*3.5. Efficacy of Iron for ADHD Treatment*

The study by Konofal and colleagues aimed to examine the contribution of iron supplementation (ferrous sulfate, 80 mg/day) in a sample of *n* = 23 children who met the criteria for ADHD, which showed that the experimental group reported more improvement than the control group in different treatment outcomes [74]: ADHD symptom levels reported by patients, parents, and teachers (particularly marked for the inattention factor), and also the presence of restless leg syndrome. The authors did not find a correlation between the baseline levels of serum ferritin levels with endpoint ADHD measures, suggesting that children with the lowest pre-treatment ferritin values did not benefit more from iron supplementation therapy than other children. In their conclusions, these authors suggested that the effectiveness of ferrous sulfate could be associated with the ADHD pathophysiology, that the benefits of restless leg syndrome could be the consequence of the improvement in the ADHD motor activity in the evening, and that iron could enhance the action of pharmacological treatment with methylphenidate and amphetamine.

The study of Panahandeh et al. in a sample of *n* = 42 children with ADHD also obtained benefits for the use of ferrous sulfate (5 mg/kg/day) plus methylphenidate (1 mg/kg/day), in the inattentiveness, hyperactivity, and impulsive symptom levels reported by parents at 2 months of treatment [75]. In the conclusions section, these authors supported the hypothesis that the contribution of iron supplementation on the ADHD improvements could be explained by the capacity of this element in the dopamine transporter density and activity, which is consistent with other studies that observed decreased thalamic iron levels in children with ADHD compared to controls [77,78].

#### *3.6. Efficacy of Including Simultaneously Iron and Zinc for ADHD Treatment*

Some randomized clinical studies have also valued the contribution of multimineralvitamin supplements which include zinc and iron for ADHD treatment in children. The rationale for selecting trails with multi-supplements therapy plans for ADHD was the low number of trails using simultaneously zinc and iron, and those identified used preparations with vitamins, dietary minerals and other nutritional elements. Therefore, considering these studies facilitates generalizability of the results related with the use of zinc–iron supplements.

The study of Rucklidge and colleagues [76] in a sample of *n* = 93 patients used Daily Essential Nutrients (DEN, with Recommended Dietary Allowances, RDA), which contains a comprehensive range of micronutrients (13 vitamins, 17 minerals, and 4 amino acids). The participants were instructed to titrate the dose up to over a week, starting with 3 capsules per day and increasing it to up to 12 capsules per day (see Table 1 for the zinc–iron content). This study obtained an intent-to-treat analysis of between-group differences with greater improvements for ADHD related with the micronutrient treatment, but specifically in the clinicians' reports assessing inattention. However, although no significant differences were found for the hyperactivity and impulsive measures between the experimental and the placebo groups, the micronutrients supplement obtained improvements in emotional regulation, aggression, and general functioning. The authors of this study concluded that the mechanisms of action of micronutrient treatments likely involves different pathways rather than pharmacological treatments, and that supplements like those used in the study may have an impact on the methylation/methionine cycle, required for the synthesis of DNA/RNA (as it was suggested by other studies [79]), and on the citric acid cycle and electron transport chain acting as co-enzymes in mitochondrial aerobic respiration and energy production. These potential effects on the physical state could also contribute to improvements in mood state and cognition functions (also suggested in the literature [80,81]).

Finally, the study of Rucklidge et al. was published later and carried out on a sample of *n* = 38 children that also used DEN, with an initial dose of 3 capsules per day which further increased to 12 capsules per day (see Table 1 for the zinc–iron content). This study showed that a broad-spectrum micronutrient formula (EMPowerplus) served as a mediator in the treatment response considering multiple ADHD measures [58]. Interestingly, only pre/post changes in the copper and ferritin levels achieved a significant moderator role on the improvement registered for the severity of ADHD: as the increase in the ferritin and the decrease in the copper highly benefited the levels of ADHD (in the three dimensions of inattentiveness, hyperactivity, and impulsivity). However, the authors indicated that these results should be interpreted with caution, and outlined the need to consider individual variability: since metabolic needs are different between the patients, as well as their genetic makeup, some children may need certain nutrients to restore optimal metabolic functioning, and others will not require specific nutrients and should not benefit from supplementations. In addition, nutrients act in a synergistic way, and therefore, changes in one can have cascading effects on others, and it was thus unlikely that increases in a specific nutrient could make a direct and unique contribution on the changes observed in a complex disorder, such as ADHD.
