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LINDA BUONANNO had been sick with irritable bowel syndrome for 15 years when she saw a TV advertisement recruiting participants for a new study. Desperate for help, she signed on, even after learning that the potential treatments she would be offered consisted of either nothing 鈥� or pills filled with nothing.

When the experiment ended, she begged the researchers to let her keep the pills. 鈥淚 felt fantastic,鈥� Buonanno says. 鈥淚 felt almost like I was before I got sick with IBS. It was the best three weeks of my life.鈥�

She has been trying to get her hands on more ever since. A replication study will start later this spring, and Buonanno is desperately hoping she gets in.

This is the placebo effect in action, and it may come as a surprise to learn that it works even when people know they are being given a sham treatment. That finding has brought with it the possibility of using placebos as therapy. The vision is of a future in which clinicians cajole the mind into healing itself and the body 鈥� without the drugs that can be nearly as much of a problem as those they purport to solve.

But before your doctor can prescribe you one of Buonanno鈥檚 pills, a lot of slippery questions must be tackled: what conditions respond to the placebo effect? Where are the boundaries of this nascent science? More importantly, can we harness it with predictable effects?

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The placebo effect has been on a considerable journey: once just a thorn in medicine鈥檚 side, it is now the latest promising way to manipulate the mind into healing the body. Placebo controls are the gold standard of clinical trials, used to figure out whether a drug works better than nothing 鈥� but instead of obeying the rules and feeling no different when given a placebo, people often report beneficial effects.

鈥淚n drug trials, the placebo effect is the background noise they have to separate out,鈥� says Ted Kaptchuk, the lead researcher behind Buonanno鈥檚 trial at Beth Israel Deaconess Medical Center in Boston. 鈥淏ut we鈥檙e saying, this noise is really important. We want to get that noise in the equation too.鈥�

We now know that when a person is given a pill they鈥檙e told is a real medication, or any of a wide range of medical interventions, including surgery, their body creates a real physiological effect. In pain studies, placebos have been shown to dampen activity in the brain鈥檚 pain-processing areas and (see 鈥淵our brain on placebo鈥�).

It may not be so surprising that pain should succumb to the power of suggestion, but the placebo effect also works on conditions that would not be considered to have a psychological component. People being treated for Parkinson鈥檚 disease with , were only told they might receive a dose of the drug . . Not even the immune system is immune: in one experiment, healthy participants spent three days taking pills containing immunosuppressant cyclosporin A 鈥� a drug used to help stop the body rejecting an organ transplant 鈥� with a fruit-flavoured drink. Five days later, they took placebo pills with the same drink. Blood tests showed that immune compounds suppressed by the actual drug also . Even faked surgical interventions have been shown to create real improvement.

Great expectations

One key to unlocking the body鈥檚 self-healing mechanisms seems to be the setting up of an expectation of improvement. And it works the other way too: if you think your drug has been replaced with a placebo, even a strong painkiller鈥檚 effects will be dulled. So how can we harness this effect, given that we know very little about how it works? In pursuit of that goal, Kaptchuk founded the Program in Placebo Studies, while groups in Germany, the UK, Italy and Australia are also studying how to integrate placebo insights into patient care.

There鈥檚 just one problem: using placebo in this way requires deceit, which falls foul of several major pillars of medical ethics, including patient autonomy and informed consent. That was why Kaptchuk decided to try being honest with patients, and how Buonanno found herself taking pills packed with inert filler from a bottle marked 鈥減lacebo鈥�.

IBS is one of those conditions, like depression and chronic pain, that is heavy with symptoms but has neither clear biological cause nor easy cure. Buonanno had spent years in pain; and no doctor or drug seemed to help.

鈥淧lacebos also work on conditions not thought to have a psychological component鈥�

The staff at the medical centre had explained to her that though the brightly coloured pills contained no medication, evidence from previous studies suggested that placebos could exert real effects in IBS by provoking a response from patients鈥� own bodies. If she wanted to maximise the placebo鈥檚 chance of working, they told her, it was important she take the pills exactly as instructed, twice a day. On the fourth day, she realised that her symptoms were gone.

Why does the honest placebo work? One theory concerns the expectations set by the intervention itself. 鈥淚t鈥檚 not just the drug, it鈥檚 everything that surrounds the drug,鈥� says Kaptchuk. Placebos are not inert substances: they are made of verbal suggestion, classical conditioning, and a lifetime鈥檚 associations learned about the cues of the medical ritual: the white coat, the office, the doctor鈥檚 manner. (). Any and all of these may cue the body鈥檚 healing powers.

The key word is 鈥渕ay鈥�: the placebo can be difficult to use. It doesn鈥檛 work for everyone, and when it does, its effects can be unpredictable. In one pain study, for instance, some people reported feeling more pain, not less, and activity in their brain鈥檚 painkilling opioid and dopamine systems decreased, instead of increasing like everyone else鈥檚. Another study flummoxed researchers by creating almost the opposite effect of what they intended: verbal suggestions , not only subjectively but also physiologically.

Even when the results go your way, it鈥檚 hard to understand why. In the small trial Buonanno participated in, . It wasn鈥檛 much better than鈥� placebo?

Much research is now under way to pin down what exactly makes any individual susceptible to the placebo response. Some studies implicate personality traits like optimism and a your own destiny. Or is it suggestibility? 鈥淗e鈥檚 such a good doctor,鈥� Buonanno says of the study gastroenterologist. 鈥淪o I said OK, I鈥檒l do anything to make anything work.鈥� Would her symptoms have still improved if she鈥檇 been more sceptical?

Other work is investigating whether any genetic links underlie the placebo response. One of Kaptchuk鈥檚 collaborators, Kathryn Hall, has found a link between that breaks down neurotransmitters including dopamine and adrenaline.

And some are even looking into doctors鈥� brains. Vitaly Napadow, a neuroscientist at Massachusetts General Hospital, plans to looks at the brains of physicians and patients simultaneously while he approximates a doctor-patient encounter 鈥� albeit half both parties in separate fMRI machines. If it works, this could begin to tease out what brain areas are involved when the doctor gets the placebo right.

In the meantime, there are already a few things doctors can do to exploit the placebo effect in clinical settings. In Germany, the . For example, giving a patient sufficient medical information helps, along with instructing them not to Google their symptoms. It鈥檚 also important to tell a patient which medications they鈥檙e taking and why. 鈥淚t sounds trivial,鈥� says Ulrike Bingel, one of the placebo team, at the University of Duisburg-Essen, Germany. But in post-operative wards, people are often hooked up to multiple IVs. 鈥淚s this a painkiller, is it a steroid, an antibiotic? If the patient doesn鈥檛 know, you might lose 50 per cent of the effect.鈥�

One form of placebo conditioning has recently had promising results, and could form part of a programme to wean people off opiate painkiller addiction (see 鈥�Sleeping it off鈥�). Buonanno鈥檚 experience hints at the power of these associations: after the study ended, she tried to continue the effect with substitute placebos from health food stores. But they didn鈥檛 look the same, and they hadn鈥檛 been prescribed to her. 鈥淣othing鈥� failed.

鈥淪he tried to buy substitute placebos from health food stores. Nothing worked鈥�

So why had it worked in the initial trial? Was it the form of the pills? The empathetic staff? The medical environment?

This spring, the new study aims to find out. Kaptchuk鈥檚 group will repeat the IBS trial, but this time it will include genetic testing, along with in-depth psychological interviews to unravel exactly which expectations and beliefs make the difference. Every word uttered by the staff will be carefully scripted to minimise the wrong impression.

While expectations come in many forms, one might be the biggest of all. 鈥淚f we鈥檙e ever going to use placebos in clinical practice, they can鈥檛 be the booby prize,鈥� Kaptchuk says. 鈥淲e have to change the culture and meaning of the word placebo.鈥�

Linda Buonnano is a good start.

Discover more about harnessing the power of your mind

This article appeared in print under the headline 鈥淭he right kind of nothing鈥�