Sometimes, a fake pill can make us feel better. Science is starting to reveal why

The Age

3 days ago

This story is part of the August 9 edition of Good Weekend. See all 13 stories.
I was a child at a time when doctors made house calls. Dr Blaxland, our family doctor for as long as I can remember, would drop in to our house whenever my brother or I were too sick or too infectious to see him at his surgery. An imposing man, he would arrive bedside in a dark suit and freshly laundered shirt, carrying a heavy gladstone bag, the stiff folds of which concertinaed open to reveal a collection of sober, confidence-inspiring instruments. Soon there would be the cool feel of the stethoscope, the glassy taper of the thermometer, the dry weight of a tongue depressor, or just the soothing touch of Dr Blaxland's antiseptic-white hand on a hot brow or thready pulse. He would take his time studying tonsils, spots, rashes, swollen glands or injured limbs, before sitting back to deliver a diagnosis, his voice firm but kind, and a treatment plan. Quite often the treatment plan was bed rest. A tonic might be recommended.
We weren't instantly cured, but we always felt better after his visit. Some part of us believed that Dr Blaxland alone had placed us on the road to recovery. An appointment at the surgery, back when doctors had more time to give care and attention, had a similar magical influence.
How much of our recovery was helped along by the mere expectation we would get better in his hands, an expectation born of his authority, his manner, his reassurance, his gleaming kit? A mind-body messaging system switched on by all those cues. A placebo effect.
The placebo effect refers to the mysterious phenomenon of a patient feeling an improvement in symptoms even after a sham treatment. The placebo might be an innocuous substance like a saline injection or a sugar pill, a sham procedure or just a persuasive setting.
A doctor with a stethoscope sitting on the end of your bed. Placebos are a fixture in drug trials, of course, as a control arm. In a randomised controlled trial, participants are given either placebo or the drug, not knowing which is which. The drug has to prove itself superior to placebo. Placebos even made headlines recently when so-called vaccine sceptic and US Secretary of Health Robert F Kennedy called for even vaccine updates to be classed as 'new drugs' and subjected to fresh placebo trials.
Belief, it seems, lies at the heart of a placebo effect. It's about expecting a treatment or procedure will do what it's said to do. Unlike real drugs, which are supposed to work whether you believe in them or not, placebos only work if you believe, at some underlying level, that they will help. It's more than just positive or wishful thinking. That belief, that expectancy, can prompt the brain to send signals to the rest of the body, letting it know how to feel better. Precisely how those neurobiological pathways work is still conjecture but, according to some placebo researchers, part of the explanation is that the expectancy leads to the release of feel-good neurotransmitters like the body's own opioids and dopamine, or sparks activity in brain regions linked to moods, emotions and self-awareness. It may do much more, yet to be understood. As neuroimaging becomes more sophisticated, the pathways and inner workings of placebo effects are becoming clearer and more credible.
Placebos have been known to improve symptoms in ways that can be measured. More often, though, patients simply feel better or are in less pain. The effects can be long-lasting and at times as good as a genuine treatment, which either says a lot for placebos or not much for the treatment. It's why drug companies dread placebo responses. If a drug on trial proves no better than the placebo, its future is dim. (That said, many drugs, including some antidepressants, are still widely prescribed even though they've struggled to show they are much better than a placebo. They work, but so do sugar pills. As we'll see, the same can be true of surgery.)
Healers of all kinds have relied forever on placebos, especially when faced with desperate patients and nothing better to offer than a bunch of leaves, a sugar pill or a trick injection. They still do, as it happens. Most Australian GPs have used a placebo at least once, according to a 2019 study by the University of Sydney's professor of psychology, Ben Colagiuri, a placebo expert, and the University of NSW's Associate Professor Kate Faasse. Some 77 per cent of GPs said they'd offered an active placebo – such as antibiotics for a virus – and 39 per cent had offered an inert placebo, such as saline or a water-based cream.
'The GPs primarily gave placebos to help their patients,' says Colagiuri, who became fascinated by placebos years ago, after reading people could even get side effects from them. 'The doctors weren't trying to dupe them. There was nothing else they could give and they thought this might help. Is it the right thing to do? That's a whole separate debate. Probably giving antibiotics [for a virus] is not ideal, but the intention was good.'
The doctors also saw themselves as having a strong role in shaping patients' expectations. A case of 'the doctor said it might help', and it did.
The idea of mind and body being intimately connected is hardly new, either. It just went out the window around the 17th century, in the West at least, with Cartesian dualism, after French philosopher René Descartes declared mind and body were fundamentally distinct substances. Now, however, placebo research is burgeoning and there's growing interest in evidence-based trials of what was once dismissed as far-fetched, including techniques such as biofeedback. Melbourne's Deakin University, for example, has a dedicated Mind-Body Research in Health Laboratory, trialling everything from hypnotherapy to wild swimming and yoga, to see if therapies can help people live better with chronic, incurable and painful conditions such as endometriosis, Crohn's disease and ulcerative colitis.
Some experiments have found people still report improvement even when they know they've been given a placebo.
Neurobiology – the study of the nervous system, including the brain – is the focus of a lot of placebo research. It's full-on in there, a dizzying rush-hour with neuronal messages flying back and forth about what's going on internally and how to deal with it. The brain, the mind, works in concert with the rest of the body in a hypersensitive way.
And the interaction is constant. In her book Placebos, Kathryn Hall, a placebo researcher in the US and an assistant professor of medicine at Harvard Medical School, refers to 'the neurobiological mechanisms that influence almost every clinical encounter we engage in, regardless of whether the treatment is active or inert'. Those mechanisms can be kickstarted just by being in a doctor's office or seeing a syringe.
Some experiments have found people still report improvement even when they know they've been given a placebo – an 'open-label' placebo. Why? It may be triggered by the simple but meaningful act of taking a pill or getting an injection. It's also possible, in a kind of double-bluff scenario, that the recipient believes it's a trick and that they're getting the real drug, labelled as placebo.
When it comes to creating expectancies, context matters. So does upbringing, our past, conditioning and other cues. If you've grown up with Western medicine, being given a treatment by a doctor in a white coat is more likely to make you believe in it than if your wacky neighbour hands it over the fence in a paper bag.
'Our placebo effects will be different,' says Colagiuri, 'based on our culture and the meaning that comes with certain things, whether it's a pill or an acupuncture needle. We're probably all capable of responding to placebos but there's no one placebo that's going to work on everyone.'
Some research, not entirely solid, has pointed to other small cues at work. Pill size (either big or very small has the most effect) and even colour. The expense of a treatment. Branding. A sham injection has more placebo power than a sham pill. Hall cites a study that found morphine wasn't as effective at reducing pain when the person couldn't see it being administered.
No magic bullet
If the fakes are so effective, you might wonder why we aren't jettisoning a whole lot of medical practices and drugs, often costly and plagued with side effects, and relying on placebos. Well, ethics, for one thing. Deceiving people about what they're getting isn't considered good form these days. For that matter, some researchers still argue the evidence of placebo efficacy is patchy and exaggerated, or hard to replicate. The fact that the effects rely so heavily on self-reporting doesn't help their case.
Also muddying the waters are factors such as natural course. Is the improvement due to the placebo effect or down to the natural course of the disease? The person might have felt better anyway, even with no treatment. Let's say they've been enrolled in a trial for a new cold drug and are in the set that gets the placebo. Lo and behold, they feel better within four or five days. The point is, that's also about the natural course of a cold.
There's also something known as reversion to the mean. Most conditions, especially those with intermittent pain, like osteoarthritis, have their peaks and troughs. People enrol in trials, or seek medical help, when their symptoms are at their worst. It's likely the symptoms will go back to being closer to the average at some point, with or without a treatment, fake or real.
And most importantly, placebo effects are not a magic bullet for everything that ails us. They might reduce pain or help people cope better with, say, post-operative recovery, a migraine or debilitating side effects of chemotherapy, but they can't kill a virus like COVID-19 or stop cancer, as far as the evidence shows. They can affect symptoms, make someone feel better, but they haven't been known to cure disease.
As British psychologist Dylan Evans cautioned in his 2003 book, Placebos: Mind over Matter in Modern Medicine: 'The placebo response is simply a rapid readjustment of the body's own natural healing mechanisms to a surge of hope, and there are limits to what these mechanisms can do, even if fuelled with industrial-strength optimism.'
Evans himself is measured about the 'power of the placebo' but has looked at the conditions they've been shown to help with. His own theory, still unproven, is that placebo pathways are linked to inflammatory responses. Some of the conditions placebos have been found to influence, to a greater or lesser extent, include pain, side effects from a treatment, depression and anxiety, mobility, insomnia, high blood sugar, gastro-intestinal and dermatological disorders, Parkinson's, hypertension, stomach ulcers and even swelling.
People tend to associate placebos with drug trials, with sugar pills, snake oil and saline solutions. But surgery, too, can induce placebo effects. It's a strong candidate, when you think about it, steeped as it is in ritual and expectation. There's nothing like that life-and-death chat with the anaesthetist, being gowned up and wheeled into an operating theatre, to create the expectation of a useful outcome. But are all operations what they're cracked up to be?
When they're put to the test, some come up short. A famous example is an operation called internal mammary artery ligation, popular in the 1940s and 1950s to treat angina. It was a painful process which involved cutting into the chest and ligating some of the arteries supplying blood to the heart. It seemed to work because most of the patients reported feeling better. Surgeons believed in it, patients believed in it, possibly as fervently as doctors and patients had believed, for about 2000 years, in the benefits of bloodletting. Then, in the late 1950s, researchers trialled a sham version, cutting into the chest, but not tying the knots. To everyone's surprise, the results were just as good. It was the first time blinded placebo controls had been used to evaluate invasive procedures. Unfortunately, even now many operations aren't subjected to those controls. They're taken more as an article of faith.
In recent years, Australian surgeon and UNSW professor of orthopaedics, Ian Harris, has championed the need for hard evidence when it comes to the benefits of a host of routinely performed operations – from spinal fusions to hysterectomies to cardiac stents, which isn't to say there's never a case for them. Harris, the author of Surgery: the Ultimate Placebo and Hippocrasy, has argued that the benefits of many surgeries are often wildly overstated and the harms understated. Both surgeons and patients have a false belief in the procedure's worth.
'There is a difference between any real, direct effectiveness of surgery,' he has said, 'and our perception of the effectiveness of surgery. That difference, which we will call the placebo effect, is the reason we tend to overestimate the true effectiveness.'
(He stresses, however, the need to nail down what's actually producing the benefit. It could be natural course. That would mean comparing surgery to placebo to no treatment or non-surgical treatment.)
Patients tend to feel better if something is done, and doctors find it hard to do nothing. A 2021 study asked a random group of Swedish surgeons if they believed there are surgical treatments where the entire treatment effect is due to placebo; 78 per cent said yes. Examples included varicose vein surgery, some types of orthopaedic surgery, gallbladder surgery for pain and hernia surgery. The surgeons also said they knew their treatments had more effect when they conveyed confidence and calm, built a positive relationship with the patient and made eye contact.
Not everyone has read the memo. Modern medicine is often profit-driven, impersonal and fast (don't waste time asking the patient how they are), and that goes some way to explaining why 'alternative' medicine is so popular, despite the cost and some dubious mechanisms. Ben Colagiuri says expectancy plays a big part there, too.
'With things like acupuncture or homeopathy,' he says, 'most studies show there's no benefit relative to a well-controlled placebo, but that doesn't mean people don't feel better after having it. It's just about, where is that improvement coming from? You have these relaxation or expectancy effects.
'There's also a lot of ritual associated with those Chinese and alternative medicines. An alternative health practitioner might be spending 30 minutes or an hour with you and they have some pretty interesting diagnostic techniques. You know, 'Stick out your tongue, oh, your tongue looks like this, give me your hand.' They're really ritualistic, and they're the kinds of things that can play into building up an expectancy.'
'When someone expects pain relief, there's a release of opioids in the brain … like the body's natural morphine.'
University of Sydney professor of psychology, Ben Colagiuri
Interestingly, microbiologist Kathryn Hall opens her own book with a story about acupuncture. For more than a year, Hall had been suffering the pain of carpal tunnel syndrome, a wrist condition. No amount of conventional medical treatment had fixed it and she found herself sliding from ibuprofen to codeine. She was a scientist working in the pharmaceutical industry at the time, so it wasn't as if she was against mainstream medicine. Still, she was loath to have surgery. One day, out of desperation, she went to an acupuncturist a friend kept recommending. In rooms that smelt of Chinese herbs, the acupuncturist went through those rituals Colagiuri describes, took Hall's pulse, inserted needles, pressed points in her arm. When it was over, Hall got back to her car and was astonished to find the pain that had plagued her for so long had completely disappeared. If it came back over the years, she would rub a certain point as instructed by the small, nimble Chinese woman and it went away again. 'Why did that work?' she wanted to know. 'Was it the power of acupuncture or just a placebo effect?'
Loading
Just a placebo effect? 'No better than a placebo', 'all in the mind'. Those expressions underestimate what a powerful force expectancy can be, even when we're unaware of it. We forget how much our brain shapes our experience, especially when it comes to the subjective business of pain.
Says Ben Colagiuri: 'Pain is probably the most well studied and well understood in terms of placebo and nocebo effects. We know that when someone expects pain relief, there's a release of opioids in the brain, which is like the body's natural morphine. You can see these effects in the brain, in the spinal cord even. There's a genuine change in their neurochemistry, if you like, that's leading them to be less susceptible to pain because of those expectancies.'
Still, it's not as much of an opioid as a pharmaceutical opioid. Says Colagiuri: 'I would definitely choose getting morphine if I had my leg broken.'
The nocebo effect
Placebo, which sounds pleasantly positive and is Latin for 'I will please', has an opposite: nocebo. Nocebo effects are when we make ourselves ill by expecting to be ill, by expecting that a drug or treatment, or even a foodstuff, will harm us. So even with a fake version, we can develop negative symptoms, get worse or fail to improve.
Associate Professor Heidi Staudacher is a dietitian and researcher at Monash University. She specialises in gut-brain health and how it relates to diet. Right now, she's doing a meta-analysis of placebo and nocebo response rates in dietary research, especially in relation to irritable bowel syndrome (IBS).
Given the 'staggering' number of people who report diet as a trigger for symptoms of IBS and similar conditions, Staudacher wants to know the role of nocebo effects. Take gluten, for example. A study among people with self-reported non-coeliac gluten sensitivity – people who didn't have an official diagnosis of coeliac disease but believed they couldn't tolerate gluten – revealed some intriguing results.
Loading
Participants were randomly given bread either with gluten or gluten-free, and it was either correctly or falsely described to them. Says Staudacher: 'The people who received gluten-containing bread and were told it was gluten-containing had greater gut symptom responses in the following several hours compared with those that got gluten-containing bread but were told it was gluten-free.'
Ditto symptom-reporting in a study using low-fat yoghurt that was labelled as high-fat. Nocebo effects can even affect blood-glucose levels, it seems. 'In one study, people were provided with a drink that was labelled sugar-free or low-sugar, but actually wasn't and vice versa,' says Staudacher. 'People's blood-sugar responses were higher with the one [falsely] labelled high-sugar. That suggests there's actual physiological responses going on, in conjunction with expectation.'
The nocebo effect is usually relatively benign, says Staudacher, but in some cases it can be debilitating. She mentions the clinical trial of an antidepressant where one of the participants overdosed on what he thought was the antidepressant but was in fact placebo. His blood pressure plummeted, he was hospitalised and given litres of fluid. Within 15 minutes of being told he'd had the placebo, he became alert, and his blood pressure and heart rate normalised.
A study among people without a diagnosis of coeliac disease – but who believed they couldn't tolerate gluten – revealed some intriguing results.
The trouble with nocebo effects is that they can discourage people from sticking to medication that could help them. Ben Colagiuri is interested in the role of social media, where everyone has a horror story to tell.
'If you see someone report side effects on social media, how does that influence your own side effects?' he says. 'We found people exposed to negative social media about COVID-19 vaccination side-effects, for example, were more likely to expect them and actually got more got more side effects when they got their vaccination. The idea of these [mass] socially acquired nocebo effects is pretty interesting.
'But we're also looking at whether you can use social modelling in a positive way to counteract some of that negative information.'
As it is for so many placebo researchers, the big question for Colagiuri is whether there's a useful, ethical way to use what we know about placebo and nocebo effects, and their psychology, in clinical practice. 'Can we adapt a treatment to capitalise on the potential benefits of placebo effects? What can we do to ethically enhance someone's expectations?' he says. 'When we talk about things like side effects, we know that if you say, 'Here's a treatment, it causes headaches,' people are more likely to get headaches because you've told them to expect them.
'So instead of saying '30 per cent of people will get headaches,' we can reframe the information: 70 per cent of people won't get headaches. That seems to reduce their expectancies and the side effects they experience. You're not lying or changing the underlying treatment but you're using knowledge of placebo/nocebo effects to change the way you communicate.'
Not all side effects are conjured up, of course, but information is persuasive. Take a 2003 trial of a beta-blocker called atenolol, with a possible side effect of impotence. Among the men not told the drug's name, only 3.1 per cent developed it. About 15 per cent developed it when given the name. But among those told both the name of the drug and that it might cause impotence, 31.2 per cent developed erectile dysfunction. The men complaining of impotence were then randomly given either a placebo or Viagra. Both worked just as well in restoring erections.
To the frustration of the pharmaceutical industry, the placebo response seems to be becoming an even bigger obstacle in drug trials. 'They're getting larger effects in the placebo groups,' says Colagiuri, 'and that makes it harder to show the superiority of their drug.' (Assuming the drug is superior.)
Loading
The industry, predictably, has been keen to find ways to weed out placebo responders from trial groups, like removing hostile jurors, even though doctors could hardly get rid of patients like that in the real world. The industry has also suggested, in a roundabout way, the problem might lie with trial participants getting too much attention, skewing results through a kind of placebo-inducing pampering: the phone calls to see how they're going, the meetings, and so on.
'That kind of attention doesn't really reflect what happens in real life,' says Colagiuri, 'so [the drug companies] are saying, 'Are we missing seeing drugs that are effective because of some ceiling effect [in trials] of placebo response?' '
That's one way of looking at it. Another is to wonder if there would be the need for quite so many new drugs or dubious procedures, so many cold-eyed tests and expensive treatments for passing ailments, or so many people disenchanted with conventional medicine, if more placebo-triggering care was shown in real life.
That's where most placebo and nocebo research is focused now. No longer on whether they exist but on how medicine can make better use of them. And there are ethical ways: 'This is a placebo but it has helped some people and it may help you.' That's been known to work. As for ethics, overselling the benefits of a drug or invasive procedure isn't very ethical either. Harnessing placebo and nocebo effects isn't going to produce miracles or be a cure-all that makes medicine redundant, but there are many who believe it could aid in making the most of whatever self-healing powers we possess. Call it the Dr Blaxland effect.