Background: Posttraumatic stress disorder (PTSD) is one of the most sex-polarized psychiatric disorder, with women exhibiting twice the prevalence of men. The biological mechanisms underlying this sex disparity are not fully understood. Growing evidence suggests that alterations of the stress-buffering endocannabinoid (eCB) system and heightened inflammation are central to PTSD pathophysiology and may contribute to sex-biases in PTSD risk and severity. Here, we examined sex-differences in levels of circulating eCBs and peripheral pro-inflammatory markers in a cohort of men and women with PTSD and non-psychiatric controls. Methods: 88 individuals with PTSD and 85 sex- and age- matched controls (HC) were retrospectively selected from the Mass General Brigham Biobank. Serum was assayed to measure circulating eCBs [anandamide (AEA), 2-arachidonyl glycerol (2-AG), oleoylethanolamide (OEA), and arachidonic acid (AA] and inflammatory markers [interleukin-1β (IL-1β), IL-6, IL-8, IL-18, tumor necrosis factor-alpha (TNFα), and C-reactive Protein (CRP)]. Linear regression was used to predict differential abundance of each analyte by disease state (PTSD/HC) within the male and female subgroups. Two-sided t-tests with Benjamini-Hochberg correction were used to examine differences across subgroups. Analyses were repeated in those with comorbid major depressive disorder. Results: Male PTSD patients showed a significant decrease in AEA, AA and OEA levels compared to male controls (p′s<.001) and to female subgroups (PTSD and HCs) (p<.001). In contrast, among females, PTSD patients showed elevated levels of IL-6 (p<.05) and IL-8 (p<.05). Both male and female PTSD patients exhibited an increase in TNFα concentrations (p<.05), compared to HCs. Similar results were obtained in the subgroup of individuals with comorbid MDD and after controlling for the FAAH 385A genotype. Conclusions: Our findings show for the first time that decrease in eCB levels is absent in women with PTSD, who in turn exhibit a broader increase in inflammatory markers, thus suggesting that biological perturbations underlying PTSD may vary by sex.

The authors have declared no competing interest.

This work has been supported by the Mary Ann Tynan Fellowship Program and the Womens Brain Initiative/Brigham and Womens Hospital. The authors acknowledge the participants and administrators of the Mass General Brigham Biobank for their contribution to this work. The authors would also like to thank Enterprise Research Infrastructure & Services at Mass General Brigham for the provision of analysis software, Robert James Glynn, PhD, ScD for valuable feedback, and support from UM1TR004408 award through Harvard Catalyst Biostatistical Consulting Program and financial contributions from Harvard University and its affiliated academic healthcare centers. The content is solely the responsibility of the authors and does not necessarily represent the official views of Harvard Catalyst, Harvard University and its affiliated academic healthcare centers, or the National Institutes of Health.

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