The brain OFF the pill: A Longitudinal Investigation of Functional Connectivity, Mood, and Cortisol Following Oral Contraceptive Discontinuation

Oral contraceptives (OCs) are widely used worldwide, yet their effects on brain function, stress biology, and mood remain incompletely understood. While previous research has primarily focused on OC use, considerably less is known about the psychological and biological changes accompanying OC discontinuation. This longitudinal study investigated changes in depressive symptoms, basal cortisol levels, and resting-state functional connectivity following combined oral contraceptive (COC) discontinuation, as well as associations between these changes. Seventy-seven healthy young women completed two assessments over a 3 – 8 month interval: COC discontinuers (dOC, n = 25), continuous COC users (OC, n = 26), and naturally cycling women (NC, n = 26). Depressive symptoms (BDI-II), plasma cortisol, and resting-state functional connectivity within the Triple Network Model (Default Mode, Salience, and Fronto-parietal Networks) were assessed at both time points. Women who discontinued COCs showed a significant increase in within-network connectivity of the Salience Network, whereas no significant network-level longitudinal changes emerged in the Default Mode or Fronto-parietal Networks. Over the same period, they also showed a significant decrease in depressive symptoms and a marked decrease in cortisol levels. Moreover, increased Salience Network connectivity was associated with greater reductions in depressive symptoms, whereas cortisol changes were associated with neither functional connectivity nor depressive symptoms. These findings contribute to a better understanding of the complex effects of OCs on brain function, stress biology, and mood, providing novel insights into the neurobiological and affective processes associated with COC use and discontinuation.