Neurotoxicity of lisdexamfetamine: Implications for neuronal health and central nervous system function

Lisdexamfetamine (LDX) is a d-amphetamine prodrug with a long-acting therapeutic profile. It has become well-known in recent years due to its widespread use in treating several psychological disorders, such as attention-deficit/hyperactivity disorder and binge eating disorder. However, concerns have been raised about its potential neurotoxic properties, particularly with long-term use. Although direct evidence of LDX-induced neurotoxicity is limited, insights can be drawn from studies on the harmful impacts of its parent compound and related amphetamines, such as amphetamine and methamphetamine, on the central nervous system. The potential mechanisms through which these drugs exert their neurotoxic effects include mitochondrial dysfunction, oxidative stress, neuroinflammation, synaptic failure, and excitotoxicity, all of which contribute to neuronal injury and death. Furthermore, amphetamines have been shown to disrupt the blood–brain barrier, likely triggered by the aforementioned mechanisms, with neuroinflammation being the most significant factor. In this review, we aim to synthesize the available knowledge on the potential mechanisms behind LDX-induced neurotoxicity and emphasize the need for future studies to better understand the long-term side effects of LDX.