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Longitudinal studies linking behavioral manifestations in CUD to the blood transcriptome are not only limited but also computationally complex. Therefore, we developed an analytical pipeline to investigate the connection between drug use behaviors during abstinence and change in the blood transcriptome. We conducted a longitudinal study with CUD (\n                    <jats:italic>n<\/jats:italic>\n                    \u2009=\u200912 subjects) and collected behavioral metrics and blood RNA\u2010seq at baseline, 3, 6, and 9\u2009months. Our analytical pipeline of the high\u2010dimensional data encompasses hierarchical k\u2010means clustering to classify subjects to responder groups based on behavioral scores and abstinence duration, in silico cell deconvolution, differential analysis with correlated multivariate testing over time, gene set enrichment analysis, and gene co\u2010expression with time splines and RNA\u2010seq data. The pipeline captured dynamic changes in behavioral scores and abstinence duration in responder groups. Genes showing differential transcript\u2010level expression were enriched in substance use and cardiovascular disease\u2010associated genetic risk loci in responder groups. Lastly, time\u2010dependent gene co\u2010expression revealed dynamic changes related to immune processes, cell cycle, RNA\u2010protein synthesis, and second messenger signaling for days of abstinence. This is a preliminary investigation, providing an innovative and scalable pipeline for blood\u2010based longitudinal RNA\u2010seq studies in CUD, potentially applicable to other substance use disorders. It outlines a data\u2010driven approach for analyzing composite longitudinal drug use behavioral phenotypes with blood\u2010based transcriptomics. We also demonstrate changes in drug use behaviors and the blood transcriptome during drug abstinence.\n                  <\/jats:p>","DOI":"10.1111\/ejn.70409","type":"journal-article","created":{"date-parts":[[2026,2,7]],"date-time":"2026-02-07T02:30:13Z","timestamp":1770431413000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Dynamic Alterations in the Blood Transcriptome Characterize Drug Use Behavior and Co\u2010Morbidities in Cocaine Use Disorder: A Preliminary Study"],"prefix":"10.1111","volume":"63","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-8792-0886","authenticated-orcid":false,"given":"Chinwe","family":"Nwaneshiudu","sequence":"first","affiliation":[{"name":"Department of Anesthesiology, Perioperative and Pain Medicine, Mount Sinai Health System Icahn School of Medicine at Mount Sinai  New York New York USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kiran","family":"Girdhar","sequence":"additional","affiliation":[{"name":"Department of Psychiatry Icahn School of Medicine at Mount Sinai  New York New York USA"},{"name":"Department of Genetics and Genomic Science Icahn School of Medicine at Mount Sinai  New York New York USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Steven\u00a0P.","family":"Kleopoulos","sequence":"additional","affiliation":[{"name":"Department of Psychiatry Icahn School of Medicine at Mount Sinai  New York New York USA"},{"name":"Department of Genetics and Genomic Science Icahn School of Medicine at Mount Sinai  New York New York USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Zhiping","family":"Shao","sequence":"additional","affiliation":[{"name":"Department of Psychiatry Icahn School of Medicine at Mount Sinai  New York New York USA"},{"name":"Department of Genetics and Genomic Science Icahn School of Medicine at Mount Sinai  New York New York USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"John\u00a0F.","family":"Fullard","sequence":"additional","affiliation":[{"name":"Department of Psychiatry Icahn School of Medicine at Mount Sinai  New York New York USA"},{"name":"Department of Genetics and Genomic Science Icahn School of Medicine at Mount Sinai  New York New York USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Eduardo\u00a0R.","family":"Butelman","sequence":"additional","affiliation":[{"name":"Department of Psychiatry Icahn School of Medicine at Mount Sinai  New York New York USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Muhammad\u00a0A.","family":"Parvaz","sequence":"additional","affiliation":[{"name":"Department of Psychiatry Icahn School of Medicine at Mount Sinai  New York New York USA"},{"name":"Department of Artificial Intelligence and Human Health Icahn School of Medicine at Mount Sinai  New York New York USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Rita\u00a0Z.","family":"Goldstein","sequence":"additional","affiliation":[{"name":"Department of Psychiatry Icahn School of Medicine at Mount Sinai  New York New York USA"},{"name":"Department of Neuroscience Icahn School of Medicine at Mount Sinai  New York New York USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Nelly","family":"Alia\u2010Klein","sequence":"additional","affiliation":[{"name":"Department of Psychiatry Icahn School of Medicine at Mount Sinai  New York New York USA"},{"name":"Department of Neuroscience Icahn School of Medicine at Mount Sinai  New York New York USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Panos","family":"Roussos","sequence":"additional","affiliation":[{"name":"Department of Psychiatry Icahn School of Medicine at Mount Sinai  New York New York USA"},{"name":"Department of Genetics and Genomic Science Icahn School of Medicine at Mount Sinai  New York New York USA"},{"name":"Department of Neuroscience Icahn School of Medicine at Mount Sinai  New York New York USA"},{"name":"Mental Illness Research Education and Clinical Center (MIRECC) James J. 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