Oral contraceptive use changes brain activity and mood in women with previous negative affect on the pill--a double-blinded, placebo-controlled randomized trial of a levonorgestrel-containing combined oral contraceptive

Psychoneuroendocrinology. 2013 Jul;38(7):1133-44. doi: 10.1016/j.psyneuen.2012.11.006. Epub 2012 Dec 6.


Objective: Most women on combined oral contraceptives (COC) report high levels of satisfaction, but 4-10% complain of adverse mood effects. The aim of this randomized, double-blinded, placebo-controlled trial was to investigate if COC use would induce more pronounced mood symptoms than placebo in women with previous history of COC-induced adverse mood. A second aim was to determine if COC use is associated with changes in brain reactivity in regions previously associated with emotion processing.

Methods: Thirty-four women with previous experience of mood deterioration during COC use were randomized to one treatment cycle with a levonorgestrel-containing COC or placebo. An emotional face matching task (vs. geometrical shapes) was administered during functional magnetic resonance imaging (fMRI) prior to and during the COC treatment cycle. Throughout the trial, women recorded daily symptom ratings on the Cyclicity Diagnoser (CD) scale.

Results: During the last week of the treatment cycle COC users had higher scores of depressed mood, mood swings, and fatigue than placebo users. COC users also had lower emotion-induced reactivity in the left insula, left middle frontal gyrus, and bilateral inferior frontal gyri as compared to placebo users. In comparison with their pretreatment cycle, the COC group had decreased emotion-induced reactivity in the bilateral inferior frontal gyri, whereas placebo users had decreased reactivity in the right amygdala.

Conclusion: COC use in women who previously had experienced emotional side effects resulted in mood deterioration, and COC use was also accompanied by changes in emotional brain reactivity. These findings are of relevance for the understanding of how combined oral contraceptives may influence mood. Placebo-controlled fMRI studies in COC sensitive women could be of relevance for future testing of adverse mood effects in new oral contraceptives.

Publication types

  • Randomized Controlled Trial
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Affect / drug effects*
  • Brain / drug effects*
  • Brain / physiopathology
  • Contraceptives, Oral, Combined / pharmacology*
  • Depression / physiopathology
  • Double-Blind Method
  • Female
  • Humans
  • Levonorgestrel / pharmacology*


  • Contraceptives, Oral, Combined
  • Levonorgestrel