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However, stress exposure may also lead to dysregulation of this system. Thus, pathways from marked stress histories, such as childhood maltreatment (CM), to smaller hippocampal volumes and MDD in humans may <jats:italic>depend<\/jats:italic> on dysregulated versus intact eCB functioning. We examined whether the relation between MDD and peripheral eCB concentrations would vary as a function of CM history. Further, we examined whether eCBs moderate the relation of CM\/MDD and hippocampal volume. Ninety-one adults with MDD and 62 healthy comparison participants (HCs) were recruited for a study from the Canadian Biomarker Integration Network in Depression program (CAN-BIND-04). The eCBs, anandamide (AEA) and 2-arachidonylglycerol (2-AG), were assessed from blood plasma. Severe CM history was assessed retrospectively via contextual interview. MDD was associated with eCBs, though not all associations were moderated by CM or in the direction expected. Specifically, MDD was associated with higher AEA compared to HCs regardless of CM history, a difference that could be attributed to psychotropic medications. MDD was also associated with higher 2-AG, but only for participants with CM. Consistent with hypotheses, we found lower left hippocampal volume in participants with versus without CM, but only for those with lower AEA, and not moderate or high AEA. Our study presents the first evidence in humans implicating eCBs in stress-related mechanisms involving reduced hippocampal volume in MDD.<\/jats:p>","DOI":"10.1038\/s41398-024-03151-z","type":"journal-article","created":{"date-parts":[[2024,10,12]],"date-time":"2024-10-12T02:01:51Z","timestamp":1728698511000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":17,"title":["Endocannabinoid concentrations in major depression: effects of childhood maltreatment and relation to hippocampal volume"],"prefix":"10.1038","volume":"14","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-4974-4815","authenticated-orcid":false,"given":"Raegan","family":"Mazurka","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kate L.","family":"Harkness","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7240-1581","authenticated-orcid":false,"given":"Stefanie","family":"Hassel","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Niclas","family":"Stensson","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nikita","family":"Nogovitsyn","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3315-5098","authenticated-orcid":false,"given":"Jordan","family":"Poppenk","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8579-4705","authenticated-orcid":false,"given":"Jane A.","family":"Foster","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Scott D.","family":"Squires","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jessie","family":"Rowe","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Roumen V.","family":"Milev","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Katherine E.","family":"Wynne-Edwards","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4075-2736","authenticated-orcid":false,"given":"Gustavo","family":"Turecki","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3198-217X","authenticated-orcid":false,"given":"Stephen C.","family":"Strother","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stephen R.","family":"Arnott","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7142-4669","authenticated-orcid":false,"given":"Raymond W.","family":"Lam","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Susan","family":"Rotzinger","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5339-7185","authenticated-orcid":false,"given":"Sidney H.","family":"Kennedy","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Benicio N.","family":"Frey","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0645-4869","authenticated-orcid":false,"given":"Leah M.","family":"Mayo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2024,10,12]]},"reference":[{"key":"3151_CR1","doi-asserted-by":"publisher","first-page":"617","DOI":"10.1001\/archpsyc.62.6.617","volume":"62","author":"RC Kessler","year":"2005","unstructured":"Kessler RC, Wai TC, Demler O, Walters EE. 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LMM is a paid consultant for Synendos Therapeutics for work unrelated to the current manuscript. RVM has received consulting and speaking honoraria from AbbVie, Allergan, Eisai, Janssen, KYE, Lallemand, Lundbeck, Otsuka, and Sunovion, and research grants from CAN-BIND, Canadian Institutes for Health Research, Janssen, Lallemand, Lundbeck, Nubiyota, Ontario Brain Institute and Ontario Mental Health Foundation. RWL has received honoraria for ad hoc speaking or advising\/consulting, or received research funds, from Abbvie, Asia-Pacific Economic Cooperation, Bausch, BC Leading Edge Foundation, Brain Canada, Canadian Institutes for Health Research, Canadian Network for Mood and Anxiety Treatments, Carnot, CB Solutions, Genome BC, Janssen, Lundbeck, Michael Smith Foundation for Health Research, MITACS, Neurotorium, Ontario Brain Institute, Otsuka, Shanghai Mental Health Center, Unity Health, Vancouver Coastal Health Research Institute, and VGH-UBCH Foundation. SCS received funding from the Ontario Brain Institute and Canadian Institutes for Health Research (MOP137097) for neuroimaging analysis in CAN-BIND, and SCS is a Senior Scientific Advisor and co-owner of ADMdx, Inc., a neuroimaging consulting company. SRA has carried out consultancy work for Indoc Research. SR holds a patent \u201cTeneurin C-Terminal Associated Peptides (TCAP) and methods and uses thereof. Inventors: David Lovejoy, R.B. Chewpoy, Dalia Barsyte, Susan Rotzinger.\u201d SHK has received research funding or honoraria from the following sources: Abbott, Alkermes, Abbvie, Brain Canada, Canadian Institutes for Health Research, Janssen, Lundbeck, Lundbeck Institute, Ontario Brain Institute, Ontario Research Fund, Otsuka, Pfizer, Servier, Sunovion and Xian-Janssen and holds stock in Field Trip Health. JAF has served on the Scientific Advisory Board for MRM Health NL and has received consulting\/speaker fees from Alphasights, Novozymes, Klaire Labs, Takeda Canada, Rothman, Benson, Hedges Inc., and WebMD.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}],"article-number":"431"}}