Micronutrients for Attention-Deficit/Hyperactivity Disorder in Youth: A Placebo-Controlled Randomized Clinical Trial

Abstract

Objective: To evaluate whether micronutrients (vitamins/minerals) benefit attention-deficit/hyperactivity disorder (ADHD) and irritability in a North American pediatric sample.

Method: A three-site 8-week placebo-controlled randomized clinical trial of micronutrients was conducted in unmedicated children ages 6-12 with ADHD and at least one impairing irritability symptom by parent report on the Child and Adolescent Symptom Inventory-5 (CASI-5). A priori-defined primary outcomes were Clinical Global Impression-Improvement (CGI-I) (CGI-I of 1 or 2 = treatment responder) and parent-rated CASI-5 composite score of ADHD, oppositional defiant, disruptive mood dysregulation, and peer conflict symptoms, including impairment scores.

Results: Of 135 randomized (mean age 9.8 years), 126 (93%) comprised the modified intention-to-treat population. Blinding was maintained. For the CGI-I, 54% of the micronutrient and 18% of the placebo group were responders (Risk Ratio=2.97, 97.5% CI: 1.50, 5.90, p<0.001). CASI-5 composite scores improved significantly for both groups (p<0.01) with a mean change of -0.31 (95% CI: -0.39, -0.23) in the micronutrient group and a mean change of -0.28 (95% CI: -0.38, -0.19) in the placebo group. But the between group difference was not significant (mean change = -0.02; 97.5% CI: -0.16, 0.12, ES = 0.07, p=0.70). The micronutrient group grew six millimeters more than the placebo group (p=0.002). No serious adverse events nor clinically significant changes from baseline in blood and urine tests occurred.

Conclusion: Micronutrients showed global benefit over placebo by blinded clinician rating, but not by parent-report CASI-5 composite rating in a population with ADHD and irritability. Micronutrients showed greater height growth. Micronutrients were well tolerated and the majority adhered to the number of capsules prescribed. This RCT replicates safety and efficacy reported for ADHD in two smaller trials of a similar formula containing all vitamins and known essential minerals in amounts between the Recommended Dietary Allowance and Upper Tolerable Intake Level.

Journal of the American Academy of Child & Adolescent Psychiatry

Micronutrients for Attention-Deficit/Hyperactivity Disorder in Youth: A Placebo-Controlled Randomized Clinical Trial

Johnstone JM, Hatsu I, Tost G, Srikanth P, Eiterman LP, Bruton A, Ast HK, Robinette LM, Stern MM, Millington EG, Gracious B, Hughes AJ, Leung BM, Arnold LE. Micronutrients for Attention-Deficit/Hyperactivity Disorder in Youth: A Placebo-Controlled Randomized Clinical Trial. J Am Acad Child Adolesc Psychiatry. 2021 Jul 21:S0890-8567(21)00473-1.

Clinician guidelines for the treatment of psychiatric disorders with nutraceuticals and phytoceuticals: The World Federation of Societies of Biological Psychiatry (WFSBP) and Canadian Network for Mood and Anxiety Treatments (CANMAT) Taskforce

The 'Micronutrient Formula' rated by this international taskforce was Daily Essential Nutrients, and was given an 'Evidence Grade' of 'A', due to a statistically significant meta-analysis (k = 2, n = 173) with statistically significant RCTs in adult and child samples. They gave the following supporting statements for Daily Essential Nutrients:

  • Meta-analytic level results have shown supportive evidence for efficacy in ADHD as a monotherapy

  • More replicated evidence required (in both adults and children)

  • This particular micronutrient formula’s efficacy cannot necessarily be extended to other multi-nutrient formulas

  • Dosing may need to be supervised (and titrated) via a health profession

  • Cost and compliance may be an issue due to a recommended dosage of 8–12 capsules per day

  • Acceptable safety data

Abstract

Objectives: The therapeutic use of nutrient-based 'nutraceuticals' and plant-based 'phytoceuticals' for the treatment of mental disorders is common; however, despite recent research progress, there have not been any updated global clinical guidelines since 2015. To address this, the World Federation of Societies of Biological Psychiatry (WFSBP) and the Canadian Network for Mood and Anxiety Disorders (CANMAT) convened an international taskforce involving 31 leading academics and clinicians from 15 countries, between 2019 and 2021. These guidelines are aimed at providing a definitive evidence-informed approach to assist clinicians in making decisions around the use of such agents for major psychiatric disorders. We also provide detail on safety and tolerability, and clinical advice regarding prescription (e.g. indications, dosage), in addition to consideration for use in specialised populations.

Methods: The methodology was based on the WFSBP guidelines development process. Evidence was assessed based on the WFSBP grading of evidence (and was modified to focus on Grade A level evidence - meta-analysis or two or more RCTs - due to the breadth of data available across all nutraceuticals and phytoceuticals across major psychiatric disorders). The taskforce assessed both the 'level of evidence' (LoE) (i.e. meta-analyses or RCTs) and the assessment of the direction of the evidence, to determine whether the intervention was 'Recommended' (+++), 'Provisionally Recommended' (++), 'Weakly Recommended' (+), 'Not Currently Recommended' (+/-), or 'Not Recommended' (-) for a particular condition. Due to the number of clinical trials now available in the field, we firstly examined the data from our two meta-reviews of meta-analyses (nutraceuticals conducted in 2019, and phytoceuticals in 2020). We then performed a search of additional relevant RCTs and reported on both these data as the primary drivers supporting our clinical recommendations. Lower levels of evidence, including isolated RCTs, open label studies, case studies, preclinical research, and interventions with only traditional or anecdotal use, were not assessed.

Conclusions: Based on the current data and clinician input, a range of nutraceuticals and phytoceuticals were given either a supportive recommendation or a provisional recommendation across a range of various psychiatric disorders. However several had only a weak endorsement for potential use; for a few it was not possible to reach a clear recommendation direction, largely due to mixed study findings; while some other agents showed no obvious therapeutic benefit and were clearly not recommended for use. It is the intention of these guidelines to inform psychiatric/medical, and health professional practice globally.

Clinician guidelines for the treatment of psychiatric disorders with nutraceuticals and phytoceuticals: The World Federation of Societies of Biological Psychiatry (WFSBP) and Canadian Network for Mood and Anxiety Treatments (CANMAT) Taskforce

Sarris J, Ravindran A, Yatham LN, Marx W, Rucklidge JJ, McIntyre RS, Akhondzadeh S, Benedetti F, Caneo C, Cramer H, Cribb L, de Manincor M, Dean O, Deslandes AC, Freeman MP, Gangadhar B, Harvey BH, Kasper S, Lake J, Lopresti A, Lu L, Metri NJ, Mischoulon D, Ng CH, Nishi D, Rahimi R, Seedat S, Sinclair J, Su KP, Zhang ZJ, Berk M. Clinician guidelines for the treatment of psychiatric disorders with nutraceuticals and phytoceuticals: The World Federation of Societies of Biological Psychiatry (WFSBP) and Canadian Network for Mood and Anxiety Treatments (CANMAT) Taskforce. World J Biol Psychiatry. 2022 Jul;23(6):424-455.

Can we predict treatment response in children with ADHD to a vitamin-mineral supplement? An investigation into pre-treatment nutrient serum levels, MTHFR status, clinical correlates and demographic variables

Abstract

Background: Intent-to-treat analyses from a randomized controlled trial showed significant between-group differences favouring micronutrient treatment on the Clinical Global Impression-Improvement, but no group differences on clinician, parent and teacher ratings of overall ADHD symptoms. There was an advantage of micronutrients over placebo in improving overall function, emotional regulation, aggression, and reducing impairment as well as improving inattention based on clinician but not parent observation. No group differences were observed on hyperactive-impulsive symptoms. We investigated predictors of response defined by pre-treatment variables.

Method: We conducted analyses of data from a clinical trial of children (7-12 years) with ADHD, whereby participants were randomized to receive micronutrients or placebo for 10 weeks followed by a 10 week open-label (OL) phase. We included only children who had been exposed to micronutrients for a full 10 week period and demonstrated satisfactory adherence, either in RCT phase (n = 40) or OL phase (those who received placebo during RCT phase; n = 31). Seven outcomes were examined: change in ADHD symptoms (clinician/parent), ADHD responder, overall responder, change in mood, change in functioning, and change in aggression. Demographic, developmental variables, current clinical and physical characteristics, MTHFR genotype at two common variants, and pre-treatment serum/plasma levels (vitamin D, B12, folate, zinc, copper, iron, ferritin, potassium, calcium, magnesium, and homocysteine) were all considered as putative predictors.

Results: Substantial nutrient deficiencies pre-treatment were observed only for vitamin D (13%) and copper (15%), otherwise most children entered the trial with nutrient levels falling within expected ranges. Regression analyses showed varying predictors across outcomes with no one predictor being consistently identified across different variables. Lower pre-treatment folate and B12 levels, being female, greater severity of symptoms and co-occurring disorders pre-treatment, more pregnancy complications and fewer birth problems were identified as possible predictors of greater improvement for some but not all outcome measures although predictive values were weak. Lower IQ and higher BMI predicted greater improvement in aggression.

Conclusions: This study replicates Rucklidge et al. (2014b) showing the limited value of using serum nutrient levels to predict treatment response although we cannot rule out that other non-assayed nutrient levels may be more valuable. Additionally, no specific demographic or clinical characteristics, including MTHFR genetic status, were identified that would preclude children with ADHD from trying this treatment approach.

Can we predict treatment response in children with ADHD to a vitamin-mineral supplement? An investigation into pre-treatment nutrient serum levels, MTHFR status, clinical correlates and demographic variables

Rucklidge JJ, Eggleston MJF, Darling KA, Stevens AJ, Kennedy MA, Frampton CM. Can we predict treatment response in children with ADHD to a vitamin-mineral supplement? An investigation into pre-treatment nutrient serum levels, MTHFR status, clinical correlates and demographic variables. Prog Neuropsychopharmacol Biol Psychiatry. 2019 Mar 8;89:181-192.

†The micronutrient formulation studied was a pre-2013 version of Truehope EMPowerplus which was co-formulated by David Hardy and Anthony Stephan. Truehope EMPowerplus is a registered trademark of The Synergy Group of Canada Inc., which was co-founded by David Hardy and Anthony Stephan in 1999. David Hardy officially resigned as a shareholder of The Synergy Group of Canada Inc. and director of Truehope Nutritional Support Ltd. in 2013 to focus his efforts exclusively on Hardy Nutritionals®.