Discussion
In the present study, supplementation with Vitamin D and magnesium in children with ADHD decreased conduct problems, social problems, and anxiety/shy scores compared with placebo intake, however, did not affect psychosomatic problems scores, significantly. To the best of our knowledge, this study is the first clinical trial to examine the effects of Vitamin D and magnesium supplementation on behavior problems in children with ADHD.
ADHD is the most clinically manifested neuropsychiatric condition which contains three diagnostic symptoms: Lack of attention, impulsivity, and hyperactivity. It is a complex disorder that is caused by genetic and environmental factors.[40] Recently, it has been revealed that dietary factors (such as Vitamin D or magnesium) play an important role among environmental factors.[16,40] Global prevalence of ADHD is about 5% in children.[1] ADHD has a high comorbidity with other psychiatric diseases such as ASD and LD.[8,41] The economic costs, especially on education and health care of children with ADHD with or without comorbid conditions, are substantial.[41,42]
To the best of our knowledge, except one adjunctive therapy,[29] there are no other studies on the effect of Vitamin D as a treatment alone or in combination with other nutrients on the severity of symptoms in children with ADHD although low 25-OH-Vitamin D3 levels have been associated with ADHD in observational studies.[16,17,29] Mohammadpour et al. conducted a randomized, double-blind placebo-controlled trial on 62 children with ADHD aged 5-12 years. They prescribed either 2000 IU Vitamin D or placebo per day in addition to methylphenidate for 8 weeks. Severity of symptoms was measured through CPRS-Revised(s), ADHD rating scale-IV, and Weekly Parent Ratings of Evening and Morning Behavior. Serum Vitamin D levels and ADHD evening symptoms improved significantly in the intervention group compared with the placebo group after 8 weeks. Small sample size, short duration of follow-up, and low doses of Vitamin D are limitations of this study.[29] Furthermore, psychosomatic problems were not assessed in this study.
Vitamin D affects various brain functions directly through its nuclear receptors (Vitamin D receptor or VDR) scattered throughout the central nervous system. Experimental and in vitro studies revealed that Vitamin D involved in several pathways in the brain including synthesis of neurotrophic agents, regulation of numerous neurotransmitters, neuroprotection, and neuroimmunomodulation. In humans, cortex, cerebellum, and limbic system, the three important parts of the brain, are involved in the behavior and are targeted by VDR. Thus, VDR polymorphisms could lead to psychiatric conditions such as ADHD, depression, and anxiety.[43,44]
We found only three interventional studies which used magnesium as a treatment and CPRS as an assessment tool in ADHD.[23,26,27] Magnesium was used in combination with other nutrients or along with standard treatment in these studies. In addition, these studies had some limitations including very small sample size and lack of blinding. Moreover, none of these three studies were assessed our subscales such as psychosomatic problems in the present study.[23,26,27]
Magnesium has an important role in regulating of various brain functions (e.g., behavior). Activity of numerous neurotransmitters such as dopamine, norepinephrine, and serotonin is dependent on magnesium. Furthermore, release of n-methyl-d-aspartate-induced norepinephrine is inhibited by magnesium.[18] Thus, as it previously has been shown, magnesium might be useful as a therapeutic agent in the treatment of ADHD.[22,23,24,25,26,27]
There is an association between serum magnesium and Vitamin D levels.[45] Vitamin D supplementation could improve serum levels of magnesium.[30,31] Similarly, magnesium intake might be associated with reduced risks of vitamin D deficiency and insufficiency.[32] Besides, magnesium could affect vitamin D production. The synthesis of 24,25(OH) 2D3 and 1,25(OH) 2D3 might be modulated by magnesium in vivo and in vitro.[33,34] Furthermore, Vitamin D and magnesium affect similar areas of the brain involved in behavior.[18,43]
Our study had several limitations: First, this study did not have a 2 × 2 factorial design to assess the effect of either Vitamin D or magnesium supplementation on the study’s variables, separately. Therefore, only the effect of combination of Vitamin D and magnesium supplements was evaluated. This could be due to our small sample size. In addition, dietary intakes of magnesium and Vitamin D were not assessed and duration of follow-up was short.