Network and receptor architectures shape brain morphometry in addiction

Substance use disorders (SUD) are chronic conditions with devastating effects on brain health, functioning, and survival. In this study, we compared brain morphometry of 2,782 individuals with SUD to 1,951 controls and assessed the topographic overlap of these differences with brain connectivity and receptor architecture. Across SUD, we identified a morphometric signature involving frontal, parietal, temporal and limbic systems that overlapped with cortical hub regions and harbored cortical and subcortical disease epicenters. Findings were highly consistent across six substances and numerous robustness and generalizability analyses. Transdiagnostic comparisons showed high spatial overlap of SUD epicenters with those of schizophrenia and bipolar disorder, suggesting shared network-constrained cortical differences. Finally, multivariate mapping revealed that SUD brain differences aligned with two neurotransmitter axes contrasting cannabinoid-opioid and dopaminergic systems. These findings indicate that addiction-related brain differences are shaped by connectome and neurotransmitter architecture, positioning brain network and neurochemical organization as key principles of SUD-related brain alterations.

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Publication Details

Journal
medRxiv
Published
2026-04-06
DOI
https://doi.org/10.64898/2026.04.03.26348150
Primary Topic
Functional Brain Connectivity Studies
Type
article
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article

Network and receptor architectures shape brain morphometry in addiction

Lianne Schmaal, Angelica M. Morales, Liesbeth Reneman, Reínout W. Wiers et al.
medRxiv
Functional Brain Connectivity Studies
article

Network and receptor architectures shape brain morphometry in addiction

Lianne Schmaal, Angelica M. Morales, Liesbeth Reneman, Reínout W. Wiers, Ramiro Salas, Louise M. Paterson, Janna Cousijn, Daniele Zullino, Beatrice Annunziata Milano, Anne Marije Kaag, Dick J. Veltman, Dara G. Ghahremani, Cleo L. Crunelle, Kathleen T. Brady, A. Schmidt, Paul Thompson, M Pieri, Chiang-Shan Ray Li, Roció Martin-Santos, Murat Yücel, Marc Walter, Anthony Juliano, Sara Larivière, Tristram A. Lett, Nadia Solowij, Reza Momenan, Samantha J. Brooks, Nicola Canessa, Martine M. Groefsema, Devarshi Pancholi, Julianne C. Flanagan, Amelie Haugg, E.J.E. Engeli, Foivos Georgiadis, Silke Bachmann, Enigma Addiction Working Group, Aimee Mcrae-Clark, Antonio Verdejo-García, S. L. Valk, Kent E. Hutchinson, E London, Chuan Fan, Rob Hester, F. Filbey, A. Batalla, Eduardo A. Garza-Villarreal, Anneke Goudriaan, B. Porjesz, Anne R. Lingford-Hughes, Ruth van Holst, Anouk Schrantee, Henrik Walter, Alain Dagher, Dan Stein, Sophia I. Thomopoulos, Edith Pomarol-Clotet, Justine Y. Hansen, Philipp Homan, Martin Paulus, Erich Seifritz, Maartje Luijten, Elliot Stein, Boris B. Quednow, Bratislav Misic, Valentina Lorenzetti, John J. Foxe, Marco Leyton, Marcus Herdener, Boris C. Bernhardt, Justin Boehmer, Jonathan Ipser, Vince Calhoun, Hugh Garavan, Matthias Kirschner
article en

Abstract

Substance use disorders (SUD) are chronic conditions with devastating effects on brain health, functioning, and survival. In this study, we compared brain morphometry of 2,782 individuals with SUD to 1,951 controls and assessed the topographic overlap of these differences with brain connectivity and receptor architecture. Across SUD, we identified a morphometric signature involving frontal, parietal, temporal and limbic systems that overlapped with cortical hub regions and harbored cortical and subcortical disease epicenters. Findings were highly consistent across six substances and numerous robustness and generalizability analyses. Transdiagnostic comparisons showed high spatial overlap of SUD epicenters with those of schizophrenia and bipolar disorder, suggesting shared network-constrained cortical differences. Finally, multivariate mapping revealed that SUD brain differences aligned with two neurotransmitter axes contrasting cannabinoid-opioid and dopaminergic systems. These findings indicate that addiction-related brain differences are shaped by connectome and neurotransmitter architecture, positioning brain network and neurochemical organization as key principles of SUD-related brain alterations.

medRxiv
University of Vermont (US), University of Geneva (CH), University of Southern California (US), Montreal Neurological Institute and Hospital (CA), Georgia Institute of Technology (US), National Institute on Drug Abuse (US), Vrije Universiteit Brussel (BE), Université de Sherbrooke (CA), Radboud University Nijmegen (NL), Emory University (US), Medical University of South Carolina (US), University of Cape Town (ZA), University of California, Los Angeles (US), Scuola Superiore Sant'Anna (IT), The University of Texas at Dallas (US), Oregon Health & Science University (US), The University of Melbourne (AU), Forschungszentrum Jülich (DE), Baylor College of Medicine (US), SUNY Downstate Health Sciences University (US), University of Basel (CH), Utrecht University (NL), Anhui Medical University (CN), University of Zurich (CH), University of Wollongong (AU), Istituto Universitario di Studi Superiori di Pavia (IT), University of Rochester Medical Center (US), University Medical Center Utrecht (NL), Yale University (US), ETH Zurich (CH), Düsseldorf University Hospital (DE), Centro de Investigación Biomédica en Red de Salud Mental (ES), Istituti Clinici Scientifici Maugeri (IT), University Hospital of Zurich (CH), Psychiatry Baselland (CH), University Hospital of Geneva (CH), National Institute on Alcohol Abuse and Alcoholism (US), Fidmag Sisters Hospitallers (ES), Universitair Ziekenhuis Brussel (BE), Max Planck Institute for Human Cognitive and Brain Sciences (DE), First Affiliated Hospital of Anhui Medical University (CN), IVO Addiction Research Institute (NL), Amsterdam University Medical Centers (NL), University Hospital in Halle (DE), Laureate Institute for Brain Research (US), Heinrich Heine University Düsseldorf (DE), University College London (GB), Imperial College London (GB), McGill University (CA), University of Colorado Anschutz Medical Campus (US), Monash University (AU), Liverpool John Moores University (GB), Geneva College (US), Charité - Universitätsmedizin Berlin (DE), Vrije Universiteit Amsterdam (NL), Australian Catholic University (AU), University of Amsterdam (NL), Universidad Nacional Autónoma de México (MX), Erasmus University Rotterdam (NL)
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