Keith Petrie sets his health psychology students a challenge each year: create your own sham treatment, snake oil or pseudo-scientific therapy – something you could theoretically charge big bucks for.
The University of Auckland professor sets the task after teaching his students about the placebo effect, the intriguing response that’s baked into every drug or treatment study: when patients feel better even though they’ve been given a treatment that’s not active, such as a sugar pill or saline solution. Placebo arms are a standard feature of drug studies; they’re there to help determine the effectiveness or otherwise of the treatment being tested. There’s always some degree of placebo response in drug studies. Do better than the placebo with your treatment, the thinking goes, and you’re on to a winner.
Petrie’s students tend to come up with creative ideas for their placebos along similar lines, he says. “They’re often some sort of machine that does powerful things; or they’re showing models to people of all the great benefits they’ll get. And, of course, there’s always megavitamin nutritional solutions for this and that.”
It’s a lighthearted exercise. But the placebo effect is the subject of serious research. Experts now believe it’s more than just something to factor in and allow for in medical research. The placebo has the potential to improve existing treatments and medications, and to teach us more about the mind-body connection when it comes to health and healing.
Crusaders such as Harvard professor of medicine Ted Kaptchuk are excited about the potential for the placebo response to enhance existing drug treatments and potentially treat pain conditions. Kaptchuk is an advocate for the potential of the placebo as an evidence-based, clinically relevant tool for relieving chronic pain. His studies have ranged across conditions including chronic back pain, irritable bowel syndrome, menopausal hot flushes, depression and cancer-related fatigue.
All in the brain
That the placebo response is simply all in the mind – an imagined effect, in other words – is an idea many of us may hold. But that’s not what’s really going on.
Petrie – one of a handful of researchers around the world who have looked at the placebo response in depth – says it’s now understood that placebos operate on the same circuitry in the brain as drugs do. Positive effects on pain in particular are seen in the same ways in the opioid system with placebo treatments and drugs alike.
Research has found that only a healthy brain can develop a placebo response.
“It seems like we have to have a pretty healthy, well-connected brain in order to get the maximum placebo response,” says Petrie. “I don’t think anyone these days argues that it’s an imaginary response. If the brain is impaired, it doesn’t seem to work as well.”
Another misconception about the placebo response is that it only applies to inert treatments (those with no active ingredient).
“What people don’t realise, I think, is the placebo response actually wraps around all treatments. So, you can have a treatment that’s very effective [but] it still has a placebo response boosting its overall effectiveness. And a treatment that’s completely worthless also has a response wrapped around it, but its total response is just due to the placebo response.”
Cue reinforcement
Many things influence how and why the placebo response works. It makes intuitive sense that expectation – what we think is going to happen when we receive a treatment – might have a major influence. So, too, does conditioning: what we’ve experienced in the past with drugs and treatments.
Social cues – observing the experiences of other people, social buzz and word of mouth – also come into play. So does the design of the placebo itself. The design, colour and shape of a placebo pill can affect how much of a response there is, Petrie says. And “two pills are usually better than one”.
When patients suspect they’re receiving an “active” treatment – if it tastes strong, for example, or fizzes in the mouth, or even creates mild side effects – it can condition them to think a placebo treatment is working better.
And in fascinating evidence that plays into how drugs are marketed, it’s been found that the name of a pill can even have an impact. In a 2019 review on placebos, Petrie and colleagues cited research findings that certain letters of a brand name can produce a link between a sound and a meaning. “Drug companies have increased their use of X and Z in drug names dramatically over recent years … the letter Z has connotations of efficacy, while the letters T and S have been shown to be associated with ideas of smaller, lighter, faster and more tolerable treatments,” Petrie wrote.
In general, more serious “treatments” have a bigger placebo response, he says. “Things like surgery or treatments that involve equipment and machinery – things that convey that this is a serious treatment.”
A famous example is a groundbreaking study conducted in 2002 on patients with osteoarthritis in their knees. Until then, the standard treatment for the condition was a surgery known as arthroscopic debridement. In the double-blind study, patients were given either the surgery, a simple saline lavage (washout) of the joint, or a sham surgery where an incision was made but no surgery performed. The patients experienced the same results no matter which group they were in – a result which showed the power of placebo, and permanently changed how doctors treated osteoarthritis.
Empathy effect
The interaction we have with health care professionals can also influence the effectiveness of a treatment.
“Clinicians who are competent and warm get a much bigger placebo response,” says Petrie.
Studies have confirmed this again and again. Researchers in a 2008 study instructed one group of clinicians to interact with participants with irritable bowel syndrome (IBS) in a highly empathetic way, asking questions and using a warm and supportive tone while administering a placebo treatment. The control group of clinicians gave the same placebo treatment, but were asked to act formally, without expressing warmth toward their patients. The results: both groups improved, but those with the empathetic doctors improved more.
One of the authors of that study was Kaptchuk. As well as being a pioneer in the study of placebos, he’s director of Harvard Medical School’s programme in placebo studies and the therapeutic encounter (PiPS) in Boston. He’s worked at Harvard since 1990 when the university recruited him from the world of Chinese medicine, where he was one of the first Westerners to train in the field in China.
“I’ve shown that we can manipulate placebos,” he explains, “analogously to a drug, [creating a] dose-dependent situation. You can give a bigger dose of placebo or a smaller dose of placebo. I showed that devices like needles, injections or procedures usually have higher placebo effects than pills.”
Genetic factor
Kaptchuk and colleagues are looking at a genetic component to the placebo response – what’s been termed the “placebome”. Some people, it’s theorised, are better at responding to both drugs and placebos because of a genetic predisposition.
He also discovered that there’s more than just expectation at play in people’s minds when it comes to placebo treatments.
Kaptchuk had anthropologists interview patients in the placebo arm of one of his IBS studies. “I asked them to tell me what was going on in people’s heads; what their experience was. I read the transcript and my jaw dropped.
“We asked people, ‘Do you expect to get better?’ And they said, ‘Huh? I’ve been to three hospitals, two acupuncturists, one chiropractic. What are you talking about, me getting better? I don’t expect to get better.’”
Taken aback, the researchers asked the obvious question: “Why did you come into this study?”
“And people would say, ‘If you told me to put on a pink tutu and pink ballet slippers and it would help my irritable bowel syndrome, I would do it. If I don’t have hope, I can’t get out of bed.’”
If the blinded placebo response is still a tricky thing to explain, the open-label placebo is a complete tongue-twister.
An open-label or “honest” placebo is what it sounds like: everyone, including the patient, knows they’re receiving a placebo treatment. They know it’s not active. And yet – and this is the bit that intrigues researchers – patients still feel benefits. In one of Kaptchuk’s studies, he found the effect of an open-label placebo to be the same as that of a double-blind placebo in patients with IBS.
How could someone who’s really suffering – with pain, say – feel less pain even though they know the treatment they’re being offered is an inert substance?
“I think we’re still trying to figure it out,” says Kaptchuk. “We know that neurotransmitters are released when patients are treated with placebos: endorphins, cannabinoids, dopamine. We know that different areas of the brain are activated and engaged when people respond to placebos … So, there’s some neurobiology, even if it can’t change pathophysiology.”
Pain and the brain
Beyond the psychology of expectation and conditioning, the doctor-patient relationship and the medical ritual aspects of placebo responses, the other mechanisms at play here are not easy to explain. The emerging science is, as Kaptchuk describes it, “at the cutting edge of the cutting edge”.
He talks about the neurocomputational theories of predictive coding and the Bayesian brain. The Bayesian brain theory describes the brain as a prediction machine, rather than a passive organ waiting for external stimulation. Predictive coding says the brain is constantly generating and updating a mental model of the environment.
People with chronic pain conditions can be highly reactive to pain; they become highly sensitive and can experience extreme pain in response to stimulus that wouldn’t be painful in others, or beyond what can be identified in terms of injury or illness. Their pain signals are unusually amplified.
“The same pathways that amplify pain … those pathways sometimes get stuck, in what we now call central sensitisation,” says Kaptchuk. “The brain keeps firing.”
This can also happen when someone has physically completely recovered from surgery or injury, but still feels pain.
Kaptchuk says when patients with central sensitisation are treated with open-label placebos, they’re put into a paradoxical situation. For some people, some of the time, that paradox nudges the brain to turn down the volume on their pain.
“The context you’re in makes you process perception, sensations and symptoms differently. Open-label placebo puts you in a totally weird context. People are … in a cauldron; it’s what my psychologist calls automatic cognitive behavioural therapy with no effort.”
In a related paradox, Kaptchuk’s studies have found that with open-label placebo, the expectation of feeling better isn’t a strong factor. In fact, he says, “The best patients we get are those coming in going, ‘I don’t believe this will work.’”
The same goes for doctors, who are typically not fans of placebo treatments, but are a necessary part of the process.
“For most people, it’s crazy. And doctors totally don’t get it … but I tell them, ‘If you think it’s crazy or feel bad about it, tell the patient that, too.’ Because that’s part of what’s going on. The bottom line is honesty here.”
Practical use
The potential for the power of the placebo response to be harnessed to improve health outcomes has advocates excited. But ethical issues come into play here, and present a big impediment to the use of traditional placebos. It would go against every doctorly instinct to prescribe a sham treatment. As Petrie puts it, “Doctors are not put on Earth to give sugar pills.”
So, what’s the future of this work? Petrie thinks there’s potential in placebos, especially open-label. But he says, the jury is still out on how exactly they could be used, and whether patients would accept them.
“You can imagine going to the doctor with some sort of pain. He says, ‘Well, good news – here’s a placebo for you.’ Your initial response is going to be, ‘This guy’s not taking me seriously.’ So, I think there are barriers.
“The bigger issue for me is really: how can we use what we know about the placebo response to improve existing treatments in medicine?”
Kaptchuk has demonstrated these possibilities in his work. In a 2021 study on patients recovering from back surgery, a group of patients was given standard opioid pain treatment alongside an honest placebo.
Every time they took a pain pill they took a clearly labelled placebo pill as well. The patients consumed 30% less morphine than those who didn’t get the placebo.
Petrie muses this could be where the practical power of placebos lies. “I think this is an interesting area, because it’s got quite a lot to teach medicine about how to boost [the body’s] natural healing, and how do we make the treatments we’ve got much more effective.
“When you look at how powerful the placebo response is, and how much money is spent on new drugs that give marginal benefits, you think, wow, how much more could we get from existing drugs by just focusing on improving the placebo response? What if we used that to boost the drugs we’ve already got?
“We could actually get a better response for a whole lot more people.”
The nocebo effect
The evil twin of the placebo effect is the nocebo effect: when patients experience a negative outcome even though they’ve been given an inert placebo treatment. It’s a twist on what’s going on in the brain with a placebo, says researcher Keith Petrie.
Just as positive expectations can affect how well a treatment works, “typically when we have negative expectations about a treatment, we are much more likely to notice side effects”, he says.
The nocebo effect has been shown in studies on vaccines, and it can happen with changes to branding and pricing of treatments, as in the case of generic versions of branded drugs.
“We’ve done quite a bit of work showing that because people have negative views of generics, when you describe a pill as a generic, they will report more side effects even if they were receiving a placebo.”
Outside the lab, this happens when drug switches occur for patients on long-term medication.
“The drug is essentially the same; it’s tested to be the same. But it changes brand or it changes colour or shape, and people notice it’s different. And then typically there’s a media story that sets off the reporting of side effects.”
One of Petrie’s studies showed that media coverage after a drug switch will result in a large rise in reported side effects. “We are quite influenced by other people taking the same drug. When we hear on the news about someone [having side effects] after a drug change … our attention tends to be drawn to those same side effects that the person’s mentioned, and then there’s an increase in the reports to the adverse reactions database.”
The nocebo effect can also arise because we misattribute symptoms. “I mean, symptoms are very common. And that’s where the nocebo effect cashes in. In studies we’ve done, if you ask people what symptoms they’ve had in the last week, the median number of symptoms was about four or five. But about 20% of the population have 10 or more symptoms. So, there’s quite a lot of material there that you can easily attribute to a drug or something in the environment or something that’s happened.”
The nocebo effect can be somewhat mitigated, Petrie has found, by simply explaining it to people. “If you tell people a little bit about the nocebo effect, they seem to be less susceptible to it. You can dampen down the response.”
He’s noticed this works well when the effect is explained with a real-life example. “You might say, ‘Imagine you’ve been around a table having a meal and someone suddenly gets ill. Then you start noticing symptoms in yourself and not feeling that great.’
“That’s just an example of the nocebo effect in action. And if we change a pill or a treatment, it can also force us to notice common symptoms that we’re experiencing, but we may now attribute them to that change. And people kind of get that, you know. They’ve seen it in action.”
Fake it til you make it
While some of the power of a placebo lies in the ritual and attention found in taking a pill or being administered a treatment – especially in a medical setting – there are other factors at play. And some of these we can all harness: it’s possible to essentially create an open-label placebo response in ourselves.
An example of this can be found in a study conducted at the University of South Australia. Researchers there found that the act of smiling can trick your mind into feeling more positive – even when it’s a fake smile.
The researchers got participants to hold a pen between their teeth, forcing their facial muscles to replicate the movement of a smile.
Lead researcher Dr Fernando Marmolejo-Ramos explained: “We found that when you forcefully practise smiling, it stimulates the amygdala – the emotional centre of the brain – which releases neurotransmitters to encourage an emotionally positive state.
“When your muscles say you’re happy, you’re more likely to see the world around you in a positive way.”
Ramos reckons that if we can trick the brain into perceiving stimuli as “happy”, we can potentially use this mechanism to help boost mental health.
The same thing can apply with other forms of self-care, including meditation and exercise. It also applies to self-talk.
There’s a decent body of evidence to show that positive affirmations – like those popularised by American self-help author Louise Hay in her rainbow-covered books – can affect mental health in beneficial ways.
Various studies have shown that using self-affirmations – statements like “I believe in myself and trust my own wisdom” or “I am confident and capable” – even when we don’t believe them – can be effective mood boosters. There’s evidence self-affirmations work for anxiety, rumination and stress. They can improve academic performance and boost physical activity and healthy eating.