**4. Discussion**

This study conducted a qualitative systematic review of the empirical evidence obtained in randomized clinical trials published since 2000 on the efficacy of zinc and iron supplementation among ADHD children and adolescents. Nine studies met the eligibility criteria and were selected. Results indicated that low zinc and iron levels were related with both higher baseline levels of ADHD severity and poorer treatment outcomes. Compared with the controlled-placebo conditions, the dietary supplements with zinc and iron were associated with improvements in ADHD severity at the end of the treatments, although the effect size of the outcomes tended to be low and/or focused on specific ADHD symptoms/measures.

Cross-sectional evidence regarding the association of zinc and iron with ADHD levels (pre-treatment associations) is consistent with other non-randomized studies that explored the contribution of these micronutrients within clinical- and population-based samples. For example, a longitudinal study with a large sample with *n* = 608 children found that zinc–iron supplementation improved attention/concentration in children over a 14-month follow-up period [82]. A positive correlation was also found between zinc and symptoms of inattentiveness in a cross-sectional study of *n* = 48 children [83].

The potential explanations about the paths between the zinc–iron levels and the various ADHD manifestations are discussed in a number of studies, which showed that lower levels of these elements in childhood (but also in older adults) could be related to a dopaminergic impairment, which could be the origin of the high inattentiveness– hyperactivity levels and the other correlates of the ADHD disease (like the presence of restless leg syndrome and other multiple sleep problems) [74,84,85]. Neuroimaging, genetic, and animal studies have also shown that decreases in dopamine transporter densities are related with decreased brain iron and zinc levels [86–88]. Zinc achieves a relevant role in the metabolism of neurotransmitters, prostaglandins, and for maintaining brain structure and function. Since zinc is necessary in the metabolism of melatonin, it is strongly implied in the regulation of dopamine (zinc is therefore considered a dopamine reuptake inhibitor). Iron is a cofactor in the tyrosine hydroxylase enzyme, and a key cofactor in the making

of neurotransmitters, including serotonin, norepinephrine, and dopamine. Brain irondeficient rodents have been associated with alterations in adenosine neurotransmission, which has provided a pathogenetic link with glutamate mechanisms and the hypersensitive corticostriatal terminals involved in some ADHD correlates [89,90].

The link between iron and zinc supplementation and the observed decrease in ADHD symptoms in the controlled clinical trials selected for this systematic review also makes sense with regard to the role of zinc and iron as dopamine reuptake inhibitors, which was precisely the core target of the stimulant medications used in the combined treatment plans for the disease. Other non-randomized studies using a combination of polyunsaturated fatty acids with zinc supplementation also showed benefits for the treatment of ADHD. For example, the observational study of Huss et al. in a large sample of *n* = 810 monitored children aged 5–12 years old showed that consumption of omega-3 and omega-6 with complementation of zinc improved ADHD symptoms, as well as other emotional problems, and sleeping disease (attention deficit, hyperactivity, and impulsivity) after 12 weeks [91]. The rationale for these results could be found in the capacity of these dietary combinations for facilitating the transmission of signals between neurons, which also contributed to improvements in attention ability, learning difficulties, and executive functions in the development of children and adolescents [92,93].

The studies included in this review support the existence of subgroups (based on the treatment outcomes and its baseline clinical correlates) that could be particularly benefitted from treatments including dietary zinc and iron supplements, such as the results of Bilici and colleagues [73]: the association found in this study between the low baseline zinc values with lower improvements in the ADHD measures suggested that zinc may be particularly important for the treatment of this disorder, improving and compensating borderline zinc nutrition. The study of Arnold and colleagues, which reanalyzed data from a randomized clinical trial with *n* = 18 children by comparing d-amphetamine with Efamol, assessed the moderate role of zinc [94], categorized the participants into three groups (as zinc-adequate, zinc-borderline, and zinc-deficient), and observed a linear relationship of d-amphetamine with zinc nutrition among the d-amphetamine group, and a quadratic (U-shaped) relationship of Efamol response to zinc (the benefit among this group was only found among the zinc-borderline condition). Finally, the research based on a secondary analysis of data collected in the study of Arnold and colleagues [71] analyzed the role of the status of iron, and determined that it was associated with ADHD symptom severity at baseline and with responses to psycho-stimulant treatment [95]. This study found an inverse correlation of serum ferritin with baseline inattention, hyperactivity, and impulsivity levels (as ferritin concentration increased, ADHD severity decreased), and also a significant correlation between serum ferritin and sensitivity to the amphetamine used for ADHD treatment (participants with higher ferritin concentrations required lower weight-adjusted doses of psychotropic treatment). These results were obtained after adjusting for the participants' sex and age. The authors concluded that iron supplementation could contribute as a potential intervention to optimize responses to psycho-stimulants in children with low iron stores at baseline. Other studies have also showed that ferritin concentration is correlated with the dose of amphetamine necessary to reach an optimal clinical response [96]. However, results in this area are few, and future research should address the question of which are the optimal doses, as well as the benefits of using supplements of multiple vitamins and minerals.

#### **5. Conclusions**

Based on the results obtained in this systematic review, the specific role of dietary nutrients with zinc and iron still seems controversial for the treatment of ADHD, being most consistent with the evidence for zinc. Moreover, although the reviewed studies found a relationship between the use of dietary supplements containing these elements with the improvement of ADHD symptoms, neither the mono-causal role of a concrete specific nutritional deficiency among ADHD children nor the role of a concrete dietary nutrient in the management of this disorder were proven (as was reported quite recently [56]). Future controlled clinical trials are needed, examining the efficacy of mineral supplementation.

The results obtained in this systematic review should be considered for combining these multi-facet interventions with additional precise interventions, specifically focused on the nutritional state and clinical profile of each patient. The ultimate objective of these treatments, including medical, psychological, and diet plans, should be to decrease the levels of ADHD, but also its multiple negative correlates, in order to achieve better performance in vigilance and sustained attention tasks, executive functioning tasks (like planning and organization), set shifting and response monitoring, and complex problem-solving.

Finally, this study should be interpreted in consideration of certain limitations. First, a meta-analysis was not conducted. Systematic reviews of treatment plans often include statistical methods to summarize the results of independent research by combining the information of selected studies (through meta-analysis) with the aim to provide more precise estimates of the effects of health care. However, it must be outlined that not all topics allow a meta-analysis to be conducted, and these concrete systematic reviews use alternative methods of synthesis described as "narrative synthesis". This was the case of our study: we did not employ meta-analyses because of the clinical heterogeneity of individual studies, with different intervention characteristics (for example, the iron/zinc supplements were administered in two trials within multi-supplements also including other trace elements, with different doses and/or frequency of doses, and with different durations), diverse outcome/effects measurement, different research settings, and differences in participants' features (such as age, baseline disease severity, other comorbid conditions, or sociodemographic variables). Since current studies have proven that this heterogeneity could cause significant inaccurate summary effects and associated conclusions, and thus misleading decision-markers [97], we opted to conduct a narrative synthesis in accordance with the current guidelines. Other characteristics of the individual studies selected for this review also impact on the generalizability capacity of our review: the limited samples sizes, the convenience samples (non-probability sampling methods were used), and the frequency of men compared to women.

**Supplementary Materials:** The following are available online at https://www.mdpi.com/article/ 10.3390/nu13114059/s1, Table S1: PRISMA 2020 main checklist.

**Author Contributions:** Conceptualization: R.G. and G.G.R.-O.; formal statistical analysis: I.L.C.-T., A.A.R.-C. and P.C.M.-S.; writing—original draft preparation: R.G. and G.G.R.-O.; writing—review and editing, I.L.C.-T., A.A.R.-C., P.C.M.-S. and A.P.-G. All authors contributed substantially to the data analysis, interpretation of data. All authors have read and agreed to the published version of the manuscript.

**Funding:** This research received no external funding.

**Conflicts of Interest:** The authors declare no conflict of interest.
