Linda B. suffered horribly from irritable bowel syndrome. It got to the point where she felt she didn't have a life; she was too wracked with pain and symptoms to leave her house. When she signed up for a medical study on the condition, she was shocked and dismayed to learn she'd be getting a placebo, not an experimental medication. What happened after she took the inert pills was even more surprising: She got better. Linda felt better, in fact, than she'd felt before she got IBS.

The strange effectiveness of "sugar pills" (or, as one medic discovered in World War II, saline injections once the morphine ran out) intrigues doctors, alternative medicine practitioners, and patients alike. In clinical trials, patients in the control group usually don't know they're getting a sugar pill—deception was thought to be key to the placebo effect, as it keeps expectations high. But in the last five years or so, researchers have shown that dispensing pills that people know are placebos can still alleviate symptoms of IBS (as they did for Linda) and depression, as long as the researchers explain that dummy pills have worked for patients in the past.

And that's just one fun fact. Recent findings also illuminate how placebos work physiologically, finally lifting the veil on what the heck is happening, both biologically and environmentally, to make sham treatments work. The placebo effect, as it turns out, isn't just in our heads; it's in our genes, our chemistry, and even our culture.

New research proves the placebo effect was never "just in your head."

Placebos don't normally cure diseases, but they can majorly alleviate subjective symptoms such as pain, discomfort, and mood. After all, says Ted Kaptchuk, Professor of Medicine at Harvard Medical School and Director of the Harvard-wide Program in Placebo Studies and the Therapeutic Encounter (PiPS), "These effects are at the core of the healing profession."

Kaptchuk wrote a classic textbook on Chinese medicine and has studied healing practices from around the world, so it's fitting that his perspective encompasses all aspects of wellness. "Our team measures the impact of the elements of health care that don't fall under the rubric of 'tricks of the trade'—in other words, the symbols, rituals, patient and provider mindsets, and therapeutic encounters," he says. "Drugs and procedures are important and often lifesaving. But in emphasizing them, we overlook or devalue things that still have great relevance in the practice of medicine."

Illustration Credit: Chloé Bulpin

Your DNA on dummy pills

You might connect susceptibility to placebos with personality traits such as open-mindedness or even naiveté. But the most exciting recent discoveries about placebos show their effects are moderated by differences in the genes that control chemical messaging systems in the brain. You might have genes that strengthen the placebo effect for you in some cases, while others do not.

Researchers at PiPS, led by microbiologist and molecular geneticist Kathryn T. Hall, Ph.D., were among the first to propose this. (Incidentally, PiPS is not a physical institution, but a consortium of researchers, plus at least one Rabbi, who meet monthly to discuss projects and ideas. "We're very placebo-like," Hall says. "We are everywhere and nowhere.") Her team combed extensively through the literature and identified "the placebome," a network of genes that influence the placebo response. (It's a portmanteau of "placebo" and "genome," or body of genes.) One of the first genes in the placebome that she pinpointed affects dopamine, a major player in the brain's reward system. Others impact the serotonin, opioid, and cannabinoid pathways.

"There are two levels to the placebo effect," Hall explains. "One is expectation and the other is a reduction of symptoms. We're not sure if these genes are modifying expectations or the experience of symptoms, but they are definitely modifying the levels of these various neurotransmitters."

A drug could actually block a "good" placebo response.

That means the placebo effect was never "just in your head." "Well," counters Hall, "neurotransmitters are in your head! So it still starts there." While placebome research is in its infancy, Hall envisions that eventually, doctors could screen patients to see who's susceptible to placebo effects and adjust medication accordingly. "What we're trying to do is boost the placebo response to make drugs more powerful, or reduce the amount of medication someone might need because of their strong placebo response," she says. That approach, of course, fits in nicely with the trend toward "personalized medicine," which promises to optimize treatment based on our individual differences.

Peter D. Kramer, M.D., a psychiatrist and author of Ordinarily Well: The Case for Antidepressants, has publicly cautioned against too much enthusiasm for placebo effects because they're often dwarfed overall by the potency of medications and surgical procedures, and limited to illnesses with subjective symptoms. Plus, he warns, the mind-body connection is so complex that it will take a long time to sort out just what combo of placebos and pills would work best for a particular person and their various ailments. "It might be that there is not one genetics of placebo response but many, so that one person is responsive when it comes to pain, one when it comes to immune protection, and so on," he says. "On one or another axis, the person simply is less liable to being 'stuck.'"

While she hasn't looked at it yet, Hall believes it's possible that genetic variations could also explain why alternative treatments such as acupuncture or hypnotherapy work so well for some people.

Illustration Credit: Chloé Bulpin

The intricate placebo-drug dance

We know there are genetic underpinnings to the placebo effect. And we know those genes act on the same brain pathways as do many meds. Put that together and you've got a problem: Pharma trials assume that placebos act independently of medications, which is why sugar pills are pitted against drugs to measure how effective the drugs are. Now it's clear, though, that placebos work with medication, not in a separate realm from them.

If a drug increases levels of dopamine, say, and you have a gene that causes a chain reaction that leaves more dopamine swimming about in your brain, the drug is going to affect you differently than it would someone whose genes make dopamine less available to them. A drug could actually block a "good" placebo response, says Hall, or it could enhance a placebo response.

In another example of placebos and meds interacting in curious ways, one study found that when patients took a migraine drug that was labeled "placebo," it worked half as well as it did for patients who took the same drug, properly labeled. Here's another: Patients informed of the sexual side effect of a medication that treats a benign enlarged prostate gland reported sexual side effects at three times the rate of patients who weren't warned of potential problems in the bedroom. It's natural to think of pills as straightforward actors on our bodies, but our expectations about them, the way they're presented to us, and our genetic makeup are all ingredients in the efficacy mix.

Hall says that ideally, drug-testing trials will change in light of these results, though it could take many years to develop new protocols. "We have identified about 25 genes in the placebome," she says. "At a minimum, I would genotype people in each drug trial and then stratify the results to look at drug-placebo interactions."

Illlustration Credit: Chloé Bulpin

The warm glow of TV...and caring practitioners

Here's a head-scratcher: The placebo effect has gotten stronger over the years in the U.S., but not in Asia or Europe. This tidbit comes from a McGill University meta-study that looked at clinical trials of chronic neuropathic pain treatments from 1990 to 2013. (By 2013, patients getting the placebos had, on average, a 30 percent decrease in their pain levels.)

It’s possible that the difference has to do with Americans' exposure to direct-to-consumer ads that tout the benefits of drugs, prompting us to believe they'll be super effective. (New Zealand is the only other country in the world where drug companies are allowed to bombard people with their aspirational, soft-focus commercials.) Another explanation: The size and length of the clinical trials in the U.S. were larger, factors associated with bigger placebo responses, though researchers don't know why. The more we unravel the mysteries of placebo, the more mysteries there are to unravel.

"Once we got to the part of the exam where I was supposed to identify my pain level, I realized it was gone. I couldn't believe it—it was totally gone."

In a review published in the New England Journal of Medicine last year, Kaptchuk sets his sights beyond the sugar pill to define placebo effects as "any improvements in patients' symptoms that come out of the therapeutic encounter, [including] health care paraphernalia and settings, emotional and cognitive engagement with clinicians, empathic and intimate witnessing, and the laying on of hands." He suggests studying all of these components of patient-healer interactions to help "nudge patients toward shifts in their perceptions of their symptoms and illness, making them less disturbed or perturbed."

Kramer wonders if this definition stretches placebo all the way into the realm of talk therapy, the effects of which (just to add another layer of complexity) could also be moderated by genes. In a clinical trial of depression, for example, "if a person has no expectations based on pill-taking but improves in the context of enhanced attention from raters, testers, and caregivers, is that response a placebo effect or a psychotherapy effect?" Kramer says. "The two sources of improvement—hopeful expectancy and the healing alliance—might have different genetic underpinnings."

Even if it's not nearly as personal or in-depth as a typical talk-therapy session, a brief interaction with a skilled and caring health professional can be potent—just as saline and sugar pills can be. Hall recently had rotator cuff surgery, a procedure with a notoriously tough recovery period. "I tried so many things," she says. "Nothing really helped. Drugs just made me tired." After two weeks, she visited her surgeon for a checkup, arriving to his office in excruciating pain. "I wasn't aware of it at the time, but looking back, he hit upon all the ideal ways of dealing with a patient. He is very confident, very calm. He looked me in the eye. He expressed empathy for my situation. He patted my arm and responded with thoughtful reflections. Once we got to the part of the exam where I was supposed to identify my pain level, I realized it was gone. I couldn't believe it—it was totally gone."

A few hours later, though, it came roaring back. "I thought about looking up some of the YouTube videos of my doctor discussing surgery to see if listening to him would work again," Hall says with a laugh. What finally took the pain away for good was a factor we can all count on, even if we can't speed it up or manipulate it: the passage of time.