October 25, 2023

Meta-analysis claims effectiveness of multi-nutrient supplements in treating ADHD, but reports inconsistent results and has methodological shortcomings

A recently published meta-analysis compared the treatment of ADHD with multi-nutrient supplements versus placebo.

Children received either placebo or Daily Essential Nutrients(Vit A 384 IU, Vit C 40 mg, Vit D 200 IU, Vit E 24 IU, Vit K 8 μg, B1 4 mg, B21.2 mg, B3 6 mg, B6 4.67 mg, B9 50 μg, B12 60 μg, B7 72 μg, B5 2 mg, Ca 88 mg, Fe 0.92 mg, P 56 mg, I 13.6 μg, Mg 40 mg, Zn 3.2 mg, Se 13.6 μg, Cu 0.48 mg, Mn0.64 mg, Cr 41.6 μg, Mo 9.6 μg, P 16 mg. Proprietary blend: Choline bitartrate, Alpha-lipoic acid, Inositol, Acety-l-carnitine (as acetyl-L-carnitine hydrochloride), Grape seed extract, Ginkgo biloba leaf extract, Methionine (asL-methionine hydrochloride), Cysteine (as N-acetyl-L-cysteine), Germanium sesquioxide (as chelate), Boron, Vanadium, Lithium orotate, Nickel. Other ingredients: Cellulose glycine 45 mg, Citric acid 26.814 mg, Magnesium stearate24 mg, Silicon dioxide 20 mg).

Adults received either placebo or EMP+ (Vit A 5760IU, Vit C 600 mg, Vit D 1440 IU, Vit E 360 IU, B1 18 mg, B2 13.5 mg, B3 90 mg,B5 21.6 mg, B6 36 mg, B9 1440 μg, B12 900 μg, Biotin 1080 μg, Pantothenic acid21.6 mg, Ca 1320 mg, Fe 13.74 mg, P 840mg, I 204 μg, Mg 600 mg, Zn 48 mg, Se204 μg, Cu 7.2 mg, Mn 9.6 mg, Cr 624 μg, Mo 144 μg, K 240 mg, Germaniumsesquioxide 20.7 mg, B 2400 μg, V 1194 μg, Ni 29.4 μg, Choline bitartrate 540mg, DL-phenylalanine 360 mg, Citrus bioflavonoids 240 mg, Inositol 180 mg,Glutamine 180 mg, L-methionine 60 mg, Gingko biloba 36 mg, grape seed extract45 mg).

Using the Global Assessment of Functioning (GAF) scale for adults, and the Children's Global Assessment Scale (CGAS) for children, the study team reported moderate improvements in overall functioning from the use of the supplements. GAF and CGAF are used by mental health clinicians and physicians to rate subjectively the social, occupational, and psychological functioning of an individual.

Yet no significant improvements were found for either clinician-rated or observer-rated ADHD Change Scores.

Moreover, the positive finding was compromised by a series of methodological shortcomings:

·        It was just barely a meta-analysis, involving only two studies.
·        The combined number of participants in the two studies was small, 173, consisting of 93 children in one study and 80 adults in the other.
·        Both studies had the same lead author, Julia J. Rucklidge, who was also a member of the meta-analysis team.

With only two studies, there was no way to evaluate publication bias.

Jeanette M. Johnstone, Andrew Hughes, Joshua Z. Goldenberg, Amy R. Romijn, and Julia J. Rucklidge, "Multinutrients for the Treatment of Psychiatric Symptoms in Clinical Samples: A Systematic Review and Meta-Analysis of Randomized Controlled Trials," Nutrients (2020) 12, 3394, https://doi:10.3390/nu12113394.

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Meta-analysis Finds Association Between Childhood Febrile Seizures and Subsequent ADHD

Febrile seizure (FS) is a type of childhood seizure accompanied by a fever. It is not caused by infection in the central nervous system or other triggers of acute seizures. It is the most common form of childhood seizure, with an occurrence of 2% to 5% in all infants and children between 6 months and 5 years old. 

Noting that “To the best of our knowledge, no systematic synthesis of literature has assessed the nature and magnitude of the association between FS and ADHD,” a Korean research team performed a systematic search of the medical literature followed by meta-analysis to explore any such association. 

Meta-analysis of twelve studies with a combined total of more than 950,000 persons found that childhood febrile seizures were associated with 90% greater odds of subsequent ADHD. Correcting for publication bias reduced this slightly to 80% greater odds of subsequent ADHD. 

Limiting the meta-analysis to the subset of four studies with over 33,000 participants that adjusted for known confounders strengthened the association. Children who had febrile seizures had greater than 2.6-fold greater odds of subsequently developing ADHD. There was no sign of publication bias, but there was substantial divergence in individual study outcomes (heterogeneity). 

Further limiting the meta-analysis to two studies with a combined 654 participants in which clinical ADHD diagnoses were made by specialists – the gold standard – produced the exact same outcome. In this case, heterogeneity dropped to zero. 

The team concluded, “Overall, our systematic review and meta-analysis has shown a significant positive association between childhood FS and later occurrence of ADHD. Our findings add to the growing body of evidence questioning the notion that childhood FS are universally benign. In addition, the results highlight the need for longitudinal studies to better understand the association between FS and ADHD.”  

August 26, 2025

Meta-analysis Finds Little Evidence in Support of Game-based Digital Interventions for ADHD

ADHD treatment usually involves a combination of medication and behavioral therapy. However, medication can cause side effects, adherence problems, and resistance from patients or caregivers. 

Numerous systematic reviews and meta-analyses have evaluated the effects of non-pharmacological interventions on ADHD. With little research specifically examining game-based interventions for children and adolescents with ADHD or conducting meta-analyses to quantify their treatment effectiveness, a Korean study team performed a systematic search of the peer-reviewed medical literature to do just that.  

The Study: 

To be included, studies had to be randomized controlled trials (RCTs) that involved children and adolescents diagnosed with ADHD. The team excluded RCTs that included participants with psychiatric conditions other than ADHD.  

Eight studies met these standards. Four had a high risk of bias.  

Meta-analysis of four RCTs with a combined total of 481 participants reported no significant improvements in either working memory or inhibition from game-based digital interventions relative to controls. 

Likewise, meta-analysis of three RCTs encompassing 160 children and adolescents found no significant improvement in shifting tasks relative to controls. 

And meta-analysis of two RCTs combining 131 participants reported no significant gains in initiating, planning, organizing, and monitoring abilities, nor in emotional control

The only positive results were from two RCTs with only 90 total participants that indicated some improvement in visuospatial short-term memory and visuospatial working memory.  

There was no indication of effect size, because the team used mean differences instead of standardized mean differences.  

Conclusion:

The team concluded, “The meta-analysis revealed that game-based interventions significantly improved cognitive functions: (a) visuospatial short-term memory … and (b) visuospatial working memory … However, effects on behavioral aspects such as inhibition and monitoring … were not statistically significant, suggesting limited behavioral improvement following the interventions.” 

Simply put, the current evidence does not support the effectiveness of game-based interventions in improving behavioral symptoms of ADHD in children and adolescents. The only positive results were from two studies with a small combined sample size, which does not qualify as a genuine meta-analysis. All the other meta-analyses performed with larger sample sizes reported no benefits. 

Understanding Teen Health and Well-being in ADHD: A Fresh Perspective from the CDC

Recent research from the Centers for Disease Control and Prevention (CDC) highlights distinct health and social-emotional challenges faced by teens diagnosed with Attention-Deficit/Hyperactivity Disorder (ADHD). This study, published in the Journal of Developmental and Behavioral Pediatrics, offers critical insights directly from the teens themselves, providing a unique view often missed when relying solely on parent or clinical reports. 

Researchers analyzed nationally representative data from July 2021 through December 2022, comparing self-reported experiences of teens aged 12 to 17 with and without ADHD. Approximately 10% of teenagers had an ADHD diagnosis, and the findings reveal specific areas where teens with ADHD face notable difficulties. 

Teenagers with ADHD reported significantly higher rates of bullying victimization and struggles in making friends compared to their peers. Surprisingly, they were less likely to report a lack of peer support, suggesting complexities in how they perceive friendships and social networks. The study underscores the importance of directly engaging teens in assessing their social relationships, rather than solely relying on parental perspectives. 

Sleep difficulties emerged as another critical issue for teens with ADHD. About 80% reported problems like difficulty waking up and irregular wake times, markedly higher than their non-ADHD counterparts. Such disruptions can exacerbate attention difficulties and emotional regulation issues, further complicating daily life for these teens. 

Excessive screen time also stood out, with nearly two-thirds of teens with ADHD spending over four hours daily on screens, excluding schoolwork. This high screen usage is concerning, given its potential negative impact on physical and mental health, including sleep quality and social interactions. 

Notably, the study found no significant differences in physical activity levels or concerns about weight between teens with and without ADHD. This finding contrasts with previous studies that have highlighted lower physical activity among children with ADHD, suggesting the need for continued research on how physical activity is measured and encouraged in this population. 

The study’s authors emphasize the importance of health promotion interventions tailored specifically for teens with ADHD. By directly engaging teens and considering their unique perspectives, interventions can better address social-emotional well-being and healthy lifestyle behaviors, ultimately improving long-term outcomes for this vulnerable group. 

Overall, this research provides compelling evidence for healthcare providers, educators, and families to focus on supporting teens with ADHD in areas of social skills, sleep hygiene, and healthy screen time habits. Such targeted support can significantly enhance the quality of life and health outcomes for adolescents navigating the challenges of ADHD.