{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"bioRxiv"}],"indexed":{"date-parts":[[2026,7,30]],"date-time":"2026-07-30T12:45:23Z","timestamp":1785415523719,"version":"3.56.0"},"posted":{"date-parts":[[2026,2,26]]},"group-title":"Neuroscience","reference-count":69,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2026,2,26]],"date-time":"2026-02-26T00:00:00Z","timestamp":1772064000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/www.biorxiv.org\/about\/FAQ#license"}],"funder":[{"award":["PJT183703"],"award-info":[{"award-number":["PJT183703"]}],"id":[{"id":"https:\/\/ror.org\/01gavpb45","id-type":"ROR","asserted-by":"publisher"}]},{"award":["Pain NeuroImaging"],"award-info":[{"award-number":["Pain NeuroImaging"]}],"id":[{"id":"https:\/\/ror.org\/0517h6h17","id-type":"ROR","asserted-by":"publisher"}]},{"name":"University of Toronto Centre for the Study of Pain"},{"name":"Ontario Ministry of Colleges, Universities, Research Excellence and Security","award":["Ontario Graduate Scholarship"],"award-info":[{"award-number":["Ontario Graduate Scholarship"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2026,6,1]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                <jats:p>Placebo analgesia\u2014pain reduction from inert treatments\u2014varies widely across individuals, yet its neurochemical basis remains poorly understood. While endogenous opioids, specifically \u03b2-endorphin, contribute to placebo effects, mu-opioid receptor blockade does not fully abolish analgesia, implicating additional systems. Here, we investigate the endogenous cannabinoid (eCB) system\u2019s contribution to placebo analgesia in 48 healthy adults using a validated placebo paradigm with blood sampling. We quantified circulating levels of eCB ligands and \u03b2-endorphin at baseline, as well as before and after placebo and control conditions to determine condition-related changes. Individual differences in placebo analgesia were associated with increases in fatty acid amide hydrolase (FAAH) substrates\u2014a composite of anandamide, palmitoylethanolamide, and oleoylethanolamide\u2014but not 2-arachidonoylglycerol or \u03b2-endorphin alone. Critically, \u03b2-endorphin moderated this relationship: FAAH substrates were strongly associated with pain reduction only when \u03b2-endorphin levels were low. These findings provide evidence that eCB and opioid systems interact in a state-dependent manner during placebo analgesia in humans, with implications for understanding individual variability in treatment responses.<\/jats:p>","DOI":"10.64898\/2026.02.25.707676","type":"posted-content","created":{"date-parts":[[2026,2,27]],"date-time":"2026-02-27T06:05:27Z","timestamp":1772172327000},"source":"Crossref","is-referenced-by-count":0,"title":["The Endocannabinoid System\u2019s Contribution to Placebo Analgesia"],"prefix":"10.64898","author":[{"ORCID":"https:\/\/orcid.org\/0009-0003-4893-2712","authenticated-orcid":false,"given":"Rossi","family":"Tomin","sequence":"first","affiliation":[{"name":"Centre for Multimodal Sensorimotor and Pain Research, Faculty of Dentistry, University of Toronto, Toronto, ON, Canada"},{"name":"University of Toronto Centre for the Study of Pain, University of Toronto, Toronto, ON, 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Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Omar","family":"Khalil","sequence":"additional","affiliation":[{"name":"Centre for Multimodal Sensorimotor and Pain Research, Faculty of Dentistry, University of Toronto, Toronto, ON, Canada"},{"name":"University of Toronto Centre for the Study of Pain, University of Toronto, Toronto, ON, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7422-1004","authenticated-orcid":false,"given":"Christine","family":"Sexton","sequence":"additional","affiliation":[{"name":"Centre for Multimodal Sensorimotor and Pain Research, Faculty of Dentistry, University of Toronto, Toronto, ON, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3995-8286","authenticated-orcid":false,"given":"Stephanie L.","family":"Bourke","sequence":"additional","affiliation":[{"name":"Centre for Multimodal Sensorimotor and Pain Research, Faculty of 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