Network and receptor architectures shape brain morphometry in addiction

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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.

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