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

Rajasekera T.; Rahman S.; Fida D.; Roy A.; Gallegos P.; Wilson J.; Wiley A.; Marusak H.; Gur T.; Hillard C. et al. · Psychoneuroendocrinology · 2026

**Background & Methods** This secondary analysis examined 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 associations between endocannabinoids (AEA, 2-AG), related lipid mediators (PEA, OEA, 2-OG), and depressive symptom severity, while examining longitudinal changes and relationships with estradiol and progesterone concentrations. **Key Findings** • Higher palmitoylethanolamide (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, suggesting a protective relationship between elevated PEA and reduced mood disturbance. • Anandamide (AEA) concentrations significantly declined over the 8-week study period (β = -0.04, p < 0.0001), independent of estradiol variability and history of major depressive disorder, potentially reflecting reduced endocannabinoid signaling capacity. • No significant associations were observed between estradiol or progesterone concentrations and endocannabinoid-related analytes, suggesting the endocannabinoid system changes during perimenopause may operate through mechanisms independent of classical gonadal steroid hormone fluctuations. **Dosage & Administration** Not reported. **Safety & Adverse Effects** Not reported. **Evidence Quality** This secondary analysis has several limitations that warrant consideration. The small sample size (n=38) and modest study duration (8 weeks) limit generalizability and longitudinal inference. The study included only women with mild-to-moderate depressive symptoms, potentially restricting applicability to more severe mood disturbances. Cross-sectional associations, particularly between PEA and depression severity, cannot establish causality. The exploratory nature of progesterone analyses and absence of significant hormone associations may reflect underpowered analyses. As an observational study without intervention or comparator group, confounding variables cannot be excluded. This represents hypothesis-generating research requiring confirmation in larger, prospective studies with comprehensive assessment of neuroinflammatory markers and functional neuroimaging to elucidate mechanistic pathways. The findings suggest endocannabinoid system dysfunction as a potential contributor to perimenopausal depression but require higher-quality evidence before clinical translation.

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