Year: 2026
Type: preprint
Study design: Observational Study
Abstract: Substance use disorders (SUD) are associated with widespread brain structural alterations, but the principles governing their regional distribution remain unclear. We tested whether SUD-related morphometric differences are shaped by normative connectivity and neurotransmitter receptor architecture. We analysed T1-weighted MRI data from 2,782 individuals with SUD (mean age 34.6 years [SD 11.2]; 33.3% female) and 1,951 healthy controls (mean age 33.8 years [SD 12.0]; 37.5% female) across 51 ENIGMA Addiction Working Group sites, spanning alcohol, amphetamine, cannabis, cocaine, nicotine and opioid use disorders. Cortical thickness (68 regions) and subcortical volume (14 structures) were quantified using harmonized ENIGMA protocols. Case-control maps were related to normative functional and structural connectomes through hub-vulnerability and epicenter analyses, and to 20 PET-derived receptor-density maps using partial least squares analysis. Across substances, SUD was associated with lower cortical thickness and subcortical volume involving frontal, parietal, temporal and limbic regions. Alterations overlapped with cortical hubs and converged on cortical and subcortical epicenters, with findings robust across six substances, biological sex and analytical approaches. SUD epicenters showed strong spatial overlap with those of schizophrenia and bipolar disorder, particularly in frontotemporal, parietal and striatal regions, distinct from mood, neurodevelopmental and obsessive-compulsive conditions. Cortical alteration patterns aligned with two neurochemical axes: one enriched in cannabinoid, opioid, metabotropic glutamate and histamine receptors, and another associated with lower dopaminergic and cholinergic marker density. These findings indicate that addiction-related brain differences are organized by normative connectome and neurotransmitter architecture, providing a systems-level framework for identifying receptor- and circuit-based targets for intervention in addiction.
Source: medRxiv
Authors: Foivos Georgiadis, Beatrice A. Milano, Sara Larivière, Kent E. Hutchinson, Vince Calhoun, Chiang-Shan Ray Li, Reza Momenan, Rajita Sinha, Dick Veltman, Ruth van Holst, Anneke Goudriaan, Maartje Luijten, Martine Groefsema, Henrik Walter, Tristram Lett, Reinout Wiers, Lianne Schmaal, Julianne Flanagan, Bernice Porjesz, Jonathan Ipser, Justin Boehmer, Nicola Canessa, Ramiro Salas, Edythe London, Martin Paulus, Dan Stein, Samantha Brooks, Liesbeth Reneman, Anouk Schrantee, Francesca Filbey, Rob Hester, Murat Yücel, Valentina Lorenzetti, Nadia Solowij, Rocío Martín-Santos, Albert Batalla, Janna Cousijn, Edith Pomarol-Clotet, Eduardo A. Garza-Villarreal, Marco Leyton, Elliot Stein, Cleo L. Crunelle, Anne M. Kaag, Antonio Verdejo-Garcia, John J. Foxe, Kathleen T. Brady, Aimee McRae-Clark, Alain Dagher, Amelie Haugg, Marc Walter, André Schmidt, Anne Lingford-Hughes, Louise M. Paterson, Angelica M. Morales, Dara G. Ghahremani, Chuan Fan, Etna J. E. Engeli, Marcus Herdener, Boris B. Quednow, Erich Seifritz, Philipp Homan, Marco De Pieri, Silke Bachmann, Daniele Zullino, Justine Y. Hansen, Bratislav Misic, Sophia I. Thomopoulos, Paul M. Thompson, Devarshi Pancholi, Anthony Juliano, Hugh Garavan, Sofie L. Valk, Boris C. Bernhardt, Matthias Kirschner, ENIGMA Addiction Working Group
Institutions: University of Zurich, Psychiatrische Universitätsklinik Zürich, Scuola Superiore Sant'Anna, University Hospital of Geneva, Université de Sherbrooke, University of Colorado Anschutz, Georgia Institute of Technology, Emory University, Yale University, National Institutes of Health, National Institute on Alcohol Abuse and Alcoholism, Amsterdam University Medical Centers, University of Amsterdam, Radboud University Nijmegen, Charité - Universitätsmedizin Berlin, The University of Melbourne, Medical University of South Carolina, SUNY Downstate Health Sciences University, University of Cape Town, Istituto Universitario di Studi Superiori di Pavia, Istituti Clinici Scientifici Maugeri, Baylor College of Medicine, University of California, Los Angeles, Laureate Institute for Brain Research, Liverpool John Moores University, The University of Texas at Dallas, Monash University, University College London, Australian Catholic University, University of Wollongong, Centro de Investigación Biomédica en Red de Salud Mental, Consorci Institut D'Investigacions Biomediques August Pi I Sunyer, Utrecht University, University Medical Center Utrecht, Erasmus University Rotterdam, Fidmag Sisters Hospitallers, Universidad Nacional Autónoma de México, Montreal Neurological Institute and Hospital, McGill University, National Institute on Drug Abuse, Vrije Universiteit Brussel, Universitair Ziekenhuis Brussel, Vrije Universiteit Amsterdam, University of Rochester Medicine, University of Rochester, University of Basel, Imperial College London, Oregon Health & Science University, First Affiliated Hospital of Anhui Medical University, ETH Zurich, University Hospital in Halle, University of Geneva, University of Southern California, University of Vermont, Forschungszentrum Jülich, Düsseldorf University Hospital, Max Planck Institute for Human Cognitive and Brain Sciences, Heinrich Heine University Düsseldorf
Language: English
Subfield: Cognitive Neuroscience
Field: Neuroscience
Domain: Life Sciences
Open Access status: green
OpenAlex ID: W7150983576
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