Neuropharmacological comparison between lisdexamfetamine and cocaine: dopaminergic mechanisms, reward circuitry and post-stimulant depressive syndrome
DOI:
https://doi.org/10.69849/3chh1q33Keywords:
psychostimulants, lisdexamfetamine, cocaine, dopamine, addictionAbstract
Psychostimulants represent a pharmacological class capable of significantly modulating monoaminergic neurotransmission within the central nervous system. Among these agents, lisdexamfetamine—widely prescribed for attention-deficit/hyperactivity disorder (ADHD)—and cocaine—an illicit stimulant associated with high addiction potential—stand out for their profound effects on dopaminergic pathways. This study aimed to compare the neuropharmacological mechanisms of these substances, focusing on dopaminergic modulation, activation of the mesolimbic reward circuit, and the depressive syndrome observed after stimulant withdrawal. A narrative literature review with a systematic search strategy was conducted using the PubMed/MEDLINE, Scopus, and Web of Science databases. Peer-reviewed studies published between 1990 and 2024 addressing mechanisms of action, addiction neurobiology, or dopaminergic effects were included. Evidence indicates that cocaine primarily acts by blocking the dopamine transporter, leading to increased extracellular dopamine concentrations. In contrast, lisdexamfetamine, after metabolic conversion into dextroamphetamine, enhances synaptic dopamine through transporter reversal and modulation of vesicular monoamine transporter activity. Both substances activate the mesolimbic reward circuitry, particularly projections connecting the ventral tegmental area and the nucleus accumbens. Although they share similar neurochemical targets, pharmacokinetic and pharmacodynamic differences lead to distinct clinical and addictive profiles.
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Copyright (c) 2026 Yuri Oliveira, Adrielly Xavier de Azevedo, Gabriel Peixoto Ribeiro, Denis Maciel Marques de Carvalho Filho, Lavínia Neves Santos de Oliveira, Ana Carolina Lima Silva, Maurício da Silva Santana, Maria Natália Carolino Sena da Silva, Bruno Baldassaro Baldi, Clarissa Garzedim Raydan (Autor)
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