Neuroprogression in substance use disorders: Integrating molecular mechanisms, brain circuitry, biomarkers, and implications for clinical staging and service design.

Substance use disorders (SUDs) are increasingly recognised as neuroprogressive conditions characterised by cumulative and dynamic alterations across multiple levels of brain organisation. This integrative narrative review synthesises current evidence on the molecular, cellular, circuit-level, and biomarker mechanisms underlying neuroprogression in SUDs and proposes a multilevel translational framework. Evidence from preclinical and clinical studies indicates that chronic exposure to psychoactive substances induces persistent neuroinflammation, oxidative stress, mitochondrial dysfunction, and epigenetic dysregulation, which collectively disrupt synaptic plasticity and promote ferroptotic processes. These alterations progressively translate into large-scale dysfunction of frontolimbic and frontostriatal circuits, contributing to impaired inhibitory control, maladaptive decision making, and increased vulnerability to relapse. Neuroimaging findings further support this model by demonstrating structural, functional, and metabolic changes associated with chronic substance use. In parallel, neurofilament light chain has emerged as a promising but non-specific research fluid biomarker of cumulative neuroaxonal damage, with potential value for linking biological alterations and clinical expression in future longitudinal and multimodal studies. From a translational perspective, this framework may inform early intervention, clinical staging, and the development of more integrated and scalable models of care. Overall, neuroprogression provides a coherent model for understanding SUDs and may contribute to guiding more precise, biologically informed approaches in addiction psychiatry.