Anxiety disorder is characterized by excessive fear or avoidance of perceived threats. Diet is a modifiable risk factor that may contribute to the pathogenesis or treatment of anxiety, depending on diet quality. Trace mineral treatments for the relief of anxiety have been investigated.
Anxiety disorder is characterized by excessive fear or avoidance of perceived threats that can be persistent and debilitating . According to the World Health Organization, 301 million people were living with an anxiety disorder in 2019 . Anxiety disorders account for 3.3% of the global burden of disease and are ranked the ninth most health-related cause for disability. The pathophysiology of anxiety involves dysfunction in brain circuits that respond to danger and can be influenced by genetics, the environment, and epigenetic factors. Nutritional psychiatry is an emerging discipline that involves the practice of using food and nutritional supplements to improve mood disorders in conjunction with conventional treatments, showing promise for enhanced methods to treat anxiety .
Diet is a modifiable risk factor that may contribute to the pathogenesis or treatment of anxiety, depending on diet quality . There is growing evidence that diet interventions based on improved dietary patterns or specific nutrients show potential for the prevention or treatment of mental health disorders . Based on evidence that food can impact mood with the influence of key nutrients on important neurobiological processes , it is imperative that diet should be considered for the preservation of mental health.
Essential dietary minerals are critical for the optimization of both physical and mental health . Although a healthy diet is the preferred way to obtain essential micronutrients, dietary supplements can also be used to meet nutritional requirements . Broad spectrum micronutrient interventions have shown promise for reducing symptoms associated with stress and anxiety . Specific mineral treatments for the relief of anxiety have also been investigated .
Zinc is an essential trace mineral in the diet due to its key role in gene expression, immune function, wound healing, and cell division . A deficiency in zinc can lead to physical health issues and mental health illnesses, including depression and anxiety . The recommended dietary allowance (RDA) for zinc increases with age and ranges from 2–13 mg . Consuming foods such as red meat, poultry, seafood, beans, nuts, whole grains, dairy, and fortified breakfast cereal will help to meet these dietary recommendations.
Zinc participates in several diverse roles within the body as a component of metalloenzymes. It provides structural integrity for many proteins and is a required cofactor for numerous metabolic reactions . Investigations into the molecular mechanisms involved in the development of mental health disorders suggest a role for zinc in the regulation of neurotransmitter systems, antioxidant activity, neurotrophic factors, and neuronal precursor cells . Additionally, zinc may be involved in regulating neurotransmitter metabolism in the hippocampus, with a potential influence on mental health and anxiety-like behaviors .
There is evidence that supports an association between dietary zinc deficiency and anxiety. For example, a study with female high school students found a positive correlation between dietary zinc intake and serum zinc levels and a corresponding inverse association between serum zinc and anxiety symptoms . Another study in female university students found an inverse association between dietary zinc intake and anxiety . In adult Japanese workers an inverse association was found between dietary zinc and anxiety symptoms . In a preclinical study, C3H/HenRj mice fed a prenatal zinc-deficient diet displayed higher anxiety-like behavior, despite being fed a postnatal zinc-sufficient diet .
Related studies that did not include a diet analysis found a similar relationship between zinc deficiency and anxiety. In children and adolescents with attention-deficit/hyperactivity disorder, low serum zinc was correlated with higher anxiety and conduct issues . In male Chinese participants, cerebrospinal fluid zinc concentrations were negatively correlated with anxiety symptoms . A study conducted in Bangladesh found that there was an imbalance of minerals in a cohort of patients with generalized anxiety disorder. The participants who suffered from anxiety had low blood serum concentrations of zinc and high serum concentrations of copper, manganese, and iron .
Zinc therapy is a treatment option that has been investigated for the alleviation of anxiety symptoms in both humans and animals. A randomized controlled trial in patients with type 2 diabetes mellitus and coronary heart disease found that a combination of zinc sulfate and magnesium oxide supplementation f significantly reduced anxiety symptoms . An intervention using zinc supplementation to treat symptoms of premenstrual syndrome (PMS) was also successful at reducing anxiety and other symptoms related to PMS in Iranian females . Another study examined the effect of zinc oxide supplementation on the mental health of school-age children in Guatemala. Although there was no significant difference in overall mental health outcomes between the control and treatment groups, the treatment group did have higher serum zinc concentrations, and increased serum zinc was associated with reduced anxiety symptoms .
Preclinical studies have also demonstrated that zinc treatments may have an anxiolytic effect. In one study, adult male Wistar rats induced with Type 1 Diabetes Mellitus were treated with either zinc gluconate or zinc sulfate. The zinc sulfate group alone showed decreased anxiety-like behavior after the treatment. Although zinc gluconate did not have the same anxiolytic outcome, it did have an antidepressant effect and neuroprotective effect . Another study conducted with male Wistar rats treated with zinc histidine dehydrate found that the impact on anxiety was dose dependent. A zinc dose of 20 mg/kg was found to have an anxiolytic effect; however, a dose of 30 mg/kg was found to have an anxiogenic effect . Zinc hydroaspartate administration in male albino Swiss mice and male Wistar rats also revealed a dose-dependent anxiolytic effect in the treatment group .
Although there is evidence to support the claim that zinc status is inversely associated with anxiety, other studies have shown conflicting results. For example, no correlation was found between serum zinc concentration and anxiety in older community-dwelling Australians  nor in Polish postmenopausal women . A cross-sectional study in elderly Iranians found no association between anxiety and dietary zinc nor serum zinc . In a prospective analysis, Australian adolescents were evaluated for potential associations between various mental health issues and dietary zinc. Although the results were trending toward statistical significance, there was no confirmed association between dietary zinc and anxiety . A study with Australian women also indicated no association between dietary zinc intake and anxiety . Although there is substantial evidence that zinc supplementation frequently has an anxiolytic effect, a study in women with postpartum depression showed a different result. In this trial, the women with postpartum depression and anxiety were treated with zinc sulfate supplements but did not experience a significant improvement in anxiety .
Copper is an essential trace mineral involved in energy production, iron metabolism, neuropeptide activation, and neurotransmitter synthesis. It also plays a role in neurohormone homeostasis, brain development, and immune system function. The RDA for copper is 900 mcg/day for adult men and women . Rich sources of copper include meat, shellfish, nuts, seeds, legumes, and dried fruit . Copper deficiency can lead to health issues such as anemia, connective tissue abnormalities, impaired growth, nervous system degeneration, and weakened immune system .
Copper is required for normal physiological function. A key physiological function of copper related to mood is its role as a cofactor for dopaminemonooxygenase, which converts dopamine to norepinephrine. Copper is also a cofactor for a variety of amine oxidases responsible for oxidizing biogenic amines such as dopamine, serotonin, and norepinephrine. In addition to its role as an enzyme cofactor, copper participates in nerve myelination and endorphin action . Thus, a copper imbalance can lead to the potential dysfunction of several neurological and physiological processes.
Currently, there is limited research that links copper deficiency with anxiety disorders. One preclinical study using male Wistar rats found that copper injections had an anxiolytic effect when assessing behaviors in the elevated plus maze and light-dark box tests . A study in adult Japanese workers found an inverse association of both zinc and copper dietary intake with anxiety and depression symptoms .
Rather than deficiency, there is more evidence to support a relationship between anxiety symptoms and copper overload. For example, Bangladesh adults with generalized anxiety disorder had significantly higher serum copper and iron levels compared to a control group . In a case–control study, the relationship between anxiety and serum copper was examined in patients with type 2 diabetes mellitus. They found a positive association between copper and anxiogenic behaviors . The impact of copper on anxiety in rodents can vary depending on the route of copper exposure. For example, although male Wistar rats injected with copper displayed anxiolytic behaviors , rats exposed to excess copper via drinking water showed anxiogenic behavior . Both studies found that copper intoxication induced a serotonergic modification in the dorsal raphe nucleus manifested as increased serotonin levels .
Although there is evidence to support the relationship between anxiety and copper overload, other studies show that there is no significant correlation. A randomized controlled trial with older community-dwelling Australians found no association between anxiety and blood copper, zinc, or copper/zinc levels . A study in pregnant Iranian adolescents found that participants with depression had elevated copper, however, there was no association between serum copper and anxiety . In Polish postmenopausal women, no relationship was found between anxiety and serum copper levels .
Iron is a vital trace element required for good health and red blood cell function. This element plays a crucial role in the early developmental stages of life and is required for proper growth and oxygen transport. The RDA for iron depends on gender and developmental stage of life: 8 mg daily for adult men, 18 mg for adult women, 27 mg during pregnancy, 9–10 mg while lactating, 8 mg for elderly, and 7–15 mg for children and adolescents . Iron deficiency is one of the most common dietary mineral deficiencies worldwide . In addition to health issues related to insufficient iron intake, such as iron deficiency anemia (IDA), iron overload is also a major health concern. Iron overload is implicated in the process of neurodegeneration and common brain-targeted diseases . Considering the biological significance of iron, maintaining iron homeostasis through proper diet is critical for health promotion and disease prevention.
Iron-dependent proteins serve many roles throughout the body. Key heme proteins include hemoglobin, myoglobin, and cytochromes . Iron is required by tyrosine hydroxylase for the synthesis of catecholamines that impact behavior, such as dopamine, epinephrine, and norepinephrine .
Several studies have examined the relationship between iron and anxiety. Many of these studies focused on patients with IDA, a common type of anemia where the blood lacks a sufficient amount of healthy red blood cells . Low iron status is often associated with higher risk for anxiety behaviors in both humans and animals. In one rodent study, weanling rats were fed either an iron-deficient diet or control diet. The iron-deficient rats showed significantly increased anxiety-like behaviors and reductions in brain iron content and dopamine receptors in the corpus striatum, prefrontal cortex, and midbrain . In a Chilean cohort, participants with iron deficiency with or without anemia in infancy were reported to have greater self-reported anxiety symptoms during adolescence . Taiwanese children and adolescents with IDA were also correlated with an increased risk for anxiety disorder . A recent study showed that serum ferritin in adolescent females was inversely correlated with both anxiety and depressive symptom severity . In a sleep study in Turkish adults, patients with IDA had higher levels of anxiety compared to the control group . Interestingly, a group of medical technology students attending the University of Santo Tomas in the Philippines showed a significant association between symptom-based IDA and anxiety for females but not for males , suggesting a potential sex difference in the development of anxiety traits.
Maternal diets that are iron-deficient can significantly impact offspring behaviors such as anxiety. For example, pregnant Long-Evans hooded rats fed a low-iron diet led to offspring with higher anxiety-like traits . Another rodent study investigated the behavior of adult Wistar rats exposed to iron deficiency during the fetal and lactational periods and subsequent impact of dietary iron replacement after the weaning period. The iron-deficient progeny displayed higher levels of anxiety-like behavior compared to the control group and did not benefit from the post-weaning iron-supplemented diet . In a scoping review regarding maternal nutrition and neurodevelopment, it was reported that inadequate nutrient intake during pregnancy, including lack of dietary iron, was associated with brain defects and an increased risk of neuropsychiatric disorders such as anxiety .
Interventions with iron supplementation treatments have proven to have a significant anxiolytic effect in many cases. In one study, elderly Canadians were assigned randomly to either a liquid nutritional supplement or control group. Iron serum increased in the treatment group, and values from the General Well-Being Questionnaire improved for anxiety . A study in patients with inflammatory bowel disease and IDA evaluated the efficacy of Sucrosomial® iron as an alternative to conventional iron supplements. The new Sucrosomial® iron supplement was not only effective at treating inflammatory bowel disease and IDA, but also improved anxiety symptoms . A clinical study in Italy evaluated the effect of Sideremil™, a liposomal iron pyrophosphate/ascorbic acid supplement, on clinical and psychological outcomes in pregnant women with IDA. They found that Sideremil™ was effective at reducing anxiety and increasing key iron-related proteins . In a prospective intervention trial, South African anemic mothers were given iron sulfate supplements and followed from 10 weeks of pregnancy to nine months postpartum. Iron status for these women was inversely associated with stress and anxiety . Premenopausal Turkish women with IDA treated with oral or parenteral iron agents had improved anxiety scores and increased serum iron after the treatment . A retrospective population-based cohort study in Taiwan compared psychiatric disorders in patients with IDA compared to a control group. The IDA group was associated with significantly higher incidence of anxiety disorders. Iron supplementation in these IDA patients was associated with a lower risk of psychiatric disorders compared to non-iron supplementation in IDA participants . Furthermore, a study evaluated Japanese children and adolescents with hypoferritinemia who received an oral iron administration for 12 weeks. The results showed that the iron supplemented group had significantly improved hypoferritinemia-related psychological symptoms .
Although most research provides evidence that iron deficiency increases the risk for anxiety disorders, other studies have revealed different results. For example, a study in women that used electroencephalographic psychometric data to assess anxiety found that iron-depleted females did not differ from the iron-sufficient group in anxiety traits . In a multicenter trial in nonanemic adult French women with fatigue, women were assigned oral ferrous sulfate or placebo for 12 weeks. Although the iron supplementation effectively decreased fatigue, there was no significant change in anxiety . A study in Japanese workers found no association between anxiety and serum iron . In a study with children, healthy Chilean infants free of IDA at age six months were randomly assigned to either an iron supplemented formula or a control formula from ages six to 12 months. At 10 years of age, the children were evaluated for social-emotional outcomes. Although the treatment group was associated with more adaptive behavior, there were no differences in behaviors related to behavioral inhibition, such as anxiety, depression, or social problems .
Selenium has many benefits as an essential nutrient in our diet. It functions as an antioxidant and helps regulate thyroid hormone metabolism, DNA synthesis, reproduction, and immune system support. The RDA for age 14 years and older is 55 mcg. Selenium-rich foods include Brazil nuts, meat, grains, and seafood . Selenium deficiency has been associated with Keshan disease, male infertility, and cognitive decline.
Selenium plays a key role in several enzymes called selenoproteins, which function primarily as antioxidants. The most highly characterized of these proteins is glutathione peroxidase. A dietary deficiency in selenium decreases the expression of glutathione peroxidase in favor of other selenoproteins, such as selenoprotein P, and can increase the risk for oxidative damage. Selenium is also required for iodine metabolism for the regulation of thyroid hormone synthesis .
Overall, the majority of evidence reveals an inverse association between selenium and anxiety, and a promising effect of selenium supplementation to alleviate anxiety symptoms. For example, in Portuguese adults with chronic renal failure under hemodialysis, higher anxiety levels were associated with selenium deficiency based on nutrient intake analysis . A study involving Chinese children found that lower selenium levels were associated with higher anxiety symptoms . Recently, two randomized, double-blinded, placebo-controlled clinical trials revealed a promising effect of combining a probiotic with selenium for the reduction of anxiety symptoms in women with polycystic ovary syndrome  and adult patients with both type 2 diabetes and coronary heart disease . Both studies found an increase in total antioxidant capacity and glutathione levels in the treatment group. Furthermore, it was found in older reports that selenium supplementation or a selenium-fortified diet may improve anxious mood .
Preclinical research has also shown that selenium-based treatments are effective for mitigating anxiety. A quinoline derivative containing selenium, 7-chloro-4-phenylselanylquinoline, shows promise as an anxiolytic agent in rodents . Other potential therapeutic agents include 6-((4-fluorophenyl) selanyl)-9H-purine  and a pyrazole-containing selenium compound .
There is evidence that demonstrates the connection between thyroid function and mental health . As selenium plays an important role in thyroid hormone metabolism, it is postulated that a selenium imbalance occurring in thyroid disease may promote anxiety disorder as a comorbidity. One study examined the relationship between selenium and anxiety in patients with euthyroid nodular goiter. There was a significant correlation between selenium deficiency and anxiety symptoms independent of thyroid hormone status .
Although most of the scientific literature suggests an inverse association between selenium status and anxiety, there is some evidence that suggests that there is no association. For example, one study evaluated the relationship between serum selenium levels and anxiety symptoms in postmenopausal women. There was no observed correlation between selenium concentrations and the corresponding anxiety .