Brain changes and neurocognitive effects associated with prolonged use of psychostimulants

Psychostimulants, such as methylphenidate and amphetamines, are the first-line treatment for Attention Deficit Hyperactivity Disorder (ADHD), a neurodevelopmental disorder characterized by inattention, impulsivity, and hyperactivity. Children may be prescribed stimulants from an early age, when the brain is still developing. While a breadth of research has focused on short-term side effects, the long-term impact of prolonged psychostimulant use remains poorly understood. Children with highly disruptive behaviours are more likely to receive medication, making it challenging for longitudinal studies to disentangle the effects of severe ADHD symptoms from drug-related side effects.

This study aims to provide causal evidence for the association between long-term psychostimulant use and changes in brain structure and neurocognitive function using Mendelian randomization (MR) and colocalization. These approaches strengthen causal inference by leveraging genetic variation that is not influenced by confounding factors such as ADHD severity or socioeconomic background.

Following systematic drug-target selection, we investigated the effects of psychostimulant targets on brain and cognitive outcomes by integrating genetic data with large-scale neuroimaging and behavioural datasets. Brain-related outcomes included global cortical surface area, cortical thickness, and subcortical volumes. Cognitive and behavioural measures comprised general intelligence, executive function, attention, impulsivity, and emotional regulation. Colocalization analyses were conducted to assess whether identified associations were likely to arise from shared causal variants, thereby increasing the robustness of the findings.

Our initial analyses indicate that a reduction in global cortical surface area, but not cortical thickness, is causally associated with prolonged psychostimulant use, potentially mediated through antagonism of adenosine receptors. We anticipate further associations involving specific cortical and subcortical regions, additional drug targets, and higher-order cognitive functions. These findings have the potential to inform more personalized pharmacological interventions for children with ADHD and contribute to a deeper understanding of the molecular pathways underlying psychostimulant mechanisms of action.