Essential Trace Elements Zinc, Iron, Copper and Attention-Deficit/Hyperactivity Disorder in Children and Adolescents: A Systematic Review and Meta-Analysis of Case–Control Studies

Essential trace elements such as zinc (Zn), iron (Fe), and copper (Cu) play a critical role in neurodevelopment, influencing key processes like neurotransmitter regulation and neuronal signaling. To synthesize the existing evidence, we conducted a systematic review and meta-analysis of case-control studies investigating the associations between these trace elements and Attention-Deficit/Hyperactivity Disorder (ADHD) in children and adolescents. A comprehensive literature search was performed up to March 2026 across multiple databases, including Web of Science, PubMed, and the Chinese National Knowledge Infrastructure. A total of 46 studies involving 5515 ADHD cases and 8166 controls were included. The results showed that Zn (SMD = -1.01, 95% CI: -1.51 to -0.52), Fe (SMD = -0.82, 95% CI: -1.52 to -0.11) and Ferritin (SMD = -0.54, 95% CI: -1.00 to -0.27) levels were significantly lower in children with ADHD than in controls, while no significant difference was observed for Cu levels (SMD = -0.55, 95% CI: -1.12 to 0.02). When the research subjects are limited to children ≤12 years old, the differences in Zn are more pronounced. Moreover, the differences in the levels of Zn, Fe, and Cu were more pronounced among children and adolescents from developing countries. These findings suggest that imbalances in Zn and Fe may be involved in the pathogenesis of ADHD. Further research is needed to validate early biomarkers of ADHD risk and to explore their potential application in clinical diagnosis and management, especially considering the high heterogeneity of the studies included in this study.