Sex Differences in Endocannabinoid and Inflammatory Markers Associated with Posttraumatic Stress Disorder

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Abstract Background Posttraumatic stress disorder (PTSD) is one of the most sex-polarized psychiatric disorders, 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.

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