Flibanserin (trade name: Addyi), approved in limited capacity by US FDA in 2015 for female sexual desire disorders in premenopausal women, is a complex and regionally selective, multifunctional, 5-HT1a receptor antagonist and 5-HT2a receptor agonist with downstream effects on dopamine, norepinephine, and serotonin in the prefrontal cortex and elsewhere. Despite being called “female Viagra” or “little pink pill” in some media sources, flibanserin’s effects are mediated through central nervous system (CNS) effects, much like an antidepressant. Flibanserin may also be considered a norepinephrine-dopamine disinhibitor (NDDI), a class of compound including the antidepressants agomelatine and fluoxetine (Prozac).
The FDA approval for flibanserin stipulated that healthcare providers communicate risk of serious side-effects associated with alcohol use prior to prescribing in the interest of keeping women safe by abstaining from alcohol use entirely; to take it immediately prior to bed in order to minimize danger from the serious potential side-effects of syncope or low blood pressure; and to discontinue use after eight weeks if no improvement was noted.
Flibanserin represents the first FDA drug approval for hypoactive sexual desire disorders (HSDD). Although flibanserin is approved for use in women, with stipulations, HSDD is a non-specific condition that may be diagnosed in men or women, with the primary criterion (in addition to low sexual desire and low rate of sexual fantasizing) being that it causes personal distress. In other words, low sexual desire without concurrent distress is not considered HSDD.
In the medical literature, drugs referred to as NDDIs are typically those where the disinhibition of the neurotransmiters norepinephrine and dopamine are the primary functional mechanism, even (as in the case of flibanserin) when other unknown secondary mechanisms may be in play where effects are documented in trials.
Material from developer Sprout Pharmaceuticals and also published medical literature suggests the demonstrated efficacy of flibanserin may best be viewed in terms of the Kinsey Institute’s “dual control model” of sexuality. In that model, “sexual arousal and associated behavior depend on 'dual control' mechanisms in the brain involving the balance of excitatory and inhibitory systems.” Specifically, dopamine activity is increased and serotonin (5-HT) receptor activity is decreased in this paradigm, leading to a change in desire and disinhibition.
Outside of literature on flibanserin this same model also explains, in theoretical terms, dysfunctional or otherwise altered and hyperactive sexual behavior in some cases, such as (for example) survivors of child sexual abuse and Parkinson’s patients using dopaminergic or dopamine receptor agonist drugs, among others.
The Dual Control model, being theoretical and paradigmatic, is far simpler than current attempts at detailed descriptive modeling, and could be considered reductionist if still effective for uncovering treatment strategies.
Sathyanarayana and Andrade, in their article “Flibanserin: Approval of a controversial drug for a controversial disorder” published in the Indian Journal of Psychiatry, provide an appropriately nuanced take on the newly approved compound:
[we] do not take a stand either for or against either the disorder or the drug. Our reasons are simple: The arguments for and against are cogent, depend on perspective, and prevent dichotomous decision-making. There is perhaps some good and some bad; gray exists between black and white, and this fact of life must be appreciated here and elsewhere.
One hopes that the step taken by the FDA will truly improve the lives of premenopausal women with acquired, generalized HSDD; time will tell. Whether the findings can be generalized to other women with HSDD remains to be established.
A concluding note: Flibanserin is dosed once nightly [in 100mg doses]; thus, if blood pressure falls, the peak effect will occur during sleep, when it will not result in a clinical adverse event. A therapeutic trial with flibanserin should not exceed 8 weeks; it is pointless to continue the drug if benefits are not observed within this time frame.
Those authors focus on a general clinical trial paradigm to derive data inferentially; for those who have a close relationship with their healthcare provider, personalized medicine, combining different treatments over time to determine what works for the individual - despite its downsides such as lack of control group and inability to distinguish a generic placebo-observatory bias occurring in the context of a drug that has real side-effects, versus a real effect unattainable from other strategies - may also offer a “better” route to addressing female sexual desire disorders.
In “Sex, Drugs, and Dual Control”, a “personalized sexual medicine drug development program” by Dutch author Jos Bloemers, it is suggested that cautious combination, under proper medical supervision, of drugs like flibanserin with other strategies with a well-demonstrated effect (such as continuous low-dose testosterone therapy, already prescribed to 4 million women in the US alone for off-label use to treat FSD), or a possible promising benefit (such as bremelanotide or MT-1), or a low-risk strategy that has demonstrated some benefit with very little risk (for example, cognitive behavioral therapy techniques) could provide the individual patient with a pronounced benefit while taking into account individual medical history and need, within the appropriate risk envelope determined by the patient and healthcare provider.
FDA Press Release (August 18, 2015) “FDA approves first treatment for sexual desire disorder” http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm458734.htm
“Sex, Drugs, and Dual Control” by Jos Bloemers (PDF) http://www.emotionalbrain.nl/sites/emotionalbrain.nl/files/Bloemers%20-%20Sex,%20Drugs%20%26%20Dual%20Control.pdf
“Flibanserin: Approval of a controversial drug for a controversial disorder” (from Journal of Indian Psychiatry) http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4623637/
Stahl SM, Sommer Bernd, Allers KA. Multifunctional Pharmacology of Flibanserin: Possible Mechanism of Therapeutic Action in Hypoactive Sexual Desire Disorder. J Sex Med. 8:1 (p15-27), Jan 2011.
Kaspervich, J. FDA approves 'female Viagra' pill Flibanserin after two rejections. The Guardian (Website), Retrieved Dec. 8 2015.
Stephen M. Stahl; S. M. Stahl (17 March 2008). Stahl's Essential Psychopharmacology: Neuroscientific Basis and Practical Applications. Cambridge University Press. p. 658.
Bancroft J, Janssen E, Sanders S, Graham C. "Sexual Inhibition and Excitation" The Kinsey Institute for Research in Sex, Gender, and Reproduction, Inc. (Website) Retrieved Dec. 8 2015.
Kingsberg SA, Clayton AH, Pfaus JG. The Female Sexual Response: Current Models, Neurobiological Underpinnings and Agents Currently Approved or Under Investigation for the Treatment of Hypoactive Sexual Desire Disorder. CNS Drugs. 2015 Nov;29(11):915-33
Sathyanarayana Rao TS, Andrade C Flibanserin. Approval of a controversial drug for a controversial disorder. Indian J Psychiatry. 2015 Jul-Sep;57(3):221-223.
Bloemers, J. "Sex, Drugs & Dual Control: A personalized sexual medicine drug development program...". Netherlands (2014).
*The latter article is intended for educational / informational purposes only. THIS PRODUCT IS INTENDED AS A RESEARCH CHEMICAL ONLY. This designation allows the use of research chemicals strictly for in vitro testing and laboratory experimentation only. Bodily introduction of any kind into humans or animals is strictly forbidden by law.