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Stress is a key risk factor for developing and maintaining OUD. While animal models report that the endocannabinoid system (ECS) plays a modulatory role in stress response, alterations of ECS stress reactivity in individuals with OUD have yet to be studied.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Objectives<\/jats:title>\n                    <jats:p>Here, we aimed to study the response of the ECS to experimentally-induced mild psychosocial stress in individuals with non-medical prescription opioid use (NMPOU) without intravenous use.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>\n                      We compared plasma concentrations of the two main endocannabinoids 2-arachidonoylglycerol (2-AG) and anandamide (AEA) along with structurally related\n                      <jats:italic>N<\/jats:italic>\n                      -acylethalonamines (NAEs) and arachidonic acid (AA) between individuals with chronic NMPOU (\n                      <jats:italic>n<\/jats:italic>\n                      \u2009=\u200921) and matched opioid-na\u00efve healthy controls (\n                      <jats:italic>n<\/jats:italic>\n                      \u2009=\u200929) after social exclusion using the Cyberball task. Blood samples were collected before stress induction, and 10, 20, 30, and 60\u00a0min after stress onset.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      We found a significant\n                      <jats:italic>GROUP*TIME<\/jats:italic>\n                      interaction for 2-AG, with controls showing increased 2-AG plasma levels after stress, contrasting with a blunted stress response in NMPOU. Both groups robustly differed in 2-AG levels at all time points after stress induction. No significant\n                      <jats:italic>GROUP*TIME<\/jats:italic>\n                      interactions were found for AEA, NAEs, and AA. Increased 2-AG levels were associated with greater\n                      <jats:italic>feelings of social inclusion<\/jats:italic>\n                      overall.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>Results suggest dysfunctional stress response at the level of the ECS in individuals with NMPOU. Specifically 2-AG might play a critical role in stress resilience and, thus, it might be a potential pharmacotherapeutic target in the treatment of OUD.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1007\/s00213-025-06950-4","type":"journal-article","created":{"date-parts":[[2025,11,5]],"date-time":"2025-11-05T01:11:59Z","timestamp":1762305119000},"page":"427-441","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["Endocannabinoid response to social stress in chronic non-medical prescription opioid users"],"prefix":"10.1007","volume":"243","author":[{"given":"Vinzenz K.","family":"Schmid","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Boris B.","family":"Quednow","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daniele","family":"Pellegata","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Philip","family":"Meier","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"J\u00fcrg","family":"Gertsch","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9823-5171","authenticated-orcid":false,"given":"Sara L.","family":"Kroll","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2025,11,5]]},"reference":[{"key":"6950_CR1","doi-asserted-by":"publisher","DOI":"10.1016\/J.PSYCHRES.2023.115586","volume":"330","author":"AM Aghaei","year":"2023","unstructured":"Aghaei AM, Saali A, Canas MA et al (2023) Dysregulation of the endogenous cannabinoid system following opioid exposure. 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