Substance Use and Addiction: From Molecular Mechanisms to Treatment

Dear Colleagues,

Substance use disorders constitute a critical global health challenge. The term "substance", from the Latin "substantia", has evolved over time, with a variety of ontological (what is it?), epistemological (how can we know it?), and metaphysical (what role does it play?) implications. Within neuroscientific and medical contexts, “substances” refer to psychoactive agents that physiologically alter mental states, and these compounds have been studied progressively in relation to use disorders, distinguished between therapeutic, recreational, and pathological patterns. Understanding these conditions requires examination of the reward circuitry—particularly the mesolimbic dopaminergic pathways—and neuroadaptive mechanisms, including receptor desensitization, synaptic remodeling, and tolerance development. 

Multidisciplinary investigation across molecular, cellular, and system levels reveals dysregulation of neurotransmitter systems, neuroplasticity, neuroinflammatory processes, and glial contributions within reward and executive control circuits. Interactions between genetic vulnerability, environmental factors, and disrupted prefrontal–limbic connectivity drive the transition from recreational to compulsive use. These insights inform therapeutic strategies, combining pharmacological interventions (agonists/antagonist therapies, novel agents targeting glutamatergic, neuroimmune/neuroendocrine pathways), neuromodulation, and biomarker-driven precision medicine, integrated with psychosocial interventions. 

Nonetheless, critical challenges persist. Limited treatment efficacy and a high relapse rate reflect inadequate clinical translation. Advancing detailed mechanistic understanding may enhance personalized paradigms. Thus, the aim of this Special Issue is to bridge knowledge gaps through integrative translational frameworks addressing substance use disorders. 

In this Special Issue, we invite submissions of original research manuscripts, reviews and meta-analyses, case reports, brief reports, opinions, and perspectives.

Dr. Davide Arillotta
Dr. Giuseppe Floresta
Prof. Dr. Fabrizio Schifano
Guest Editors

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