ADHD Medications and Preadolescent Brain Structure: Patterns of Cortical Attenuation from the ABCD Study

Attention-deficit/hyperactivity disorder (ADHD) is the most common neurodevelopmental disorder in the U.S., and the stimulant and nonstimulant medications used to treat ADHD are among the most widely prescribed treatments in youth. Stimulants-including amphetamine-based (AMP) and methylphenidate-based (MPH) medications-act primarily on dopaminergic and noradrenergic systems, while nonstimulants (NS) more selectively target noradrenergic pathways. Although pharmacotherapy is the most clinically effective treatment, its neurostructural effects remain poorly understood. Leveraging the Adolescent Brain Cognitive Development• Study (ABCD Study®), we used a machine learning approach to identify neuroanatomical targets of medications, followed by linear mixed-effects modeling to estimate the effects of ADHD status and medication class (AMP, MPH, NS) on cortical thickness, surface area, and cortical and subcortical volumes. ADHD was not associated with statistically significant differences; however, a consistent pattern emerged in which AMP and MPH effects attenuated ADHD effects, suggesting that stimulant medications may attenuate ADHD-related cortical patterns. NS medications showed a similar, albeit weaker, effect pattern. Notably, AMP and/or MPH use was associated with significant effects in the right entorhinal cortex and the right banks of the superior temporal sulcus, potentially reflecting overcompensatory effects, as well as in the left posterior cingulate, possibly indicating de novo medication-related differences.