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The aim of this study was to investigate neuroinflammation, neuronal damage and potential changes in the orexin system or beta\u2010amyloid metabolism in the cerebrospinal fluid (CSF) of individuals undergoing opioid substitution therapy (OST). This cross\u2010sectional study investigates CSF biomarkers in individuals undergoing OST, compared to control subjects. Participants receiving OST were recruited from the outpatient clinic at the Department of Psychiatry, Sahlgrenska University Hospital, Gothenburg (Sweden). Each participant provided a complete medical history, including details of drug use over the past 6 months, followed by a lumbar puncture to obtain CSF samples. Molecules associated with neuroinflammation, neuronal and glial damage, beta\u2010amyloid metabolism and orexinergic function were analysed in the participants' CSF, alongside electrolyte levels. Specifically, we analysed levels of sTREM\u20102, YKL\u201040, IL\u20101\u03b2, IL\u20106, IL\u20108, IL\u201010, TNF\u2010\u03b1, AXL, MER, TYRO3, GAS6, NfL, GFAP, total tau (T\u2010tau), phosphorylated tau (P\u2010tau), neurogranin, A\u03b240, A\u03b242, the A\u03b242\/A\u03b240 ratio, orexin\u2010A, sPDGFR\u2010\u03b2 and electrolytes. The study included 15 control subjects and 17 in the opioid substitution group. Patients undergoing opioid substitution therapy exhibited elevated levels of sTREM\u20102, A\u03b242\/A\u03b240 ratio and NfL in their CSF. Conversely, concentrations of Na<jats:sup>+<\/jats:sup> and Cl<jats:sup>\u2212<\/jats:sup> were lower compared to controls. No significant differences were found between groups for other biomarkers, including orexin\u2010A. However, when normalized to A\u03b240 levels, YKL\u201040, IL\u20108, TYRO3 and P\u2010Tau were also elevated in individuals with opioid dependence. Elevated biomarkers of neuroimmune activation, neuronal damage and beta\u2010amyloid metabolism in opioid dependence suggest CNS inflammation as a contributor to its pathophysiology. Reduced electrolyte levels imply disrupted CSF water regulation, possibly linked to impaired glial function. These findings highlight both neural and non\u2010neural mechanisms in opioid dependence.<\/jats:p>","DOI":"10.1111\/adb.70053","type":"journal-article","created":{"date-parts":[[2025,6,2]],"date-time":"2025-06-02T11:33:06Z","timestamp":1748863986000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Cerebrospinal Fluid Biomarkers in Opioid Dependence: Evidence of Neuroimmune Activation and Ion Composition Changes, Without Alteration in Orexin\u2010A"],"prefix":"10.1111","volume":"30","author":[{"given":"Tim","family":"Lyckenvik","sequence":"first","affiliation":[{"name":"Department of Physiology Institute of Neuroscience and Physiology, Sahlgrenska Academy at the University of Gothenburg  Gothenburg Sweden"},{"name":"Department of Neurology Sahlgrenska University Hospital  Gothenburg 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