Associations of endocannabinoids and related lipid mediators with depressive symptoms during perimenopause

Perimenopause is associated with increased vulnerability to depressive symptoms, partly driven by fluctuations in gonadal steroid hormones, particularly estradiol. The neurobiological mechanisms underlying this vulnerability remain unclear. Alterations in the endocannabinoid system (ECS) during perimenopause may represent a mechanistic pathway contributing to mood disturbance, given its role in emotion regulation and stress responsivity, as well as its modulation by estradiol. However, circulating endocannabinoids have not been examined in relation to perimenopausal depressive symptoms or estradiol variability.

This secondary analysis included 242 repeated measures from 38 perimenopausal women with untreated mild-to-moderate depressive symptoms enrolled in an 8-week longitudinal observational study. Linear mixed models evaluated: (i) associations of endocannabinoids (N-arachidonoylethanolamine [AEA], 2-arachidonoylglycerol [2-AG]) and related lipids (palmitoylethanolamide [PEA], oleoylethanolamide [OEA], 2-oleoylglycerol [2-OG]) with depressive symptom severity; (ii) longitudinal changes in these analytes; and (iii) associations between ECS-related lipid analytes and estradiol concentrations. Exploratory analyses examined progesterone associations.

Higher PEA concentrations were inversely associated with depressive symptom severity (β = -0.27; 95% CI [-0.49, -0.05]; p = 0.01), independent of estradiol variability. AEA concentrations declined significantly over time (β = -0.04, p < 0.0001), independent of estradiol variability and history of major depressive disorder. No significant associations of estradiol or progesterone concentrations with endocannabinoid-related analytes were observed.

Select endocannabinoids and related lipids show distinct patterns during the menopausal transition. Associations of higher PEA concentrations with lower depressive symptom severity potentially reflect modulation of neurosteroid and inflammatory pathways implicated in perimenopausal mood disturbances. In contrast, declining AEA may reflect reduced endocannabinoid signaling, contributing to vulnerability to depressive symptoms.