Prescription Stimulant-Induced Neurotoxicity: Mechanisms, outcomes, and relevance to ADHD

Abstract

Attention-deficit/hyperactivity disorder (ADHD) is a relatively prevalent neuropsychiatric and neurodevelopmental condition characterized in the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition ( DSM-5 ) as difficulty sustaining attention and maintaining tasks at hand, heightened distractibility, and other deficits in executive functioning. Prescription stimulants—amphetamine (AMP) and methylphenidate (MPH)—are the first-line treatment(s) for ADHD in both pediatric and adult populations and exist in many formulations. Troublingly, the non-medical use (NMU) of amphetamine and methylphenidate is more prevalent in the American population, especially on college and university campuses, than the condition of interest. The neurotoxicological profile and NMU epidemiology of prescription stimulants is of direct relevance to primary care physicians and psychiatrists as they are the providers most frequently tasked with the treatment of ADHD and the surveillance of substance misuse behaviors in the young adult population. As comprehensive literature reviews of the mechanisms and potential adverse sequelae of prescription stimulant-induced neurotoxicity intended for medical clinicians have been quite sparse in the last decade—especially given the gravity of the issue—this article includes a brief primer on ADHD etiology and pathophysiology; considers the current state of NMU epidemiology; reviews the mechanisms of action of AMP and MPH; and, finally, summarizes known molecular and clinical manifestations of AMP and MPH neurotoxicity.