Sex differences in endocannabinoid and inflammatory markers associated with posttraumatic stress disorder

Posttraumatic stress disorder (PTSD), a severe psychiatric disorder that predominantly affect women, is characterized by heightened inflammation and perturbations of the stress-buffering endocannabinoid system. However, whether these alterations contribute to PTSD pathophysiology in both men and women is largely unknown. This case-control study examined sex-differences in circulating levels of endocannabinoids (eCBs) and pro-inflammatory markers in a cohort of individuals with PTSD and non-psychiatric controls. Eighty-eight patients with PTSD and 85 sex- and age- matched healthy controls (HCs) were retrospectively selected from the Mass General Brigham Biobank. Serum samples were assayed to measure circulating levels of eCBs [N-arachidonoylethanolamine (AEA), 2-arachidonoylglycerol (2-AG), oleoylethanolamide (OEA), and arachidonic acid (AA)] and pro-inflammatory markers [interleukin-1β (IL-1β), IL-6, IL-8, IL-18, tumor necrosis factor-alpha (TNF-α), and C-reactive Protein (CRP)]. Our results showed distinct molecular profiles based on sex and PTSD diagnosis. Male PTSD patients exhibited decreased levels of AEA, AA and OEA compared to both male controls (p's < 0.001 to 0.05) and to the female subgroups (PTSD and HCs) (p < 0.01). In contrast, female PTSD patients showed elevated levels of IL-6 and IL-8 compared to the other subgroups (p's < 0.010), although only a trend-level effect in IL-6 levels persisted when examining the magnitude of group differences (PTSD vs HCs) across sexes. Similar results were obtained after controlling for the FAAH 385 A genotype and in the subgroup of individuals with comorbid MDD. These findings suggest that distinct neurobiological mechanisms may underlie PTSD in men and women and highlight the need for sex-based therapeutic approaches.