**1. Introduction**

Attention-deficit hyperactivity disorder (ADHD) is a neurodevelopmental disorder, usually beginning in early childhood and with a chronic progression to adulthood with several negative consequences, such as low self-esteem, difficulties in interpersonal relationships, and problems in school learning [1]. Subtypes according to the Diagnostic and Statistical Manual of Mental Disorders (5th edition) are inattention (being unable to keep focus), hyperactivity (excess movement that is not fitting to the setting) and impulsivity (hasty acts that occur without thought) [2]. Epidemiological studies indicate that ADHD is one of the most common mental disorders affecting children [3,4], with prevalence in the childhood–adolescent community ranging between 2% and 8% globally [5,6]. High prevalence rates persist in adult ADHD patients, into the range of 2.6% to 6.8% [7,8].

Etiological research outlines that ADHD constitutes a complex condition with multiple interactive factors [9]. Specific causes of the disorder are yet to be determined, but various contributing risk factors have been identified, including genetics [10–13], epigenetics [14,15], problems during pregnancy (such as stress, substance use, and other mental and physical diseases) [16–18], premature birth [19,20], obstetric and neonatal complications [21–24], and infections [25,26]. Neuropsychological mechanisms have also been identified in the onset and course of ADHD, such as brain injuries [27], neuroanatomical substrates related with genuine motor dysfunction [28] and deficient decision-making [29]. Diet-related factors (such as vitamin and/or mineral deficiencies) have also been evidenced to contribute to the levels of ADHD and the progression of the disease [30–32].

Diverse treatment plans have demonstrated to improve the symptoms of ADHD, usually combining medication (stimulants and non-stimulants have proved efficacy) with behavioral therapy [33,34]. Empirical-based pharmacological plans that have been used for decades include methylphenidate, amphetamine, atomoxetine, and guanfacine [35,36]. However, some children using these medications only experience partial relief of symptoms, which persist even with a change in medication or adjustment in dose [37]. Additionally, a number of patients with medication report significant adverse effects, such as loss of appetite, irritability, and sleep disorders [38,39]. Other typical ADHD correlates, such as restless leg syndrome, also persist despite medication [40,41].

On the other hand, despite growing pharmacological discoveries, mental disorders (such as ADHD) have shown a gradual rise during the last few decades, and rates are expected to continue increasing in the coming years [42–44]. Interestingly, it has been observed that worsening mental health within developed countries could be related to diet habits (more precisely, to the transition to more calorically dense ones) and to lower levels of physical activity [45]. Centered in the area of ADHD, various studies have shown harmful effects of the diet in the onset and progression of ADHD, including the use of preservatives and food additives [46,47]. Within this research area, it has also been observed that changes in the diet style could improve treatment efficiency for ADHD, particularly the utilization of some minerals and vitamins [48].

Dietary models have proved to be relevant to both metabolic performance and individuals' behavior. Restriction and elimination diets have been tested in ADHD treatments [49], and supplements and nutritional products have also been used as complementary intervention plans [50,51]. Studies assessing the specific role of iron and zinc on the course of ADHD have observed the deficiency of both minerals in most cases of hyperactivity [52]. Zinc is an essential mineral involved in numerous cellular metabolic processes, required for the catalytic activity of a large number of enzymes, implied in the accurate functioning of the immune system and with a role in the protein synthesis, DNA synthesis, and cell division [53]. Zinc also contributes to normal growth and development from pregnancy to adolescence, and harmonizes the performance of dopamine and melatonin [54]. Iron is a cofactor mineral that systematizes the production of dopamine and norepinephrine, an essential element participating in a wide variety of metabolic processes, including oxygen transport, deoxyribonucleic acid synthesis, and electron transport [55].

Some studies have analyzed the contribution of zinc and iron on ADHD occurrence, but conflicting findings have been obtained [56]. As a trend, compared to healthy control groups, lower levels of iron and zinc have been observed in children diagnosed with ADHD, but it is not clear whether changes in nutrient levels in blood tests mediate treatment outcomes in children with ADHD who consume mineral supplements [57,58], or even what sub-groups could particularly benefit from.

On the basis of the controversial results published regarding the role of dietary nutrients with zinc and iron for the treatment of ADHD [59,60], we performed this qualitative systematic review aimed to provide an updated account of the evidence published in randomized clinical trials assessing the efficacy of both supplements in the treatment of ADHD among children and adolescents.

#### **2. Materials and Methods**

#### *2.1. Procedure*

This systematic review was done in accordance with the eligible criteria reported in the *Preferred Reporting Items for Systematic Reviews and Meta-Analysis* (PRISMA) [61] (see Table S1, Supplementary Material), the *Assessment of Multiple Systematic Review* (AMSTAR) [62] and the *Cochrane Handbook for Systematic Reviews of Interventions* [63].

#### *2.2. Inclusion and Exclusion Criteria*

Medline, PsychINFO, Web of Science, and Google Scholar databases were searched. The search was further limited to the next inclusion criteria: (1) studies which examined treatments for ADHD; (2) which were based on randomized-controlled clinical trials; (3) which were published in English/Spanish language; (4) which were published in peer-reviewed Journals between January 2000 and July 2021; (5) which aimed to assess the efficacy of a nutritional intervention through iron or zinc supplementation; (6) which assessed clinical samples of ADHD patients diagnosed according to the Diagnostic and Statistical Manual of Mental Disorders (DSM) criteria, the 4th [64] or 5th [2] versions; (7) which analyzed participants with an age range between 5 to 18 years old; and (8) which used validated self-report instruments for measuring ADHD-related problems before and after treatment.

Specifically excluded from this systematic review were non-pill-based treatment modalities, such as behavioral interventions, neurofeedback, restriction, or alternative food exclusion diets or chiropractic interventions. No restrictions were considered for the longitudinal follow-up and interventions for the control group.

#### *2.3. Research and Selection of Studies*

The research was conducted on 20 July 2021. The strategy research (keywords and search sequence) for each database was:


Two authors of this systematic review independently analyzed the title and abstract of each record, according to the inclusion/exclusion criteria. Only studies meeting the eligibility criteria were then extracted. Data validation was discussed by the same authors, and disagreements were resolved by discussion and if needed by consulting a third team member until a consensus was reached.

The authors also extracted data of the identified screening records to be described and evaluated in the results section. The information considered for applying the eligibility criteria was: the date and location of publication, type of publication, sample size, participants' sex and age range, study design, type and duration of the treatment, and measures and outcomes (changes in the ADHD status, metabolic levels, and other psychological areas).

#### *2.4. Study Quality Assessment*

The *Consolidated Standards of Reporting Trials* guidelines were employed (CONSORT-2010) [65]) for assessing the study quality. This checklist is used worldwide to improve reported randomized controlled clinical trials through a list of 25 items for assessing the title (inclusion of the design type), elaboration of the abstract (structured and completed), background and explanation of the rationale, definition of the objectives and hypothesis, description of the trial design (including important changes to methods after trial commencement and reasons), eligibility criteria for participants, the setting and location where the data were collected, intervention description (sufficient details to allow replication), completely defined outcome measures, sample size calculation (or power analysis), the method used to generate the random allocation sequence (including type of randomization), use of blinding methods, statistical procedures used for the analyses, results description (including comparison at baseline), discussion of the results (including limitations and generalizability), and other information (registration, protocol, and funding).

In addition, two checklists were used. First, the guidance elaborated by the National Institute for Health and Care Excellence: The NICE Methodology Checklist for Randomized Controlled Trials [66], which includes items structured in four sections: (a) assessment of the selection bias (appropriate method of randomization used, adequate concealment of allocation and comparability at baseline); (b) assessment of the performance bias (the comparison groups received the same care apart from the interventions, and using doubleblind method); (c) assessment of the attrition bias (the groups followed for an equal length of time, and comparable treatment completion); and (d) assessment of detection bias (adequate length of follow-up, use of precise definition for the outcomes, valid and reliable methods for measuring the outcomes and triple-blind method used). Second, the Critical Appraisal Skills Programme (CASP) Randomized Controlled Trial Standard Checklist [67], which includes a set of items organized in four sections: (a) validity of the study design (clearly focused research question, randomized assignment of the participants to groups and complete follow-up); (b) using adequate methodology procedures (blinded methods, similarity between the groups at the start of the controlled trial, and groups receiving the same level of care); (c) results reported comprehensively, including the estimate of the effect sizes and carrying out a cost-effectiveness analysis cost; and 4) applicability of the results (generalization features and value provided by the intervention).

The risk of bias was also assessed using the Cochrane Risk of Bias 2 checklist [68], based on seven domains: (a) the randomization process, (b) deviations from intended intervention/s, (c) missing outcome data, (d) outcome measurement/s, (e) selection of the reported results, (f) incomplete reporting, and (g) power calculation (or sample size justification).

The assessment of the methodological quality was rated by authors of this systematic review, and discrepancies were discussed and solved.

#### **3. Results**

#### *3.1. Descriptive for the Selected Studies*

The number of studies identified through database-searching was *n* = 123. After removing duplicate articles, *n* = 97 studies were screened and *n* = 9 were finally selected on the basis of the title-abstract and the eligibility criteria (Figure 1 contains the search flow-chart).

The randomized clinical trials included in the synthesis reported data for ADHD samples of children and adolescents aged 5 to 15 years old. Zinc sulfate was administered in *n* = 5 studies, iron in *n* = 2 studies, and multi-supplements containing both compounds in a *n* = 2 study. Clinical improvement was verified using standardized measurement tools for versions for parents, teachers, and/or children. Laboratory blood screening tests were also applied (at least) at baseline and at the end of the treatment.

Table 1 includes the description of the *n* = 9 randomized controlled trials of supplements with zinc and iron for the treatment of ADHD, such as: identification of the study, sample size (N), supplement administered to the experimental group, age range and mean, gender distribution, duration of the study, and the standardized measures employed for measuring the ADHD symptoms, and other related problems.

#### *3.2. Assessment of the Methodological Quality, Adherence and Competence*

Tables 2–4 contains the results of the assessment with the CONSORT, NICE, and CASP checklists for the *n* = 9 selected studies included in the systematic review. Many studies met most of the criteria. The most incomplete items were the calculation of the sample size (or the power estimation based on the sample size of the groups), carrying out a triple-blinded study [the selected studies were double-blinded (patients and researchers were unaware of whether the treatment was administered), but it was not reported whether the team analyzing the data was also unaware of which groups' data they were evaluating], obtaining the precision of the estimates (through confidence intervals or other alternative standardized effect size measures) and carrying out a cost-effectiveness analysis cost).
