From Neuroadaptation to Neuroprogression: Rethinking Chronic Cocaine Exposure Through a Model of Cocaine-Related Cerebropathy

<b>Background:</b> Chronic cocaine exposure is increasingly associated with persistent brain alterations, yet it remains unclear whether these changes reflect reversible neuroadaptation, accelerated brain ageing, or a degeneration-like trajectory in a vulnerable subgroup. This Perspective proposes a neuroprogressive vulnerability framework-referred to as <i>cocaine-specific encephalopathy/cerebropathy</i> only in a heuristic sense-to organise heterogeneous evidence without implying a distinct neurodegenerative disease entity. <b>Methods:</b> We conducted a structured, critical synthesis of peer-reviewed human and preclinical literature (PubMed, Scopus, Web of Science; inception to December 2025), integrating neuroimaging (MRI/DTI/fMRI/PET/SPECT), neuropathology/post-mortem findings, neurochemical and molecular mechanisms, and neuropsychological outcomes, with explicit attention to confounders (polysubstance use, psychiatric and medical comorbidity, HIV, vascular risk, abstinence duration). <b>Results:</b> Convergent evidence supports a multi-hit vulnerability model in which chronic stimulant exposure may weaken neural resilience through dopaminergic dysregulation, oxidative stress, mitochondrial dysfunction, neuroinflammatory signalling, and putative α-synuclein-related mechanisms. Human imaging studies consistently implicate fronto-striato-limbic circuits and suggest possible cerebellar involvement, but findings are heterogeneous and often cross-sectional; direct evidence of progressive neuronal loss or disease-defining proteinopathies attributable to cocaine remains limited. <b>Conclusions:</b> Rather than asserting cocaine-induced classic neurodegeneration, we outline an exploratory framework in which chronic cocaine exposure may increase susceptibility to neuroprogressive impairment in a subset of biologically vulnerable individuals. Longitudinal multimodal studies combining advanced imaging, biomarkers, and phenotypic stratification are needed to clarify causality, temporal progression, and reversibility with sustained abstinence.