How the new ‘female Viagra’ work

The libido enhancement drug flibanserin (trade name Addyi) took center stage last week after winning long-sought approval from the U.S. Food and Drug Administration (FDA). The coverage from advocates and nonbelievers has run the gamut—advice, caution, and criticism likely to confuse undecided—but curious—onlookers. But exactly how Addyi drums up sex drive is still murky.
The drug has a long backstory. It was originally investigated in 1995 by pharmacologist Franco Borsini and a team of researchers at Boehringer Ingelheim Italia in Milan as an antidepressant because of its ability to regulate neurotransmitters—the brain’s chemical-signaling molecules. In particular, the team suspected that the drug regulated three key neurotransmitters thought to influence mood: serotonin, dopamine, and norepinephrine. A clinical trial found it did little to alleviate depression, but did seem to have an effect on mood. It just wasn’t the mood the researchers were expecting. These early trials tipped clinicians to flibanserin’s more prominent role in sexual health, as female subjects had higher scores on the Arizona Sexual Experience Scale, a survey that asks participants to rate their satisfaction on a variety of sexual health topics, like how often participants felt sexual desire and how intense that desire was.
A separate group of researchers, also at Boehringer Ingelheim, completed their first clinical trials to explore flibanserin as a libido-enhancer in 2008. They measured levels of desire through a journal-based evaluation in which subjects recorded their levels of sexual drive on a daily basis. But FDA twice concluded that the resulting increases in libido were not statistically significant, and regulators were wary of potentially dangerous side effects like dizziness, sleepiness, nausea, and fainting.
So what turned FDA’s red light green? For one: the parameters of the trials. Clinical investigator on the latest Addyi trials Sheryl Kingsberg explains that the evaluation of sexual desire in the brain is not a particularly clear-cut measurement. As the three clinical trials progressed over the course of about 8 years, so did techniques in determining desire, says Kingsberg, a reproductive biology and psychology researcher at University Hospitals Case Medical Center in Cleveland, Ohio, and consultant to Sprout Pharmaceuticals, which bought flibanserin from Boehringer Ingelheim in 2011, and was in turn purchased last week by Valeant Pharmaceuticals. The results from the latest trials, in 2014, focused on three endpoints: sexual function index (where women answered questions about sexual experience and rated levels of sexual desire on a scale of one to five over the last 28 days), satisfied sexual events, and distress felt from a low libido. Overall, women reported about one more positive sexual experience per month, and about 10% more of the patients who took Addyi reported meaningful improvements, according to a survey of those three categories, compared with a placebo group. By these measures, FDA approved Addyi as the first drug meant to kindle desire.
Though it’s been nicknamed the “female Viagra,” the two drugs function in very different ways—Viagra aims to enhance performance whereas Addyi aims to balance chemicals in the brain that correlate to desire. Still, researchers have only a rough sense of what the drug does to the brain. Stephen Stahl, a psychologist at University of California, San Diego, and researchers from Boehinger Ingelheim wanted to clarify how it works on a chemical level. In a 2011 paper in The Journal of Sexual Medicine that reviews previous studies of its mechanisms, they explain it in this way: Serotonin, which is thought to impede sexual interest, has two types of receptors in the brain. 5-HT1A acts like brakes for serotonin production, and 5-HT2A accelerates production. Flibanserin works by enhancing 5-HT1A (putting on the brakes) and inhibiting 5-HT2A (stopping acceleration). Between the two, serotonin production is heavily downregulated. Additionally, flibanserin’s downregulation of serotonin decreases the firing of certain neurons thought to regulate the release of other neurotransmitters, namely, dopamine and norepinephrine (both thought to enhance sexual interest). The exact mechanism for these transient shifts in neurotransmitter levels, however, is still largely unknown.
Stahl says that these same mechanisms probably elicit the side effects that concern potential users—flibanserin’s effect on a serotonin receptor called 5-HT1A likely causes dizziness and nausea, and its effects on another, 5-HT2A, are likely linked to sleepiness. The clinical trials also showed that combining alcohol and flibanserin exacerbates these effects. Trials after the drug is on the market (slated for October) will take a closer look at how alcohol really interacts with the drug. For now, FDA has cautioned users with a black-box warning.