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

## TL;DR

This paper explores how chronic cocaine use may lead to brain changes resembling neurodegeneration in some individuals, suggesting a need for better research on how and why this happens.

## Contribution

The paper introduces a new framework for understanding cocaine-related brain vulnerability as a potential neuroprogressive condition rather than classic neurodegeneration.

## Key findings

- Chronic cocaine exposure may weaken neural resilience through mechanisms like dopaminergic dysregulation and oxidative stress.
- Human imaging studies show consistent involvement of fronto–striato–limbic circuits but lack evidence of progressive neuronal loss.
- The paper advocates for longitudinal studies to clarify the progression and reversibility of cocaine-related brain changes.

## Abstract

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—referred to as cocaine-specific encephalopathy/cerebropathy only in a heuristic sense—to 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 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. 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.