Placebos work. Why?

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This is Unexplainable.

I'm Noam Hasenfeld, hanging out here with our reporter, Brian Resnick.

Hey.

And Brian, you got an unanswered scientific question you want to get into?

Yeah, you know I do.

Okay.

But before we get into it, I want to pose a scenario to you.

Hit me.

I want you to imagine this.

Let's say you go to the doctor's office and you have this huge headache.

You're just complaining.

You're nauseous.

It's just nothing's going right for you.

And the doctor, she gives you a prescription for sugar pills, like placebos, and tells you to take them.

Okay.

How would you feel?

I mean, definitely not great.

I also wouldn't exactly know how to fill that prescription.

Maybe you just take it to the candy store, obviously.

Yeah, yeah.

I mean, there was this story back when I was in elementary school that the nurse used to give band-aids to people if they had a headache, just sort of put a band-aid on their forehead.

You know what?

See, your nurse, your elementary school nurse, was on to something.

Wait, what do you mean?

You know about the placebo effect.

Yeah, sure.

That's when you take sugar pills and then you actually get better.

Right.

For a long time, like doctors would overlook that or they would like brush it away, say, like, oh, that's just the placebo effect.

It's like getting in the way of our real medicine.

Okay.

But scientists are realizing like it's kind of powerful and really useful and we should spend more time understanding and harnessing it.

I mean, do we have some ideas of how the placebo effect works?

We have some ideas, but it's changing.

For decades, doctors basically thought the placebo effect came down to just hiding things from patients, that placebos would only work if patients didn't know if they were taking a placebo or if they thought what they were taking was like a real drug.

I mean, that seems like obvious, right?

That in order for a placebo to work, you can't know it's a placebo, right?

Yeah, because you kind of have to believe in it.

Okay.

And, you know, that type of concealment was really troubling for this researcher I've been talking to, Ted Kapchuk.

He's a professor of medicine at Harvard who studies the placebo effect.

First of all, I was in my heart

miserable because everything I was studying had to do with concealment or deception.

He was doing all these studies on the placebo effect and seeing that it worked,

but he could never bring it out into the real world because of that deception.

Right, because I guess outside of studies or trials, you can't just conceal stuff from patients, right?

Exactly.

Did he know about how the patients might feel about being deceived?

He was curious about that.

And so he asked the patients, how do you feel?

You might be on a placebo, you might not.

Does that bother you?

And it turns out it gave them a lot of anxiety.

They worried about being on placebo every day.

And they said, what does that mean about my condition if I got better on placebo?

Why don't we just give people placebos, address their concerns at the bottom, that it's not a bad thing to respond to placebo, that normal people, everyone responds to placebos, that you don't have to believe in it.

You just have to take it.

You mean just like tell people right out the gate that they're on a placebo?

Could that even work?

Ted was on a mission to find out.

My team said, Ted, this is the stupidest idea you've come up with yet.

He did a study.

He took 80 people with irritable bowel syndrome.

This is a really painful chronic condition.

It's very hard to treat.

And for half of this group, he gave them really nothing at all.

And the other half of the people, he gave them placebo.

The bottle said open label.

The prescription pad said open label placebo.

Open label, like being open about the fact that it's a placebo.

Yeah, just being completely honest.

Like this is, it's on the bottle.

And Ted's instructions to the placebo group are really simple.

All I want you to do is take the pill.

twice a day.

You don't have to believe it.

You don't have to think it's going to work.

Just let's try it.

He gave them also some like education about the placebo effect and how it might help them.

And always we said to our patients, we don't know if it will work for you.

And the patients were okay with that.

The patients were okay with just getting a placebo.

Oh, they thought it was pretty out there.

Patients would say, that's crazy.

How could you believe this?

And our doctors always said, I don't know if I believe this either.

We're testing this out.

And then the results blew everyone's mind.

It was like, holy God, they're getting better, much better.

After 21 days, these placebo patients, they felt significantly better than the people who got nothing at all.

And the magnitude of the effect is dramatic.

I mean, we're talking about real improvement.

How is that even possible?

I know, right?

You know, it's really still hard for me to believe.

This went against everything like scientists thought they knew about placebos.

There are some caveats here.

Like, this was a small study, you know, just 80 people.

And it was also, it it was advertised as this mind-body kind of intervention, which just might attract a certain type of person to it.

And the last caveat is that the patients reported their own symptoms.

But that said, like there seemed to be something there.

Like this idea, open-label placebos, has been replicated with other conditions, treating chronic pain, treating hot flashes, fatigue, allergies, arthritis, anxiety, depression.

There's just been these like long-term follow-up studies, like following people for five years.

But Ted,

he still doesn't know how this all works.

I watched the data real carefully, and

there may be things I'm missing.

Did people get better on average?

Absolutely.

Was the average improvement equivalent to a good drug?

Usually.

So I could say that, but when I treat a patient, I still don't know what the magic is that you have to put in the soup.

What's the limit here?

Like how many conditions could placebos work for?

Could we just give everyone placebos, tell them they're on placebos, and then suddenly we've solved all these complicated conditions?

So I think it's really important to be really precise and careful about what exactly placebo works for and what it doesn't.

Placebo works on subjective symptoms.

So, you know, you can have an objective problem with you.

You broke your arm and there's like a hairline fracture in it.

You can see it on an x-ray.

Yeah, you could see it.

The subjective symptoms would be like the throbbing, stabbing pain you get from that.

Like that is something that's processed by your mind.

Some people might report more pain, less pain.

It's really individual.

It's subjective.

But this is still a big deal, right?

I mean, if you can get benefits from a placebo while knowing it's a placebo, that sort of changes the basic definition of a placebo, right?

Yeah, it blows it up.

It shows that like that origin story was really a myth.

We need a new definition.

Okay.

My definition of placebo, I think it's a really basic question.

It's the positive health benefits people receive in the context of a clinical interaction that's due to the rituals, symbols, and behaviors that surround the pill.

What Ted is saying here is that placebo is a type of theater.

It's a charged environment

when a person's sick sick and goes to a healer.

The drama of medicine by itself is a potent form of healing.

By drama, he means like props, characters, narrative.

A pill is a prop in the story of medicine.

A doctor wearing a lab coat and being like really attentive to you is a character in the story of medicine.

These are all things that kind of get into your brain and

this isn't all for show.

Like they really provoke something real and healing.

I guess that doesn't necessarily surprise me.

When I go see a play or something,

I can still feel the drama, even if I know there's a curtain, even if you know, like, I know the cast list, I know that they're faking it, but I can still feel the emotion, right?

So I could know that I'm getting a placebo and I might still feel the effect.

Oh, if you cry during a play, they're real tears, you know?

You know, and for placebos, like the theater is the doctor's office.

And is Ted feeling better about this?

Does he feel better that he doesn't have to conceal placebos?

Oh, he is so, so relieved.

What we're selling here is honesty.

And honesty is

something that's so important in the healthcare system.

And

placebo has abused that ethics for so long.

Now placebos are like broken out of this myth that you need concealment to make this effect work.

The myth has been destroyed.

And that makes them so much like stranger and more powerful than we've really realized.

And once you destroy the myth, you open up all new kinds of questions.

It really makes you think: like, what's possible here?

Coming up next, how it might be possible to harness the placebo effect without even using a placebo.

Are you tired of lying to people?

Is the endless grind of deception and deceit getting you down?

Then try honesty.

It's honestly the best.

Don't believe me?

Just listen to Cindy, a real person, talking about how honesty changed her life.

I used to lie all the time for no reason.

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But now, I can tell you that my name isn't Cindy, it's Mandy, and I'm only reading this because it's my job.

Honesty.

It's the best policy.

So if you're giving someone a placebo, maybe try honesty.

Side effects of honesty may include awkward conversations, getting as good as you give, not being invited to parties, and lots of time spent marveling at the wonder that is the human body.

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Explain.

Okay, we're back.

Brian, in the first half of the show, you were saying that you don't need to lie to people for the placebo effect to happen.

And you're saying that now you can take a placebo, know that you're taking a placebo, and still feel better, like still get the placebo effect.

So the obvious question here is, how does this work?

That is the question.

Researchers aren't exactly sure why.

Ted doesn't know.

But I did talk to Darwin Guevara.

He's this placebo researcher at Michigan State University.

And he was totally inspired by Ted's work here.

Like when he was in grad school, he read Ted's original open label placebo paper and it just like,

oh, he just saw stars.

Yeah, it was very gung-ho about it.

It's like they figured it out.

He's a total Ted Stan.

He's like his biggest fan.

It's like meeting your favorite rapper.

So what does Darwin think is going on in the brain when you know you're on a placebo and you still end up feeling better?

So there are two possible mechanisms here.

One is expectations and the other is conditioning.

Okay, let's start with expectations.

Expectations is just like you believing that something's going to work.

If you believe a placebo might make you feel better, it might help you feel better, it just might.

So if you believe the band-aid is going to cure your headache, it might cure your headache yeah yeah and darwin studies open label placebos on things like anxiety and depression he actually even looks at how these placebos change signals in the brain and he sets expectations with with education really simple he just tells people about the research on open label placebos and how it's helped people and he tells them like it just might like help them with their anxiety

i i show you graphs of studies that have shown open label placebos work.

I explain to you the possible mechanisms of why it works.

And let's say you leave there knowing that, okay, I'm a little skeptical.

I don't know if this is going to work, but it might work.

But I'm paying closer attention now to my anxiety.

When you start to pay attention to different things, you actually might feel different things.

You can't be anxious forever.

So there's a natural dip in your anxiety.

And then you're taking pills.

And then you make the attribution that maybe maybe this noticeable decline in anxiety may have to do with the placebo pills.

You connect this potentially random dip in your anxiety with taking the placebo.

Now you start believing more that it's working and you make that psychological association so now that the more that you take it, the more that you feel better and now it just creates a cycle of placebo effect.

All right, so expectations basically, if you think something's going to make you feel better, your brain can kind kind of like nudge you in that direction.

What about the second one, conditioning?

That's like Pavlov's dogs ringing a bell, kind of salivating when you hear the bell?

Yeah, exactly.

And so for conditioning, you don't need to believe in the placebos for them to work.

Just the act of taking the treatment leads to you feeling better, even if you remove the active ingredients or the actual treatment.

Conditioning is just a learned response.

And like, there are kind of neurological studies on this.

Let's say you give someone a real drug several days in a row for four days.

And then on the fifth day, you give them a placebo that looks like, you know, the real drug they've been taking.

When they get the placebo, sometimes their bodies will like respond to that placebo as if it is the real drug, or at least like, you know, move in the direction of the real drug.

You don't need to believe in it.

It's just like an automatic response.

So one way is you have to believe in placebos for them to work or maybe expect some positive changes.

And because you're believing in those changes, they actually happen.

And the other way, it doesn't really matter what you believe.

It's just that you've been conditioned to associate taking a pill with feeling better.

And when you take the pill, your body starts feeling better.

Yeah,

but this is where things start to get a little weird.

Okay.

So think about the thing that starts those expectations or starts this conditioned response.

The thing in this drama, it doesn't have to be a pill.

Okay, it can be like a syringe or an inhaler or something.

Yeah, it can be a lot of things, but here's something kind of spooky.

It doesn't even have to be a physical object.

We do not need the placebos to study placebo effects.

This is Luana Koloka.

She's a neuroscientist.

She studies lots of different ways to get at the placebo effect.

What does that even mean?

How can you get a placebo effect without a placebo?

You invoke invoke more drama.

Okay.

So Luana, she used to be a physician.

And back when she was seeing patients, she noticed like the more she saw them, the better some of these patients seemed to feel.

I realized that some of them were feeling well just by meeting me or because of the encounter.

Just that interaction between doctor and patient seemed to be so powerful.

And so Luana conducted a study.

Okay.

So this was a study on people who had just gotten out of surgery.

So, you know, surgery is very painful.

And so after surgery, you're put on like very powerful painkillers, like morphine.

Half the participants in the study, they weren't told when the morphine injections were happening.

Like they had an IV thing in their arm and just like a robot pump managed their medication.

But for the other half of the group, whenever the injection started, a doctor or, you know, a caregiver would come in and say, now we're going to start your treatment.

Exactly.

The idea is to know that they are being treated.

So, both of the scenarios, they're getting the same exact substance in their IV, but in one of the scenarios, the doctor is like telling them all about it.

Yeah, they're getting the same thing.

Same drug, same dose.

These drugs, these already powerful drugs, produced even stronger painkilling effects when people knew when the injections were starting.

Oh, sometimes almost twice larger.

Like twice as strong.

So, just knowing that they were on a drug made them improve twice as much?

Yeah.

It's really stark.

Just raising the awareness of being treated.

So raising awareness of being treated changed the clinical outcome.

And this still counts as the placebo effect?

Yeah, there's no pill here.

There's no extra props, but it's still the placebo effect.

I like to imagine this as if we have a switch on, switch off of our expectations.

So we switch on the part of the brain that account for expectation of an outcome, expectation that you feel better because you are being treated.

Having a doctor switch on these expectations, it actually has an evil twin.

It's called the nocebo effect.

Okay.

And this is when doctors can actually switch on a negative expectation.

Luana told us about the study that showed if a doctor told patients they were turning off pain medication, even when they weren't, that expectation could completely reverse the effects of strong opioids.

We reverse completely the action of opioids.

That is how much words are critical in clinical settings.

Words are critical.

This is drama.

you know,

character.

It matters who is treating you.

And it matters what they say.

And if doctors are really careful about this and they're knowledgeable about the placebo effect, they could potentially use this drama and squeeze like more healing out of normal medicine.

Any treatment can produce a different outcome based on the way we deliver the drug.

That can be powerful.

Open label placebos have like opened the door a little bit.

Like we can, we can use more of the placebo effect in everyday medicine because you don't have to lie to people.

But what Luana is saying is like the placebo effect, we don't need to just reduce it down to just giving people pills.

Right, right.

So is Luana just all in on open label placebos now?

She's actually not sure.

Like if we just give people sugar pills and then send them on their way, is that really the right call?

Does this make a difference?

Will this hurt the perception of treatment in medicine?

Could this hurt the perception of how people think about their doctors?

Where does that leave us then on open label placebos?

It feels feels like it's something that is pushing the edge of medicine.

It's something that we see can help us treat hard to treat pain.

It's something that seems to have some potential dangers.

Yeah.

You know, especially right now, talking about trust in medicine feels like a very important topic to talk about.

How can we balance the concerns about open label placebos with their potential help for people?

This is how I see it.

The placebo effect is like money we're we're leaving on the table in terms of like therapeutic value, either in helping people when we don't have really good drugs to treat them or squeezing more out of the drugs that we do have.

For a long while, like the placebo effect was just like kind of hand-waved away.

Like, oh, it's just the placebo effect.

It's just the thing that, you know, we need to clear to prove that like a medicine actually works.

But Ted Kapchak thinks that this has led medicine to ignore the healing power here.

It was being ignored that people were getting better.

You know, there's a lot of things medicine doesn't treat very well.

Like, you know, we've seen the opioid epidemic where opioids have been prescribed in huge numbers and just such disastrous effects and still people are in pain.

Have you seen patients in chronic pain?

People, their lives are miserable.

The largest cause of disability in the world and the United States is low back pain.

They're not getting relief.

If there's there's this extra bit of therapy that doesn't have disastrous, like addicting qualities, like opioids, and you can use it and squeeze more out of medicine in every interaction that someone has with a doctor, at the end of the day, if people are in pain, we should help them.

Brian Resnick is a senior science reporter at Vox.

This episode was produced by Meredith Hotnot with edits from Noam Hasenfeld and Jillian Weinberger.

We had music from Noam and mixing from me, Christian Ayala.

The rest of the team includes Bird Pinkerton and Mandy Nguyen, who fact-checked this episode, and Liz Kelly Nelson is the VP of Vox Audio.

You can sign up for our newsletter at vox.com/slash unexplainable and feel free to send any thoughts to unexplainable at vox.com.

Unexplainable is part of the Vox Media Podcast Network.

We'll be back in your feed next Wednesday.

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