Objective: With dual focus on structured, objective quantification of parent observations of child's behavior and identifying behaviors most amenable to change, this report examines Parent Target Problems (PTP) as a secondary outcome in a randomized clinical trial (RCT) of children with attention-deficit/ hyperactivity disorder (ADHD) in which one primary outcome, Clinical Global Impression-Improvement, showed a significant advantage of multinutrients over placebo and the other, Likert-type parent ratings, showed significant improvement in both groups, without significant difference between them.
Method: In a multisite 8-week RCT of broad-spectrum micronutrients ("multinutrients"), parents of children ages 6-12 (N = 126, 73% male, 88% white) with ADHD and emotional dysregulation nominated their child's most concerning problem(s) at baseline and quantified them by frequency, duration, impairment, and consequences. At subsequent visits, parents re-quantified the problem(s). Blinded child psychiatrists independently reviewed the PTPs and rated change at two timepoints compared to baseline. PTPs were grouped into 9 categories. Mean ratings were compared between active and placebo groups and explored by category.
Results: By week 8, a significant separation favored multinutrients: 38% of the multinutrient group were "definitely improved" or better, compared to 25% of the placebo group, and ratings of "no change" or "worse" occurred in 35% with placebo versus 23% with multinutrients (p = 0.04). Inattention (72.2%) and emotional dysregulation (69.1%) were the most frequently reported PTP categories. Inattention and internalizing symptoms improved more with multinutrients than placebo (p = 0.01, d = 0.55; p = 0.03, d = 0.80, respectively). The multinutrient advantage was not significant for 7 other symptoms, including hyperactivity/impulsivity, aggression, autistic symptoms, or emotional dysregulation/irritable oppositionality.
Conclusions: This secondary analysis found that the multinutrients, compared to placebo, were associated with improvements in parental concerns overall, and in two domains specifically: inattention and internalizing symptoms (anxiety/depression), but not in seven domains: hyperactivity/impulsivity, aggression, autistic symptoms or physiological symptoms, peer relationships or emotional dysregulation/irritable oppositionality.
Problems most concerning to parents of children with ADHD and emotional dysregulation in a randomized controlled trial of multinutrients: MADDY secondary analysis
Tost G, Srikanth P, Bruton A, Hatsu IE, Leung BM, Ast HK, Eiterman LP, Robinette LM, Williams C, Gracious B, Eugene Arnold L, Johnstone JM. Eur Child Adolesc Psychiatry. 2024 May 31.
Objectives: The 8-week Micronutrients for ADHD in Youth (MADDY) randomized controlled trial (N = 126, age 6-12) of broad-spectrum multinutrients for ADHD with emotional dysregulation found 3 times as many responders with multinutrients (54%) compared to placebo (18%) by Clinical Global Impression-Improvement (CGI-I). Our primary aim for this analysis tests the hypothesis that those with poor overall diet quality at baseline benefit more. The second aim is to explore whether specific components of diet quality moderate treatment response.
Methods: 124 children (69 multinutrients, 55 placebo) had diet quality assessed using the Healthy Eating Index-2015 (HEI-2015). For each potential moderator, the outcome CGI-I at week 8 (RCT-end), was modeled two ways: (1) as a dichotomous variable: responder/non-responder, with responders defined by a rating of 1 or 2 'very much' or 'much improved,' all else equals non-responder using logistic regression, and (2) as a dimensional improvement outcome from 1 = very much improved to 7 = very much worse, using linear regression.
Results: HEI-2015 total score did not moderate treatment response [odds ratio = 1.00 (95% CI: 0.90,1.10), p = 0.984] or improvement [β = -0.01 (95% CI: -0.06,0.04), p = 0.648]. However, total vegetable intake moderated level of improvement in exploratory analysis [β = -0.48 (95% CI: -0.82, -0.13), p = 0.007]: those with higher baseline vegetable intake showed greater benefit from multinutrients compared to placebo.
Conclusions: Multinutrients may benefit children with ADHD and irritability regardless of overall diet quality. The finding that higher baseline vegetable intake may improve response to multinutrients deserves further exploration, including dietary effect on gut microbiota and absorption of multinutrients and parental factors.
Treatment response to supplemental nutrients for ADHD is independent of diet quality: the MADDY Study RCT
Robinette LM, Hatsu IE, Johnstone JM, Bruton AM, Leung BMY, Arnold LE. Treatment response to supplemental nutrients for ADHD is independent of diet quality: the MADDY Study RCT. Nutr Neurosci. 2024 Apr;27(4):319-328.
The association of household food insecurity with symptoms of attention deficit hyperactivity disorder (ADHD) and emotional dysregulation in children was examined in this study. We utilized baseline data from 134 children aged 6-12 years who were enrolled in a clinical trial investigating multinutrient supplementation as a treatment for ADHD and emotional dysregulation. Household food security status was assessed using the 18-item US Household Food Security Survey Module. The symptoms of ADHD and emotional dysregulation disorders (oppositional defiant disorder (ODD) and disruptive mood dysregulation disorder (DMDD)) were assessed using the Child and Adolescent Symptom Inventory-5 and other comorbid emotional dysregulation symptoms were assessed using the Strengths and Difficulties Questionnaire (SDQ). Multiple linear regression determined associations between household food security status and symptoms of ADHD, ODD and DMDD, emotional symptoms and conduct problems. Household food insecurity was associated with more severe emotional symptoms (β = 2.30; 95% CI = 0.87-3.73; p = 0.002), conduct problems (β = 1.15; 95% CI = 0.01-2.30; p = 0.049) and total difficulties scores (β = 4.59; 95% CI = 1.82-7.37; p = 0.001) after adjusting for covariates (child's sex, parent marital status, household income, parental anxiety and other parental psychopathology). In unadjusted analyses, household food insecurity was also associated with increased ODD (β = 0.58; 95% CI = 0.21-0.95; p = 0.003) and DMDD symptoms (β = 0.69; 95% CI = 0.20-1.19; p = 0.006), but these associations attenuated to non-significance after adjusting for all covariates. Household food insecurity was associated with more severe emotional dysregulation symptoms. Discussing and addressing food insecurity may be appropriate initial steps for youths with ADHD and emotional dysregulation.
Household Food Insecurity Is Associated with Symptoms of Emotional Dysregulation in Children with Attention Deficit Hyperactivity Disorder: The MADDY Study.
Hatsu IE, Eiterman L, Stern M, Lu S, Johnstone JM, Leung BMY, Srikanth P, Robinette L, Tost G, Odei JB, Gracious BL, Arnold LE. Household Food Insecurity Is Associated with Symptoms of Emotional Dysregulation in Children with Attention Deficit Hyperactivity Disorder: The MADDY Study. Nutrients. 2022 Mar 20;14(6):1306.
Conclusions
Multinutrients combining 4 or more ingredients, mindfulness, and polyunsaturated fatty acids showed replicated, consistent moderate effects and can be encouraged as secondary treatments in combination with primary treatments or if a primary treatment is not a fit for the participant and their family.
Summary
Attention-deficit hyperactivity disorder (ADHD) affects approximately 5% of children and adolescents globally and
is associated with negative life outcomes and socioeconomic costs. First-generation ADHD treatments were
predominantly pharmacological; however, increased understanding of biological, psychological, and environmental
factors contributing to ADHD has expanded non-pharmacological treatment possibilities. This Review provides
an updated evaluation of the efficacy and safety of non-pharmacological treatments for paediatric ADHD,
discussing the quality and level of evidence for nine intervention categories. Unlike medication, no
non-pharmacological treatments showed a consistent strong effect on ADHD symptoms. When considering broad
outcomes (eg, impairment, caregiver stress, and behavioural improvement), multicomponent (cognitive)
behaviour therapy joined medication as a primary ADHD treatment. With respect to secondary treatments,
polyunsaturated fatty acids showed a consistent modest effect on ADHD symptoms when taken for at least
3 months. Additionally, mindfulness and multinutrient supplementation with four or more ingredients showed
modest efficacy on non-symptom outcomes. All other non-pharmacological treatments were safe; clinicians might
tolerate their use but should educate families of childrenand adolescents with ADHD on the disadvantages,
including costs, burden to the service user, absence of proven efficacy relative to other treatments, and delay of
proven treatment.
Non-pharmacological interventions for attention-deficit hyperactivity disorder in children and adolescents
Sibley MH, Bruton AM, Zhao X, Johnstone JM, Mitchell J, Hatsu I, Arnold LE, Basu HH, Levy L, Vyas P, Macphee F, Gonzalez ES, Kelley M, Jusko ML, Bolden CR, Zulauf-McCurdy C, Manzano M, Torres G. Non-pharmacological interventions for attention-deficit hyperactivity disorder in children and adolescents. Lancet Child Adolesc Health. 2023 Mar 9:S2352-4642(22)00381-9.
The Micronutrients for ADHD in Youth (MADDY) study was an 8-week double-blind RCT of broad spectrum multinutrients (BSMN) for ADHD with emotional dysregulation in children ages 6–12. Primary outcome Clinical Global Impressions-Improvement (CGI-I) showed 3 times as many responders with BSMN (54%) as placebo (18%). Since diet is the primary source of nutrients intake, and diet quality corresponds with nutritional outcomes, this study seeks to determine the role of baseline diet quality as a moderator of treatment response to test the hypothesis that those with poor diet quality should benefit more.
124 children (69 BSMN, 55 placebo) in the intent-to-treat analysis had diet quality assessed by Healthy Eating Index-2015 (HEI-2015) component and total scores from the VioscreenTM FFQ. Primary outcome was odds of treatment response, defined by a rating of 1 or 2 (very much or much improved) on CGI-I at week 8. Sensitivity analysis used CGI-I at week 8 as a dimensional outcome (from 1 = very much improved to 7 = very much worse). Logistic regressions were conducted for the primary analysis and linear regressions for the sensitivity analysis, with HEI scores entered as potential moderators.
Total HEI-2015 score did not moderate treatment response [odds ratio = 1.00 (95% CI: 0.90,1.10), p = 0.994] or improvement [β= −0.01 (95% CI: −0.06,0.04), p = 0.655]. HEI component scores also did not moderate treatment response, though total vegetable intake moderated level of improvement [β= −0.48 (95% CI: −0.82, −0.13), p = 0.007]: those with higher vegetable intake showed greater improvement with BSMN but not with placebo.
BSMN may benefit children with ADHD and irritability regardless of diet quality. The finding that higher baseline vegetable intake possibly predisposes to improvement with BSMN is puzzling and worth further exploration of potential mechanisms such that a higher vegetable intake may promote the absorption or utilization of the multinutrients.
Diet Quality as a Moderator of Response to Multinutrients for ADHD and Emotional Dysregulation: The MADDY RCT.
Robinette L, Hatsu I, Johnstone J, Leung B, Arnold LE. Diet Quality as a Moderator of Response to Multinutrients for ADHD and Emotional Dysregulation: The MADDY RCT. Curr Dev Nutr. 2022 Jun 14;6(Suppl 1):395.
ABSTRACT
Objective: The Pediatric Adverse Event Rating Scale (PAERS) measured adverse events of children
aged 6–12 years with ADHD and emotional dysregulation in the Micronutrients for ADHD in Youth
(MADDY) study, an eight week multi-site randomized clinical trial of a broad-spectrum multinutrient
treatment. Treatment sensitivity of the PAERS was assessed by calculating the treatment difference in
change of the item scores from baseline to end of the RCT.
Methods: Principal component analysis retained 14 “adverse events” (out of 43 in the PAERS) that
reflected ADHD symptoms and emotional dysregulation and was used to group the variables of interest.
A combined score ranging from 0 to 5 was created based on symptom presence, functional
impairment, and severity. Mean score change was calculated from baseline to week 8 by treatment
(multinutrient vs placebo) with intention-to-treat and per-protocol samples. The study has been registered
on clinicaltrials.gov as Micronutrients for ADHD in Youth (MADDY) Study, trial registration #
NCT03252522 (https://clinicaltrials.gov/ct2/show/NCT03252522).
Results: The 126 children in the ITT sample had a mean age of 9.8 (SD = 1.7), with majority (73%)
male, and 72% diagnosed with ADHD prior to the study screening. Baseline presence of PAERS symptoms
was similar between treatment groups: the highest proportion was ADHD symptoms, followed
by Irritable symptoms. The micronutrient group showed a greater decrease (improvement) in the
mean anxiety combined score than the placebo group with a between-group difference in change of
- 0.36 (95% CI: - 0.67, - 0.04; p¼.03) with ITT data and - 0.48 (95% CI: - 0.81, - 0.15; p = .005) with
per-protocol (n = 93) data.
Conclusion: The multinutrient supplement did not result in more adverse events than placebo, suggesting
it is a safe intervention. In addition to assessing actual adverse events, the PAERS may be a
useful adjunct outcome measure for ADHD behaviors.
Paediatric adverse event rating scale: a measure of safety or efficacy? Novel analysis from the MADDY study
Brenda M. Y. Leung, Priya Srikanth, Barbara Gracious, Irene E. Hatsu, Gabriella Tost, Valerie Conrad, Jeanette M. Johnstone & L. Eugene Arnold (2022) Paediatric adverse event rating scale: a measure of safety or efficacy? Novel analysis from the MADDY study, Current Medical Research and Opinion, 38:9, 1595-1602.
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
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.
Background: Parents' lived experiences of having a child with ADHD may shape their decision making regarding ADHD treatment options for their child. The aim of this study was to explore parents' experiences of living with a child with ADHD in the family and how their experiences influence their perspectives on treatment preferences and priorities.
Methods: A phenomenological qualitative design was used. Semistructured interviews were conducted with parents of children with ADHD who were enrolled in a multisite randomized controlled trial. Interviews were transcribed verbatim, and transcripts at each site were double coded. Initial codes were derived directly from the text. Qualitative data were analysed with an inductive approach.
Results: Twenty-three parents were interviewed: eight from Alberta, Canada; eight from Portland, Oregon, USA; and seven from Columbus, Ohio, USA. Among the parents, 69% were married, 86% completed college education and 52% reported household income over $80,000. Among the children, the mean age was 9.6 years (SD = 1.8 years), 78% were boys and 48% were never medicated for their ADHD. Two major themes emerged from the analysis. Theme 1 was 'impact of ADHD on families within and outside the home' with the following subthemes: 'reconfiguring the home life', 'trial-and-error of accommodations at school' and 'responding to social pressures to fit in'. Theme 2 was 'enabling appropriate and accessible treatments for families' with the following subthemes: 'finding the "right fit" with professionals and treatments' and 'factors influencing inequitable access to treatments'.
Conclusions: Parents described shared experiences and identified similar barriers, preferences and priorities for ADHD treatments regardless of demographic differences by site. Families desired access to family-centred, multimodal approaches to ADHD treatment. Further research is needed to identify the specific structural changes to healthcare, services and policies that will better support this approach.
Parents' priorities and preferences for treatment of children with ADHD: Qualitative inquiry in the MADDY study
Lu SV, Leung BMY, Bruton AM, Millington E, Alexander E, Camden K, Hatsu I, Johnstone JM, Arnold LE. Parents' priorities and preferences for treatment of children with ADHD: Qualitative inquiry in the MADDY study. Child Care Health Dev. 2022 Sep;48(5):852-861.
Objective: We investigated whether changes in serum nutrient levels mediate clinical response to a micronutrient intervention for ADHD. Method: Data were compiled from two ADHD trials (8-10 weeks), one in adults† (n = 53) and one in children (n = 38). Seven outcomes included change in ADHD symptoms, mood, overall functioning (all clinician-rated) as well as response status. Change in serum/plasma nutrient levels (vitamins B12 and D, folate, ferritin, iron, zinc, and copper) were considered putative mediators. Results: A decrease in ferritin and an increase in copper were weakly associated with greater likelihood of being identified as an ADHD responder; none of the other nutrient biomarkers served as mediators. Conclusion: Further research looking at nutrients more broadly from other tissues are required to confirm these initial observations of the limited value of nutrient levels in deciphering mechanism of action. Monitoring these biomarkers on their own is unlikely helpful in understanding clinical response to a broad-spectrum micronutrient approach.
Do Changes in Blood Nutrient Levels Mediate Treatment Response in Children and Adults With ADHD Consuming a Vitamin-Mineral Supplement?
Rucklidge JJ, Eggleston MJF, Boggis A, Darling K, Gorman B, Frampton CM. J Atten Disord. 2021 Jun;25(8):1107-1119. Epub 2019 Nov 9.
Abstract
It has been widely hypothesized that both diet and the microbiome play a role in the regulation of attention-deficit/hyperactivity disorder (ADHD) behaviour. However, there has been very limited scientific investigation into the potential biological connection. We performed a 10-week pilot study investigating the effects of a broad spectrum micronutrient administration on faecal microbiome content, using 16S rRNA gene sequencing.
The study consisted of 17 children (seven in the placebo and ten in the treatment group) between the ages of seven and 12 years, who were diagnosed with ADHD. We found that micronutrient treatment did not drive large-scale changes in composition or structure of the microbiome.
However, observed OTUs significantly increased in the treatment group, and showed no mean change in the placebo group. The differential abundance and relative frequency of Actinobacteria significantly decreased post- micronutrient treatment, and this was largely attributed to species from the genus Bifidobacterium. This was compensated by an increase in the relative frequency of species from the genus Collinsella.
Further research is required to establish the role that Bifidobacterium contribute towards neuropsychiatric disorders; however, these findings suggest that micronutrient administration could be used as a safe, therapeutic method to modulate Bifidobacterium abundance, which could have potential implications for modulating and regulating ADHD behaviour.
Our pilot study provides an initial observation into this area of research, and highlights an interesting avenue for further investigation in a larger cohort. Furthermore, these novel results provide a basis for future research on the biological connection between ADHD, diet and the microbiome.
Human gut microbiome changes during a 10 week Randomised Control Trial for micronutrient supplementation in children with attention deficit hyperactivity disorder
Aaron J. Stevens, Rachel V. Purcell, Kathryn A. Darling, Matthew J. F. Eggleston, Martin A. Kennedy & Julia J. Rucklidge. Scientific Reportsvolume 9, Article number: 10128, 2019
Abstract
Objectives
Attention-deficit/hyperactivity disorder (ADHD) is a neuropsychiatric disorder with increasing global prevalence and high heritability commonly diagnosed in childhood. Current pharmaceutical treatment options provide a poor long-term risk: benefit ratio. Nutrition has significant effects on neurological functioning, and increasing evidence exists to support the use of multinutrients as alternative treatment for ADHD. The goal of this study is to assess the efficacy and tolerability of a multinutrient supplement as an alternative treatment for ADHD and co-occurring mood dysregulation symptoms.
Methods
The Multinutrients in ADHD Youth study is a fully-funded, multi-site, randomized double-blinded clinical trial for adolescents ages 6–12 years (n = 135). The study is 16 weeks in total, with an 8-week randomized controlled trial (RCT) followed by an 8-week open label (OL) phase. During the RCT phase, participants are assigned to either the treatment or placebo group at a 3:2 ratio. Study outcomes of ADHD symptoms include child's inattention, hyperactivity and mood dysregulation, which are assessed using validated questionnaires. Outcome data for the OL phase of the study were analyzed using end of RCT phase as baseline given that the RCT component of the study is still blinded.
Results
Preliminary findings based on the OL phase compared ADHD symptoms following 8 weeks of open label supplementation (n = 27 families). A significant decrease in symptom count was found for inattention (P ≤ 0.001), hyperactivity (P ≤ 0.001), ODD (P ≤ 0.001) and DMDD (P ≤ 0.001).
Conclusions
This study is the first adequately powered RCT in North America to investigate the effects of multinutrients supplements on ADHD symptoms among children. Preliminary findings indicate a trend in the improvements of ADHD symptoms of inattention, hyperactivity, ODD and DMDD in the OL phase of the study.
Funding Sources
Foundation for the Center of Excellence in Mental Health, Canada; The Ohio State University Department of Human Sciences, College of Education and Human Ecology; The Ohio State University Wexner Medical Center, Clinical Research Center.
Multinutrients for ADHD Youth (MADDY) Trial: Preliminary Trends for Treatment
Madeline Stern, Leanna Perez, Jeanette Johnstone, Barbara Gracious, Brenda Leung, Eugene Arnold, Gabriella Tost, Irene Hatsu. Current Developments in Nutrition, Volume 3, Issue Supplement 1, June 2019, https://doi.org/10.1093/cdn/nzz050.P16-028-19
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.
Exposure times and dosage required for dietary components to modify DNA methylation patterns are largely unknown.
Aim: This exploratory research represents the first genome-wide analysis of DNA methylation changes during a randomized-controlled-trial (RCT) for dietary supplementation with broad spectrum vitamins, minerals and amino acids in humans.
Methods: Genome-wide changes in methylation from paired, peripheral blood samples were assessed using the Infinium Methylation EPIC 850 K array.
Results: Methylation increased at 84% of the most significant differentially methylated CpGs; however, none showed significance after adjustment for genome-wide testing.
Conclusion: Micronutrient supplementation is unlikely to have a substantial biological effect on DNA methylation over 10 weeks; however, the trend toward hypermethylation that we observed is likely to become more marked with longer exposure periods.
Methylomic changes in response to micronutrient supplementation and MTHFR genotype.
Stevens AJ, Rucklidge JJ, Darling KA, Eggleston MJ, Pearson JF, Kennedy MA. Epigenomics. 2018 Sep 4;10(09):1201-14.
BACKGROUND:
Evaluation of broad-spectrum micronutrient (vitamins and minerals) treatment for childhood ADHD has been limited to open-label studies that highlight beneficial effects across many aspects of psychological functioning.
METHOD:
This is the first fully blinded randomized controlled trial of medication-free children (n = 93) with ADHD (7-12 years) assigned to either micronutrients (n = 47) or placebo (n = 46) in a 1:1 ratio, for 10 weeks. All children received standardized ADHD assessments. Data were collected from clinicians, parents, participants and teachers across a range of measures assessing ADHD symptoms, general functioning and impairment, mood, aggression and emotional regulation.
RESULTS:
Intent-to-treat analyses showed significant between-group differences favouring micronutrient treatment on the Clinical Global Impression-Improvement (ES = 0.46), with 47% of those on micronutrients identified as 'much' to 'very much' improved versus 28% on placebo. No group differences were identified on clinician, parent and teacher ratings of overall ADHD symptoms (ES ranged 0.03-0.17). However, according to clinicians, 32% of those on micronutrients versus 9% of those on placebo showed a clinically meaningful improvement on inattentive (OR = 4.9; 95% CI: 1.5-16.3), but no group differences on improvement in hyperactive-impulsive symptoms (OR = 1.0; 95% CI: 0.4-2.5). Based on clinician, parent and teacher report, those on micronutrients showed greater improvements in emotional regulation, aggression and general functioning compared to placebo (ES ranged 0.35-0.66). There were two dropouts per group, no group differences in adverse events and no serious adverse events identified. Blinding was successful with guessing no better than chance.
CONCLUSIONS:
Micronutrients improved overall function, reduced impairment and improved inattention, emotional regulation and aggression, but not hyperactive/impulsive symptoms, in this sample of children with ADHD. Although direct benefit for core ADHD symptoms was modest, with mixed findings across raters, the low rate of adverse effects and the benefits reported across multiple areas of functioning indicate micronutrients may be a favourable option for some children, particularly those with both ADHD and emotional dysregulation. Trial registered with the Australian New Zealand Clinical Trials Registry ACTRN12613000896774.
Vitamin-mineral treatment improves aggression and emotional regulation in children with ADHD: a fully blinded, randomized, placebo-controlled trial.
Rucklidge JJ, Eggleston MJF, Johnstone JM, Darling K, Frampton CM. J Child Psychol Psychiatry. 2017 Oct 2.
Objective: Despite widespread use, there is little data investigating the long-term impact of micronutrients on psychiatric disorders. This study investigated the naturalistic outcome 1-year post-baseline of a randomized controlled trials (RCT) that compared micronutrients with placebo in 80 adults with ADHD.
Method: All participants were contacted and clinician-rated questionnaires completed.
Results: A total of 72 (90%) of the sample participated; although there was significant regression in psychiatric functioning from the end-of-trial on all measures, outcomes remained significantly improved from baseline. Dominant treatment from the end-of-treatment to follow-up was investigated as a mediator of outcome; those staying on the micronutrients performed better than those who switched to medications or discontinued micronutrients. Cost was the most substantial reason why people stopped micronutrient treatment. Conclusion: For the small number of participants who stayed on micronutrients, the benefits conferred through the controlled trial were maintained. The results are limited by small sample, lack of blinding, expectation, and reliance on self-report of symptoms.
Vitamin–Mineral Treatment of ADHD in Adults: A 1-Year Naturalistic Follow-Up of a Randomized Controlled Trial
Rucklidge JJ, Frampton CM, Gorman B, Boggis A. Vitamin-Mineral Treatment of ADHD in Adults. J Atten Disord. 2017 Apr;21(6):522-532.
In January 2014, The British Journal of Psychiatry published the results of a double-blind controlled trial which provided evidence of efficacy for micronutrients† (vitamins and minerals) in the treatment of ADHD symptoms in adults, with a reassuring safety profile.
As a follow-up to the adult trial, and pilot study for a RCT in childhood ADHD, the Journal of Child and Adolescent Psychopharmacology recently published the results of a study which treated 14 children with Attention-Deficit/Hyperactivity Disorder (ADHD) using micronutrients† instead of medication.
The study demonstrated the clinical benefit, feasibility, and safety of broad-spectrum micronutrients in the treatment of childhood ADHD.
In the recently published study, medication-free children were treated with a micronutrient formula† for eight weeks and then taken off it for four weeks—with the on-off cycle repeating itself over a six-month period.
Modified Brinley plots revealed a reduction in ADHD symptoms, improved mood, and improved overall functioning during intervention phases, and deterioration in ADHD symptoms, mood, and overall functioning during the withdrawal phases. Reliable change analyses, Cohen's d and percent superiority effect sizes, 95% confidence intervals and t tests confirmed clinically and statistically significant change between the intervention and withdrawal phases, with large effect sizes observed pre- to post-exposure of micronutrients (d = 1.2–2.2) on ADHD symptoms during intervention phases. Seventy-one percent of participants showed at least a 30% decrease in ADHD symptoms by the end of the second treatment phase, and 79% were identified as “much improved” or “very much improved” at the end of the second phase (5 months) based on the clinician-rated CGI when considering functioning generally. The SDQ showed that these benefits occurred across other areas of functioning including emotional symptoms, conduct problems, and prosocial behaviours. The children's self-reports confirmed the improvements. Excellent adherence to treatment occurred throughout, side effects were mild and transitory, and no safety issues were identified through blood analyses.
The researchers said the results were so effective that some parents were reluctant to take their children off the micronutrients† for the full four weeks. They noted “When they came off the micronutrients†, some children’s symptoms returned within days, which was a good indication of their effectiveness.”
Clinically Significant Symptom Reduction in Children with Attention-Deficit/Hyperactivity Disorder Treated with Micronutrients: An Open-Label Reversal Design Study
Gordon HA, Rucklidge JJ, Blampied NM, Johnstone JM. J Child Adolesc Psychopharmacol. 2015 Dec;25(10):783-98. doi: 10.1089/cap.2015.0105. PubMed PMID: 26682999; PubMed Central PMCID: PMC4702182.
A micronutrient formulation co-developed† by Hardy Nutritionals® founder David Hardy, showed “statistically robust improvements” in the first-ever double-blind study to test the effectiveness and safety of a multivitamin-mineral treatment for adult ADHD. Researchers from the University of Canterbury and the University of Otago, New Zealand, randomized 80 adults diagnosed with ADHD to take either the micronutrient formulation or identical-looking placebo pills for 8 weeks. Most of the study participants had at least one psychiatric diagnosis in addition to ADHD. Additional diagnoses included multiple anxiety disorders, major depressive disorder, dysthymia, bipolar disorder, reading disability, and alcohol/substance misuse or dependence. The nutrient group reported more than double the improvement in attention, hyperactivity, and impulsivity symptoms, compared with the placebo group. Clinical psychologists rated more than twice as many people in the nutrient group ‘very much’ or ‘much’ improved in overall symptoms. They also rated moderate and severely depressed participants in the nutrient group as having nearly double the improvement in depression symptoms. Researchers found that the micronutrients were completely safe; there were no differences in side effects between the two groups.
Vitamin–mineral treatment of attention-deficit hyperactivity disorder in adults: double-blind randomised placebo-controlled trial.
Rucklidge JJ, Frampton CMA, Gorman B, Boggis A. The British Journal of Psychiatry. 2014 Feb;204(2): doi: 10.1192/bjp.bp.113.132126 [Epub ahead of print]
Dr. Julia Rucklidge conducted nutrient assays on study participants in her 8 week double-blind RCT using micronutrient treatment† for adult ADHD. Using this extensive data set, she performed a post-hoc analysis of the original study in an attempt to determine if blood levels of nutrients in adult ADHD patients could be used to predict whether or not they would respond to micronutrient treatment. The blood markers measured were Vitamin D, Vitamin B12, Folate, Iron, Zinc, Copper, and Ferritin.
With the exception of Vitamin d (27% of participants deficient), nutrient deficiencies were slight or non-existent for the majority of participants at the beginning of the trial. In spite of the fact that only one participant exhibited iron deficiency, low iron levels were associated with higher baseline depression scores (p=0.009). No other nutrient significantly correlated with baseline psychiatric scores.
Throughout the course of the trial, micronutrient treatment was associated with significant increases in blood Vitamin D, Vitamin B12, and Folate (all p<0.001), but only Vitamin D was also identified as one of the nutrient markers that showed a statistically significant effect on treatment response.
The nutrient markers affecting treatment response were: ferritin, vitamin D, and copper. Greater ferritin at baseline correlated with being an ADHD responder (p=0.027). (ADHD response was defined as ≥30% decrease in symptom scores for a comprehensive combination of outcome measures. Of the 64 original study participants with complete nutrient assays, 39 (60.9%) were identified as ADHD responders.) Lower baseline vitamin D was predictive of greater improvements in depression (p=0.011) and global functioning (p=0.045) scores, and lower baseline copper levels predicted greater response in the depression (p=0.002) and clinical global improvement (p=0.007) outcome measures.
From among the non-nutrient variables measured, the researchers identified developmental history as the only noticeable predictor of response. This means that people with a history of developmental risk factors (e.g., slow to talk, walk, read, toilet train) may benefit even more from micronutrient treatment than those who developed normally as a child. It is also worth noting that several participants who reported alcohol or drug use at baseline later reported a reduction or cessation of these behaviours during micronutrient treatment, suggesting the possible value of nutrients in addiction therapy.
Only a few significant associations were identified between baseline biomarkers and outcomes, but, despite the difficulty in predicting the outcome for any given person, micronutrient treatment proved very effective – providing substantial ADHD symptom reduction for over half of the adults in this study.
Moderators of treatment response in adults with ADHD treated with a vitamin-mineral supplement
Rucklidge JJ, Johnstone J, Gorman B, Boggis A, Frampton CM. Prog Neuropsychopharmacol Biol Psychiatry. 2014 Apr 3;50:163-71. doi:10.1016/j.pnpbp.2013.12.014. Epub 2013 Dec 26. PubMed PMID: 24374068.
A 24-year-old woman who experienced dramatic improvement in her ADHD and depression symptoms for more than 2 years while taking a micronutrient formulation co-developed† by Hardy Nutritionals® founder David Hardy later experienced a recurrence of her former psychiatric symptoms as a result of a severe yeast infection. Her physical symptoms included an overall flu-like feeling; a chronic sore throat and runny nose; cravings for sugary and starchy foods; gastrointestinal cramps; and rashes and itching on her legs, groin, genital and rectal areas. Psychiatric symptoms included severe moodiness, inability to experience pleasure, and chronic irritability. These physical and psychiatric symptoms persisted for several months despite her ongoing use of a prescription antifungal cream. The woman began taking four capsules of olive leaf extract (identical to our Hardy Nutritionals™ Olive Leaf Extract) as well as two capsules of probiotics (identical to our Hardy Nutritionals™ Greens & Probiotics) daily to treat the yeast infection, in addition to her regular therapeutic dose of the micronutrients. After a week and a half, the woman’s physical and psychiatric symptoms both improved, including disappearance of her rashes, cessation of the chronic itching, elimination of her runny nose, and improved mood and energy levels. After 2 months, she had returned to her previous level of function. During a year of follow-up, researchers found that the woman continued to enjoy relief from the physical and psychiatric symptoms caused by the yeast infection as long as she continued to take the Olive Leaf Extract.
Could yeast infections impair recovery from mental illness? A case study using micronutrients and olive leaf extract for the treatment of ADHD and depression.
Rucklidge JJ. Advances in Mind-Body Medicine. 2013 Summer;27(3):14-8.
Scientists observed while conducting previous studies that many study participants whose psychiatric symptoms were treated successfully with a micronutrient formulation co-developed† by Hardy Nutritionals® founder David Hardy tended to reduce or eliminate use of alcohol, cigarettes and cannabis on their own. This study details one case in which on-off micronutrient use resulted in off-on cigarette and cannabis smoking as well as off-on psychiatric symptoms. Micronutrients provide the necessary precursors and cofactors for adequate neurotransmitter production and regulation. In this way, micronutrients assist with mood regulation, help reduce anxiety, and directly affect brain reward circuitry, all of which can help individuals to successfully stop drug use.
Use of micronutrients attenuates cannabis and nicotine abuse as evidenced from a reversal design: a case study.
Harrison R, Rucklidge JJ, Blampied N. Journal of Psychoactive Drugs. 2013 Jun;45(2):168-178.
Researchers investigated the therapeutic effects of a micronutrient formulation co-developed† by Hardy Nutritionals® founder David Hardy in 7 children with bipolar disorder. The children’s additional psychiatric diagnoses included attention deficit hyperactivity disorder, oppositional defiant disorder, major depressive disorder, generalized anxiety disorder, conduct disorder, and obsessive-compulsive disorder. The children experienced a 37% decrease in depression scores and a 45% decrease in mania scores over 8 weeks. Side effects were minor and transient—mostly temporary gastric discomfort.
Feasibility of a nutritional supplement as treatment for pediatric bipolar spectrum disorders.
Frazier EA, Fristad MA, Arnold LE. Journal of Alternative and Complementary Medicine. 2012 Jul;18(7):678-85.
Researchers studied the impact of a micronutrient formulation co-developed† by Hardy Nutritionals® founder David Hardy on neurocognitive functioning in 14 adults with attention deficit hyperactivity disorder (ADHD) and severe mood dysregulation over an 8-week period. Significant improvement was observed in the ADHD-micronutrient group, but not the control group, across a range of verbal abilities, including verbal learning, verbal cognitive flexibility and fluency, and verbal inhibition. These neurocognitive improvements were large and consistent with improved psychiatric functioning.
Can micronutrients improve neurocognitive functioning in adults with ADHD and severe mood dysregulation? A pilot study.
Rucklidge JJ, Harrison R, Johnstone J. Journal of Alternative and Complementary Medicine. 2011 Dec;17(12):1125-31.
A 7.1-magnitude earthquake in Christchurch, New Zealand created a natural experiment for measuring the protective effects of a micronutrient formulation co-developed† by Hardy Nutritionals® founder David Hardy on mood, anxiety and stress. Prior to the earthquake, researchers had assessed mood, anxiety and stress levels in a group of 33 adults diagnosed with attention deficit hyperactivity disorder, and they chose to repeat the same measures after the earthquake. Scores showed that the 16 participants taking micronutrients were more resilient to the effects of the earthquake than the 17 individuals not taking any supplement. This effect was particularly marked for depression scores.
Post-earthquake psychological functioning in adults with attention-deficit/hyperactivity disorder: positive effects of micronutrients on resilience.
Rucklidge JJ, Blampied, NM. New Zealand Journal of Psychology. 2011;40(4):51.
The role of good nutrition for resilience in the face of stress is a topic of interest, but difficult to study. A 7.1 earthquake took place in the midst of research on a micronutrient treatment† for Attention-Deficit/Hyperactivity Disorder (ADHD), providing a unique opportunity to examine whether individuals with ADHD taking micronutrients demonstrated more emotional resilience post-earthquake than individuals with ADHD not taking micronutrients. Thirty-three adults with ADHD were assessed twice following the earthquake using a measure of depression, anxiety and stress also completed at some point pre-earthquake (baseline). Seventeen were not taking micronutrients at the time of the earthquake (control group), 16 were (micronutrient group). While there were no between-group differences one week post-quake (Time 1), at two weeks post-quake (Time 2), the micronutrient group reported significantly less anxiety and stress than the controls (effect size 0.69). These between group differences could not be explained by other variables, such as pre-earthquake measures of emotions, demographics, psychiatric status, and personal loss or damage following the earthquake. The results suggest micronutrients may increase resilience to ongoing stress and anxiety associated with a highly stressful event in individuals with ADHD and are consistent with controlled studies showing benefit of micronutrients for mental health.
Micronutrients reduce stress and anxiety following a 7.1 earthquake in adults with Attention-Deficit/Hyperactivity Disorder
Rucklidge JJ, Johnstone J, Harrison R, Boggis A. 2011. Psychiatry Research, 189:281-87.
Scientists analyzed data from 120 children with pediatric bipolar disorder who were treated with a micronutrient formulation co-developed† by Hardy Nutritionals® founder David Hardy for at least 6 months. 24% of these children also had a diagnosis of attention deficit hyperactivity disorder (ADHD). Their results were compared with an additional 41 children who were diagnosed with ADHD alone. Children with a bipolar diagnosis showed a 59% decline in symptoms, whereas children with ADHD showed a 40% decrease in symptoms. The duration of symptom reduction suggests that benefits of micronutrient treatment were not attributable to placebo or expectancy effects. Of those taking psychiatric medications, more than half were able to completely discontinue them over a 6-month period. Medication use by the remainder of children was reduced by 74% during the same time period.
Database analysis of children and adolescents with bipolar disorder consuming a micronutrient formula.
Rucklidge JJ, Gately D, Kaplan BJ. BioMed Central Psychiatry. 2010 Sep 28;10:74.
Researchers documented the effects of a micronutrient formulation co-developed† by Hardy Nutritionals® founder David Hardy on psychiatric and neurocognitive functioning in a naturalistic off-on-off-on design. A 21-year old female with bipolar II disorder, attention deficit hyperactivity disorder (ADHD), social anxiety, and panic disorder began taking a vitamin-mineral formulation following a documented 8-year history of ongoing psychiatric symptoms that were not well managed by medications. After 8 weeks on the formula, she showed significant improvements in mood, anxiety, and hyperactivity/impulsivity. She then chose to come off the formula. After 8 weeks, her depression scores returned to pre-treatment levels, and anxiety and ADHD symptoms worsened dramatically. When the formula was reintroduced, all psychiatric symptoms showed gradual improvements. After one year, she was in remission of all mental illness diagnoses. Her neurocognitive changes mirrored behavioral changes, showing improved processing speed, variability in response, and verbal memory.
Successful treatment of bipolar disorder II and ADHD with a micronutrient formula: a case study.
Rucklidge JJ, Harrison R. CNS Spectrums. 2010 May;15(5):289-95.
Researchers treated nine unselected children with mood and behavioral problems with a micronutrient formulation co-developed† by Hardy Nutritionals® founder David Hardy. The children’s psychiatric diagnoses included attention deficit hyperactivity disorder, bipolar disorder, depression, oppositional defiant disorder, obsessive-compulsive disorder, generalized anxiety disorder, Asperger syndrome, and Prader-Willi syndrome. After a minimum of 8 weeks of micronutrient treatment, the children’s behavior improved significantly in the following areas: anxious and depressed mood, thought problems, interpersonal relationship problems, attention problems, social problems, withdrawn behavior, disruptive behavior, delinquent behavior, aggressive behavior, and self-harm behavior.
Improved mood and behavior during treatment with a mineral-vitamin supplement: an open-label case series of children.
Kaplan BJ, Fisher JE, Crawford SG, Field CJ, Kolb B. Journal of Child and Adolescent Psychopharmacology. 2004 Spring;14(1):115-22.
Researchers describe two medication-free boys with unstable mood and explosive rage who took a micronutrient formulation co-developed† by Hardy Nutritionals® founder David Hardy followed by reversal and re-treatment. The boys’ diagnoses included pervasive developmental disorder with Asperger characteristics, attention deficit hyperactivity disorder, obsessive-compulsive disorder, and autism. Both boys benefited significantly from the micronutrient formula: mood, angry outbursts, delinquent behavior, social and attention problems, and anxious/obsessional symptoms improved when initially treated, returned when they discontinued treatment, and remitted when the micronutrient treatment was reintroduced. During a follow-up of over 2 years, both boys continued to be stable while taking the micronutrient treatment.
Treatment of mood lability and explosive rage with minerals and vitamins: two case studies in children.
Kaplan BJ, Crawford SG, Gardner B, Farrelly G. Journal of Child and Adolescent Psychopharmacology. 2002 Fall;12(3):205-19.
Researchers treated 11 adults diagnosed with various types of bipolar disorder for an average of 44 weeks with a micronutrient formulation co-developed† by Hardy Nutritionals® founder David Hardy. The adults’ additional diagnoses included attention deficit hyperactivity disorder, dysthymic disorder, and obsessive-compulsive disorder. The adults experienced a 55% reduction in depression symptoms, a 60% reduction in mania symptoms, and a 66% reduction in general psychiatric symptoms. Their psychiatric medication use decreased by more than 50%. The only reported side effect, nausea, was infrequent, minor, and transitory.
Effective mood stabilization with a chelated mineral supplement: an open-label trial in bipolar disorder.
Kaplan BJ, Simpson JS, Ferre RC, Gorman CP, McMullen DM, Crawford SG. The Journal of Clinical Psychiatry. 2001 Dec;62(12):936-44.