{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,7]],"date-time":"2026-10-07T07:25:16Z","timestamp":1791357916410,"version":"4.3.1"},"reference-count":255,"publisher":"MDPI AG","issue":"6","license":[{"start":{"date-parts":[[2026,3,14]],"date-time":"2026-03-14T00:00:00Z","timestamp":1773446400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["JCM"],"abstract":"<jats:p>Background: 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\u2014referred to as cocaine-specific encephalopathy\/cerebropathy only in a heuristic sense\u2014to organise heterogeneous evidence without implying a distinct neurodegenerative disease entity. Methods: 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). Results: 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 \u03b1-synuclein\u2013related mechanisms. Human imaging studies consistently implicate fronto\u2013striato\u2013limbic 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. Conclusions: 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.<\/jats:p>","DOI":"10.3390\/jcm15062222","type":"journal-article","created":{"date-parts":[[2026,3,16]],"date-time":"2026-03-16T08:41:26Z","timestamp":1773650486000},"page":"2222","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["From Neuroadaptation to Neuroprogression: Rethinking Chronic Cocaine Exposure Through a Model of Cocaine-Related Cerebropathy"],"prefix":"10.3390","volume":"15","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-7457-6008","authenticated-orcid":false,"given":"Manuel Glauco","family":"Carbone","sequence":"first","affiliation":[{"name":"Division of Psychiatry, Department of Medicine and Surgery, University of Insubria, Viale Luigi Borri 57, 21100 Varese, Italy"},{"name":"VP Dole Research Group, G. De Lisio Institute of Behavioural Sciences, Via di Pratale, 3, 56121 Pisa, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6324-0576","authenticated-orcid":false,"given":"Icro","family":"Maremmani","sequence":"additional","affiliation":[{"name":"VP Dole Research Group, G. De Lisio Institute of Behavioural Sciences, Via di Pratale, 3, 56121 Pisa, Italy"},{"name":"Department Faculty of Medicine, Saint Camillus International University of Health Sciences, Via di Sant\u2019Alessandro 8, 00131 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7935-3524","authenticated-orcid":false,"given":"Filippo","family":"Della Rocca","sequence":"additional","affiliation":[{"name":"VP Dole Research Group, G. De Lisio Institute of Behavioural Sciences, Via di Pratale, 3, 56121 Pisa, Italy"},{"name":"Addiction Unit, Department of Mental Health and Addictions, ASL 5 Liguria NHS, Via Dalmazia 1, 19124 La Spezia, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0000-8279-3144","authenticated-orcid":false,"given":"Giulia","family":"Gastaldello","sequence":"additional","affiliation":[{"name":"Division of Psychiatry, Department of Medicine and Surgery, University of Insubria, Viale Luigi Borri 57, 21100 Varese, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0004-0338-9434","authenticated-orcid":false,"given":"Luca","family":"Mazzetto","sequence":"additional","affiliation":[{"name":"Division of Psychiatry, Department of Medicine and Surgery, University of Insubria, Viale Luigi Borri 57, 21100 Varese, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alessandro","family":"Bellini","sequence":"additional","affiliation":[{"name":"Division of Psychiatry, Department of Medicine and Surgery, University of Insubria, Viale Luigi Borri 57, 21100 Varese, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Roberta","family":"Rizzato","sequence":"additional","affiliation":[{"name":"Psychiatry Unit, Department of Mental Health, Addiction Prevention and Treatment, ASST Sette Laghi\u2014Ospedale di Circolo e Fondazione Macchi, Viale Luigi Borri 57, 21100 Varese, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rossella","family":"Miccich\u00e8","sequence":"additional","affiliation":[{"name":"Psychiatry Unit, Department of Mental Health, Addiction Prevention and Treatment, ASST Sette Laghi\u2014Ospedale di Circolo e Fondazione Macchi, Viale Luigi Borri 57, 21100 Varese, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2184-5240","authenticated-orcid":false,"given":"Beniamino","family":"Tripodi","sequence":"additional","affiliation":[{"name":"Division of Psychiatry, Department of Medicine and Surgery, University of Insubria, Viale Luigi Borri 57, 21100 Varese, Italy"},{"name":"Division of Psychiatry, Department of Mental Health and Addictions, ASST Crema, Via Largo Ugo Dossena 2, 26013 Crema, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Claudia","family":"Tagliarini","sequence":"additional","affiliation":[{"name":"Psychiatric Diagnosis and Treatment Service, Department of Mental Health, Sant\u2019Elia Hospital, ASP 2 Caltanissetta, 93100 Caltanissetta, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7211-5689","authenticated-orcid":false,"given":"Maurice","family":"Dematteis","sequence":"additional","affiliation":[{"name":"Department of Pharmacology and Addiction Medicine, Faculty of Medicine, Grenoble Alpes University Hospital, Grenoble Institute of Neurosciences, Universit\u00e9 Grenoble Alpes, INSERM U1216, Site Sant\u00e9\u2014All\u00e9e des Alpes, 38000 Grenoble, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7728-3705","authenticated-orcid":false,"given":"Angelo Giovanni Icro","family":"Maremmani","sequence":"additional","affiliation":[{"name":"VP Dole Research Group, G. 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