Selenium was discovered in 1817 in Gripsholm, a Swedish city, by a Swedish chemist Jacob Berzelius. Selenium is a commonly occurring element in nature. It can be found in the atmosphere, lithosphere, biosphere, and hydrosphere of the Earth. The amount of this element present in nature and in the human organism is very diverse depending on the geographic region and diet.

The total amount of selenium in a human organism is ~3–20 mg.

Selenium is a trace element that is naturally present in many foods, added to others, and available as a dietary supplement. Selenium, which is nutritionally essential for humans, is a constituent of more than two dozen selenoproteins that play critical roles in reproduction, thyroid hormone metabolism, DNA synthesis, and protection from oxidative damage and infection.

Selenium is incorporated into selenoproteins that have a wide range of pleiotropic effects, ranging from anti oxidant and anti-inflammatory effects to the production of active thyroid hormone. In the past 10 years, the discovery of disease associated polymorphisms in seleno protein genes has drawn attention to the relevance of selenoproteins to health. The essential biological importance of selenium is associated with its occurrence in proteins and enzymes. Several selenium-dependent enzymes in which the active center contains selenium in the form of selenocysteine moiety have been identified. The best-characterized selenoenzymes commonly occurring in mammals are glutathione peroxidase, selenoprotein P, and thyroxine 5-deiodinase. Glutathione peroxidase and selenoprotein P catalyze redox reactions. Other enzymatic proteins that are involved in important functions of the organisms are formate dehydrogenase, nicotinic acid hydroxylase, glycine reductase, thiolase, and xanthine dehydrogenase.

Low selenium status has been associated with increased risk of mortality, poor immune function, and cognitive decline.

Higher selenium status or selenium supplementation has antiviral effects, is essential for successful male and female reproduction, and reduces the risk of autoimmune thyroid disease. Prospective studies have generally shown some benefit of higher selenium status on the risk of prostate, lung, colorectal, and bladder cancers, but findings from trials have been mixed, which probably emphasises the fact that supplementation will confer benefit only if intake of a nutrient is inadequate.

The eff ects of selenium on human health are multiple and complex, necessitating further research to optimize the benefits and reduce the risks of this potent trace mineral. 1, Reference: Marek Kieliszek; Selenium–Fascinating Microelement, Properties and Sources in Food; Molecules. 2019 Apr; 24(7): 1298. Published online 2019 Apr 3. doi: 10.3390/molecules24071298 2, Reference: Sunde RA. Selenium. In: Ross AC, Caballero B, Cousins RJ, Tucker KL, Ziegler TR, eds. Modern Nutrition in Health and Disease. 11th ed. Philadelphia, PA: Lippincott Williams & Wilkins; 2012:225-37 3 Reference: Rayman, M. P. (2012). Selenium and human health. The Lancet, 379(9822), 1256–1268. doi:10.1016/s0140-6736(11)61452-9

Prolonged selenium deficiency in human organism leads to serious diseases. Deficiency of this element adversely affects the functioning of the cardiovascular system and can be a direct cause of myocardial infarction. It is associated with endemic diseases: Keshan and Kashin-Beck.

As a result of epidemiological studies, it was concluded that moderate deficiency of selenium in daily diet affects the development of diseases resulting from reduced immunity. Selenium deficiency in daily diet can adversely affect the functioning of the nervous system. Among individuals with selenium deficiency, development of depression, or intensification of anxiety is observed; Alzheimer’s disease is also developed. This element is considered to be crucial in reducing the virulence of HIV and in decreasing the progression to full-blown AIDS. Selenium deficiency in pregnant women negatively affects the development of the embryo. Excess of selenium can be toxic to the organism. Acute selenium poisoning is rarely observed. The accurate determination of harmful doses of selenium is difficult because of the occurrence of various chemical forms of this element. A toxic effect on the organism can be exerted by both organic and inorganic forms of selenium. Toxicity of selenium (depends on the dose) is associated with competitive inhibition between selenium and sulfur, leading to the onset of sulfur metabolism (transformation). Selenium may substitute sulfur in amino acids (cysteine and methionine), whereas the inorganic compounds displace sulfur during the synthesis of mercapturic acids and during the reaction of selenites with thiol groups. 2 Reference: Marek Kieliszek; Selenium–Fascinating Microelement, Properties and Sources in Food; Molecules. 2019 Apr; 24(7): 1298. Published online 2019 Apr 3. doi: 10.3390/molecules24071298 

Groups at Risk of Selenium Inadequacy

Selenium deficiency is rare and selenium deficiency in isolation rarely causes overt illness. The following groups are among those most likely to have inadequate intakes of selenium.

1. People living in selenium-deficient regions

People in some countries whose diet consists primarily of vegetables grown in low-selenium areas are at risk of deficiency. The lowest selenium intakes in the world are in certain parts of China, where large proportions of the population have a primarily vegetarian diet and soil selenium levels are very low. Average selenium intakes are also low in some European countries, especially among populations consuming vegan diets. Although intakes in New Zealand were low in the past, they rose after the country increased its importation of high-selenium wheat.

2. People undergoing kidney dialysis

Selenium levels are significantly lower in patients undergoing long-term hemodialysis than in healthy individuals. Hemodialysis removes some selenium from the blood. In addition, hemodialysis patients are at risk of low dietary selenium intakes due to anorexia resulting from uremia and dietary restrictions. Although selenium supplementation increases blood levels in hemodialysis patients, more evidence is needed to determine whether supplements have beneficial clinical effects in these individuals.

3. People living with HIV

Selenium levels are often low in people living with HIV, possibly because of inadequate intakes (especially in developing countries), excessive losses due to diarrhea, and malabsorption. Observational studies have found an association between lower selenium concentrations in people with HIV and an increased risk of cardiomyopathy, death, and, in pregnant women, HIV transmission to offspring and early death of offspring. 3 Reference:https://ods.od.nih.gov/factsheets/Selenium-HealthProfessional/

Selenium in the diet. Adults who are not found or established to be deficient in selenium are normally required 55 mcg (micrograms) for men and for women, but for pregnant women 60 mcg of selenium per day

Reference Atsauce: https://ods.od.nih.gov/factsheets/Selenium-HealthProfessional/ 

Selenium can interact with certain medications, and some medications can have an adverse effect on selenium levels. One example is provided below. Individuals taking this and other medications on a regular basis should discuss their selenium status with their healthcare providers.

Cisplatin

Cisplatin, an inorganic platinum chemotherapy agent, is used to treat ovarian, bladder, lung, and other cancers. Cisplatin can reduce selenium levels in hair and serum but whether these reductions have a clinically significant impact is not known. Some small studies have shown that selenium supplementation can reduce cisplatin’s toxicity but the authors of a Cochrane review concluded that the evidence that selenium supplementation alleviates the side effects of chemotherapy is insufficient.

Health Risks from Excessive Selenium

Chronically high intakes of the organic and inorganic forms of selenium have similar effects. Early indicators of excess intake are a garlic odor in the breath and a metallic taste in the mouth. The most common clinical signs of chronically high selenium intakes, or selenosis, are hair and nail loss or brittleness. Other symptoms include lesions of the skin and nervous system, nausea, diarrhea, skin rashes, mottled teeth, fatigue, irritability, and nervous system abnormalities. 1 Reference:https://ods.od.nih.gov/factsheets/Selenium-HealthProfessional/

There are a number of indications that selenium is important to the brain: during selenium depletion the brain receives a priority supply; the turnover rate of some neurotransmitters is altered in selenium deficiency; supplementation with selenium reduced intractable epileptic seizures in children; low plasma selenium concentrations in the elderly were significantly associated with senility and accelerated cognitive decline and brain selenium concentration in Alzheimer’s patients was only 60% of that in controls. Furthermore, the brain is deficient in catalase, thus peroxidation products such as hydrogen peroxide and primary peroxides must be removed by the antioxidant selenoenzymes.

A beneficial effect of selenium status on mood has been shown, at least when selenium status is “marginal”. In three studies, low selenium status was associated with a significantly greater incidence of depression and other negative mood states such as anxiety, confusion, and hostility.

Serum selenium concentrations decline with age. Marginal or deficient selenium concentrations might be associated with age-related declines in brain function, possibly due to decreases in selenium’s antioxidant activity.

Selenium, incorporated into specific seleno-enzymes, is essential to proper thyroid function and protect cells from oxidative damage induced by H2O2 during thyroid hormone synthesis while study has shown that oxidative stress markers are associated with cognitive decline in a highly cognitive functioning population. 

Selenium-dependent glutathione reductase and selenoproteins are important for their antioxidant activity, which is vital for the protection of the organism. Selenium affects the metabolic pathways by changing the activity of selenoproteins and plays a role in cellular defense against oxidative stress. Selenium concentration regulates the expression of selenoproteins. Different selenium concentrations may affect immunity and energy metabolism diversely. Increased levels of stress biomarkers have been reported in depression in recent studies, and this suggests that oxidative stress may be an important factor in the pathogenesis of depression. Selenium may have a protective role against anxiety and depression, possibly due to its protective effect on oxidative stress.

Lastly, selenium could potentially exert antidepressant effects through its modulatory role in various neurotransmitter systems. Selenium has been found to have significant modulatory effects on the dopaminergic, serotonergic, and noradrenergic systems, which are all involved in the physiopathology of depression and other psychiatric illnesses.

References: 1 Reference: Rayman, M. P. (2000). The importance of selenium to human health. The Lancet, 356(9225), 233–241. doi:10.1016/s0140-6736(00)02490-9 2 Reference: Berr, C., Balansard, B., Arnaud, J., Roussel, A.-M., & Alpérovitch, A. (2000). Cognitive Decline Is Associated with Systemic Oxidative Stress: The EVA Study. Journal of the American Geriatrics Society, 48(10), 1285–1291. doi:10.1111/j.1532-5415.2000.tb02603.x 3 Reference: Ruggeri, R. M., D’Ascola, A., Vicchio, T. M., Campo, S., Gianì, F., Giovinazzo, S., … Trimarchi, F. (2019). Selenium exerts protective effects against oxidative stress and cell damage in human thyrocytes and fibroblasts. Endocrine. doi:10.1007/s12020-019-02171-w 4 Reference: Elif Turan and Ozgul Karaaslan; The Relationship between Iodine and Selenium Levels with Anxiety and Depression in Patients with Euthyroid Nodular Goiter; Oman Med J. 2020 Jul; 35(4): e161. Published online 2020 Jul 31. doi: 10.5001/omj.2020.84 5 Reference: Wang, J., Um, P., Dickerman, B., & Liu, J. (2018). Zinc, Magnesium, Selenium and Depression: A Review of the Evidence, Potential Mechanisms and Implications. Nutrients, 10(5), 584. doi:10.3390/nu10050584

Selenium, an essential trace element for humans, has a direct effect on thyroid hormone metabolism and oxidation-reduction processes. The functioning of the thyroid gland is critically dependent on iodine and selenium, in order to ensure that it functions properly. An insufficient amount of selenium in the body is associated with an increased risk of thyroid disease.1

Selenium can be considered the key to the health of the thyroid gland. It is a necessary trace element for the synthesis and functioning of thyroid hormones. The concentration of selenium in the thyroid gland is higher than in any other organ in the body. Selenium works with iodine to activate three different selenium-dependent iodothyronine deiodinases, which can then activate or deactivate thyroid hormones. All three isoforms of deiodinases are selenium-containing enzymes, so dietary or supplemental selenium is essential for triiodothyronine (T3) production. This process (and selenium) is essential for normal growth, development and metabolism.2

Selenium deficiency is associated with hypothyroidism, Hashimoto's disease, an enlarged thyroid gland, thyroid cancer, and Graves' disease.

One study of 1,900 participants found a relationship between serum selenium concentrations and the size of the thyroid gland. A protective effect of selenium against enlarged thyroid gland and thyroid tissue damage was observed. In this particular study, these results were only significant for female participants.3

Another study looked at the effect of selenium on Graves' orbitopathy (when the thyroid gland produces too much thyroid hormone). The researchers compared treatment with selenium to treatment with pentoxifylline (Pentilin), an anti-inflammatory drug. The selenium treatment group reported improved quality of life and slowed the progression of Graves' orbitopathy compared to the pentoxifylline (Pentilin) treatment group.4 1 Atsauce: 1) Wichman, J., Winther, K. H., Bonnema, S. J., & Hegedüs, L. (2016). Selenium Supplementation Significantly Reduces Thyroid Autoantibody Levels in Patients with Chronic Autoimmune Thyroiditis: A Systematic Review and Meta-Analysis. Thyroid, 26(12), 1681–1692. doi:10.1089/thy.2016.0256 2) Triggiani, V., Tafaro, E., Giagulli, V., Sabba, C., Resta, F., Licchelli, B., & Guastamacchia, E. (2009). Role of Iodine, Selenium and Other Micronutrients in Thyroid Function and Disorders. Endocrine, Metabolic & Immune Disorders - Drug Targets, 9(3), 277–294. doi:10.2174/187153009789044392 3) Derumeaux, H., Valeix, P., Castetbon, K., Bensimon, M., Boutron-Ruault, M., Arnaud, J., & Hercberg, S. (2003). Association of selenium with thyroid volume and echostructure in 35- to 60-year-old French adults. European Journal of Endocrinology, 148(3), 309–315. doi:10.1530/eje.0.1480309 4) Marcocci, C., Kahaly, G. J., Krassas, G. E., Bartalena, L., Prummel, M., Stahl, M., … Wiersinga, W. (2011). Selenium and the Course of Mild Graves’ Orbitopathy. New England Journal of Medicine, 364(20), 1920–1931. doi:10.1056/nejmoa1012985

1. For a long time, selenium was considered a toxic element. Poisoning with this element led to the development of severe anemia, bone stiffness, hair loss, and blindness. These symptoms have been observed in humans and animals in areas where the content of this element in the soil was ~1000 times greater in comparison with soils with an average amount of selenium in the other regions of the world.
2. Selenium gets its name from the Greek word "selene," which means "moon." Selene was the Greek goddess of the moon.
3. Selenium is a nonmetal. Like many nonmetals, it exhibits different colors and structures (allotropes) depending on the conditions.
4. Brazil nuts are high in selenium, even if they are grown in soil that is not rich in the element. A single nut provides enough selenium to meet the daily requirement for a human adult.
5. The primary use of selenium is to decolorize glass, to color glass red, and to make the pigment China Red. Other uses are in photocells, in laser printers and photocopiers, in steels, in semiconductors, and in assorted medicinal preparations.
6. Selenium is protective against mercury poisoning.

Zinc is an essential bio-element, which plays a fundamental role in a wide range of biochemical processes. This metal is a major component of various proteins and is an important modulator of the immune and nervous systems. It is the second most abundant trace metal in humans after iron and it is the only metal which appears in all enzyme classes.

Zinc is involved in numerous aspects of cellular metabolism. It is required for the catalytic activity of over 300 enzymes and 1000 transcription factors and it plays a role in immune function, protein synthesis, wound healing, DNA synthesis and cell division. Zinc also supports normal growth and development during pregnancy, childhood, and adolescence and is required for proper sense of taste and smell.

In the brain, zinc is stored in specific synaptic vesicles by glutamatergic neurons and can modulate neuronal excitability. It plays a key role in synaptic plasticity and so in learning. Zinc homeostasis also plays a critical role in the functional regulation of the central nervous system. Dysregulation of zinc homeostasis in the central nervous system that results in excessive synaptic zinc concentrations is believed to induce neurotoxicity through mitochondrial oxidative stress (e.g., by disrupting certain enzymes involved in the electron transport chain), the dysregulation of calcium homeostasis, glutamatergic neuronal excitotoxicity, and interference with intraneuronal signal transduction. 1 Reference: Nowak G., Szewczyk B.: Mechanism contributing to antidepressant zinc actions. Pol. J. Pharmacol., 2002, 54, 587–592. PMID: 12866713 2 Reference: Prakash A, Bharti K, Majeed AB (April 2015). "Zinc: indications in brain disorders". Fundam Clin Pharmacol. 29 (2): 131–149. doi:10.1111/fcp.12110. PMID 25659970. S2CID 21141511 3 Reference: https://ods.od.nih.gov/factsheets/Zinc-HealthProfessional/

At the same time, studies have shown a correlation between zinc deficiency and thyroid gland hormone levels. Zinc is necessary for the proper functioning of the enzyme deiodinase, which activates the inactive thyroxine (T4) hormone into a more active form - triiodothyronine (T3), ensuring all thyroid gland functions in the human body. 4 Reference: Maxwell, C., & Volpe, S. L. (2007). Effect of Zinc Supplementation on Thyroid Hormone Function. Annals of Nutrition and Metabolism, 51(2), 188–194. doi:10.1159/000103324

Zinc affects several aspects of the immune system. It is crucial for the normal development and function of innate immune cells, neutrophils and natural killer or NK cells. Zinc deficiency also affects macrophages – large cells that draw in and digest foreign particles. Zinc deficiency affects phagocytosis, intracellular killing and cytokine production. Zinc deficiency negatively affects the growth and function of T and B cells. Zinc’s ability to act as an antioxidant and stabilise membranes suggests that it plays a role in preventing free radical-induced injury during inflammatory processes. 5 Reference: Prasad AS. Zinc in human health: effect of zinc on immune cells. Mol Med. 2008 May-Jun;14(5-6):353-7. doi: 10.2119/2008-00033.Prasad. PMID: 18385818; PMCID: PMC2277319.

Zinc deficiency is characterized by growth retardation, loss of appetite, and impaired immune function. In more severe cases, zinc deficiency causes hair loss, diarrhea, delayed sexual maturation, impotence, hypogonadism in males, and eye and skin lesions. Weight loss, delayed healing of wounds, taste abnormalities, and mental lethargy can also occur. Many of these symptoms are non-specific and often associated with other health conditions; therefore, a medical examination is necessary to ascertain whether a zinc deficiency is present. People at risk of zinc deficiency or inadequacy need to include good sources of zinc in their daily diets.

Groups at Risk of Zinc Inadequacy

1. People with gastrointestinal and other diseases

Gastrointestinal surgery and digestive disorders (such as ulcerative colitis, Crohn’s disease, and short bowel syndrome) can decrease zinc absorption and increase endogenous zinc losses primarily from the gastrointestinal tract and, to a lesser extent, from the kidney. Other diseases associated with zinc deficiency include malabsorption syndrome, chronic liver disease, chronic renal disease, sickle cell disease, diabetes, malignancy, and other chronic illnesses. Chronic diarrhea also leads to excessive loss of zinc.

2. Vegetarians

The bioavailability of zinc from vegetarian diets is lower than from non-vegetarian diets because vegetarians do not eat meat, which is high in bioavailable zinc and may enhance zinc absorption. In addition, vegetarians typically eat high levels of legumes and whole grains, which contain phytates that bind zinc and inhibit its absorption.

3. Pregnant and lactating women

Pregnant women, particularly those starting their pregnancy with marginal zinc status, are at increased risk of becoming zinc insufficient due, in part, to high fetal requirements for zinc. Lactation can also deplete maternal zinc stores.

4. Older infants who are exclusively breastfed

Breast milk provides sufficient zinc (2 mg/day) for the first 4–6 months of life but does not provide recommended amounts of zinc for infants aged 7–12 months, who need 3 mg/day. In addition to breast milk, infants aged 7–12 months should consume age-appropriate foods or formula containing zinc. Zinc supplementation has improved the growth rate in some children who demonstrate mild-to-moderate growth failure and who have a zinc deficiency.

5. People with sickle cell disease

Results from a large cross-sectional survey suggest that 44% of children with sickle cell disease have a low plasma zinc concentration, possibly due to increased nutrient requirements and/or poor nutritional status. Zinc deficiency also affects approximately 60%–70% of adults with sickle cell disease. 

6. Alcoholics

Approximately 30%–50% of alcoholics have low zinc status because ethanol consumption decreases intestinal absorption of zinc and increases urinary zinc excretion. In addition, the variety and amount of food consumed by many alcoholics is limited, leading to inadequate zinc intake. 6 Reference: https://ods.od.nih.gov/factsheets/Zinc-HealthProfessional/  

Zinc in the diet. Adults who are not found or established to be deficient in Zinc are normally required 11 mg for men, 8 mg for women and 11 mg for pregnant women of Zinc per day

Reference Atsauce: https://ods.od.nih.gov/factsheets/Zinc-HealthProfessional/

Zinc supplements have the potential to interact with several types of medications. A few examples are provided below. Individuals taking these medications on a regular basis should discuss their zinc intakes with their healthcare providers.

1. Antibiotics

Both quinolone antibiotics (such as Cipro®) and tetracycline antibiotics (such as Achromycin® and Sumycin®) interact with zinc in the gastrointestinal tract, inhibiting the absorption of both zinc and the antibiotic. Taking the antibiotic at least 2 hours before or 4–6 hours after taking a zinc supplement minimizes this interaction.

2. Penicillamine

Zinc can reduce the absorption and action of penicillamine, a drug used to treat rheumatoid arthritis. To minimize this interaction, individuals should take zinc supplements at least 2 hours before or after taking penicillamine.

3. Diuretics

Thiazide diuretics such as chlorthalidone (Hygroton®) and hydrochlorothiazide (Esidrix® and HydroDIURIL®) increase urinary zinc excretion by as much as 60%. Prolonged use of thiazide diuretics could deplete zinc tissue levels, so clinicians should monitor zinc status in patients taking these medications. 1 Reference: Lomaestro BM, Bailie GR. Absorption interactions with fluoroquinolones. 1995 update. Drug Saf 1995;12:314-33. [PubMed abstract] 2 Reference: Penttilä O, Hurme H, Neuvonen PJ. Effect of zinc sulphate on the absorption of tetracycline and doxycycline in man. Eur J Clin Pharmacol 1975;9:131-4. [PubMed abstract] 3 Reference: Natural Medicines Comprehensive Database. Zinc. 4 Reference: Brewer GJ, Yuzbasiyan-Gurkan V, Johnson V, Dick RD, Wang Y. Treatment of Wilson’s disease with zinc: XI. Interaction with other anticopper agents. J Am Coll Nutr 1993;12:26-30. [PubMed abstract] 5 Reference: Wester PO. Urinary zinc excretion during treatment with different diuretics. Acta Med Scand 1980;208:209-12. [PubMed abstract]

Zinc is found in abundance in the human brain. Patients with depression may have decreased consumption of food sources rich in zinc and consistently low dietary zinc intakes may contribute to depressive symptoms by further lowering available zinc, therefore zinc supplementation may have a potential influence on depressive symptoms. In preclinical studies, single- or long- term treatment with zinc has been shown to have antidepressant-like effects.

According to recently introduced hypotheses of antidepressant action, one of major goals to be modified by an antidepressant is the NMDA glutamate receptor. The mechanism of antidepressant activity of zinc might be related to its direct antagonism at NMDA receptor. Besides the central nervous system, zinc is also involved in the immune/inflammatory regulation in depressive disorders.

In the hippocampus and cortex, zinc ions regulate synaptic transmission or act as neurotransmitters, modulating many ligand- and voltage-gated ion channels. Disruption of zinc homeostasis in these regions has been implicated in many disturbances in cognition, behavioral and emotional regulation through mechanisms of decreased neurogenesis and neuronal plasticity.

Zinc deficiency has also been implicated in the endocrine pathway of depression. Persistently high levels of cortisol have been implicated in the development of depression via hyperactivity of the hypothalamic–pituitary–adrenal (HPA) axis. Increased plasma cortisol levels could, therefore, potentially mediate the relationship between zinc deficiency and depression.

The relationship between serum zinc levels and depression could be partially explained by reverse causation, whereby depression influences the intake, bioavailability or biological regulation of zinc. Oxidative stress and its accompanying immune-inflammatory response have been linked to the pathophysiology of depression. In response to oxidative stress, levels of pro-inflammatory cytokines (e.g., interleukin 1 (IL-1) and IL-6) increase and, in turn, decrease of the level of albumin and increase the synthesis of metallothioneins. Albumin is the main zinc transporter, and a decrease in albumin coupled with an increase in metallothioneins may compound to decrease serum levels of zinc.

References 1 Reference: Elham Ranjbar, Jamal Shams, Masoumeh Sabetkasaei, Minoo M-Shirazi, Bahram Rashidkhani, Ali Mostafavi, Eiliyaz Bornak, Javad Nasrollahzadeh; Effects of zinc supplementation on efficacy of antidepressant therapy, inflammatory cytokines, and brain-derived neurotrophic factor in patients with major depression; 2 Reference: Pilc A., Kodziñska A., Nowak G.: A role for glutamate in the treatment of anxiety and depression: focus on group I metabotropic glutamate (mGlu) receptors. Drugs Fut., 2002, 27, 753–763. 3 Reference: Jessica Wang, Phoebe Um, Barbra A. Dickerman and Jianghong Liu1; Zinc, Magnesium, Selenium and Depression: A Review of the Evidence, Potential Mechanisms and Implications; Nutrients. 2018 May; 10(5): 584. Published online 2018 May 9. doi: 10.3390/nu10050584

Zinc is an essential element involved in many basic biochemical reactions of the thyroid gland. Zinc is necessary for the production of the hormones triiodothyronine (T3), thyroxine (T4) and thyroid-stimulating hormone (TSH).

T4 is the main thyroid gland hormone, which is a kind of bodyreserve, while T3 is a much more active hormone. If necessary, one molecule of iodine is separated from T4, and it turns into an active hormone - T3.

This trace element participates in the synthesis of thyrotropin-releasing hormone (TRH) in the hypothalamus and in the synthesis of thyrotropin or thyroid-stimulating hormone (TSH) in the pituitary gland.1

Some studies have shown that zinc deficiency and low zinc concentration in the serum can cause changes in thyroid gland structure and thyroid gland hormone metabolism. Also, studies have shown that taking zinc can increase the concentration of thyroid gland hormones.1

In a study where subjects took zinc supplements, they had improvements in all thyroid gland hormone levels (especially T3) as well as in the rate of metabolism in the state of rest. Another study showed that taking zinc alone or in combination with selenium can improve thyroid gland function in women with hypothyroidism.2

Zinc deficiency can cause hypothyroidism. On the other hand, hypothyroidism can cause zinc deficiency because thyroid gland hormones are needed for zinc absorption. 1 Atsauce: 1) Beserra, J. B., Morais, J. B. S., Severo, J. S., Cruz, K. J. C., de Oliveira, A. R. S., Henriques, G. S., & do Nascimento Marreiro, D. (2021). Relation Between Zinc and Thyroid Hormones in Humans: a Systematic Review. Biological Trace Element Research. doi:10.1007/s12011-020-02562-5 2) Mahmoodianfard, S., Vafa, M., Golgiri, F., Khoshniat, M., Gohari, M., Solati, Z., & Djalali, M. (2015). Effects of Zinc and Selenium Supplementation on Thyroid Function in Overweight and Obese Hypothyroid Female Patients: A Randomized Double-Blind Controlled Trial. Journal of the American College of Nutrition, 34(5), 391–399. doi:10.1080/07315724.2014.926161

Zinc has been found to be an essential trace element for the immune system. However, at the cellular and molecular level, the mechanisms of zinc actions on the immune system are relatively recent and its effects are diverse. 1 Reference: Rink, L. (2000). Zinc and the immune system. Proceedings of the Nutrition Society, 59(04), 541–552. doi:10.1017/s0029665100000781

Adequate levels of zinc in the body are essential for the formation and function of different populations of lymphocytes (the main immune cells), such as the division, maturation and differentiation (development into different forms) of T-cells (or T-lymphocytes); lymphocyte response to mitogens (small bioactive proteins or peptides that induce cells to start dividing or increase the rate of division). At the same time, zinc is important for programming lymphoid and myeloid cell death; gene transcription and biomembrane function. Lymphocytes are one of the types of cells activated by zinc. Zinc is a structural component of various proteins, neuropeptides, hormone receptors and polynucleotides. Zinc deficiency results in rapid and marked atrophy of the thymus, impaired cell-mediated cutaneous sensitivity and lymphopenia. Primary and secondary antibody responses are reduced in zinc deficiency, particularly for those antigens that require T-cell help, such as those in heterologous red blood cells. In addition, antibody response and the generation of splenic cytotoxic T-cells after immunisation are reduced. Zinc also inhibits the production of tumour necrosis factor, which is implicated in the pathophysiology of cachexia and wasting in acquired immune deficiency syndrome. 2 :Reference: Baum MK, Shor-Posner G, Campa A. Zinc status in human immunodeficiency virus infection. J Nutr. 2000 May;130(5S Suppl):1421S-3S. doi: 10.1093/jn/130.5.1421S. PMID: 10801954.

In short, zinc is absolutely essential for the functioning of the thymus and the normal functioning of the immune system. Zinc prevents immunodeficiency by stimulating antibody synthesis and providing antiviral effects.

1. The element was probably named by the alchemist Paracelsus after the German word Zinke and supposedly meant "tooth-like, pointed or jagged" (metallic zinc crystals have a needle-like appearance). Zink could also imply "tin-like" because of its relation to German zinn meaning tin.
2. The oldest known pills were made of the zinc carbonates hydrozincite and smithsonite. The pills were used for sore eyes and were found aboard the Roman ship Relitto del Pozzino, wrecked in 140 BC.
3. Alchemists burned zinc metal in air and collected the resulting zinc oxide on a condenser. Some alchemists called this zinc oxide lana philosophica, Latin for "philosopher's wool", because it collected in wooly tufts, whereas others thought it looked like white snow and named it nix album.
4. Zinc is a natural insect repellent and sun screen, protecting lips and skin.
5. Zinc is 100% recyclable. Over 80% of the zinc available for recycling is currently recycled.

Gamma-Aminobutyric acid (GABA), discovered in 1950, is an amino acid produced naturally in the brain. GABA functions as a neurotransmitter, facilitating communication among brain cells. GABA’s big role in the body is to reduce the activity of neurons in the brain and central nervous system (CNS), which in turn has a broad range of effects on the body and mind, including increased relaxation, reduced stress, a more calm, balanced mood, alleviation of pain, and a boost to sleep.

Amino acid neurotransmitters are critical for the function of the CNS; they have fast actions, producing responses within few milliseconds playing an important role in brain functions and neurological diseases. 

Under stress conditions certain metabolites, like GABA, are depleted, therefore, additional nutrients are required to replace these metabolites. As the quantities of nutrition vary from one individual to another and the difficulties to obtain these nutrients from food so a better alternative is to consume the required additional nutrients as enriched functional food and/or food supplements.

GABA is synthesised in tissues from glutamic acid via the enzyme glutamic acid decarboxylase (GAD), with pyridoxal-5-phosphate (P5P) acting as a cofactor.

Outside of the CNS, GABA is synthesised by the colonic microflora. As the major inhibitory neurotransmitter, GABA counteracts over excitation in the brain, and has been described as acting like a ‘brake’ on the neuronal circuitry during times of increased stress. Following its release from GABAergic nerve terminals, it acts on both GABA-A and GABA-B receptors, with a net inhibitory effect.

The GABA-A receptors regulate brain excitability and are responsible for GABA’s immediate synaptic inhibitory effects. As low GABA levels are associated with anxiety, depression, insomnia and epilepsy, medications that target these GABA receptors have been developed. There are many pharmaceutical medications, alcohol and psychoactive drugs that produce their anxiolytic, analgesic, anticonvulsant, and sedative effects by modulating GABA-A receptor activity or by blocking the reuptake of GABA by GABA transporter (GAT) proteins.

In addition to its effect on the brain, high doses of GABA (5-10g single dose) have been shown to exert effects on the endocrine system, including increases in plasma growth hormone levels, although the clinical significance of these effects is currently unknown. 1 References: Abdou, A. M., Higashiguchi, S., Horie, K., Kim, M., Hatta, H., & Yokogoshi, H. (2006). Relaxation and immunity enhancement effects of γ-Aminobutyric acid (GABA) administration in humans. BioFactors, 26(3), 201–208. doi:10.1002/biof.5520260305 2 Reference: GABA. Natural Medicines monograph 2014. Viewed 10 Oct 2015, https://naturalmedicines.therapeuticresearch.com/

GABA is likely safe when taken in the amounts commonly found in foods. It is possibly safe when taken in larger amounts as medicine. Doses of up to 1.5 grams daily have been used for up to one month. 

1. Not recommended during pregnancy or lactation.
2. GABA may decrease blood pressure in hypertensive individuals. If you take GABA in addition to taking blood pressure medication, your blood pressure may drop too low.
3. Use with caution in patients taking synthetic GABA agonist medications or herbs that interact with the GABAergic system (e.g. Valeriana officinalis, Hypericum perforatum). If additional sedative/relaxant effects are required, start GABA supplementation slowly and at a low dose.

GABA agonist medications: Baclofen, Zolpidem, Progabide, AZD 3355, Tramiprosate, Gaboxadol, Adipiplon, Arbaclofen Placarbil, Lesogaberan, Muscimol, Phenibut, Zaleplon u.c.

1. Unlike synthetic GABA-agonist drugs, natural GABA is virtually without side effects.

Possible side effects

GABA oral supplements are generally well tolerated by healthy adults. Some people may experience negative side effects, including:

• Gastric distress.
• Nausea.
• Diminished appetite.
• Constipation.
• Burning throat.
• Drowsiness and fatigue.
• Muscle weakness.
• Shortness of breath, at very high doses.

References 1 Reference:https://www.webmd.com/vitamins/ai/ingredientmono-464/gamma-aminobutyric-acid-gaba 2 Reference:https://go.drugbank.com/categories/DBCAT000427 3 Reference:https://www.fxmedicine.com.au/blog-post/gamma-aminobutyric-acid-gaba-monograph

GABA (Gamma-Aminobutyric acid) Deficiency

People with certain medical conditions may have lower levels of GABA. Some of these conditions include:

• Seizure disorders
• Anxiety
• Chronic stress
• Depression
• Difficulty concentrating and memory problems
• Muscle pain and headaches
• Insomnia and other sleep problems
• Low GABA activity is also associated with substance use disorders.

Some people with these conditions take GABA supplements to help manage their symptoms, but GABA is found naturally in varieties of green, black, and oolong tea, as well as in fermented foods including kefir, yogurt, and tempeh. Other foods contain GABA or may boost its production in the body, including whole grains, fava beans, soy, lentils, and other beans; nuts including walnuts, almonds, and sunflower seeds; fish including shrimp and halibut; citrus, tomatoes, berries, spinach, broccoli, potatoes, and cocoa. However, these symptoms have many psychological and physical causes, so you should talk to your doctor before treating them with a supplement. 4 Reference: National Library of Medicine, GABA-transaminase deficiency; https://www.healthline.com/health/gamma-aminobutyric-acid#uses https://www.psychologytoday.com/us/blog/sleep-newzzz/201901/3-amazing-benefits-gaba

More than 300 million people are affected by major depressive disorder (MDD), and limitations in the access to and effectiveness

of MDD treatment have made it the leading cause of disability world-wide. Despite long-standing efforts to identify the pathophysiology of depression, the underlying neurobiological determinants remain largely undefined. The relatively low rate of heritability, approximately 37%, the absence of variants with substantial impact on depression risk, the polygenic nature of depression risk, and the heterogeneity of depression have contributed to the difficulty in identifying genetic determinants of susceptibility. 

Environmental factors, such as trauma and stressful life events, contribute to depression risk through altering brain structure, chemistry, and function. Chronic exposure to social, psychological, or physical stressors provides useful contexts for studying how the brain transduces environmental stress exposure into depression.

The mechanisms underlying the pathophysiology and treatment of depression and stress-related disorders remain unclear, but studies in depressed patients and rodent models are beginning to yield promising insights. These studies demonstrate that depression and chronic stress exposure cause atrophy of neurons in cortical and limbic brain regions implicated in depression, and brain imaging studies demonstrate altered connectivity and network function in the brains of depressed patients. Studies of the neurobiological basis of the these alterations have focused on both the principle, excitatory glutamate neurons, as well as inhibitory GABA interneurons. Dysfunction of the central gamma-aminobutyric system has long been associated with anxiety spectrum disorders. While GABA neurons make up a smaller fraction of the total neuronal population, approximately 15%–20% compared to glutamate, inhibitory neurotransmission and balance with excitatory transmission are critical for normal brain function.

Based on evidence of altered glutamate and functional connectivity, it is not surprising that there is also evidence of disrupted GABA neurotransmission that contributes to the neurobiology of MDD.

Briefly, depression is often associated with decreased GABAergic function, while various antidepressant (AD) manipulations tend to increase it; low GABA function is proposed to be an inherited biological marker of vulnerability for depression; positive modulators of GABA-A receptors can have AD actions, while GABA-A negative modulators often produce depression. There is a large body of evidence to confirm that GABAergic anxiolytic drugs do produce AD effects in patients.

Summarizing, it seems likely that there are overlapping GABAergic mechanisms of anxiety and depression due to: 

1. common neurochemical mechanisms;
2. similar brain structures involved in the regulation of anxiety and depression; 
3. common genetic origins of anxiety and depression; and 
4. overlapping or correlation in neuropsychopharmacological effects of drugs.

Numerous studies have demonstrated a direct correlation between major depressive disorders and significantly decreased GABA concentrations in the brain. This is not to say that GABA deficiency causes depression but that it plays an important role as part of the overall treatment of depression, PMS, ADHD, bipolar disorder, panic, fear, mental blocks, a racing mind and anxiety. Doctors frequently prescribe benzodiazepines for most of these conditions but the major drawback to their use is that they can be addictive. GABA supplementation is not addictive and it is one nutrient that can be used to help facilitate withdrawal from benzodiazepines.

The optimal dose of GABA varies with the need and the individual. The usual anti-anxiety doses for most adults are between 500 and 5000 mg daily in divided doses. 1 Reference: Ronald S. Duman, Gerard Sanacora and John H. Krystal; Department of Psychiatry, Yale University School of Medicine;  Altered Connectivity in Depression: GABA and Glutamate Neurotransmitter Deficit and Reversal by Novel Treatments; DOI:https://doi.org/10.1016/j.neuron.2019.03.013 2 Reference: Kalueff, A. V., & Nutt, D. J. (2007). Role of GABA in anxiety and depression. Depression and Anxiety, 24(7), 495–517. doi:10.1002/da.20262 3 Reference: Dr. Zoltan P. Rona, M.D., M.Sc. Defuse Stress and Calm Nerves Naturally

1. Alcohol is believed to mimic GABA's effect in the brain, binding to GABA receptors and inhibiting neuronal signaling.
2. Alongside GABAergic mechanisms, GABA has also been detected in other peripheral tissues including intestines, stomach, Fallopian tubes, uterus, ovaries, testes, kidneys, urinary bladder, the lungs and liver, albeit at much lower levels than in neurons.
3. In 1883, GABA was first synthesized, and it was first known only as a plant and microbe metabolic product.
4. GABA is also found in plants. It is the most abundant amino acid in the apoplast of tomatoes. Evidence also suggests a role in cell signalling in plants.
5. GABA tea is tea that has undergone a special oxygen-free fermentation process, and as a result has accumulated GABA in tea leaves. This technology has been created in Japan. 

Crocus, genus of about 75 low-growing cormose species of plants of the iris family (Iridaceae). Crocuses are native to the Alps, southern Europe, and the Mediterranean area and are widely grown for their cuplike blooms in early spring or fall. Spring-flowering plants have a long floral tube that allows the ovary to remain belowground, sheltered from climatic changes. The flowers close at night and in dull weather. Saffron, used for dye, seasoning, and medicine, is the dried feathery orange tip of the pistils of the lilac or white, autumn-flowering saffron crocus (Crocus sativus) of western Asia. Saffron crocus generally blooms with purple flowers in the autumn. The plant grows about 10 to 30 cm high.

Saffron is the dried elongated stigmas and styles of the blue-purple saffron crocus. Saffron stigmas contain four major bioactive compounds: crocins (family of six mono-glycosyl or di-glycosyl polyene esters), crocetin (a natural carotenoid dicarboxylic acid precursor of crocin), picrocrocin (monoterpene glycoside precursor of safranal and product of zeaxanthin degradation) and safranal. It appears that crocin and safranal inhibit reuptake of dopamine, norepinephrine, and serotonin. Saffron has the potential to enhance mental health through its antidepressant properties and, in a recent meta-analysis, was confirmed to be effective for the treatment of depression. 1 Atsauce: https://www.britannica.com/plant/Crocus#ref172302 2 Reference: Lopresti, A. L., & Drummond, P. D. (2014). Saffron (Crocus sativus) for depression: a systematic review of clinical studies and examination of underlying antidepressant mechanisms of action. Human Psychopharmacology: Clinical and Experimental, 29(6), 517–527. doi:10.1002/hup.2434   3 Mazidi, M., Shemshian, M., Mousavi, S. H., Norouzy, A., Kermani, T., Moghiman, T., … Ferns, G. A. A. (2016). A double-blind, randomized and placebo-controlled trial of Saffron (Crocus sativus L.) in the treatment of anxiety and depression. Journal of Complementary and Integrative Medicine, 13(2). doi:10.1515/jcim-2015-0043

When taken by mouth: Saffron is likely safe in food amounts and when taken as a medicine for up to 26 weeks. Some possible side effects include dry mouth, anxiety, agitation, drowsiness, low mood, sweating, nausea or vomiting, constipation or diarrhea, change in appetite, flushing, and headache. Allergic reactions can occur in some people.

Taking large amounts of saffron by mouth is possibly unsafe. High doses of 5 grams or more can cause poisoning. Doses of 12-20 grams can cause death.

Pregnancy and breast-feeding: Taking saffron by mouth in amounts larger than what is normally found in food is likely unsafe. Larger amounts of saffron can make the uterus contract and might cause a miscarriage.

There isn't enough reliable information to know if saffron is safe to use when pregnant or breast-feeding. Stay on the safe side and stick to food amounts.

Bipolar disorder: Saffron seems to be able to affect mood. There is a concern that it might trigger excitability and impulsive behavior (mania) in people with bipolar disorder. Don't use saffron if you have this condition.

Allergies to Lolium, Olea (includes olive), and Salsola plant species: People who are allergic to these plants might also be allergic to saffron.

Interactions. When used as a supplement, saffron may cause problems for people on blood pressure medicine or blood thinners. Check with your doctor before using it if you are taking medication. 1 Atsauce: www.webmd.com/vitamins/ai/ingredientmono-844/saffron

Depressive disorder is one of the most prevalent psychiatric diseases and has been estimated to affect up to 21% of the world’s population. Majority of patients are often reluctant to take synthetic antidepressant drugs in their appropriate doses because of the anticipated side effects such as the inability to drive a car, dry mouth, constipation, and libido. Hence, plant extracts are some of the most attractive sources of new drugs and have been shown to produce a better result with low side effects in the treatment of depression. 

The benefits of saffron as an antidepressant are well-documented. Almost 150 volatile and nonvolatile compounds are obtained from the chemical analysis of this plant. Fewer than 50 constituents elucidated and identified so far showed phytochemical characteristics.

Crocin and saffron extract had been revealed to prevent memory and spatial learning impairment because of chronic-induced stress. Prophylactic property of saffron against memory deficiency had been proposed to occur as the result of the correlation between the antioxidant activity of saffron and the impairment because of oxidative stress. Akhondzadeh et al., in 2004, had shown saffron extract to be equally efficient to imipramine during double-blind and randomized trial conducted over 6 weeks. The dried saffron petal also had been revealed to be effective in mild-to-moderate depression based on 6 weeks of double-blind randomized clinical trials. Crocin (30 mg/day), the main antioxidant constituent of saffron stigmas, was shown to amplify the effects of selective serotonin reuptake inhibitors in treating patients with mild-to-moderate depression with the absence of substantial side effects based on the observation of 4 weeks of randomized, double-blind, prospective, placebo-controlled pilot clinical trial with 40 patients of major depressive disorder.

Another study (in this double-blind, placebo-controlled and randomized trial, patients were randomly assigned to receive capsule of petal of C. sativus 30 mg/day (BD) (Group 1) and capsule of placebo (BD) (Group 2) for a 6-week study) showed that patients with mild-to-moderate depression receiving petal of C. sativus experienced statistically significant benefits in their mood after 6 weeks treatment. The clinical relevance of these findings was emphasized by the improvements seen in the Hamilton Depression Rating Scale measures in the saffron group. Moreover, there were no significant differences in the two groups in terms of observed side effects. It has been reported that stigma of C. sativus has antidepressant effect by at least three clinical trials (Akhondzadeh et al., 2004, 2005; Noorbala et al., 2005). 1 Reference: Mohammad J. Siddiqui, Mohammed S. M. Saleh, Siti N. B. Binti Basharuddin, Siti H. Binti Zamri, Mohd H. bin Mohd Najib, Muhammad Z. bin Che Ibrahim, Nur A. binti Mohd Noor, Hanin N. Binti Mazha, Norazian Mohd Hassan, and Alfi Khatib; Saffron (Crocus sativus L.): As an Antidepressant; J Pharm Bioallied Sci. 2018 Oct-Dec; 10(4): 173–180. doi: 10.4103/JPBS.JPBS_83_18 2 Reference: Akhondzadeh S, Fallah-Pour H, Afkham K, Jamshidi AH, Khalighi-Cigaroudi F. Comparison of Crocus sativus L. and imipramine in the treatment of mild to moderate depression: a pilot double-blind randomized trial [ISRCTN45683816] BMC Complement Altern Med. 2004;4:12. 3 Reference: Esmail Moshiria, Afshin Akhondzadeh Bastib, Ahamad-Ali Noorbalac, Amir-Hossein Jamshidid, Seyed Hesameddin Abbasie, Shahin Akhondzadeh; Crocus sativus L. (petal) in the treatment of mild-to-moderate depression: A double-blind, randomized and placebo-controlled trial; Phytomedicine 13 (2006) 607–611

1. Saffron crocus smells a little like vanilla and spice, and the dried stigmas add a distinct flavor to foods like Spanish paella, rice dishes, and bouillabaisse. 
2. The origin of the word saffron is the French term “Safran,” which was derived from the Latin word “safranum” and yellowish in color, phytochemical analysis have revealed that the color is mainly because of the degraded carotenoid compounds, crocin and crocetin.
3. The stigma of saffron has been used as a medicine over 3600 years ago. Saffron was used in various opioid preparations for pain relief (sixteenth to nineteenth centuries). Also, saffron has been used in coloring tunics in the region of Spain and by the Babylonian culture around 2400 BC.
4. At a retail price of up to $11 000 per kg, it is the world’s most expensive spice, reflected by the labour intensiveness associated with its production. Each of the flowers has three red-colored stigma, and one stigma of saffron weighs approximately 2 mg. 150 000 crocus blossoms or 450 000 hand-picked stigmas to produce just 1 kg of this unique spice.
5. Quantities of 10 g or more can cause an abortion and the lethal dose in human is 20 g
6. Saffron is used for depression in Persian traditional medicine. Indeed, it is a Persian herb with a history as long as the Persian Empire itself.