The Science Behind The Placebo Effect

DESSA: This is Science Friday. I’m musician and writer Dessa, filling in for Ira Flatow.

Later in the hour, we’re going to talk about technoableism and how those seemingly inspirational videos about scientific breakthroughs might be muddying the real stories of disability technology.

But earlier this month an FDA panel agreed that a common decongestant ingredient, phenylephrine, which is found in drugs like Sudafed and NyQuil, doesn’t work. And this pains me as a NyQuil fan, fam.

While the panel agreed that phenylephrine isn’t dangerous, it doesn’t work any better than a placebo. Which made us wonder, how well do placebos work? And how come they work even when people know they’re getting a placebo?

Here to talk more about the current landscape of placebo research is my guest Ted J. Kaptchuk, professor of medicine at Harvard Medical School and director of Placebo Studies and Therapeutic Encounter at Beth Israel Deaconess Medical Center. Welcome to Science Friday.

TED KAPTCHUK: Thanks for having me.

DESSA: OK. Can I ask– the FDA panel’s pronouncement on phenylephrine– the objection was that this substance wasn’t working any better than a placebo– how did you respond when you first heard that news break?

TED KAPTCHUK: When I heard that, the question is, how did they know there was a placebo effect? The data is really coming from two very good randomized controlled trials that tested phenylephrine versus a placebo, and there was no difference. But what was in that placebo is more than just placebo effects.

Common colds with congestion go away by themselves. The only way you would know if it was a placebo effect is if you had a third arm that actually had just watch and wait, no treatment. And you would say, oh, is the placebo treatment more than nothing? And nothing is not doing anything. Giving a placebo includes the rituals, the symbols, and the acts of human kindness that are surrounding pills.

DESSA: That’s hugely helpful. And it feels like that was a piece that hasn’t been discussed, yeah, in the way that–

TED KAPTCHUK: It’s never discussed.

DESSA: OK. So let’s dispel confusion. Can you give me the quick and dirty definition of placebo?

TED KAPTCHUK: Sure. A placebo, first of all, is not the effect of an inert substance. Inert substances don’t have effects. Placebos are what surrounds inert substance or placebo pills. That includes rituals, symbols, uncertainty, hope, and acts of human kindness. That combustible mix sometimes, in some people, makes people get better. And that’s what a placebo effect is.

DESSA: OK. So it sounds like what you’re doing there is differentiating an inert substance that I might receive in that ritual environment of a doctor’s office, with the care, the consultation, the expectation, from an inert substance that’s like eating a red Skittle by myself. It really has to be loaded with that cultural freight, is that right?

TED KAPTCHUK: Yeah. I’m going to say that it doesn’t have to be too much loaded. Because, especially when you’re dealing with chronic pain patients– which I think placebos are mainly helpful for– is just encountering a supportive, kind doctor in just normal routine care actually will elicit a placebo effect.

DESSA: And I think when most of us think of the placebo effect, we often do think of that inert substance. We imagine a little white pill, with no medicine in it. What are the other form factors that a placebo can take?

TED KAPTCHUK: I mean, anything that essentially doesn’t have any impact on a patient’s condition could be called a placebo. Honest placebos don’t have side effects. The dogma in medicine has been, since we began using placebo controls, is that, if you know it’s a placebo, you won’t get a placebo effect.

You have to fool, conceal, or deceive patients to get a placebo effect. Honest placebo– what’s usually called open label placebo– is giving patients placebo pills and telling them, it doesn’t have a pharmacological effect, but in some people, some of the time, just taking the pills, even if you don’t believe it, even if you think it’s crazy, will sometimes make the mind reformulate signals, perceptions, or symptoms, and may have benefit for a person. That’s what honest placebo might mean.

DESSA: And I think that’s really counterintuitive and fascinating for most of us.

TED KAPTCHUK: It’s totally counterintuitive. Our patients say, you must be kidding. And we say, listen, you don’t have to do this if you don’t want to. And we’re trying it out. And if you decide to be in our study, all you have to do is take it twice a day for a number of weeks in the study. And people find it really hard.

And we have to tell people that, listen, this does not mean it’s in your head that you’re getting a placebo response. In fact, the body has an internal pharmacy that releases neurotransmitters, like endorphins, cannabinoids– we know it activates specific quantifiable areas in the brain– that actually change how you perceive symptoms.

DESSA: When you talk about an honest placebo– I think I’ve also heard the term open label placebo, where the patients who were receiving it know it’s a placebo. Is that one way to address what might be complicated ethical issues in providing people an inert substance?

TED KAPTCHUK: Yeah, open-label placebo is the usual way our team describe an honest placebo. And basically, it is being very clear, with absolute transparency and honesty, that what we’re giving you is a placebo. And you don’t have to believe it, expect it, or hope it’s going to help. And placebos have been tainted by trickery, by deception, by concealment.

And the idea that a placebo pill, with no active ingredient, can still have benefits, can still have impact on patients for their benefit, is against the traditional dogma. And it’s only in the last 10, 15 years that the evidence has been accumulating that placebos can benefit patients even when they know it’s placebo.

And the reason that’s really critical ethically is, any form of open-label placebo is a transparent, honest, and full informed consent. There’s no deception or concealment. Placebos are really a tricky thing. They’ve been tainted by a myth or superstition that they work because you think you’re going to get better. It’s actually deeper than that. It’s your body is doing something that tells it it can modulate the symptoms, turn down the false fires of many chronic symptoms, and actually deliver some comfort.

DESSA: And just to be clear– I think when you talk about this tainting of our association and our understanding of placebos, you’re talking about the deception that was involved when we would provide an inert substance to a patient who didn’t know that they were receiving an inert substance. Is that correct?

TED KAPTCHUK: Absolutely. Or concealed in a randomized controlled trial, which is ethical. But it still has this idea of trickery

DESSA: OK. So in your studies more generally, can you tell me when and how are placebos most helpful in medicine, and what are the limits?

TED KAPTCHUK: Placebos don’t shrink tumors. Placebos don’t help malaria. What placebos are especially good for is chronic illnesses with chronic symptoms. And what happens is, many chronic symptoms are really the brain and nervous system being hyperactive– almost like a false alarm– and it amplifies the symptoms that we have.

And what happens with placebos, when taking the placebo– not thinking about placebos, but taking placebos– being in that ritual, the brain gets some feeling that it should turn down the volume. It doesn’t have to amplify or increase the signal. And it’s really a form of changing what the message is that the brain is interpreting in terms of discomfort. And it’s mainly chronic symptoms that I think you have placebo effects. There are others, but that’s the main place you see large, consistent placebo effects.

DESSA: So one of the studies I know that you’ve been personally involved in explores the promise of placebo treatment in patients who are receiving methadone to treat opioid addiction. And I know that that works with an honest placebo. So it’s one where patients are aware of the fact that they’re receiving a placebo. But can you describe that study and what you found so far?

TED KAPTCHUK: Yeah, that’s a really exciting experiment. The first author, principal investigator, is Annabelle Belcher, at the University of Maryland. I was the last author and supportive character, but she deserves all the credit. What was interesting about that study– many things were interesting– was that we used open label placebo.

And half the patients received their absolute usual care, half the patients received their usual care, plus placebo. So it had an open label in it, but also we added conditioning because it’s very easy to condition with opioids in the same way that you condition with Pavlov’s dogs. You give them food with a bell, food with a bell. The third time, you just give them the bell, they get the same reaction.

So in this experiment, we were hoping and we did find that we gave them the methadone, an opioid, plus the placebo, for a week or two. And eventually we were hoping that the fake pill would have the effect of the opioid. And to our surprise, 100 patients were able to stay in the methadone program much more than the people without the placebo pill. We followed them for three months.

And the reason it was important– the main problem with most methadone programs is people drop out. Much fewer people dropped out of the program because of the placebo pill.

DESSA: It blew my mind reading that study. That was like a pause, point at the computer screen, and mouth along with the words, to realize that, first of all, I hadn’t been familiar with a conditioned open label placebo.

So you’re providing patients with a methadone pill alongside a placebo, hoping to create then that association just like in the Pavlovian model, where you ring a bell, you ring a bell, you ring a bell every time you serve dinner. And essentially, the bell itself elicits that salivary response. And it sounds like, at least in this first population, you’re finding that the reported symptoms of the opioid users, they’re lessening. There’s some relief in the symptoms that they’re hoping to treat. Is that right?

TED KAPTCHUK: Yeah. I want to say that open-label placebo, plus conditioning, is much newer. There’s been at least a dozen trials showing that open-label placebo, compared to no treatment or usual care, has a significant impact on illnesses like low back pain, irritable bowel syndrome, migraine headache, knee osteoarthritis, and cancer-related fatigue– even menopause, hot flashes.

DESSA: And you’ve been studying this field of research for a long time. Can you tell me, what is the most surprising finding of the past few years? What are you most excited about now?

TED KAPTCHUK: It’s still hard, counterintuitively, on some level because I believed the myth that you have to trick people to get placebo effects. I’m still amazed at the fact that we’re getting these effects. And hopefully, hopefully we’ll be able at some point to use them.

DESSA: And do you think doctors will ever use these placebos fully?

TED KAPTCHUK: I want to tell you, it’s going to be slow. You will need more research to convince people. And doctors’ self-identity is related to, we don’t use placebos. That said, I recently had conversations and hearings with the FDA, and I’m pretty sure there’s not any regulatory barriers to using it– and in a week, I think a little more clarification is going to happen– but that’s clearly what’s happening. And ethically, it conforms to the AMA’s Code of Ethics.

So I think it’s going to be a slow process, but I’m hoping that, for people that have not gotten benefit for very common symptoms, like low back pain, migraine, irritable bowel syndrome, cancer-related fatigue, that at some point, people will see that after the third failure of a drug, maybe we should try a placebo.

DESSA: Professor Kaptchuk, thanks so much for taking the time to talk with me.

TED KAPTCHUK: Thank you so much for inviting me.

DESSA: That was Ted Kaptchuk, professor of medicine at Harvard Medical School.

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