Over the past couple decades, placebo research has gone from a fringe endeavor to mainstream brain science. And while it’s impossible to know just what role placebos play in traditional medicine across the world, neuroscientists have uncovered a few clues that shed some light on how sucking on someone’s knee actually can relieve them of pain.

Placebo effects take many forms–some are purely statistical (the term “regression to the mean” applies to anyone who gets better after a treatment but would have done the same even without it). Others apply to patients simply trying to please a doctor. Most, like with my knee (which started aching again the next day or so), are temporary. But we now know that much of what we call the placebo effect is chemical–where the brain actually self-medicates with its own pre-existing drugs.

“Every time we receive a treatment or a surgical procedure or [an injection,] we expect analgesia. We expect to get better,” said Luana Colloca, a placebo expert at the University of Maryland. “Any kind of expectation for improvement can trigger descending pain modulation in the brain.”

The discovery of this internal pain modulation began in the 1970s when scientists found that some placebo effects were linked to endorphins–or internal opioids–being released in the brain. Over the next couple decades, a few dedicated experts pieced together how those and other chemicals were triggered by simple beliefs, or expectations, as psychologists call them.

In the 2000s, placebos entered the mainstream when scientists began to see these interactions in brain imaging machines. Suddenly, they could see how expectation triggered the release of various neurotransmitters: dopamine in Parkinson’s patients as well as cannabinoids, serotonin, or opioids in patients told they were taking actual medicine. In other experiments, people even responded after being told that the pill was a placebo.

Scientists have since shown that placebos can produce powerful, measurable experiences triggered by conscious or unconscious expectations. Conscious expectations are generated through, among other things, the power of the storytelling. Magnets, cosmic rays, ancient magic, mysterious toxins, science-y sounding explanations, all of these can catch our imagination and enhance a placebo effect.

Unconscious placebos are triggered by conditioning (such as the hundreds of times you’ve taken a pill in your life and felt relief) or by subtle signals around you. Imagine walking into a doctor’s office in a dingy loft littered with musical instruments and car repair manuals. Imagine the doctor wearing ripped jeans and a parka over an undershirt. How much confidence would you have in the treatment?

Colloca said that expectation can trigger the brain to release pre-existing–or endogenous–opioids in the brain. “Endogenous opioids are very similar to exogenous opioids like oxycodone and many other opioids that we use daily in clinical practice to reduce pain. These mechanisms are quite powerful.”

Colloca said that the subtle signals of a doctor’s office–the stethoscope, the white coat, the poster of the human body–play a key role in triggering expectation. In fact, many patients report feeling better as soon as they step into a hospital.

To demonstrate the effect of expectation, Colloca sits NewsHour producer Nsikan Akpan in a chair and straps a device to his arm that can deliver painful burning sensations. For 20 minutes she shows him a green light just before giving him minor pain and a red light before a more powerful burning sensation.

Standing behind the technician controlling his torture, I watch as each burn is paired with the correct color. Then, in the last few minutes, she changes it without saying anything. Every burn is near his highest pain threshold, though the colors keep changing. Sure enough, whenever he sees the green light, he barely registers the pain he’s feeling.

"Pain, depression, irritable bowel syndrome, anxiety, Parkinson’s disease, and even addiction seem particularly susceptible to placebo."

“I literally cannot believe that I wasn’t feeling the lower heat,” he said once the truth is revealed.

Akpan’s distorted pain experience is a classic placebo response. But not all placebos are this effective. Some conditions seem to naturally respond better than others. Pain, depression, irritable bowel syndrome, anxiety, Parkinson’s disease, and even addiction seem particularly susceptible to placebo. Others that may also join the list are autism, autoimmune disorders, asthma and immune response. Meanwhile, cancer, obsessive compulsive disorder, and Alzheimer’s disease don’t seem to respond as well to placebo.

But more than that, placebo effects pop up in all manner of unexpected places like sexual dysfunction, athletics and even making Coke taste better than Pepsi. In fact, once you start looking for them, placebos sneak into every part of our lives because expectation is in every part of our lives.

“It’s really a family of mechanisms,” said Tor Wager, a neuroscientist and placebo expert at the University of Colorado, Boulder, who did some of the earliest imaging studies of placebos. “If you were to get in a virtual reality roller coaster, you would feel your stomach turn. That’s a type of placebo.”

Wager, who now focuses mostly on chronic pain, is an expert in how the placebo effect can be used to ease suffering. And nowhere is that more obvious than Huautla de Jimenez, Oaxaca.