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Although regular CU beginning in adolescence is expected to blunt dopamine-related neurophysiology, this hypothesis has not been tested in adolescents due to methodological limitations. However, neurophysiology contributing to dopamine can be noninvasively indexed via subcortical tissue iron measured with magnetic resonance imaging (MRI). We examined adolescent CU quantity, frequency, and problems in relation to tissue iron in regions with high dopamine activity, hypothesizing that greater CU would be linked to less tissue iron. Adolescents (\n                    <jats:italic>n<\/jats:italic>\n                    \u2009=\u200981; 64.2% female) aged 14\u201317 reporting either fewer than 5 lifetime cannabis episodes (\n                    <jats:italic>n<\/jats:italic>\n                    \u2009=\u200947) or more than 11 episodes (\n                    <jats:italic>n<\/jats:italic>\n                    \u2009=\u200934), with limited alcohol and nicotine use and no other illicit substance use, completed substance use assessments and an MRI. We calculated the inverse of the normalized T2* measurement (1\/nT2*; lower values indicate less tissue iron) from resting-state functional scans by assessing relative T2* decay. 1\/nT2* was estimated using subcortical masks for hypothesized regions. Lower 1\/nT2* signal was associated with increased daily concentrate hits (\n                    <jats:italic>b<\/jats:italic>\n                    \u2009=\u2009\u20130.01,\n                    <jats:italic>p<\/jats:italic>\n                    \u2009&lt;\u20090.001), cannabis hours high (\n                    <jats:italic>b<\/jats:italic>\n                    \u2009=\u2009\u20130.01,\n                    <jats:italic>p<\/jats:italic>\n                    \u2009=\u20090.016), CU frequency (\n                    <jats:italic>b<\/jats:italic>\n                    \u2009=\u2009-0.01,\n                    <jats:italic>p<\/jats:italic>\n                    \u2009=\u20090.01), and cannabis use disorder (CUD) severity (\n                    <jats:italic>b<\/jats:italic>\n                    \u2009=\u2009\u20130.01,\n                    <jats:italic>p<\/jats:italic>\n                    \u2009=\u20090.003). Post-hoc analyses highlighted the VTA as a key region. Results align with reduced dopamine-related neurophysiology associated with CU in adult and animal samples, and have implications for understanding adolescent CUD development. Measuring 1\/nT2* offers an innovative, non-invasive method to index neurobiological alterations in adolescent CU.\n                  <\/jats:p>","DOI":"10.1038\/s41386-026-02444-9","type":"journal-article","created":{"date-parts":[[2026,6,2]],"date-time":"2026-06-02T17:41:02Z","timestamp":1780422062000},"page":"2152-2162","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["The role of subcortical brain tissue iron as an indicator of dopamine neurophysiology in adolescent cannabis use"],"prefix":"10.1038","volume":"51","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-6508-3973","authenticated-orcid":false,"given":"Sarah A.","family":"Thomas","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Meghan A.","family":"Gonsalves","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gillian","family":"LeBlanc","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elizabeth","family":"Lorenc","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jane","family":"Metrik","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8451-0523","authenticated-orcid":false,"given":"Michael","family":"Frank","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sarah","family":"Ryan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Emily","family":"Olenik","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Leslie","family":"Brick","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anthony","family":"Spirito","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5180-6694","authenticated-orcid":false,"given":"Jodi","family":"Gilman","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,6,2]]},"reference":[{"key":"2444_CR1","doi-asserted-by":"publisher","unstructured":"Adams ZW, Dellucci TV, Agley J, Bixler K, Sullivan M, Hinckley JD, et al. 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