Lisdexamfetamine: an over(re)view

Abstract

Background: Lisdexamfetamine (LDX), a prodrug of d-amphetamine, is a pharmaceutical used in the treatment of neuropsychiatric disorders, including attention-deficit/hyperactivity disorder (ADHD) (1). Objective: Herein we aimed to comprehensively review LDX pharmacokinetics, pharmacodynamics, clinical efficacy, safety profile, and forensic implications. Methods: A literature search was conducted in PubMed without a limitation period using the keywords LDX, pharmacokinetics/dynamics, clinical use and efficiency, among others related. All types of articles were included. Results: LDX undergoes rapid absorption via peptide transporter 1 (PepT1) in the small intestine, achieving C_max within 1–2h (2-5), and is hydrolyzed in erythrocytes by an unidentified aminopeptidase, into d-amphetamine and l-lysine (5, 6). Excretion occurs primarily via urine (96.4%), with minimal fecal elimination (0.3%) (2). Pharmacokinetic studies indicate that LDX does not significantly alter the activity of CYP1A2, CYP2D6, and CYP3A4 (7), suggesting low potential for drug-drug interactions. Its stimulant activity results from trace amine-associated receptor 1 (TAAR1) activation, monoamine oxidase (MAO) inhibition, and reverse transport of the vesicular monoamine transporter 2 (VMAT2), dopamine transporter (DAT), norepinephrine transporter (NAT), and serotonin transporter (SERT), increasing dopamine levels in synaptic cleft (1, 8). Common adverse effects of LDX include dizziness, somnolence, appetite suppression, headache, nausea, and fatigue (9). Concerns regarding growth suppression arise mainly in the first year of treatment and diminishing thereafter (9, 10). Although LDX exhibits a lower reinforcing potential than d-amphetamine (11), supra-therapeutic doses may induce similar abuse liability and toxicity. However, its higher lethal dose threshold (five times that of amphetamines) reduces overdose risk (12). Conclusions: LDX therapeutic efficacy in ADHD is well-established, with superior outcomes relative to other stimulant medications. In forensic context, differentiating between therapeutic and illicit consumption remains a critical challenge. Given its potential applications beyond ADHD, further large-scale studies are warranted to elucidate the full scope of LDX’s pharmacological and clinical utility.