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

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.

Keywords: Endocannabinoids; Fear; Inflammation; PTSD; Sex Differences.

Figure 1.

Sex differences in circulating endocannabinoids characterized by decreased AEA (A; p=0.004), AA (B; p=0.004), and OEA (C; p=0.021) in males with PTSD. Females with PTSD showed increased 2-AG, compared to female HC (D, p=0.025). Data represent log2-transformed means ± SEM in pmol/mL.

Figure 2.

Higher concentrations of circulating IL-6 (B, p=0.013), IL-8 (C, p=0.025), and TNFα (E, p=0.029) in females with PTSD, compared to female HC. Greater concentration of TNFα (E, p=0.031) in males with PTSD, compared to male HC. Data represent log2-transformed means ± SEM in pg/mL or mg/L.