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.

Background: Attention-Deficit/Hyperactivity Disorder (ADHD) in adults is frequently accompanied by psychiatric comorbidities that worsen outcomes and complicate treatment. Pharmacological management is central in care, yet its impact on co-occurring disorders remains uncertain. This systematic review evaluated the effectiveness of commonly prescribed medications for adult ADHD (methylphenidate, atomoxetine, bupropion, and lisdexamfetamine) on comorbid mood, anxiety, personality, and substance use disorders. Tricyclic antidepressants were also included in the search strategy; however, no eligible adult studies assessing imipramine or desipramine in patients with ADHD and psychiatric comorbidity were identified. Methods: A systematic search of the literature was conducted to identify studies examining these medications in adults with ADHD and at least one psychiatric comorbidity. Eligible studies reported clinical outcomes for both ADHD symptoms and the co-occurring disorder. Data were extracted and narratively synthesized, with particular attention paid to treatment effects and sources of heterogeneity. Results: Across the included studies, pharmacological treatments consistently improved core ADHD symptomatology. Their effects on psychiatric comorbidity were more variable. Some evidence suggested beneficial outcomes for selected anxiety disorder subtypes and for features of Cluster B personality disorders, possibly related to reductions in emotional dysregulation and impulsivity. Findings regarding substance use disorders were mixed: several studies reported reduced craving or substance use, but long-term stabilization was inconsistent. Marked heterogeneity in study design, populations, and outcome measures limited comparability. Conclusions: Current pharmacological treatments for adult ADHD show reliable efficacy for core symptoms but inconsistent benefits across comorbid psychiatric conditions. While targeted improvements may occur in specific domains, the evidence base is insufficient to define optimal long-term strategies for adults with ADHD and complex comorbidity. Rigorous, longitudinal studies are needed to clarify medication effects on distinct comorbid profiles and to inform integrated treatment planning.

Background: Attention-Deficit/Hyperactivity Disorder (ADHD) in adulthood is frequently associated with complex psychiatric comorbidity, including high rates of Substance Use Disorders (SUDs), which may influence treatment outcomes. Although pharmacological treatments are effective for core ADHD symptoms, real-world response remains heterogeneous, and the contribution of specific substance-related and neurodevelopmental factors to treatment response is not fully understood. Methods: This retrospective observational study examined a real-world cohort of 67 adults with ADHD treated pharmacologically in a specialized outpatient setting. ADHD was diagnosed according to DSM-5-TR criteria using the Diagnostic Interview for ADHD in Adults (DIVA-5). Autism spectrum disorder (ASD) was recorded based on documented pre-existing specialist diagnoses and confirmed clinically at baseline. Psychiatric comorbidities and substance use disorders, including alcohol and cannabis use disorders, were assessed according to DSM-5-TR criteria. Clinical response was defined using the Clinical Global Impression–Improvement scale (CGI-I; responders = scores 1–3). Exploratory binary logistic regression analyses were used to identify clinical factors associated with treatment response. Given the limited sample size, revised multivariable models were specified parsimoniously on the basis of a priori clinical relevance. Results: At follow-up, 48 of 67 patients (71.6%) met criteria for clinical response. In revised parsimonious multivariable models, alcohol use disorder (OR ≈ 0.08–0.10, p = 0.010–0.026) and cannabis use disorder (OR ≈ 0.20–0.24, p = 0.014–0.028) were consistently associated with reduced odds of clinical response. Autism spectrum disorder showed a descriptive trend toward lower response rates but did not retain statistical significance after adjustment (p ≈ 0.11–0.15). Conclusions: In adults with ADHD treated in routine clinical practice, alcohol and cannabis use disorders were associated with a reduced likelihood of achieving clinically meaningful improvement under routine pharmacological care, whereas autism spectrum disorder showed a trend toward lower response that was not stable enough to support firm conclusions. These findings should be considered exploratory given the retrospective design, limited sample size, and lack of systematic treatment exposure measures.

Background: Chronic pain, opioid use, and mental health disorders frequently co-occur in older adults, forming a complex and mutually reinforcing triad. Neurobiological ageing processes—such as neuroinflammation, dopaminergic decline, and impaired top-down regulation—may increase vulnerability to maladaptive coping strategies, including opioid misuse. This review aims to integrate neurobiological, affective, and clinical evidence to propose a unified neuropsychiatric framework for understanding the intersection between chronic pain, emotional distress, and opioid vulnerability in later life, while highlighting implications for integrated treatment and opioid stewardship. Methods: This structured narrative review synthesised interdisciplinary evidence from neuroscience, geriatric psychiatry, and pain medicine. The literature was thematically organised to examine shared neurobiological and psychosocial mechanisms underlying chronic pain, affective disorders, and opioid use disorder (OUD) in older adults, with attention to treatment strategies and stewardship principles. Results: Converging evidence suggests a neuroprogressive continuum linking chronic pain, emotional distress, opioid misuse, and cognitive decline. Key mechanisms include frontolimbic dysfunction, impaired reward processing, and chronic allostatic load. Therapeutic approaches that integrate analgesia with emotional regulation—such as buprenorphine, serotonin–noradrenaline reuptake inhibitors (SNRIs), and multimodal tapering strategies—may offer neuroprotective benefits. Effective opioid stewardship appears to require integrated functional, cognitive, and affective monitoring. Conclusions: Pain management in older adults may benefit from moving beyond symptom-focused approaches toward a neuropsychiatric model of care aimed at preserving homeostatic balance across sensory, emotional, and motivational domains. Within this framework, opioid therapy can be conceptualised as a potential means of functional and neuroaffective restoration, rather than solely as a strategy for risk reduction.