What Can Placebo Responses Teach Us About Women’s Sexual Desire?

Last week, the FDA brought together researchers, clinicians, women with lived experience, and other experts for a full-day workshop on testosterone use in menopausal women.

I watched the entire presentation live from my office. And I welcomed that conversation.

Women’s sexual health has been understudied for far too long, and women experiencing distressing low sexual desire deserve treatments that have been properly studied, appropriately dosed, and demonstrated to be both effective and safe.

As reviewed during the workshop, there is evidence that testosterone can improve sexual desire in some postmenopausal women with hypoactive sexual desire disorder (HSDD). There are also important questions that remain — including how best to measure testosterone in women, which women are most likely to benefit, how meaningful improvements should be measured, whether benefits are maintained when treatment is stopped, and what we know about long-term safety. These were among the knowledge gaps the FDA convened the workshop to examine.

But as I’ve continued thinking about the discussion, there is another question arising from the research that I believe deserves more attention.

What happens to the women receiving placebo?

This question is critically important to examine not only because placebo responses can make drug trials more difficult. But because understanding why women improve — even when they aren’t receiving the active drug — may tell us something useful about sexual desire itself.

First, what do we mean by a placebo response?

An important distinction is often lost in conversations about placebo.

A placebo response is the improvement observed among people randomized to placebo condition in a clinical trial. That doesn’t necessarily mean the placebo itself caused the improvement. Rather, there are other factors associated with being in a treatment study, regardless of the medication given, that likely contribute to improvement.

Symptoms fluctuate. People may enter studies when symptoms are particularly troublesome and subsequently those symptoms improve simply with the passage of time. Repeatedly measuring an experience, especially sexual response, can change how closely we pay attention to it. Expectations can matter, and the more we pay attention to something, the more our expectations about it improving can actually materialize. We also know that tracking something can change our behaviour.

So improvement in a placebo group can reflect several different processes that are worth us naming.

And placebo responses certainly aren’t unique to sexual health research. They occur across clinical trials studying a variety of health issues, particularly when studies measure symptoms and patient-reported experiences.

So the fact that women receiving placebo in sexual-desire trials improve does not, by itself, prove anything unique about sexual desire.

But what those women are doing differently during a trial might.

Women in placebo groups can substantially improve.

Placebo responses have been substantial in trials of treatments for women’s sexual difficulties.

One 2009 study that reviewed 16 studies found significant improvements on one or more major outcomes among women receiving placebo in most of the trials examined, with effect sizes predominantly in the moderate range. The authors also found some evidence suggesting particularly strong placebo responses among postmenopausal women and women with HSDD. (Review of placebo response in female sexual dysfunction trials)

A 2018 meta-analysis reached a similar conclusion. Across eight randomized controlled trials involving 1,723 women receiving placebo, sexual-function scores improved substantially. The analyses found that approximately 68% of the improvement was accounted for by the placebo response. (Meta-analysis of placebo response in female sexual dysfunction)

This issue has also surfaced in randomized clinical trials of testosterone products specifically for women with low desire.

More than a decade ago, two large Phase III clinical trials evaluated a testosterone gel called LibiGel in surgically menopausal women with HSDD. Testosterone levels increased, but the trials failed to demonstrate statistically significant superiority over placebo on their efficacy endpoints. Subsequent clinical guidance has described the unexpectedly large placebo response and suggested that regular clinic visits, daily diary reminders, and expectations of improvement may have contributed to such a high placebo response.

It is easy to look at a result like that primarily as a clinical-trial problem.

But I think there is another question worth asking: What was actually changing for the women in the placebo group?

An inactive treatment doesn’t necessarily mean an inactive experience.

A woman participating in a clinical trial may be receiving an inactive medication, but she is not necessarily having an inactive experience.

For perhaps the first time, someone may be asking detailed questions about her sexual wellbeing. This is communicating to her that her health, and her sexual health, matter.

She may be tracking her desire, arousal and sexual experiences. She may be paying more attention to sexual cues that trigger desire, and to her bodily sensations. She may be discussing concerns she has rarely spoken about.

She may change her behaviour.

Her partner may change their behaviour.

Researchers Andrea Bradford and Cindy Meston explored this question by studying women assigned to the placebo arm of a pharmaceutical trial for female sexual arousal disorder. Approximately one-third experienced clinically significant improvement. Importantly, improvement in sexual function was strongly associated with changes in the frequency of satisfying sexual encounters during the trial. (Bradford and Meston placebo-arm study)

That doesn't tell us that sexual behaviour explains the entire placebo response. Nor does it mean that these women improved because their symptoms weren't biologically real.

It tells us that taking an inactive treatment isn't the same thing as doing nothing.

The brain and body are not competing explanations.

This distinction matters because women’s sexual health has long suffered from an artificial divide.

Either a problem is biological, or it is psychological.

Either we treat the body, or we treat the mind.

But human sexual response doesn’t work that way.

The brain is part of the body. And few would argue that the brain is the largest sex organ.

Attention, expectation, learning, and emotion involve biological processes. They can influence which sexual cues we notice, how we interpret them, how our bodies respond, and whether an experience is perceived as pleasurable, threatening, distracting, or simply irrelevant.

Sexual desire can also be influenced by pain, medications, sleep, health, stress, mood, body image, relationships, previous experiences, beliefs about sex, culture, and what else is happening in a woman’s life.

None of this means hormones don't matter.

It means hormones operate within a much larger sexual-response system where context and environment matter. A lot.

What about psychological treatments?

The same scientific scrutiny should apply to psychological treatments.

In our own randomized controlled trial of eSense, women with Sexual Interest/Arousal Disorder were randomized to an online cognitive behavioural therapy program, an online mindfulness-based program, or a waitlist control. Both active interventions produced significantly greater improvements in sexual desire/arousal and sexual distress than the waitlist condition.

But participants couldn’t be blinded to whether they were receiving an intervention, and a waitlist isn't equivalent to an active placebo control in a drug trial. Our study therefore cannot tell us precisely how much of the improvement resulted from the therapy specific aspects in the CBT and mindfulness arms.

That is an important limitation.

It also illustrates why this question becomes particularly interesting when we study psychological treatments.

CBT deliberately works with patterns of thinking and behaviour. Mindfulness deliberately works with attention, awareness and responses to bodily sensations. Both ask women to engage differently with aspects of their sexual experience.

In a drug trial, some of these changes may happen incidentally as part of participating in the trial.

In psychological treatment, some of them are deliberately targeted as part of the treatment.

What if we studied the response rather than simply trying to overcome it?

Clinical trials need placebo groups for good reason.

If we want to know whether a medication has a specific pharmacological effect, we need to determine whether women receiving that medication improve more than women receiving placebo. And we need to make sure everything the person experiences in those two arms are identical, except for the contents of the drug they received.

And importantly, some randomized trials have demonstrated benefits of testosterone beyond placebo. That evidence is one reason testosterone is recommended by international professional societies for appropriately selected postmenopausal women with HSDD.

So a large placebo response does not mean testosterone doesn’t work.

But perhaps we become so focused on whether a drug can outperform placebo that we overlook another scientifically interesting question: Why are some women in the placebo group improving at all?

One analysis comparing treatments for decreased sexual desire provides an intriguing perspective. Across the studies examined, average effect sizes were approximately 1.0 for hormonal and non-hormonal medications, and 1.0 for CBT or mindfulness-based interventions. The effect size for placebo was approximately 0.55.

For women assigned to a waitlist, it was just 0.05. (Analysis of treatment effects for decreased sexual desire)

The comparison shouldn't be interpreted as evidence that placebo is a treatment for low desire.

But the striking difference between placebo and simply waiting raises a worthwhile question.

What happens when a woman becomes an active participant in addressing her sexual wellbeing?

Is it expectations?

Attention?

Tracking sexual experiences?

Permission to pay attention to her sexual wellbeing?

Changes in sexual behaviour?

Changes involving her partner?

The experience of having a concern validated and taken seriously?

Or some combination of these factors?

We don't yet know.

But surely those questions are worth investigating.

More treatments — not narrower explanations.

This is ultimately why I believe the current conversation about testosterone matters.

I want women to have more treatment options, not fewer.

If a testosterone product formulated specifically for women can be shown to provide meaningful benefit with an acceptable safety profile, women should have access to that option.

But adding another treatment shouldn't narrow our understanding of what we are treating.

Healthcare systems are very good at delivering treatments that can be prescribed. Psychological and behavioural treatments can be harder to access. They require clinicians to know they exist, patients to understand that they are legitimate treatments with meaningful benefits, appropriate referral pathways and ways of delivering care that women can realistically access.

That doesn't make medication less valuable.

But it can make medication more visible.

Women experiencing distressing sexual concerns may benefit from hormonal treatment. Others may need treatment for pain or pelvic health concerns, psychological treatment, relationship interventions, medication changes, or some combination of approaches.

The important question isn't which category of treatment should win.

It’s what is best for this particular woman.

The FDA workshop has opened an important conversation about the evidence required for testosterone products for women.

As that conversation continues, I hope we remain curious about all of the evidence — including what happens in the placebo group.

Because placebo responses aren't proof that sexual desire is “psychological.”

They aren't proof that testosterone doesn't work.

And they aren't unique to sexual health research.

But they may be clues worth investigating.

Clues about attention.

Expectation.

Behaviour.

Relationships.

Context.

And the extraordinary interaction between the brain and body that makes human sexual desire so complex.

Women deserve appropriately studied treatments.

They also deserve the whole picture.