Next Article in Journal
The Relative Content and Distribution of Absorbed Volatile Organic Compounds in Rats Administered Asari Radix et Rhizoma Are Different between Powder- and Decoction-Treated Groups
Next Article in Special Issue
Mechanochemical P-derivatization of 1,3,5-Triaza-7-Phosphaadamantane (PTA) and Silver-Based Coordination Polymers Obtained from the Resulting Phosphabetaines
Previous Article in Journal
An Underestimated Factor: The Extent of Cross-Reactions Modifying APIs in Surface-Modified Liposomal Preparations Caused by Comprised Activated Lipids
Previous Article in Special Issue
New Horizons in Chemical Functionalization of Endohedral Metallofullerenes
Font Type:
Arial Georgia Verdana
Font Size:
Aa Aa Aa
Line Spacing:
Column Width:

Magnesium, Iron, Zinc, Copper and Selenium Status in Attention-Deficit/Hyperactivity Disorder (ADHD)

Laboratory of Nutrition and Functional Food Science, NatuRA (Natural Products and Food Research and Analysis), Department of Pharmaceutical Sciences, University of Antwerp, Universiteitsplein 1, B-2610 Wilrijk, Belgium
Author to whom correspondence should be addressed.
Molecules 2020, 25(19), 4440;
Submission received: 8 July 2020 / Revised: 23 September 2020 / Accepted: 25 September 2020 / Published: 27 September 2020


In this study, we critically review the literature concerning the relation of Mg, Fe, Zn, Cu and Se and attention-deficit/hyperactivity disorder (ADHD). Elemental status is estimated using peripheral blood parameters, hair, urine, daily intake and response to supplementation. The observed associations between concentration levels of the elements Mg, Fe, Zn, Cu and Se and ADHD symptoms are contradictory. This is partly due to the heterogeneity and complexity of the disorder. As a trend, lower ferritin and zinc levels can be observed. However, this correlation is not causative, as illustrated by placebo-controlled trials reporting conflicting evidence on the efficacy of supplementation. Well-defined studies on changes in concentration levels of the elements in relation to ADHD symptoms before and after treatment with therapeutics it will be possible to shed more light on the significance of these elements in this behavioral disorder. The discussion on whether a change in concentration of an element is cause or consequence of ADHD is not within the scope of this article.
ADHD; Mg; Fe; Zn; Cu; Se; elemental status

1. Introduction

Attention-deficit/hyperactivity disorder (ADHD) is a neurodevelopmental disorder characterized by inappropriate levels of impulsive behavior, hyperactivity and/or inattention [1]. Although ADHD is a common disorder in childhood, adolescence and adulthood, this review focuses on childhood ADHD since the adult form shows other characteristics. Together with schizophrenia, autism and epilepsy, ADHD is one of the most-studied neurodevelopmental disorders. Depending on definition and study, this disorder is relatively common, affecting an estimated 5% to 12% of school-aged children [2]. Although numerous associations between potential etiological factors are published, such associations do not address causality and that not all are biologically relevant. Associations mentioned in the etiology and pathology of ADHD include genetic factors [3], interaction of genes and nutrition [4], epigenetic [5,6,7] and, environmental elements, together with stress. Nutrition and diet were also reviewed as influencing factors [8], as restriction and elimination diets have been tried in ADHD treatments [9]. Supplements [10], herbal and nutritional products (complementary medicine) [11] and their effects on the disorder have been thoroughly discussed. As potential causes for ADHD in children, oxidative stress [12], metal toxicity [13], decreased methylation of relevant genes [14], cerebral hypoperfusion [15] and mitochondrial dysfunctions [16] have been mentioned as potential causes. Gut microbiota have been recently associated with dietary patterns and linked to susceptibility to ADHD [17]. Dietary immunomodulation [18] and antioxidant treatment [19] have been discussed by our research group in some preview papers. An etiologic classification of ADHD [20] and dietary sensitivities for this disorder [21] have been reviewed.
In this paper, a literature search was performed on the status of Fe, Cu, Zn, Mg and Se and ADHD in children and adolescents, then reported observations were critically reviewed. Attention deficit disorder (ADD) also forms part of the ADHD spectrum; however, this search was limited to publications in which ADHD is explicitly mentioned. The review is limited to ADHD in children and adolescents. Hence, papers on the adult form of this disease were excluded [22,23] because of the possible interference of additional factors that may jeopardize conclusions and hamper comparison with children and adolescents (work, environmental pollution, alcohol abuse, smoking attitudes).
Literature was screened for publications between January 2010 and March 2020. Important older references mentioned in some papers are also included. We consulted PubMed, Science Direct, Web of Science and Google Scholar for the search. The terms ADHD, the various elements, elemental status, blood level and daily intake of Fe, Cu, Zn, Se and Mg were used as keywords in various combinations. Publications in other languages with an English summary were included. Plasma, or serum, was the principal monitored medium, but also red blood cells, hair, urine and daily intake were included to evaluate the elemental status. Although normal values for the various elements could be geographically different, the ADHD group was always compared with a control group for the same region. Concluding that there were deficiencies or excessive levels can only be done by using biological activity measurements of related proteins. Most of the time, the elements act as cofactors in various enzymes and proteins, and therefore could interfere in the etiology of ADHD. However, these proteins (studied in metallomes) were not included in this search strategy. Publications could mention only one element, or a combination with other elements could be presented.
The overall aim was to discuss found relations between the various parameters used for evaluating the elemental status and ADHD in children and adolescents and observed response on supplementation.

2. Magnesium (Mg)

Magnesium (Mg2+) is the second most abundant cation in the human intracellular compartment and is of great physiological importance [24]. It plays an important role in over 300 metabolic reactions involved in protein synthesis, nucleic acid production and cellular energy generation [25]. Therefore, low levels of magnesium have been associated with a number of chronic diseases. The role of magnesium in nerve tissue has been discussed [26]. Magnesium’s involvement in ADHD pathogenesis can originate from its role in the apoptosis of nerve cells by controlling the glutamate N-methyl-aspartate pathway [27] and its critical role in the conversion of essential fatty acids to omega-6 and omega-3 polyunsaturated fatty acids, which are important cofactors in the desaturase enzymes implicated in hyperactive behavior [28].

2.1. Magnesium Status

Magnesium deficiency is linked to disturbances in cognitive capability, leading to symptoms such as: fatigue, lack of concentration, nervousness, mood swings and aggression [29]. Since these symptoms are common in ADHD, it is not surprising that in most studies lower serum magnesium levels are reported for patients with ADHD compared to healthy subjects [30,31,32,33,34,35,36,37]. Nevertheless, in a minority of clinical studies ADHD patients have similar [38,39] or even higher serum levels than their healthy counterparts [28,40]. However, two recent reviews and meta-analyses on serum magnesium levels concluded that children with ADHD have lower levels than those without ADHD [41,42]. Four studies could be found, where lower erythrocyte magnesium levels [38,43,44,45] or lower Mg2+-ATPase activity have been identified [45]. Possibly intracellular magnesium is a better indicator of Mg status. Increased blood concentration, on the other hand could be due to therapeutic stimulant medications, as demonstrated [46]. Mg levels in saliva were significantly decreased in ADHD patients [47], as well as in hair [42,48]. Only one older publication could be found on magnesium in urine, reporting lower levels in ADHD subjects compared to healthy controls [30].

2.2. Magnesium Supplementation

A study in Australia showed a statistically significant association between higher dietary Mg intake and reduced externalizing behavior problems in adolescents [49]. Since a lower intake of magnesium in ADHD has been reported [50,51] many supplementation studies have been carried out to correct the magnesium homeostasis. Generally, these have been done in combination with omega-3 fatty acids, zinc and other minerals [29,45,52,53,54,55,56,57,58]. Some authors claimed that Mg supplementation may reduce ADHD symptoms in children with or at high risk of deficiency of this mineral [52,58]. However, systematic reviews [10,59,60,61] lead to the conclusion that evidence for efficacy of Mg supplementation in a non-Mg deficient ADHD population is lacking [10] and therefore cannot be recommended without demonstrated Mg deficiency in the treatment of ADHD [60].

3. Iron (Fe)

Iron is one the earliest described essential elements in humans. It is well studied in the field of hematology. Iron also plays an important role in basic brain function [62]. This element is a major cofactor of tyrosine hydroxylase, which is necessary for the synthesis of dopamine [63]. Therefore, iron deficiency may lead to a lower dopamine production and enhanced ADHD symptoms. Dopamine-receptor density and transport into the brain [64], but also a functional impairment in the dopamine-rich basal ganglia [65] can be important in the etiology of ADHD [66] Iron deficiency has been shown to affect cognitive motor, social and emotional functions in children [67] and is therefore thought to have a role in ADHD pathophysiology [68]. Hence, many studies have investigated the relationship between iron status and ADHD [68,69,70]. Various peripheral parameters on iron are considered: serum iron, serum transferrin, serum ferritin, hematocrit, hemoglobin, mean corpuscular volume (MCV), red blood cells (RBC) and total iron binding capacity (TIBC) levels. Quite recently, one publication on serum hepcidin levels could be found [71]. Furthermore, brain-iron and daily intake may be used as a measure of the mineral status, while the results on iron supplementation could be of some value in further evaluating the role of iron in ADHD.

3.1. Iron Status

3.1.1. Peripheral Parameters

Literature data on the peripheral parameters of iron status in ADHD patients, compared to healthy controls and in relation to symptoms of ADHD is summarized in Table 1. Serum iron ferritin levels—considered to be a reliable indicator of body iron deposits—are mainly used to determine iron deficiency. Alternatively, serum iron levels or transferrin [72,73] have been mentioned, although results are controversial. Nevertheless, most of the studies indicate lower serum ferritin levels in ADHD patients [32,33,69,70,71,74,75,76,77,78,79,80,81,82,83,84,85,86,87,88,89,90,91,92,93,94]. Other reports found no significant relationship [89,95,96,97,98,99,100]. Only one (older) publication claimed to find higher levels [28]. In general, no differences in parameters related to anemia were observed compared to healthy controls: for serum iron [28,70,94,96], for transferrin, MCV [72] or whole blood [101]. To offer some explanation for these inconsistent results, perhaps research should focus on hepcidin, an important protein in iron metabolism and homeostasis of brain-iron [73]. The high levels of this protein found in ADHD patients may cause loss of iron homeostasis, but further studies are required to establish a definite conclusion [71].

3.1.2. Hair and Urine Iron Levels

Iron levels in hair [30,102] and in urine [30] were found to be lower in patients compared to healthy controls.

3.1.3. Brain Levels

Low thalamic iron level may play a role in the pathophysiology of ADHD. Three studies could be found on brain-iron levels in ADHD by using magnetic resonance imaging (MRI). In one of these studies Cortese et al. [85] found that thalamic iron levels in an ADHD group was significantly lower than the healthy controls. There was no significant correlation observed between the brain-iron levels and the level of ferritin in serum. Two other studies [103,104] compared brain-iron indices of medication-naïve ADHD patients with these of psychostimulant-treated ADHD patients and completely healthy controls. Iron analysis in the striatal and thalamic region of the medication-naïve ADHD patients revealed significantly lower levels than those in the other groups. Brain iron seems not only to be a noninvasive diagnostic biomarker that responds to treatment [103], it also seems that brain-iron levels in ADHD normalize as a function of treatment duration [104].

3.1.4. Daily Intake

Most publications mention lower intake of Fe in ADHD children [55,56,105]. The treatment with methylphenidate may result in reduced appetite, and hence a lower intake of nearly all food components [55,56]. However, it was quite remarkable that the intake of overweight ADHD children was significantly lower compared to the normal weight ADHD group [106]. Authors do not offer any explanation for this observation. Only one older publication mentioned higher Fe intake in Taiwanese ADHD children, resulting in high blood-iron levels [107].

3.2. Iron Supplementation

Due to the low iron status found in most studies on ADHD patients, supplementation has been carried out with varying success. An iron preparation was mentioned as 80 mg/day [108] or 5 mg/kg/day [90]. Some of the studies reported that supplementation was effective in children with risk of iron deficiency and is well-tolerated [33,108,109,110]. Other researchers claimed that supplementation is effective especially in the inattentive subtype of the disorder [111], that it decreases risk of cardiovascular events during treatment with ADHD drugs [112]—or that it can be used as an intervention to optimize response to psychostimulants at a lower dose [91]. Sometimes a combination with Zn supplements was superior to iron alone in alleviating ADHD symptoms, as well as for improvement in performance in IQ tests [113]. The effect of iron supplements on iron blood parameters and on behavioral and cognitive symptoms in ADHD children without iron-deficiency merits further investigations [10,90]. After a systematic review of 11 randomized controlled trials, the authors claimed that more evidence was needed for an indication of an effect of iron (as well as magnesium and zinc) on the treatment of ADHD [61]. Indeed, iron overload (measured by higher serum ferritin levels) can become a risk factor for oxidative damage [90,111] and used as a marker of oxidative stress [114].

4. Zinc (Zn)

Zinc is an essential trace element, required for various cellular functions through proteins, enzymes and zinc-fingers [115]. Disturbance of Zn homeostasis is related to various disorders. Its role in metabolic syndrome and diabetic implications has been discussed in detail [116,117]. Enzymes involved in cell membrane stabilization or required for metabolism of neurotransmitters, melatonin [118] and prostaglandins are using zinc as cofactor. Dopamine transport is also regulated by this element [119,120]. In boys with ADHD the effects of zinc on information processing have been described [121].

4.1. Zinc Status

4.1.1. Serum Zinc Levels

Case-control trials in several geographical areas have demonstrated lower zinc levels in children diagnosed with ADHD compared to healthy controls [30,32,33,55,82,101,121,122,123,124,125,126,127]. There has been discussion in literature on the lower values of zinc in children with ADHD [128], but without report of a range of normal levels clinical significance thereof is questionable. Only two publications could be found without difference in serum Zn levels [28,129]. Several meta-analyses suggest a significant association between low zinc levels and the diagnosis of ADHD [120,124,130,131]. An ongoing double-blind, placebo and active treatment controlled multicenter trial with ADHD children monitors the effect of PycnogenolR by measuring various parameters, including serum zinc concentrations [132].

4.1.2. Hair and Urine Zinc Levels

Generally, lower zinc levels in hair were published in ADHD [30,48,102]. Isolated reports mentioned no difference [129] or even higher levels in hair of ADHD children [48]. However, the latter article would be more informative if this observation could be related to altered zinc levels in serum. Only one (older) publication could be found on zinc levels in urine of ADHD patients. Furthermore, here, patient baseline urinary zinc was significantly lower than in normal controls [133].

4.1.3. Daily Intake

Nearly all studies found lower daily intake of zinc in ADHD children [49,50,55,56,125]. In only one publication zinc intake was not different in ADHD compared to healthy controls [28].

4.2. Zinc Supplementation

Although above mentioned observations suggest an association between low Zn status and ADHD, it has not been demonstrated that zinc deficiency is a causative factor for ADHD nor that zinc treatment is recommended, Zn supplementation studies have been carried out. Randomized, placebo-controlled trials of zinc supplementation either as an adjuvant to psychostimulant treatment or as monotherapy have provided conflicting evidence of efficacy [29,53,58,59,61,113,120,134,135,136,137,138,139,140,141,142]. Notwithstanding these large amount of studies, evidence is insufficient to recommend zinc supplementation, unless in areas with a high deficiency in Zn [143]. Furthermore, the dose and the form of zinc supplementation varied widely between the trials, so an optimal dosing strategy is not apparent [10].

5. Copper (Cu)

Copper is involved in catecholamine metabolism via beta-hydroxylase and monoaminoxidase (MAO). Higher copper concentrations lead to lower dopamine levels in rats [144]. In children, no correlation could be observed between whole blood Cu concentration levels and ADHD scores [101], nor was serum or plasma copper concentration different from that of normal controls [32,54,145]. In one publication a statistically insignificant higher (p  >  0.05) copper blood level, compared to this in the with ADHD was associated with a decreased serum Cu/Zn SOD (superoxide dismutase)-level [146]. Lower levels of copper, as found in an older publication [104], were confirmed by the group of Rucklidge [140,141]. However, the lower baseline Cu concentrations seem to have limited value for the identification of responders to treatment with a vitamin-mineral supplement, which was also demonstrated for a similar supplementation study on adults with ADHD [147]. The Cu/Zn ratio may be more important than the elemental concentrations separately, as Skalny and coworkers proved recently [127]. They claimed that an elevated Cu/Zn ratio may significantly contribute to the risk of ADHD or its severity and/or comorbidity. One publication mentioned a 19% reduction in the values of copper in hair of ADHD patients, compared to controls [48]. Analysis of food intake and nutrient status in children with ADHD shows lower Cu levels in children with a predisposition for ADHD [50]. No relation was observed between copper exposure during pregnancy and ADHD symptomatology at the age of 4 years [148]. As a consequence of these contradictory findings Cu supplementation studies have not been carried out or could not be found.

6. Selenium (Se)

Selenium (Se) is an essential element in a number of selenoproteins, including glutathione peroxidase (GPx), a family of enzymes that protects against oxidative injury by catalyzing the breakdown of hydrogen peroxides [149]. There are approximately 24 human genes encoding for selenoproteins [150]. Insufficient intake of Se results in increased risk of developing many chronic degenerative diseases. Keshan disease, for instance, is a typical example of endemic heart failure due to severe Se deficiency [151]. Therefore, it is believed that maintenance of Se status at a certain level is essential for human health. In most publications, assessment of Se status by measurement in serum or plasma, erythrocytes, platelets or whole blood has been reported. Some authors claim that a better assessment can be achieved by measuring the GPx-activity in whole blood or platelets. Serum or plasma reflects the recent daily intake, whereas erythrocytes accumulate Se and presumably reflect the intake over their 120-day lifespan [152]. Sometimes toenail [153] or hair [154,155] concentration is measured as a long-term parameter in Se status evaluation. Some biomarkers, such as the selenoproteins and particularly GPx 3 and SEPP1, directly provide information on biologic effect of the Se status and are of value in identifying nutritional Se deficiency and tracking responses of deficient individuals to Se treatment [156]. Since this trace element is an essential part of antioxidant enzymes, it can be linked to efficiency in lowering oxidative stress in ADHD. However, no significant differences in Se levels between controls and ADHD children could be found [126]. Low intake of Se was observed in ADHD groups compared to controls [55,56], although another study claimed to find no difference in Se intake [157]. Nevertheless, food rich in Se was inversely associated with ADHD [125]. Relatively higher umbilical cord Se level was observed for children, which afterwards manifested ADHD [158]. However, this single observation should be interpreted with caution.

7. Conclusions

The possible associations of the elemental status of Mg, Fe, Zn, Cu and Se with ADHD occurrence were reviewed. For some elements (Fe, measured as ferritin level and Mg), there is a trend of reporting lower values in the blood of ADHD patients. However, for both these elements, there were contradictory findings. This was also observed for other elements. These conflicting results mentioned in literature may depend largely on the amount of diagnostic parameters [159], treatments already received by patients, heterogeneity of the studies and variation in the daily intake of the various elements. Besides the limited number of studies carried out and found for each element, differences in the sampled population (gender, ethnicity, age, sample size) can jeopardize conclusions. Children and adolescents were not always in the same intervals of age. Other factors that were not mentioned in studies but were considered in the meta-analyses include stress, thyroid hormones and time at which the blood sample was taken. These variables may be important to consider in future research.
The discussion remains whether low status of various elements results from a decreased appetite as a consequence of ADHD medication. Another explanation of lower daily intake may be that patients with ADHD have an impaired ability to sit still during the meals, leave table earlier and have decreased nutritional intake for various nutrients. Therefore, daily intake should not be taken into account in assessing elemental status of the various elements. The discussion on whether a change in concentration of an element is cause or consequence of ADHD is not within the scope of this article. Evidence and arguments for supplementation of the various elements (alone or in combination) is insufficient, unless in a severe deficient status. Maybe, measurement of the nutrients or using peripheral parameters will evolve in the future into other directions. Research on biometals (metallomics), metalloproteins, metalloenzymes, chaperones (metallomes), as well as the application of genomics, proteomics and metabolomics, can contribute to an acceleration and improvement of identification of biomarkers in diagnosis and treatment of ADHD [160]. In this way new ADHD-biomarkers can be established and accepted [161].


All authors declare that they did not received any funding for the preparation of this review.

Conflicts of Interest

The authors declare no conflict of interest.


  1. APA (American Psychiatric Association). Diagnostic and statistical manual of mental disorders, 4th ed.; American Psychiatric Association: Washington, DC, USA, 2013. [Google Scholar]
  2. Scahill, L.; Schwab-Stone, M. Epidemiology of ADHD in school-age children. Child Adolesc. Psychiatr. Clin. N. Am. 2000, 9, 541–555. [Google Scholar] [CrossRef]
  3. Akutagava-Martins, G.C.; Rohde, L.A.; Hutz, M.H. Genetics of attention-deficit/hyperactivity disorder: An update. Expert Rev. Neurother. 2016, 16, 145–156. [Google Scholar] [CrossRef] [PubMed]
  4. Field, S.S. Interaction of genes and nutritional factors in the etiology of autism and attention deficit/hyperactivity disorders: A case control study. Med. Hypotheses 2014, 82, 654–661. [Google Scholar] [CrossRef] [PubMed]
  5. Schuch, V.; Utsumi, D.A.; Costa, T.V.M.M.; Kulikowski, L.D.; Muszkat, M. Attention Deficit Hyperactivity Disorder in the Light of the Epigenetic Paradigm. Front. Psychiatry 2015, 6, 126. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  6. Cecil, C.A.; Walton, E.; Barker, E.D. Prenatal diet and childhood ADHD: Exploring the potential role of IGF2 methylation. Epigenomics 2016, 8, 1573–1576. [Google Scholar] [CrossRef] [Green Version]
  7. Walton, E.; Pingault, J.-B.; Cecil, C.A.; Gaunt, T.R.; Relton, C.C.; Mill, J.; Barker, E.D. Epigenetic profiling of ADHD symptoms trajectories: A prospective, methylome-wide study. Mol. Psychiatry 2016, 22, 250–256. [Google Scholar] [CrossRef]
  8. Millichap, J.G.; Yee, M.M.; Oliveira, C.; Nasr, A.; Brindle, M.; Wales, P.W. The Diet Factor in Attention-Deficit/Hyperactivity Disorder. Pediatrics 2012, 129, 330–337. [Google Scholar] [CrossRef] [Green Version]
  9. Rytter, M.J.H.; Andersen, L.B.B.; Houmann, T.; Bilenberg, N.; Hvolby, A.; Mølgaard, C.; Michaelsen, K.F.; Lauritzen, L. Diet in the treatment of ADHD in children—A systematic review of the literature. Nord. J. Psychiatry 2014, 69, 1–18. [Google Scholar] [CrossRef] [Green Version]
  10. Mulqueen, J. Nutritional supplements for the treatment of attention-deficit hyperactivity disorder. Child Adolesc. Psychiatr. Clin. N. Am. 2014, 23, 883–897. [Google Scholar]
  11. Sarris, J.; Kean, J.; Schweitzer, I.; Lake, J. Complementary medicines (herbal and nutritional products) in the treatment of Attention Deficit Hyperactivity Disorder (ADHD): A systematic review of the evidence. Complement. Ther. Med. 2011, 19, 216–227. [Google Scholar] [CrossRef]
  12. Chovanová, Z.; Muchová, J.; Sivonova, M.; Dvorakova, M.; Žitňanová, I.; Waczulikova, I.; Trebatická, J.; Škodáček, I.; Ďuračková, Z. Effect of polyphenolic extract, Pycnogenol®, on the level of 8-oxoguanine in children suffering from attention deficit/hyperactivity disorder. Free Radic. Res. 2006, 40, 1003–1010. [Google Scholar] [CrossRef] [PubMed]
  13. Braun, J.M.; Kahn, R.S.; Froehlich, T.; Auinger, P.; Lanphear, B.P. Exposures to Environmental Toxicants and Attention Deficit Hyperactivity Disorder in U.S. Children. Environ. Health Perspect. 2006, 114, 1904–1909. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  14. Dvorakova, M.; Sivonova, M.; Trebaticka, J.; Skodacek, I.; Waczulikova, I.; Muchova, J.; Durackova, Z. The effect of polyphenolic extract from pine bark, Pycnogenol on the level of glutatione in children suffering from attention deficit hyperactivity disorder (ADHD). Redox Rep. 2006, 11, 163–172. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  15. Amen, D.; Carmichael, B. High-Resolution Brain SPECT Imaging in ADHD. Ann. Clin. Psychiatry 1997, 9, 81–86. [Google Scholar] [CrossRef] [PubMed]
  16. Richardson, A. Omega-3 fatty acids in ADHD and related neurodevelopmental disorders. Int. Rev. Psychiatry 2006, 18, 155–172. [Google Scholar] [CrossRef]
  17. Wang, L.-J.; Yang, C.-Y.; Chou, W.-J.; Lee, M.-J.; Chou, M.-C.; Kuo, H.-C.; Yeh, Y.-M.; Lee, S.-Y.; Huang, L.-H.; Li, S.-C. Gut microbiota and dietary patterns in children with attention-deficit/hyperactivity disorder. Eur. Child Adolesc. Psychiatry 2019, 29, 287–297. [Google Scholar] [CrossRef]
  18. Verlaet, A.; Noriega, D.B.; Hermans, N.; Savelkoul, H.F.J. Nutrition, immunological mechanisms and dietary immunomodulation in ADHD. Eur. Child Adolesc. Psychiatry 2014, 23, 519–529. [Google Scholar] [CrossRef]
  19. Verlaet, A.; Maasakkers, C.M.; Hermans, N.; Savelkoul, H.F.J. Rationale for Dietary Antioxidant Treatment of ADHD. Nutrients 2018, 10, 405. [Google Scholar] [CrossRef] [Green Version]
  20. Millichap, J.G. Etiologic Classification of Attention-Deficit/Hyperactivity Disorder. Pediatrics 2008, 121. [Google Scholar] [CrossRef]
  21. Stevens, L.J.; Kuczek, T.; Burgess, J.R.; Hurt, E.; Arnold, L.E. Dietary Sensitivities and ADHD Symptoms: Thirty-five Years of Research. Clin. Pediatr. 2010, 50, 279–293. [Google Scholar] [CrossRef]
  22. Comai, S.; Bertazzo, A.; Vachon, J.; Daigle, M.; Toupin, J.; Côté, G.; Gobbi, G. Trace elements among a sample of prisoners with mental and personality disorders and aggression: Correlation with impulsivity and ADHD indices. J. Trace Elem. Med. Biol. 2019, 51, 123–129. [Google Scholar] [CrossRef] [PubMed]
  23. Lopez, R.; Franchi, J.-A.M.; Chenini, S.; Gachet, M.; Jaussent, I.; Dauvilliers, Y. Restless legs syndrome and iron deficiency in adults with attention-deficit/hyperactivity disorder. Sleep 2019, 42, 42. [Google Scholar] [CrossRef] [PubMed]
  24. Glasdam, S.-M.; Glasdam, S.; Peters, G.H. The Importance of Magnesium in the Human Body. Adv. Appl. Microbiol. 2016, 73, 169–193. [Google Scholar] [CrossRef] [Green Version]
  25. Ford, E.S.; Mokdad, A.H. Dietary Magnesium Intake in a National Sample of U.S. Adults. J. Nutr. 2003, 133, 2879–2882. [Google Scholar] [CrossRef] [Green Version]
  26. Torimitsu, K.; Furukawa, Y.; Tsukada, S. Role of magnesium in nerve tissue. Clin. Calcium 2012, 22, 1197–1203. [Google Scholar]
  27. Lau, A.; Tymianski, M. Glutamate receptors, neurotoxicity and neurodegeneration. Eur. J. Physiol. 2010, 460, 525–542. [Google Scholar] [CrossRef]
  28. Antalis, C.; Stevens, L.J.; Campbell, M.; Pazdro, R.; Ericson, K.; Burgess, J.R. Omega-3 fatty acid status in attention-deficit/hyperactivity disorder. Prostaglandins Leukot. Essent. Fat. Acids 2006, 75, 299–308. [Google Scholar] [CrossRef]
  29. Huss, M.; Völp, A.; Stauss-Grabo, M. Supplementation of polyunsaturated fatty acids, magnesium and zinc in children seeking medical advice for attention-deficit/hyperactivity problems—An observational cohort study. Lipids Health Dis. 2010, 9, 105. [Google Scholar] [CrossRef] [Green Version]
  30. Kozielec, T.; Starobrat-Hermelin, B.; Kotkowiak, L. Deficiency of certain trace elements in children with hyperactivity. Psychiatr. Polska 1994, 28, 345–353. [Google Scholar]
  31. Nogovitsina, O.R.; Levitina, E.V. Diagnostic value of examination of the magnesium homeostasis in children with attention deficit syndrome with hyperactivity. Klin. Lab. Diagn. 2005, 5, 17–19. [Google Scholar]
  32. Mahmoud, M.M.; El-Mazary, A.-A.M.; Maher, R.M.; Saber, M.M. Zinc, ferritin, magnesium and copper in a group of Egyptian children with attention deficit hyperactivity disorder. Ital. J. Pediatr. 2011, 37, 60. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  33. Villagomez, A.; Ramtekkar, U. Iron, Magnesium, Vitamin D, and Zinc Deficiencies in Children Presenting with Symptoms of Attention-Deficit/Hyperactivity Disorder. Children 2014, 1, 261–279. [Google Scholar] [CrossRef] [PubMed]
  34. Bener, A.; Kamal, M. Predict Attention Deficit Hyperactivity Disorder? Evidence -Based Medicine. Glob. J. Health Sci. 2013, 6, 47–57. [Google Scholar] [CrossRef] [Green Version]
  35. Gröber, U.; Schmidt, J.; Kisters, K. Magnesium in Prevention and Therapy. Nutrients 2015, 7, 8199–8226. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  36. El Baza, F.; AlShahawi, H.A.; Zahra, S.; Abdelhakim, R.A. Magnesium supplementation in children with attention deficit hyperactivity disorder. Egypt. J. Med. Hum. Genet. 2016, 17, 63–70. [Google Scholar] [CrossRef] [Green Version]
  37. Elbaz, F.; Zahra, S.; Hanafy, H. Magnesium, zinc and copper estimation in children with attention deficit hyperactivity disorder (ADHD). Egypt. J. Med. Hum. Genet. 2017, 18, 153–163. [Google Scholar] [CrossRef] [Green Version]
  38. Mousain-Bosc, M.; Roche, M.; Rapin, J.; Bali, J.-P. Magnesium VitB6 intake reduces central nervous system hyperexcitability in children. J. Am. Coll. Nutr. 2004, 23, 545S–548S. [Google Scholar] [CrossRef]
  39. Arnold, L.E.; Bozzolo, H.; Hollway, J.; Cook, A.; DiSilvestro, R.A.; Bozzolo, D.R.; Crowl, L.; Ramadan, Y.; Williams, C. Serum Zinc Correlates with Parent- and Teacher- Rated Inattention in Children with Attention-Deficit/Hyperactivity Disorder. J. Child Adolesc. Psychopharmacol. 2005, 15, 628–636. [Google Scholar] [CrossRef] [Green Version]
  40. Irmisch, G.; Thome, J.; Reis, O.; Häßler, F.; Weirich, S. Modified magnesium and lipoproteins in children with attention deficite hyperactivity disorder (ADHD). World J. Biol. Psychiatry 2011, 12, 63–65. [Google Scholar] [CrossRef]
  41. Effatpanah, M.; Rezaei, M.; Effatpanah, H.; Effatpanah, Z.; Kord-Varkaneh, H.; Mousavi, S.M.; Fatahi, S.; Rinaldi, G.; Hashemi, R. Magnesium status and attention deficit hyperactivity disorder (ADHD): A meta-analysis. Psychiatry Res. 2019, 274, 228–234. [Google Scholar] [CrossRef]
  42. Huang, Y.-H.; Zeng, B.-Y.; Li, D.-J.; Cheng, Y.-S.; Chen, T.-Y.; Liang, H.-Y.; Yang, W.-C.; Lin, P.-Y.; Chen, Y.-W.; Tseng, P.-T.; et al. Significantly lower serum and hair magnesium levels in children with attention deficit hyperactivity disorder than controls: A systematic review and meta-analysis. Prog. Neuro-Psychopharmacol. Biol. Psychiatry 2019, 90, 134–141. [Google Scholar] [CrossRef] [PubMed]
  43. Mousain-Bosc, M.; Roche, M.; Polge, A.; Pradal-Prat, D.; Rapin, J.; Bali, J. Improvement of neurobehavioral disorders in children supplemented with magnesium-vitamin B6. I. Attention deficit hyperactivity disorders. Magnes. Res. 2006, 19, 46–52. [Google Scholar] [PubMed]
  44. Kozielec, T.; Starobrat-Hermelin, B. Assessment of magnesium levels in children with attention deficit hyperactivity disorder (ADHD). Magnes. Res. 1997, 10, 143–148. [Google Scholar] [PubMed]
  45. Nogovitsina, O.R.; Levitina, E.V. Neurological aspects of the clinical features, pathophysiology, and corrections of impairments in attention deficit hyperactivity disorder. Neurosci. Behav. Physiol. 2007, 37, 199–202. [Google Scholar] [CrossRef]
  46. Schmidt, M.E.; Kruesi, M.J.; Elia, J.; Borcherding, B.G.; Elin, R.J.; Hosseini, J.; McFarlin, K.E.; Hamburger, S. Effect of dextroamphetamine and methylphenidate on calcium and magnesium concentration in hyperactive boys. Psychiatry Res. Neuroimaging 1994, 54, 199–210. [Google Scholar] [CrossRef]
  47. Archana, E.; Pai, P.; Prabhu, B.K.; Shenoy, R.P.; Prabhu, K.; Rao, A. Altered Biochemical Parameters in Saliva of Pediatric Attention Deficit Hyperactivity Disorder. Neurochem. Res. 2011, 37, 330–334. [Google Scholar] [CrossRef]
  48. Tinkov, A.A.; Mazaletskaya, A.L.; Ajsuvakova, O.P.; Bjørklund, G.; Huang, P.-T.; Chernova, L.N.; Skalny, A.A.; Skalny, A.V. ICP-MS Assessment of Hair Essential Trace Elements and Minerals in Russian Preschool and Primary School Children with Attention-Deficit/Hyperactivity Disorder (ADHD). Biol. Trace Elem. Res. 2019, 196, 400–409. [Google Scholar] [CrossRef]
  49. Black, L.; Allen, K.; Jacoby, P.; Trapp, G.; Gallagher, C.; Byrne, S.; Oddy, W. Low dietary intake of magnesium is associated with increased externalizing behaviors in adolescents. Public Health Nutr. 2015, 18, 1824–1830. [Google Scholar] [CrossRef] [Green Version]
  50. Kiddie, J.Y.; Weiss, M.D.; Kitts, D.D.; Levy-Milne, R.; Wasdell, M.B. Nutritional Status of Children with Attention Deficit Hyperactivity Disorder: A Pilot Study. Int. J. Pediatr. 2010, 2010, 1–7. [Google Scholar] [CrossRef] [Green Version]
  51. Berlin, K.S.; Lobato, D.J.; Pinkos, B.; Cerezo, C.S.; Leleiko, N.S. Patterns of Medical and Developmental Comorbidities Among Children Presenting With Feeding Problems: A Latent Class Analysis. J. Dev. Behav. Pediatr. 2011, 32, 41–47. [Google Scholar] [CrossRef]
  52. Nogovitsina, O.R.; Levitina, E.V. Effect of MAGNE-B6 on the clinical and biochemical manifestations of the syndrome of attention deficit and hyperactivity in children. Eksp. Klin. Farmakol. 2006, 69, 74–77. [Google Scholar] [PubMed]
  53. Rucklidge, J.J.; Johnstone, J.M.; Kaplan, B.J. Nutrient supplementation approaches in the treatment of ADHD. Expert Rev. Neurother. 2009, 9, 461–476. [Google Scholar] [CrossRef] [PubMed]
  54. Starobrat-Hermelin, B. The effect of deficiency of selected bio-elements on hyperactivity in children with certain specified mental disorders. Ann. Acad. Med. Stetin. 1998, 44, 297–314. [Google Scholar]
  55. Dura, T.T.; Diez, B.V.; Yoldi, P.M.; Aguilera, A.S. Dietary patterns in patients with attention deficit hyperactivity disorder. Pediatrics 2014, 80, 206–213. [Google Scholar]
  56. Durá-Travé, T.; Gallinas-Victoriano, F. Caloric and nutrient intake in children with attention deficit hyperactivity disorder treated with extended-release methylphenidate: Analysis of a cross-sectional nutrition survey. JRSM Open 2014, 5, 1–7. [Google Scholar] [CrossRef]
  57. Moghaddam, M.F.; Rakhshani, T.; Khosravi, M. Effectiveness of Methylphenidate Supplemented by Zinc, Calcium, and Magnesium for Treatment of ADHD Patients in the City of Zahedan. Shiraz E-Med. J. 2016, 17, 40019. [Google Scholar] [CrossRef] [Green Version]
  58. Lange, K.W.; Hauser, J.; Lange, K.M.; Makulska-Gertruda, E.; Nakamura, Y.; Reissmann, A.; Sakaue, Y.; Takano, T.; Takeuchi, Y. The Role of Nutritional Supplements in the Treatment of ADHD: What the Evidence Says. Curr. Psychiatry Rep. 2017, 19. [Google Scholar] [CrossRef]
  59. Curtis, L.; Patel, K. Nutritional and Environmental Approaches to Preventing and Treating Autism and Attention Deficit Hyperactivity Disorder (ADHD): A Review. J. Altern. Complement. Med. 2008, 14, 79–85. [Google Scholar] [CrossRef]
  60. Ghanizadeh, A. A systematic review of magnesium therapy for treating attention deficit hyperactivity disorder. Arch. Iran. Med. 2013, 16, 412–417. [Google Scholar]
  61. Azadbakht, L.; Hariri, M. Magnesium, iron, and zinc supplementation for the treatment of attention deficit hyperactivity disorder: A systematic review on the recent literature. Int. J. Prev. Med. 2015, 6, 83. [Google Scholar] [CrossRef]
  62. Andrews, N.C. Disorders of Iron Metabolism. N. Engl. J. Med. 1999, 341, 1986–1995. [Google Scholar] [CrossRef] [PubMed]
  63. Wigglesworth, J.; Baum, H. Iron dependent enzymes in the brain. In Brain Iron: Neurochemical and Behavioral Aspects; Youdim, M., Ed.; Taylor and Francis: New York, NY, USA, 1988; pp. 25–66. [Google Scholar]
  64. Erikson, K.M.; Jones, B.C.; Hess, E.J.; Zhang, Q.; Beard, J.L. Iron deficiency decreases dopamine D1 and D2 receptors in rat brain. Pharmacol. Biochem. Behav. 2001, 69, 409–418. [Google Scholar] [CrossRef] [Green Version]
  65. Youdim, M.B.; Ben-Shachar, D.; Yehuda, S. Putative biological mechanisms of the effect of iron deficiency on brain biochemistry and behavior. Am. J. Clin. Nutr. 1989, 50, 607–617. [Google Scholar] [CrossRef] [PubMed]
  66. Castellanos, F.X. Toward a Pathophysiology of Attention-Deficit/Hyperactivint Disorder. Clin. Pediatrics 1997, 36, 381–393. [Google Scholar] [CrossRef] [PubMed]
  67. Lozoff, B.; Beard, J.; Connor, J.; Felt, B.; Georgieff, M.; Schallert, T. Long-Lasting Neural and Behavioral Effects of Iron Deficiency in Infancy. Nutr. Rev. 2006, 64, S34–S91. [Google Scholar] [CrossRef] [Green Version]
  68. Cortese, S.; Angriman, M.; Lecendreux, M.; Konofal, E. Iron and attention deficit/hyperactivity disorder: What is the empirical evidence so far? A systematic review of the literature. Expert Rev. Neurother. 2012, 12, 1227–1240. [Google Scholar] [CrossRef]
  69. Cortese, S.; Angriman, M. Attention-Deficit/Hyperactivity Disorder, Iron Deficiency, and Obesity: Is There a Link? Postgrad. Med. 2014, 126, 155–170. [Google Scholar] [CrossRef]
  70. Wang, Y.; Huang, L.; Zhang, L.; Qu, Y.; Mu, D. Iron Status in Attention-Deficit/Hyperactivity Disorder: A Systematic Review and Meta-Analysis. PLoS ONE 2017, 12, e0169145. [Google Scholar] [CrossRef] [Green Version]
  71. Yazici, K.U.; Yazici, I.P.; Ustundag, B. Increased Serum Hepcidin Levels in Children and Adolescents with Attention Deficit Hyperactivity Disorder. Clin. Psychopharmacol. Neurosci. 2019, 17, 105–112. [Google Scholar] [CrossRef] [Green Version]
  72. Kwon, H.J.; Lim, M.H.; Ha, M.; Kim, E.-J.; Yoo, S.J.; Kim, J.W.; Paik, K.C. Transferrin In Korean Children With Attention Deficit Hyperactivity Disorder. Psychiatry Investig. 2011, 8, 366–371. [Google Scholar] [CrossRef] [Green Version]
  73. Fleming, R.E.; Bacon, B.R. Orchestration of iron homeostasis. N. Engl. J. Med. 2005, 352, 1741–1744. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  74. Konofal, E.; Lecendreux, M.; Arnulf, I.; Mouren, M.-C. Iron Deficiency in Children With Attention-Deficit/Hyperactivity Disorder. Arch. Pediatr. Adolesc. Med. 2004, 158, 1113–1115. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  75. Millichap, J.G.; Yee, M.M.; Davidson, S.I. Serum Ferritin in Children With Attention-Deficit Hyperactivity Disorder. Pediatr. Neurol. 2006, 34, 200–203. [Google Scholar] [CrossRef] [PubMed]
  76. Öner, P.; Dirik, E.B.; Taner, Y.; Caykoylu, A.; Anlar, O. Association between low serum ferritin and restless legs syndrome in patients with attention deficit hyperactivity disorder. Tohoku J. Exp. Med. 2007, 213, 269–276. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  77. Konofal, E.; Cortese, S.; Marchand, M.; Mouren, M.-C.; Arnulf, I.; Lecendreux, M. Impact of restless legs syndrome and iron deficiency on attention-deficit/hyperactivity disorder in children. Sleep Med. 2007, 8, 711–715. [Google Scholar] [CrossRef]
  78. Öner, P.; Oner, O. Relationship of ferritin to symptom ratings children with attention deficit hyperactivity disorder: Effect of comorbidity. Child Psychiatry Hum. Dev. 2007, 39, 323–330. [Google Scholar] [CrossRef]
  79. Oner, O.; Alkar, O.Y.; Oner, P. Relation of ferritin levels with symptom ratings and cognitive performance in children with attention deficit–hyperactivity disorder. Pediatr. Int. 2008, 50, 40–44. [Google Scholar] [CrossRef] [Green Version]
  80. Cortese, S.; Konofal, E.; Bernardina, B.D.; Mouren, M.-C.; Lecendreux, M. Sleep disturbances and serum ferritin levels in children with attention-deficit/hyperactivity disorder. Eur. Child Adolesc. Psychiatry 2009, 18, 393–399. [Google Scholar] [CrossRef] [Green Version]
  81. Juneja, M.; Jain, R.; Singh, V.; Mallika, V. Iron deficiency in Indian children with attention deficit hyperactivity disorder. Pediatrics 2010, 47, 955–958. [Google Scholar] [CrossRef]
  82. Oner, O.; Oner, P.; Bozkurt, O.H.; Odabas, E.; Keser, N.; Karadag, H.; Kızılgün, M.; Kizilgün, M. Effects of Zinc and Ferritin Levels on Parent and Teacher Reported Symptom Scores in Attention Deficit Hyperactivity Disorder. Child Psychiatry Hum. Dev. 2010, 41, 441–447. [Google Scholar] [CrossRef] [Green Version]
  83. Tan, L.-N.; Wei, H.-Y.; Zhang, Y.-D.; Lu, A.-L.; Li, Y. Relationship between serum ferritin levels and susceptibility to attention deficit hyperactivity disorder in children: A Meta analysis. Zhongguo Dang Dai Er Ke Za Zhi 2011, 13, 722–724. [Google Scholar] [PubMed]
  84. Lahat, E.; Heyman, E.; Livne, A.; Goldman, M.; Berkovitch, M.; Zachor, D. Iron deficiency in children with attention deficit hyperactivity disorder. Isr. Med. Assoc. J. 2011, 13, 530–533. [Google Scholar] [PubMed]
  85. Cortese, S.; Azoulay, R.; Castellanos, F.X.; Chalard, F.; Lecendreux, M.; Chechin, D.; Delorme, R.; Sebag, G.; Sbarbati, A.; Mouren, M.-C.; et al. Brain iron levels in attention-deficit/hyperactivity disorder: A pilot MRI study. World J. Biol. Psychiatry 2011, 13, 223–231. [Google Scholar] [CrossRef] [PubMed]
  86. Oner, P.; Oner, O.; Azik, F.M.; Çöp, E.; Munir, K.M. Ferritin and hyperactivity ratings in attention deficit hyperactivity disorder. Pediatr. Int. 2012, 54, 688–692. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  87. Öner, P.; Oner, O.; Cop, E.; Munir, K.M. Effect of Ferritin on Short-Term Treatment Response in Attention Deficit Hyperactivity Disorder. Klin. Psikofarmakol. 2012, 22, 325–331. [Google Scholar] [CrossRef] [Green Version]
  88. Bener, A.; Kamal, M.; Bener, H.; Bhugra, D. Higher Prevalence of Iron Deficiency as Strong Predictor of Attention Deficit Hyperactivity Disorder in Children. Ann. Med. Health Sci. Res. 2014, 4, S291–S297. [Google Scholar] [CrossRef]
  89. Percinel, I.; Yazici, K.U.; Ustundag, B.; Yazıcı, K.U. Iron Deficiency Parameters in Children and Adolescents with Attention-Deficit/Hyperactivity Disorder. Child Psychiatry Hum. Dev. 2015, 47, 259–269. [Google Scholar] [CrossRef]
  90. Sever, Y.; Ashkenazi, A.; Tyano, S.; Weizman, A. Iron Treatment in Children with Attention Deficit Hyperactivity Disorder. Neuropsychobiology 1997, 35, 178–180. [Google Scholar] [CrossRef]
  91. Calarge, C.A.; Farmer, C.A.; DiSilvestro, R.; Arnold, L.E. Serum Ferritin and Amphetamine Response in Youth with Attention-Deficit/Hyperactivity Disorder. J. Child Adolesc. Psychopharmacol. 2010, 20, 495–502. [Google Scholar] [CrossRef] [Green Version]
  92. Bala, K.A.; Kaba, S.; Mutluer, T.; Doğan, S.Z.; Doğan, M.; Aslan, O. Hormone disorder and vitamin deficiency in attention deficit hyperactivity disorder (ADHD) and autism spectrum disorders (ASDs). J. Pediatrics Endocrinol. Metab. 2016, 29, 1077–1082. [Google Scholar] [CrossRef] [Green Version]
  93. Islam, K.; Seth, S.; Saha, S.; Roy, A.; Das, R.; Datta, A.K. A study on association of iron deficiency with attention deficit hyperactivity disorder in a tertiary care center. Indian J. Psychiatry 2018, 60, 131–134. [Google Scholar] [CrossRef] [PubMed]
  94. Janka, Z. Tracing trace elements in mental functions. Ideggyogy Sz. 2019, 72, 367–379. [Google Scholar] [CrossRef] [PubMed]
  95. Abou-Khadra, M.K.; Amin, O.R.; Shaker, O.G.; Rabah, T.M. Parent-reported sleep problems, symptom ratings, and serum ferritin levels in children with attention-deficit/hyperactivity disorder: A case control study. BMC Pediatrics 2013, 13, 217. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  96. Menegassi, M.; De Mello, E.D.; Guimarães, L.R.; Matte, B.C.; Driemeier, F.; Pedroso, G.L.; Rohde, L.A.; Schmitz, M. Food intake and serum levels of iron in children and adolescents with attention-deficit/hyperactivity disorder. Rev. Bras. Psiquiatr. 2009, 32, 132–138. [Google Scholar] [CrossRef] [Green Version]
  97. Donfrancesco, R.; Parisi, P.; Vanacore, N.; Martines, F.; Sargentini, V.; Cortese, S. Iron and ADHD: Time to move beyond serum ferritin levels. J Atten. Disord. 2013, 17, 347–357. [Google Scholar] [CrossRef]
  98. Romanos, M.; Tiesler, C.M.T.; Koletzko, S.; Berdel, D.; Von Berg, A.; Hoffmann, B.; Schaaf, B.; Herbarth, O.; Lehmann, I.; Bauer, C.-P.; et al. No cross-sectional and longitudinal association of ferritin and symptoms of attention-deficit-/hyperactivity disorder in a large population-based sample of children: Results from the GINIplus and LISAplus studies. ADHD Atten. Deficit Hyperact. Disord. 2013, 5, 313–320. [Google Scholar] [CrossRef] [PubMed]
  99. Tseng, P.-T.; Cheng, Y.-S.; Yen, C.-F.; Chen, Y.-W.; Stubbs, B.; Whiteley, P.; Carvalho, A.F.; Li, D.-J.; Chen, T.-Y.; Yang, W.-C.; et al. Peripheral iron levels in children with attention-deficit hyperactivity disorder: A systematic review and meta-analysis. Sci. Rep. 2018, 8, 788. [Google Scholar] [CrossRef]
  100. Magula, L.; Moxley, K.; Lachman, A. Iron deficiency in South African children and adolescents with attention deficit hyperactivity disorder. J. Child Adolesc. Ment. Heal. 2019, 31, 85–92. [Google Scholar] [CrossRef]
  101. Yang, R.-W.; Zhang, Y.; Gao, W.; Lin, N.; Li, R.; Zhao, Z. Blood Levels of Trace Elements in Children with Attention-Deficit Hyperactivity Disorder: Results from a Case-Control Study. Biol. Trace Elem. Res. 2018, 187, 376–382. [Google Scholar] [CrossRef]
  102. Tabatadze, T.; Kherkheulidze, M.; Kandelaki, E.; Kavlashvili, N.; Ivanashvili, T. Attention deficit hyperactivity disorder and heavy metal and essential trace element concentrations. Is there a link? Georgian Med. News 2018, 284, 88–92. [Google Scholar]
  103. Adisetiyo, V.; Jensen, J.H.; Tabesh, A.; Deardorff, R.L.; Fieremans, E.; Di Martino, A.; Gray, K.M.; Castellanos, F.X.; Helpern, J.A. Multimodal MR imaging of brain iron in attention deficit hyperactivity disorder: A noninvasive biomarker that responds to psychostimulant treatment? Radiology 2014, 272, 524–532. [Google Scholar] [CrossRef] [Green Version]
  104. Adisetiyo, V.; Gray, K.M.; Jensen, J.H.; Helpern, J.A. Brain iron levels in attention-deficit/hyperactivity disorder normalize as a function of psychostimulant treatment duration. NeuroImage Clin. 2019, 24, 101993. [Google Scholar] [CrossRef]
  105. Konikowska, K.; Regulska-Ilow, B.; Rózańska, D. The influence of components of diet on the symptoms of ADHD in children. Rocz. Państwowego Zakładu Hig. 2012, 63, 127–134. [Google Scholar]
  106. Jang, B.Y.; Bu, S.Y. Nutritional Status of Korean Children and Adolescents with Attention Deficit Hyperactivity Disorder (ADHD). Clin. Nutr. Res. 2017, 6, 112–121. [Google Scholar] [CrossRef] [Green Version]
  107. Chen, J.-R.; Hsu, S.-F.; Hsu, C.-D.; Hwang, L.-H.; Yang, S.-C. Dietary patterns and blood fatty acid composition in children with attention-deficit hyperactivity disorder in Taiwan. J. Nutr. Biochem. 2004, 15, 467–472. [Google Scholar] [CrossRef] [PubMed]
  108. Konofal, E.; Lecendreux, M.; Deron, J.; Marchand, M.; Cortese, S.; Zaïm, M.; Mouren, M.C.; Arnulf, I. Effects of Iron Supplementation on Attention Deficit Hyperactivity Disorder in Children. Pediatr. Neurol. 2008, 38, 20–26. [Google Scholar] [CrossRef] [PubMed]
  109. Konofal, E. Effectiveness of Iron Supplementation in a Young Child With Attention-Deficit/Hyperactivity Disorder. Pediatrics 2005, 116, e732–e734. [Google Scholar] [CrossRef] [Green Version]
  110. Cortese, S.; Lecendreux, M.; Bernardina, B.D.; Mouren, M.C.; Sbarbati, A.; Konofal, E. Attention-deficit/hyperactivity disorder, Tourette’s syndrome, and restless legs syndrome: The iron hypothesis. Med. Hypotheses 2008, 70, 1128–1132. [Google Scholar] [CrossRef]
  111. Soto-Insuga, V.; Calleja, M.; Prados, M.; Castano, C.; Losada, R.; Ruiz-Falco, M. Role of iron in the treatment of attention deficit-hyperactivity disorder. An. Pediatr. 2013, 79, 230–235. [Google Scholar] [CrossRef]
  112. Parisi, P.; Villa, M.P.; Donfrancesco, R.; Miano, S.; Paolino, M.C.; Cortese, S. Could treatment of iron deficiency both improve ADHD and reduce cardiovascular risk during treatment with ADHD drugs? Med. Hypotheses 2012, 79, 246–249. [Google Scholar] [CrossRef]
  113. El-Baz, F.M.; Youssef, A.M.; Khairy, E.; Ramadan, D.; Youssef, W.Y. Association between circulating zinc/ferritin levels and parent Conner’s scores in children with attention deficit hyperactivity disorder. Eur. Psychiatry 2019, 62, 68–73. [Google Scholar] [CrossRef] [PubMed]
  114. Robberecht, H.; Hermans, N. Biomarkers of Metabolic Syndrome: Biochemical Background and Clinical Significance. Metab. Syndr. Relat. Disord. 2016, 14, 47–93. [Google Scholar] [CrossRef] [PubMed]
  115. Uwitonze, A.M.; Ojeh, N.; Murererehe, J.; Atfi, A.; Razzaque, M.S. Zinc Adequacy Is Essential for the Maintenance of Optimal Oral Health. Nutrients 2020, 12, 949. [Google Scholar] [CrossRef] [Green Version]
  116. Robberecht, H.; De Bruyne, T.; Hermans, N. Biomarkers of the metabolic syndrome: Influence of minerals, oligo- and trace elements. J. Trace Elem. Med. Biol. 2017, 43, 23–28. [Google Scholar] [CrossRef] [PubMed]
  117. Dubey, P.; Thakur, V.; Chattopadhyay, M. Role of Minerals and Trace Elements in Diabetes and Insulin Resistance. Nutrients 2020, 12, 1864. [Google Scholar] [CrossRef]
  118. Dodig-Curkovic, K.; Dovhani, J.; Curkovic, M.; Dodig-Radic, D.D. The role of zinc in the treatment of hyperactivity disorder in children. Acta. Med. Croat. 2009, 63, 307–313. [Google Scholar]
  119. Lepping, P.; Lepping, P.; Huber, M. Role of Zinc in the Pathogenesis of Attention-Deficit Hyperactivity Disorder. CNS Drugs 2010, 24, 1. [Google Scholar] [CrossRef]
  120. Arnold, L.E.; DiSilvestro, R.A. Zinc in Attention-Deficit/Hyperactivity Disorder. J. Child Adolesc. Psychopharmacol. 2005, 15, 619–627. [Google Scholar] [CrossRef]
  121. Yorbik, O.; Ozdag, M.F.; Olgun, A.; Senol, M.G.; Bek, S.; Akman, S. Potential effects of zinc on information processing in boys with attention deficit hyperactivity disorder. Prog. Neuro-Psychopharmacol. Biol. Psychiatry 2008, 32, 662–667. [Google Scholar] [CrossRef]
  122. Toren, P.; Eldar, S.; Sela, B.-A.; Wolmer, L.; Weitz, R.; Inbar, D.; Koren, S.; Reiss, A.; Weizman, R.; Laor, N. Zinc deficiency in attention-deficit hyperactivity disorder. Biol. Psychiatry 1996, 40, 1308–1310. [Google Scholar] [CrossRef]
  123. Bekaroğlu, M.; Asian, Y.; Gedik, Y.; Değer, O.; Mocan, H.; Erduran, E.; Karahan, C. Relationships Between Serum Free Fatty Acids and Zinc, and Attention Deficit Hyperactivity Disorder: A Research Note. J. Child Psychol. Psychiatry 1996, 37, 225–227. [Google Scholar] [CrossRef] [PubMed]
  124. Sun, G.-X.; Wang, B.-H.; Zhang, Y.-F. Relationship between serum zinc levels and attention deficit hyperactivity disorder in children. Zhongguo Dang Dai Er Ke Za Zhi 2015, 17, 980–983. [Google Scholar] [PubMed]
  125. Zhou, F.; Wu, F.; Zou, S.; Chen, Y.; Feng, C.; Fan, G. Dietary, Nutrient Patterns and Blood Essential Elements in Chinese Children with ADHD. Nutrients 2016, 8, 352. [Google Scholar] [CrossRef] [PubMed]
  126. Viktorinova, A.; Ursínyová, M.; Trebatická, J.; Uhnakova, I.; Ďuračková, Z.; Masanova, V. Changed Plasma Levels of Zinc and Copper to Zinc Ratio and Their Possible Associations with Parent- and Teacher-Rated Symptoms in Children with Attention-Deficit Hyperactivity Disorder. Biol. Trace Elem. Res. 2015, 169, 1–7. [Google Scholar] [CrossRef]
  127. Skalny, A.V.; Mazaletskaya, A.L.; Ajsuvakova, O.P.; Bjørklund, G.; Skalnaya, M.G.; Chao, J.C.-J.; Chernova, L.N.; Shakieva, R.A.; Kopylov, P.Y.; Skalny, A.A.; et al. Serum zinc, copper, zinc-to-copper ratio, and other essential elements and minerals in children with attention deficit/hyperactivity disorder (ADHD). J. Trace Elem. Med. Biol. 2020, 58, 126445. [Google Scholar] [CrossRef]
  128. Yang, R.-W.; Gao, W.; Li, R.; Zhao, Z. Were Plasma Trace Element Levels Changed in the Children with ADHD? Biol. Trace Elem. Res. 2015, 168, 516–517. [Google Scholar] [CrossRef]
  129. Luo, J.; Mo, Y.; Liu, M. Blood and hair zinc levels in children with attention deficit hyperactivity disorder: A meta-analysis. Asian J. Psychiatry 2020, 47, 101805. [Google Scholar] [CrossRef]
  130. Scassellati, C.; Bonvicini, C.; Faraone, S.V.; Gennarelli, M. Biomarkers and Attention-Deficit/Hyperactivity Disorder: A Systematic Review and Meta-Analyses. J. Am. Acad. Child Adolesc. Psychiatry 2012, 51, 1003–1019.e20. [Google Scholar] [CrossRef]
  131. Arnold, L.E.; Hurt, E.; Lofthouse, N. Attention-deficit/hyperactivity disorder: Dietary and nutritional treatments. Child Adolesc. Psychiatr. Clin. N. Am. 2013, 22, 381–402. [Google Scholar] [CrossRef]
  132. Verlaet, A.; Ceulemans, B.; Verhelst, H.; Van West, D.; De Bruyne, T.; Pieters, L.; Savelkoul, H.F.J.; Hermans, N. Effect of Pycnogenol® on attention-deficit hyperactivity disorder (ADHD): Study protocol for a randomised controlled trial. Trials 2017, 18, 145. [Google Scholar] [CrossRef] [Green Version]
  133. Arnold, L.E.; Votolato, N.A.; Kleykamp, D.; Baker, G.B.; Bornstein, R.A. Does Hair Zinc Predict Amphetamine Improvement of Add/Hyperactivity? Int. J. Neurosci. 1990, 50, 103–107. [Google Scholar] [CrossRef] [PubMed]
  134. Akhondzadeh, S.; Mohammadi, M.R.; Khademi, M. Zinc sulfate as an adjunct to methylphenidate for the treatment of attention deficit hyperactivity disorder in children: A double blind and randomized trial [ISRCTN64132371]. BMC Psychiatry 2004, 4, 9. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  135. Bilici, M.; Yildirim, F.; Kandil, S.; Bekaroğlu, M.; Yildirmiş, S.; Değer, O.; Ulgen, M.; Yildiran, A.; Aksu, H.; Yıldırım, F.; et al. Double-blind, placebo-controlled study of zinc sulfate in the treatment of attention deficit hyperactivity disorder. Prog. Neuro-Psychopharmacol. Biol. Psychiatry 2004, 28, 181–190. [Google Scholar] [CrossRef]
  136. Uckardes, Y.; Ozmert, E.; Unal, F.; Yurdakok, K. Effects of zinc supplementation on parent and teacher behavioral rating scores in low socioeconomic level Turkish primary school children. Acta. Paediatr. 2009, 98, 731–736. [Google Scholar] [CrossRef]
  137. Zamora, J.; Velásquez, A.; Troncoso, L.; Barra, P.; Guajardo, K.; Castillo-Duran, C. Zinc in the therapy of the attention-deficit/hyperactivity disorder in children. A preliminar randomized controlled trial. Arch. Latinoam. Nutr. 2011, 61, 242–246. [Google Scholar] [PubMed]
  138. Arnold, L.E.; DiSilvestro, R.A.; Bozzolo, D.; Bozzolo, H.; Crowl, L.; Fernandez, S.; Ramadan, Y.; Thompson, S.; Mo, X.; Abdel-Rasoul, M.; et al. Zinc for Attention-Deficit/Hyperactivity Disorder: Placebo-Controlled Double-Blind Pilot Trial Alone and Combined with Amphetamine. J. Child Adolesc. Psychopharmacol. 2011, 21, 1–19. [Google Scholar] [CrossRef] [Green Version]
  139. Dorreh, F.; Salehi, B.; Mohammadbeigi, A.; Sheykholeslam, H.; Moshiri, E. Omega-3 and Zinc supplementation as complementary therapies in children with attention-deficit/hyperactivity disorder. J. Res. Pharm. Pr. 2016, 5, 22–26. [Google Scholar] [CrossRef]
  140. Rucklidge, J.J.; Eggleston, M.J.; Darling, K.A.; Stevens, A.J.; Kennedy, M.A.; Frampton, C.M. Can we predict treatment response in children with ADHD to a vitamin-mineral supplement? An investigation into pre-treatment nutrient serum levels, MTHFR status, clinical correlates and demographic variables. Prog. Neuro-Psychopharmacology Biol. Psychiatry 2019, 89, 181–192. [Google Scholar] [CrossRef]
  141. Rucklidge, J.J.; Eggleston, M.J.F.; Boggis, A.; Darling, K.; Gorman, B.; Frampton, C.M. Do Changes in Blood Nutrient Levels Mediate Treatment Response in Children and Adults With ADHD Consuming a Vitamin-Mineral Supplement? J. Atten. Disord. 2019. [Google Scholar] [CrossRef]
  142. Noorazar, S.G.; Malek, A.; Aghaei, S.M.; Yasamineh, N.; Kalejahi, P. The efficacy of zinc augmentation in children with attention deficit hyperactivity disorder under treatment with methylphenidate: A randomized controlled trial. Asian J. Psychiatry 2020, 48, 101868. [Google Scholar] [CrossRef]
  143. Ghanizadeh, A.; Berk, M. Zinc for treating of children and adolescents with attention-deficit hyperactivity disorder: A systematic review of randomized controlled clinical trials. Eur. J. Clin. Nutr. 2012, 67, 122–124. [Google Scholar] [CrossRef] [PubMed]
  144. Yu, W.-R.; Jiang, H.; Wang, J.; Xie, J. Copper (Cu2+) induces degeneration of dopaminergic neurons in the nigrostriatal system of rats. Neurosci. Bull. 2008, 24, 73–78. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  145. Kul, M.; Kara, M.; Unal, F.; Tüzün, Z.; Akbiyik, F. Serum Copper and Ceruloplasmin Levels in Children and Adolescents with Attention Deficit Hyperactivity Disorder. Klin. Psikofarmakol. 2014, 24, 139–145. [Google Scholar] [CrossRef] [Green Version]
  146. Russo, A. Decreased Serum Cu/Zn SOD Associated with High Copper in Children with Attention Deficit Hyperactivity Disorder (ADHD). J. Central Nerv. Syst. Dis. 2010, 2, 9–14. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  147. Rucklidge, J.J.; Johnstone, J.M.; Gorman, B.; Boggis, A.; Frampton, C.M. Moderators of treatment response in adults with ADHD treated with a vitamin–mineral supplement. Prog. Neuro-Psychopharmacol. Biol. Psychiatry 2014, 50, 163–171. [Google Scholar] [CrossRef]
  148. Forns, J.; Fort, M.; Casas, M.; Cáceres, A.; Guxens, M.; Gascon, M.; Garcia-Esteban, R.; Julvez, J.; Grimalt, J.O.; Sunyer, J. Exposure to metals during pregnancy and neuropsychological development at the age of 4 years. NeuroToxicology 2014, 40, 16–22. [Google Scholar] [CrossRef]
  149. Zachara, B.A. Selenium and selenium-dependent antioxidants in chronic liver disease. Adv. Clin. Chem. 2015, 68, 131–151. [Google Scholar]
  150. Kieliszek, M. Selenium–Fascinating Microelement, Properties and Sources in Food. Molecules 2019, 24, 1298. [Google Scholar] [CrossRef] [Green Version]
  151. Zhou, H.; Wang, T.; Li, Q.; Li, D. Prevention of Keshan Disease by Selenium Supplementation: A Systematic Review and Meta-analysis. Biol. Trace Elem. Res. 2018, 186, 98–105. [Google Scholar] [CrossRef]
  152. Robberecht, H.; De Bruyne, T.; Hermans, N. Association between selenium status and metabolic syndrome and its biomarkers. Trace Elem. Electrol. 2020, in press. [Google Scholar]
  153. Filippini, T.; Ferrari, A.; Michalke, B.; Grill, P.; Vescovi, L.; Salvia, C.; Malagoli, C.; Malavolti, M.; Sieri, S.; Krogh, V.; et al. Toenail selenium as an indicator of environmental exposure: A cross-sectional study. Mol. Med. Rep. 2017, 15, 3405–3412. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  154. Chen, Z.; Li, H.; Yang, L.; Wang, W.; Li, Y.; Gong, H.; Guo, M.; Nima, C.; Zhao, S.; Wang, J.; et al. Hair Selenium Levels of School Children in Kashin–Beck Disease Endemic Areas in Tibet, China. Biol. Trace Elem. Res. 2015, 168, 25–32. [Google Scholar] [CrossRef] [PubMed]
  155. Liu, H.; Yu, F.; Shao, W.; Ding, D.; Yu, Z.; Chen, F.; Geng, D.; Tan, X.; Lammi, M.; Guo, X. Associations between selenium content in hair and Kashin-Beck disease/Keshan disease in children in North-western China; a prospective cohort study. Biol. Trace Elem. Res. 2018, 184, 16–23. [Google Scholar] [CrossRef] [PubMed]
  156. Combs, J.G.F.; Combs, G.F. Biomarkers of Selenium Status. Nutrients 2015, 7, 2209–2236. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  157. Naeini, A.A.; Nasim, S.; Najafi, M.; Ghazvini, M.; Hassanzadeh, A. Relationship between antioxidant status and attention deficit hyperactivity disorder among children. Int. J. Prev. Med. 2019, 10, 41. [Google Scholar] [CrossRef] [PubMed]
  158. Ode, A.; Rylander, L.; Gustafsson, P.; Lundh, T.; Källén, K.; Olofsson, P.; Ivarsson, S.A.; Rignell-Hydbom, A. Manganese and selenium concentrations in umbilical cord serum and attention deficit hyperactivity disorder in childhood. Environ. Res. 2015, 137, 373–381. [Google Scholar] [CrossRef]
  159. Faraone, S.V.; Bonvicini, C.; Scassellati, C. Biomarkers in the Diagnosis of ADHD—Promising Directions. Curr. Psychiatry Rep. 2014, 16, 497. [Google Scholar] [CrossRef]
  160. Scassellati, C.; Bonvicini, C.; Benussi, L.; Ghidoni, R.; Squitti, R. Neurodevelopmental disorders: Metallomics studies for the identification of potential biomarkers associated to diagnosis and treatment. J. Trace Elem. Med. Biol. 2020, 60, 126499. [Google Scholar] [CrossRef]
  161. Thome, J.; Ehlis, A.-C.; Fallgatter, A.J.; Krauel, K.; Lange, K.W.; Riederer, P.; Romanos, M.; Taurines, R.; Tucha, O.; Uzbekov, M.G.; et al. Biomarkers for attention-deficit/hyperactivity disorder (ADHD). A consensus report of the WFSBP task force on biological markers and the World Federation of ADHD. World J. Biol. Psychiatry 2012, 13, 379–400. [Google Scholar] [CrossRef]
Table 1. Peripheral parameters of Fe status in attention-deficit/hyperactivity disorder (ADHD) patients compared to controls and relation with ADHD symptoms (“: the same as above; “-”: no additional remarks).
Table 1. Peripheral parameters of Fe status in attention-deficit/hyperactivity disorder (ADHD) patients compared to controls and relation with ADHD symptoms (“: the same as above; “-”: no additional remarks).
ParameterConcentration LevelObservations/RemarksReference
SimilarLow ferritin is related with sleep disturbances[95]
No relationship with symptoms[96]
No difference in ferritin level[97]
No difference in ferritin level[98]
No causative relationship[33]
Link with ADHD and obesity[69]
Systematic review[70]
Contribution to ADHD[74]
No causative relationship[75]
Increased risk of restless legs[76]
Increased risk of restless legs[77]
Higher behavioral problems[78]
Related with behavioral, but not with cognitive problems[79]
Relation with sleep disturbances[80]
Inverse correlation with conners rating scale[81]
Higher hyperactivity[82]
After meta-analysis: higher susceptibility to ADHD[83]
Inverse correlation with conners rating scale[84]
Lower than in psychiatric controls[85]
Hyperactivity, reported by parents[86]
No relation with treatment outcome[87]
Associated with ADHD[88]
Correlated with hyperactivity scores[89]
Positive response on Fe supplementation[90]
Related to ADHD[91]

Share and Cite

MDPI and ACS Style

Robberecht, H.; Verlaet, A.A.J.; Breynaert, A.; De Bruyne, T.; Hermans, N. Magnesium, Iron, Zinc, Copper and Selenium Status in Attention-Deficit/Hyperactivity Disorder (ADHD). Molecules 2020, 25, 4440.

AMA Style

Robberecht H, Verlaet AAJ, Breynaert A, De Bruyne T, Hermans N. Magnesium, Iron, Zinc, Copper and Selenium Status in Attention-Deficit/Hyperactivity Disorder (ADHD). Molecules. 2020; 25(19):4440.

Chicago/Turabian Style

Robberecht, Harry, Annelies A. J. Verlaet, Annelies Breynaert, Tess De Bruyne, and Nina Hermans. 2020. "Magnesium, Iron, Zinc, Copper and Selenium Status in Attention-Deficit/Hyperactivity Disorder (ADHD)" Molecules 25, no. 19: 4440.

Article Metrics

Back to TopTop