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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).
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).
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 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).
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).
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).
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.
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.
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).
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).
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).
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).
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).
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) 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).
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).
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).
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).
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).
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.
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.
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.
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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