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Natural Medicine Journal

June 1, 2022

Vitamins and Minerals for Pediatric Attention-Deficit/Hyperactivity Disorder (ADHD)

Uncertain findings from a placebo-controlled clinical trial

Adrienne Adler-Neal

Despite flaws in the study’s data analysis, supplementing with vitamin D and magnesium may be helpful interventions for ADHD in children.

Reference

Hemamy M, Pahlavani N, Amanollahi A, et al. The effect of vitamin D and magnesium supplementation on the mental health status of attention-deficit hyperactive children: a randomized controlled trial. BMC Pediatr. 2021;21(1):178.

Study Objective          

To assess the effects of vitamin D and magnesium supplementation on the mental health of children diagnosed with ADHD

Design

Double-blind, randomized, placebo-controlled, single-institution clinical trial

Participants

Investigators recruited 74 children between March and May of 2016.

  1. Aged 6 to 12 years
  2. Levels of serum 25-hydroxycholecalciferol vitamin D [25(OH)], less than 30 ng/dL at baseline
  3. Prior diagnosis of ADHD with at least 6 out of 9 criteria for inattention and 6 out of 9 criteria for hyperactivity based upon the DSM IV
  4. Serum magnesium less than 2.3 mg/dL

Exclusion criteria:

  1. Individuals taking a multivitamin/mineral supplement before or during the study
  2. Individuals diagnosed with any other chronic medical or psychiatric disorders

Overall characteristics of study participants:

  1. Mean age of participants = 9.11 years of age (SD 1.61)
  2. Sixty-six participants completed the study
  3. No significant group differences at baseline in age, weight, height, gender, body mass index (BMI), or methylphenidate dosage
  4. The participants who completed the study were predominantly male (46/66) and of normal weight (38/66; with 9 participants obese, 15 overweight, and 4 underweight)
  5. Per the methods section, the participants on average took ~31 mg/kg of methylphenidate. However, this likely was a publication error as 31 mg/kg is an exceedingly high dose of methylphenidate. It is unclear what dose was given to the children in this study

Intervention   

Those randomized to the treatment group received oral vitamin D (50,000 IU/week) and an oral tablet of magnesium (6 mg/kg/day) with lunch for 8 weeks. The form of the nutrients was not disclosed in the publication (ie, vitamin D3 vs D2 or magnesium chelate). Those assigned to the control group received placebo pills that closely matched the appearance of the active treatments.

Study Parameters Assessed          

At baseline, investigators measured participants height, weight, and body mass index (BMI) and obtained blood levels of 25(OH)D and magnesium. The children’s parents completed a strengths and deficits questionnaire (SDQ) at baseline and at the end of the 8-week study.

The SDQ has 5 subscales, which measure functioning related to emotional symptoms, hyperactivity, conduct, peer problems, and prosocial behavior. The emotional and peer-problems subscales together comprise the “internalizing” score, whereas the conduct and hyperactivity scales together create the “externalizing” score.

Investigators used SPSS software to analyze the data. Chi-square and Mann-Whitney assessed general group differences in outcomes, whereas an ANCOVA was used to measure the impact of group assignment on outcomes of interest when controlling for age, sex, BMI, and methylphenidate dose at follow-up.

Primary Outcome Measures           

The primary outcome measure was SDQ scores.

Key Findings               

  1. There were statistically significant increases in circulating levels of both 25(OH)D and magnesium at the end of 8 weeks in the intervention group compared to the control group.
  2. According to the authors (see commentary below for a critique on the validity), there were significant between-group differences in “emotional problems (P=0.001), conduct problems (P=0.002), peer problems (P=0.001), prosocial score (P=0.007), total difficulties (P=0.001), externalizing score (P=0.001), and internalizing score (P=0.001) compared with children treated with the placebo.”
  3. Overall, girls had lower mean scores on the majority of the SDQ components at intervention follow-up regardless of group assignment.

Practice Implications

Attention-deficit/hyperactivity disorder (ADHD) is diagnosed in approximately 9.4% of youth in America, increasing at an alarming rate since 1990, when diagnoses numbered fewer than 1 million.1 Of these individuals, it is estimated that more than half take a stimulant medication.1

Children with ADHD are diagnosed as having abnormalities in activity levels, ability to sustain attention, and impulsivity that cause an “impact,” according to the most recent Diagnostic and Statistical Manual of Mental Disorders (DSM-5), in at least 2 areas of functioning, commonly the child’s home and school environments. Despite the public health consequences of this condition, the risk factors associated with a diagnosis of ADHD are unknown. However, significant recent advances demonstrate potential interactions between genetic predisposition and environmental factors (specifically changes in a dopamine D4 receptor in combination with organophosphate exposure and oxidative stress) can increase the odds of developing ADHD over 11-fold.2 Studies have demonstrated that many commonly used artificial food colorings may be associated with increased hyperactivity in children.3

Stimulants, such as methylphenidate, are standard-of-care drugs for children with ADHD. Unfortunately, about 30% of children with ADHD experience adverse effects from stimulants,4 likely contributing to the high prevalence of integrative medicine (IM) approaches in this population. In a small survey of children with ADHD, the use of IM approaches 67%, with the most popular IM modalities being modified diet, vitamins and/or minerals, dietary supplements, aromatherapy, and chiropractic.5 Commonly prescribed supplements for ADHD include omega-3 fatty acids, zinc, magnesium, broad-spectrum micronutrients (BSM), and iron. However, the evidence varies significantly in quantity and quality for each of these interventions.

Perhaps the most robust evidence exists for omega-3 supplementation. One meta-analysis of the 10 highest quality randomized controlled trials (RCTs) found that omega-3 fatty acids are “modestly effective” for ADHD.6 In regard to BSM, 2 double-blind, randomized, placebo-controlled trials in children with ADHD demonstrated improvements in the Clinical Global Impressions Scale.7,8 The studied BSM product contains 30 vitamins and minerals and selected amino acids and antioxidants.

Only preliminary evidence exists for the role of vitamin D supplementation in ADHD, with 1 recent meta-analysis concluding that vitamin D may be effective when used with methylphenidate but that the quality of current evidence is low.9 While children with ADHD often have low magnesium levels,10 it remains unknown whether supplementation improves outcomes. According to a recent meta-analysis, ferritin levels are lower in children with ADHD, and the severity of ADHD was more severe in those children who were iron deficient.11 One RCT demonstrated that iron supplementation in children with ADHD and low ferritin levels improves symptoms on the ADHD Rating Scale and the Clinical Global Impression Scale.12

Of note, the current study examined the role of vitamin D and magnesium supplementation together on mental health outcomes, whereas data related to behavior problems (as measured by the Conners Parent Rating Scale-48) are presented elsewhere. The authors report statistically significant differences at follow-up in peer problems, total difficulties, and internalizing between those receiving the active treatment and those receiving placebo pills.

However, notable limitations of the study make it difficult to form broad-reaching interpretations. For example, the coadministration of vitamin D and magnesium limits any implications that can be drawn about each individually. Secondly, unfortunately, the differences in SDQ subscales were measured at follow-up without statistically accounting for baseline scores. When pre-intervention scores are not statistically accounted for, no inferences can be made about between-group differences in outcomes, given that any variability seen could be wholly attributable to baseline differences between groups and not in any way related to the intervention itself. This, in itself, nullifies any implications that can be made about the findings of this paper.

When pre-intervention scores are not statistically accounted for, no inferences can be made about between-group differences in outcomes, given that any variability seen could be wholly attributable to baseline differences between groups and not in any way related to the intervention itself.

Finally, the use of “partial eta” as an effect-size measure for ANCOVAs, as opposed to the traditional “partial eta-squared,” is puzzling, given that this is not a statistically validated measure and throws into question the true magnitude of the effect sizes noted. Taken together, the overall quality of this article appears poor, which limits any significant conclusions that can be drawn from it and the study it represents.

Despite these limitations, it seems judicious to test for vitamin D levels in children with ADHD and supplement as necessary, especially given the potential role of vitamin D in modulating brain structure, neurochemistry, and possible dopaminergic pathways.13

Additionally, magnesium levels are statistically lower in children with ADHD, and given magnesium’s role in reducing glutamate activity, it makes mechanistic sense that supplementation could assist with behavioral and mental health outcomes.14 Again, it seems reasonable to supplement with magnesium at safe doses, while monitoring for adverse side effects. Different formulations are often used depending on other symptom profiles (such as the presence of constipation) and affordability/access. Magnesium citrate can be particularly helpful in children with coexisting constipation, whereas magnesium glycinate has a more bowel-neutral profile.

Placing the current evidence for nutritional approaches to ADHD in context, it is important to consider addressing deficiencies, such as vitamin D, iron, and magnesium, when they exist, while fortifying the other micronutrient needs of the developing brain.

BSMs have been shown to be effective in 2 RCTs and effect sizes are larger than what is demonstrated in this paper for magnesium and vitamin D alone. While significant levels of vitamin D deficiency require supplementation beyond what is contained in BSM formulations, the dosages of magnesium in the 2 most-studied broad-spectrum micronutrient formulas (ie, Hardy Nutritionals Daily Essential Nutrients and TrueHope EMPowerPlus) range from 160 to 600 mg per day. Taken together, in children with ADHD, it may be reasonable based upon combined evidence and pill burden to recommend a BSM formula, omega-3 fatty acids, and additional vitamin D and iron supplementation above what is available in the broad-spectrum formulas for those with significant deficiencies.

It is important to note that the 2 above BSM formulations can interact with stimulants by potentiating their effects. Because of this, it is wise to work with a provider who has experience cross-titrating these medications to avoid adverse side effects. While the majority of these recommendations would still be classified as “preliminary,” fortunately the evidence for integrative techniques in ADHD is rapidly evolving and shows significant potential for optimizing the treatment of this difficult condition.

Categorized Under

Adrienne Adler-Neal

Adrienne Adler-Neal is a PGY-2 psychiatry resident at UT Southwestern in Dallas. She obtained her undergraduate degree from the University of Pennsylvania, where she majored in biological basis of behavior, and went on to attain an MPH from the University of Memphis. She then completed the combined MD/PhD program at Wake Forest School of Medicine where her doctoral work focused on examining the biological and neural mechanisms underlying mindfulness-based analgesia. Her current research interests involve developing and validating brief psychological interventions for the treatment of depression and anxiety. She hopes to incorporate novel psychotherapeutic and integrative medicine techniques into her future psychiatric practice.

Amelia Villagomez, MD

Amelia Villagomez, MD, attended medical school at Texas A&M, completed her general psychiatry at Yale, a fellowship in child/adolescent psychiatry at Boston Children’s Hospital, and a fellowship in integrative medicine at the Andrew Weil Center for Integrative Medicine. Currently, Dr. Villagomez has a private practice in Fort Worth, Texas, and is a clinical assistant professor of psychiatry at the University of Arizona where she trains residents, fellows, and faculty in integrative psychiatry.

Noshene Ranjbar, MD

Noshene Ranjbar, MD, completed medical school at the University of Virginia, psychiatry residency at the University of Arizona, child and adolescent psychiatry fellowship at Boston Children’s Hospital/ Harvard Medical School, and integrative medicine fellowship at the Andrew Weil Center for Integrative Medicine. Board certified in general psychiatry, child & adolescent psychiatry, and integrative medicine, Dr. Ranjbar is currently associate clinical professor of psychiatry at the University of Arizona. She is co-founder of the Integrative Psychiatry Program at the UA, while also serving as faculty with The Center for Mind-Body Medicine, the Andrew Weil Center for Integrative Medicine, and the Integrative Psychiatry Institute.

References

  1. Centers for Disease Control and Prevention. Attention-deficit/hyperactivity disorder (ADHD) data and statistics. Centers for Disease Control and Prevention website. https://www.cdc.gov/ncbddd/adhd/data.html. Accessed May 20, 2022.
  2. Chang CH, Yu CJ, Du JC, et al. The interactions among organophosphate pesticide exposure, oxidative stress, and genetic polymorphisms of dopamine receptor D4 increase the risk of attention deficit/hyperactivity disorder in children. Environ Res. 2018;160:339-346.
  3. McCann D, Barrett A, Cooper A, et al. Food additives and hyperactive behaviour in 3-year-old and 8/9-year-old children in the community: a randomised, double-blinded, placebo-controlled trial. Lancet. 2007;370(9598):1560-7.
  4. Storebo OJ, Krogh HB, Ramstad E, et al. Methylphenidate for attention-deficit/hyperactivity disorder in children and adolescents: Cochrane systematic review with meta-analyses and trial sequential analyses of randomised clinical trials. BMJ. 2015;351:h5203.
  5. Sinha D, Efron D. Complementary and alternative medicine use in children with attention deficit hyperactivity disorder. J Paediatr Child Health. 2005;41(1-2):23-26.
  6. Chang JP, Su KP, Mondelli V, Pariante CM. Omega-3 polyunsaturated fatty acids in youths with attention deficit hyperactivity disorder: a systematic review and meta-analysis of clinical trials and biological studies. Neuropsychopharmacology. 2018;43(3):534-545.
  7. Johnstone JM, Hatsu I, Tost G, et al. Micronutrients for attention-deficit/hyperactivity disorder in youths: a placebo-controlled randomized clinical trial. J Am Acad Child Adolesc Psychiatry. 2022;61(5):647-661.
  8. Rucklidge JJ, Eggleston MJF, Johnstone JM, Darling K, Frampton CM. Vitamin-mineral treatment improves aggression and emotional regulation in children with ADHD: a fully blinded, randomized, placebo-controlled trial. J Child Psychol Psychiatry. 2018;59(3):232-246.
  9. Gan J, Galer P, Ma D, Chen C, Xiong T. The effect of vitamin D Supplementation on attention-deficit/hyperactivity disorder: a systematic review and meta-analysis of randomized controlled trials. J Child Adolesc Psychopharmacol. 2019;29(9):670-687.
  10. Effatpanah M, Rezaei M, Effatpanah H, et al. Magnesium status and attention deficit hyperactivity disorder (ADHD): a meta-analysis. Psychiatry Res. 2019;274:228-234.
  11. Tseng PT, Cheng YS, Yen CF, et al. Peripheral iron levels in children with attention-deficit hyperactivity disorder: a systematic review and meta-analysis. Sci Rep. 2018;8(1):788.
  12. Konofal E, Lecendreux M, Deron J, et al. Effects of iron supplementation on attention deficit hyperactivity disorder in children. Pediatr Neurol. 2008;38(1):20-26.
  13. Cui X, Gooch H, Groves NJ, et al. Vitamin D and the brain: key questions for future research. J Steroid Biochem Mol Biol. 2015;148:305-309.
  14. Papadopol V, Nechifor M. Magnesium in neuroses and neuroticism. In: Vink R, Nechifor M, eds. Magnesium in the Central Nervous System. Adelaide (AU): University of Adelaide Press; 2011.

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