{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"medRxiv"}],"indexed":{"date-parts":[[2026,3,25]],"date-time":"2026-03-25T14:24:30Z","timestamp":1774448670494,"version":"3.50.1"},"posted":{"date-parts":[[2026,3,23]]},"group-title":"Psychiatry and Clinical Psychology","reference-count":56,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2026,3,23]],"date-time":"2026-03-23T00:00:00Z","timestamp":1774224000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2026,3,23]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                <jats:sec>\n                  <jats:title>Importance<\/jats:title>\n                  <jats:p>Polysubstance use is common, but substance use associations with neuroimaging measures have largely been investigated within individual drug types. Whether effects are substance-specific or -general, and how predispositional risk and exposure contribute, remains unclear.<\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>Objective<\/jats:title>\n                  <jats:p>Identify shared and unique associations between substance use and brain structure, and characterize the contributions of predispositional risk and environmental exposure, in a large sample of young adults in the US.<\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>Design<\/jats:title>\n                  <jats:p>This cross-sectional family-based study used data from the Human Connectome Project (2017 release, collected from 2012-2015).<\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>Setting<\/jats:title>\n                  <jats:p>Data were collected at Washington University in St. Louis, MO, USA.<\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>Participants<\/jats:title>\n                  <jats:p>Twins, non-twin siblings, and singletons with magnetic resonance imaging (MRI) and substance use self-report were included in the analysis. Data were analyzed in 2025.<\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>Exposure<\/jats:title>\n                  <jats:p>History of substance use was assessed using the Semi-Structured Assessment for the Genetics of Alcoholism. Variables included lifetime use, heavy or past-year hazardous use, and age of use onset for alcohol, marijuana, tobacco, and illicit drugs. Additionally, alcohol and marijuana dependence were assessed.<\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>Main Outcomes and Measures<\/jats:title>\n                  <jats:p>Linear mixed-effect models examined associations between substance use and brain structure, with an initial focus on past-year hazardous alcohol use, as 95% of the sample endorsed lifetime alcohol use. Analyses then tested associations with other substance use variables, and whether effects were shared or substance-specific. Between-family, within-family, and genetic variance component analyses tested risk and exposure effects.<\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>Results<\/jats:title>\n                  <jats:p>\n                    1,113 participants (N = 445 families; ages 22 - 37;\n                    <jats:italic>M=<\/jats:italic>\n                    28.8,\n                    <jats:italic>SD<\/jats:italic>\n                    =3.7) had no missing data for the primary analyses. Hazardous alcohol use was negatively associated with global brain thickness (\n                    <jats:italic>\u03b2<\/jats:italic>\n                    = \u22120.12,\n                    <jats:italic>p<\/jats:italic>\n                    &lt; 0.001), which explained all other regional and global associations. Of the drugs with a shared-effect on global brain thickness, only lifetime marijuana use explained unique variance over alcohol (\n                    <jats:italic>\u03b2<\/jats:italic>\n                    = \u22120.08,\n                    <jats:italic>p<\/jats:italic>\n                    = 0.013). Within-family analyses found evidence for unique putative exposure effects of both alcohol (\n                    <jats:italic>\u03b2<\/jats:italic>\n                    = \u22120.11,\n                    <jats:italic>p<\/jats:italic>\n                    &lt; 0.001) and marijuana use (\n                    <jats:italic>\u03b2<\/jats:italic>\n                    = \u22120.07,\n                    <jats:italic>p<\/jats:italic>\n                    = 0.002) on global thickness. Marijuana use further showed a predispositional effect, both in between-family comparisons (\n                    <jats:italic>\u03b2<\/jats:italic>\n                    = \u22120.11,\n                    <jats:italic>p<\/jats:italic>\n                    = 0.007) and genetic variance component analyses (\n                    <jats:italic>\u03c1G<\/jats:italic>\n                    = \u22120.2\n                    <jats:italic>, p<\/jats:italic>\n                    = 0.004), which were not explained by alcohol use.\n                  <\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>Conclusions and Relevance<\/jats:title>\n                  <jats:p>Brain structural associations with substance use reflect substance-general and -specific effects, as well as a combination of predispositional and exposure effects. Findings suggest that the negative consequences of polysubstance use may reflect the additive effects of multiple unique exposures.<\/jats:p>\n                <\/jats:sec>","DOI":"10.64898\/2026.03.20.26348897","type":"posted-content","created":{"date-parts":[[2026,3,24]],"date-time":"2026-03-24T04:55:27Z","timestamp":1774328127000},"source":"Crossref","is-referenced-by-count":0,"title":["Brain Structure and Substance Use: Disentangling Risk, Exposure, and Drug-Specific Effects"],"prefix":"10.64898","author":[{"ORCID":"https:\/\/orcid.org\/0009-0002-5005-0148","authenticated-orcid":false,"given":"Daniella A","family":"Fernandez","sequence":"first","affiliation":[{"name":"Department of Pharmacology and Toxicology, Medical College of Wisconsin, Milwaukee, WI"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6659-357X","authenticated-orcid":false,"given":"David AA","family":"Baranger","sequence":"additional","affiliation":[{"name":"Department of Pharmacology and Toxicology, Medical College of Wisconsin, Milwaukee, WI"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"54368","reference":[{"key":"2026032505500691000_2026.03.20.26348897v1.1","doi-asserted-by":"publisher","DOI":"10.2105\/AJPH.2024.307979"},{"key":"2026032505500691000_2026.03.20.26348897v1.2","unstructured":"Substance Abuse and Mental Health Services Administration. 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