight or obese women (40, 41). Yet, current available data remain insufficient to support the use of chromium supplements as a weight-loss strategy (42). In the US, the claim that chromium picolinate promotes weight loss is not allowed on supplement labels because it is unsubstantiated (34, 35).  

Reduces insulin resistance

Despite stating that scientific evidence is severely limited, the US FDA allows a single claim on supplement labels: "One small study suggests that chromium picolinate may reduce the risk of insulin resistance, and therefore possibly may reduce the risk of type 2 diabetes. FDA concludes, however, that the existence of such a relationship between chromium picolinate and either insulin resistance or type 2 diabetes is highly uncertain." (35, 43).

Disease Treatment

Type 2 diabetes mellitus

Type 2 diabetes mellitus is characterized by chronic hyperglycemia (elevated blood glucose concentration) and insulin resistance. Because resistance to insulin is usually associated with a compensatory rise in insulin secretion, circulating insulin concentrations in people with type 2 diabetes may be higher than in healthy individuals. Yet, the resistance of peripheral tissues (especially liver and skeletal muscle) to insulin also implies that the physiological effects of insulin are reduced.

Since cell culture and rodent models of diabetes have implicated chromium in the regulation of insulin sensitivity and blood glucose levels, the relationship between chromium nutritional status and type 2 diabetes mellitus has generated considerable scientific interest. Early reports observed that individuals with overt type 2 diabetes for over two years had higher rates of urinary chromium loss than healthy individuals (44). Small, well-designed studies of chromium supplementation in individuals with type 2 diabetes showed no improvement in blood glucose control, although they provided some evidence of reduced insulin concentrations and improved blood lipid profiles (45). In 1997, the results of a placebo-controlled trial conducted in China indicated that chromium supplementation might be beneficial in the treatment of type 2 diabetes (46). One hundred and eighty participants were randomized to receive either a placebo or chromium supplements in the form of chromium picolinate at either 200 μg/day or 1,000 μg/day. After four months of treatment, fasting blood glucose concentrations were found to be 15% to 19% lower in those who took 1,000 μg/day of chromium compared to those who took the placebo. Yet, blood glucose concentrations in those taking 200 μg/day of chromium did not differ significantly from those who took placebo. Chromium picolinate at either 200 μg/day or 1,000 μg/day was also associated with reduced insulin concentrations compared to placebo. The level of glycated hemoglobin A1c (HbA1c), a measure of glycemic control over the past four months, was also significantly reduced in both chromium-supplemented groups. However, a number of limitations made it difficult to extrapolate the results to the US population (47). Besides, the study was excluded from meta-analyses of randomized controlled trials due to insufficient data quality (29, 48).

In a recent systematic review and meta-analysis of randomized controlled trials in patients with type 2 diabetes, chromium supplementation (50-1,000 μg/day for 4 to 25 weeks) reduced concentrations of fasting plasma glucose (23 trials) and insulin (14 trials), and improved HbA1c values (18 trials) (49). These effects were not dose dependent (49). Yet, other meta-analyses in patients with type 2 diabetes did not find significant benefits of chromium supplementation on fasting glucose and insulin (50) or HbA1C (51). Moreover, a systematic review on 20 randomized controlled trials found that only a handful of chromium supplementation studies resulted in glycemic changes that are considered clinically meaningful, i.e., consistent with treatment goals of a 7.2-mmol/dL decrease in fasting glucose, a decrease of 0.5% in HbA1c, or reaching ≤7% HbA1c (52).   

Gestational diabetes

Few studies have examined the effects of chromium supplementation on gestational diabetes mellitus, a condition that is estimated to affect 5.8% to 9.2% of pregnant women in the US (53). The occurrence of gestational diabetes during pregnancy is associated with insufficient insulin secretion and glucose intolerance of variable severity (54). Peripheral insulin resistance usually increases in the second or third trimester of pregnancy. Because elevated maternal blood glucose concentrations can have adverse effects on the developing fetus, women with gestational diabetes are at increased risk of pregnancy complications (55). After delivery, impaired glucose tolerance generally reverts to normal glucose tolerance. However, nearly one-third of women who have had gestational diabetes develop postpartum glucose intolerance (prediabetes or type 2 diabetes) (56, 57). The question also arises as to whether low chromium levels might be an effect rather than a contributing factor in gestational diabetes.

An observational study in pregnant women did not find serum chromium levels to be associated with measures of glucose tolerance or insulin resistance in late pregnancy (58). However, it is not known whether measures of serum chromium levels truly reflect tissue chromium levels and chromium status during pregnancy. A more recent prospective study following 425 pregnant women also failed to find a correlation between serum chromium concentrations and incidence of gestational diabetes (59). A cross-sectional study of 90 pregnant women in southern India found that those with gestational diabetes had significantly lower serum chromium concentrations compared to gestational diabetes-free women. Given the above mixed results, it should be noted that different methods were used to measure circulating chromium concentrations in each study. Also, it is possible that nutritional chromium status may vary among ethnically distinct populations so that studies including pregnant women from different ethnic backgrounds and/or geographical areas would give different results.

In addition, there is currently insufficient evidence to evaluate the effect of supplemental chromium on gestational diabetes. Women with gestational diabetes whose diets were supplemented with 4 μg of chromium per kilogram of body weight daily as chromium picolinate for eight weeks had decreased fasting blood glucose and insulin concentrations compared to those who took a placebo. Yet, insulin therapy rather than chromium picolinate was required to normalize severely elevated blood glucose levels (6, 60).

Metabolic syndrome

Metabolic syndrome is a combination of medical conditions, including hypertension, dyslipidemia, central obesity, and insulin resistance, that places one at increased risk for cardiovascular disease and type 2 diabetes mellitus (see the page: Metabolic Syndrome). A prospective cohort study that followed 3,648 young US adults for 23 years found an inverse association between toenail chromium concentration measured at baseline and risk of developing metabolic syndrome (61). An inverse association between plasma chromium concentration and metabolic syndrome was also observed in a case-control study in 4,282 Chinese adults (62). However, low toenail and plasma chromium may be the result of metabolic syndrome, rather than suggesting a cause or contributing factor.

Only a few randomized controlled trials have examined whether chromium supplementation might benefit patients with metabolic syndrome. In a randomized, double-blind, placebo-controlled trial in 65 patients with metabolic syndrome, 300 μg/day of supplemental chromium (from chromium-enriched yeast) for 24 weeks had no effect on measured parameters of glucose, insulin, and lipid metabolism (63). While large-scale trials would be needed, there is presently no evidence that chromium can help treat metabolic syndrome.

Polycystic ovary syndrome

Polycystic ovary syndrome (PCOS) is a common endocrine disorder affecting women of childbearing age, with an estimated worldwide prevalence of 21% (64). The disorder has a multifactorial etiology and is characterized by menstrual irregularities, polycystic ovaries, and infertility. Similar to metabolic syndrome, women with PCOS often have various metabolic abnormalities, including dyslipidemia, obesity (especially abdominal obesity), impaired glucose tolerance, insulin resistance, and are at increased risk for developing type 2 diabetes mellitus (65).

Several randomized controlled trials have evaluated whether chromium supplementation might help treat PCOS, but the results are conflicting. A 2017 systematic review and meta-analysis of seven clinical trials found that chromium picolinate supplementation (of either 200 μg/day or 1,000 ug/day) for 8 to 24 weeks decreased BMI (3 studies), lowered free testosterone concentration (5 studies), and decreased fasting serum insulin concentration (5 studies) but had no effect on concentrations of fasting blood glucose (4 studies), total testosterone (3 studies), luteinizing hormone (3 studies), or follicle-stimulating hormone (2 studies) (66). However, other recent systematic reviews and meta-analyses have concluded that chromium supplementation in women with PCOS does not result in significant or clinically meaningful health benefits, including with respect to glucose and insulin metabolism (67-69).


Food sources

The amount of chromium in food is variable and has been measured accurately in relatively few foods. Presently, there is no large database for the chromium content of food. Whole-grain products, high-bran cereals, green beans, broccoli, nuts, and egg yolk are good sources of chromium. Processed meats may also be high in chromium, depending on the processing equipment and method (70). Foods high in simple sugars, such as sucrose and fructose, are usually low in chromium and may actually promote chromium excretion (6, 71). Estimated average chromium intakes in the US range from 23 μg/day-29 μg/day for adult women and 39-54 μg/day for adult men (5). The chromium content of some foods is listed in Table 2 and expressed in micrograms (μg) (72). Since chromium content varies significantly between different batches of the same food, the information provided in the table should serve only as a guide to the chromium content of food.

Table 2. Some Food Sources of Chromium
Food Serving Chromium (μg)
Broccoli ½ cup 11.0
Green beans ½ cup 1.1
Potatoes (mashed) 1 cup 2.7
Grape juice 8 fl. ounces 7.5
Orange juice 8 fl. ounces 2.2
Beef 3 ounces 2.0
Turkey breast 3 ounces 1.7
Turkey ham (processed) 3 ounces 10.4
Waffle 1 (~2.5 ounces) 6.7
Bagel 1 2.5
English muffin 1 3.6
Apple w/ peel 1 medium 1.4
Banana 1 medium 1.0 


Trivalent chromium is available as a supplement in several forms, including chromium chloride, chromium nicotinate, chromium picolinate, and high-chromium yeast. These are available as stand-alone supplements or in combination products, including multivitamin/mineral supplements. Doses typically range from 100 to 300 μg of elemental chromium in single-nutrient supplements and from 10 to 180 μg in multivitamin/mineral supplements (73).

Much of the research on impaired glucose tolerance and type 2 diabetes mellitus uses chromium picolinate as the source of chromium, although investigations suggest that its bioavailability may not be greater than that of dietary chromium (74). Some concerns have been raised over the long-term safety of chromium picolinate supplementation (see Safety).



Hexavalent chromium (chromium VI; Cr6+) is a recognized carcinogen, with inhalation causing lung, nasal, and sinus cancers (75). Exposure to hexavalent chromium in dust has been associated with an increased incidence of lung cancer and is known to cause inflammation of the skin (dermatitis).

In contrast, there is little evidence that trivalent chromium (chromium III; Cr3+) is toxic to humans. The toxicity from oral intakes is considered to be low because ingested chromium is poorly absorbed, and most absorbed chromium is rapidly excreted in the urine (76). Because no adverse effects have been convincingly associated with excess intake of trivalent chromium from food or supplements, the Food and Nutrition Board (FNB) of the Institute of Medicine (now the National Academy of Medicine) did not set a tolerable upper intake level (UL) for chromium. Yet, despite limited evidence for adverse effects, the FNB acknowledged the possibility of a negative impact of high oral intakes of supplemental trivalent chromium on health and advised caution (5).

Chromium picolinate

Most of the concerns regarding the long-term safety of trivalent chromium supplementation arise from several studies in cell culture, suggesting trivalent chromium, especially in the form of chromium picolinate, may increase DNA damage (77-80). A study in 10 women taking 400 μg/day of chromium as chromium picolinate found no evidence of increased oxidative damage to DNA as measured by antibodies to an oxidized DNA base (81).

Many studies have demonstrated the safety of daily doses of up to 1,000 μg of chromium for several months (46, 82). However, there have been a few isolated reports of serious adverse reactions to chromium picolinate. Kidney failure was reported five months after a six-week course of 600 μg/day of chromium in the form of chromium picolinate (83), while kidney failure and impaired liver function were reported after the use of 1,200 to 2,400 μg/day of chromium in the form of chromium picolinate over a period of four to five months (84). Additionally, a 24-year old healthy male reportedly developed reversible, acute renal failure after taking chromium picolinate-containing supplements for two weeks (85). Individuals with pre-existing kidney or liver disease may be at increased risk of adverse effects and should limit supplemental chromium intake (5).

Drug interactions

Little is known about drug interactions with chromium in humans. Large doses of calcium carbonate or magnesium hydroxide-containing antacids decreased chromium absorption in rats. In contrast, non-steroidal anti-inflammatory drugs, aspirin and indomethacin, can increase chromium absorption in rats (7).

Linus Pauling Institute Recommendation

The lack of any known indicators of chromium nutritional status in humans makes it difficult to determine the level of chromium intake most likely to promote optimum health, if such exists. Following the Linus Pauling Institute recommendation to take a multivitamin/mineral supplement containing 100% of the daily values (DV) of most nutrients may provide 10 to 180 μg/day of chromium, which is generally considered safe.

Older adults (>50 years)

Although the requirement for chromium is not known to be higher for older adults, one study found that chromium concentrations in hair, sweat, and urine decreased with age (86). Following the Linus Pauling Institute recommendation to take a multivitamin/mineral supplement containing 100% of the daily values (DV) of most nutrients should provide sufficient chromium for older adults.

Because impaired glucose tolerance, type 2 diabetes mellitus, and metabolic syndrome are associated with serious health problems, individuals with any of these conditions should seek medical advice if considering the use of high-dose chromium supplements.

Authors and Reviewers

Originally written in 2001 by:
Jane Higdon, Ph.D.
Linus Pauling Institute
Oregon State University

Updated in April 2003 by:
Jane Higdon, Ph.D.
Linus Pauling Institute
Oregon State University

Updated in June 2007 by:
Victoria J. Drake, Ph.D.
Linus Pauling Institute
Oregon State University

Updated in October 2014 by:
Barbara Delage, Ph.D.
Linus Pauling Institute
Oregon State University

Updated in November 2022 by:
Victoria J. Drake, Ph.D.
Linus Pauling Institute
Oregon State University

Reviewed in January 2023 by:
John B. Vincent, Ph.D.
Professor, Department of Chemistry
The University of Alabama
Tuscaloosa, Alabama

Copyright 2001-2023  Linus Pauling Institute


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  • Copper is an essential cofactor for oxidase enzymes that catalyze oxidation-reduction reactions in various metabolic pathways. These copper-dependent enzymes, or cuproenzymes, participate in, for example, energy (ATP) production, iron metabolism, connective tissue formation, and neurotransmission. (More information) 
  • Dietary copper insufficiency in humans has been infrequently described; however, copper depletion may occur due to intestinal defects, high supplemental zinc intake, or in genetic conditions such as Menkes disease. Intestinal copper absorption is severely impaired in Menkes disease, leading to systemic copper deficiency. Symptoms of low body copper include anemia, bone and connective tissue abnormalities, and neurological dysfunction. (More information)
  • Assessing copper status in humans is challenging, since no definitive biomarkers exist for detecting moderate, or subclinical, copper deficiency. The development of more precise and sensitive biomarkers of copper nutritional status is thus a critical area for future research. (More information)
  • Copper imbalance in humans increases risks of bone demineralization and osteoporosis, fatty liver disease, liver disease mortality, and cardiovascular and neurodegenerative diseases. In certain pathological states, dysregulation of copper homeostasis may not be a primary outcome but could rather be secondary to some aspect of disease pathogenesis(More information)
  • Accurately assessing dietary copper intake is difficult since the copper content of many foods has not been firmly established. Organ meats, shellfish, nuts, seeds, wheat-bran cereals, and whole-grain products are, however, recognized as good sources of dietary copper. (More information)
  • Copper toxicity is rare, being most frequently associated with Wilson disease, a rare inborn error of metabolism that causes copper overload initially in the liver and then subsequently in other tissues, particularly the brain. Toxic effects of copper overload in Wilson disease include disruption of lipid metabolism, as well as damage to mitochondria. Toxic copper accumulation is also observed in Indian Childhood Cirrhosis and Endemic Tyrolean Infantile Cirrhosis (or Idiopathic Copper Toxicosis). No causal genetic defects have been linked to these latter disorders, although increased susceptibility to excess copper has been proposed. (More information)

Copper (Cu) is an essential trace element for humans and other mammals. In biological systems, copper readily shifts between the cuprous (Cu1+) and cupric (Cu2+) forms. The redox properties of copper underlie its important role in oxidation-reduction reactions and in scavenging free radicals (1). Although Hippocrates is said to have prescribed copper compounds to treat diseases as early as 400 B.C. (2), scientists are still uncovering new information regarding the functions of copper in the human body (3)


Copper is critical for the function of several essential enzymes known as cuproenzymes, which are integral parts of various metabolic pathways (4, 5). Physiologic functions of these copper-dependent enzymes, and the biochemical pathways in which they function (6, 7), are outlined below. 

Energy production

The copper-dependent enzyme cytochrome c oxidase (CCO) plays a critical role in cellular energy production in mitochondria by catalyzing the reduction of molecular oxygen (O2) to water (H2O), thereby generating an electrical gradient that is required for ATP production (8). Redox-active copper contained within the CCO enzyme complex is required for the electron transfer reactions that are critical for its function.

Connective tissue formation

Another cuproenzyme, lysyl oxidase (LOX), is required for the cross-linking of collagen and elastin fibers, which is essential for the formation of strong and flexible connective tissue. LOX function is critical for bone formation and maintenance of connective tissue in the heart and blood vessels (2).

Iron metabolism

Multi-copper oxidases (MCOs) are copper-dependent ferroxidases that function in iron homeostasis. MCOs oxidize ferrous iron (Fe2+) to the ferric (Fe3+) form, which enables binding to transferrin (the main iron carrier) in the blood, thus allowing iron transport to sites of utilization (e.g., the bone marrow). The MCOs include: (1) ceruloplasmin (CP), which contains 60%-95% of plasma copper; (2) a membrane-bound form of CP (GPI-CP), expressed in brain and other tissues; and (3) the membrane-bound ferroxidases hephaestin (HEPH) and zyklopen, which function in the intestine and placenta, respectively (9, 10). CP knockout (Cp-/-) mice accumulate excess hepatic iron but have normal copper status (11, 12). Similarly, humans with aceruloplasminemia, who lack functional CP, display iron overload in liver, brain, and retina but have no observable defects in copper homeostasis (13). Moreover, absorption of dietary iron and iron mobilization from storage sites (e.g., liver) are impaired in copper deficiency, when CP and HEPH activity is reduced, further supporting a role for the MCOs in iron metabolism (14).

Central nervous system

Several physiological processes within the brain and nervous system, including neurotransmitter synthesis and formation and maintenance of myelin, depend upon catalysis mediated by cuproenzymes. Dopamine β-hydroxylase, for example, catalyzes the conversion of dopamine to the neurotransmitter norepinephrine (15). Also, CCO is required for the biosynthesis of phospholipids, which are critical structural components of the myelin sheath (2).

Melanin biosynthesis

The cuproenzyme tyrosinase (TYR) is required for the biosynthesis of melanin in melanocytes, which is critical for normal pigmentation of hair, skin, and eyes (2). Low TYR activity most likely explains the achromotrichia seen in copper-deficient laboratory and agricultural animals, and the depigmentation noted in severely copper-depleted patients with Menkes disease.


Superoxide dismutase (SOD) functions as an antioxidant by catalyzing the conversion of reactive oxygen species, such as the superoxide anion (O2-) and the hydroxyl radical (•OH), to hydrogen peroxide (H2O2), which is subsequently reduced to water by other antioxidant systems (16). Two forms of SOD contain copper: copper/zinc SOD (SOD1), which is expressed in most cells, including red blood cells; and extracellular SOD (EcSOD), which is highly expressed in the lungs and found at lower levels in plasma (2). Also, as outlined above, ceruloplasmin has antioxidant properties relating to iron metabolism. The ferroxidase activity of ceruloplasmin may prevent ferrous iron (Fe2+) from participating in harmful free-radical-generating reactions via Fenton chemistry (16).

Regulation of gene expression

Copper-related gene expression pathways seem to be mainly regulated at a post-translation level, in some cases via protein trafficking-related mechanisms that respond to intracellular copper levels (17). Cytosolic copper may also influence mRNA expression levels of specific genes, in a dose-dependent manner (18-20), implicating possible transcriptional regulation. For example, intracellular copper may alter the redox state of cells and thus induce oxidative stress, which can activate signal transduction pathways that increase the expression of genes encoding proteins involved in the detoxification of reactive oxygen species (21).

Nutrient interactions


Adequate copper nutritional status is necessary for normal iron metabolism and red blood cell production and function. Copper depletion results in an iron deficiency-like anemia, and iron accumulates in the livers of copper-deficient animals. The development of anemia during copper deficiency may be linked to low CP activity, impaired iron release from stores in the liver, and reduced iron delivery to the erythroid marrow, thus leading to iron-restricted erythropoiesis (see Iron metabolism) (2). However, this may not be the whole story, as was recently suggested by longtime copper researcher, Dr. Joseph R. Prohaska (Univ. of Minnesota, Duluth) (22). Copper depletion also reduces CP activity in humans, leading to hepatic iron overload and thus increasing risk for oxidative damage and liver cirrhosis (14). Oral copper supplementation restored normal serum CP levels and plasma ferroxidase activity, and corrected iron metabolism defects in a copper-deficient subject (23). Moreover, infants fed a formula with a high-iron content absorbed less copper than infants fed a low-iron formulation, suggesting that high iron intakes may interfere with copper absorption in infants (24). This observation was also confirmed in rats and mice, where high dietary iron caused copper depletion, thus increasing the copper nutritional requirement (25, 26).


Excess intake of supplemental zinc, at doses of 50 mg/day or more for extended periods of time, may result in copper depletion. The mechanism may relate to increased synthesis of metallothionein (MT), an intracellular zinc- and copper-binding protein. MT has a stronger affinity for copper than zinc, so high levels of MT induced by excess zinc may trap copper within enterocytes thus limiting its bioavailability. This postulate, however, was called into question by studies done in MT-deficient mice, in which high enteral zinc still decreased copper absorption, suggesting that high zinc may block a copper transporter (27). Conversely, elevated copper intakes have not been found to affect zinc nutritional status (2, 24). Moreover, zinc supplementation at 10 mg/day for eight weeks restored normal plasma copper/zinc ratios in 65 subjects on long-term hemodialysis who initially exhibited low serum zinc and high copper. Whether improving zinc and copper status of hemodialysis patients can impact clinical outcomes, however, needs to be assessed (28).


Evidence of copper-fructose interactions comes mainly from studies using experimental animals. High-fructose diets exacerbated copper deficiency in male rats, but not in pigs whose gastrointestinal system is anatomically and functionally more like humans. Also, very high levels of dietary fructose (20% of total calories) did not result in copper depletion in humans, suggesting that fructose intake does not result in copper depletion at levels relevant to normal diets (2, 24). However, high fructose consumption and low copper availability may be risk factors for functional copper deficiency in patients with non-alcoholic fatty liver disease (29).  

Vitamin C

Although vitamin C supplements have produced copper deficiency in guinea pigs (30), the effect of vitamin C supplementation on copper nutritional status in humans is less clear. Two small studies in healthy, young adult men indicated that ceruloplasmin oxidase activity may be impaired by relatively high doses of supplemental vitamin C. In one study, vitamin C intakes of 1,500 mg/day for two months resulted in a significant decline in CP oxidase activity (31). In the other study, supplements of 605 mg/day of vitamin C for three weeks resulted in decreased CP oxidase activity, although copper absorption did not decline (32). Neither of these studies found vitamin C supplementation to adversely affect copper nutritional status.


Clinically evident, or frank, dietary copper deficiency is relatively uncommon. Serum copper and CP levels may fall to 30% of normal in cases of severe copper deficiency. Hypocupremia is also observed in genetic disorders of copper metabolism, including Wilson disease (WD) and aceruloplasminemia; however, neither disorder has been linked to low dietary copper intake. One of the most common clinical signs of copper deficiency is an anemia that is unresponsive to iron therapy but is corrected by copper supplementation. It was hypothesized that this anemia could result from defective iron mobilization due to decreased CP activity, yet individuals with inherited aceruloplasminemia do not always develop overt anemia (33). Moreover, in copper-deficient swine, intestinal iron absorption is impaired but iron distribution among tissues/organs is normal (34-36). Low serum iron from reduced absorption is an unlikely cause of this anemia since intravenous provision of iron did not correct it. An alternative postulate is that copper-deficiency anemia is caused principally by impaired hemoglobin production and red blood cell proliferation, and a shortened erythrocyte lifespan. These physiological processes are thus likely to require copper. Copper deficiency may also lead to neutropenia, which can increase susceptibility to infection. Copper depletion studies demonstrated that low copper might affect erythroid and myeloid cell lineages, supporting a role for copper in the regulation of blood cell proliferation and maturation (37, 38). More research is clearly needed to further define the mechanisms underlying copper deficiency-induced anemia and neutropenia (4, 39). Furthermore, osteoporosis and other abnormalities of bone development have been described in copper-deficient, low-birth-weight infants and young children. Less common features of copper deficiency may include impaired growth, depigmentation, and development of neurological pathologies (2, 8)

Biomarkers of copper status

Currently, there is not a sensitive and specific biomarker to detect copper inadequacy in humans (5, 40-42). Blood copper (43) and ceruloplasmin concentrations are reduced in severe copper deficiency (3, 6). However, both of these parameters are also influenced by pregnancy, inflammation, and infection (5), thus limiting the usefulness of these assays to estimate body copper status. Experimental work has recently identified other copper-related biomarkers, including erythrocyte copper Cu/Zn superoxide dismutase (SOD1) and copper chaperone for superoxide dismutase (44-46), but further experimental validation is required, including clinical testing in humans.  

Individuals at risk of deficiency

Bovine milk is relatively low in copper, and cases of copper deficiency have been reported in infants fed only cow's milk formula (47). Other individuals at elevated risk for copper deficiency include premature and low-birth-weight infants; individuals with severe burns (48) or prolonged diarrhea, which accelerate copper losses; infants and children recovering from malnutrition; and individuals with malabsorption syndromes, including celiac disease, Crohn’s disease, and short bowel syndrome, possibly due to surgical removal of large portions of the intestine (48-50). Also, gastric bypass surgery for morbid obesity significantly increases the risk for copper depletion (51-53). Individuals receiving intravenous total parenteral nutrition lacking copper or those on certain restricted diets may also require supplementation with copper (and other trace elements) (2, 8). Moreover, copper deficiency in infants with cholestasis has been linked to long-term parenteral nutrition lacking copper (54). Case reports indicated that cystic fibrosis patients may also be at increased risk of copper insufficiency (55, 56). And finally, excessive zinc intake has been associated with secondary copper deficiency in individuals taking zinc supplements or using zinc-enriched dental creams (57-59).

Acquired copper deficiency

Copper deficiency is atypical in the general population; however, it was recently suggested that copper deficiency may be more widespread than currently recognized, and that (covert) pathophysiological links exist between low copper nutritional status and Alzheimer’s disease, ischemic heart disease (60), myelodysplastic syndrome, and postmenopausal osteoporosis (61). Part of the rationale for such an assertion relates to the difficulty in clinically evaluating the copper status of humans, so moderate to even severe copper deficiency is unlikely to be detected in individuals with no notable risk factors (62). Firmly establishing links between low copper status and increased risk for these, and possibly other, chronic diseases awaits further epidemiological and clinical testing. Furthermore, a neurological syndrome associated with copper deficiency was recently described in adults (63). The symptoms included central nervous system demyelination, polyneuropathy, myelopathy, and inflammation of the optic nerve. The etiology is unknown and risk factors have not been established (see Individuals at risk of deficiency). Case reports suggested that copper malabsorption underlies this disorder, but mutations in the gene encoding the main intestinal copper exporter, ATP7A, were not detected in affected patients (see Inherited copper deficiency) (64). Oral copper supplementation (2 mg/day) normalized serum copper and CP concentrations, and stabilized individuals afflicted with the disease and significantly improved their quality of life. Optimal duration and dose of copper administration has not, however, been experimentally evaluated (63).

Inherited copper deficiency

ATPase copper transporting alpha, or ATP7A, is a dual function Cu1+-transporting ATPase that is expressed in most cell types, except for, notably, hepatocytes. ATP7A transports copper from the cytosol into the trans-Golgi (TGN), where cuproenzymes are synthesized within the secretory pathway, and exports copper from cells. Mutations in ATP7A, which underlie Menkes disease (MD), critically block copper export from enterocytes and vascular endothelial cells (65). Impaired absorption of dietary copper results in systemic copper deficiency in MD. Decreased cuproenzyme expression/activity is caused by low intracellular copper, and defective copper transport into the TGN. Copper accumulation in microvascular endothelial cells in the blood-brain barrier reduces copper transport into the brain, leading to low brain copper and reduced cuproenzyme activity in neurons. Other mutations in ATP7A have been linked to a less severe neurological copper deficiency disorder called occipital horn syndrome (OHS). The clinical features of MD include intractable seizures, connective tissue disorders, subdural hemorrhage, and hair abnormalities (so called "kinky hair"). OHS patients exhibit muscular hypotonia and connective tissue abnormalities, including formation of exostoses on occipital bones. Subcutaneous injections of copper-histidine improve copper-related metabolic functions in MD and OHS patients. Copper entry into the brain, however, remains limited (reviewed in 66). Furthermore, gene therapy approaches have been recently validated in a pre-clinical mouse model of MD, with long-term goals of using such treatments in humans with the disease (67, 68). Recently, another inherited copper-deficiency disorder was described in identical twin male infants, who were homozygous for a novel missense variant in the gene encoding copper transporter 1 (CTR1) (69). This genetic aberration caused a distinctive autosomal recessive syndrome of infantile seizures and neurodegeneration, consistent with profound central nervous system copper deficiency. Disease pathology was most likely caused by defective intestinal copper transport which resulted in severe systemic copper deficiency. This outcome is supported by experimental laboratory studies which demonstrated that intestine-specific ablation (deletion) of CTR1 significantly impaired absorption of dietary copper in mice (70).   

Copper Excess

Inherited copper overload

Patients with Wilson disease (WD) may have increased risk for copper toxicosis even at copper intakes in the normal range. WD is an autosomal recessive disorder that is typified by defective copper distribution and storage (71). The disease is caused by mutations in the ATP7B gene, which encodes a copper-transporting ATPase that is highly expressed in liver and brain. Dysfunctional ATP7B disrupts copper flux in these organs. A recent review provides a nice summary of this devastating human disease (72). WD prevalence is ~1:30,000 individuals globally (73), although much higher prevalence rates have been reported. It was suggested that differences in the penetrance of disease-causing genetic variants explain the apparent discrepancy between epidemiological and genetic prevalence studies of WD (74).

In WD, redox-active copper accumulates in liver, brain, and cornea due to impaired ATP7B-mediated copper excretion, which increases oxidative stress leading to eventual tissue and organ damage. Untreated WD patients are likely to develop liver damage, cancer, and eventual hepatic failure, and severe hemolytic crisis. Elevated brain copper content can lead to neurological damage, and copper accumulation in the eye in so-called Kayser-Fleisher rings can result in abnormal eye movements. Blood concentrations of ceruloplasmin are characteristically low in WD patients, since hepatic ATP7B is required for its biosynthesis, and urinary copper losses may be enhanced. Early intervention can prevent development of some of the most severe pathophysiological outcomes. Treatments for WD include zinc supplementation, which attenuates enteral copper absorption, and/or copper chelation therapy with penicillamine or trientine (75).

Other genetic copper-overload disorders

Additional pathologies associated with liver copper loading include Indian childhood cirrhosis (ICC) and idiopathic copper toxicosis (ICT). In ICC, notable liver copper loading and progressive liver failure are observed (76). In contrast to Wilson disease when ceruloplasmin is low, in ICC, ceruloplasmin is normal or elevated. ICC is most likely caused by inadvertent excess copper ingestion, possibly from the use of copper-lined, food/beverage storage containers in a genetically susceptible individual. It seems likely that the unknown genetic defect in ICC relates to the efficiency of excretion of excess copper in the bile, but this has not been definitively established. Also, about one-third of ICC patients have α-1-antitrypsin deficiency, which calls into question a primary role for copper in disease outcomes (77). ICT is another hepatic copper overload disorder that predominantly afflicts infants and children. ICT displays autosomal recessive inheritance, and an unidentified genetic aberration results in defective copper metabolism leading to an increased susceptibility to excess copper. Affected individuals are at increased risk for copper-related, hepatic toxicosis due to inadvertent consumption of excess copper. However, the source of extra copper remains unidentified in many ICT patients, perhaps suggesting a more complex disease pathogenesis (78).

The Recommended Dietary Allowance (RDA)

A variety of bioindicators were used to establish the RDA for copper, including plasma copper concentration, serum ceruloplasmin activity, superoxide dismutase activity in red blood cells, and platelet copper concentration (24). However, whether these are accurate and sensitive biomarkers of copper nutritional status uncertain (40). Also, estimates of copper concentrations in various foods and water sources may not be accurate and reliable (40, 62). The RDA for copper reflects the results of depletion-repletion studies and is based on the prevention of deficiency (Table 1). For infants up to one year of age, an adequate intake (AI) was established due to the lack of experimental evidence to set a requirement.

Table 1. Recommended Dietary Allowance (RDA) for Copper
Life Stage Age Range Males (μg/day) Females (μg/day)
Infants  0-6 months 200 (AI) 200 (AI)
Infants  7-12 months  220 (AI) 220 (AI)
Children  1-3 years  340 340
Children  4-8 years  440 440
Children  9-13 years  700 700
Adolescents  14-18 years  890 890
Adults  ≥19 years 900 900
Pregnancy  all ages   - 1,000
Breast-feeding  all ages   -  1,300

Disease Prevention

Cardiovascular disease

Severe copper deficiency results in cardiomyopathy in some animal species (79); however, this pathology differs from the atherosclerotic cardiovascular disease that is prevalent in humans (24). Outcomes of cardiovascular disease (CVD)-related clinical studies in humans are inconsistent, possibly since the copper status of participants is uncertain given the lack of reliable biomarkers of copper nutritional status. Ionic copper is a pro-oxidant, and it can oxidize low-density lipoprotein (LDL) in the test tube. CP can also stimulate LDL oxidation in the laboratory setting (80). As such, some researchers have proposed that excess copper could increase the risk for developing atherosclerosis by promoting the oxidation of LDL in vivo. However, there is scant experimental evidence to support this possibility. Moreover, superoxide dismutase and ceruloplasmin have known antioxidant properties, leading some experts to propose that copper deficiency, rather than copper excess, increases the risk for cardiomyopathy (81, 82). Outcomes of observational and intervention studies relating copper nutritional status to relative risk for CVD are summarized below.  

Observational studies

Observational studies have linked elevated serum copper levels to an increased risk for developing CVD. For example, a prospective cohort study examined serum copper levels in more than 4,500 men and women 30 years of age and older in the United States (83). During the subsequent 16 years, 151 participants died from coronary heart disease (CHD). After adjusting for other risk factors, those with serum copper levels in the two highest quartiles had a significantly greater risk of dying from CHD. Case-control studies conducted in Europe also had similar outcomes. For example, a case-cohort study of 2,087 adults in Germany reported an association between higher serum copper concentrations and increased risk of incident CVD, including myocardial infarction and stroke (84). Another study in 60 patients with chronic heart failure or ischemic heart disease reported that serum copper was a predictor of short-term outcomes (85). Higher serum copper was also linked to an increased risk of heart failure in a prospective cohort study of 1,866 middle-aged and older men in Finland (86). Another prospective cohort study in 4,035 middle-aged men in France reported that high serum copper levels were significantly related to a 50% increase in all-cause mortality; however, serum copper was not significantly associated with CVD mortality in this study (87). Serum copper was also elevated in patients with rheumatic heart disease (88). In sum, these studies may indicate that high serum copper reflects elevated body copper content, which increases oxidative stress and accelerates tissue/organ damage and disease development. Importantly, however, most copper in the serum is contained within CP, up to 90% depending upon the species, with the remaining, smaller proportion of serum copper bound to albumin or α2-macroglobulin (89, 90). Serum CP is an acute-phase reactant protein, with levels increasing by up to 50% as a result of trauma or infection and during chronic inflammatory states. Changes in circulating CP are associated with proportional changes in serum copper levels, independent of body copper status. Therefore, elevated serum copper in CHD patients may simply reflect increased CP production due to the inflammation that typifies atherosclerosis. Collectively, these observations raise concerns about linking elevated serum copper to increased tissue copper content and chronic disease development in humans (91).

In contrast to the observational findings discussed above linking high serum copper levels to heart disease, two autopsy studies found copper levels in cardiac muscle were actually lower in patients who died of CHD than in those who died of other causes (92). Additionally, the copper content of white blood cells has been positively correlated with the degree of patency of coronary arteries in CHD patients (93, 94). Further, patients with a history of myocardial infarction (MI) had lower concentrations of copper-dependent, extracellular superoxide dismutase than those without a history of MI (95). Thus, due to the lack of specific, reliable biomarkers of copper nutritional status, it is not clear whether copper is related to cardiovascular disease. It is also important to note that altered copper metabolism may be symptomatic of a cardiovascular condition, rather than a factor that primarily influences its development.

Studies examining dietary intake of copper are scarce. In a prospective cohort study in Japan, which included 58,646 participants followed for a median of 19 years, dietary copper intake — measured by a food frequency questionnaire — was not associated with CHD mortality (96). Yet, this study associated higher copper intakes with an increased risk of mortality from stroke and other cardiovascular diseases (96).

Notably, it was suggested that elevated plasma copper concentrations could be linked to high circulating homocysteine levels in individuals with cardiovascular disease (97-99). Increased blood homocysteine may precipitate development of arterial wall lesions and increase risk of CVD (100); however, this matter is currently open to debate (101). In animal models, copper-homocysteine interactions were linked to impaired vascular endothelial function (102, 103). Copper restriction in experimental animals decreased homocysteine levels and reduced incidence of atherogenic lesions (104, 105), but it is not known whether copper imbalance contributes to a possible atherogenic effect of homocysteine in humans (106).

Intervention studies

Small studies in adults deprived of dietary copper documented adverse changes in blood cholesterol, including increased total and LDL cholesterol concentrations and decreased HDL cholesterol concentrations (107), but these outcomes were not confirmed in other studies (108). For example, in one recent study, copper supplementation of 2 to 3 mg/day for 4 to 8 weeks did not result in clinically significant changes in blood cholesterol levels (81, 109, 110). Additionally, 8 mg/day of copper for six months had no effect on blood cholesterol levels (111). Interpretation of these outcomes is, however, challenging since the copper status of participants was presumably not well defined. Additional research failed to link increased copper intake to elevated oxidative stress. In a multi-center, placebo-controlled clinical trial, copper supplementation of 3 or 6 mg/day for six weeks did not result in increased susceptibility of LDL to oxidation by copper (112). Moreover, supplementation with 3 or 6 mg/day of copper did not increase oxidative damage to red blood cells (113). Collectively, these studies indicated that copper intakes several times above the RDA do not increase oxidative stress, at least as measured by these assays in these populations.

Summary: Copper and cardiovascular disease

Although free copper and CP can promote LDL oxidation in the laboratory, there is little evidence that high dietary copper increases oxidative stress in the human body. Increased serum copper levels have been associated with increased CVD risk, as outlined above, but the significance of these findings is unclear due to the complex association among serum copper, CP, and inflammatory mediators. Clarification of the relationships of copper intake, copper nutritional status, CP levels, and CVD risk thus requires further research.

Immune system function

Copper is known to play several important roles in the development and maintenance of immune system function, including innate and adaptive immunity (reviewed in 114). Neutropenia is a clinical sign of copper deficiency in humans. Adverse effects of insufficient copper on immune system function appear most pronounced in infants. For example, infants with Menkes disease, a genetic copper-deficiency disorder, suffer from frequent and severe infections (115, 116). Moreover, in a study of 11 malnourished infants with evidence of copper deficiency, the ability of white blood cells to engulf pathogens increased significantly after one month of copper supplementation (117). Moreover, 11 men on a low-copper diet (0.66 mg/day of copper for 24 days and 0.38 mg/day for another 40 days) showed an impaired monocyte proliferative response in an ex vivo immune challenge assay (118). Mechanistic studies also support a role for copper in the innate immune response to bacterial and viral infections (reviewed in 119, 120). Severe copper deficiency thus has adverse effects on immune system function; however, whether marginal copper insufficiency impairs immunity in humans has not been established.


Progressive decrease of bone mineral density (BMD) is commonly observed in the elderly, frequently leading to development of osteopenia (pre-osteoporosis) and osteoporosis. Women are more often affected by osteoporosis than men, (e.g., prevalence ratio is 5:1 in non-Hispanic whites) (121), primarily due to the postmenopausal reduction in the production of estrogen, which is essential for maintaining strength of muscle, bone, and connective tissue (122). Osteoporosis is associated with an increased risk of falls, bone fracture, and mortality in individuals over 65 years of age (123).

Osteoporosis has been reported in infants with severe copper deficiency (124, 125), but how copper depletion affects bone and connective tissue health in adults is less certain. One recent investigation documented bone resorption (breakdown) in 11 healthy adult males consuming marginal copper for six weeks (0.7 mg/day) (126). Also, supplementation of 3 to 6 mg/day of copper for six weeks had no effect on biochemical markers of bone resorption or bone formation in two studies of healthy adult men and women (127, 128). An effect of copper deficiency on bone integrity seems likely, since a copper-dependent enzyme, lysyl oxidase (LOX), is required for the maturation (cross-linking) of collagen, a key element in the organic matrix of bone. In individuals with marginal copper intake and less efficient copper absorption, such as the elderly, it seems plausible that LOX activity is decreased, possibly increasing risk for bone and connective tissue effects.  

Observational studies

Collectively, research examining the role of copper nutritional status in age-related osteoporosis is limited. An early study found that serum copper levels in 46 elderly patients with hip fractures were significantly lower than those of age-matched controls (129). Another study, however, found no differences in serum copper levels among postmenopausal women with normal BMD (N=40), osteopenia (N=40), or osteoporosis (N=40) (130). A cross-sectional study showed that blood copper concentrations were lower than the normal reference range in postmenopausal women with osteopenia (N=28) and osteoporosis (N=23) (131). In another cross-sectional study in 728 postmenopausal women, 491 of which had confirmed osteoporosis, lower serum copper concentrations were associated with osteoporosis in the younger women (ages 40-59 years) but not the older women (ages 60-80 years) (132). Furthermore, in a national survey in the US, including 8,224 adults (compiling data from NHANES 2007-2010, 2013-2014, and 2017-2018), higher daily copper intakes (from diet and supplements) were associated with higher BMD at the femur and lumbar spine and a lower risk of osteoporosis (133).

Intervention studies

Limited studies of copper supplementation and bone health outcomes have been undertaken. A small study in perimenopausal women, who consumed ~1 mg of dietary copper daily, reported decreased loss of BMD from the lumbar spine after copper supplementation of 3 mg/day for two years (134). Additionally, a two-year, double-blind, placebo-controlled trial in 59 postmenopausal women found that daily intake of supplemental calcium plus trace minerals, including 2.5 mg of copper, resulted in maintenance of spinal BMD.  Supplemental calcium or trace minerals, alone, were not as effective at preventing loss of bone density (135). Another randomized, double-blind, placebo-controlled study in 224 healthy, postmenopausal women ages 51 to 80 years, found daily supplementation with 600 mg of calcium, 2 mg of copper, and 12 mg of zinc for two years decreased whole-body BMD compared to supplemental calcium alone. Another trial showed that BMD was reduced in subjects with dietary copper intakes below the RDA (0.9 mg/day), but copper supplementation did not prevent the progressive loss of BMD as well as a calcium regimen alone (136). Finally, several studies have suggested that tooth loss might be related to defects in the maintenance of BMD (137, 138). When compared with 20 healthy-matched controls, 50 patients (mean age, 47.5 years) with low spinal BMD and advanced tooth wear were found to have significantly lower copper content in tooth enamel. However, despite evidence of bone demineralization, serum copper levels in this population were similar to those of the healthy group (139). In sum, additional research is required to draw meaningful conclusions regarding the effects of marginal copper depletion and copper supplementation on bone metabolism and risk for developing age-related osteoporosis.

Neurodegenerative diseases

Alzheimer's disease

Cognitive deterioration in individuals with Alzheimer’s disease (AD) is linked to the presence of β-amyloid plaques and abnormal Tau protein-forming aggregates. The possibility that copper imbalance is involved in the onset of AD is under investigation. A recent meta-analysis of case-control studies described higher blood concentrations of copper in AD patients (N=2,929) as compared to healthy subjects (N=3,547), from a total of 46 studies reviewed (140). Also, ‘free’ serum copper (i.e., not bound to CP) was higher in AD patients (N=1,595) than in healthy control subjects (N=2,399), representing 18 total studies. These observations were confirmed in another recent review of published studies (141). An additional meta-analysis of 12 case-control studies revealed AD patients had lower copper concentrations in various brain regions compared to healthy controls (142), further exemplifying dysregulation of copper homeostasis in Alzheimer’s disease.

Among the many hypotheses supporting a role for copper in AD onset or progression includes copper involvement in the formation of senile plaques through hypermetallation of the β-amyloid peptides, possibly leading to zinc depletion, enhanced oxidative stress, and brain damage (143-145). Recent research has also identified polymorphisms in the ATP7B gene that may be associated with the risk of developing copper imbalance and AD (140, 142). ATP7B is a copper-transporting ATPase expressed in the liver and brain. Impairment of ATP7B function causes Wilson disease, which is typified by elevated ‘free’ copper level in blood and copper accumulation in liver and brain.

Additional research is required to determine whether genetic variation could influence individual susceptibility to environmental exposure of high copper levels. Copper administered in drinking water was associated with development of enhanced pathological features in animal models of AD (146, 147). One study in a rabbit model reported that combining a high-cholesterol diet and copper (0.12 mg/L in drinking water) impaired cognition (146). A prospective cohort study in 3,718 elderly participants in the Chicago Health and Aging Project, followed for 5.5 years, evaluated the impact of fat and copper intakes using food frequency questionnaires on cognitive function. For individuals with high intakes of saturated and trans fat, cognitive decline was greater for those in the highest quintile of total copper intake compared to the lowest quintile (median intake of 2.75 vs. 0.88 mg copper per day) (148).

Although dysfunctional copper metabolism is suggested as a risk factor for AD, it could also be symptomatic of the disease, rather than causative. Moreover, it is still unclear whether copper supplementation or restriction could delay the progression of AD. A small, double-blind, placebo-controlled trial in 68 individuals with mild AD found that supplementation of 8 mg/day of copper for one year delayed the decrease of the β-amyloid peptide Aβ42 in cerebrospinal fluid; a decrease in Aβ42 has been linked to cognitive deterioration (149). This delay, however, was not associated with improved cognitive performance (150). Relating to the use of zinc supplementation to block copper absorption in Wilson disease, slow-release zinc acetate administration (150 mg/day for six months) in a randomized, placebo-controlled study of 60 patients with mild-to-moderate AD resulted in a decrease in serum ‘free’ copper and stabilization of cognition deficits (143). A specific role for copper was not, however, determined in these notable outcomes. In summary, additional human studies are needed to clarify the role of copper in AD prevention, development, and progression.

Parkinson's disease

Neurologically presenting Wilson disease and inherited aceruloplasminemia are characterized by copper accumulation in the brain and development of neurological symptoms, including dystonia and cognitive impairment, that resemble Parkinson’s disease (PD) (151). Disruption of copper homeostasis has been documented in PD (152). Copper depletion occurs in brain regions with loss of neurons in PD patients (153, 154). Moreover, some studies have documented lower serum copper and/or CP concentrations in PD patients compared to healthy controls (155-157). Dietary copper intake did not, however, relate to the risk of developing PD in two small case-control studies (158, 159). As in AD, further research is required to elucidate whether copper imbalance contributes to the pathogenesis of PD.

Nonalcoholic fatty liver disease

Similar to findings from animal models (160), human studies have documented low circulating copper (161, 162) or low hepatic copper content (161, 163, 164) in adults and children with nonalcoholic fatty liver disease. An inverse association between hepatic copper content and liver disease severity has also been observed (163, 165). However, it is not known whether low dietary intake of copper might be a contributor to disease pathogenesis or whether dysregulated copper metabolism is only a manifestation of liver disease.


Food sources

Copper is found in a wide variety of foods and is most plentiful in organ meats, shellfish, nuts, and seeds. Wheat-bran cereals and whole-grain products are also good sources of copper. According to national surveys (NHANES), the mean dietary intake of copper in the US is 1.1 mg/day for adult women and 1.3 mg/day for adult men (166), levels that exceed the established RDA for copper for adults of 900 µg/day (see Table 1). The estimated copper content of some foods that are relatively rich in copper is listed in Table 2. For more information on the nutrient content of foods, search USDA's FoodData Central.

Table 2. Some Food Sources of Copper
Food Serving Copper (μg)
Beef liver 1 ounce 4,133
Oysters 6 medium sized 2,400
Alaska king crab meat 3 ounces 1,000
Blue crab meat 3 ounces 692
Cashews  1 ounce 624
Clams 3 ounces 585
Sunflower seed kernels 1 ounce 519
Hazelnuts 1 ounce 496
Almonds 1 ounce 292
Lentils ½ cup 249
Mushrooms, white 1 cup 223
Chocolate, semisweet 1 ounce 198
Peanut butter 2 tablespoons 185
Shredded wheat cereal 2 biscuits 179


Identification of those at risk for copper depletion is challenging since sensitive and specific, copper nutrition-related bioindicators have yet to be identified. Nonetheless, a range of copper supplements are available for purchase, including cupric oxide, copper gluconate, copper sulfate, and copper amino acid chelates (167). The relative bioavailability of these different chemical forms of copper, however, has not yet been established in humans (168). Copper supplements may contain a few µg up to 15 mg of elemental copper, which exceeds the UL for copper by 1.5 fold (169). Moreover, copper is typically included in multivitamin/mineral supplements (169) and added to fortified breakfast cereals. Supplementation of adults with 10 mg/day of cupric gluconate for 12 weeks did not cause copper toxicity (170). Importantly, however, higher copper intakes could be detrimental in some at-risk (unknown) individuals. Copper supplementation of infants should be approached with caution since homeostatic regulators of copper absorption and excretion are not fully developed, thus increasing the potential for copper toxicosis. From a clinical perspective, copper overload most frequently presents in biliary atresia, biliary cirrhosis and in WD patients, and as such, individuals suffering from these conditions should avoid taking supplemental copper.



Copper toxicity is rare in the general population. Acute copper poisoning has occurred by storing beverages in copper-containing containers, as well as from contaminated water supplies (171). Guideline values for copper in drinking water have been set by the US Environmental Protection Agency (1.3 mg/liter) and by the World Health Organization (2 mg/liter) (172). Symptoms of acute copper toxicity include abdominal pain, nausea, vomiting, and diarrhea; such symptoms help prevent additional ingestion and absorption of copper. More serious signs of acute copper toxicity include severe liver damage, kidney failure, coma, and death.

Of more concern from a nutritional standpoint is the possibility of liver damage resulting from long-term exposure to lower doses of copper. In generally healthy individuals, daily doses of up to 10,000 μg (10 mg) have not resulted in liver damage. The US Food and Nutrition Board has thus set the tolerable upper intake level (UL) in adults at 10 mg/day of copper from food and supplements combined (Table 3) (24). It should be noted that individuals with genetic disorders affecting copper metabolism (e.g., Wilson disease, Indian childhood cirrhosis, and idiopathic copper toxicosis) may be at risk for adverse effects of chronic copper toxicity at significantly lower intake levels. There is some concern that the UL of 10 mg/day might be too high. For example, one study in adult men who consumed 7.8 mg/day of copper for 147 days showed that they loaded excess copper during that time, and some indices of immune function and antioxidant status suggested that these functions were adversely affected by the high intakes of copper (173, 174). However, another study did not report any adverse effects in individuals supplemented with 8 mg/day of copper for six months (150).

Table 3. Tolerable Upper Intake Level (UL) for Copper
Life Stage (age range) UL (μg/day)
Infants (0-12 months)* Not established 
Children (1-3 years) 1,000 
Children (4-8 years)   3,000 
Children (9-13 years)   5,000 
Adolescents (14-18 years) 8,000 
Adults (≥19 years) 10,000
*Source of intake should be from food and formula only.

Drug interactions

Relatively little is known about the interaction of copper with drugs. Penicillamine is used to bind copper and enhance its elimination in Wilson disease, a genetic disorder resulting in hepatic copper overload. Because penicillamine dramatically increases the urinary excretion of copper, individuals taking the medication for reasons other than copper overload may have an increased dietary copper requirement. Additionally, antacids may interfere with copper absorption when used in very high amounts (2). Also, the anti-tuberculosis drug ethambutol may chelate copper in mitochondria and reduce cytochrome c oxidase activity specifically in optic nerve axons, possibly contributing to optic neuropathy which is a documented side-effect of this drug (175).

Linus Pauling Institute Recommendation

The RDA for copper (900 μg/day for adults) is sufficient to prevent deficiency, but the lack of clear biomarkers of copper nutritional status in humans makes it difficult to determine the level of copper intake most likely to promote optimum health or prevent chronic disease. A varied diet should provide enough copper for most people. For those who are concerned that their diet may not provide adequate copper, a multivitamin/mineral supplement will generally provide at least the RDA for copper.

Older adults (>50 years)

Because aging has not been associated with significant changes in the requirement for copper, our recommendation for older adults is the same as that for adults 50 and younger (176).

Authors and Reviewers

Originally written in 2001 by:
Jane Higdon, Ph.D.
Linus Pauling Institute
Oregon State University

Updated in April 2003 by:
Jane Higdon, Ph.D.
Linus Pauling Institute
Oregon State University

Updated in January 2008 by:
Victoria J. Drake, Ph.D.
Linus Pauling Institute
Oregon State University

Updated in December 2013 by:
Barbara Delage, Ph.D.
Linus Pauling Institute
Oregon State University

Updated in October 2022 by:
Victoria J. Drake, Ph.D.
Linus Pauling Institute
Oregon State University

Reviewed and updated in July 2023 by:
James F. Collins, Ph.D.
Food Science & Human Nutrition department
University of Florida

Reviewed in July 2023 by:
Jason Burkhead, Ph.D.
Biological Sciences department
University of Alaska, Anchorage

Copyright 2001-2023  Linus Pauling Institute


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  • Fluoride is the ionic form of the naturally occurring fluorine element. The anion increases the structural stability of teeth and bones through interactions with calcium phosphates. (More information)
  • The daily intake recommendations for fluoride are based on the safest and most effective intakes to prevent dental caries. (More information)
  • The use of fluoridated dental products and adequate intakes of fluoride reduce the occurrence of caries throughout life by promoting tooth mineralization and re-mineralization. Large randomized, placebo-controlled studies are needed to evaluate whether the topical application of fluoridated agents could also prevent dental erosion. (More information)
  • Epidemiological and clinical evidence is currently limited to support a role for water fluoridation in the prevention of osteoporosis and bone fracture. (More information)
  • Therapeutic trials have found a dose-dependent effect of fluoride on fracture risk in osteoporotic patients. However, the occurrence of numerous side effects warrants additional studies to guarantee that safe and effective doses can be used alone or in combination with current therapies. (More information)
  • The major sources of systemic and topical fluoride are drinking water, foods and beverages made with fluoridated water, infant formulas, and fluoride-containing oral care products. Fluoridated salt and milk are currently available outside the US in Europe, Latin America, and Southeast Asia. (More information)
  • While increased exposure to fluoride has led to a decline in dental caries, the prevalence of white speckling or mottling of the permanent teeth, known as dental fluorosis, has increased. Bone tissue homeostasis may also be affected by excess fluoride intake. (More information)

Fluorine occurs naturally as the negatively charged ion, fluoride (F-). Fluoride is considered a trace element because only small amounts are present in the body (about 2.6 grams in adults), and because the daily requirement for maintaining dental health is only a few milligrams a day. About 95% of the total body fluoride is found in bones and teeth (1). Although its role in the prevention of dental caries (tooth decay) is well established, fluoride is not generally considered an essential mineral element because humans do not require it for growth or to sustain life (2). However, if one considers the prevention of chronic disease (dental caries) an important criterion in determining essentiality, then fluoride might well be considered an essential trace element (3)


Fluoride is absorbed in the stomach and small intestine. Once in the bloodstream it rapidly enters mineralized tissue (bones and developing teeth). At usual intake levels, fluoride does not accumulate in soft tissue. The predominant mineral elements in bone are crystals of calcium and phosphate, known as hydroxyapatite crystals. Fluoride's high chemical reactivity and small radius allow it to either displace the larger hydroxyl (-OH) ion in the hydroxyapatite crystal, forming fluoroapatite, or to increase crystal density by entering spaces within the hydroxyapatite crystal. Fluoroapatite hardens tooth enamel and stabilizes bone mineral (4).

Nutrient interactions

Both calcium and magnesium form insoluble complexes with fluoride and are capable of significantly decreasing fluoride absorption when present in the same meal. However, the absorption of fluoride in the form of monofluorophosphate (unlike sodium fluoride) is unaffected by calcium. Also, a diet low in chloride (salt) has been found to increase fluoride retention by reducing urinary excretion of fluoride (1).


In humans, the only clear effect of inadequate fluoride intake is an increased risk of dental caries (tooth decay) for individuals of all ages. Epidemiological investigations of patterns of water consumption and the prevalence of dental caries across various US regions with different water fluoride concentrations led to the development of a recommended optimum range of fluoride concentration of 0.7-1.2 milligrams/liter (mg/L) or parts per million (ppm); the lower concentration was recommended for warmer climates where water consumption is higher, and the higher concentration was recommended for colder climates. In 2015, the US Department of Health and Human Services recommended that all community water systems adjust the fluoride concentration to 0.7 mg/L, as more recent studies did find a relationship between water intake and outdoor air temperature. This recommendation was made in an effort to reduce the risk of dental fluorosis (see below) and in light of the widespread availability of fluoride from other sources, including fluoride-containing oral-care products (5). A number of studies conducted prior to the introduction of fluoride-containing toothpastes demonstrated that the prevalence of dental caries was 40% to 60% lower in communities with optimal water fluoride concentrations than in communities with low water fluoride concentrations (6).

The Adequate Intake (AI)

The Food and Nutrition Board (FNB) of the US Institute of Medicine updated its recommendations for fluoride intake in 1997. Because data were insufficient to establish a Recommended Dietary Allowance (RDA), Adequate Intake (AI) levels were set based on estimated intakes that have been shown to reduce the occurrence of dental caries most effectively without causing the unwanted side effect of tooth enamel mottling known as dental fluorosis (0.05 mg/kg of body weight) (Table 16). See the section below on Safety for a discussion of dental fluorosis.

Table 1. Adequate Intake (AI) for Fluoride
Life Stage Age Males (mg/day) Females (mg/day)
Infants  0-6 months 0.01 0.01
Infants  7-12 months  0.5 0.5
Children  1-3 years  0.7 0.7
Children  4-8 years  1.0 1.0
Children  9-13 years  2.0 2.0
Adolescents  14-18 years  3.0 3.0
Adults  19 years and older 4.0 3.0
Pregnancy  all ages  - 3.0
Breast-feeding  all ages  - 3.0

Disease Prevention

Dental caries (cavities and tooth decay)

Specific cariogenic (cavity-causing) bacteria (mainly Streptococcus mutans and Streptococcus sobrinus) found in dental plaque are capable of metabolizing fermentable carbohydrates (sugars) and converting them to organic acids that can dissolve sensitive tooth enamel. If unchecked, the bacteria may penetrate deeper layers of the tooth and progress into the soft pulp tissue at the center. Untreated caries can lead to severe pain, local infection, tooth loss or extraction, nutritional problems, and serious systemic infections in susceptible individuals (7). Dental caries — both treated and untreated — contribute to diminished overall oral health, which, in turn, may affect systemic health. For example, some observational studies have suggested a link between systemic inflammation in individuals with periodontal (gum) infection and insulin resistance (8), type 2 diabetes mellitus (9)hypertension (10), and coronary heart disease (11). Moreover, the bacterium causing periodontitis, Porphyromonas gingivalis, may be linked to rheumatoid arthritis (12, 13). Poor oral health in general may constitute a risk factor for coronary heart disease (14) and other cardiovascular diseases (15, 16)

Systemic effects of fluoride on teeth

Increased fluoride exposure, most commonly through community water fluoridation, has been found to decrease the incidence of dental caries in children and adults (17, 18). Between 1976 and 1987, clinical studies in several countries demonstrated that the addition of fluoride to community water supplies (0.7-1.2 ppm) reduced caries by 30%-60% in primary (baby) teeth and 15%-35% in permanent teeth (19). A 2015 review and meta-analysis of prospective observational studies found a 35% and 26% reduction in number of decayed, missing, and filled primary and permanent teeth with consumption of fluoridated versus non-fluoridated water, respectively (20). While fluoride’s prevention of dental caries is primarily through topical action, fluoride consumed in water appears to have a systemic effect in children before all teeth have erupted — typically through 12 years of age.

Fluoride is incorporated into the developing enamel of teeth and increases the resistance to caries. Since the caries preventative effect of fluoride is also topical (surface) in children after teeth have erupted and in adults, the optimal protection achieved by fluoridated water likely occurs through both systemic exposure before and after tooth eruption and topical exposure after tooth eruption.

Topical effects of fluoride on teeth

Research has indicated that the primary action of fluoride occurs topically after the teeth erupt into the mouth. Ingested fluoride is secreted in the saliva and contributes to topical protection. When enamel is partially demineralized by organic acids, fluoride in the saliva can enhance the remineralization of enamel through its interactions with calcium and phosphate. Fluoride containing remineralized enamel is more resistant to acid attack and demineralization. In salivary concentrations associated with optimum fluoride intake, fluoride has been found to inhibit bacterial enzymes, resulting in reduced acid production by cariogenic bacteria (7, 17).

The use of topically applied fluoride-containing products, including toothpaste, gel, varnish, and mouth rinse, is thought to have contributed to the substantial decrease in the prevalence of caries over the last decades (21). A 2013 meta-analysis of fluoride interventions in children and adolescents (up to 16 years of age) found that the application of fluoride varnish for at least one year was associated with a 37% reduction in decayed, missing, and filled tooth surfaces in decayed tooth surfaces of primary teeth; the anti-caries effect on the permanent teeth corresponded to a 43% decrease compared to no treatment or placebo (22). A recent (2021) meta-analysis of topical fluoride reviewed 15 clinical trials with 9,541 participants. Specifically, the meta-analysis evaluated 14 trials of fluoride varnish compared to placebo or no fluoride and one trial of fluoride foam, and found that topical fluoride reduced dental caries increment by about one tooth surface over a two-year period (23). The same meta-analysis also found that fluoride varnish significantly prevented any incident dental caries, but only for children who were younger than 2 years of age (23)

The effects of fluoride-containing toothpaste has been more extensive. A 2017 meta-analysis of 96 randomized controlled trials, including more than 65,000 participants, found tooth brushing with a fluoridated toothpaste reduced caries in primary teeth of children and in permanent teeth of adults compared to brushing with non-fluoridated toothpaste (24). In participants overall, use of toothpastes containing 1,000 to 1,500 ppm of fluoride had a caries-preventative effect compared to use of toothpastes with lower fluoride concentrations or with non-fluoridated toothpastes (24). A systematic review of 17 clinical trials found use of fluoridated toothpaste effectively reduced dental caries in primary teeth of children younger than 6 years who were at high risk of developing dental caries (25).

Dental erosion (tooth wear)

The attack of dental hard tissue by acids other than those produced by the bacterial plaque may lead to the loss of tooth enamel, also known as dental erosion. Factors involved in dental erosion include acidic foods and beverages (e.g., carbonated drinks) and acid reflux (26). The protective effect of fluoridated agents against dental erosion has mainly been observed in in vitro studies (reviewed in 26). Nevertheless, a meta-analysis of four small, randomized trials examining the effect of fluoride in toothpaste, varnish, and saliva on dental erosion did not find any overall benefit compared to placebo (27). Larger clinical studies are needed to evaluate whether topical fluoride applications can prevent dental erosion and/or reduce the progression of existing erosive lesions. 


Although fluoride in pharmacologic doses has been shown to be a potent therapeutic agent for increasing spinal bone mass (see Disease Treatment), there is little evidence that water fluoridation at optimum levels for the prevention of dental caries is helpful in the prevention of osteoporosis. The majority of studies conducted to date have failed to find clinically significant differences in bone mineral density (BMD) or fracture incidence when comparing residents of areas with fluoridated water supplies to residents in areas without fluoridated water supplies (28,  29). However, two studies found that drinking water fluoridation was associated with decreased incidence of hip fracture in the elderly. In addition, one study in Italy found a significantly greater risk of femoral (hip) fractures in men and women residing in an area with low water fluoridation (0.05 ppm) compared to the risk in a similar population whose water supply was naturally fluoridated (1.45 ppm) at higher than optimum levels for prevention of dental caries (30). Another study in Germany found no significant difference in BMD between residents of a community whose water supply had been optimally fluoridated for 30 years (1 ppm) compared with those who resided in a community without fluoridated water. However, this study reported that the incidence of hip fracture in men and women, aged 85 years or older, was significantly lower in the community with fluoridated water compared to the community with non-fluoridated water, despite higher calcium levels in the non-fluoridated water supply (31). Another community-based study in 1,300 women found that elevated serum fluoride concentrations were not related to BMD or to osteoporotic fracture incidence (32). Finally, a nationwide cohort study in Sweden found no association between chronic exposure to fluoridated water and incidence of hip fracture (33). A 2015 meta-analysis, which pooled results of 13 prospective cohort studies and one case-control study, found that fluoride exposure in drinking water was not associated with risk of hip fracture (34).

Moreover, because bone mineral accretion early in life affects risk for osteoporosis in later adulthood, studies have examined the association of fluoride intake during adolescence and bone outcomes. Reports from the Iowa Bone Development Study, an ongoing prospective cohort study, indicate little to no association of fluoride intake during childhood and adolescence with measures of bone microstructure throughout adolescence (35-37) and into early adulthood (38).

Disease Treatment


Osteoporosis is characterized by decreased bone mineral density (BMD) and increased bone fragility and susceptibility to fracture. In general, decreased BMD is associated with increased risk of fracture. However, the usual relationship between BMD and fracture risk does not always hold true when very high (pharmacologic) doses of fluoride are used to treat osteoporosis. Most available therapies for osteoporosis (e.g., estrogen, calcitonin, and bisphosphonates) decrease bone loss (resorption), resulting in very small increases in BMD. Pharmacologic doses of fluoride are capable of producing large increases in the BMD of the lumbar spine. Overall, therapeutic trials of fluoride in patients with osteoporosis have not consistently demonstrated significant decreases in the occurrence of vertebral fracture despite dramatic increases in lumbar spine BMD (39). A meta-analysis of 11 controlled studies, including 1,429 participants, found that fluoride treatment resulted in increased BMD at the lumbar spine but was not associated with a lower risk of vertebral fractures (40). This meta-analysis also found that higher concentrations of fluoride were associated with increased risk of non-vertebral fractures after four years of treatment. Early studies using high doses of fluoride (>20 mg/day) may have induced rapid bone mineralization in the absence of adequate calcium and vitamin D, resulting in denser bones that were not mechanically stronger (41, 42). Analysis of bone architecture has also shed some light on the inconsistent effect of fluoride therapy in reducing vertebral fractures. Research has indicated that osteoporosis may be associated with an irreversible change in the architecture of bone known as decreased trabecular connectivity. Normal bone consists of a series of plates interconnected by thick rods. Severely osteoporotic bone has fewer plates, and the rods may be fractured or disconnected (decreased trabecular connectivity) (43). Despite fluoride therapy increasing bone density, it probably cannot reduce bone resorption and restore connectivity in patients with severe bone loss. Thus, fluoride therapy may be less effective in osteoporotic individuals who have already lost substantial trabecular connectivity (39, 44).

On the other hand, randomized controlled trials using lower fluoride doses (≤20 mg/day), intermittent dosage schedules, or slow-release formulations (enteric coated sodium fluoride) have demonstrated a decreased incidence of vertebral and non-vertebral fractures along with increased bone density of the lumbar spine (45). Yet, bone biopsies from postmenopausal, osteoporotic women treated with 20 mg/day of fluoride showed evidence of abnormal bone mineralization despite calcium and vitamin D supplementation (46). Additionally, a randomized, double-blind, placebo-controlled study did not find any increase in lumbar spine BMD in 180 postmenopausal women with osteopenia (early osteoporosis) who were given daily supplements of up to 10 mg/day of fluoride for one year (47). Additional studies are required to assess whether a safe dose of fluoride can be found to maximize bone formation while preventing mineralization defects.

Safety of fluoride therapy for osteoporosis

Serious side effects have been associated with the high doses of fluoride used to treat osteoporosis (45). They include gastrointestinal irritation, joint pain in the lower extremities, and the development of calcium deficiency and stress fractures. The reasons for the occurrence of lower extremity joint pain and stress fractures in patients taking fluoride for osteoporosis remain unclear, but they may be related to rapid increases in bone formation without sufficient calcium to support such an increase (39). Presently, enteric coated sodium fluoride or monofluorophosphate preparations offer a lower side effect profile than the high-dose sodium fluoride used in earlier trials. Additionally, sufficient calcium and vitamin D must be provided to support fluoride-induced bone formation. Although fluoride therapy may be beneficial for the treatment of osteoporosis in appropriately selected and closely monitored individuals, uncertainty about its safety and benefit in reducing fractures has kept the US Food and Drug Administration (FDA) from approving fluoride therapy for osteoporosis (48). Combinations of lower doses of fluoride with antiresorptive agents, such as estrogen or bisphosphonates, may improve therapeutic results while minimizing side effects (49, 50). Yet, randomized studies have shown that the risk of fractures remained unchanged whether treatments include fluoride, antiresorptives, or both (45, 46). Additional studies are warranted to determine whether any treatment combinations could provide substantial therapeutic benefits over monotherapy.


Water fluoridation

The major source of dietary fluoride in the US diet is drinking water. Controlled addition of fluoride to water is used by communities as a public health measure to adjust fluoride concentration in drinking water to prevent dental caries. Originally, an optimal range of 0.7 to 1.2 milligrams (mg) per liter (corresponding to 0.7-1.2 ppm) was established, which was shown to decrease the incidence of dental caries while minimizing the risk of dental fluorosis and other adverse effects. In 2015, the US Department of Health and Human Services recommended that the optimal concentration in drinking water be set at 0.7 ppm (see Safety) (51). Approximately 73% of the US population receives water with sufficient fluoride for the prevention of dental caries (52). The average fluoride intake for adults living in fluoridated communities ranges from 1.4 to 3.4 mg/day compared to 0.3 to 1 mg/day in non-fluoridated areas (6). Since well water can vary greatly in its fluoride content, people who consume water from wells should have the fluoride content of their water tested by their local water district or health department. Water fluoride testing may also be warranted in households that use home water treatment systems. While water softeners are not thought to change water fluoride levels, reverse osmosis systems, distillation units, and some water filters have been found to remove significant amounts of fluoride from water. However, Brita-type carbon-charcoal filters do not remove fluoride (6, 48).

Bottled water sales have grown exponentially in the US in the last decades, and studies have found that most bottled waters contain sub-optimal levels of fluoride, although there is considerable variation (53). For example, a study of 105 different bottled water products in the Greater Houston metropolitan area found that over 80% had fluoride concentrations of less than 0.4 ppm; only 5% of the tested products had fluoride concentrations within the recommended range (54). Several other studies have reported similar findings, with most bottled waters relatively low in fluoride, but a few in the optimal range or higher (55-57). The FDA-approved claim that "drinking fluoridated water may reduce the risk of tooth decay" is only used by bottlers when the water contains greater than 0.6 ppm of fluoride but no more than 1.0 ppm of fluoride. However, bottlers are not required to provide the fluoride concentration in bottled water unless fluoride was added (58).

Infant formulas

While consumption of fluoride from water presents very little risk of adverse effects in adults except in extreme circumstances (see Safety), consumption of relatively large amounts of water mixed with formula concentrates appears to increase the risk for the development of dental fluorosis in infants (59-61). One study found that, on average, at least half of all fluoride ingested by infants 6 months and younger was from water mixed with formula concentrates (62). The study of 49 commercially available infant formulas in the Chicago area showed that milk-based ready-to-feed, liquid concentrate, and powdered formulas (reconstituted with deionized water) had mean fluoride concentrations of 0.15 ppm, 0.27 ppm, and 0.12 ppm, respectively (63). Fluoride content was significantly higher in soy-based compared to milk-based liquid concentrate formulas (0.50 ppm vs. 0.27 ppm). Using average body weights and total formula intakes during the first year of life, the authors estimated that the risk of exceeding the tolerable upper intake level (UL) for fluoride ingestion was minimal when liquid concentrate and powdered formulas were reconstituted with water containing less than 0.5 ppm of fluoride, but the risk was maximal with 1.0 ppm fluoridated water. Fluoride-free or low-fluoride water labeled as "deionized," "purified," "demineralized," "distilled," or "produced through reverse-osmosis" can be used in order to minimize the risk for mild fluorosis (58). However, infants between 6 and 12 months may not reach the adequate intake of fluoride if they are fed ready-to-feed formulas or formulas reconstituted with water containing less than 0.4 ppm (63).

For additional information on fluoride and infant formulas, see the CDC website.

Food and beverage sources

The fluoride content of most foods is low (less than 0.05 mg/100 grams or 0.5 ppm). Rich sources of fluoride include tea, which concentrates fluoride in its leaves, and marine fish that are consumed with their bones (e.g., sardines). Foods made with mechanically separated (boned) chicken, such as canned meats, hot dogs, and infant foods, also add fluoride to the diet (64). In addition, certain fruit juices, particularly grape juices, often have relatively high fluoride concentrations (65). Foods generally contribute only 0.3-0.6 mg of the daily intake of fluoride. An adult male residing in a community with fluoridated water has an intake range from 1 mg/day-3 mg/day. Intake is less than 1 mg/day in non-fluoridated areas (2). Table 2 provides a range of fluoride content for a few fluoride-rich foods. For more information on the fluoride content of foods and beverages, search the USDA national fluoride database

Table 2. Some Food Sources of Fluoride
Food Serving Fluoride (mg) Fluoride (ppm)*
Black tea 100 mL  (3.5 fluid ounces) 0.25-0.39  2.5-3.9 
Fruit juice 100 mL (3.5 fluid ounces) 0.02-0.21 0.2-2.1
Crab (canned) 100 g (3.5 ounces) 0.21 2.1
Rice (cooked) 100 g (3.5 ounces) 0.04 0.4
Fish (cooked) 100 g (3.5 ounces) 0.02 0.2
Chicken 100 g (3.5 ounces) 0.015 0.15
*1.0 part per million (ppm) = 1 milligram/liter (mg/L)

Fluoride supplements

Fluoride supplements — available only by prescription in the US — are intended for infants 6 months and older and children up to 16 years of age living in areas with suboptimal water fluoridation for the purpose of bringing their intake to approximately 1 mg/day (6). The American Dental Association Council on Scientific Affairs recommends the prescription of fluoride supplements only to children at high risk of developing dental caries (66). The supplemental fluoride dosage schedule in Table 3 was recommended by the American Dental Association, the American Academy of Pediatric Dentistry, and the American Academy of Pediatrics (66, 67). It requires knowledge of the fluoride concentration of local drinking water, as well as other possible sources of fluoride intake. For more detailed information regarding fluoride and the prevention of dental caries, visit the American Dental Association website. 

Table 3. American Dental Association Fluoride Supplement Schedule
Age Fluoride Ion Level in Drinking Water (ppm)*
<0.3 ppm 0.3-0.6 ppm >0.6 ppm
Birth - 6 months None None None
6 months - 3 years 0.25 mg/day** None None
3 years - 6 years 0.50 mg/day 0.25 mg/day None
6 years - 16 years 1.0 mg/day 0.50 mg/day None
*1.0 part per million (ppm) = 1 milligram/liter (mg/L)
**2.2 mg sodium fluoride contains 1 mg fluoride ion.


Fluoridated toothpastes (1,000-1,100 ppm of fluoride) are very effective in preventing dental caries but also add considerably to fluoride intake of children, especially young children who are more likely to swallow toothpaste. Researchers estimate that children under 6 years of age may ingest an average of 0.3 mg of fluoride from toothpaste with each brushing. Children under the age of 6 years who ingest more than two or three times the recommended fluoride intake are at increased risk of a white speckling or mottling of the permanent teeth, known as dental fluorosis (see Safety section below). A major source of excess fluoride intake in this age group comes from swallowing fluoride-containing toothpaste. To prevent dental fluorosis while providing optimum protection from tooth decay, it is recommended that parents supervise children under 6 years of age while brushing with fluoridated toothpaste. In addition to discouraging the swallowing of toothpaste, children should be supervised during teeth brushing, and young children should be encouraged to use very small amounts of toothpaste — a "smear amount" (a thin layer of toothpaste that covers less than half of the bristle surface of a child-size toothbrush; size equivalent to a grain of rice) for children younger than 3 years, and no more than a pea-sized application of toothpaste for children 3 to 6 years of age (25, 68-70). Interestingly, it has been suggested that the management of the fluorosis risk in young children who ingest fluoridated toothpaste could include the use of toothpaste formulation that reduces gastrointestinal absorption and bioavailability of fluoride  (71).

Salt fluoridation

Fluoridation of salt has been implemented in several countries worldwide as an alternative to water fluoridation to promote the ingestion of fluoride and improve oral care. Since the fluoridation of water is extensively practiced in the US, fluoride is not added to salt. Observational studies have shown that the incidence of teeth with caries dramatically decreased in the regions where salt fluoridation programs were developed (reviewed in 72). While concerns around hypertension and the monitoring of population intakes should be addressed, no adverse health effects linked to the fluoridation of salt have been reported (reviewed in 73). According to the World Health Organization (WHO), salt fluoridation and, to a lesser extent, milk fluoridation, are affordable alternatives to improve oral hygiene in areas where access to oral health services is limited and fluoridation of public water is not feasible (74).

Mouth rinses

Mouth rinses that contain fluoride are available over-the-counter in the US. Such products often contain 0.05% sodium fluoride, which translates to about 1 mg of fluoride per 5 mL (one teaspoon) (70). Due to the risk of accidental ingestion, fluoride-containing mouth rinses are not recommended for young children (70)

Professionally applied fluoride products

Professionally applied fluoride products, including fluoride foams, gels, varnish, and silver diamine fluoride, are highly concentrated (9,000 to 44,800 ppm of fluoride) and applied topically to the teeth by dentists, dental hygienists, or other healthcare professionals (75). Because of their high concentrations, they are potential sources of fluoride; however, due to their infrequent use (every 3-6 months) and small amounts used per application, professionally applied fluoride products are not significant sources of fluoride when used as directed (75)


Adverse effects

Fluoridation of public drinking water in the US was initiated more than 70 years ago. Since then, a number of adverse effects have been attributed to water fluoridation. However, extensive scientific research has uncovered no evidence of increased risks of cancer, heart disease, kidney disease, liver disease, thyroid disease, Alzheimer's disease, birth defects, or Down's syndrome (51, 76, 77).

A number of observational studies, mostly published in Chinese journals, have investigated the association between fluoride content in drinking water and children’s neurodevelopment. Two meta-analyses of observational studies, mainly conducted in China, found lower intelligence quotients (IQs) in children exposed to higher fluoride concentrations in drinking water (78, 79). Serious limitations, including substantial heterogeneity among studies and co-occurrence of neurotoxicants in drinking water, hinder the strength of these findings and their application to US settings. The Academy of Nutrition and Dietetics has estimated that only limited evidence supports an association between fluoride content in water and the IQs of children (58). A prospective study in a New Zealand population-based cohort followed for nearly four decades found no association between fluoride exposure in the context of community water fluoridation programs and IQs measured during childhood and at age 38 years (80). A series of recent studies by a research group in Canada have raised concern over a possible link between higher maternal fluoride exposures during pregnancy and lower IQ (81-83), cognitive delay (84), and attention-deficit/hyperactivity disorder (85) in offspring. However, these studies have been widely criticized for shortcomings in measuring fluoride intake, only reporting significant relationships among subgroups, and being observational and subject to residual confounding. Thus, high-quality prospective studies with more definitive fluoride intake measures and better control of confounders are needed to determine whether fluoride might have neurotoxic effects at usual intake levels.   

Acute toxicity

Fluoride is toxic when consumed in excessive amounts, so concentrated fluoride products should be used and stored with caution to prevent the possibility of acute fluoride poisoning, especially in children and other vulnerable individuals. The lowest dose that could trigger adverse symptoms is considered to be 5 mg/kg of body weight, with the lowest potentially fatal dose considered 15 mg/kg of body weight. Nausea, abdominal pain, and vomiting almost always accompany acute fluoride toxicity. Other symptoms like diarrhea, excessive salivation and tearing, sweating, and generalized weakness may also occur (77). In order to prevent acute fluoride poisoning, the American Dental Association has recommended that no more than 120 mg of fluoride (224 mg of sodium fluoride) be dispensed at one time (48). The use of high doses of fluoride to treat osteoporosis has been associated with some adverse effects, which are discussed in the Disease Treatment section above.

Dental fluorosis

Dental fluorosis, also called enamel fluorosis, is a result of excess fluoride intake during the period of tooth formation, with the critical window of susceptibility being the first eight years of life, as this corresponds to the eruption of the permanent teeth (86). Once the tooth enamel has formed, dental fluorosis cannot develop (87). The mildest form of dental fluorosis is detectable only to the trained observer and is characterized by small opaque white flecks or spots on the enamel of the teeth. Moderate dental fluorosis is characterized by mottling and mild staining of the teeth, and severe dental fluorosis results in marked staining and pitting of the teeth. In its moderate to severe forms, dental fluorosis becomes a cosmetic concern when it affects the incisors and canines (front teeth). Dental fluorosis is a dose-dependent condition, with higher fluoride intakes being associated with more pronounced effects on the teeth.

The incidence of mild and moderate dental fluorosis has increased over the past decades, mainly due to increasing fluoride intake from reconstituted infant formula and toothpaste, although inappropriate use of fluoride supplements may also contribute (61). According to a US national survey, the National Health and Nutrition Examination Survey (NHANES) 1999-2004, 23% of people aged 6 to 49 years (n=16,051) had some degree of dental fluorosis (88). National data from NHANES 2011-2012 found that the prevalence of fluorosis among children and adolescents (n=2,283), ages 6 to 19 years, was much higher at 57% (89); however, a quality assessment of these data raised concerns about their validity and suggested such results were not biologically plausible (90). In 1997, the US Food and Nutrition Board (FNB) of the Institute of Medicine set the tolerable upper intake level (UL) for fluoride based on the prevention of moderate enamel fluorosis (Table 4) (6).

Table 4. Tolerable Upper Intake Level (UL) for Fluoride
Age Group UL (mg/day)
Infants 0-6 months 0.7
Infants 7-12 months 0.9
Children 1-3 years 1.3
Children 4-8 years   2.2
Children 9-13 years   10.0
Adolescents 14-18 years 10.0
Adults 19 years and older 10.0

The current US EPA maximum allowable level of fluoride in drinking water is 4 mg/L; the EPA also has a non-enforceable standard fluoride level of 2 mg/L to prevent moderate dental fluorosis (91). The EPA recently conducted a six-year review of drinking water standards and concluded that the limit of fluoride in drinking water is not a candidate for regulatory revision at this time (92).

Skeletal fluorosis

Intake of fluoride at excessive levels for long periods of time may lead to changes in bone structure known as skeletal fluorosis. The early stages of skeletal fluorosis are characterized by increased bone mass, detectable by x-ray. If very high fluoride intake persists over many years, joint pain and stiffness may result from the skeletal changes. The most severe form of skeletal fluorosis is known as "crippling skeletal fluorosis," which may result in calcification of ligaments, immobility, muscle wasting, and neurological problems related to spinal cord compression. While skeletal fluorosis is endemic in many world regions with naturally high fluoride concentrations in drinking water, crippling skeletal fluorosis may occur only when fluoride intake exceeds 10 mg/day for at least 10 years (6, 93). Rare cases of skeletal fluorosis in the US have been observed in consumers of large volumes of tea (94-97). Because of the potential risk for skeletal fluorosis, as well as the risks for pitting of tooth enamel and bone fracture, the US EPA set the maximum level of fluoride allowed in drinking water at 4 mg/L (98). The agency also recommended limiting fluoride in drinking water at 2 mg/L to prevent dental fluorosis in children; however, this is only a guideline and not enforceable by law (see the US EPA website).

Drug interactions

Calcium supplements, as well as calcium and aluminum-containing antacids, can decrease the absorption of fluoride. It is best to take these products two hours before or after fluoride supplements (99).

Linus Pauling Institute Recommendation

The safety and public health benefits of optimally fluoridated water for prevention of tooth decay in people of all ages have been well established. The Linus Pauling Institute supports the recommendations of the American Dental Association and the Centers for Disease Control and Prevention, which include optimally fluoridated water and the use of fluoride toothpaste, fluoride mouth rinse, fluoride varnish, and when necessary, fluoride supplementation. Due to the risk of fluorosis, any fluoride supplementation should be prescribed and closely monitored by a dentist or physician.

Authors and Reviewers

Originally written in 2001 by:
Jane Higdon, Ph.D.
Linus Pauling Institute
Oregon State University

Updated in April 2003 by:
Jane Higdon, Ph.D.
Linus Pauling Institute
Oregon State University

Updated in September 2007 by:
Victoria J. Drake, Ph.D.
Linus Pauling Institute
Oregon State University

Updated in November 2013 by:
Barbara Delage, Ph.D.
Linus Pauling Institute
Oregon State University

Updated in November 2021 by:
Victoria J. Drake, Ph.D.
Linus Pauling Institute
Oregon State University

Reviewed in December 2021 by:
John J. Warren, D.D.S., M.S.
Preventive & Community Dentistry
College of Dentistry
The University of Iowa

Copyright 2001-2023  Linus Pauling Institute


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90. National Center for Health Statistics, National Center for Chronic Disease Prevention and Health Promotion. Data quality evaluation of the dental fluorosis clinical assessment data from the National Health and Nutrition Examination Survey, 1999–2004 and 2011–2016. National Center for Health Statistics. Vital Health Stat 2(183); 2019.

91. US Environmental Protection Agency. New fluoride risk assessment and relative source contribution documents; 2011.

92. US Environmental Protection Agency. Six-year review 3 of drinking water standards. Available at: https://www.epa.gov/dwsixyearreview/six-year-review-3-drinking-water-standards. Accessed 11/22/21.

93. Whitford GM. The Metabolism and Toxicity of Fluoride. Basel: S. Karger AG; 1996.

94. Hallanger Johnson JE, Kearns AE, Doran PM, Khoo TK, Wermers RA. Fluoride-related bone disease associated with habitual tea consumption. Mayo Clin Proc. 2007;82(6):719-724.  (PubMed)

95. Whyte MP, Totty WG, Lim VT, Whitford GM. Skeletal fluorosis from instant tea. J Bone Miner Res. 2008;23(5):759-769.  (PubMed)

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98. US Environmental Protection Agency. Fact sheet: Questions and answers on fluoride. January 2011. Available at: https://www.epa.gov/sites/default/files/2015-10/documents/2011_fluoride_questionsanswers.pdf. Accessed 11/22/21.

99. Minerals. Drug Facts and Comparisons. St. Louis: Facts and Comparisons; 2000:27-51.  


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  • Iodine is a key component of thyroid hormones, which are required throughout life for normal growth, neurological development, and metabolism. (More information)
  • Insufficient iodine intake impairs the production of thyroid hormones, leading to a condition called hypothyroidism. Iodine deficiency results in a range of adverse health disorders with varying degrees of severity, from thyroid gland enlargement (goiter) to severe physical and mental retardation known as cretinism. (More information)
  • Iodine deficiency-induced hypothyroidism has adverse effects in all stages of development but is most damaging to the developing brain. Maternal iodine deficiency during pregnancy can result in maternal and fetal hypothyroidism, as well as miscarriage, preterm birth, and neurological impairments in offspring. (More information)
  • Even in areas with voluntary/mandatory iodization programs and in iodine-replete countries, pregnant women, lactating mothers, and young infants are among the most vulnerable to iodine deficiency due to their special requirements during these life stages. (More information)
  • The recommended dietary allowance (RDA) for iodine intake is 150 micrograms (μg)/day in adults, 220 μg/day in pregnant women, and 290 μg/day in breast-feeding women. During pregnancy and lactation, the fetus and infant are entirely reliant on maternal iodine intake for thyroid hormone synthesis. (More information)
  • Thyroid accumulation of radioactive iodine (131I) increases the risk of developing thyroid cancer, especially in children. In case of radiation emergencies, current preventive measures include the distribution of pharmacologic doses of potassium iodide that would reduce the risk of significant uptake of 131I by the thyroid gland. (More information)
  • Seafood is an excellent source of dietary iodine. Dairy products, grains, eggs, and poultry contribute substantially to dietary iodine intakes in the US. (More information)
  • More than 120 countries worldwide have introduced programs of salt fortification with iodine in order to correct iodine deficiency in populations. (More information)
  • In iodine-deficient populations, a rapid increase in iodine intake may precipitate iodine-induced hyperthyroidism. The risk of iodine-induced hyperthyroidism is especially high in older people with multi-nodular goiter. (More information)
  • In iodine-sufficient adults, long-term iodine intake above the tolerable upper intake level (UL) of 1,100 μg/day may increase the risk of thyroid disorders, including iodine-induced goiter and hypothyroidism. (More information)

Iodine (I), a non-metallic trace element, is required by humans for the synthesis of thyroid hormones. Iodine deficiency is an important health problem throughout much of the world. Most of the Earth's iodine, in the form of the iodide ion (I-), is found in oceans, and iodine content in the soil varies with region. The older an exposed soil surface, the more likely the iodine has been leached away by erosion. Mountainous regions, such as the Himalayas, Atlas, Andes, and Alps; flooded river valleys, such as the Ganges River plain in India; and many inland regions, such as central Asia and Africa, central and eastern Europe, and the Midwestern region of North America are among the most severely iodine-deficient areas in the world (1)


Iodine is an essential component of the thyroid hormones, triiodothyronine (T3) and thyroxine (T4), and is therefore essential for normal thyroid function. To meet the body's demand for thyroid hormones, the thyroid gland traps iodine from the blood and incorporates it into the large (660 kDa) glycoprotein thyroglobulin. The hydrolysis of thyroglobulin by lysosomal enzymes gives rise to thyroid hormones that are stored and released into the circulation when needed. In target tissues, such as the liver and the brain, T4 (the most abundant circulating thyroid hormone) can be converted to T3 by selenium-containing enzymes known as iodothyronine deiodinases (DIOs) (Figure 1; see also Nutrient interactions). T3 is the physiologically active thyroid hormone that can bind to thyroid receptors in the nuclei of cells and regulate gene expression. In this manner, thyroid hormones regulate a number of physiologic processes, including growth, development, metabolism, and reproductive function (2).

Figure 1. Iodine Intake and Thyroid Function. In response to thyrotropin-releasing hormone (TRH) secretion by the hypothalamus, the pituitary gland secretes thyroid-stimulating hormone (TSH), which stimulates iodine trapping, thyroid hormone synthesis, and release of T3 (triiodothyronine) and T4 (thyroxine) by the thyroid gland. When dietary iodine intake is sufficient, the presence of adequate circulating T4 and T3 feeds back at the level of both the hypothalamus and pituitary, decreasing TRH and TSH production. When circulating T4 levels decrease, the pituitary increases its secretion of TSH, resulting in increased iodine trapping as well as increased production and release of both T3 and T4. Dietary iodine deficiency results in inadequate production of T4. In response to decreased blood levels of T4, the pituitary gland increases its output of TSH. Persistently elevated TSH levels may lead to hypertrophy of the thyroid gland, also known as goiter.

[Figure 1 - Click to Enlarge]

The regulation of thyroid function is a complex process that involves the hypothalamus and the pituitary gland. In response to thyrotropin-releasing hormone (TRH) secretion by the hypothalamus, the pituitary gland secretes thyroid-stimulating hormone (TSH), which stimulates iodine trapping, thyroid hormone synthesis, and release of T4 and T3 by the thyroid gland. The presence of adequate circulating T4 and T3 feeds back at the level of both the hypothalamus and pituitary, decreasing TRH and TSH production (Figure 2). When circulating T4 levels decrease, the pituitary gland increases its secretion of TSH, resulting in increased iodine trapping, as well as increased production and release of both T3 and T4. Iodine deficiency results in inadequate production of T4. In response to decreased blood T4 concentrations, the pituitary gland increases its output of TSH. Persistently elevated TSH levels may lead to hypertrophy (enlargement) of the thyroid gland, also known as goiter (see Deficiency) (3).

Figure 2. The Hypothalamic-Pituitary-Thyroid Axis. In response to thyrotropin-releasing hormone (TRH) secretion by the hypothalamus, the pituitary gland secretes thyroid-stimulating hormone (TSH). TSH stimulates iodine trapping and thyroid hormone synthesis by the thyroid gland and the release of T3 (triiodothyronine) and T4 (thyroxine) into the circulation. When dietary iodine intake is sufficient, the presence of adequate serum T4 and T3 concentrations feeds back at the level of both the hypothalamus and pituitary gland, decreasing TRH and TSH production. When circulating T4 concentrations decrease, the pituitary gland increases its secretion of TSH, stimulating iodine trapping and production and release of both T3 and T4. In the case of iodine deficiency, persistently elevated TSH levels may lead to hypertrophy of the thyroid gland, also known as goiter.

[Figure 2 - Click to Enlarge]


The thyroid gland of a healthy adult concentrates 70-80% of a total body iodine content of 15-20 mg and utilizes about 80 μg of iodine daily to synthesize thyroid hormones. In contrast, chronic iodine deficiency can result in a dramatic reduction of the iodine content in the thyroid well below 1 mg (1). Iodine deficiency is recognized as the most common cause of preventable brain damage in the world. The spectrum of iodine deficiency disorders (IDD) includes mental retardation, hypothyroidism, goiter, and varying degrees of other growth and developmental abnormalities (4). The World Health Organization (WHO) estimated that over 30% of the world’s population (2 billion people) have insufficient iodine intake as measured by median urinary iodine concentrations below 100 μg/L (5). Moreover, about one-third of school-age children (6-12 years old) worldwide (241 million children in 2011) have insufficient iodine intake (6, 7). Major international efforts have produced dramatic improvements in the correction of iodine deficiency in the 1990s, mainly through the use of iodized salt in iodine-deficient countries (4). Although about 70% of households in the world now have access to iodized salt (8), mild-to-moderate iodine deficiency remains a public health concern in at least 30 countries; there are no iodine excretion data available for 42 other countries, including Israel, Syria, and Sierra Leone (7). For more information on the international effort to eradicate iodine deficiency, visit the websites of the Iodine Global Network (formerly the International Council for the Control of Iodine Deficiency Disorders) and the WHO.

Biomarkers of iodine status

More than 90% of ingested iodine is excreted in the urine within 24-48 hours such that daily iodine intakes in a population can be extrapolated from measures of median spot urinary iodine concentrations (9, 10). According to WHO criteria, population iodine deficiency is defined by median urinary iodine concentrations lower than 150 micrograms (μg)/L for pregnant women and 100 μg/L for all other groups (Table 1). Adequate intakes correspond to median urinary iodine concentrations of 100-199 μg/L in school-age children and 150-249 μg/L in pregnant women (Table 1). While median urinary iodine concentration is a population indicator of recent dietary iodine intake, multiple collections of 24-hour urinary iodine are preferable to estimate intake in individuals (9-11).

Table 1. WHO Criteria for Assessment of Iodine Nutrition through Population-based Median Urinary Iodine Concentrations (4)
Population Group Median/Range of Urinary Iodine Concentrations (μg/L) Iodine Intake
Children (<2 years) <100 Insufficient
≥100 Adequate
Children (≥6 years), adolescents, and adults* <100 Insufficient
100-199 Adequate
200-299 More than adequate
>300 Excessive
Pregnant women <150 Insufficient
150-249 Adequate
250-499 More than adequate
≥500 Excessive
Breast-feeding women# <100 Insufficient
≥100 Adequate

*Excludes pregnant or lactating women.
#Given that iodine requirements are increased in breast-feeding women (see The RDA), the numbers for median urinary excretion concentrations are lower than one would expect because iodine is also excreted in breast milk.

In many countries, serum TSH concentration is used in the screening for congenital hypothyroidism in newborns. Newborn TSH can be used as an indicator of population iodine status. Yet, in older children and adults, serum TSH is not a sensitive indicator of iodine status as concentrations are usually maintained within a normal range despite frank iodine deficiency (12). Serum thyroglobulin concentration in school-age children is a sensitive marker of iodine status in populations (13). In areas of endemic goiter, changes in thyroid size reflect long-term iodine nutrition (months to years). Assessment of the goiter rate in a population is used to define the severity of iodine deficiency, as well as to monitor the long-term impact of sustained salt iodization programs (4, 10). Finally, serum thyroid hormone concentrations do not adequately reflect iodine nutrition in populations (1).

Iodine deficiency disorders

All the adverse effects of iodine deficiency in animals and humans are collectively termed iodine deficiency disorders (reviewed in 1). Thyroid enlargement, or goiter, is one of the earliest and most visible signs of iodine deficiency. It is a physiologic adaptation of the thyroid gland in response to persistent stimulation by TSH (see Function). In mild iodine deficiency, thyroid enlargement may be enough to maximize the uptake of available iodine and provide the body with sufficient thyroid hormones. Yet, large goiters can obstruct the trachea and esophagus and damage the recurrent laryngeal nerves.

More severe cases of iodine deficiency result in impaired thyroid hormone synthesis known as hypothyroidism. Adequate iodine intake will generally reduce the size of goiters, but the reversibility of the effects of hypothyroidism depends on an individual's life stage. Iodine deficiency-induced hypothyroidism has adverse effects in all stages of development but is most damaging to the developing brain. In addition to regulating many aspects of growth and development, thyroid hormones are important for the migration, proliferation, and differentiation of specific neuronal populations, the overall architecture of the brain’s cortex, the formation of axonal connections, and the myelination of the central nervous system, which occurs both before and shortly after birth (reviewed in 14).

The effects of iodine deficiency at different life stages are discussed below.

Pregnancy and lactation

Daily iodine requirements are significantly increased in pregnant and breast-feeding women because of (1) the increased thyroid hormone production and transfer to the fetus in early pregnancy before the fetal thyroid gland becomes functional, (2) iodine transfer to the fetus during late gestation, (3) increased urinary iodine excretion, and (4) iodine transfer to the infant via breast milk (see also The RDA) (12, 15).

During pregnancy, the size of the thyroid gland is increased by 10% in women residing in iodine-sufficient regions and increased by 20%-40% in those living in iodine-deficient regions (16). Iodine deficiency during pregnancy can result in hypothyroidism in women. Maternal hypothyroidism has been associated with increased risk for preeclampsia, miscarriage, stillbirth, preterm birth, and low-birth-weight infants (reviewed in 16). In addition, severe iodine deficiency during pregnancy may result in congenital hypothyroidism and neurocognitive deficits in the offspring (see Prenatal development) (12).

Iodine-deficient women who are breast-feeding may not be able to provide sufficient iodine to their infants who are particularly vulnerable to the effects of iodine deficiency (see Newborns and infants) (17). A daily prenatal supplement of 150 μg of iodine, as recommended by the American Thyroid Association (ATA) (16), will help to ensure that US pregnant and breast-feeding women consume sufficient iodine during these critical periods. In iodine-deficient areas where iodized salt is not available, the Iodine Global Network (IGN; formerly the International Council for the Control of Iodine Deficiency Disorders), the World Health Organization (WHO), and UNICEF recommend that lactating women receive a single annual dose of 400 mg of iodine (or 250 μg/day) and exclusively breast-feed for at least six months. When breast-feeding is not possible, direct supplementation of the infant (<2 years old) with a single annual dose of 200 mg of iodine (or 90 μg/day) is advised (4). A randomized and placebo-controlled trial recently demonstrated that maternal supplementation (with a single 400-mg dose of iodine) improved the iodine status of breast-fed infants more efficiently than direct infant supplementation (with a single 100 mg-dose of iodine) for a period of at least six months (18). Yet, supplementation of lactating women failed to increase maternal urinary iodine concentrations above 100 μg/L, suggesting that supplemented mothers remained deficient in iodine (18).

Prenatal development

Fetal iodine deficiency is caused by iodine deficiency in the mother (see Pregnancy and lactation). During pregnancy, before the fetal thyroid gland becomes functional at 16-20 weeks’ gestation, maternal thyroxine (T4) crosses the placenta to promote normal embryonic and fetal development. Hence, maternal iodine deficiency and hypothyroidism can result in adverse pregnancy complications, including fetal loss, placental abruption, preeclampsia, preterm delivery, and congenital hypothyroidism in the offspring (16). The effects of maternal hypothyroidism on the offspring depend on the timing and severity of in utero iodine deficiency. A severe form of congenital hypothyroidism may lead to cretinism, a condition associated with irreversible mental retardation. The clinical picture of neurological cretinism in the offspring includes severe mental and physical retardation, deafness, mutism, and motor spasticity.

A myxedematous form of cretinism has been associated with coexisting iodine and selenium deficiency in central Africa (see Nutrient interactions) and is characterized by a less severe degree of mental retardation than in neurological cretinism. Yet, affected individuals exhibit all the features of severe hypothyroidism, including severe growth retardation and delayed sexual maturation (12). Two longitudinal cohort studies (one in the UK and one in Australia) recently observed that even mild-to-moderate iodine deficiency during pregnancy was associated with reduced scores of IQ and various measures of literacy performance in children 8 to 9 years of age (19, 20)

Newborns and infants (up to one year of age)

Infant mortality is higher in areas of severe iodine deficiency than in iodine-replete regions, and several studies have demonstrated an increase in childhood survival upon correction of the iodine deficiency (8, 21, 22). Infancy is a period of rapid brain growth and development. Sufficient thyroid hormone, which depends on adequate iodine intake, is essential for normal brain development. Even in the absence of congenital hypothyroidism, iodine deficiency during infancy may result in abnormal brain development and, consequently, impaired intellectual development (23, 24).

Children and adolescents

Iodine deficiency in children and adolescents is often associated with goiter. The incidence of goiter peaks in adolescence and is more common in girls than boys. School-age children in iodine-deficient areas show poorer school performance, lower IQs, and a higher incidence of learning disabilities than matched groups from iodine-sufficient areas. Three meta-analyses of mainly cross-sectional studies concluded that chronic iodine deficiency was associated with reduced mean IQ scores by 7-13.5 points in participants (primarily children) (25-27). However, these observational studies did not distinguish between iodine deficiency during pregnancy and during childhood, and such observational studies may be confounded by social, economic, and educational factors that influence child development.


Inadequate iodine intake may also result in goiter and hypothyroidism in adults. Although the effects of hypothyroidism are more subtle in the brains of adults than children, research suggests that hypothyroidism results in poor social and economic achievements due to low educability, apathy, and reduced work productivity (28). Other symptoms of hypothyroidism in adults include fatigue, weight gain, cold intolerance, and constipation.

Finally, because iodine deficiency induces an increase in the iodine trapping capacity of the thyroid, iodine-deficient individuals of all ages are more susceptible to radiation-induced thyroid cancer (see Disease Prevention), as well as to iodine-induced hyperthyroidism after an increase in iodine intakes (see Safety) (2).

Individuals and populations at risk of iodine deficiency

While the risk of iodine deficiency for populations living in iodine-deficient areas without adequate iodine fortification programs is well recognized, concerns have been raised that certain subpopulations in countries considered iodine-sufficient may not consume adequate iodine (7, 29). The greater use of methods assessing iodine status (see Biomarkers of iodine status) has shown that iodine deficiency also occurs in areas where the prevalence of goiter is low, in coastal areas, in highly developed countries, and in regions where iodine deficiency was previously eliminated (4).

The US is currently considered to be iodine-sufficient. Yet, in recent years, dietary intakes of iodine in the US population have decreased. Data from the latest US National Health and Nutrition Examination Survey (NHANES 2009-2010) indicated that the median urinary iodine concentration for the general population was 144 μg/L compared to 164 μg/L reported in previous assessments (NHANES 2005-2006 and 2007-2008) (30, 31). In addition to regional differences across the US, ethnic variations have been found. In all age groups, median urinary iodine concentrations were shown to be lower in African Americans than in Hispanics and Caucasians.

In addition, median urinary iodine concentrations in nonpregnant women of childbearing age and pregnant women indicate that mild iodine deficiency has re-emerged in the US in recent years (31).

Nonpregnant women

Data from US NHANES 2007-2010 indicated that 37.3% of nonpregnant women (ages 15-44 years) had urinary iodine concentrations lower than 100 μg/L, reflecting potentially insufficient iodine intakes (see Biomarkers of iodine status) (31). Only one-fifth of nonpregnant women reported using iodine-containing supplements in an earlier NHANES (2001-2006) (32). Yet, adequate intakes of iodine in women of childbearing age (150 μg/day; see The RDA) are essential for optimum stores of iodine, especially if they are considering pregnancy. Some experts suggested a daily consumption of 250 μg of iodine before conception to ensure adequate thyroid hormone production and iodine supply to the embryo and fetus during pregnancy (see Pregnancy and lactation) (12).

Pregnant women

There are no statistics on the global burden of iodine deficiency in pregnant women, but national and regional data suggest that this group is especially vulnerable. Given the increased iodine requirements during pregnancy, the median urinary iodine concentration should be at least of 150 μg/L (see Biomarkers of iodine status). Pooled data from NHANES 2005-2010 reported that US pregnant women had a median urinary iodine concentration of 129 μg/L, and the lowest median concentration (109 μg/L) was observed during the first trimester of gestation, when the embryo/fetus relies exclusively on maternal thyroid hormones (31).

Breast-feeding women

While data regarding the iodine status of breast-feeding women in the US are limited, dietary intakes that were inadequate during pregnancy are likely to be insufficient in a significant fraction of breast-feeding women (33, 34). A systematic review of the literature recently reported suboptimal dietary iodine intakes in breast-feeding women in some countries with a mandatory fortification program, including Denmark, Australia, and India (35). The American Thyroid Association (ATA) recommends that all North American women who are pregnant or breast-feeding supplement their dietary iodine intake with 150 μg/day of iodine (36).

Breast-fed and weaning infants

The body of a healthy newborn contains only about 300 μg of iodine, which makes newborns extremely vulnerable to iodine deficiency (28), and breast-fed infants are entirely reliant on maternal iodine intakes for thyroid hormone synthesis. Even in areas covered by a salt iodization program, weaning infants are at high risk of iodine deficiency, especially if they are not receiving iodine-containing infant formula (17).

Individuals consuming special diets

Diets that exclude iodized salt, fish, and seaweed have been found to contain very little iodine (9). Individuals consuming branded weight-loss foods may also be at risk of inadequate intakes (37). A small US cross-sectional study in 78 vegetarians and 63 vegans reported median urinary iodine concentrations of 147 μg/L and 78.5 μg/L, respectively, suggesting inadequate iodine intakes among vegans (38). Two cases of goiter and/or hypothyroidism have also been recently reported in children following restrictive diets to control esophageal inflammation (eosinophilic esophagitis) (39) or allergies (40).

Patients requiring parenteral nutrition

Although iodine is usually not added to parenteral nutrition (PN) solutions, topical iodine-containing disinfectants and other adventitious sources provide substantial amounts of iodine to some PN patients such that the occurrence of iodine deficiency is unlikely. Yet, deficiency might occur, especially in preterm infants with limited body stores, if chlorhexidine-based antiseptics replace iodinated antiseptics (28, 41).

Nutrient interactions

Concurrent deficiencies in selenium, iron, or vitamin A may exacerbate the effects of iodine deficiency (reviewed in 42).


While iodine is an essential component of thyroid hormones, the selenium-containing iodothyronine deiodinases (DIOs) are enzymes (or selenoenzymes) required for the conversion of T4 to the biologically active thyroid hormone, T3 (see the article on Selenium). DIO1 activity may also be involved in regulating iodine homeostasis (43). In addition, glutathione peroxidases are selenoenzymes that protect the thyroid gland from hydrogen peroxide-induced damage during thyroid hormone synthesis (44). A randomized, placebo-controlled study in 151 pregnant women at risk of developing autoimmune thyroid disease found that selenium supplementation (200 μg/day in the form of selenomethionine) at 12 weeks of gestation until 12 months’ postpartum reduced the risk of thyroid dysfunction and permanent hypothyroidism (45). However, another trial (the Selenium in Pregnancy Intervention Trial) found no benefit of selenium supplementation (60 μg/day from 12-14 weeks of gestation to delivery) over placebo on circulating autoantibody concentrations in pregnant women mildly deficient in iodine (46).

The epidemiology of coexisting iodine and selenium deficiencies in central Africa has been linked to the prevalence of myxedematous cretinism, a severe form of congenital hypothyroidism accompanied by mental and physical retardation. Selenium deficiency may be only one of several undetermined factors that might exacerbate the detrimental effects of iodine deficiency (42). Besides, results from randomized controlled intervention trials have shown that correcting only the selenium deficiency may have a deleterious effect on thyroid hormone metabolism in school-age children with co-existing selenium and iodine deficiency (47, 48). Finally, selenium deficiency in rodents was found to have little impact on DIO activities as it appears that selenium is being supplied in priority for adequate synthesis of DIOs at the expense of other selenoenzymes (44)


Severe iron-deficiency anemia can impair thyroid metabolism in the following ways: (1) by altering the TSH response of the pituitary gland; (2) by reducing the activity of thyroid peroxidase that catalyzes the iodination of thyroglobulin for the production of thyroid hormones; and (3) in the liver by limiting the conversion of T4 to T3, increasing T3 turnover, and decreasing T3 binding to nuclear receptors (49). It is estimated that goiter and iron-deficiency anemia coexist in up to 25% of school-age children in west and north Africa (42). A randomized controlled study in iron-deficient children with goiter showed a greater reduction in thyroid size following the consumption of iodized salt together with 60 mg/day of iron four times per week compared to placebo (50). Additional interventions have confirmed that correcting iron-deficiency anemia improved the efficacy of iodine supplementation to mitigate thyroid disorders (reviewed in 42, 49).

Vitamin A

In north and west Africa, vitamin A deficiency and iodine deficiency-induced goiter may coexist in up to 50% of children. Vitamin A status, like other nutritional factors, appears to influence the response to iodine prophylaxis in iodine-deficient populations (51). Vitamin A deficiency in animal models was found to interfere with the pituitary-thyroid axis by (1) increasing the synthesis and secretion of thyroid-stimulating hormone (TSH) by the pituitary gland, (2) increasing the size of the thyroid gland, (3) reducing iodine uptake by the thyroid gland and impairing the synthesis and iodination of thyroglobulin, and (4) increasing circulating concentrations of thyroid hormones (reviewed in 52). A cross-sectional study of 138 children with concurrent vitamin A and iodine deficiencies found that the severity of vitamin A deficiency was associated with higher risk of goiter and higher concentrations of circulating TSH and thyroid hormones (51). These children received iodine-enriched salt together with vitamin A (200,000 IU at baseline and at 5 months) or a placebo in a randomized, double-blind, 10-month trial. Vitamin A supplementation significantly decreased TSH concentration and thyroid volume compared to placebo (51). In another trial, vitamin A supplementation alone (without iodine) to iodine-deficient children reduced the volume of the thyroid gland, as well as TSH and thyroglobulin concentrations (53). Yet, supplemental vitamin A had no additional effect on thyroid function/hormone metabolism when children were also given iodized oil.


Some foods contain substances that interfere with iodine utilization or thyroid hormone production; these substances are called goitrogens. The occurrence of goiter in the Democratic Republic of Congo has been related to the consumption of cassava, which contains linamarin, a compound that is metabolized to thiocyanate and blocks thyroidal uptake of iodine (1). In iodine-deficient populations, tobacco smoking has been associated with an increased risk for goiter (54, 55). Cyanide in tobacco smoke is converted to thiocyanate in the liver, placing smokers with low iodine intake at risk of developing a goiter. Moreover, thiocyanate affects iodine transport into the lactating mammary gland, leading to low iodine concentrations in breast milk and impaired iodine supply to the neonates/infants of smoking mothers (2). Some species of millet, sweet potatoes, beans, and cruciferous vegetables (e.g., cabbage, broccoli, cauliflower, and Brussels sprouts) also contain goitrogens (1). Further, the soybean isoflavones, genistein and daidzein, have been found to inhibit thyroid hormone synthesis (56). Most of these goitrogens are not of clinical importance unless they are consumed in large amounts or there is coexisting iodine deficiency. Industrial pollutants, such as perchlorate (see Safety), resorcinol, and phthalic acid, may also be goitrogenic (1, 57).

The Recommended Dietary Allowance (RDA)

The RDA for iodine was reevaluated by the Food and Nutrition Board (FNB) of the Institute of Medicine (IOM) in 2001 (Table 2). The recommended amounts were calculated using several methods, including the measurement of iodine uptake in the thyroid glands of individuals with normal thyroid function (9). Similar recommendations have been made by several organizations, including the American Thyroid Association (ATA) (16, 58), the World Health Organization (WHO), the Iodine Global Network (IGN; formerly the International Council for the Control of Iodine Deficiency Disorders), and the United Nations Children’s Fund (UNICEF) (4). Of note, the WHO, IGN, and UNICEF recommend daily intakes of 250 μg of iodine for both pregnant and breast-feeding women (4).

Table 2. Recommended Dietary Allowance (RDA) for Iodine
Life Stage Age Males (μg/day) Females (μg/day)
Infants  0-6 months 110 (AI) 110 (AI)
Infants  7-12 months   130 (AI)   130 (AI) 
Children  1-3 years  90  90 
Children 4-8 years  90  90 
Children  9-13 years  120  120 
Adolescents  14-18 years  150  150 
Adults  19 years and older 150  150 
Pregnancy  all ages  220
Breast-feeding  all ages  290

Disease Prevention

Radiation-induced thyroid cancer

Radioactive iodine, especially iodine 131 (131I), may be released into the environment as a result of nuclear reactor accidents, such as the 1986 Chernobyl nuclear accident in Ukraine and the 2011 Fukushima Daiichi nuclear accident in Japan. Thyroid accumulation of radioactive iodine increases the risk of developing thyroid cancer, especially in children (59). The increased iodine trapping activity of the thyroid gland in iodine deficiency results in increased thyroid accumulation of radioactive iodine (131I). Thus, iodine-deficient individuals are at increased risk of developing radiation-induced thyroid cancer because they will accumulate greater amounts of radioactive iodine. Potassium iodide administered in pharmacologic doses (up to 130 mg for adults) within 48 hours before or eight hours after radiation exposure from a nuclear reactor accident can significantly reduce thyroid uptake of 131I and decrease the risk of radiation-induced thyroid cancer (60). The prompt and widespread use of potassium iodide prophylaxis in Poland after the 1986 Chernobyl nuclear reactor accident may explain the lack of a significant increase in childhood thyroid cancer compared to fallout areas where potassium iodide prophylaxis was not widely used (61). In the US, the Nuclear Regulatory Commission (NRC) requires that consideration be given to potassium iodide as a protective measure for the general public in the case of a major release of radioactivity from a nuclear power plant (62). See also the US FDA’s Potassium Iodide Information.

Disease Treatment

Fibrocystic breast changes

Fibrocystic breast changes constitute a benign (non-cancerous) condition of the breasts, characterized by lumpiness and discomfort in one or both breasts. Cyst formation and fibrous changes in the appearance of breast tissue occur in at least 50% of premenopausal women and are not usually associated with an increased risk of breast cancer (63). The cause of fibrocystic changes is not known, but variations in hormonal stimulation during menstrual cycles may trigger changes in breast tissue (63).

A few observational studies also suggested an association between benign breast diseases (including but not limited to fibrocystic changes) and thyroid disorders. Recently, a small case-control study (166 cases vs. 72 controls) showed that the frequency of benign breast diseases was greater in women with nodular goiter (54.9%) or Hashimoto thyroiditis (47.4%) than in euthyroid controls (29.2%) (64). Conversely, the prevalence of anti-thyroid autoimmunity and hypothyroidism was found to be significantly higher in women with benign breast diseases compared to controls (65, 66). Interestingly, correcting hypothyroidism with supplemental T4 was found to improve some of the benign breast disease symptoms, including breast pain (mastalgia) and nipple discharge (65).

In estrogen-treated rats, iodine deficiency leads to changes similar to those seen in fibrocystic breasts, while iodine repletion reverses those changes (67). An uncontrolled study of 233 women with fibrocystic changes found that treatment with aqueous molecular iodine (I2) at a dose of 0.08 mg of I2/kg of body weight daily over 6 to 18 months was associated with improvement in pain and other symptoms in over 70% of participants (68). About 10% of the study participants reported side effects that were described by the investigators as minor. A double-blind, placebo-controlled trial of aqueous molecular iodine (0.07-0.09 mg of I2/kg of body weight daily for six months) in 56 women with fibrocystic changes found that 65% of the women taking molecular iodine reported improvement compared to 33% of those taking the placebo (68). A double-blind, placebo-controlled trial in 87 women with documented breast pain reported that molecular iodine (1.5, 3, or 6 mg/day) for six months improved overall pain (69). In this study, 38.5% of the women receiving 1.5 mg/day, 37.9% of those receiving 3 mg/day, and 51.7% of those receiving 6 mg/day reported at least a 50% reduction in self-assessed breast pain compared to 8.3% in the placebo group.

Large-scale, controlled clinical trials are needed to determine the therapeutic value of molecular iodine in fibrocystic breasts. Besides, the doses of iodine used in these studies (1.5 to 6 mg/day for a 60 kg person) are higher than the tolerable upper intake level (UL) recommended by the Food and Nutrition Board of the Institute of Medicine and should only be used under medical supervision (see Safety).


Food sources

Data from the ongoing US Total Diet Study, which monitors the levels of some contaminants and nutrients in food products, indicates that dietary iodine intakes in adults range between 138 and 268 micrograms (μg)/day. Considerably higher average intakes (304-353 μg/day of iodine) were reported for boys 14 to 16 years of age (70).

Seafood is rich in iodine because marine animals can concentrate the iodine from seawater. Certain types of edible seaweed (e.g., wakame) are also very rich in iodine (71). The iodine content of food that is grown or raised on a particular soil depends on the iodine content of this soil. In the US, dairy products contribute up to 90% of total estimated iodine intakes in infants, at least 70% in children (ages, 2-10 years), 53%-63% in adolescents (ages, 14-16 years), and about 50% in adults (70). In the UK and northern Europe, iodine levels in dairy products tend to be lower in summer when cattle are allowed to graze in pastures with low soil iodine content (9).

Other good sources of dietary iodine include eggs, fruit, grain products, and poultry (70). Processed foods can contribute to iodine intake if iodized salt or food additives, such as calcium iodate and potassium iodate, are added during production. Yet, in the US, virtually no iodized salt is used in the manufacturing of processed food and fast food products, and the food industry is not required to list the iodine content on food packaging (72). Table 3 lists the iodine content of some iodine-rich foods in micrograms (μg). Because the iodine content of foods can vary considerably, these values should be considered approximate (73).

Table 3. Some Food Sources of Iodine
Food Serving Iodine (μg)
Salt (iodized) 1 gram 77
Cod 3 ounces* 99
Shrimp 3 ounces 35
Fish sticks 2 fish sticks 35
Tuna, canned in oil 3 ounces (½ can) 17
Milk (cow's) 1 cup (8 fluid ounces) 99
Egg, boiled 1 large 12
Navy beans, cooked ½ cup 32
Potato with peel, baked 1 medium 60
Turkey breast, baked 3 ounces 34
Seaweed ¼ ounce, dried Variable; may be greater than 4,500 μg (4.5 mg)
*A three-ounce serving of meat is about the size of a deck of cards.


Over-the-counter iodine supplements

Potassium iodide is available as a nutritional supplement, typically in combination products, such as multivitamin/mineral supplements. Iodine makes up approximately 77% of the total weight of potassium iodide (56). A multivitamin/mineral supplement that contains 100% of the daily value (DV) for iodine provides 150 μg of iodine. Although most people in the US consume sufficient iodine in their diets (see Sources), an additional 150 μg/day is unlikely to result in excessive iodine intake. The American Thyroid Association (ATA) recommends prenatal supplementation with 150 μg/day of iodine and advises against the ingestion of ≥500 μg/day of iodine from iodine, potassium iodine, and kelp supplements for children and adults, and during pregnancy and lactation (see also Safety) (36, 74).

Iodine fortification programs

The fortification of salt with iodine is a feasible and inexpensive method to eliminate iodine deficiency, and salt iodization programs have been implemented in almost all countries. In North America, salt fortification with iodine is mandated in Canada and some parts of Mexico, but only voluntary in the US such that only 52% of US table salt is iodized and only one-fifth of the total salt consumed in the US is iodized (72, 75). Potassium iodide (KI), cuprous iodide (CuI), and potassium iodate (KIO3) are used to iodize salt. The US Food and Drug Administration (FDA) recommends between 46 and 76 μg of iodine per gram of salt in iodized salt. However, the recent analysis of 88 US iodized food-grade salt samples revealed that the iodine content was below the recommended range in 52% of the samples and above the range in 7% of the samples (76).

In other countries, salt commonly contains 20-50 μg of iodine per gram of salt, depending on local regulations (76). In countries like Denmark (77), Australia (78, 79), and New Zealand (80), the use of iodized salt in the bread-making process is mandated. Additional approaches have been explored, including sugar fortification (81), egg fortification (82), use of iodized salt in the preparation of fermented fish and fish sauce (83), and use of iodine-rich crop fertilizers (84). In addition, fortification of livestock feeds with iodine and the use of iodophors for sanitation during milking contribute to increasing iodine content in dairy products (85). Finally, annual doses of iodized vegetable oil are administered orally or intramuscularly to individuals in iodine-deficient populations who do not have access to iodized salt (4, 56).


Acute toxicity

Acute iodine poisoning is rare and usually occurs only with doses of many grams. Symptoms of acute iodine poisoning include burning of the mouth, throat, and stomach, fever, nausea, vomiting, diarrhea, a weak pulse, cyanosis, and coma (1).

Excessive iodine intakes

Risk of iodine-induced hyperthyroidism in iodine-deficient individuals

Iodine supplementation programs in iodine-deficient populations have been associated with an increased incidence of iodine-induced hyperthyroidism (IIH), especially in older people with multi-nodular goiter (86). Iodine intakes of 150-200 μg/day have been found to increase the incidence of IIH in iodine-deficient populations. Iodine deficiency increases the risk of developing autonomous thyroid nodules that are unresponsive to TSH control (see Function). These autonomous nodules may then overproduce thyroid hormones in response to sudden iodine supply. IIH symptoms include weight loss, tachycardia (high pulse rate), muscle weakness, and skin warmth. IIH can be dangerous in individuals with underlying heart disease. Yet, because the primary cause of nodular goiter and IIH is chronic iodine deficiency, the benefit of iodization programs largely outweighs the risk of IIH in iodine-deficient populations (1).

Risk of hypothyroidism in iodine-sufficient individuals

In iodine-sufficient individuals, excess iodine intake is most commonly associated with elevated blood concentrations of thyroid stimulating hormone (TSH) that inhibit thyroid hormone production, leading to hypothyroidism and goiter. A slightly elevated serum TSH concentration without a decrease in serum T4 or T3 is the earliest sign of abnormal thyroid function when iodine intake is excessive. In iodine-sufficient adults, elevated serum TSH has been found at chronic iodine intakes of ≥750 μg/day in children and ≥1,700 μg/day in adults. Because various edible seaweed species substantially contribute to traditional Asian meals, average Japanese dietary intakes are estimated to range between 1,000 and 3,000 μg of iodine/day (71). Iodine-induced goiter and hypothyroidism are not uncommon in Japan and can be reversed by restricting seaweed intake (71). Prolonged intakes of more than 18,000 μg/day (18 mg/day) increase the incidence of goiter in adults. In newborns, iodine-induced goiter and hypothyroidism can be due to either high maternal intakes or high exposure to iodized antiseptics (87). In order to minimize the risk of adverse health effects, the Food and Nutrition Board of the US Institute of Medicine set a tolerable upper intake level (UL) for iodine that is likely to be safe in almost all individuals. The UL values for iodine are listed in Table 4 by age group; the UL does not apply to individuals who are being treated with iodine under medical supervision (74).

Table 4. Tolerable Upper Intake Level (UL) for Iodine
Age Group UL (μg/day)
Infants 0-12 months Not possible to establish*
Children 1-3 years 200
Children 4-8 years   300
Children 9-13 years   600
Adolescents 14-18 years 900
Adults 19 years and older 1,100
*Source of intake should be from food and formula only.
Individuals with increased sensitivity to excess iodine intake

Individuals with iodine deficiency and those with preexisting thyroid disease, including nodular goiter, autoimmune Hashimoto thyroiditis, Graves disease, and a history of partial thyroidectomy, may be sensitive to iodine intake levels considered safe for the general population and may not be protected by the UL for iodine (9). Infants, the elderly, and pregnant and lactating women may also be more susceptible to excess iodine (see Supplements) (74).

Do elevated and/or insufficient iodine intakes increase the risk of thyroid cancer?

Over the past decades, the incidence of thyroid cancer has increased worldwide. In the US, the incidence of thyroid cancer — representing 4% of all newly diagnosed cancers — has increased from 4.9 cases per persons in 1983 to 14.7 cases per 100,000 persons in 2011, but mortality rate from thyroid cancer has remained low (about 0.5 per 100,000 persons) (88). Accounting for over 80% of all thyroid cancers, thyroid papillary cancer is less aggressive and has a better prognosis than thyroid follicular cancer or anaplastic thyroid cancer. The increasing incidence of thyroid cancer worldwide is likely due at least in part to the improved screening and diagnosis activities. However, because it has coincided with the introduction of iodine fortification programs, a possible contribution of increased iodine intakes has been hypothesized. Yet, in the US, the increasing incidence of thyroid cancers (primarily papillary cancer) over the last few decades was paralleled with a reduction in average iodine intake (89).

Ecologic studies also suggested that iodine prophylaxis in populations that were previously iodine deficient was associated with an increased incidence of the papillary rather than the follicular cancer subtype, and with a reduced incidence of the more aggressive anaplastic thyroid cancer (89). While changes in iodine intakes appear to affect the histological type of thyroid cancer, it is not yet clear whether iodine deficiency and/or iodine excess increase the risk of thyroid cancer (88).

Drug interactions

Amiodarone, a medication used to prevent abnormal heart rhythms, contains high levels of iodine and may affect thyroid function (90, 91). Antithyroid drugs used to treat hyperthyroidism, such as propylthiouracil (PTU), methimazole, and carbimazole, may increase the risk of hypothyroidism. Additionally, the long-term use of lithium to treat mood disorders may increase the risk of hypothyroidism (92). Further, the use of pharmacologic doses of potassium iodide may decrease the anticoagulant effect of warfarin (coumarin) (56).


Perchlorate is an oxidizing agent found in rocket propellants, airbags, fireworks, herbicides, and fertilizer. Mainly as a result of human activity, perchlorate has been found to contaminate drinking water and many foods (57). Chronic exposure to perchlorate concentrations at levels greater than 20 μg per kg body weight (bw) per day interferes with iodine uptake by the thyroid gland and may lead to hypothyroidism (93). The US Environment Protection Agency (EPA) recommends that daily oral exposure to perchlorate should not exceed 0.7 μg/kg bw to protect the most sensitive population, i.e., the fetuses of pregnant women who might be deficient in iodine and/or hypothyroid (94). Among all age groups, children aged two years have the highest estimated perchlorate intakes per day with 0.35-0.39 μg/kg bw/day. Average estimated intakes of perchlorate in US adults range between 0.08 and 0.11 μg/kg bw/day (70).

Linus Pauling Institute Recommendation

The RDA for iodine is sufficient to ensure normal thyroid function. There is presently no evidence that iodine intakes higher than the RDA are beneficial. Most people in the US consume sufficient iodine in their diets, making supplementation unnecessary.

Pregnant and breast-feeding women

Given the importance of sufficient iodine during prenatal development and infancy, pregnant and breast-feeding women should take a supplement that provides 150 μg of iodine per day (see Deficiency).

Older adults (>50 years)

Because aging has not been associated with significant changes in the requirement for iodine, the LPI recommendation for iodine intake is not different for older adults.

Authors and Reviewers

Originally written in 2001 by:
Jane Higdon, Ph.D.
Linus Pauling Institute
Oregon State University

Updated in April 2003 by:
Jane Higdon, Ph.D.
Linus Pauling Institute
Oregon State University

Updated in July 2007 by:
Victoria J. Drake, Ph.D.
Linus Pauling Institute
Oregon State University

Updated in March 2010 by:
Victoria J. Drake, Ph.D.
Linus Pauling Institute
Oregon State University

Updated in August 2015 by:
Barbara Delage, Ph.D.
Linus Pauling Institute
Oregon State University

Reviewed in August 2015 by:
Elizabeth N. Pearce, M.D., M.Sc.
Associate Professor of Medicine
Boston University School of Medicine

Copyright 2001-2023  Linus Pauling Institute 


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79.  Clifton VL, Hodyl NA, Fogarty PA, et al. The impact of iodine supplementation and bread fortification on urinary iodine concentrations in a mildly iodine deficient population of pregnant women in South Australia. Nutr J. 2013;12:32.  (PubMed)

80.  Skeaff SA, Lonsdale-Cooper E. Mandatory fortification of bread with iodised salt modestly improves iodine status in schoolchildren. Br J Nutr. 2013;109(6):1109-1113.  (PubMed)

81.  Eltom M, Elnagar B, Sulieman EA, et al. The use of sugar as a vehicle for iodine fortification in endemic iodine deficiency. Int J Food Sci Nutr. 1995;46(3):281-289.  (PubMed)

82.  Charoensiriwatana W, Srijantr P, Teeyapant P, Wongvilairattana J. Consuming iodine enriched eggs to solve the iodine deficiency endemic for remote areas in Thailand. Nutr J. 2010;9:68.  (PubMed)

83.  Chanthilath B, Chavasit V, Chareonkiatkul S, Judprasong K. Iodine stability and sensory quality of fermented fish and fish sauce produced with the use of iodated salt. Food Nutr Bull. 2009;30(2):183-188.  (PubMed)

84.  Weng HX, Liu HP, Li DW, Ye M, Pan L, Xia TH. An innovative approach for iodine supplementation using iodine-rich phytogenic food. Environ Geochem Health. 2014;36(4):815-828.  (PubMed)

85.  Zimmermann MB. Symposium on 'Geographical and geological influences on nutrition': Iodine deficiency in industrialised countries. Proc Nutr Soc. 2010;69(1):133-143.  (PubMed)

86.  Laurberg P, Nohr SB, Pedersen KM, et al. Thyroid disorders in mild iodine deficiency. Thyroid. 2000;10(11):951-963.  (PubMed)

87.  Nishiyama S, Mikeda T, Okada T, Nakamura K, Kotani T, Hishinuma A. Transient hypothyroidism or persistent hyperthyrotropinemia in neonates born to mothers with excessive iodine intake. Thyroid. 2004;14(12):1077-1083.  (PubMed)

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  • Iron is an essential component of hundreds of proteins and enzymes that support essential biological functions, such as oxygen transport, energy production, and DNA synthesis. Hemoglobin, myoglobin, cytochromes, and peroxidases require iron-containing heme as a prosthetic group for their biological activities. (More information)
  • Because the body excretes very little iron, iron metabolism is tightly regulated. In particular, the iron regulatory hormone, hepcidin, blocks dietary iron absorption, promotes cellular iron sequestration, and reduces iron bioavailability when body iron stores are sufficient to meet requirements. (More information)
  • Iron status can be assessed in healthy men and nonpregnant women using laboratory tests that measure serum ferritin (iron-storage protein), serum iron, total iron binding capacity, saturation of transferrin (the main iron carrier in blood), and soluble transferrin receptor. (More information)
  • Iron deficiency results from an inadequate supply of iron to cells following depletion of the body’s reserves. Microcytic anemia occurs when body iron stores are so low that hemoglobin synthesis and red blood cell formation are severely impaired. (More information)
  • Iron deficiency is the most common nutritional deficiency worldwide, affecting primarily children, women of childbearing age, pregnant women, frequent blood donors, and individuals with certain medical conditions. (More information)
  • Much of our iron requirement is met through recycling iron from senescent red blood cells. The recommended dietary allowance (RDA) for iron is 8 mg/day for men and postmenopausal women, 18 mg/day for premenopausal women, and 27 mg/day for pregnant women. (More information)
  • Iron deficiency with or without anemia in children has been associated with poor cognitive development, poor school achievement, and abnormal behavior patterns. Limited evidence suggests that iron supplementation has no effect on psychomotor development and cognitive function of anemic iron-deficient infants younger than three years but may improve attention and concentration in older children, adolescents, and women with anemia and/or iron deficiency. (More information)
  • Heme iron comes from hemoglobin and myoglobin in animal food sources and represents 10%-15% of total dietary iron intake of meat eaters. Yet, because it is much better absorbed than nonheme iron found in both plant and animal food sources, heme iron contributes up to 40% of total absorbed iron. (More information)
  • Toxic iron deposition in vital organs in patients affected by hereditary hemochromatosis has been associated with numerous chronic conditions, including liver cancer and type 2 diabetes mellitus. Increased heme iron intake and/or loss of iron homeostasis might also increase the risk of chronic disease in individuals free of genetic disorders. (More information)
  • Iron supplementation may cause gastrointestinal irritation, nausea, vomiting, diarrhea, or constipation, and interfere with the absorption and efficacy of certain medications, including antibiotics and drugs used to treat osteoporosis, hypothyroidism, or Parkinson’s disease symptoms. (More information)

Iron is the fourth most abundant element of Earth’s crust and one of the best studied micronutrients in nutrition science (1, 2). It is a key element in the metabolism of all living organisms. Iron exists in two biologically relevant oxidation states: the ferrous form (Fe2+) and the ferric form (Fe3+). Iron is an essential component of hundreds of proteins and enzymes supporting essential biological functions, such as oxygen transport, energy production, DNA synthesis, and cell growth and replication.


Heme is an iron-containing compound found in a number of biologically important molecules (Figure 1). Some, but not all, iron-dependent proteins are heme-containing proteins (also called hemoproteins). Iron-dependent proteins that carry out a broad range of biological activities may be classified as follows (1, 3):

  • Globin-heme: nonenzymatic proteins involved in oxygen transport and storage (e.g., hemoglobin, myoglobin, neuroglobin)
  • Heme enzymes involved in electron transfer (e.g., cytochromes a, b, f; cytochrome c oxidase) and/or with oxidase activity (e.g., sulfite oxidase, cytochrome P450 oxidases, myeloperoxidase, peroxidases, catalase, endothelial nitric oxide synthase, cyclooxygenase)
  • Iron-sulfur (Fe-S) cluster proteins with oxidoreductase activities involved in energy production (e.g., succinate dehydrogenase, isocitrate dehydrogenase, NADH dehydrogenase, aconitase, xanthine oxidase, ferredoxin-1) or involved in DNA replication and repair (DNA polymerases, DNA helicases)
  • Nonheme enzymes that require iron as a cofactor for their catalytic activities (e.g., phenylalanine, tyrosine, tryptophan, and lysine hydroxylases; hypoxia-inducible factor (HIF) prolyl and asparaginyl hydroxylases; ribonucleotide reductase)
  • Nonheme proteins responsible for iron transport and storage (e.g., ferritin, transferrin, haptoglobin, hemopexin, lactoferrin).

Iron-containing proteins support a number of functions, some of which are listed below.

Figure 1. Structure of Heme b.

Oxygen transport and storage

Globin-hemes are heme-containing proteins that are involved in the transport and storage of oxygen and, to a lesser extent, may act as free radical scavengers (1). Hemoglobin is the primary protein found in red blood cells and represents about two-thirds of the body's iron (3). The vital role of hemoglobin in transporting oxygen from the lungs to the rest of the body is derived from its unique ability to acquire oxygen rapidly during the short time it spends in contact with the lungs and to release oxygen as needed during its circulation through the tissues. Myoglobin functions in the transport and short-term storage of oxygen in muscle cells, helping to match the supply of oxygen to the demand of working muscles (1). A third globin called neuroglobin is preferentially expressed in the central nervous system, but its function is not well understood (4).

Electron transport and energy metabolism

Cytochromes are heme-containing enzymes that have important roles in mitochondrial electron transport required for cellular energy production and thus life. Specifically, cytochromes serve as electron carriers during the synthesis of ATP, the primary energy storage compound in cells. Cytochrome P450 (CYP) is a family of enzymes involved in the metabolism of a number of important biological molecules (including organic acids; fatty acids; prostaglandins; steroids; sterols; and vitamins A, D, and K), as well as in the detoxification and metabolism of drugs and pollutants. Nonheme iron-containing enzymes in the citric acid cycle, such as NADH dehydrogenase and succinate dehydrogenase, are also critical to energy metabolism (1)

Antioxidant and beneficial pro-oxidant functions 

Catalase and some peroxidases are heme-containing enzymes that protect cells against the accumulation of hydrogen peroxide, a potentially damaging reactive oxygen species (ROS), by catalyzing a reaction that converts hydrogen peroxide to water and oxygen. As part of the immune response, some white blood cells engulf bacteria and expose them to ROS in order to kill them. The synthesis of one such ROS, hypochlorous acid, by neutrophils is catalyzed by the heme-containing enzyme myeloperoxidase (1).

In addition, in the thyroid gland, heme-containing thyroid peroxidase catalyzes the iodination of thyroglobulin for the production of thyroid hormones such that thyroid metabolism can be impaired in iron deficiency and iron-deficiency anemia (see Nutrient Interactions).

Oxygen sensing

Inadequate oxygen (hypoxia), such as that experienced by those who live at high altitudes or those with chronic lung disease, induces compensatory physiologic responses, including increased red blood cell formation (erythropoiesis), increased blood vessel growth (angiogenesis), and increased production of enzymes utilized in anaerobic metabolism. Hypoxia is also observed in pathological conditions like ischemia/stroke and inflammatory disorders. Under hypoxic conditions, transcription factors known as hypoxia-inducible factors (HIF) bind to response elements in genes that encode various proteins involved in compensatory responses to hypoxia and increase their synthesis. Iron-dependent enzymes of the dioxygenase family, HIF prolyl hydroxylases and asparaginyl hydroxylase (factor inhibiting HIF-1 [FIH-1]), have been implicated in HIF regulation. When cellular oxygen tension is adequate, newly synthesized HIF-α subunits (HIF-1α, HIF-2α, HIF-3α) are modified by HIF prolyl hydroxylases in an iron/2-oxoglutarate-dependent process that targets HIF-α for rapid degradation. FIH-1-induced asparaginyl hydroxylation of HIF-α impairs the recruitment of co-activators to HIF-α transcriptional complex and therefore prevents HIF-α transcriptional activity. When cellular oxygen tension drops below a critical threshold, prolyl hydroxylase can no longer target HIF-α for degradation, allowing HIF-α to bind to HIF-1β and form a transcription complex that enters the nucleus and binds to specific hypoxia response elements (HRE) on target genes like the erythropoietin gene (EPO) (5)

DNA replication and repair

Ribonucleotide reductases (RNRs) are iron-dependent enzymes that catalyze the synthesis of deoxyribonucleotides required for DNA replication. RNRs also facilitate DNA repair in response to DNA damage. Other enzymes essential for DNA synthesis and repair, such as DNA polymerases and DNA helicases, are Fe-S cluster proteins. Although the underlying mechanisms are still unclear, depletion of intracellular iron was found to inhibit cell cycle progression, growth, and division. Inhibition of heme synthesis also induced cell cycle arrest in breast cancer cells (6).

Iron is required for a number of additional vital functions, including growth, reproduction, healing, and immune function.


Systemic regulation of iron homeostasis

While iron is an essential mineral, it is potentially toxic because free iron inside the cell can lead to the generation of free radicals causing oxidative stress and cellular damage. Thus, it is important for the body to systemically regulate iron homeostasis. The body tightly regulates the transport of iron throughout various body compartments, such as developing red blood cells (erythroblasts), circulating macrophages, liver cells (hepatocytes) that store iron, and other tissues (7). Intracellular iron concentrations are regulated according to the body’s iron needs (see below), but extracellular signals also regulate iron homeostasis in the body through the action of hepcidin.

Hepcidin, a peptide hormone primarily synthesized by liver cells, is the key regulator of systemic iron homeostasis. Hepcidin can induce the internalization and degradation of the iron-efflux protein, ferroportin-1; ferroportin-1 regulates the release of iron from certain cells, such as enterocytes, hepatocytes, and iron-recycling macrophages, into plasma (8). When body iron concentration is low and in situations of iron-deficiency anemia, hepcidin expression is minimal, allowing for iron absorption from the diet and iron mobilization from body stores. In contrast, when there are sufficient iron stores or in the case of iron overload, hepcidin inhibits dietary iron absorption, promotes cellular iron sequestration, and reduces iron bioavailability. Hepcidin expression is up-regulated in conditions of inflammation and endoplasmic reticulum stress and down-regulated in hypoxia (9). In Type 2B hemochromatosis, deficiency in hepcidin due to mutations in the hepcidin gene, HAMP, causes abnormal iron accumulation in tissues (see Iron Overload). Of note, hepcidin is also thought to have a major antimicrobial role in the innate immune response by limiting iron availability to invading microorganisms (see Iron withholding defense during infection) (10).

Regulation of intracellular iron

Iron-responsive elements (IREs) are short sequences of nucleotides found in the messenger RNAs (mRNAs) that code for key proteins in the regulation of iron storage, transport, and utilization. Iron regulatory proteins (IRPs: IRP-1, IRP-2) can bind to IREs and control mRNA stability and translation, thereby regulating the synthesis of specific proteins, such as ferritin (iron storage protein) and transferrin receptor-1 (TfR; controls cellular iron uptake) (1, 2).

When the iron supply is low, iron is not available for storage or release into plasma. Less iron binds to IRPs, allowing the binding of IRPs to IREs. The binding of IRPs to IREs located in the 5’end of mRNAs coding for ferritin and ferroportin-1 (iron efflux protein) inhibits mRNA translation and protein synthesis. Translation of mRNA that codes for the key regulatory enzyme of heme synthesis in immature red blood cells is also reduced to conserve iron. In contrast, IRP binding to IREs in the 3’ end of mRNAs that code for TfR and divalent metal transporter-1 (DMT1) stimulates the synthesis of iron transporters, thereby increasing iron uptake into cells (1, 2).

When the iron supply is high, more iron binds to IRPs, thereby preventing the binding of IRPs to IREs on mRNAs. This allows for an increased synthesis of proteins involved in iron storage (ferritin) and efflux (ferroportin-1) and a decreased synthesis of iron transporters (TfR and DMT1) such that iron uptake is limited (2). In the brain, IRPs are also prevented from binding to the 5’end of amyloid precursor protein (APP) mRNA, allowing for APP expression. APP stimulates iron efflux from neurons through stabilizing ferroportin-1. In Parkinson’s disease (PD), APP expression is inappropriately suppressed, leading to iron accumulation in dopaminergic neurons (11, 12).

Iron withholding defense during infection

Iron is required by most infectious agents to grow and spread, as well as by the infected host in order to mount an effective immune response. Sufficient iron is critical for the differentiation and proliferation of T lymphocytes and the generation of reactive oxygen species (ROS) required for killing pathogens (13). During infection and inflammation, hepcidin synthesis is up-regulated, serum iron concentrations decrease, and concentrations of ferritin (the iron storage protein) increase, supporting the idea that sequestering iron from pathogens is an important host defense mechanism (2).

Recycling of iron

Total body content of iron in adults is estimated to be 2.3 g in women and 3.8 g in men (2). The body excretes very little iron; basal losses, menstrual blood loss, and the need of iron for the synthesis of new tissue are compensated by the daily absorption of a small proportion of dietary iron (1 to 2 mg/day). Body iron is primarily found in red blood cells, which contain 3.5 mg of iron per g of hemoglobin. Senescent red blood cells are engulfed by macrophages in the spleen, and about 20 mg of iron can be recovered daily from heme recycling. The released iron is either deposited to the ferritin of spleen macrophages or exported by ferroportin-1 (iron efflux protein) to transferrin (the main iron carrier in blood) that delivers iron to other tissues. Iron recycling is very efficient, with about 35 mg being recycled daily (1).

Assessment of iron status

Measurements of iron stores, circulating iron, and hematological parameters may be used to assess the iron status of healthy people in the absence of inflammatory disorders, parasitic infection, and obesity. Commonly used iron status biomarkers include serum ferritin (iron-storage protein), serum iron, total iron binding capacity (TIBC), and saturation of transferrin (the main iron carrier in blood; TSAT). Soluble transferrin receptor (sTfR) is also an indicator of iron status when iron stores are depleted. In iron deficiency and iron-deficiency anemia, the abundance of cell surface-bound transferrin receptors that bind diferric transferrin is increased in order to maximize the uptake of available iron. Therefore, the concentration of sTfR generated by the cleavage of cell-bound transferrin receptors is increased in iron deficiency. Hematological markers, including hemoglobin concentration, mean corpuscular hemoglobin concentration, mean corpuscular volume of red blood cells, and reticulocyte hemoglobin content can help detect abnormality if anemia is present (9, 14).

Of note, serum ferritin is an acute-phase reactant protein that is up-regulated by inflammation. Importantly, serum hepcidin concentration is also increased by inflammation to limit iron availability to pathogens. Therefore, it is important to include inflammation markers (e.g., C-reactive protein, fibrinogen) when assessing iron status to rule out inflammation (14).

Nutrient Interactions

Vitamin A

Vitamin A deficiency often coexists with iron deficiency and may exacerbate iron-deficiency anemia by altering iron metabolism (15). Vitamin A supplementation has been shown to have beneficial effects on iron-deficiency anemia and improve iron nutritional status among children and pregnant women (15, 16). The combination of vitamin A and iron seems to reduce anemia more effectively than either supplemental iron or vitamin A alone (17). Vitamin A may facilitate the mobilization of iron from storage sites to developing red blood cells for incorporation into hemoglobin (15, 16). Moreover, studies in rats have shown that iron deficiency alters plasma and liver levels of vitamin A (18, 19).


Adequate copper nutritional status is necessary for normal iron metabolism and red blood cell formation. Anemia is a clinical sign of copper deficiency, and iron has been found to accumulate in the livers of copper-deficient animals, indicating that copper (via copper-containing ceruloplasmin) is required for iron transport to the bone marrow for red blood cell formation (20). The connection between copper availability and iron metabolism has also been established in humans; copper deficiency can lead to secondary ceruloplasmin deficiency and hepatic iron overload and/or cirrhosis (21). Oral copper supplementation restored normal ceruloplasmin levels and plasma ferroxidase activity and corrected the iron metabolism disorder in a copper-deficient subject (22). Moreover, infants fed a high-iron formula absorbed less copper than infants fed a low-iron formula, suggesting that high iron intakes may interfere with copper absorption in infants (23).


Zinc is essential to maintain adequate erythropoiesis. When zinc deficiency coexists with iron deficiency, it may exacerbate iron-deficiency anemia (24). On the other hand, high doses of iron supplements, taken together with zinc supplements on an empty stomach, may inhibit the absorption of zinc. When taken with food, supplemental iron does not appear to inhibit zinc absorption. Iron-fortified foods have not been found to impair zinc absorption (25, 26).


The presence of calcium decreases iron absorption from both nonheme (i.e., most supplements and food sources other than meat, poultry, and seafood) and heme sources (27). However, calcium supplementation up to 12 weeks has not been found to change iron nutritional status, probably due to a compensatory increase in iron absorption (28). Individuals taking iron supplements should take them two hours apart from calcium-rich food or supplements to maximize iron absorption.


Severe iron-deficiency anemia can impair thyroid metabolism in the following ways: (1) by altering the thyroid-stimulating hormone response of the pituitary gland; (2) by reducing the activity of thyroid peroxidase that catalyzes the iodination of thyroglobulin for the production of thyroid hormones; and (3) in the liver by limiting the conversion of T4 to T3, increasing T3 turnover, and decreasing T3 binding to nuclear receptors (29). It is estimated that goiter and iron-deficiency anemia coexist in up to 25% of school-age children in west and north Africa (30). A randomized controlled study in iron-deficient children with goiter showed a greater reduction in thyroid size following the consumption of iodized salt together with 60 mg/day of iron four times per week compared to placebo (31). Additional interventions have confirmed that correcting iron-deficiency anemia improved the efficacy of iodine supplementation to mitigate thyroid disorders (reviewed in 29, 30).


Levels of iron deficiency

Iron deficiency is the most common nutrient deficiency in the US and the world. Levels of iron deficiency are listed below from least to most severe.

Storage iron depletion

Iron stores are depleted, but the functional iron supply is not limited. 

Early functional iron deficiency

Before the development of frank anemia, the supply of functional iron to tissues, including bone marrow, is inadequate such as to impair erythropoiesis.  

Iron-deficiency anemia

By definition, anemia is present when individual hemoglobin concentrations fall below two standard deviations of the distribution mean for hemoglobin in a healthy population of the same gender and age and living at the same altitude (32). In 2013, iron-deficiency anemia was the leading cause of years lived with disability in children and adolescents in the 50 most populous countries. The countries with the highest prevalence of iron-deficiency anemia in individuals younger than 19 years were Afghanistan (41%) and Yemen (39.8%); India contributed the largest number of cases of anemia (147.9 million). The prevalence in the US was estimated to be 19.3% with nearly 16 million cases of iron-deficiency anemia in children and adolescents (33).

Iron-deficiency anemia occurs when there is inadequate iron to support normal red blood cell formation. The anemia of iron deficiency is usually characterized as microcytic and hypochromic, i.e., red blood cells are measurably smaller than normal and their hemoglobin content is decreased such that they are paler than normal. At this stage of iron deficiency, symptoms may be a result of inadequate oxygen delivery due to anemia and/or suboptimal function of iron-dependent enzymes. Changes in hematological parameters are used in the clinical diagnosis of iron-deficiency anemia (see Assessment of iron status). It is important to remember that iron deficiency is not the only cause of anemia, and that the diagnosis or treatment of iron deficiency solely on the basis of anemia may lead to misdiagnosis or inappropriate treatment of the underlying cause (34). See also the articles on Folate and Vitamin B12 for information on other nutritional causes of anemia.

Symptoms of iron deficiency

Most of the symptoms of iron deficiency are a result of the associated anemia and may include fatigue, rapid heart rate, palpitations, and rapid breathing on exertion. Iron deficiency impairs athletic performance and physical work capacity in several ways. In iron-deficiency anemia, the reduced hemoglobin content of red blood cells results in decreased oxygen delivery to active tissues. Decreased myoglobin levels in muscle cells limit the amount of oxygen that can be delivered to mitochondria for oxidative metabolism. Iron depletion also decreases the oxidative capacity of muscle by diminishing the mitochondrial content of cytochromes and other iron-dependent enzymes required for electron transport and ATP synthesis (see Function) (35).

Poor thyroid function and impaired thyroid hormone synthesis likely disrupt the ability to maintain a normal body temperature on exposure to cold in iron-deficient individuals (see Function). Iron deficiency may also impair neutrophil phagocytosis and microbicidal activity and T-lymphocyte proliferative responses to infection (1). Severe iron-deficiency anemia may result in brittle and spoon-shaped nails, sores at the corners of the mouth, taste bud atrophy, and a sore tongue. In rare cases, advanced iron-deficiency anemia may cause difficulty in swallowing due to the formation of webs of tissue in the throat and esophagus due to a degradation of the pharyngeal muscles (36). The development of esophageal webs, also known as Plummer-Vinson syndrome, may require a genetic predisposition in addition to iron deficiency. Iron deficiency and iron-deficiency anemia in early childhood have been shown to impair psychomotor development and induce short- and long-term behavioral and cognitive alterations (reviewed in 37). Further, pica, a behavioral disturbance characterized by the consumption of non-food items, may be a symptom and a cause of iron deficiency (38).

Individuals at increased risk of iron deficiency

Life stage groups with increased requirements

Neonates and infants up to six months of age: Inadequate maternal iron body stores and anemia during pregnancy may reduce the duration of gestation and birth weight; preterm and/or low body-weight newborns are at increased risk of iron-deficiency anemia (14). Pregnancy complications, including preeclampsia and gestational diabetes mellitus, may also lead to low iron stores in preterm and term infants (14).

Most of the 150 to 250 mg of iron present in a full-term healthy newborn is accumulated during the third trimester of pregnancy and is sufficient for the first four to six months of life (34). Iron stores are essential for infants less than six months of age because breast milk is relatively poor in iron (0.2 mg/L-0.4 mg/L), and intestinal absorption of iron remains low until six months of age. High iron requirements during this period of sustained and rapid growth rate can worsen the deficit in body iron in preterm infants (14). Moreover, a review of randomized controlled trials suggested that infants with an early umbilical cord clamping (≤1 min after birth) are at least twice more likely to be iron-deficient at three to six months compared to those with delayed cord clamping (39). Yet, healthy full-term infants have little need for external sources of iron before six months of age (1).

Infants and children between the ages of 6 months and 3 years: A full-term infant's iron stores are usually sufficient to last for the early months of life, but there is an increased risk of iron deficiency for infants older than six months (1). Given the sustained need of iron for increasing tissue mass, blood volume, and replenishing iron stores, the recommended dietary allowance (RDA) for iron is 11 mg/day for infants aged seven to 12 months, as established by the US Institute of Medicine (see Table 1).

The RDA for iron is 7 mg/day for toddlers aged 1 to 3 years old. Based on the US National Health and Nutrition Examination Survey (NHANES) 1999-2002 data, the prevalence of iron deficiency in toddlers aged 12 to 35 months varies from 6.6%-15.2%, and the prevalence of iron-deficiency anemia is 0.9%-4.4%, depending on ethnicity and socioeconomic status (14).

Of note, the World Health Organization (WHO) and the American Academy of Pediatrics recommend universal screening for anemia at one year of age. Yet, a recent report by the US Preventive Services Task Force (USPSTF) stated there was insufficient evidence to assess the benefits versus harms of screening (34, 40).

Adolescents: Early adolescence is period of rapid growth. Blood loss that occurs with menstruation in adolescent girls adds to the increased iron requirement of adolescence (1). The RDA of iron is 11 mg/day and 15 mg/day for adolescent boys and girls, respectively (see Table 1).

Nonpregnant women of childbearing age: Based on data from NHANES 2003-2006, the percentage of US women with two out of three markers of iron status (i.e., hemoglobin, ferritin, and % transferrin saturation) below cutoff values for deficiency was 9.8% in nonpregnant women (41).

The use of oral contraceptives decreases menstrual blood losses and is thus associated with improved iron status compared to intrauterine devices (copper coil) (1).

Breast-feeding is associated with lower dietary iron needs, allowing for the repletion of iron stores depleted during pregnancy and delivery. However, iron repletion may be incomplete in high-parity women who are therefore at increased risk of iron deficiency (41).

Pregnant women: The requirement for iron is significantly increased during pregnancy due to increased iron utilization by the developing fetus and placenta, as well as maternal blood volume expansion (42). Analysis of data from NHANES 2005-2006 found that 18.1% of pregnant women (mean age, 27.5 years) were deficient in iron, as assessed by the log ratio of soluble transferrin receptor to serum ferritin (43). The prevalence of iron deficiency was greater during the second (20.7%) and third (29.7%) trimesters compared to the first trimester (4.5%) of gestation. Further, iron deficiency in pregnancy was found to be more prevalent in Mexican (23.6%) and Black Americans (29.6%) than in non-Hispanic White Americans (13.9%) (43).

Individuals with chronic blood losses

Chronic bleeding or acute blood loss may result in iron deficiency. One milliliter (mL) of blood with a hemoglobin concentration of 150 g/L contains 0.5 mg of iron. Thus, chronic loss of very small amounts of blood may result in iron deficiency.

Parasitic infestation: A common cause of chronic blood loss and iron deficiency in developing countries is intestinal parasitic infection (44).

Frequent blood donation: Individuals who donate blood frequently, especially menstruating women, may need to increase their iron intake to prevent deficiency because each 500 mL of blood donated contains between 200 and 250 mg of iron (45, 46)

Regular intense exercise: Daily iron losses have been found to be greater in athletes involved in intense endurance training. This may be due to expanding blood cell mass and muscle mass, increased microscopic bleeding from the gastrointestinal tract (with the regular use of anti-inflammatory drugs), or increased fragility and hemolysis of red blood cells (47). The Food and Nutrition Board estimates that the average requirement for iron may be 30% higher for those who engage in regular intense exercise (25).

Individuals with decreased iron absorption

Celiac disease: Celiac disease (celiac sprue) is an autoimmune disorder estimated to occur in 1% of the population. When people with celiac disease consume food or products that contain gluten, the immune system response damages the intestinal mucosa, which may result in nutrient malabsorption and iron-deficiency anemia (48).

Atrophic gastritis: This condition is usually associated with the presence of antibodies directed towards stomach cells and has been implicated in pernicious anemia (see the article on Vitamin B12). Atrophic gastritis simultaneously impairs the absorption of both vitamin B12 and iron; yet, in menstruating women, iron deficiency may occur years before the depletion of vitamin B12 body stores (47).

Helicobacter pylori infection: H. pylori infection is associated with iron-deficiency anemia, especially in children, even in the absence of gastrointestinal bleeding. Data from NHANES 2000-2001 in individuals older than three years showed that the presence of iron deficiency (based on serum ferritin concentrations) was 40% more prevalent in those infected with H. pylori than in H. pylori-free individuals (49). Occult gastrointestinal bleeding and competition for dietary iron by bacteria may explain iron deficiency in infected individuals. Moreover, Helicobacter pylori infection may also play a role in the pathogenesis of atrophic gastritis (47).

Inflammatory bowel diseases (IBD): Iron-deficiency anemia is commonly reported among patients with IBD (e.g., ulcerative colitis, Crohn’s disease), likely due to both impaired intestinal absorption of iron and blood loss from ulcerated mucosa (50).

Gastric bypass surgery: Some types of gastric bypass (bariatric) surgery increase the risk of iron deficiency by causing malabsorption of iron, among other nutrients (51).

Obesity: An inverse association between body weight and iron status has been reported in several observational studies in children and adults (52, 53). Higher hepcidin expression in obese people may impair iron absorption despite adequate dietary intake of iron. Weight loss might lower serum hepcidin concentration and improve iron status in obese individuals (9).

Anemia of chronic disease: Acute and chronic inflammation may lead to abnormally low circulating concentrations of iron and to the development of anemia. This type of anemia of inflammation, also known as anemia of chronic disease (ACD), is commonly observed in inflammatory disorders, cancer, critical illness, trauma, chronic infection, and parasitic infestation. It is thought that anemia develops because dietary iron absorption and iron mobilization from body stores are inhibited by inflammation-induced hepcidin up-regulation (see also Systemic regulation of iron homeostasis) (9).

Other causes of iron deficiency

Vegetarian diet with inadequate sources of iron: Because iron from plants (nonheme iron) is less efficiently absorbed than that from animal sources (see Sources), the US Food and Nutrition Board (FNB) of the Institute of Medicine (IOM) estimated that the bioavailability of iron from a vegetarian diet was only 10% versus 18% from a mixed Western diet. Therefore, the recommended dietary allowance (RDA) of iron for individuals consuming a completely vegetarian diet may be 1.8 times higher than the RDA for non-vegetarians (25). Yet, a vegetarian diet does not appear to be associated with an increased risk of iron deficiency when it includes whole grains, legumes, nuts, seeds, dried fruit, iron-fortified cereal, and green leafy vegetables (see Sources) (54).

Chronic kidney disease (CKD): Iron losses in CKD patients are due to significant gastrointestinal blood loss (1.2 L blood loss/year corresponding to ~400 mg iron/year) compared to individuals with normal kidney function (0.83 mL blood loss/day corresponding to ~100 mg iron/year). Estimated blood losses are even larger in patients on hemodialysis, and iron losses may be 1,000 to 2,000 mg/year or higher. Persistent inflammation in CKD patients may also contribute to inadequate iron supply for red blood cell formation despite adequate body iron stores (55).

The Recommended Dietary Allowance (RDA)

The RDA for iron was revised in 2001 and is based on the prevention of iron deficiency and maintenance of adequate iron stores in individuals eating a mixed diet (Table 1; 25).

Table 1. Recommended Dietary Allowance (RDA) for Iron
Life Stage Age Males (mg/day) Females (mg/day)
Infants 0-6 months 0.27 (AI) 0.27 (AI)
Infants 7-12 months 11 11
Children 1-3 years 7 7
Children 4-8 years 10 10
Children 9-13 years 8 8
Adolescents 14-18 years 11 15
Adults 19-50 years 8 18
Adults 51 years and older 8 8
Pregnancy all ages - 27
Breast-feeding 18 years and younger - 10
Breast-feeding 19 years and older - 9

Disease Prevention

Prevention or alleviation of iron deficiency or iron-deficiency anemia can limit the impact of iron inadequacy and defective erythropoiesis on the following health conditions and diseases.

Impaired psychomotor, cognitive, and intellectual development in children

Iron is critical for the development of the central nervous system, and iron deficiency is thought to be especially detrimental during the prenatal and early postnatal periods. Iron-dependent enzymes are required for nerve myelination, neurotransmitter synthesis, and normal neuronal energy metabolism (56). Most observational studies have found relationships between iron deficiency — with or without anemia — in children and poor cognitive development, poor school achievement, and abnormal behavior patterns (reviewed in 37). Whether psychomotor and mental deficits may be attributed to the lack of iron, only, or to a combination effect of iron deficiency and low hemoglobin concentrations — like in iron-deficiency anemia and anemia of inflammation — in early childhood remains unclear (14).

A recent systematic review of six small placebo-controlled trials (published between 1978 and 1989) in children with iron-deficiency anemia younger than 27 months found no convincing evidence that iron therapy (for less than 11 days) had any consistent effect on measures of psychomotor and mental development within 30 days of treatment initiation (57). Only one randomized, double-blind trial in anemic, iron-deficient infants examined the impact of iron therapy for four months and found a significant benefit on indices of cognitive development that needs to be further confirmed (58). A review of five randomized controlled trials in non-anemic, iron-deficient infants (0-9 months old) suggested an improvement in psychomotor (but not mental) development throughout the first 18 months of life (59). Iron supplementation in early infancy (4 to 6 months) also failed to demonstrate any long-term effect on cognitive performance and school performance at the age of 9 years compared to placebo (60). At present, evidence supporting any benefits of iron therapy on neurodevelopment outcomes in infants with iron deficiency, with or without anemia, remains limited.

Iron therapy might be more effective at improving cognitive outcomes in older children with anemia and/or iron deficiency. A systematic review of 17 randomized controlled trials found that iron supplementation had no effect on mental development of children under the age of 27 months but modestly improved scores of mental development in children over seven years of age (61). A more recent meta-analysis of randomized controlled trials in children older than six years, adolescents, and women with iron deficiency, anemia, or iron-deficiency anemia suggested that supplemental iron could improve attention and concentration irrespective of participants’ iron status (62). A potential improvement in IQ measures with iron therapy was also reported in anemic participants regardless of their iron status. No additional benefits were observed regarding measures of memory performance, psychomotor function, and school achievements.

Alterations in brain functions due to iron deficiency are likely to be resistant to iron therapy when they occur in early childhood. Long-term consequences of early life iron deficiency may include poor socioeconomic achievements and increased risk of certain psychopathologies, including anxiety, depression, and schizophrenia (56).

Adverse pregnancy outcomes

Epidemiological studies provide strong evidence of an association between severe anemia in pregnant women and adverse pregnancy outcomes, such as low birth weight, preterm birth, and neonatal and maternal mortality (63). Although iron deficiency can be a major contributing factor to severe anemia, evidence that iron-deficiency anemia causes poor pregnancy outcomes is still lacking. In addition, iron supplementation during pregnancy was shown to improve iron status and hematological parameters in women but failed to significantly reduce adverse pregnancy outcomes, including low birth weight and/or prematurity, neonatal death, and congenital anomalies (64). Moreover, routine supplementation during pregnancy had no effect on the length of gestation or newborn Apgar scores (40). Nevertheless, most experts consider the control of maternal anemia to be an important part of prenatal health care, and the IOM recommends screening for anemia in each trimester of pregnancy (65).

The requirement for iron is greatly increased in the second and third trimesters, and the RDA for pregnant women is 27 mg/day of iron (see The Recommended Dietary Allowance) (25). The American College of Obstetricians and Gynecologists recommend screening all pregnant women for anemia and advise iron supplementation when required (66). Nonetheless, the US Preventive Services Task Force (40) and the American Academy of Family Physicians (67) consider that evidence is lacking to evaluate the harms and benefits of screening for iron-deficiency anemia and supplementing with iron during pregnancy.

In malaria-endemic regions, however, iron supplementation may improve pregnancy outcomes when provided in conjunction with measures of prevention and management of malaria. Two recent randomized, placebo-controlled trials failed to find an increased risk of malaria infection in both iron-deficient and iron-replete pregnant women supplemented with iron, supporting the use of universal iron supplementation in malaria-endemic countries that adopt malaria intermittent preventive treatment (IPT) (68, 69).

Lead toxicity

Children who are chronically exposed to lead, even in small amounts, are more likely to develop learning disabilities, behavioral problems, and have low IQs. Deficits in growth and neurologic development may occur in the infants of women exposed to lead during pregnancy and lactation. In adults, lead toxicity may result in kidney damage and high blood pressure. Although the use of lead in paint products, gasoline, and food cans has been discontinued in the US, lead toxicity continues to be a significant health problem, especially in children living in inner cities (70). In 2012, the US Centers for Disease Control and Prevention set the reference value for blood lead concentration at 5 micrograms per deciliter (μg/dL) to identify children at risk. Yet, there is no known blood lead concentration below which children are 100% safe (71).

Iron deficiency and lead poisoning share a number of the same risk factors, including low socioeconomic status, ethnic minority groups, and residence in urban areas. Iron deficiency may increase the risk of lead poisoning in children, especially by increasing the intestinal absorption of lead via the DMT1 intestinal transporter (72). However, the use of iron supplementation in lead poisoning might be reserved for children who are truly iron deficient or for iron-replete children with chronic lead exposure (e.g., living in lead-exposed housing) (72)

Disease Treatment

Restless legs syndrome

Restless legs syndrome (RLS; also called Willis-Ekbom disease) is a neurologic movement disorder of unknown etiology. People with RLS experience unpleasant sensations resulting in an irresistible urge to move their legs and transient relief with movement. These sensations are more common at rest and often interfere with sleep (73). The prevalence of RLS is higher in women than in men and increases with age (74). This syndrome appears to be inherited in about 50% of patients but has also been related to chronic kidney failure (73). Iron deficiency may be involved in RLS development, possibly by affecting the activity of tyrosine hydroxylase, a rate limiting iron-dependent enzyme in the synthesis of the neurotransmitter, dopamine (74). The management of RLS includes iron therapy and the use of drugs like dopamine agonists (73). Current clinical evidence is insufficient to evaluate whether iron therapy may help relieve some RLS symptoms (74). Yet, the Medical Advisory Board of the Willis-Ekbom Disease Syndrome Foundation suggests that iron status should be assessed in all patients with RLS, and iron therapy be attempted on a case-by-case basis in those who might benefit from it (73).     


Food sources

The amount of iron in food or supplements that is absorbed and used by the body is influenced by the iron nutritional status of the individual and whether or not the iron is in the form of heme. Because it is absorbed by a different mechanism than nonheme iron, heme iron is more readily absorbed and its absorption is less affected by other dietary factors (2). In an attempt to improve body iron status, iron absorption is enhanced in individuals who are anemic or iron deficient compared to iron-replete individuals.

Heme iron

Heme iron comes mainly from hemoglobin and myoglobin in meat, poultry, and fish. Although heme iron accounts for only 10%-15% of the iron found in the diet, it may provide up to one-third of total absorbed dietary iron (54). The absorption of heme iron is less influenced by other dietary factors than that of nonheme iron (27)

Nonheme iron

Plants, dairy products, meat, and iron salts added to food and supplements are all sources of nonheme iron. The absorption of nonheme iron is strongly influenced by enhancers and inhibitors present in the same meal (27).

Enhancers of nonheme iron absorption

  • Vitamin C (ascorbic acid): Vitamin C strongly enhances the absorption of nonheme iron by reducing dietary ferric iron (Fe3+) to ferrous iron (Fe2+) and forming an absorbable, iron-ascorbic acid complex (75)
  • Other organic acids: Citric, malic, tartaric, and lactic acids have some enhancing effects on nonheme iron absorption (1)
  • Meat, poultry, and fish: Aside from providing highly absorbable heme iron, meat, fish, and poultry also enhance nonheme iron absorption. The mechanism for this enhancement of nonheme iron absorption is not clear (1, 25)

Inhibitors of nonheme iron absorption

  • Phytic acid (phytate): Phytic acid, present in legumes, whole grains, nuts, and seeds, inhibits nonheme iron absorption, probably by binding to it. Small amounts of phytic acid (5 to 10 mg) can reduce nonheme iron absorption by 50%. The absorption of iron from legumes, such as soybeans, black beans, lentils, mung beans, and split peas, has been shown to be as low as 2% (25). Food preparation, including soaking, germination, fermentation, and cooking, can help remove or degrade phytic acid (27).
  • Polyphenolic compounds: Polyphenolic compounds in coffee, black tea, and herbal tea can markedly inhibit the absorption of nonheme iron (76). This effect may be reduced by the presence of vitamin C (27, 77).
  • Soy protein: Soy protein, such as that found in tofu, has an inhibitory effect on iron absorption that is only partly related to its phytic acid content (27, 77).
  • Calcium: Calcium appears to affect iron absorption from both heme and nonheme sources. Yet, its effect appears to be limited when one consumes a wide variety of food with varied levels of enhancers and inhibitors of iron absorption (27).

National surveys in the US have indicated that the average dietary intake of iron is 16 to 18 mg/day in men, 12 mg/day in pre- and postmenopausal women, and about 15 mg/day in pregnant women (25). Thus, the majority of premenopausal and pregnant women in the US consume less than the RDA for iron, and many men consume more than the RDA (see The Recommended Dietary Allowance). In the US, most grain products are fortified with nonheme iron. The iron content of some relatively iron-rich foods is listed in milligrams (mg) in Table 2. For more information on the nutrient content of specific foods, search USDA's FoodData Central.

Table 2. Some Food Sources of Iron
Food Serving Iron (mg)
Beef 3 ounces* 1.6
Chicken, liver, cooked, pan-fried 1 ounce 3.6
Oysters, Pacific, cooked 6 medium  13.8
Oysters, Eastern, cooked 6 medium   3.9
Clams, cooked, steamed 3 ounces   2.4
Tuna, light, canned in water 3 ounces   1.3
Mussels, cooked, steamed 3 ounces  5.7
Raisin bran cereal 1 cup  5.8-18.0
Raisins, seedless 1 small box (1.5 ounces)   0.8
Prune juice 6 fluid ounces  2.3
Prunes (dried plums) ~5 prunes (1.7 ounces)   0.4
Potato, with skin, baked 1 medium potato  1.8
Quinoa, cooked  ½ cup 1.4
Spinach, cooked 1 cup  6.4
Swiss chard, cooked, boiled ½ cup 2.0
Beans, white, cooked ½ cup 3.3
Lentils, cooked ½ cup 3.3
Tofu, regular, raw ½ cup  6.6
Hazelnuts, dry-roasted 1 ounce 1.3
Cashews 1 ounce 1.9
*A three-ounce serving of meat is about the size of a deck of cards.


Iron supplements are indicated for the prevention and treatment of iron deficiency and iron deficiency anemia. Individuals who are not at risk of iron deficiency (e.g., adult men and postmenopausal women) should not take iron supplements without an appropriate medical evaluation. A number of iron supplements are available, and different forms provide different proportions of elemental iron. Ferrous sulfate heptahydrate is 20% elemental iron, ferrous sulfate monohydrate is 33% elemental iron, ferrous gluconate is 12% elemental iron, and ferrous fumarate is 33% elemental iron. If not stated otherwise, the iron discussed in this article is elemental iron.

Iron Overload

Deregulation of intestinal iron absorption will result in iron overload because the body cannot excrete excess iron (2). However, iron overload due to prolonged iron supplementation is very rare in healthy individuals without a genetic predisposition. Several genetic disorders may lead to pathological accumulation of iron in the body despite normal iron intake. Supplementation of individuals who are not iron deficient should be avoided due to the frequency of undetected inherited diseases and recent concerns about the more subtle effects of chronic excess iron intake (see Diseases associated with iron overload).

Inherited iron-overload diseases

Hereditary hemochromatosis

Hereditary hemochromatosis (HH) refers to late-onset, autosomal recessive disorders of iron metabolism that result in iron accumulation in the liver, heart, and other tissues. Disorders may lead to cirrhosis of the liver, diabetes mellitus, cardiomyopathy (heart muscle damage), hypogonadism, arthropathy (joint problems), and increased skin pigmentation (reviewed in 78). There are four main types of HH, which are classified according to the specific gene that is mutated. The most common type of HH, called Type 1 or HFE-related HH, results from mutations in the HFE gene (79, 80). The majority of Type 1 HH cases are homozygous for mutation C282Y G>A (rs1800560) in the HFE gene. Another mutation found in 4% of patients with Type 1 HH is H63D C>G (rs1799945) in the HFE gene. The protein encoded by the HFE gene is thought to play a role in regulating intestinal absorption of dietary iron and with sensing the body’s iron stores (81). HFE gene mutations are associated with an increased cellular uptake of iron. With a typical disease onset before age 30, juvenile hemochromatosis (HH Type 2) is much rarer than Type 1 HH and results from genetic mutations affecting either hemojuvelin (Type 2A) or hepcidin (Type 2B) function (82). HH Type 3 results from mutations in the transferrin receptor 2 gene (TFR2), and HH Type 4 (also called Ferroportin disease) results from mutations in the gene encoding ferroportin-1 (SLC40A1), a protein important in the export of iron from cells (see Regulation). Type 4 HH is the second most common inherited iron overload disorder after Type 1 HH (78).

Iron overload in HH is treated by phlebotomy, the removal of 500 mL of blood at a time, at intervals determined by the severity of the iron overload. Chelation therapy is an alternate option to deplete iron in HH patients who cannot undergo phlebotomy treatment. Individuals with HH are advised to avoid supplemental iron, but generally not told to avoid iron-rich food. High-dose vitamin C regimens may worsen iron overload in patients with HH (75). Alcohol consumption is strongly discouraged due to the increased risk of cirrhosis of the liver (83). Genetic testing, which requires a blood sample, is available for those who may be at risk for HH, for example, individuals with a family history of hemochromatosis. 

Other inherited conditions

Other genetic disorders leading to iron overload include aceruloplasminemia, hypotransferrinemia, Friedreich’s ataxia, and porphyria cutanea tarda (2)

Acquired iron-overload diseases

Iron overload may develop in individuals with severe hereditary anemias that are not caused by iron deficiency. Excessive dietary absorption of iron may occur in response to the body's continued efforts to form red blood cells. Beta-thalassemia is characterized by defective hemoglobin A synthesis due to mutations in the β-globin gene. Patients affected by thalassemia intermedia do not require blood transfusion as do those affected by the most severe form of the disease (called thalassemia major), yet they develop iron overload due to increased intestinal iron absorption (84). Other anemic patients at risk of iron overload include those with sideroblastic anemia, hemolytic anemia, pyruvate kinase deficiency, and thalassemia major, especially because they are treated with numerous transfusions. Patients with hereditary spherocytosis and thalassemia minor do not usually develop iron overload unless they are misdiagnosed as having iron deficiency and treated with large doses of iron over many years. Iron overload has also been associated with hemodialysis and chronic liver diseases (metabolic, viral, and alcoholic) (2).

Diseases associated with iron overload

Toxic iron deposition in vital organs in hereditary hemochromatosis (HH) has been associated with an increased incidence of liver cancer, type 2 diabetes mellitus, and neurodegenerative disease. Iron overload might also increase the risk of chronic disease in HH-free individuals. Nevertheless, whether iron tissue accumulation in those unaffected by genetic disorders is due to high dietary iron intakes is not yet fully understood (1).


Hereditary hemochromatosis that is characterized by abnormal hepatic iron accumulation is a risk factor for liver cancer (hepatocellular carcinoma; HCC). Iron accumulation is thought to function as a carcinogen by increasing oxidative stress that causes damage to lipids, proteins, and DNA. A meta-analysis of nine observational studies found an increased HCC risk with the C282Y mutation in the HFE gene of healthy participants and patients with chronic liver disease (see Iron Overload) (85). Other meta-analyses have reported associations between HFE gene mutations C282Y and H63D and increased risks of overall cancer (86, 87). However, studies reporting on HFE gene mutations and risk of cancer at extra-hepatic sites are rather scarce and/or inconsistent. Some, but not all, observational studies found significant associations between the C282Y mutation and risk of colorectal (88), breast (88, 89), and epithelial ovarian cancer (90). The presence of the H63D mutation in the HFE gene was linked to an increased risk of leukemia (91, 92) and gastric cancer (93).

Whether high dietary iron could increase the risk of cancer in individuals without hemochromatosis has also been investigated. The consumption of red or processed meat (but not white meat), rich in heme iron, has been linked to an increased risk of colorectal cancer (CRC) (94). Exposure to carcinogenic compounds (called heterocyclic amines) generated when meat is cooked at high temperatures and to carcinogenic N-nitroso compounds formed in the gastrointestinal tract following consumption of red and processed meat may explain such an association (95). Several meta-analyses of observational studies have also suggested a potential association of heme iron in red meat with CRC (96-98). This has been explained by an increased exposure of colonic cells to potentially damaging N-nitroso compounds and lipid peroxidation end-products derived from heme iron-catalyzed reactions (99). Further, recent results from the large European Prospective Investigation into Cancer and Nutrition (EPIC) study suggested a higher risk of esophageal adenocarcinoma with high intakes of red/processed meat and heme iron (100).

Cardiovascular disease

Experimental studies have suggested a role for iron-induced oxidative stress in vessel wall damage and the development of atherosclerosis, which underlies most forms of cardiovascular disease (101). However, epidemiological studies of iron nutritional status and cardiovascular disease in humans have yielded conflicting results. A recent systematic review and meta-analysis of 17 prospective cohort studies in 156,427 participants (9,236 cases of coronary heart disease [CHD] or myocardial infarction [MI]) did not find evidence to support the existence of strong associations between a number of different measures of iron status and CHD/MI (102). Only individuals in the highest versus lowest tertile of serum transferrin saturation exhibited an 18% lower incidence of CHD/MI (102). Another meta-analysis of 21 prospective studies found serum transferrin saturation and serum iron to be inversely associated with the risk of CHD. However, the authors noted that most studies failed to adjust for the confounding effects of inflammation (103). The review also reported an inverse association between CHD incidence and total dietary iron intake, but dietary heme iron was positively associated with CHD incidence (103). Although the relationship between iron stores and CHD/MI requires further clarification, it would be prudent for those who are not at risk of iron deficiency (e.g., adult men and postmenopausal women) to avoid excess iron intake (see the LPI Rx for Health). 

Type 2 diabetes mellitus and metabolic syndrome

Individuals with hereditary hemochromatosis (HH) are known to be at a heightened risk of developing type 2 diabetes mellitus (104). Increasing evidence also suggests a role for iron excess in the pathogenesis of type 2 diabetes independent of hemochromatosis. Cross-sectional, case-control, and prospective cohort studies have reported an increased risk of type 2 diabetes (105) and metabolic syndrome (106) with high versus low ferritin concentrations (reflecting iron body stores) after adjustment for inflammation. It is currently unclear how other indices of iron status relate to the risk of type 2 diabetes (107-110). Iron overload-induced oxidative stress in patients with HH is thought to damage pancreatic β-cells and impair insulin secretion. In subjects free of HH, iron excess might damage the liver, interfering with glucose metabolism and triggering insulin resistance, rather than impair β-cell function (111, 112). Iron removal by phlebotomy has been shown to improve metabolic parameters in subjects with type 2 diabetes (113) and metabolic syndrome (114). Additional randomized controlled trials are needed to determine whether lowering body stores of iron will aid in the prevention of type 2 diabetes and metabolic syndrome.

Neurodegenerative disease

Iron is required for normal brain and nerve function through its involvement in cellular metabolism, as well as in the synthesis of neurotransmitters and myelin. Deregulation of iron homeostasis has been observed in a number of neurodegenerative diseases, including Alzheimer’s disease, Parkinson’s disease, and amyotrophic lateral sclerosis (ALS; Lou Gehrig’s disease) (115-117). The abnormal accumulation of iron in the brain does not appear to be a result of increased dietary iron, but rather a disruption in the complex process of cellular iron regulation (117). Brain iron accumulation can result in increased oxidative stress, and the brain is particularly susceptible to oxidative damage. Mechanisms behind the disruption of iron homeostasis in the brain of patients affected by neurodegenerative disease are actively being investigated. For example, studies using genetically modified mouse models indicated that the suppression of amyloid precursor protein (APP) expression by upstream nitric oxide (NO) elevation (11) or loss of Tau protein (12) could impair neuronal export of iron and lead to iron accumulation in specific brain regions affected in Parkinson’s disease. A pilot, double-blind, placebo-controlled trial in patients with early-stage Parkinson’s disease demonstrated oral administration of the iron chelator, deferiprone, for 12 months reduced iron deposition in the part of the brain called substantia nigra and improved motor performance without compromising systemic iron homeostasis (118, 119).




Accidental overdose of iron-containing products is the single largest cause of poisoning fatalities in children under six years of age. Although the oral lethal dose of elemental iron is approximately 180 to 250 mg/kg of body weight, considerably less has been fatal. Symptoms of acute toxicity may occur with iron doses of 20 to 60 mg/kg of body weight. Iron overdose is an emergency situation because the severity of iron toxicity is related to the amount of elemental iron absorbed. Acute iron poisoning produces symptoms in four stages: (1) Within one to six hours of ingestion, symptoms may include nausea, vomiting, abdominal pain, tarry stools, lethargy, weak and rapid pulse, low blood pressure, fever, difficulty breathing, and coma; (2) If not immediately fatal, symptoms may subside for about 24 hours; (3) Symptoms may return 12 to 48 hours after iron ingestion and may include serious signs of failure in the following organ systems: cardiovascular, kidney, liver, hematologic (blood), and central nervous system; and (4) Long-term damage to the central nervous system, liver (cirrhosis), and stomach may develop two to six weeks after ingestion (25, 120).

Adverse effects

At therapeutic levels used to treat iron deficiency, iron supplements may cause gastrointestinal irritation, nausea, vomiting, diarrhea, or constipation. Stools will often appear darker in color. Iron-containing liquids can temporarily stain teeth, but diluting the liquid helps to prevent this effect (120). Taking iron supplements with food instead of on an empty stomach may relieve gastrointestinal effects. The Food and Nutrition Board (FNB) of the Institute of Medicine based the tolerable upper intake level (UL) for iron on the prevention of gastrointestinal distress (Table 3). The UL for adolescents (14-18 years) and adults, including pregnant and breast-feeding women, is 45 mg/day. It should be noted that the UL is not meant to apply to individuals being treated with iron under close medical supervision. Individuals with hereditary hemochromatosis or other conditions of iron overload, as well as individuals with alcoholic cirrhosis and other liver diseases, may experience adverse effects at iron intake levels below the UL (25).

Table 3. Tolerable Upper Intake Level (UL) for Iron
Age Group UL (mg/day)
Infants 0-12 months 40
Children 1-13 years 40
Adolescents 14-18 years 45
Adults 19 years and older 45

Drug interactions

Medications that decrease stomach acidity, such as antacids, histamine (H2) receptor antagonists (e.g., cimetidine, ranitidine), and proton-pump inhibitors (e.g., omeprazole, lansoprazole), may impair iron absorption. Taking iron supplements at the same time as the following medications may result in decreased absorption and efficacy of the medication: carbidopa and levodopa (Sinemet), levothyroxine (Synthroid, Levoxyl), methyldopa (Aldomet), penicillamine (Cuprimine, Depen), quinolones, tetracyclines, and bisphosphonates (120). Therefore, it is best to take these medications two hours apart from iron supplements. Cholestyramine (Questran) and colestipol (Colestid), used to lower blood cholesterol concentrations, should also be taken at least four hours apart from iron supplements because they may interfere with iron absorption (121)

Does iron supplementation increase the risk of malaria in malaria-endemic regions?

Despite the critical functions of iron in the immune response, the nature of the relationship between iron status and susceptibility to infection, especially with respect to malaria, has been controversial. Because iron withholding is a recognized defense mechanism against pathogens (see Iron withholding defense during infection), concerns have been raised regarding the safety of iron supplementation, especially in iron-replete children living in malaria-endemic regions (122).

Iron supplementation of children residing in the tropics has been associated with increased risk of clinical malaria and other infections like pneumonia (123, 124). A randomized controlled trial in 24,076 children (ages, 1-35 months) living in a malaria-endemic region of eastern Africa (Tanzania) investigated the effects of supplemental iron and folic acid, with or without zinc, compared to the effects of zinc alone or a placebo, on all-cause mortality and hospital admissions (125). The administration of iron, folic acid, and/or zinc was found to increase the risk of serious adverse effects, hospital admission, and death, and was therefore prematurely halted. Further analyses of the trial revealed that iron-replete children were more likely than iron deficient-children (with or without anemia) to be at risk of adverse effects following iron supplementation (125). Such a potential risk of adverse effects with routine iron supplementation was not observed in preschool children in settings without malaria (southern Nepal) (126).

A recent review of 35 trials indicated that iron supplementation did not increase the risk of clinical malaria or other parasitic diseases, infections, and all-cause mortality in children living in malaria-endemic regions in which prevention and management of malaria are available (127). Moreover, a pooled analysis of three high-quality trials demonstrated that supplemental iron combined with anti-malarial treatment protected children against clinical malaria and improved hematological parameters (127). The World Health Organization (WHO) currently recommends the provision of iron supplementation in infants and children, together with measures of malaria prevention, diagnosis, and treatment in malaria-endemic areas (128).

Linus Pauling Institute Recommendation

Following the RDA for iron should provide sufficient iron to prevent deficiency without causing adverse effects in most individuals. Although sufficient iron can be obtained through a varied diet, a considerable number of people do not consume adequate iron to prevent deficiency. A multivitamin/mineral supplement containing 100% of the daily value (DV) for iron provides 18 mg of elemental iron. While this amount of iron may be beneficial for premenopausal women, it is well above the RDA for men and postmenopausal women.

Adult men and postmenopausal women

Since hereditary hemochromatosis is not uncommon and the effects of long-term dietary iron excess on chronic disease risk are not yet clear, men and postmenopausal women who are not at risk of iron deficiency should take a multivitamin/mineral supplement without iron. A number of multivitamins formulated specifically for men or those over 50 years of age do not contain iron.

Older adults (>50 years)

Moderately elevated iron stores might be much more common than iron deficiency in middle-age and older individuals (129). Thus, older adults should not generally take nutritional supplements containing iron unless they have been diagnosed with iron deficiency. Moreover, it is extremely important to determine the underlying cause of the iron deficiency, rather than simply treating it with iron supplements (see The Recommended Dietary Allowance).

Authors and Reviewers

Originally written in 2001 by:
Jane Higdon, Ph.D.
Linus Pauling Institute
Oregon State University

Updated in March 2003 by:
Jane Higdon, Ph.D.
Linus Pauling Institute
Oregon State University

Updated in January 2006 by:
Jane Higdon, Ph.D.
Linus Pauling Institute
Oregon State University

Updated in August 2009 by:
Victoria J. Drake, Ph.D.
Linus Pauling Institute
Oregon State University

Updated in April 2016 by:
Barbara Delage, Ph.D.
Linus Pauling Institute
Oregon State University

Reviewed in May 2016 by:
Marianne Wessling-Resnick, Ph.D.
Professor of Nutritional Biochemistry
Department of Genetics and Complex Diseases
Harvard T.H. Chan School of Public Health

The 2016 update of this article was underwritten, in part, by a grant from Bayer Consumer Care AG, Basel, Switzerland.

Copyright 2001-2023  Linus Pauling Institute


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Magnesium plays important roles in the structure and the function of the human body. The adult human body contains about 25 grams (g) of magnesium. About 50 to 60% of all the magnesium in the body is found in the skeleton and the remainder is found in soft tissue, primarily in muscle. Magnesium is the second most abundant intracellular cation after potassium. Blood contains less than 1% of total body magnesium. Only the free, ionized form of magnesium (Mg2+) is physiologically active. Protein-bound and chelated magnesium serve to buffer the pool of free, ionized magnesium (1).


Magnesium is involved in more than 300 essential metabolic reactions, some of which are discussed below (2).

Energy production

The metabolism of carbohydrates and fats to produce energy requires numerous magnesium-dependent chemical reactions. Magnesium is required by the adenosine triphosphate (ATP)-synthesizing protein in mitochondria. ATP, the molecule that provides energy for almost all metabolic processes, exists primarily as a complex with magnesium (MgATP) (3).

Synthesis of essential molecules

Magnesium is required for a number of steps during synthesis of deoxyribonucleic acid (DNA), ribonucleic acid (RNA), and proteins. Several enzymes participating in the synthesis of carbohydrates and lipids require magnesium for their activity. Glutathione, an important antioxidant, requires magnesium for its synthesis (3).

Structural roles

Magnesium plays a structural role in bone, cell membranes, and chromosomes (3).

Ion transport across cell membranes

Magnesium is required for the active transport of ions like potassium and calcium across cell membranes. Through its role in ion transport systems, magnesium affects the conduction of nerve impulses, muscle contraction, and normal heart rhythm (3).

Cell signaling

Cell signaling requires MgATP for the phosphorylation of proteins and the formation of the cell-signaling molecule, cyclic adenosine monophosphate (cAMP). cAMP is involved in many processes, including the secretion of parathyroid hormone (PTH) from the parathyroid glands (see the articles on Vitamin D and Calcium for information on the role of PTH in the body) (3).

Cell migration

Calcium and magnesium concentrations in the fluid surrounding cells affect the migration of a number of different cell types. Such effects on cell migration may be important in wound healing (3).

Nutrient interactions


High doses of zinc in supplemental form apparently interfere with the absorption of magnesium. One study reported that zinc supplements of 142 mg/day (well above the tolerable upper intake level (UL) of 40 mg/day for zinc) in healthy adult males significantly decreased magnesium absorption and disrupted magnesium balance (the difference between magnesium intake and magnesium loss) (4)


Large increases in the intake of dietary fiber have been found to decrease magnesium utilization in experimental studies. However, the extent to which dietary fiber affects magnesium nutritional status in individuals with a varied diet outside the laboratory is not clear (2, 3).


Dietary protein intake may affect magnesium absorption. One study in adolescent boys found that magnesium absorption was directly related to protein intake, with magnesium absorption the lowest when protein intake was less than 30 g/day (5).

Vitamin D and calcium

The active form of vitamin D (calcitriol) may slightly increase intestinal absorption of magnesium (6). However, it is not clear whether magnesium absorption is calcitriol-dependent as is the absorption of calcium and phosphate. High calcium intake has not been found to affect magnesium balance in most studies. Inadequate blood magnesium concentrations are known to result in low blood calcium concentrations, resistance to parathyroid hormone (PTH) action, and resistance to some of the effects of vitamin D (2, 3).


Risk factors

Magnesium deficiency in healthy individuals who are consuming a balanced diet is quite rare because magnesium is abundant in both plant and animal foods and because the kidneys are able to limit urinary excretion of magnesium when intake is low. The following conditions increase the risk of magnesium deficiency (7):

  • Gastrointestinal disorders: Prolonged diarrhea, Crohn's disease, malabsorption syndromes, celiac disease, surgical removal of a portion of the small intestine, and intestinal inflammation due to radiation may all lead to magnesium depletion.
  • Renal disorders (magnesium wasting): Diabetes mellitus and long-term use of certain diuretics (see Drug interactions) may result in increased urinary loss of magnesium. Multiple other medications can also result in renal magnesium wasting (3).
  • Endocrine and metabolic disorders: Several conditions, such as diabetes mellitus, parathyroid gland disorders, phosphate depletion, primary aldosteronism, and even excessive lactation, can lead to magnesium depletion.

Poor dietary intake, gastrointestinal problems, and increased urinary loss of magnesium may all contribute to magnesium depletion in people suffering from alcoholism. Older adults have relatively low dietary intakes of magnesium (8, 9). Intestinal magnesium absorption tends to decrease with age, and urinary magnesium excretion tends to increase with age; thus, suboptimal dietary magnesium intake may increase the risk of magnesium depletion in the elderly (2).

Signs and symptoms

Although severe magnesium deficiency is uncommon, it has been induced experimentally. When magnesium deficiency was induced in humans, the earliest sign was a decrease in serum magnesium concentration. Hypomagnesemia usually describes serum magnesium concentrations less than 0.74 millimoles/liter (mmol/L) or 1.40 milliequivalents/liter (mEq/L) or 1.70 milligrams/deciliter (mg/dL). Over time, serum calcium concentration also began to decrease (hypocalcemia) despite adequate dietary calcium. Hypocalcemia persisted despite increased secretion of parathyroid hormone (PTH), which regulates calcium homeostasis. Usually, increased PTH secretion quickly results in the mobilization of calcium from bone and normalization of blood calcium concentration. As the magnesium depletion progressed, PTH secretion diminished to low concentrations. In addition to hypomagnesemia, signs of severe magnesium deficiency included hypocalcemia, low serum potassium concentrations (hypokalemia), retention of sodium, low circulating PTH concentrations, neurological and muscular symptoms (tremor, muscle spasms, tetany), loss of appetite, nausea, vomiting, and personality changes (3).

While mild magnesium deficiency may not elicit clinical symptoms, it may be associated with an increased risk of developing chronic diseases (see Disease Prevention) (1).

Assessing magnesium status

There is currently no reliable indicator of magnesium status. The magnesium tolerance test, which basically determines magnesium retention (using 24-h urine collection) following the intravenous administration of magnesium, is considered to be the gold standard (1). If this method is a good indicator of hypomagnesemia in adults, it appears to be poorly sensitive to changes in magnesium status in healthy people. Moreover, the method is invasive and cumbersome, and thus difficult to use routinely (10). Another method to assess magnesium status is through measurements of plasma ionized magnesium, which represents the physiologically active form of magnesium. However, it is unknown whether plasma ionized magnesium reflect body stores (10).

In practice, magnesium status is usually determined through assessments of dietary magnesium intake, serum magnesium concentration, and/or urinary magnesium concentration (10). However, each of these indicators has limitations. Although predominantly used in epidemiological studies and the sole indicator available to clinicians, serum magnesium concentration has been found to poorly respond to magnesium supplementation. Regarding dietary intakes of magnesium, about 30 to 40% of ingested magnesium is absorbed, yet absorption varies with the amount of magnesium ingested and with the food matrix composition. Finally, a state of magnesium deficiency has not been associated to a clear cutoff concentration of magnesium in the urine. Urinary magnesium concentration fluctuates rapidly with dietary intakes, but measurements of 24-hour urinary magnesium can be used in addition to other indicators to assess population status. Presently, a combination of all three markers — dietary, serum, and urinary magnesium — may be used to get a valid assessment of magnesium status (reviewed in 10).

The Recommended Dietary Allowance (RDA)

In 1997, the Food and Nutrition Board of the Institute of Medicine increased the Recommended Dietary Allowance (RDA) for magnesium, based on the results of tightly controlled balance studies that utilized more accurate methods of measuring magnesium (Table 1) (2). Balance studies are useful for determining the amount of a nutrient that will prevent deficiency; however, such studies provide little information regarding the amount of a nutrient required for chronic disease prevention or optimal health.

Table 1. Recommended Dietary Allowance (RDA) for Magnesium
Life Stage Age Males (mg/day) Females (mg/day)
Infants  0-6 months 30 (AI*) 30 (AI)
Infants  7-12 months  75 (AI) 75 (AI)
Children  1-3 years  80 80
Children 4-8 years 130 130
Children  9-13 years  240 240
Adolescents  14-18 years  410 360
Adults  19-30 years  400 310
Adults  31 years and older  420 320
Pregnancy  18 years and younger  - 400
Pregnancy  19-30 years - 350
Pregnancy  31 years and older - 360
Breast-feeding  18 years and younger - 360
Breast-feeding  19-30 years - 310
Breast-feeding  31 years and older - 320
*Adequate Intake      

Disease Prevention

Metabolic syndrome

Metabolic syndrome refers to the concomitant presentation of several metabolic disorders in an individual, including dyslipidemia, hypertension, insulin resistance, and obesity (11). People with metabolic syndrome are at greater risk of developing type 2 diabetes mellitus, cardiovascular disease, and some types of cancer (12-14). A 2015 analysis of data from the US National Health and Nutrition Examination Survey (NHANES 2001-2010) in 9,148 adults (mean age, 50 years) found a 32% lower risk of metabolic syndrome in those in the highest versus lowest quantile of magnesium intake (≥355 mg/day versus <197 mg/day) (15). Several meta-analyses of primarily cross-sectional studies have also reported an inverse association between dietary magnesium intake and risk of metabolic syndrome (16-18). Moreover, lower serum magnesium concentrations have been reported in individuals with metabolic syndrome compared to controls (18, 19). However, circulating magnesium represents only 1% of total body stores and is tightly regulated; thus, serum magnesium concentrations do not best reflect magnesium status (1). At present, additional evidence is needed from prospectively designed studies to inform the potential relationship between dietary and circulating magnesium and the risk of metabolic syndrome.

Systemic inflammation, which contributes to the development of metabolic disorders, has been inversely correlated with magnesium intakes in a cross-sectional study of 11,686 women (≥45 years). In this study, the lowest prevalence of metabolic syndrome was found in the group of women in the highest quintile of magnesium intakes (median intake, 422 mg/day) (20). Several randomized controlled trials also reported a reduction in circulating C-reactive protein (CRP) — a marker of inflammation — following oral magnesium supplementation (21). This might constitute a potential mechanism through which magnesium could play a role in the prevention of metabolic disorders.

Cardiovascular disease

Hypertension (high blood pressure)

Large prospective cohort studies have examined the relationship between magnesium and blood pressure. However, the fact that foods high in magnesium (fruit, vegetables, whole grains) are frequently high in potassium and dietary fiber has made it difficult to evaluate the independent effect of magnesium on blood pressure. Findings from large cohorts, including the Health Professionals Follow-up Study (HPFS) (22), the Nurses’ Health Study (NHS) (23), the Atherosclerosis Risk in Communities (ARIC) study (24), and the Coronary Artery Risk Development in Young Adults (CARDIA) study (25), have been summarized in a recent meta-analysis (26). The pooled analysis of seven prospective studies showed an 8% lower risk of hypertension with higher versus lower dietary magnesium intakes (26). In one of these studies, data from 5,511 men and women followed for a median period of 7.6 years found that the highest concentrations of urinary magnesium corresponded to a 25% reduction in the risk of hypertension, whereas there was no association between plasma magnesium concentrations and the risk of hypertension (27). There was also no evidence of an association between circulating magnesium concentrations and the risk of hypertension in a meta-analysis of three prospective cohort studies (26).

The relationship between magnesium intake and risk of hypertension suggests that improving diet quality or using magnesium supplements might play a role in the prevention of hypertension in those with inadequate dietary intakes.

Vascular calcification

The buildup of plaque inside arterial walls — a process called atherosclerosis — is an early event in the development of cardiovascular disease. The calcification of atherosclerotic plaques that occurs with the progression of atherosclerosis has been associated with a three- to four-fold increase in the risk of cardiovascular events and mortality (28).

Individuals with chronic kidney disease (CKD): Abnormalities in mineral and bone metabolism are not uncommon in individuals with impaired kidney function and have been associated with an increased risk of cardiovascular disease and mortality (29, 30). In particular, elevated blood phosphorus concentration and increased deposition of calcium phosphate within the vasculature are thought to promote vascular calcification. Since magnesium can function as a calcium antagonist, it has been suggested that it could be utilized to slow down or reverse the calcification of vessels observed in patients with CKD. In a cross-sectional study in patients with pre-dialysis CKD, higher serum magnesium concentrations were associated with lower coronary artery calcification density scores in those in the higher end of normal serum phosphorus concentrations (i.e., ≥3.4 mg/dL) (31). One small randomized, placebo-controlled trial in participants with pre-dialysis CKD examined the effect of oral, slow-release magnesium hydroxide on the calcification propensity of serum by measuring the time needed for primary calciprotein particles (containing amorphous calcium phosphate) to transform into secondary calciprotein particles (containing crystalline hydroxyapatite) (32). Increased serum calcification propensity has been associated with greater risk of mortality in patients with impaired kidney function (33, 34). The trial found an increase in serum magnesium concentration and a reduction in serum calcification propensity — i.e., an increase in the time needed for 50% of the transformation to occur (T50) — with 720 mg/day of supplemental magnesium for eight weeks compared to placebo (32). Serum calcification propensity was also reduced when magnesium concentration was increased (from 1 to 2 mEq/L for 28 days) in the dialysate of patients with established kidney failure (35). A larger randomized controlled trial in patients with pre-dialysis CKD is underway to examine further the effect of oral magnesium on markers of vascular calcification, markers of mineral and bone metabolism, incidence of cardiovascular events, and deterioration of kidney function (36).

Individuals with normal kidney function: The cross-sectional analysis of data from 2,695 middle-aged participants in the Framingham Heart Study showed that the odds of having coronary artery calcification was 58% lower in those in the highest versus lowest quartile of total magnesium intakes (median values, 427 mg/day versus 259 mg/day) (37). Serum magnesium concentration was also found to be inversely associated with vascular calcification in recent population-based cross-sectional studies (38-40). No research has yet examined whether improving magnesium status of generally healthy people could play a role in atherosclerosis prevention.

Risk of cardiovascular disease

Dietary magnesium intakes: Several large prospective cohort studies, including the Health Professionals Follow-up Study (HPFS) and the Nurses’ Health Study (NHS), have examined magnesium intakes in relation to cardiovascular outcomes. In the most recent analysis of the NHS, which followed nearly 90,000 female nurses for 28 years, those in the highest quintile of magnesium intake had a 39% lower risk of fatal myocardial infarction (but not nonfatal coronary heart disease [CHD]) compared to those in the lowest quintile (>342 mg/day versus <246 mg/day) (41). A meta-analysis of nine prospective cohort studies, mostly conducted in participants without cardiovascular disease at baseline, reported a 22% lower risk of CHD per 200 mg/day incremental intake in dietary magnesium (42). A more recent meta-analysis by Fang et al. (43) included six studies and reported a 10% lower risk of CHD with higher versus lower dietary magnesium intakes.

Higher magnesium intakes were associated with an 8 to 11% reduction in stroke risk in two meta-analyses of prospective studies, each including over 240,000 participants (44, 45). The most recent pooled analysis of 14 studies found a 12% lower risk of stroke with higher versus lower magnesium intakes and estimated a 7% risk reduction of stroke associated with each 100-mg increment in daily magnesium intake (43)

Only two prospective studies have examined the risk of heart failure in relation to magnesium intakes. The pooled analysis suggested a 31% lower risk of heart failure with higher dietary magnesium intakes (43).

Finally, a meta-analysis of 13 prospective studies in over 475,000 participants reported that the risk of total cardiovascular events, including stroke, nonfatal myocardial infarction, and CHD, was 15% lower in individuals with higher intakes of magnesium (46). However, in the recent meta-analysis of eight studies by Fang et al. (43), there was no association between dietary magnesium intake and risk of total cardiovascular disease.

It is important to note that while these prospective cohort studies assessed the association between dietary magnesium and cardiovascular disease, they did not account for the use of supplemental magnesium by a significant fraction of participants.

Serum magnesium concentrations: One large prospective study (almost 14,000 men and women) associated higher serum magnesium concentrations with a lower risk of CHD in women but not in men (47). This study was included in a meta-analysis of four studies that showed no evidence of a reduced risk of CHD with increasing serum magnesium concentrations (42). In contrast, a 0.2 mmol/L increment in serum magnesium concentration was associated with a 30% lower risk of total cardiovascular disease in a pooled analysis of eight prospective cohort studies (42). In the recently published British Regional Heart Study that followed 3,523 men for a mean 15 years, there was no association between serum magnesium concentration and incidental CHD events, yet serum magnesium concentration was inversely associated with the risk of heart failure (48).

Cardiovascular mortality

A number of early studies found lower cardiovascular-related mortality in populations who routinely consume "hard" water. Hard (alkaline) water is generally high in magnesium but may also contain more calcium and fluoride than "soft" water, making the cardioprotective effects of hard water difficult to attribute to magnesium alone (49). Additionally, meta-analyses of prospective studies have found no associations between magnesium intake and cardiovascular (50) or all-cause mortality (43). In a prospective analysis of NHANES data from 14,353 participants, followed for a median period of 28.6 years, the risk of all-cause and stroke mortality was significantly increased in those with low rather than normal serum concentrations of magnesium (<0.7 mmol/L versus 0.8-0.89 mmol/L) (51). In contrast, hypermagnesemia (serum magnesium concentration >0.89 mmol/L) — rather than hypomagnesemia — in people with heart failure was associated with an increased risk of cardiovascular and all-cause mortality (52).

Aneurysmal subarachnoid hemorrhage

Occurrence of hypomagnesemia has been reported in patients who suffered from a subarachnoid hemorrhage (a type of stroke) caused by the rupture of a cerebral aneurysm (53). Poor neurologic outcomes following an aneurysmal subarachnoid hemorrhage (aSAH) have been linked to inappropriate calcium-dependent contraction of arteries (known as cerebral arterial vasospasm), leading to delayed cerebral ischemia (54). Because magnesium is a calcium antagonist and potent vasodilator, several randomized controlled trials have examined whether intravenous magnesium sulfate infusions could reduce the incidence of vasospasm after aSAH. A meta-analysis of nine randomized controlled trials found that magnesium therapy after aSAH significantly reduced vasospasm but failed to prevent neurologic deterioration or decrease the risk of death (55). Another meta-analysis of 13 trials in 2,413 aSAH sufferers concluded that the infusion of magnesium sulfate had no benefit regarding neurologic outcome and mortality, despite a reduction in the incidence of delayed cerebral ischemia (56). The post-hoc analysis of a small randomized controlled trial suggested that maintaining magnesium sulfate infusion for 10 days post-aSAH or until signs of vasospasm disappear might protect against secondary cerebral infarction when markers of vasoconstriction and reduced brain perfusion are present (57, 58). Current evidence does not support the use of magnesium supplementation in clinical practice for aSAH patients beyond magnesium status normalization.

Complications of heart surgery

Atrial arrhythmia (also called atrial fibrillation) is a condition defined as the occurrence of persistent heart rate abnormalities; such arrhythmias often complicate the recovery of patients after cardiac surgery. The use of magnesium in the prophylaxis of postoperative atrial arrhythmia after coronary artery bypass grafting has been evaluated as a sole or adjunctive agent to classical antiarrhythmic molecules (namely, β-blockers and amiodarone) in several prospective, randomized controlled trials. A meta-analysis of 21 intervention studies showed that intravenous magnesium infusions could significantly reduce postoperative atrial arrhythmia in treated compared to untreated patients (59). The results of a more recent meta-analysis of 22 placebo-controlled trials suggested that magnesium may effectively reduce atrial arrhythmia when administered post-operatively, as a bolus, and for more than 24 hours (60). However, another meta-analysis of four trials found that magnesium was no more effective than other antiarrhythmic agents (60). Moreover, the meta-analysis of five randomized controlled trials also suggested that intravenous magnesium added to β-blocker treatment did not decrease the risk of atrial arrhythmia compared to β-blocker alone and was associated with more adverse effects (bradycardia and hypotension) (61). Presently, high-quality evidence is still lacking to support the use of magnesium in the prophylaxis of post-operative atrial fibrillation and other arrhythmias in patients with contraindications to first-line antiarrhythmic agents (60).

Diabetes mellitus

Public health concerns regarding the epidemics of obesity and type 2 diabetes mellitus and the prominent role of magnesium in glucose metabolism have led scientists to investigate the relationship between magnesium intake and type 2 diabetes mellitus. A prospective cohort study that followed more than 25,000 individuals, 35 to 65 years of age, for seven years found no difference in incidence of type 2 diabetes mellitus when comparing the highest (377 mg/day) quintile of magnesium intake to the lowest quintile (268 mg/day) (62). However, inclusion of this study in a meta-analysis of eight cohort studies showed that the risk of type 2 diabetes was inversely correlated with magnesium intake (62). The most recent meta-analysis of 25 prospective cohort studies, including 637,922 individuals and 26,828 new cases of type 2 diabetes mellitus, found that higher magnesium intakes were associated with a 17% lower risk of type 2 diabetes mellitus (63). Several meta-analyses conducted to date reported an 8 to 15% decrease in the risk of developing type 2 diabetes mellitus with each 100 mg-increment in dietary magnesium intake (63-66).

Insulin resistance, characterized by alterations in both insulin secretion by the pancreas and insulin action on target tissues, has been linked to inadequate magnesium status. A cross-sectional analysis of the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) consortium, which included 15 cohorts with a total of 52,684 diabetes-free participants, showed that magnesium intakes were inversely associated with fasting insulin concentrations after multiple adjustments, including various lifestyle factors, body mass index (BMI), caffeine intake, and fiber intake (65). It is thought that pancreatic β-cells, which secrete insulin, could become less responsive to changes in insulin sensitivity in magnesium-deficient subjects (67). A randomized, double-blind, placebo-controlled trial that enrolled 97 healthy adults with significant hypomagnesemia (serum magnesium concentration ≤0.70 mmol/L) showed that daily consumption of 638 mg of magnesium (from a solution of magnesium chloride) for three months improved the function of pancreatic β-cells, resulting in lower fasting glucose and insulin concentrations (68). In a follow-up randomized controlled trial, the administration of 382 mg/day of magnesium for four months to participants (mean age, 42 years) with both hypomagnesemia (serum magnesium concentration <0.74 mmoles/L) and impaired fasting glucose improved serum magnesium concentrations, as well as fasting and post-load glucose concentrations (69). Other metabolic markers, including serum triglycerides, HDL-cholesterol, and a measure of insulin resistance, also improved in magnesium- versus placebo-treated individuals (69). Additionally, similar metabolic improvements have been reported following the supplementation of magnesium (382 mg/day for four months) to participants who were both hypomagnesemic and lean yet metabolically obese (i.e., with metabolic disorders usually associated with obesity) (70). In another study, supplementation with 365 mg/day of magnesium (from magnesium aspartate hydrochloride) for six months reduced insulin resistance in 27 overweight individuals with normal values of serum and intracellular magnesium (71). This latter study suggests that magnesium might have additional effects on glucose tolerance and insulin sensitivity that go beyond the normalization of serum magnesium concentrations in hypomagnesemic individuals.



Although decreased bone mineral density (BMD) is the primary feature of osteoporosis, other osteoporotic changes in the collagenous matrix and mineral composition of bone may result in bones that are brittle and more susceptible to fracture (72). Around 60% of total body magnesium is stored in the skeleton and is known to influence both bone matrix and bone mineral metabolism. Magnesium at the surface of bones is also available for dynamic exchange with blood (73). As the magnesium content of bone mineral decreases, hydroxyapatite crystals of bone may become larger and more brittle. Some studies have found lower magnesium content and larger hydroxyapatite crystals in bones of women with osteoporosis compared to disease-free women (74). Inadequate serum magnesium concentrations are known to result in low serum calcium concentrations, resistance to parathyroid hormone (PTH) action, and resistance to some of the effects of vitamin D (calcitriol), all of which can lead to increased bone loss (see the articles on Vitamin D and Calcium). Lower serum magnesium concentrations may not be unusual in postmenopausal women with osteoporosis (75), and hypomagnesemia has been reported as an adverse effect of using the prescription drug teriparatide (Forteo) in the treatment of osteoporosis (76).

Higher dietary magnesium intakes have been associated with increased site-specific (77) and total-body BMD (78) in observational studies, including studies of older adults. More recently, a large cohort study conducted in almost two-thirds of the Norwegian population found the level of magnesium in drinking water to be inversely associated with the risk of hip fracture (79). In the Women’s Health Initiative study, data analysis from 4,778 participants (mean age, 63 years) followed for about seven years showed that higher magnesium intakes were associated with higher hip and whole-body BMD but not with reduced hip or total fractures (80). Moreover, the highest versus lowest quintile of total magnesium intakes was associated with a 23% increased risk of lower arm and wrist fractures (80). In a case-cohort study nested within the European Prospective Investigation into Cancer and Nutrition (EPIC)-Norfolk study, which included 5,319 individuals, total magnesium and potassium intakes were found to be inversely associated with heel bone (calcaneus) broadband ultrasound attenuation (BUA) measurements — which are predictive of the risk of incidental fracture — and with the risk of hip fractures (81).

Few studies have addressed the effect of magnesium supplementation on BMD or osteoporosis in humans. In a small group of postmenopausal women with osteoporosis, magnesium supplementation of 750 mg/day for six months followed by 250 mg/day for 18 more months resulted in increased BMD at the wrist after one year, with no further increase after two years of supplementation (82). A study in postmenopausal women who were taking estrogen replacement therapy and a multivitamin supplement found that supplementation with an additional 400 mg/day of magnesium and 600 mg/day of calcium resulted in increased BMD at the heel compared to postmenopausal women receiving estrogen replacement therapy only (83). A more recent randomized controlled study conducted in 20 postmenopausal women with osteoporosis suggested that high-dose supplementation with magnesium citrate (1,830 mg/day) for one month could reduce the rapid rate of bone loss that characterizes osteoporosis (84). Evidence is not yet sufficient to suggest that supplemental magnesium in excess of the RDA could be effective in the prevention of osteoporosis unless normalization of serum magnesium concentration is required (85).


Sarcopenia is a condition characterized by a loss of skeletal muscle mass that increases frailty and risk of falls in older adults (86). Several cross-sectional studies have reported a positive association between dietary magnesium intakes and proxy measures of skeletal muscle mass in middle-age and older adults (87-90). A 2014 randomized controlled study in 139 physically active and healthy older women (mean age, 71.5 years) found little-to-no impact of magnesium supplementation (900 mg/day of magnesium oxide) for 12 weeks on body composition and muscle strength, yet the Short Physical Performance Battery [SPPB] test score — a composite indicator of physical function — improved (91). More research is needed to examine further the effect of magnesium supplementation on body composition, muscle strength, and physical performance in older adults, whether physically active or sedentary, and with normal or inadequate magnesium status.

Disease Treatment

The use of pharmacologic doses of magnesium to treat specific disorders is discussed below. Although many of the cited studies utilized supplemental magnesium at doses considerably higher than the tolerable upper intake level (UL), which is 350 mg/day set by the Food and Nutrition Board (see Safety), it is important to note that these studies were all conducted under medical supervision. Because of the potential side effects of high doses of magnesium, especially in the presence of impaired kidney function, any disease treatment trial using oral magnesium doses higher than the UL should be conducted under medical supervision. Moreover, intravenous magnesium has been used in the management of several conditions.

Pregnancy complications

Preeclampsia and eclampsia

Preeclampsia and eclampsia are hypertensive disorders of pregnancy that may occur at any time after 20 weeks’ gestation and persist up to six weeks following birth. Preeclampsia (sometimes called toxemia of pregnancy) affects approximately 4% of pregnant women in the US (92). Preeclampsia is defined as the presence of elevated blood pressure (hypertension), protein in the urine, and severe swelling (edema) during pregnancy (93). Eclampsia occurs with the addition of seizures to the triad of preeclamptic symptoms and is a significant cause of perinatal and maternal mortality (93, 94). Although cases of preeclampsia are at high risk of developing eclampsia, one-quarter of eclamptic women do not initially exhibit preeclamptic symptoms (95).

Although lower magnesium concentrations have been reported in the blood and brain of women with preeclampsia than in healthy pregnant women, there is no evidence that magnesium imbalance may cause adverse pregnancy events. A 2014 meta-analysis of 10 randomized controlled trials found no effect of oral magnesium salt administration during normal and at-risk pregnancies on the risk of preeclampsia, perinatal mortality, and small-for-gestational age infants (96).

For many years, high-dose intravenous magnesium sulfate has been the treatment of choice for preventing eclamptic seizures that may occur in association with severe preeclampsia in pregnancy or during labor (97, 98). A systematic review of seven randomized trials in 1,396 women with eclampsia compared the effect of magnesium sulfate administration with diazepam (a known anticonvulsant) treatment on perinatal outcomes. Risks of recurrent seizures and maternal death were significantly reduced by the magnesium regimen compared to diazepam. Moreover, the use of magnesium for the care of eclamptic women resulted in newborns with higher Apgar scores; there was no significant difference in the risk of preterm birth and perinatal mortality (95). Additional research has confirmed that infusion of magnesium sulfate should always be considered in the management of severe preeclampsia and eclampsia to prevent initial and recurrent seizures (99). Moreover, the World Health Organization (WHO) recommends the use of magnesium sulfate — administered either intramuscularly or intravenously — as first-line treatment for the prevention of eclampsia in women with severe preeclampsia, in preference to other anticonvulsants (100). Further research is needed to evaluate the efficacy of magnesium salt infusion in eclampsia prophylaxis in women with mild preeclampsia (101). In addition, it is unclear whether prolonging magnesium use post-partum in women who presented with severe preeclampsia during pregnancy is necessary to lower the risk of eclampsia after delivery (102).

Perinatal neuroprotection

While intravenous magnesium sulfate is included in the medical care of preeclampsia and eclampsia, the American College of Obstetricians and Gynecologists (ACOG) and the Society for Maternal-Fetal Medicine support its use in two additional situations: specific conditions of short-term prolongation of pregnancy and neuroprotection of the fetus in anticipated premature delivery (103).

Preterm birth, which is defined by the premature delivery of an infant between the 20th and 37th weeks of estimated gestation, is associated with an increased risk of perinatal mortality and both short- and long-term morbidity. The ACOG approves the use of different classes of drugs — known as tocolytics — that are meant to delay delivery for long enough so that antenatal corticoids can be used to accelerate lung maturation in the fetus of women at imminent risk of preterm labor (104). A 2014 meta-analysis of 37 trials found that intravenous infusion of magnesium sulfate was no more efficacious than commonly used tocolytics (e.g., β-adrenergic receptor agonists, calcium channel blockers, prostaglandin inhibitors) in delaying delivery or preventing serious infant outcomes (105). Very limited evidence also suggested that high- versus low-dose magnesium infusion may reduce the length of hospital stays in neonates admitted to intensive care units (106).

The relationship between magnesium sulfate and risk of cerebral damage in premature infants has been assessed in observational studies. A meta-analysis of six case-control and five prospective cohort studies showed that the use of magnesium significantly reduced the risk of cerebral palsy, as well as mortality (107). However, the high degree of heterogeneity among the cohort studies and the fact that corticosteroid exposure (which is known to decrease antenatal mortality) was higher in the cases of children exposed to magnesium compared to controls imply a cautious interpretation of the results. Nonetheless, a meta-analysis of five randomized controlled trials, which included 5,493 women at risk of preterm birth and 6,135 babies, found that magnesium therapy given to mothers delivering before term decreased the risk of cerebral palsy by 32% without causing severe adverse maternal events, but this treatment did not reduce the risk of other neurologic impairments or mortality in early childhood (108). Another meta-analysis conducted on five randomized controlled trials found that intravenous magnesium administration to newborns who suffered from perinatal asphyxia could be beneficial in terms of short-term neurologic outcomes, although there was no effect on mortality (109). Additional trials are needed to evaluate the long-term benefits of magnesium in pediatric care.

Cardiovascular disease


While results from intervention studies have not been entirely consistent (2), the latest review of the data highlighted a therapeutic benefit of magnesium supplements in treating hypertension. A 2012 meta-analysis examined 22 randomized, placebo-controlled trials of magnesium supplementation conducted in 1,173 individuals with either normal blood pressure (normotensive) or hypertension (treated with medication or untreated). Oral supplementation with magnesium (mean dose of 410 mg/day; range of 120 to 973 mg/day) for a median period of 11.3 months significantly reduced systolic blood pressure by 2 to 3 mm Hg and diastolic blood pressure by 3 to 4 mm Hg (110); a greater effect was seen at higher doses (≥370 mg/day). The results of 19 of the 22 trials included in the meta-analysis were previously reviewed together with another 25 intervention studies (111). The systematic examination of these 44 trials suggested a blood pressure-lowering effect associated with supplemental magnesium in hypertensive but not in normotensive individuals.

Magnesium doses required to achieve a decrease in blood pressure appeared to depend on whether participants with high blood pressure were treated with antihypertensive medications, including diuretics. Intervention trials on treated participants showed a reduction in hypertension with magnesium doses from 243 mg/day to 486 mg/day, whereas untreated patients required doses above 486 mg/day to achieve a significant decrease in blood pressure. A more recent meta-analysis of randomized controlled studies with 2,028 participants found that supplemental magnesium at a median dose of 368 mg/day (range: 238-960 mg/day) for a median duration of three months (range: 3 weeks-6 months) increased serum magnesium concentration by 0.05 mmol/L (27 trials) and reduced systolic blood pressure by 2 mm Hg and diastolic blood pressure by 1.78 mm Hg (37 trials) (112). A 2017 meta-analysis restricted to trials in participants with underlying preclinical (insulin resistance or prediabetes) or clinical conditions (type 2 diabetes mellitus or coronary heart disease) found a 4.18 mm Hg reduction in systolic blood pressure and a 2.27 mm Hg reduction in diastolic blood pressure with supplemental doses of magnesium ranging between 365 mg/day and 450 mg/day for one to six months (113).

While oral magnesium supplementation may be helpful in hypertensive individuals who are depleted of magnesium due to chronic diuretic use and/or inadequate dietary intake (7), several dietary factors play a role in hypertension. For example, adherence to the DASH diet — a diet rich in fruit, vegetables, and low-fat dairy and low in saturated and total fats — has been linked to significant reductions in systolic and diastolic blood pressures (114). See the topic page: High Blood Pressure.


Vascular endothelial cells line arterial walls where they are in contact with the blood that flows through the circulatory system. Normally functioning vascular endothelium promotes vasodilation when needed, for example, during exercise, and inhibits the formation of blood clots. Conversely, endothelial dysfunction results in widespread vasoconstriction and coagulation abnormalities. In cardiovascular disease, chronic inflammation is associated with the formation of atherosclerotic plaques in arteries. Atherosclerosis impairs normal endothelial function, increasing the risk of vasoconstriction and clot formation, which may lead to heart attack or stroke (reviewed in 115). A recent systematic review identified six randomized controlled trials that examined the effect of pharmacologic doses of oral magnesium on vascular endothelial function (116). Three out of six trials, which included individuals with coronary artery disease (117), diabetes mellitus (118), or hypertension (119), reported an improvement in flow-mediated dilation (FMD) with supplemental magnesium compared to control. In other words, the normal dilation response of the brachial (arm) artery to increased blood flow was improved. In contrast, there was no evidence of an effect of magnesium supplementation on FMD in three trials conducted in hemodialysis patients (120) or healthy participants with normal (121) or high body mass index (BMI) (122). A pooled analysis of the six trials in 262 participants found that supplementation with 107 to 730 mg/day of magnesium for one to six months resulted in an overall improvement of FMD, regardless of the health status or baseline magnesium concentrations of participants (116).

The measurement of the thickness of the inner layers of the carotid arteries is sometimes used as a surrogate marker of atherosclerosis (123). Higher serum magnesium concentrations have been associated with reduced carotid intima-media thickness (CIMT) in all women and in Caucasian men participating in the Atherosclerosis Risk in Communities (ARIC) study (124). A meta-analysis of four small (145 participants in total) and heterogeneous intervention studies found no effect of magnesium supplementation (98.6 to 368 mg/day for 2 to 6 months) on CIMT (116).

Survival after myocardial infarction

Results from several randomized, placebo-controlled trials have suggested that an intravenous magnesium administered early after a suspected myocardial infarction could decrease the risk of death. The most influential study was a randomized, placebo-controlled trial in 2,316 patients that found a significant reduction in mortality in the group of patients given intravenous magnesium sulfate within 24 hours of suspected myocardial infarction (7.8% all-cause mortality in the experimental group vs. 10.3% all-cause mortality in the placebo group) (125). Follow-up from one to five years after treatment revealed that the mortality from cardiovascular disease was 21% lower in the magnesium-treated group (126). However, a larger placebo-controlled trial in more than 58,000 patients found no significant reduction in five-week mortality in patients treated with intravenous magnesium sulfate within 24 hours of suspected myocardial infarction, resulting in controversy regarding the efficacy of this treatment (127). A US survey of the treatment of more than 173,000 individuals with acute myocardial infarction found that only 5% were given intravenous magnesium in the first 24 hours post-infarction and that mortality was higher in this group compared to the group of patients not treated with magnesium (128). A 2007 systematic review of 26 clinical trials, including 73,363 participants, concluded that intravenous magnesium administration does not appear to reduce post-myocardial infarction mortality and thus should not be utilized as a treatment (129). Thus, the use of intravenous magnesium sulfate in the therapy of acute myocardial infarction remains controversial.

Diabetes mellitus

Magnesium depletion has been associated with type 1 (insulin-dependent) and type 2 diabetes mellitus, as well as with gestational diabetes. Low serum concentrations of magnesium (hypomagnesemia) have been reported in 13.5 to 47.7% of individuals with type 2 diabetes mellitus (130). One cause of the depletion may be an increased urinary loss of magnesium caused by an increased urinary excretion of glucose that accompanies poorly controlled diabetes. Magnesium depletion has been shown to increase insulin resistance in a few studies and may adversely affect blood glucose control in diabetes mellitus (see also Diabetes mellitus under Disease Prevention) (131). A small study in nine individuals with type 2 diabetes mellitus reported that supplemental magnesium (300 mg/day for 30 days), in the form of a liquid, magnesium-containing salt solution, improved fasting insulin but not fasting glucose concentrations (132). One randomized, double-blind, placebo-controlled study in 63 individuals with type 2 diabetes mellitus and hypomagnesemia found that those taking an oral magnesium chloride solution (638 mg/day of elemental magnesium) for 16 weeks had improved measures of insulin sensitivity and glycemic control compared to those taking a placebo (133). The most recent meta-analysis of nine randomized, double-blind, controlled trials concluded that oral supplemental magnesium lowered fasting plasma glucose concentrations in individuals with diabetes (134). However, magnesium supplementation did not improve other markers of glucose homeostasis, such as glycated hemoglobin (HbA1c) concentration, fasting and post-glucose load insulin concentrations, and measures of insulin resistance (134). Another meta-analysis of trials that included participants either at-risk of diabetes mellitus or with diabetes mellitus suggested that evidence to support a benefit of magnesium supplementation on measures of insulin resistance was stronger in subjects who were magnesium deficient than in those with normal serum concentrations of magnesium (135). Correcting existing magnesium deficiencies may improve glucose metabolism and insulin sensitivity in subjects with diabetes, but it remains uncertain whether magnesium supplementation can have any therapeutic benefit in patients with adequate magnesium status.


The occurrence of hypomagnesemia may be greater in patients with asthma than in individuals without asthma (136). Several clinical trials have examined the effect of intravenous magnesium infusions on acute asthmatic attacks in children or adults who did not respond to initial treatment in the emergency room. Indeed, magnesium can promote bronchodilation in subjects with asthma by interfering with mechanisms like the activation of N-methyl D-aspartate (NMDA) receptors that trigger bronchoconstriction through facilitating calcium influx in airway smooth muscle cells (137). In a meta-analysis of six (quasi) randomized controlled trials in 325 children with acute asthma treated with a short-acting β2-adrenergic receptor agonist (e.g., salbutamol) and systemic steroids, intravenous magnesium sulfate treatment improved measurements of the respiratory function and reduced the risk of hospital admission by 30% compared to control (138). Another meta-analysis of randomized controlled trials primarily conducted in adults with asthma exacerbations indicated that single infusions of 1.2 to 2 g of magnesium sulfate over 15 to 30 minutes could reduce the risk of hospital admission and improve lung function after initial treatments failed (i.e., oxygen, short-acting β2 agonist, and steroids) (139).

The use of nebulized, inhaled magnesium for treating asthma has also been investigated. A recent systematic review of 25 randomized controlled trials, including adults, children, or both, found little evidence that inhaled magnesium sulfate alone or along with a β2-adrenergic receptor agonist and/or a muscarinic anticholinergic (e.g., ipratropium) could improve pulmonary function in patients with acute asthma (140). In addition, oral magnesium supplementation is of no known value in the management of chronic asthma (141-143).

Pain management

The potential analgesic effect of magnesium is attributed in particular to its capacity to block NMDA receptors, which are located in the brain and spinal cord and are involved in pain transduction (144).

Post-operative pain

Several intervention studies have examined the role of magnesium on pain control and analgesic requirement in patients during the immediate post-surgery period.

After cesarean section: Pain management strategies after cesarean section usually involve the injection of an analgesic into either the epidural space (for epidural analgesia) or the subarachnoid space (for spinal [intrathecal] analgesia). A recent meta-analysis of nine randomized controlled trials summarized the evidence regarding the potential use of magnesium sulfate to control or relieve postoperative pain in 827 women who underwent cesarean section (145). All the trials evaluated the effect of a first-line analgesic regimen (i.e., bupivacaine or lidocaine, with or without opioids) with and without the addition of magnesium sulfate. The results suggested that the anesthesia (8 studies) and sensory blockade (6 studies) lasted longer in women who received the additional magnesium sulfate. The use of magnesium sulfate also resulted in lower pain score (3 studies) and in lower postoperative consumption of analgesics (4 studies). Additionally, there was no difference in occurrence of side effects between regimens (145). A recent randomized controlled trial in 60 healthy women undergoing elective cesarean section confirmed that the addition of magnesium sulfate to a bupivacaine/opioid regimen increased the duration of spinal anesthesia and lowered the pain level, yet did not improve the potency of bupivacaine (146). In another study in women with mild preeclampsia who received an epidural injection of ropivacaine after cesarean section, spinal infusion of magnesium sulfate increased the duration of sensory and motor blockade, as well as the time before patients requested an analgesic, compared to midazolam (147).

After a variety of other surgeries: The efficacy of intravenous magnesium has also been examined for local, regional, or systemic pain control following a range of different surgeries. A review of four small randomized controlled studies suggested that, when added to local analgesics, magnesium infusion to patients undergoing tonsillectomy might decrease pain and incidence of laryngospasm, extend the time to first post-operative analgesic requirement, and reduce the number of post-operative analgesic requests (148). Similar observations were reported in two additional meta-analyses, yet there was discrepancy regarding the ability of magnesium to alleviate pain (149, 150). Indeed, the review of eight trials by Xie et al. (150), of which only two scored pain using the same scale, showed no pain reduction with magnesium compared to control. Finally, both meta-analyses reported no reduction in risk of post-operative nausea and vomiting with intravenous magnesium administration (148, 150). A 2018 meta-analysis of four randomized controlled trials in 263 patients also suggested that magnesium sulfate infusion may help reduce pain scores at 2 and 8 hours (but not 24 hours) after laparoscopic cholecystectomy (151). Recent studies have examined the use of magnesium sulfate for pain control after other surgeries, including hysterectomy (152, 153), spinal surgery (154, 155), or during endoscopic sinus (156) or cochlear implantation (157) surgery. Despite conflicting results or reports of limited benefits of magnesium, further research is needed before any conclusions can be drawn.

Neuropathic pain

The effect of magnesium on neuropathic pain has been examined in some clinical studies. The intravenous administration of magnesium sulfate was found to partially or completely alleviate pain in patients with postherpetic neuralgia, a type of neuropathic pain caused by herpes zoster infection (shingles) (158, 159). In a more recent randomized controlled trial in 45 patients with either postherpetic neuralgia or neuropathic pain of traumatic or surgical origin, oral supplementation of magnesium failed to improve measures of pain and quality of life compared to a placebo (160). Another trial is underway to examine the impact of intravenous magnesium with ketamine on neuropathic pain (161).

Migraine headaches

Lower intracellular magnesium concentrations (in both red blood cells and white blood cells) have been reported in individuals who suffer from recurrent migraine headaches compared to migraine-free individuals (162). Additionally, the incidence of hypomagnesemia also appeared to be greater in women who experience migraines with menstruation compared to women without menstrual migraines (163).

A few intervention studies have examined whether an increase in intracellular magnesium concentration with supplemental (oral) magnesium could help decrease the frequency and severity of migraine headaches in affected individuals. Two early placebo-controlled trials demonstrated modest decreases in the frequency of migraine headaches after supplementation with 600 mg/day of magnesium (162, 164). Another placebo-controlled trial in 86 children with frequent migraine headaches found that oral magnesium oxide (9 mg/kg body weight/day) reduced headache frequency over the 16-week intervention (165). However, there was no reduction in the frequency of migraine headaches with 485 mg/day of magnesium in another placebo-controlled study conducted in 69 adults suffering migraine attacks (166). The efficiency of magnesium absorption varies with the type of oral magnesium complex, and this might explain the conflicting results. Although no serious adverse effects were noted during these migraine headache trials, 19 to 40% of individuals taking the magnesium supplements have reported diarrhea and gastric irritation.

The efficacy of magnesium infusions was also investigated in a randomized, single-blind, placebo-controlled, cross-over trial of 30 patients with migraine headaches (167). The administration of 1 gram of intravenous magnesium sulfate ended the attacks, abolished associated symptoms, and prevented recurrence within 24 hours in nearly 90% of the subjects. While this promising result was confirmed in another trial (168), two additional randomized, placebo-controlled studies found that magnesium sulfate was less effective than other molecules (e.g., metoclopramide) in treating migraines (169, 170). The most recent meta-analysis of five randomized, double-blind, controlled trials reported no beneficial effect of magnesium infusion for migraine in adults (171). Another two more recent intervention studies suggested that magnesium sulfate infusion could be more effective and faster than dexamethasone/metoclopramide (172) or caffeine citrate (173) to relieve pain in patients with acute migraine.

The efficacy of magnesium should be examined in larger studies that consider the magnesium status of migraine sufferers (174).

Critical injury or illness

Hypomagnesemia is not uncommon in patients admitted to intensive care units (ICU). Two recent meta-analyses of prospective and retrospective cohort studies reported serum magnesium concentrations ≤0.75 mmol/L in ICU patients at admission or within 24 hours following admission to be associated with a greater need for mechanical ventilation, longer ICU stay, and higher risk of hospital mortality (175, 176). A pooled analysis of three studies also suggested a higher risk of sepsis in ICU patients with hypomagnesemia (175). A recent prospective study conducted in patients admitted with severe head injury found better neurological outcomes after six months in those who presented with normal serum magnesium concentrations at admission compared to those with hypomagnesemia (serum magnesium concentrations <0.65 mmol/L) (177). However, evidence is currently unavailable to suggest that magnesium administration could improve outcomes in critically ill or severely injured patients (178).


Food sources

The analysis of US national nutrition survey data (NHANES 2003-2006) showed an average magnesium intake in adults (ages ≥19 years) of 278 mg/day when only unfortified food sources were considered (179). Considering all sources of magnesium intakes (i.e., unfortified and fortified food and supplements), the average intake in adults was estimated to be around 330 mg/day — a value close to the estimated average requirements (EAR) for magnesium — suggesting that about one-half of the adult population may be at risk of magnesium inadequacy (179). Yet, the long-term consequences of inadequate dietary intakes remain unclear (1).

Since magnesium is part of chlorophyll, the green pigment in plants, green leafy vegetables are good sources of magnesium. Unrefined grains (whole grains) and nuts also have high magnesium content. Meats and milk have an intermediate content of magnesium, while refined foods generally have the lowest. Water is a variable source of intake; harder water usually has a higher concentration of magnesium salts (2). Some foods that are relatively rich in magnesium are listed in Table 2, along with their magnesium content in milligrams (mg). For more information on the nutrient content of foods, search USDA's FoodData Central.

Table 2. Some Food Sources of Magnesium
Food Serving Magnesium (mg)
Brazil nuts 1 ounce (6 kernels) 107
Cereal, oat bran ½ cup dry 96
Brown rice, medium-grain, cooked 1 cup 86
Cashews 1 ounce (16 kernels) 83
Fish, mackerel, cooked 3 ounces 82
Spinach, frozen, chopped, cooked ½ cup 78
Almonds 1 ounce (23 kernels) 77
Swiss chard, chopped, cooked ½ cup 75
Lima beans, large, immature seeds, cooked ½ cup 63
Cereal, shredded wheat 2 biscuits 61
Avocado 1 fruit 58
Cereal, all bran (whole wheat) ½ cup, dry 57
Peanuts 1 ounce (28 peanuts) 48
Molasses, blackstrap 1 tablespoon 48
Hazelnuts 1 ounce (21 kernels) 46
Chickpeas, mature seeds, cooked ½ cup 39
Milk, 1% fat 8 fluid ounces 39
Banana 1 medium 32


Magnesium supplements are available as magnesium oxide, magnesium hydroxide, magnesium gluconate, magnesium chloride, and magnesium citrate salts, as well as a number of amino acid chelates like magnesium aspartate. Magnesium hydroxide, oxide, or trisilicate salts are used as antacids to mitigate gastric hyperacidity and symptoms of gastroesophageal reflux disease (180).



Adverse effects have not been identified from magnesium occurring naturally in food. However, adverse effects from excessive magnesium have been observed with intakes of various magnesium salts (i.e., supplemental magnesium) (6). The initial symptom of excess magnesium supplementation is diarrhea — a well-known side effect of magnesium that is used therapeutically as a laxative. Individuals with impaired kidney function are at higher risk for adverse effects of magnesium supplementation, and symptoms of magnesium toxicity have occurred in people with impaired kidney function taking moderate doses of magnesium-containing laxatives or antacids. Elevated serum concentrations of magnesium (hypermagnesemia) may result in a fall in blood pressure (hypotension). Some of the later effects of magnesium toxicity, such as lethargy, confusion, disturbances in normal cardiac rhythm, and deterioration of kidney function, are related to severe hypotension. As hypermagnesemia progresses, muscle weakness and difficulty breathing may occur. Severe hypermagnesemia may result in cardiac arrest (2, 3). The Food and Nutrition Board (FNB) of the US Institute of Medicine set the tolerable upper intake level (UL) for magnesium at 350 mg/day; this UL represents the highest level of daily supplemental magnesium intake likely to pose no risk of diarrhea or gastrointestinal disturbance in almost all individuals. The FNB cautions that individuals with renal impairment are at higher risk for adverse effects from excess supplemental magnesium intake. However, the FNB also notes that there are some conditions that may warrant higher doses of magnesium under medical supervision (2).

Table 3. Tolerable Upper Intake Level (UL) for Supplemental Magnesium
Age Group UL (mg/day)
Infants 0-12 months Not possible to establish*
Children 1-3 years 65 
Children 4-8 years   110 
Children 9-13 years   350 
Adolescents 14-18 years 350 
Adults 19 years and older 350 
*Source of intake should be from food and formula only.

Drug interactions

Magnesium interferes with the absorption of digoxin (a heart medication), nitrofurantoin (an antibiotic), and certain anti-malarial drugs, which could potentially reduce drug efficacy. Bisphosphonates (e.g., alendronate, etidronate), which are drugs used to treat osteoporosis, and magnesium should be taken two hours apart so that the absorption of the bisphosphonates is not inhibited (181, 182). Magnesium has also been found to reduce the efficacy of chlorpromazine (a tranquilizer), penicillamine, oral anticoagulants, and the quinolone and tetracycline classes of antibiotics (181, 182). Intravenous magnesium might inhibit calcium entry into smooth muscle cells and lead to hypotension and muscular weakness if administered with calcium channel blockers (e.g., nifedipin, nicardipin) (182). Because intravenous magnesium has increased the effects of certain muscle-relaxing medications used during anesthesia, it is advisable to let medical staff know if you are taking oral magnesium supplements, laxatives, or antacids prior to surgical procedures. Moreover, long-term use (three months or longer) of proton-pump inhibitors (drugs used to reduce the amount of stomach acid) may increase the risk of hypomagnesemia (183, 184). High doses of furosemide (Lasix) and some thiazide diuretics (e.g., hydrochlorothiazide), if taken for extended periods, may interfere with magnesium reabsorption in the kidneys and result in magnesium depletion (182). Many other medications may also result in renal magnesium loss (3).

Linus Pauling Institute Recommendation

The Linus Pauling Institute supports the latest RDA for magnesium intake (400 to 420 mg/day for men and 310 to 320 mg/day for women). Despite magnesium being plentiful in foods, it is considered a shortfall nutrient (see the article on Micronutrient Inadequacies in the US Population). Following the Linus Pauling Institute recommendation to take a daily multivitamin/mineral supplement might ensure an intake of at least 100 mg/day of magnesium. Few multivitamin/mineral supplements contain more than 100 mg of magnesium due to its bulk. Eating a varied diet that provides green vegetables, whole grains, and nuts daily should provide the rest of an individual's magnesium requirement.

Older adults (>50 years)

Older adults are less likely than younger adults to consume enough magnesium to meet their needs and should therefore take care to eat magnesium-rich foods in addition to taking a multivitamin/mineral supplement daily (see the article on Micronutrient Inadequacies: Subpopulations at Risk). Since older adults are also more likely to have impaired kidney function, they should avoid taking more than 350 mg/day of supplemental magnesium without medical consultation (see Safety).

Authors and Reviewers

Originally written in 2001 by:
Jane Higdon, Ph.D.
Linus Pauling Institute
Oregon State University

Updated in April 2003 by:
Jane Higdon, Ph.D.
Linus Pauling Institute
Oregon State University

Updated in August 2007 by:
Victoria J. Drake, Ph.D.
Linus Pauling Institute
Oregon State University

Updated in October 2013 by:
Barbara Delage, Ph.D.
Linus Pauling Institute
Oregon State University

Updated in November 2018 by:
Barbara Delage, Ph.D.
Linus Pauling Institute
Oregon State University

Reviewed in February 2019 by:
Stella L. Volpe, Ph.D., RDN, ACSM-CEP, FACSM
Professor and Chair
Department of Nutrition Sciences
Drexel University

Copyright 2001-2023  Linus Pauling Institute


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Manganese is a mineral element that is both nutritionally essential and potentially toxic. The derivation of its name from the Greek word for magic remains appropriate, because scientists are still working to understand the diverse effects of manganese deficiency and manganese toxicity in living organisms (1).


Manganese (Mn) plays an important role in a number of physiologic processes as a constituent of multiple enzymes and an activator of other enzymes (2).

Antioxidant function

Manganese superoxide dismutase (MnSOD) is the principal antioxidant enzyme in the mitochondria. Because mitochondria consume over 90% of the oxygen used by cells, they are especially vulnerable to oxidative stress. The superoxide radical is one of the reactive oxygen species produced in mitochondria during ATP synthesis. MnSOD catalyzes the conversion of superoxide radicals to hydrogen peroxide, which can be reduced to water by other antioxidant enzymes (3).


A number of manganese-activated enzymes play important roles in the metabolism of carbohydrates, amino acids, and cholesterol (4). Pyruvate carboxylase, a manganese-containing enzyme, and phosphoenolpyruvate carboxykinase (PEPCK), a manganese-activated enzyme, are critical in gluconeogenesis — the production of glucose from non-carbohydrate precursors. Arginase, another manganese-containing enzyme, is required by the liver for the urea cycle, a process that detoxifies ammonia generated during amino acid metabolism (3). In the brain, the manganese-activated enzyme, glutamine synthetase, converts the amino acid glutamate to glutamine. Glutamate is an excitotoxic neurotransmitter and a precursor to an inhibitory neurotransmitter, γ-aminobutyric acid (GABA) (5, 6).

Bone and cartilage formation

Manganese deficiency results in abnormal skeletal development in a number of animal species. Manganese is the preferred cofactor of enzymes called glycosyltransferases; these enzymes are required for the synthesis of proteoglycans that are needed for the formation of healthy cartilage and bone (7).

Wound healing

Wound healing is a complex process that requires increased production of collagen. Manganese is required for the activation of prolidase, an enzyme that functions to provide the amino acid, proline, for collagen formation in human skin cells (8). A genetic disorder known as prolidase deficiency results in abnormal wound healing among other problems and is characterized by abnormal manganese metabolism (7). Glycosaminoglycan synthesis, which requires manganese-activated glycosyltransferases, may also play an important role in wound healing (9).

Nutrient interactions


Iron and manganese share common absorption and transport proteins, including the divalent metal transporter 1, the lactoferrin receptor, transferrin, and ferroportin (reviewed in 10). Absorption of manganese from a meal decreases as the meal's iron content increases (7). Iron supplementation (60 milligrams [mg]/day for four months) has been associated with decreased blood manganese concentrations and decreased MnSOD activity in leukocytes, indicating a reduction in manganese nutritional status (11).

Additionally, an individual's iron status can affect manganese bioavailability. Intestinal absorption of manganese is increased during iron deficiency and decreased when iron stores are elevated (i.e., high ferritin concentrations) (12). Small studies have found increased blood concentrations of manganese in iron-deficient infants (13) and children (14), and a national survey of adults residing in South Korea found men and women with low ferritin levels had higher blood concentrations of manganese compared to those with normal ferritin levels (15). In this analysis, anemia was associated with higher blood concentrations of manganese in women but not in men (15). Men generally absorb less manganese than women, which may be related to the fact that men usually have higher iron stores than women (16). Iron deficiency has also been shown to increase the risk of manganese accumulation in the brain (17).


Supplemental magnesium (200 mg/day) has been shown to slightly decrease manganese bioavailability in healthy adults, either by decreasing manganese absorption or by increasing its excretion (18).


In one set of studies, supplemental calcium (500 mg/day) slightly decreased manganese bioavailability in healthy adults. As a source of calcium, milk had the least effect, while calcium carbonate and calcium phosphate had the greatest effect (18). Several other studies have found minimal effects of supplemental calcium on manganese metabolism (19).


Although manganese is a nutritionally essential mineral, it is potentially toxic; thus, it is important for the body to tightly regulate manganese homeostasis. While the exact mechanisms that govern manganese homeostasis are not completely understood, systemic regulation is achieved through intestinal control of manganese absorption and hepatic excretion of manganese into bile (20). At the cellular level, influx of manganese into cells is regulated by several different transport proteins, including the transferrin receptor, the divalent metal transporter 1 (DMT 1), zinc-interacting proteins 8 and 14 (ZIP8 and ZIP14), as well as others (reviewed in 21). Efflux of manganese from cells is accomplished by various transporters, including SLC30A10; the sodium-calcium exchanger; and the iron transporter, ferroportin (reviewed in 22). Moreover, subcellular organelles (i.e., the nucleus, mitochondria, Golgi apparatus, lysosome, endosome) utilize various transporters for manganese trafficking within the cell, but the exact mechanisms of regulation are not fully understood (21).


Manganese deficiency has been observed in a number of animal species, but manganese deficiency is not a concern in humans. Signs of manganese deficiency vary among animal species and may include impaired growth, impaired reproductive function, skeletal abnormalities, impaired glucose tolerance, and altered carbohydrate and lipid metabolism. In humans, demonstration of a manganese deficiency syndrome has been less clear (2, 7). A child on long-term total parenteral nutrition (TPN) lacking manganese developed bone demineralization and impaired growth that were corrected by manganese supplementation (23). Young men who were fed a low-manganese diet developed decreased serum cholesterol concentrations and a transient skin rash (24). Blood concentrations of calcium, phosphorus, and alkaline phosphatase were also elevated, which may indicate increased bone remodeling as a consequence of insufficient dietary manganese. Young women fed a manganese-poor diet developed mildly abnormal glucose tolerance in response to an intravenous (IV) infusion of glucose (19). Overall, manganese deficiency is quite rare, and there is more concern for toxicity related to manganese overexposure (see Safety).

The Adequate Intake (AI)

Because there was insufficient information on manganese requirements to set a Recommended Dietary Allowance (RDA), the Food and Nutrition Board (FNB) of the Institute of Medicine (now the National Academy of Medicine) set an adequate intake (AI). Since overt manganese deficiency has not been documented in humans eating natural diets, the FNB based the AI on average dietary intakes of manganese determined by the Total Diet Study — an annual survey of the mineral content of representative American diets (4). AI values for manganese are listed in Table 1 in milligrams (mg)/day by age and gender. Manganese requirements are increased in pregnancy and lactation (4).

Table 1. Adequate Intake (AI) for Manganese
Life Stage Age Males
Infants  0-6 months 0.003 0.003
Infants  7-12 months   0.6  0.6
Children  1-3 years  1.2 1.2
Children  4-8 years  1.5 1.5
Children  9-13 years  1.9 1.6
Adolescents  14-18 years  2.2 1.6
Adults  19 years and older 2.3 1.8
Pregnancy  all ages  2.0
Breast-feeding  all ages  2.6

Disease Prevention

Low dietary manganese intake or low levels of manganese in blood or tissue have been associated with various chronic diseases. Although manganese insufficiency is not currently thought to cause the diseases discussed below, more research may be warranted to determine whether suboptimal manganese nutritional status contributes to certain disease processes.


Early studies found women with osteoporosis had decreased plasma or serum concentrations of manganese and an enhanced plasma response to an oral dose of manganese (25, 26), suggesting they may have lower manganese status than women without osteoporosis. However, more recent studies in postmenopausal women have reported conflicting results, with one study finding lower blood manganese concentrations among women with osteoporosis compared to those without osteoporosis (27) and another finding no differences (28). A study in healthy postmenopausal women found that a supplement containing manganese (5 mg/day), copper (2.5 mg/day), and zinc (15 mg/day) in combination with a calcium supplement (1,000 mg/day) was more effective than the calcium supplement alone in preventing spinal bone loss over a two-year period (29). However, the presence of other trace elements in the supplement makes it impossible to determine whether manganese supplementation was the beneficial agent for maintaining bone mineral density.

Diabetes mellitus

In animal models, manganese deficiency results in impaired insulin secretion and glucose intolerance similar to diabetes mellitus (30); however, results of human studies on manganese and type 2 diabetes have been somewhat conflicting. Manganese intake was inversely associated with type 2 diabetes in 71,270 French women participating in the E3N-EPIC cohort study (31). In an analysis of two prospective cohorts of Chinese adults (ages 20-74 years at baseline), followed for a mean of 4.2 and 5.3 years, higher dietary intakes of manganese were associated with a lower risk of type 2 diabetes; these associations were independent of dietary total antioxidant capacity, a measure of dietary antioxidant intake (32). Most recently, a prospective cohort study of 19,862 adults (ages 40-79 at baseline) participating in the Japan Collaborative Cohort Study, followed for five years, found higher dietary intake of manganese to be associated with a lower risk of type 2 diabetes in women but not in men (33).

While these studies of dietary manganese intake are suggestive of a protective association with type 2 diabetes, studies employing biomarkers of manganese intake – either blood concentrations of manganese or urinary manganese excretion — have reported mixed results. Most studies conducted have been small case-control studies; studies to date have reported blood manganese concentrations in patients with diabetes were higher (34-36), lower (37), or similar (38-40) compared to blood manganese concentrations in controls without diabetes. Additionally, a case-control study that included 3,228 adults in China reported a U-shaped relationship between plasma concentration of manganese and type 2 diabetes, meaning those with low or high blood concentrations had a higher odds of diabetes when compared to those with an intermediate blood concentration of manganese (41). In a cross-sectional analysis of adults participating in the Korean National Health and Nutrition Examination Survey, blood concentrations of manganese were significantly lower among those with diabetes compared to those without diabetes (42). Further, one case-control study found higher urinary manganese excretion in patients with diabetes compared to controls without diabetes (37). Results of case-control studies are more likely to be distorted by bias (i.e., the selection bias with the selection of cases and controls, as well as dietary recall bias) than results of prospective cohort studies.

Moreover, one study of functional manganese status found the activity of the antioxidant enzyme, MnSOD, to be lower in the white blood cells of patients with diabetes than in those without diabetes (43). When given at the same time as an oral glucose challenge, an acute oral dose of 15 mg or 30 mg manganese did not improve glucose tolerance in subjects with diabetes or in controls without diabetes (44).

Although manganese appears to play a role in glucose metabolism, it is not clear whether higher manganese status might improve glucose tolerance and protect against the development of type 2 diabetes mellitus.

Epilepsy (seizure disorders)

Manganese deficient rats are more susceptible to seizures than manganese sufficient rats, and rats that are genetically prone to epilepsy have lower than normal brain and blood manganese concentrations. Certain subgroups of humans with epilepsy reportedly have lower whole blood manganese concentrations than control subjects without epilepsy (45). One study found blood manganese concentrations of individuals with epilepsy of unknown origin were lower than those of individuals whose epilepsy was induced by trauma (e.g., head injury) or disease (46), suggesting a possible genetic relationship between epilepsy and abnormal manganese metabolism. While manganese deficiency does not appear to be a cause of epilepsy in humans, the relationship between manganese metabolism and epilepsy deserves further research (7, 45, 47).


Food sources

In the US, estimated average intakes of dietary manganese range from 2.1 to 2.3 mg/day for men and 1.6 to 1.8 mg/day for women (4). Surveys have found those adhering to a vegetarian diet have manganese intakes of up to 7.0 mg/day (reviewed in 48). Rich sources of manganese include whole grains, legumes, nuts, leafy vegetables, and teas (49). Foods high in phytic acid, such as beans, seeds, nuts, whole grains, and soy products, or foods high in oxalic acid, such as cabbage, spinach, and sweet potatoes, may slightly inhibit manganese absorption. Although teas are rich sources of manganese, the tannins present in tea may moderately reduce the absorption of manganese (18). Intakes of other minerals, including iron, calcium, and phosphorus, have been found to limit retention of manganese (4). The manganese content of some manganese-rich foods is listed in milligrams (mg) in Table 2. For more information on the nutrient content of foods, search USDA’s FoodData Central database (50).

Table 2. Some Food Sources of Manganese
Food Serving Manganese (mg)
Pineapple, raw ½ cup, chunks 0.77
Pineapple juice ½ cup (4 fl. oz.) 0.63
Pecans 1 ounce (19 halves) 1.28
Almonds 1 ounce (23 whole kernels) 0.62
Peanuts 1 ounce 0.55
Peanut butter, smooth style, no salt 2 tablespoons 0.53
Instant oatmeal (prepared with water) 1 packet 0.99
Raisin bran cereal 1 cup 0.78-3.02
Brown rice, long-grain, cooked ½ cup 0.99
Whole-wheat bread 1 slice 0.70
Pinto beans, cooked ½ cup 0.39
Lima beans, cooked ½ cup 0.49
Navy beans, cooked ½ cup 0.48
Spinach, cooked ½ cup 0.84
Sweet potato, cooked ½ cup, mashed 0.44
Tea (green) 1 cup (8 ounces) 0.41-1.58
Tea (black) 1 cup (8 ounces) 0.18-0.77

Breast milk and infant formulas

Infants are exposed to varying amounts of manganese depending on their source of nutrition. Manganese concentrations in breast milk, cow-based formula, and soy-based formula range from 3 to 10 micrograms/liter (μg/L), 30 to 50 μg/L, and 200 to 300 μg/L, respectively. However, the bioavailability of manganese from breast milk is higher than from infant formulas, and manganese deficiencies in breast-fed infants or toxicities in formula-fed infants have not been reported (20).


Manganese concentrations in drinking water range from 1 to 100 micrograms (μg)/L, but most sources contain less than 10 μg/L (51). The US Environmental Protection Agency (EPA) recommends 0.05 mg (50 μg)/L as the maximum allowable manganese concentration in drinking water (52).


Several forms of manganese are found in supplements, including manganese gluconate, manganese sulfate, manganese ascorbate, and amino acid chelates of manganese. Manganese is available as a stand-alone supplement or in combination products (53). Relatively high levels of manganese ascorbate may be found in a bone/joint health product containing chondroitin sulfate and glucosamine hydrochloride (see Safety).

Parenteral nutrition

Manganese may be present in solutions of parenteral nutrition either included as a trace element or as an incidental contaminant (see Intravenous manganese in the Safety section) (54, 55).



Inherited manganese-overload disorders

Autosomal recessive mutations in the SLC30A10 gene, which encodes a manganese transporter expressed in the liver and brain, causes a manganese overload syndrome. Such loss-of-function mutations lead to manganese accumulation in certain brain regions and in the liver, causing hypermanganesemia, dystonia parkinsonism, and hepatic dysfunction at an early age (56, 57). Autosomal recessive mutations in the SLC39A14 gene have also been reported, leading to hypermanganesemia and similar a neurological phenotype, but liver disease is absent with this specific mutation (58). Chelation therapy is important to treat these inherited manganese-overload disorders (59).

Inhaled manganese

Manganese toxicity may result in multiple neurologic problems and is a well-recognized health hazard for people who inhale manganese dust, such as welders, miners, and smelters (1, 4). Unlike ingested manganese, inhaled manganese is transported directly to the brain before it can be metabolized in the liver (60, 61). The symptoms of manganese toxicity generally appear slowly over a period of months to years. In its worst form, manganese toxicity can result in a permanent neurological disorder with symptoms similar to those of Parkinson's disease, including tremors, difficulty walking, and facial muscle spasms. This syndrome, often called manganism, is sometimes preceded by psychiatric symptoms, such as irritability, aggressiveness, and even hallucinations (62, 63). Additionally, environmental or occupational inhalation of manganese can cause an inflammatory response in the lungs (64), with clinical symptoms including cough, acute bronchitis, and decreased lung function (65).

Methylcyclopentadienyl manganese tricarbonyl (MMT)

Methylcyclopentadienyl manganese tricarbonyl (MMT) is a manganese-containing compound used in gasoline as an anti-knock additive. Although it has been used for this purpose in Canada for more than 20 years, uncertainty about adverse health effects from inhaled exhaust emissions kept the US EPA from approving its use in unleaded gasoline. In 1995, a US court decision made MMT available for widespread use in unleaded gasoline (60). A study in Montreal, where MMT had been used for more than 10 years, found airborne manganese levels to be similar to those in areas where MMT was not used (66). Another Canadian study found higher concentrations of respirable manganese in an urban versus a rural area, but average concentrations in both areas were below the safe level set by the US EPA (67). The impact of long-term exposure to low levels of MMT combustion products, however, has not been thoroughly evaluated and will require additional study (68).

A single case of reversible neurotoxicity and seizures following unintentional MMT ingestion has been documented: a 54-year old man accidentally drank an MMT-containing anti-knock agent that he assumed was an energy drink due so similar product labeling (69).

Ingested manganese

Limited evidence suggests that high manganese intakes from drinking water may be associated with neurological symptoms similar to those of Parkinson's disease. Severe neurological symptoms were reported in 25 people who drank water contaminated with manganese — and probably other contaminants — from dry cell batteries for two to three months (70). Water manganese concentrations were found to be 14 mg/L almost two months after symptoms began and may have already been declining (1). A study of older adults in Greece found a high prevalence of neurological symptoms in those exposed to water manganese levels of 1.8 to 2.3 mg/L (71), while a study in Germany found no evidence of increased neurological symptoms in people drinking water with manganese levels ranging from 0.3 to 2.2 mg/L compared to those drinking water containing less than 0.05 mg/L of manganese (72). Manganese in drinking water may be more bioavailable than manganese in food. However, none of the studies measured dietary manganese, so total manganese intake in these cases is unknown. In the US, the EPA recommends 0.05 mg/L as the maximum allowable manganese concentration in drinking water (52), but the World Health Organization does not currently have a health-based limit for manganese in drinking water (73, 74).

Additionally, several cross-sectional studies have associated high levels of manganese in drinking water with cognitive and behavioral deficits in children (reviewed in 75). For example, a cross-sectional study of 362 children (ages 6-13 years) in Canada found children with the highest manganese concentrations in home tap water (median of 216 μg/L) had a 6.2-point lower Full Scale IQ (lower Performance IQ but not Verbal IQ) than those with lowest manganese levels in home tap water (median of 1 μg/L) (76). A cohort study that followed 287 of these children for a mean of 4.4 years found that exposure to higher concentrations of manganese in drinking water was linked to a lower Performance IQ among girls but a higher Performance IQ among boys (77). Additionally, a prospective cohort study among 1,265 children in Bangladesh did not find manganese concentration in drinking water (medians of 0.20 mg/L during pregnancy and 0.34 mg/L at 10 years) to be associated with any measure of cognitive ability (i.e., IQ, verbal comprehension, perceptual reasoning, working memory, processing speed) when assessed at age 10 (78). Yet, this study associated manganese in drinking water with higher risks of conduct problems among boys and low prosocial scores among girls (78). In a population-based cohort study in Denmark that followed 643,401 children, exposure to higher manganese concentrations in drinking water was linked to a heightened risk of one subtype of attention-deficit hyperactive disorder (79). Specifically, exposure to a manganese concentration in drinking water of at least 100 μg/L was associated with a 51% higher risk of the ADHD-Inattentive subtype in girls and a 20% higher risk in boys, in comparison to exposure of <5 μg/L — using these exposure comparisons, a 9% increased risk of ADHD-Overall was observed in girls and no difference found in boys (79).

Only a few adverse effects of manganese intake from supplements have been documented. A single case of manganese toxicity was reported in a person who took large amounts of mineral supplements for years (51), while another case was reported as a result of a person taking a Chinese herbal supplement (62). More recently, Parkinson’s disease was reported in a woman taking 100 mg/day of manganese chloride for at least two years, followed by 30 mg/day for two months (80).

Manganese toxicity resulting from food alone has not been reported in humans, even though certain vegetarian diets could provide up to 20 mg/day of manganese (4, 51).

Intravenous manganese

Manganese neurotoxicity has been observed in individuals receiving total parenteral nutrition (TPN), both as a result of excessive manganese in the solution and as an incidental contaminant (54). Neonates are especially vulnerable to manganese-related neurotoxicity (81). Infants receiving manganese-containing TPN can be exposed to manganese concentrations about 100-fold higher than breast-fed infants (20). Because of potential toxicities, some argue against including manganese in parenteral nutrition (82).

Individuals with increased susceptibility to manganese toxicity

  • Chronic liver disease: Manganese is eliminated from the body mainly in bile. Thus, impaired liver function may lead to decreased manganese excretion. Manganese accumulation in individuals with cirrhosis or liver failure may contribute to neurological problems and Parkinson's disease-like symptoms (1, 53).
  • Infants and children: Compared to adults, infants and children have higher intestinal absorption of manganese, as well as lower biliary excretion of manganese (83). Thus, infants and children are especially susceptible to any negative, neurotoxic effects of manganese. Indeed, several studies in school-aged children have reported deleterious cognitive and behavioral effects following excessive manganese exposure (76, 84-90). Additional studies have associated higher manganese exposures during pregnancy with cognitive and motor deficits in children under six years of age (reviewed in 75).
  • Iron-deficient populations: Iron deficiency has been shown to increase the risk of manganese accumulation in the brain (17).
  • Individuals with occupational exposures to airborne manganese, such as welders, miners, and smelters (reviewed in 21).
  • Abusers of the illicit drug, methcathinone (ephedrone): Intravenous use of manganese-contaminated methcathinone (i.e., when the drug is synthesized with potassium permanganate as the oxidant) can cause lasting neurological damage and a parkinsonism disorder (91, 92).

Due to the severe implications of manganese neurotoxicity, the Food and Nutrition Board (FNB) of the Institute of Medicine (now the National Academy of Medicine) set very conservative tolerable upper intake levels (UL) for manganese; the ULs are listed in Table 3 according to age (4).

Table 3. Tolerable Upper Intake Level (UL) for Manganese
Age Group UL (mg/day)
Infants 0-12 months Not possible to establish*
Children 1-3 years 2
Children 4-8 years 3
Children 9-13 years 6
Adolescents 14-18 years 9
Adults 19 years and older 11
*Source of intake should be from food and formula only.

Drug interactions

Magnesium-containing antacids and laxatives and the antibiotic medication, tetracycline, may decrease the absorption of manganese if taken together with manganese-containing foods or supplements (53).

High levels of manganese in supplements marketed for bone/joint health

Two studies have found that supplements containing a combination of glucosamine hydrochloride, chondroitin sulfate, and manganese ascorbate are beneficial in relieving pain due to mild or moderate osteoarthritis of the knee when compared to a placebo (93, 94). The dose of elemental manganese supplied by the supplements was 30 mg/day for eight weeks in one study (94) and 40 mg/day for six months in the other study (93). No adverse effects were reported during either study, and blood manganese concentrations were not measured. Neither study compared the treatment containing manganese ascorbate to a treatment containing glucosamine hydrochloride and chondroitin sulfate without manganese ascorbate, so it is impossible to determine whether the supplement would have resulted in the same benefit without high doses of manganese.

Linus Pauling Institute Recommendation

The adequate intake (AI) for manganese (2.3 mg/day for adult men and 1.8 mg/day for adult women) appears sufficient to prevent deficiency in most individuals. The daily intake of manganese most likely to promote optimum health is not known. Following the Linus Pauling Institute’s recommendation to take a multivitamin/mineral supplement containing 100% of the daily values (DV) of most nutrients will generally provide 2.3 mg/day of manganese. Because of the potential for toxicity and the lack of information regarding benefit, manganese supplementation beyond 100% of the DV (2.3 mg/day) is not recommended. There is presently no evidence that the consumption of a manganese-rich plant-based diet results in manganese toxicity.

Older adults (>50 years)

The requirement for manganese is not known to be higher for older adults. However, liver disease is more common in older adults and may increase the risk of manganese toxicity by decreasing the elimination of manganese from the body (see Toxicity). Manganese supplementation beyond 100% of the DV (2.3 mg/day) is not recommended. 

Authors and Reviewers

Originally written in 2001 by:
Jane Higdon, Ph.D.
Linus Pauling Institute
Oregon State University

Updated in June 2007 by:
Victoria J. Drake, Ph.D.
Linus Pauling Institute
Oregon State University

Updated in March 2010 by:
Victoria J. Drake, Ph.D.
Linus Pauling Institute
Oregon State University

Updated in April 2021 by:
Victoria J. Drake, Ph.D.
Linus Pauling Institute
Oregon State University

Reviewed in May 2021 by:
Michael Aschner, Ph.D.
Professor and Chair, Department of Molecular Pharmacology
Professor, Dominick P. Purpura Department of Neuroscience
Professor, Department of Pediatrics
Albert Einstein College of Medicine

Copyright 2001-2023  Linus Pauling Institute


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  • The molybdenum atom is part of the molybdenum cofactor in the active site of four enzymes in humans: sulfite oxidase, xanthine oxidase, aldehyde oxidase, and mitochondrial amidoxime reducing component. (More information)
  • Excess molybdenum intake causes fatal copper deficiency diseases in grazing animals. Their rumen is the site of high sulfide generation, and the interaction of molybdenum with sulfur results in the formation of thiomolybdates. Tetrathiomolybdate, a thiomolybdate with four sulfur atoms, can form complexes with copper preventing its absorption and blocking the activity of copper-dependent enzymes. (More information)
  • In humans, tetrathiomolybdate therapy has been developed for Wilson's disease, a genetic disease in which the accumulation of copper in tissues leads to liver and brain damage. More recently, tetrathiomolybdate use has been explored for the treatment of cancer and inflammatory diseases. (More information)
  • Mutations in the molybdenum cofactor biosynthetic pathway lead to the combined deficiency of all molybdenum-dependent enzymes. Molybdenum cofactor deficiency Type A is due to mutations in the MOCS1 gene, while Type B deficiency is caused by mutations in MOCS2. Both Type A and Type B deficiencies result in the loss of sulfite oxidase activity, also observed in isolated sulfite oxidase deficiency and characterized by severe neurologic abnormalities in affected patients. (More information)
  • A new treatment option for molybdenum cofactor deficiency Type A is now available in the US. Intravenous administration of a replacement drug for cyclic pyranopterin monophosphate may help correct the metabolic disorder and prevent neurologic deterioration in patients with Type A deficiency. Patients with Type B deficiency do not lack this molecule and therefore cannot benefit from this treatment. However, one study showed that pyridoxine supplementation in these patients could alleviate suffering by abolishing seizures. (More information)
  • The molybdenum content of foods depends on the molybdenum content of soils, which can vary considerably. Variation in esophageal cancer incidence worldwide has been linked to the molybdenum content in soils and food. Similar observations have been made in order to identify the factors associated with a population's extended lifespan. (More information)

Molybdenum is an essential trace element for virtually all life forms. It functions as a cofactor for a number of enzymes that catalyze important chemical transformations in the global carbon, nitrogen, and sulfur cycles (1). Thus, molybdenum-dependent enzymes are not only required for human health, but also for the health of our ecosystem.


The biological form of the molybdenum atom is an organic molecule known as the molybdenum cofactor (Moco) present in the active site of Moco-containing enzymes (molybdoenzymes) (2). In humans, molybdenum is known to function as a cofactor for four enzymes (3):

  • Sulfite oxidase catalyzes the transformation of sulfite to sulfate, a reaction that is necessary for the metabolism of sulfur-containing amino acids (methionine and cysteine). Recent evidence also indicates a role for sulfite oxidase in the reduction of nitrite to nitric oxide (4).
  • Xanthine oxidase catalyzes the breakdown of nucleotides (precursors to DNA and RNA) to form uric acid, which contributes to the plasma antioxidant capacity of the blood.
  • Aldehyde oxidase and xanthine oxidase catalyze hydroxylation reactions that involve a number of different molecules with similar chemical structures. Xanthine oxidase and aldehyde oxidase also play a role in the metabolism of drugs and toxins (5).
  • Mitochondrial amidoxime reducing component (mARC) was described fairly recently (6), and its precise function is still under investigation. Initial studies showed that mARC forms a three-component enzyme system with cytochrome b5 and NADH/cytochrome b5 reductase that catalyzes the detoxification of mutagenic N-hydroxylated bases (7). mARC reduces various N-hydroxylated compounds and plays an important role in prodrug metabolism (8, 9). Moreover, recent studies have found a separate function of this enzyme system: the reduction of nitrite to nitric oxide (10). Two isoforms of the mARC enzyme are known to exist in humans, mARC1 and mARC2 (11).

Of these enzymes, sulfite oxidase is known to be crucial for human health (12). Hereditary xanthinuria, characterized by a deficiency in xanthine oxidase (Type I) or by a deficiency in both xanthine oxidase and aldehyde oxidase (Type II), can be asymptomatic. However, in less than half of the cases, affected individuals exhibit a range of health issues of variable severity (13, 14).

Nutrient interactions


An early study reported that molybdenum intakes of 500 μg/day and 1,500 μg/day from sorghum increased urinary copper excretion (2). However, the results of a more recent, well-controlled study indicated that very high dietary molybdenum intakes (up to 1,500 μg/day) did not adversely affect copper nutritional status in eight, healthy young men (15).


Excess dietary molybdenum has been found to result in copper deficiency in grazing animals (ruminants). In the digestive tract of ruminants, the formation of compounds containing sulfur and molybdenum, known as thiomolybdates, prevents the absorption of copper and can cause fatal copper-dependent disorders (16, 17). Tetrathiomolybdate (TM) is a molecule that can form high-affinity complexes with copper, controlling free copper (copper that is not bound to ceruloplasmin), and inhibiting copper chaperones and copper-containing enzymes (18, 19). TM's ability to lower free copper levels is exploited in the treatment of Wilson's disease, a genetic disorder characterized by copper accumulation in tissues responsible for hepatic and neurologic disorders. Neurologic worsening has been linked with toxic levels of free copper in the serum of neurologically presenting patients. TM therapy seems able to stabilize neurologic status and prevent neurologic deterioration in these patients, as opposed to the standard initial treatment of choice (20).

Copper is also a required cofactor for enzymes involved in inflammation and angiogenesis that are known to accelerate cancer progression and metastasis. Copper depletion studies employing TM have been initiated in patients with advanced malignancies with the aim of preventing disease progression or relapse. These pilot trials showed promising results in individuals with metastatic kidney cancer (21), metastatic colorectal cancer (22), and breast cancer with high risk of relapse (23). TM was relatively well-tolerated and stabilized disease or prevented relapse in correlation with copper depletion. TM's efficacy has also been investigated in animal models of inflammatory and immune-related diseases (24, 25), but clinical studies are needed to evaluate whether copper depletion might stabilize diseases and improve survival in humans, as suggested by a trial of TM therapy with patients with biliary cirrhosis (26).


Dietary molybdenum deficiency has never been observed in healthy people (2).

Acquired molybdenum deficiency

The only documented case of acquired molybdenum deficiency occurred in a patient with Crohn's disease on long-term total parenteral nutrition (TPN) without molybdenum added to the TPN solution (27). The patient developed rapid heart and respiratory rates, headaches, and night blindness, and ultimately became comatose. The patient was diagnosed with defects in uric acid production and sulfur amino acid metabolism. The patient's clinical condition improved and the amino acid intolerance disappeared when the TPN solution was discontinued and instead supplemented with molybdenum in the form of ammonium molybdate (300 μg/day) (27).

Inherited molybdenum cofactor deficiency

Because molybdenum functions only in the form of the Moco in humans, any disturbance of Moco metabolism can disrupt the function of all molybdoenzymes. Current understanding of the essentiality of molybdenum in humans is based largely on the study of individuals with very rare inborn metabolic disorders caused by a deficiency in Moco. Moco is synthesized de novo by a multistep metabolic pathway involving four genes: MOCS1, MOCS2, MOCS3, and GPHN (see Figure 1 below). To date, more than 60 mutations affecting mostly MOCS1 and MOCS2 have been identified (28).

The absence of a functional Moco has a direct impact on the activity of the molybdoenzymes. Metabolic disorders specifically associated with deficiency in sulfite oxidase activity include an accumulation of sulfite, taurine, S-sulfocysteine, and thiosulfate (see Figure 2 below). This metabolic profile is identical to that observed in isolated sulfite oxidase deficiency (ISOD), an inherited condition caused by mutations in the SUOX gene that codes for sulfite oxidase (29). Compared with ISOD, Moco deficiency (MocoD) also affects the xanthine pathway and leads to an accumulation of hypoxanthine and xanthine, and low to undetectable uric acid concentrations in blood (see Figure 3 below). MocoD and ISOD have been diagnosed in more than 100 individuals worldwide. However the global prevalence of MocoD is likely to be underestimated as a result of a failure to diagnose or to report (28, 30, 31). The incidence of MocoD has been recently estimated at one in 100,000 to 200,000 live births (32).

Both MocoD and ISOD result from recessive traits, meaning that only individuals who inherit two copies of the abnormal gene (one from each parent) develop the disease. Individuals who inherit only one copy of the abnormal gene are known as carriers of the trait but do not exhibit any symptoms. ISOD and MocoD can be diagnosed relatively early in pregnancy (10-14 weeks' gestation) by enzyme activity assays using amniotic cell and chorionic villus sampling and by genetic testing (30, 33). These disorders typically occur in the first days of life, although a few cases of MocoD with late presentation have been described (34-37). The loss of sulfite oxidase activity in ISOD and MocoD leads to severe neurological dysfunction characterized by cerebral atrophy, mental retardation, intractable seizures, and dislocation of ocular lenses. At present, it is not clear whether the neurologic effects are a result of the accumulation of a toxic metabolite, such as sulfite, or inadequate sulfate production. Patients with ISOD and MocoD were also found with elevated excretion of α-amino adipic semialdehyde (α-AASA) (38). α-AASA accumulation is the metabolic signature of a deficiency in α-AASA dehydrogenase observed in patients with pyridoxine-dependent epilepsy. The enzymatic deficiency in these individuals causes an increase in α-AASA and its cyclic form piperideine-6-carboxylate (P6C). P6C can trap pyridoxal-5-phosphate (PLP), the active form of vitamin B6 (pyridoxine), leading to a deficiency in PLP, which is corrected with supplemental pyridoxine. A decrease in PLP has also been observed in the cerebrospinal fluid from ISOD and MocoD patients (39). It is not clear whether sulfite is responsible for the accumulation of α-AASA and the deficiency in PLP in ISOD and MocoD patients. Nevertheless, pyridoxine and folic acid supplementation in patients with MocoD successfully normalized the PLP level and abolished seizures in two patients with mutations in MOCS2 (MocoD Type B) (40). Although anti-seizure medications and dietary restriction of sulfur-containing amino acids may be beneficial in some cases (41), there are no treatment options for patients with mutations in the MOCS2, GPHN (MocoD Type C), or SUOX genes. Pyridoxine supplementation is an option being considered to alleviate specific clinical features in patients.

A successful treatment using cyclic pyranopterin monophosphate (cPMP) has been described for patients with mutations in the MOCS1 gene (i.e., those with MocoD Type A) (42). The MOCS1 gene controls the initial step in the Moco biosynthetic pathway, catalyzing the conversion of guanosine triphosphate into cPMP. Therefore, patients with mutations in the MOCS1 gene lack cPMP. Daily administration of cPMP to patients resolved all metabolic abnormalities associated with defective sulfite oxidase and xanthine pathways and prevented further signs of neurologic deterioration (43, 44). Early diagnosis and initiation of treatment are essential to ensure success (44). A prospective cohort study of 16 young infants, followed for five years, found that intravenous cPMP treatment was associated with clinical improvement in most infants with MocoD Type A but not in those with MocoD Type B (42). The US Food and Drug Administration recently approved the cPMP replacement drug, fosdenopterin (brand name: Nulibry), for intravenous treatment of MocoD Type A (45). Since cPMP replacement therapy can only benefit MocoD Type A, additional treatment methods are required. A mouse model for MocoD Type B has been recently developed, which may aid in the development of a therapy for those suffering from the MOSC2 mutation (46)

Figure 1. Molybdenum Cofactor Biosynthesis. Molybdenum cofactor (Moco) is synthesized de novo by a multistep metabolic pathway involving four genes: MOCS1, MOCS2, MOCS3, and GPHN.


Figure 2. Sulfur Amino Acid Metabolism.

Figure 3. Figure 3. Uric Acid Production. Adenine is converted to hypoxanthine; hypoxanthine is converted to xanthine via the enzymes, xanthine oxidase and aldehyde oxidase. Xanthine can be further metabolized to uric acid via xanthine oxidase.

The Recommended Dietary Allowance (RDA)

The recommended dietary allowance (RDA) for molybdenum was most recently revised in January 2001 by the Food and Nutrition Board of the Institute of Medicine (now the National Academy of Medicine) (2). It was based on the results of nutritional balance studies conducted in eight, healthy young men under controlled laboratory conditions (47, 48). The RDA values for molybdenum are listed in Table 1 in micrograms (μg)/day by age and gender. Adequate intake (AI) levels were set for infants based on mean molybdenum intake from human milk, exclusively. The Daily Value (DV), derived from the RDA, is 45 μg/day for individuals 4 years of age or older (49).

Table 1. Recommended Dietary Allowance (RDA) for Molybdenum
Life Stage Age Males (μg/day) Females (μg/day)
Infants  0-6 months 2 (AI) 2 (AI)
Infants  7-12 months   3 (AI)  3 (AI)
Children  1-3 years  17 17
Children 4-8 years  22 22
Children  9-13 years  34 34
Adolescents  14-18 years  43 43
Adults  19 years and older 45 45
Pregnancy  all ages  50
Breast-feeding  all ages  50

Disease Prevention

Esophageal cancer

Linxian is a small region in northern China where the incidence of cancer of the esophagus and stomach is very high (10 times higher than the average in China and 100 times higher than the average in the US). The soil in this region is low in molybdenum and other mineral elements; therefore, dietary molybdenum intake is also low. Studies conducted in other areas of low and high incidence of esophageal cancer showed that content of molybdenum and zinc in hair and nails is significantly lower in inhabitants of high-risk regions compared to cold spots. Moreover, esophageal cancer patients display reduced content of the trace elements compared to healthy relatives (50, 51).

Increased intake of nitrosamines, which are known carcinogens, may be one of a number of dietary and environmental factors that contributes to the development of esophageal cancer in residents of high-risk regions. Adding ammonium molybdate to the soil may help decrease the risk of esophageal cancer by limiting nitrosamine exposure. It is not clear whether dietary molybdenum supplementation is beneficial in decreasing the risk of esophageal cancer. A placebo-controlled, intervention trial conducted in the Linxian area found that supplementation with molybdenum (30 μg/day) and vitamin C (120 mg/day) for 5.25 years did not decrease the incidence or mortality from esophageal cancer (52-54). The 25-year follow-up of this trial found that co-supplementation with these two micronutrients actually led to small increases in risk of death from gastri