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Mechanistic investigation in humans remains constrained by ethical limitations, uncontrolled exposure histories, and ecological confounds. Parkinson's disease treated with dopamine replacement therapy provides a human framework for investigating addiction\u2010relevant mechanisms under controlled dopaminergic modulation. We performed a narrative synthesis of clinical, neuropsychological, pharmacological, neuroimaging, and electrophysiological evidence linking impulse control disorders and dopamine dysregulation syndrome in Parkinson's disease to dimensional and circuit\u2010based models of addiction. We examined phenotypic and neurobiological convergences, experimental opportunities, and translational relevance while outlining its boundary conditions. A subset of Parkinson's disease patients exposed to dopamine replacement treatment develops impulse control disorders and dopamine dysregulation syndrome. Impulse control disorders comprise heterogeneous behavioral phenotypes that share selected dimensions with behavioral addictions, whereas dopamine dysregulation syndrome most closely approximates pharmacological substance use disorders. These phenotypes share selected addiction\u2010related dimensions, including craving, impaired control, compulsive reward\u2010seeking, and persistence despite harm, while showing partial clinical and neurobiological convergence with behavioral addictions and substance use disorders. Parkinson's disease patients with neuropsychiatric fluctuations may represent a sensitized vulnerability state in which dopaminergic modulation dynamically influences reward processing, motivation, and compulsive behaviors. Parkinson's disease under dopamine replacement therapy enables within\u2010subject dopaminergic manipulation, longitudinal observation, prospective assessment of vulnerability traits, multimodal neurobiological investigation, and reduced environmental confounding. It therefore provides a unique human window for investigating addiction\u2010relevant mechanisms under controlled dopaminergic modulation, complementing animal models while remaining constrained by disease\u2010specific boundary conditions.<\/jats:p>","DOI":"10.1111\/pcn.70118","type":"journal-article","created":{"date-parts":[[2026,8,12]],"date-time":"2026-08-12T06:55:52Z","timestamp":1786517752000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Parkinson's disease under dopamine replacement therapy as a human framework for studying addiction\u2010relevant mechanisms"],"prefix":"10.1111","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-5744-6829","authenticated-orcid":false,"given":"Vanessa","family":"Fleury","sequence":"first","affiliation":[{"name":"Department of Neurology Geneva University Hospital  Geneva Switzerland"},{"name":"Faculty of Medicine University of Geneva, Rue Michel\u2010Servet 1  Geneva Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elvira","family":"Pirondini","sequence":"additional","affiliation":[{"name":"Rehabilitation Neural Engineering Laboratories University of Pittsburgh  Pittsburgh Pennsylvania USA"},{"name":"Physical Medicine and Rehabilitation University of Pittsburgh  Pittsburgh Pennsylvania USA"},{"name":"Bioengineering University of Pittsburgh  Pittsburgh Pennsylvania USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Damien","family":"Benis","sequence":"additional","affiliation":[{"name":"Department of Neurology Geneva University Hospital  Geneva Switzerland"},{"name":"Neuroscience of Emotion and Affective Lab University of Geneva  Geneva Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tiffany","family":"Corbet","sequence":"additional","affiliation":[{"name":"Department of Neurology Geneva University Hospital  Geneva Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gabriel","family":"Thorens","sequence":"additional","affiliation":[{"name":"Addictology Division, Mental Health and Psychiatry Department Geneva University Hospital  Geneva Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christian","family":"L\u00fcscher","sequence":"additional","affiliation":[{"name":"Department of Neurology Geneva University Hospital  Geneva Switzerland"},{"name":"Faculty of Medicine University of Geneva, Rue Michel\u2010Servet 1  Geneva Switzerland"},{"name":"Department of Basic Neurosciences, Faculty of Medicine University of Geneva  Geneva Switzerland"},{"name":"Synapsy Center for Mental Health Research University of Geneva  Geneva Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Paul","family":"Krack","sequence":"additional","affiliation":[{"name":"Department of Neurology Inselspital, University Hospital Bern, University of Bern  Bern Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2026,8,11]]},"reference":[{"key":"e_1_2_13_2_1","doi-asserted-by":"crossref","first-page":"834","DOI":"10.1176\/appi.ajp.2013.12060782","article-title":"DSM\u20105 criteria for substance use disorders: Recommendations and rationale","volume":"170","author":"Hasin DS","year":"2013","journal-title":"Am. 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