Placebos Work Even if You Know They’re Fake: But How?

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Pills tablets medicine in a spin

Physicians have long believed that some form of deception is essential to the placebo effect: after all, if you tell people that you’re giving them a fake drug, why would they respond by getting better? But new research suggests that it may one day be possible to use placebos in everyday medicine without misleading patients into thinking they might get active treatment. The study, which was published in the journal PloS One, included 80 patients suffering from irritable bowel syndrome (IBS), a condition that causes abdominal pain, bloating and frequent bouts of either constipation, diarrhea or cycling between the two. There is no specific treatment other than managing symptoms, which can range from mild to severe. (More on Adderall May Not Make You Smarter, But It Makes You Think You Are)

Participants — who were mainly on the severe end of the spectrum — were randomized to receive either a placebo or no treatment. Those given the placebo were told that they would be taking “placebo pills made of an inert substance, like sugar pills, that have been shown in clinical studies to produce significant improvement in IBS symptoms through mind-body self-healing processes.”

They were instructed that taking the medication at the times and doses prescribed was “critical.” In essence, the researchers revealed that they were using placebos — but, unlike the approach used in typical trials, they told patients that the pills work. The no-treatment group simply interacted with the medical staff in appointments of the same length as those given the placebo. All patients stayed on medication schedules or diets they were already following — no changes were allowed during treatment. (More on Explaining Why Meditators May Live Longer)

Study co-author Ted Kaptchuk, Associate Professor of Medicine at Harvard Medical School, was astonished by the results. “The effect size is astronomical,” he said, explaining that “59% on placebo got better versus 35% on no treatment. The magnitude of that effect compares to [those of] the most powerful drugs ever tested for IBS and they have terrible side effects and are very rarely used.”

So what could explain these results? Jon-Kar Zubieta, research professor at the Molecular and Behavioral Neuroscience Institute of the University of Michigan, has studied the effects of placebos on the brain. He says, “There are some conditions where placebos can be very effective, one is pain, another is depression, another is Parkinsonism and probably IBS.”

Zubieta has studied the chemical responses of the brains of participants who were told they might receive either a new painkiller or a placebo while they underwent a procedure that induced muscle pain. Researchers told participants that, “they ‘may or may not receive active medication and that this will enhance your body’s ability to counter pain.’ It’s kind of the same thing they did in this paper, but we didn’t [outright] tell them it was placebo.” says Zubieta. (More on Spend Too Much For Those Shoes? Blame Your Genes)

In patients who saw significant pain relief on placebos, Zubieta’s research found increased firing of dopamine neurons in brain regions linked to the expectation of pleasure and relief, particularly the nucleus accumbens. There was also increased activation of the brain’s natural morphine-like painkillers, the endogenous opioids.  Both circuits make sense as places placebos might act, one in producing expectation of relief, the other in reducing pain and anxiety.  Other conditions involving pain and depression that tend to respond to placebos have been shown to affect these brain regions as well.

Interestingly, in Zubieta’s studies there were also patients who reported that their pain got worse when they were given the unlabeled placebo. “About 15% of the volunteers not only didn’t respond [to the placebo but said] they actually had more pain,” says Zubieta, “When we looked at those with respect to [neurotransmitter activity] dopamine and opioids went in exactly the opposite direction [compared to those who saw pain relief].” (More on Perspective: Kicking Drugs After Columbia Bust)

Still, with a possible mechanism suggesting that in the majority of people placebos can be used without lies, should doctors start introducing them to treat conditions that are known to be responsive? Even Kaptchuk is cautious. “This is just the first step to see whether there are ethical ways to harness the placebo effect,” he says, “In order to be clinically applicable, it would have to be replicated in a much larger sample and continued for a much longer period of time.”

Zubieta adds some additional caveats, noting that the study participants were recruited through advertisements that sought people to test a “novel mind body management” treatment for IBS. Such advertising could select participants who were most susceptible to placebo effects, thereby skewing the results. He also notes that the patients’ recovery was based on self reported subjective effects. “That should be checked against objective measures like heart rate, skin conductance, functional changes in the brain, then you can really quantify what’s going on,” he says. (More on Does Suffering From Withdrawal Really Mean You’re Addicted?)

Indeed, a recent Cochrane review examining the impact of placebos across multiple conditions found that in most cases, placebos did not produce useful effects — except, as Kaptchuk notes in his paper — in studies that were specifically looking for placebo effects. And despite all the advances in research on the placebo effect, many of its aspects  remain mysterious and confounding.  For example, Zubieta is currently investigating why heroin addicts who buy fake drugs but believe they’re the real thing don’t get a placebo high. “They become very well trained at differentiating between their drug and something else,” says Zubeita.

Determining how that works could shed further insight on how to best produce a placebo effect — and no, the idea is not to save addicts money by allowing them to get high without real drugs. Rather it is to delve deeper into the workings of the brain, and use what’s learned to treat pain and illness in new and untapped ways.