Wednesday, December 9, 2009

I Wanna Be Sedated

(Cross-posted to Turner & Kowalski)

A few weeks ago, the German pharmaceutical company Boehringer Ingelheim completed a Phase III clinical trial (results of which were presented at the 12th Congress of the European Society for Sexual Medicine last month in Lyon, France) of a drug it hopes to market as a treatment for Hypoactive Sexual Desire Disorder in women.

The drug in question is flibanserin, which had been tested as an antidepressant in the 1990s and found not to be very effective. It has also been studied in animals, to test for anti-anxiety and anti-psychotic properties, but neither of those effects were demonstrated sufficiently to warrant any clinical trials in humans.

Flibanserin interacts with three major receptors in brain, nerve and blood-vessel tissue: first, there's the 5-HT-1A receptor (5-HT, or 5-hydroxytryptamine, being another name for serotonin), to which flibanserin binds with relatively high affinity. Though it exhibits a huge preference for this receptor in cloned tissue, it binds with about equal affinity to it and to the 5-HT-2A receptor in vivo. (See this review article for a detailed discussion of the pharmacology of flibanserin; I will attempt to summarize what I think is most relevant here).

Once it does bind to the 5-HT-1A receptor, flibanserin acts to boost its activity. This activity consists of setting the receptor's associated G proteins loose in the cell to block the production of cyclic AMP, a "second messenger" molecule that can go on to tell the cell to do all sorts of different things. (There's a cartoon illustration here of this process occurring in a neuron, with the anti-anxiety medication busiprone acting as the 5-HT-1A agonist. Though flibanserin acts a little differently than busiprone does --- it acts preferentially on somewhat different tissue types --- the general process within the cell is the same; the only difference would be where exactly it binds to the receptor, and what exact conformational changes it induces in the receptor to lead to the dissociation of the G proteins).

Though it might seem like blocking this receptor would cause the cell to do nothing, it's a bit more complicated than that. Due to the different ways in which different biological processes are regulated, the absence of a signal might activate some processes even as it suppresses others.


Some of the physiological processes which are activated by suppression of cyclic AMP (through the action of serotonin receptor 1A) include: peripheral vasodilation (i.e., dilating blood vessels throughout the body), which leads to both lower blood pressure and lower body temperature; stimulation of the vagus nerve, which causes the heart rate to slow; release of dopamine in the brain, which leads to, among other things, feelings of pleasure and satiety; faster, shallower breathing; release of norepinephrine in specific parts of the brain, which induces pupil constriction in the eyes; and reduction in extracellular levels of serotonin, glutamate and acetylcholine in the brain (the latter two of which are excitatory neurotransmitters that encourage neurons to fire; having less of them around will have a dampening effect on brain activity in general).


Flibanserin also acts on two other receptors: the aforementioned 5-HT receptor 2A, and the dopamine receptor D4.

It acts as an antagonist on 5-HT receptor 2A, binding to it and inhibiting its function. This is a somewhat complementary mechanism to its activation of 5-HT receptor 1A, since the latter receptor triggers an inhibitory cascade, while the former's action is excitatory --- i.e., rather than blocking cAMP synthesis, 5-HT receptor 2A, on ligand binding, stimulates it, leading to a variety of intracellular activities: in neurons, it leads them to fire, or to be more receptive to passing along electrical signals from adjacent neurons; in smooth muscle cells, it triggers contractions; in platelet cells, it leads them to clump together and speed up blood clotting and wound healing; through stimulation of the "pacemaker" neurons that control the heartbeat, it leads the heart to beat faster, and, through stimulation of neurons in the cortex (5-HT-2A receptors are particularly dense in sensory areas of the brain; according to Wikipedia, this receptor is a major target for a lot of powerful hallucinogenic drugs, like mescaline, psilocin and LSD), heighten sensory perception and sharpen learning, thought and emotion, particularly anxiety.

In short, both of the major pathways by which flibanserin affects the nervous system serve to slow down physiological processes, quiet the mind, and dull the senses. It's a sedative, as Borsini et al. make clear in the "Behavioral Effects" section of their review article on the "Pharmacology of Flibanserin":

Rats seem more sensitive than mice to the inhibitory effects of flibanserin on motor activity. In fact, reduced motor activity was observed at doses of 8 to 16 mg/kg, i.p. [intraperitoneally], in rats, and no reduction in motor activity was seen with doses up to 32 mg/kg, i.p., in mice. Flibanserin induced failure to grasp the wire in the traction test ... in 50% of mice at a dose of about 45 mg/kg, i.p., or 95 mg/kg, p.o. At 64 mg/kg, p.o., mice also displayed hypomotility and hypothermia. These effects were more pronounced at 128 mg/kg. At this high dose, the following additional alterations were also observed: reduced grip strength, ptosis [droopy eyelids] and head weaving, and occasional catalepsy.

Sedating effects were also apparent in the recently-released results of the clinical trials in humans, which Neuroskeptic summarizes here:

What about the side effects? There's a whole poster about them. 100 mg nightly caused 14% of patients to drop out [of the trial] due to side effects, vs. 7% of placebo - so 7% of people decided it wasn't worth it. It caused dizziness, nausea, fatigue, somnolence - and bizarrely, also insomnia. 50 mg daily was worse than 100 mg nightly, which suggests that taking this at night, rather than in the morning, is a good idea. But given what it's meant to treat, you'd want to do that anyway, right?

But this leads into my biggest problem with this data. It's obvious from the side effects data that the drug is a sedative - it makes you tired and sleepy. The animal data confirm this. It's much more likely to put you to sleep than it is to make you enjoy sex in any given month. Off the top of my head I suspect it's a sedative because it's a 5HT2A antagonist.

(Neuroskeptic also points out the cheesy names of individual trials --- the overall study was made up of several trials at different sites in North America and Europe, each one involving about five hundred participants, and each one named for a different kind of flower. DAHLIA, DAISY, VIOLET, and --- of course --- ORCHID. Subtle.)

Neuroskeptic also raises the point --- which I agree with --- that that flibanserin's mild aphrodisiac effect might be an artifact of its sedating effect. A sedative that's not so powerful it just knocks you out relaxes you, lowers your inhibitions:

Any sedative can increase sexual desire as anyone who has ever been to a bar will know. So whether this drug actually has an aphrodisiac effect, as opposed to just being a sleeping pill, is anyone's guess. To find out, you'd need to compare it to a sleeping pill, say, Valium. Or a couple glasses of wine. Until someone does that, we don't know if this drug is destined to be the next big thing or a big disappointment.

I can think of several possible instances in which that might be enough to dramatically improve someone's sex life. It might be that for women with vaginismus (a condition in which the vagina clenches and spasms, sometimes painfully, whenever anything enters it) who want to have penetrative sex but can't*, the sedating effect might allow us to relax enough to do that. Along similar lines, people who have PTSD from being raped, but who are now in a relationship they chose with a partner they trust, and genuinely want to have sex with, but who nevertheless find certain sex acts (or maybe even all sex acts) triggering, might want something to help minimize the reflexive physiological effects of their trauma. Finally, women who lose interest in sex in the context of a long-term relationship, which might well include shared spaces, shared responsibilities, and shared relationships with both/all partners' friends and relatives, might find this medication helpful in banishing everyday stresses that might otherwise kill the mood.

However, as both of those articles (as well as this one) indicate, a purely mechanical "fix" is only a good idea when the problem is also mechanical --- as in my first example, of the straight woman with vaginismus who wants to have penetrative sex but can't, because her vaginal muscles contract uncontrollably. (I would actually recommend this pill more wholeheartedly to people who are suffering from some kind of overarousal --- "arousal" here in the physiological sense, not the strictly sexual --- that actually interferes with sex, as in vaginismus, or an anxiety/overload problem, than I would to people whose libidos have greatly diminished over time for unknown reasons, because, while the latter group might be in just as much distress over their impoverished sex life, I am less confident a sedative would actually help them much in that department).

In some (most?) of the other cases, where an underlying problem in the woman's --- or the couple's --- life, like, say, an unequal distribution of household labor, leads her not to want as much sex with her partner because she's exhausted, angry, depressed, alienated or feeling unappreciated, no pill can correct that, and implying that any problems the relationship may have are the woman's fault because she's "frigid" or "wired wrong" or whatever seems to me like it would only aggravate any feelings of anger or alienation she might have.

This About Sexuality column spells out all the additional, not purely physiological factors that influence sexual desire:

Defining Sexual Desire

Sexual desire is not an easy thing to define, as even researchers involved in the flibanserin studies acknowledge. The model presented by BI [Boehringer Ingelheim] researchers involves breaking down desire into three elements, which include:

Drive, referring to spontaneous sexual interest that is somehow biological or hardwired (what this actually looks like is only a guess).

Belief & values, including social, cultural, ethnic, religious, and other factors that impact how often we might feel sexual desire, how intensely we feel it, and how comfortable we are with it.

Motivation, which considers all the psychological and interpersonal factors creating a willingness to be sexual and feel sexual desire.

The pitch from BI researchers is that while good treatments exist for low sexual desire caused by beliefs, values, and motivation, we don't have anything to treat the drive component (which they call the "biologic" component). They believe that flibanserin treats the drive component of sexual desire.

...

BI conducted several studies in North America and Europe involving over 5,000 pre-menopausal women who had been diagnosed with HSDD. In their publicity campaign, they focus on the North American studies (more on that below) and included just over 1,300 women. The average age was 35 and most of the women were married and the average length of relationships was over 10 years.

...

They haven't offered any rationale for why the drug produced statistically significant results in the "biologic" component in North America but not in Europe. I suspect the answer to that question may be messy as it would likely refer back to non-"biologic" elements of sexual desire, thus pointing out a problem with the premise of the research.

After the six month study there were participants who stopped taking the drug [and] reported that their sexual desire did not diminish. Whether this suggests that the drug is having a permanent effect on their brain chemistry, or that brain chemistry is not in fact a significant factor in most cases of low sexual desire remains to be explained.

Finally, I was interested to hear one of the researchers say that most women in the study reported that their low sexual desire crept up on them over a period of time. If, as the researchers argue, problems with low desire are drive related, hard-wired or biological, why would they appear slowly? Are they suggesting that there are precipitating factors influencing low sexual desire? If so, would effective treatment not want to address those factors before they go altering the brain chemistry of otherwise healthy women? One consideration in a low desire creep may be age, but these studies were of pre-menopausal women with an average age of 35.

Besides the brushing aside of interpersonal or environmental factors, like relationship difficulties, stress, or an unequal division of labor (whether inside the home, outside it or both), and the assumption that, in any heterosexual relationship where one partner wants sex a lot more than the other (and, of course, it's assumed that the "one partner" is male and the "other" female --- women with high levels of sexual desire and men with low levels are heavily stigmatized, and either ignored or pathologized in most discussions of sexual health), the third feminist qualm I have about a libido-boosting pill for women (and, specifically, this particular libido-boosting pill for women) relates to agency.

People who are socialized into a feminine role** in this culture are already bombarded, almost from birth, with lessons in objecthood. Our bodies, our time, our attention, our space --- none of these things are really seen as ours; they're all considered more or less public property, and the things we choose to do with them not important or legitimate in their own right. We learn to be passive, especially in the company of men. Whatever it is, he needs it more than you do. His needs, wants, ambitions, and dreams are real. What are yours?

In the face of this training, women learn to seriously second-guess their own wishes. For me, personally, this means that I set much higher minimum standards for "no" than I do for "yes." I have to be really, really averse to something to say "no" to it, while to say "yes," all I have to do is not have any serious qualms about it. Mildly ambivalent? That's a yes. Apathetic? A yes. Vague distaste that can't be explained or articulated? Yes again.

This is, of course, a very bad thing when the propositions being agreed to so dutifully, but with so little real enthusiasm or volition, involve doing fairly invasive things to one's body.

*This category, you can see in this comment thread at IBTP, does not include all women with vaginismus or vulvar pain. Many of the commenters there are perfectly happy with their penetration-free sex lives, or with their voluntary celibacy. This latter notion --- that there are people who either do not feel sexual desire, or who don't feel it particularly strongly and are more or less indifferent to sex, and that these states of being are perfectly healthy --- is still not shared by many people, as this asexual blogger demonstrates.

**Not all of whom grow up to be women

5 comments:

Lydia Encyclopedia said...

Thank you for breaking this down. I don't have any scientific background to speak of, but when I read about this, my brain's "baloney alarm" was going off like mad.

Lindsay said...

Well, that's one spam comment deleted --- I wonder how many more there'll be.

(I've been getting a lot of spam comments lately, mostly on old posts, and I worry particularly about this one because its subject matter might be a magnet for keyword-targeted spambots...)

Lindsay said...

@Lydia,

You're welcome!

Yes, the press for this drug is particularly misleading, since flibanserin is being billed as a "female Viagra" (oh crap, that's sure to bring in the spambots!), when it is actually designed to do something totally different. Viagra enhances blood flow to a, um, strategic area of male anatomy, thus ensuring that, when he *wants* to have sex, he is physically able to do so. The rationale behind flibanserin for low sexual desire seems to revolve around boosting desire itself, which is separate from, and a precursor to, sexual arousal.

Flora said...

I've been highly doubtful that this drug is all it's cracked up to be, too, but I admit that I am wondering about the extent to which women are actually buying into the idea that lack of sexual desire means something is wrong with them. I have been seeing a lot of panic around the idea that Big Pharma is trying to sell women a fix for sexual issues that they don't perceive as problems, and apparent fear that an enormous number of women have already bought into or are on the verge of buying into the idea that something is wrong with them just on the basis of pharmaceutical propaganda. But while this may just be a function of the circles I tend to hang around in and read blogs in, I've seen far more women outraged at the idea that someone is trying to sell them a pill to boost their libido than women who are deciding this is what they've wanted all along and that they can't wait to try it.

Incidentally, though, I do want to thank you for mentioning vaginismus as an example of a sexual problem with an actual physical cause and as being worthy of medical treatment-- it may seem like a small thing, but even in feminist circles, it can be incredibly frustrating to repeatedly run up against people who apparently don't believe that physical causes for sexual pain and discomfort exist, and derail all conversations about them in favor of complaints about Big Pharma and unrealistic media images of sex. The I Blame The Patriarchy post you linked to, though, really isn't the best treatment of the issue of vaginismus from a feminist standpoint-- there's a response and discussion to it here, from the perspective of someone who actually experiences vaginismus. (Disclosure of interests: I'm technically a guest blogger at Feminists With FSD-- am still working on my first article for it, and didn't write the one I linked-- but I felt I might as well disclose that. I definitely don't want to look as though I'm trying to spam a blog that I'm affiliated with; the IBTP post just appeared to me to be another case of a non-disabled person talking about a disability without knowing or talking to anyone who has the actual disability.)

Lindsay said...

Thanks for your comment, Flora --- I'll add your link into the post, maybe in place of the other one.

(I have also linked to that post, or at least to the comments thereon, elsewhere in my post. I'll keep the link to the comments section, because I think that thread does a good job of showing the diversity of opinion among feminist women with vaginismus/vulvar pain).

I've also observed a lot more skeptical, outraged blog posts than any other kind, but I've chalked that up to my frequenting mostly feminist websites.