I have rabies. I’m absolutely sure of it. I mean, I can't really tell, but that’s the silent killer, right? You don’t know you’re rabid till it’s all over, and you’re foaming at the mouth and biting your student tutor on the leg. Despite being completely safe here in Australia with its complete lack of rabies-having animals, I’m still pretty sure I’ve managed to catch it. Next week it will all be over for me and my tutor. Sorry, James.

 

Of course, it’s not actually rabies that I’ve contracted, but a much more common condition:

Medical Student Syndrome (1). Last week in my lectures, we learned all the ins, outs, and symptoms of the rabies virus. So, naturally, now we all have it. This health-related anxiety is a prime example of how our human brains can trick us into experiencing phantom symptoms. The same cognitive veil is used in clinical trials all over the world in order to test the efficacy of new drugs. We’ve all felt it. That moment when you question, ‘Is this real, or is my mind making its reality?’

 

We call this the placebo effect. The placebo effect is crucial to modern and historical experimental design. The ‘trickable’ nature of the human mind has changed the course of drug development as we know it. The effects’ success hinges on a patient's belief that they are receiving treatment for their ailment. The simple belief in a cure can often result in real physiological changes in an individual. This makes the placebo effect a very powerful tool in the development of new drugs for the market. In a placebo-controlled trial, half of the sample population will be blindly given a placebo, and the other half of the drug being tested. In order for a potential treatment to be considered effective, it must produce more significant results than the placebo group (2).

 

We must improve our approach to designing and researching hypotheses. Can we use what we know about the placebo effect to make more accurate claims about modern pharmaceutical development?

 

Well, in 2017, Dr. Sara Vanbheim of the Arctic University of Norway published a study that brought into consideration the possible effects of differing sexual characteristics on placebo efficacy (3). This idea could restructure the way experiments are designed going forward and potentially provoke a possible review of drugs already on the market. Is it possible that traditionally marginalised groups are underrepresented in the clinical trial process? Can we restructure experiments to be more inclusive? Are changes even really necessary? These questions were investigated through the compilation and calculation of placebo and nocebo effects on men and women over multiple previously conducted studies mostly centering around physical pain and the administration of analgesia.

 

The term ‘nocebo’ defines the antithesis of a placebo (4), referring to adverse side effects a

subject feels when given an inert version of the test drug. While placebos tend to have an

analgesic effect, nocebos often cause negative effects or emotions when the subjects are told that they should expect/anticipate them.

 

Before discussing any of these questions, it is worth noting that the Norwegian study focuses

solely on classic sexual differences between cis-gender men and women. Though both keywords ‘gender’ and ‘sex’ were included in the study, research surrounding the specific effects of gender identity and gender-affirming therapies on placebos has not been thoroughly conducted as of 2023. It is with this focus that the following hypotheses are stated (3):

 

“1) placebo responses would be stronger or more frequently observed in males than in females,

2) nocebo responses would be stronger or more frequently observed in females than in males,

3) verbally induced placebo responses would be more frequently observed in males than in females, and

4) conditioned nocebo responses would be more frequently observed in females than in males.”

 

Results concluded that there was indeed a significant correlation between sex and

placebo/nocebo effects when concerning pain relief. But what is truly fascinating is that while

men received elevated levels of a placebo effect, such as reduced symptoms and analgesia,

women were more susceptible to hyperalgesia and negative emotions. Those supposed ‘side effects’ appear to weigh more heavily on women (3).

 

What does this say about how men and women process pain and information? The Norwegian study discusses the role of ‘psychophysiological mechanisms’ in pain pathways. Or, more simply, How stress and anxiety can affect the pain the brain perceives. In 8 of the 12 studies, men experienced significantly stronger analgesic effects from the placebo than women (3). It is plausible that men react more strongly to pain induced by stress hormones. This would explain why when taking a placebo, their anxiety level would decrease, and they would receive higher levels of analgesia than their female counterparts (3). Another study, upon which the Norwegian argument builds, investigates placebo delivery methods and their effect on perceived pain in men and women. In this study, men relied far more on verbal queues to provide analgesia, whereas women received a more significant effect from classic conditioning (5).

 

These studies bring into question both the methodological and physiological effects of placebos on different sexes. What do these differences tell us about how men and women perceive the world? And what does this mean for the future of the placebo?

 

The result of all of these studies is to show not whether placebos are bad or good, reliable or unreliable, but instead to highlight the differences in the physiological and psychological links when looking at different groups of people. At its core, a placebo is simply a trick of the brain, a psychological mirage. While the basis and reliability of placebos can be debated at length, their effect on the human brain teaches us something about ourselves societally. In all areas of medicine, the inclusion of people from all different backgrounds, genders, ethnicities, and ages is crucial so professionals know how to identify and treat various manifestations of a disease with grace and care.

 

Now I know James responds better to verbal commands; I’ll be sure to tell him he has rabies the next time I see him.