Amphetamines revisited with focus on current pharmacology, cognitive effects, and treatment strategies

The story of amphetamine began in the late nineteenth century and gained medical relevance in the 1930s through its therapeutic applications, ranging from decongestant effects to psychiatric uses in depression and narcolepsy. Its potential for misuse, particularly methamphetamine (METH), soon raised major concerns. Pharmacologically, amphetamines modulate dopamine and norepinephrine in the prefrontal cortex, enhancing attention; however, prolonged METH use produces marked cognitive decline, impairing verbal learning, memory, executive ability, working memory, and social cognition. Neuroimaging studies reveal damage to white matter pathways, especially the left superior longitudinal fasciculus and right corticospinal tract, correlating with impulsivity and executive dysfunction. METH also disrupts glutamate and gamma-aminobutyric acid balance and exerts neurotoxic effects on dopamine and serotonin systems, contributing to hippocampal atrophy and dysregulation of genes involved in synaptic plasticity. These multilevel impairments arise from mechanisms including neuroinflammation, excitotoxicity, oxidative and nitrosative stress, endoplasmic reticulum stress, mitochondrial dysfunction, apoptosis, and altered autophagy. Despite expanding mechanistic understanding, treatment options for METH use disorder remain limited. Current agents such as methylphenidate, amphetamine, lisdexamfetamine, and modafinil offer modest short-term benefits, mainly reducing early withdrawal or improving certain cognitive functions, yet show weak long-term efficacy, poor abstinence outcomes, and low treatment retention. No medication has demonstrated durable clinical benefit. By integrating neurobiological and therapeutic evidence, this review highlights the persistent gap between mechanistic knowledge and effective clinical management. It underscores the urgent need for targeted, mechanism-based therapies and provides a foundation for future translational research aimed at improving treatment outcomes for individuals affected by METH use disorder.