Several lines of evidence suggest that the neurotransmitter imbalance, neuroinflammation and defective immunoregulation, circadian system dysfunction and altered neural viability and neurodegeneration are pathophysiological processes related to attention-deficit/hyperactivity disorder (ADHD) disorder and their comorbidities.

We reviewed the literature for evidence that explains how the mechanisms of action (MoAs) of methylphenidate (MPH) and lisdexamfetamine dimesylate (LDX) act on these pathophysiological processes and control ADHD symptomatology.

More evidence has been found on the effect of MPH and LDX on neurotransmitter imbalance and neural viability and neurodegeneration. Regarding their role in neuroinflammation and defective immunoregulation as well as circadian system, there are few data available.

Despite the published studies on MPH and LDX, the few published molecular data available are based on animal models. Further studies are necessary to improve the knowledge of ADHD pathophysiology and how the MoAs of the MPH and LDX differentially modulate ADHD pathophysiology and control its symptomatology.