Mechanism of Action of Addyi (Flibanserin)
Addyi (flibanserin) works as a multifunctional serotonin modulator, specifically acting as a 5-HT1A receptor agonist and 5-HT2A receptor antagonist, which shifts the balance between inhibitory and excitatory neurotransmitters to enhance sexual desire in premenopausal women with hypoactive sexual desire disorder (HSDD). 1
Neurobiological Mechanism
Flibanserin targets the neurobiological imbalance underlying HSDD by modulating serotonin pathways in the brain. 2 The drug's dual action on serotonin receptors is designed to address the neurotransmitter dysregulation thought to contribute to low sexual desire. 1
As a postsynaptic 5-HT1A agonist, flibanserin activates these receptors, while simultaneously blocking 5-HT2A receptors as an antagonist. 3 This combined action shifts the neurochemical balance toward increased dopamine and norepinephrine activity (excitatory neurotransmitters that promote sexual desire) while reducing excessive serotonin activity (an inhibitory neurotransmitter that can suppress sexual function). 1
Clinical Effects
The neurophysiological effects translate into measurable clinical improvements: approximately 1 additional satisfying sexual event every 2 months compared to placebo. 4, 5 While this may seem modest, it represents a statistically significant improvement in women with HSDD. 6
Flibanserin improves multiple domains of sexual function beyond just desire, including reductions in distress related to low sexual desire and improvements in overall sexual function scores. 3, 7 In pooled analyses of pivotal trials, women taking flibanserin 100 mg at bedtime showed significant improvements in satisfying sexual events (mean change 2.1 vs 1.2 for placebo), Female Sexual Function Index desire domain scores, and reductions in sexual distress. 7
Dosing and Administration
- The FDA-approved dose is 100 mg taken once daily at bedtime. 4, 3 This bedtime dosing is critical because it helps mitigate common side effects like dizziness and somnolence, which occur in approximately 10-12% of patients. 7, 2
Important Caveats
Flibanserin is a nonhormonal treatment option, distinguishing it from testosterone or other hormonal approaches sometimes used off-label for HSDD. 2 This makes it particularly relevant for women who cannot or prefer not to use hormonal therapies.
The mechanism differs fundamentally from bremelanotide (the other FDA-approved HSDD treatment), which works as a melanocortin receptor agonist rather than through serotonin modulation. 4
Common adverse effects include dizziness (10.5%), somnolence (11.8%), fatigue (10.3%), and nausea, with rare cases of syncope. 3, 2 These side effects are comparable to other CNS-active medications and are generally manageable with proper bedtime dosing. 2