Morphine has been used as a powerful pain reliever for more than a century. So when neuroscientist John Levine recruited patients reeling from pain after a recent operation in the 1980s to study how a placebo compared to morphine for pain relief, you wouldn't think there'd be much of a contest. Levine gave half of the patients a secret dose of morphine and gave the other half an out-in-the-open injection of something described as a powerful painkiller — but which was actually regular old saline solution. The results were a startling illustration of the power of placebo: both groups reported the same degree of pain relief. The patients who expected to feel better from the out-in-the-open saline injection did feel better, just as much as those who got real morphine without knowing it.

If you think that's weird, just wait until you hear what a team of Italian researchers did. For a study published in the journal Pain in 2001, the team hooked each patient up to an IV, inflated a blood-pressure cuff around their non-dominant arm (which was pointed at the sky to drain as much blood as possible), and had them squeeze a hand exerciser over and over until the pain became unbearable. (Those brave souls.) Next, they administered the medication. Some of the patients got an open, visible injection of non-opioid painkiller and some got a hidden injection. As predicted by the placebo effect, the people with the open injection reported more relief than those with the hidden injection.

But there was a twist: some of the patients' injections also included naloxone, which blocks opioid receptors. The patients who got the open injection of painkiller (which wasn't an opioid) plus naloxone (which, as we said, blocks opioids) felt just as little relief as the ones who got a hidden injection of just painkiller. It appeared that the placebo effect was making the patients' bodies produce opioid painkillers all on their own, and when those opioid receptors were cut off, the pain relief stopped too.

It seemed that with each placebo treatment, the human body was responding to its expectation of relief. What researchers couldn't figure out, though, was why some people seemed to have dramatic placebo responses while others would have hardly any. Since placebo controls are designed to level the playing field in scientific studies, that threw a wrench in the works.

That's why a discovery in 2012 by Harvard Medical School researcher Kathryn Hall and her team was so groundbreaking: they found a gene responsible for the placebo effect. It's all in differences in the catechol-o-methyltransferase gene, or COMT, which controls the level of dopamine in the brain's prefrontal cortex. Previous research has shown that people with the high-dopamine version of the COMT gene are more likely to seek rewards and feel pain more intensely than people with the low-dopamine version. The team wondered if this gene might play a role in the placebo effect, too.

The researchers divided people suffering from irritable bowel syndrome into three groups, told one they were on the waiting list for treatment, and gave the other two different versions of a placebo: one got fake acupuncture by a cold, curt practitioner and the other got the same acupuncture by a warm, caring practitioner. Sure enough, participants with the high-dopamine version of the gene felt slightly better even after seeing the cold-shoulder therapist and were six times as likely to say their symptoms improved with the caring practitioner as their low-dopamine COMT gene counterparts. The low-dopamine folks, in contrast, didn't improve much regardless of the placebo treatment. The researchers were right on the money.

Since then, Hall and other Harvard researchers have identified a whole network of genes that play a role in the placebo effect — a network they call the placebome. This is huge — an unpredictable placebo response has been thwarting many painkiller trials in recent years, and if researchers could design their trials around these specific genes, they might be able to demonstrate bigger effects with fewer participants (and less expense). But in a more personal sense, it might explain why some people swear by every fad treatment under the sun, while others can't seem to get relief wherever they look. People are different! This is just one more way that's true.

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