Multinutrient supplements may ease biological stress in children with ADHD

Children with attention-deficit/hyperactivity disorder (ADHD) who took a multinutrient supplement for eight weeks showed reduced levels of reactive oxygen metabolites, according to a new analysis of biological samples collected during a previously published randomized controlled trial. These findings suggest that improved oxidative balance may be one of the ways multinutrient treatment helps reduce behavioral symptoms in some children with ADHD.

ADHD is one of the most commonly diagnosed neurodevelopmental conditions in children. It is characterized by patterns of inattention, hyperactivity, and impulsivity that interfere with functioning in academic, social, and family settings. While its causes are not fully understood, researchers have increasingly focused on the role of oxidative stress as a possible contributing factor.

Oxidative stress occurs when there is an imbalance between the production of reactive oxygen species and the body’s ability to neutralize them with antioxidants. This imbalance can damage cells and may be particularly harmful to the brain, which consumes high levels of oxygen and has limited antioxidant defenses.

The study, published in the Journal of Attention Disorders, builds on earlier work from the Micronutrients for ADHD in Youth (MADDY) trial. That randomized controlled trial showed that children ages 6 to 12 who took a broad-spectrum multinutrient supplement had greater behavioral improvements than those who took a placebo. In the new analysis, researchers examined blood plasma samples from a subset of 77 children who participated in the original trial. Their goal was to find out whether the supplement influenced markers of oxidative stress and antioxidant activity, and whether those changes were related to clinical improvements.

“Children with ADHD often struggle not only with attention and behavior but also with poor eating habits which can lead to nutrient deficiencies,” explained study authors Lisa M. Robinette, a
postdoctoral scientist at the Abigail Wexner Research Institute at Nationwide Children’s Hospital, and Irene Hatsu, an associate professor of human sciences at The Ohio State University.

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“Previous clinical trials suggested that broad-spectrum multinutrient supplements containing all essential vitamins, minerals, and some amino acids, can improve ADHD symptoms. This study is a secondary analysis of one of those trials, which showed behavioral improvements in children with ADHD taking multinutrients compared to placebo. To examine how the multinutrients produced benefits in children with ADHD, we explored the links between improvements and changes in antioxidant and oxidative stress pathways, which are believed to be important in brain health.”

To evaluate oxidative balance, the researchers looked at several biological markers in the blood. These included glutathione peroxidase and glutathione reductase, two antioxidant enzymes involved in the body’s defense system. They also measured the oxidative stress index, which reflects the ratio between oxidative damage (reactive oxygen metabolites) and antioxidant capacity (biological antioxidant potential). Blood samples were collected before the start of the trial and again after eight weeks of daily supplementation with either the multinutrient formula or placebo.

After eight weeks, children who had taken the multinutrient supplement showed a significant reduction in reactive oxygen metabolites, while those who received placebo experienced an increase. The difference between the two groups was statistically significant. This suggests that the supplement helped reduce the level of oxidants in the body.

A similar trend was observed for the oxidative stress index, but the difference did not meet the conventional threshold for statistical significance unless samples with signs of hemolysis were excluded. The antioxidant capacity, as measured by biological antioxidant potential, did not change significantly in either group. Similarly, there were no meaningful group differences in the activity levels of the two antioxidant enzymes.

“We expected that the multinutrient group would have increased antioxidant capacity, since many of the nutrients included support antioxidant defenses,” Robinette and Hatsu told PsyPost. “Instead, we found that while oxidative stress markers went down, antioxidant enzyme activity and capacity did not change significantly. This was somewhat surprising, and it suggests that nutrients may help reduce the production of harmful oxidative molecules rather than boosting antioxidant enzymes directly.”

Although the reduction in oxidative stress markers was modest, the pattern of results indicates that the multinutrient supplement may have supported the body’s ability to manage oxidative damage. The researchers also explored whether changes in oxidative stress might help explain the behavioral improvements observed in the original trial. Statistical models hinted at a possible mediating role, with reductions in reactive oxygen metabolites being associated with a higher likelihood of clinical response to the supplement. However, these relationships did not reach statistical significance and were considered exploratory.

The supplement used in the trial contained a wide range of vitamins, minerals, amino acids, and antioxidant compounds. Many of these nutrients, such as selenium, zinc, and vitamins C and E, are involved in the body’s antioxidant defense system. Selenium, for example, is a required component of the glutathione peroxidase enzyme, while riboflavin and niacin support the activity of glutathione reductase. Given the number of nutrients that contribute to redox balance, a broad-spectrum approach may help support biological systems that regulate oxidative stress.

“Our study found that children with ADHD who took multinutrient supplements for eight weeks showed a reduction in markers of oxidative stress, while those on placebo did not,” Robinette and Hatsu explained. “This suggests that multinutrients may support the body’s ability to cope with biological stress. While not a cure, these results add to evidence that nutrition can play a role in supporting mental health in children.”

While the findings provide evidence that multinutrient treatment can reduce markers of oxidative stress in children with ADHD, the researchers note some limitations. One is the relatively small sample size, especially when it came to evaluating sex-specific effects. The placebo group in this subsample had a higher proportion of females than the treatment group, which could have influenced some of the results. The researchers accounted for this by including sex as a covariate in their analyses and confirmed that baseline oxidative stress levels were similar between boys and girls.

Another limitation is that plasma measurements may not fully reflect what is happening in the brain, which is the organ most directly implicated in ADHD. The antioxidant enzyme glutathione peroxidase is found at much higher concentrations in red blood cells than in plasma, and levels can be affected by sample handling. While the researchers measured hemoglobin and conducted sensitivity analyses to address possible effects of hemolysis, more direct measures of oxidative stress in neural tissue would be needed to draw firm conclusions about brain-specific effects.

“Importantly, as it was a secondary analysis of clinical trial data, it was not originally designed to answer this specific research question,” the researchers noted. “In addition, the eight-week timeframe is short, and we don’t yet know how long-term nutrient supplementation might influence oxidative stress and ADHD symptoms. Larger and longer studies, designed specifically for this purpose, are needed.”

Despite these limitations, the study contributes to a growing body of research suggesting that oxidative stress plays a role in neurodevelopmental disorders. Previous studies have found elevated levels of reactive oxygen metabolites in children with ADHD and autism spectrum disorder compared to typically developing peers. Other work has suggested that antioxidant status may be related to symptom severity. Some studies have also examined how nutritional interventions, including antioxidants and omega-3 fatty acids, affect oxidative stress levels, but findings have been inconsistent.

This analysis is among the first to examine whether changes in oxidative stress may help explain how a multinutrient supplement produces behavioral improvements in children with ADHD. While the study does not provide definitive evidence of a causal link, it raises the possibility that reducing oxidative damage could be part of the mechanism. The fact that reductions in reactive oxygen metabolites were associated with better clinical outcomes suggests that oxidative stress might be a target worth exploring in future interventions.

“Our long-term goal is to better understand the biological underpinnings of ADHD and how nutrition can support children’s mental health,” Robinette and Hatsu told PsyPost. “We want to identify which children are most likely to benefit from nutrient approaches, and how these interventions work in the body. Ultimately, we hope this will help develop more personalized and accessible treatment options.”

“I think it’s important to emphasize that nutritional interventions are not yet a replacement for other evidence-based ADHD treatments, but they show promise as an additional tool for families. Such approaches may not only improve ADHD symptoms but also support long-term health.”

The study, “Multinutrients Decrease Oxidative Stress in Children With ADHD: Mediation/Moderation Analysis of Randomized Controlled Trial Data,” was authored by Lisa M. Robinette, Irene E. Hatsu, Olorunfemi Adetona, Chieh-Ming Wu, Jeanette M. Johnstone, Alisha M. Bruton, Hayleigh K. Ast, James B. Odei, Ouliana Ziouzenkova, Brenda M. Y. Leung, and L. Eugene Arnold.