A Radical New Hypothesis in Medicine: Give Patients Drugs They Know Don’t Work

Why the placebo effect is weirder and potentially more useful than we imagined.




Harvard medicine professor Ted Kaptchuk is at the bleeding edge of a radical new treatment in medicine: giving patients pills that don’t work.

“Our patients tell us it’s nuts,” he says. “The doctors think it’s nuts. And we just do it. And we’ve been getting good results.”

In medicine, placebo pills are typically used as a tool to test the effectiveness of real drugs. In a double-blind, placebo-controlled clinical trial, which researchers consider the gold standard for testing a drug’s effects, patients (and the doctors running the trial) don’t know who’s taking the real drug and who’s taking the placebo.

Kaptchuk has a twist on this: His own randomized controlled trials found that giving patients open-label placebos — sugar pills that the doctors admit are sugar pills — improved symptoms of certain chronic conditions that are among the hardest for doctors to treat, including irritable bowel syndrome and lower back pain. And he wonders if chronic fatigue — a hard-to-define, hard-to-treat, but still debilitating condition — will be a good future target for this research.

Overall, he’s trying to show how the “intangibles” of medicine “actually change how people experience illnesses,” he says.

Kaptchuk is a bit of an outsider in medicine. “Everyone denigrates the placebo,” he said (repeatedly). “The whole profession is against the placebo effect.” But he’s a cautious scientist, saying it’s much too early for doctors to begin prescribing sugar pills to people for these conditions.

But as he explained in our conversation that follows, which has been edited for length and clarity, there’s good reason to be cautiously enthusiastic about their potential.

The placebo effect isn’t just about expectations


Brian Resnick

Let’s start off simple. What is a placebo?

Ted Kaptchuk

The usual definition is that “it’s the effect of an inert pill,” but that’s an oxymoron. An inert pill can’t have an effect. So the whole vocabulary of placebo is problematic.

What I usually say is, “The placebo effect is a surrogate marker for everything that surrounds a pill.” And that includes rituals, symbols, doctor-patient encounters. … It’s basically the water that medicine swims in.

Placebo effects accompany real drugs. Morphine given without a person knowing — surreptitiously, in a IV drip — is 50 percent less effective than when it is given in front of them. That’s the placebo effect.

What’s going on in the patient’s [mind] is that the rituals of medicine, the symbols of medicine, and a warm, empathic doctor (in the context of a clinical encounter) activate neurotransmitters in the brain, activates specific quantifiable and relevant brain regions that release these neurotransmitters. And they modulate symptoms.

The placebo effect is a way about finding out what is it that’s usually not paid attention to in medicine — the intangible that we often forget when we rely on good drugs and procedures. We don’t pay attention to what surrounds those procedures that actually have impact on illness and health.

Brian Resnick

So when you get a sugar pill placebo, it’s your expectations to get better that make you feel a bit better?

Ted Kaptchuk

Thinking you’re going to get better is not what makes you better. That’s the mind-cure idea: It doesn’t happen. It’s not the way it is.

Brian Resnick

Really?

Ted Kaptchuk

I’m a little bit of a standard deviation or two out from consensus.

People think this is about mind over matter. But all my patients are people who have been to many doctors before. They don’t have positive expectations about getting better. They’ve been to 10 doctors already.

Brian Resnick

So you said all these factors that make up the placebo — the ritual of going to the doctor, being with a caregiver, engaging with “symbols” of medicine — actually make the changes in the brain. What impact do those changes have?

Ted Kaptchuk

Placebos only affect what the brain can modulate. It’s not going to shrink a tumor. It’s not going to deal with malaria. But it will deal with pain, fatigue, and nausea. Or will deal with feeling malaise. But it’s not going to deal with killing bacteria. That doesn’t happen on the level of the brain.

“I’m really tired about doing research that people say is about deception and tricking people”


Brian Resnick

Your research has taken placebos from being a methodological tool in scientific research — a way to figure out if an ingredient in a drug really works — to now something that may be a treatment in itself. How did that happen?

Ted Kaptchuk

Medicine has managed to ignore the effects in the placebo arm for a long, long time. The phrase “it’s nothing but a placebo” is a form of denigration, it’s a form of delegitimatization, it’s a way of disparaging whatever is going on.

The first phase of my research was showing how powerful a placebo could be potentially: showing that it actually changes how people experience illnesses, and that it has neurobiological correlates. Your brain releases endorphins that lower the pain. We’re showing that it makes major changes in people’s lives.

I had been around people on placebos for so many years. And I noticed that people were always worried if they were on placebos. If they got better, the would worry, “Maybe I made it up in my head.”

About five years ago, I said to myself, “I’m really tired about doing research that people say is about deception and tricking people.”

Let’s just try to see if we can be honest, transparent: Is it possible that [the placebo effect] would work giving a placebo pill and telling people the truth? People said I was nuts.

The first open-label study we did was in irritable bowel syndrome.

People on no treatment got about 30 percent better. And people who were given an open-label placebo got 60 percent improvement in the adequate relief of their irritable bowel syndrome.

Brian Resnick

Interesting. Did you compare those results to what happens when you gave patients real drugs?

Ted Kaptchuk

We’re doing that in a current study, a replication of that with a more elaborate study. The [National Institutes of Health] just gave us $2.5 million to see if open-label placebo is different than double-blind [placebo controlled], and different from the drugs.

But the effect size in the first study was as good as any drug that improves irritable bowel on the market. [The effect size between the no-treatment group and the open-label placebo group was .79 standard deviations, which is considered to be a large effect. Read more about that study here.]

Brian Resnick

Did the objective symptoms of their case improve some biological measure, or was it just their subjective experience?

Ted Kaptchuk

There’s no objective marker [for IBS].

I’ve deliberately chosen illnesses [to study with open-label placebos] that don’t have objective markers. It’s hard for the brain to change our physiology. It’s relatively easy for the brain to change how we feel.

Your whole life is disrupted in irritable bowel syndrome. It’s a very painful thing. People can’t go out. They can’t live without knowing where the bathroom is. They’re in pain a lot of the time. They can’t eat all kinds of things, and they don’t know what they can eat. But there’s no biology there. It’s functional.

It’s something that’s very hard for doctors to treat. People go and get many, many exams. They go to many doctors, and they can’t find anything. And they try painkillers, antidepressants, antibiotics — they try all kinds of drugs. Some people respond. Some drugs approved for clinical care show some improvement over placebos. The distance between the drug and placebo in those trials is not very good. It’s certainly barely clinically meaningful.

The mystery of why the placebo effect still works when it’s out in the open


Brian Resnick

So you use open-label placebos to help people with hard-to-explain symptoms -- like IBS, malaise, fatigue — does that give you some insight into how these aliments arise? Is irritable bowel syndrome, in some way, a brain problem? Which isn't to say the patients are "making it up" or "it's all in their head."

Ted Kaptchuk

All illnesses have a psychosomatic component. IBS, like many illnesses, has a large brain-gut connection. It has a clear physical component, including bowel disturbances. But medicine cannot find an underlying pathophysiology.

You have to remember that in all the objectively measurable illnesses, like cancer, even heart disease, there are components of it that are not [objectively measurable]. There are angina pains, or you have enlarged prostate, but in some people that doesn’t seem to matter. And in some people, it really interrupts their life totally. We don’t shrink the prostate [with placebo]; we actually make it so it doesn’t matter as much. [It could treat anything that] there’s an element of room for the brain to interpret, experience, feel differently.

We have great drugs, but they don’t often treat symptoms that well. What really bothers people are the symptoms. The symptoms are things they can perceive that are modulated by the brain.

Brian Resnick

What I still can’t wrap my mind around: Okay, the placebo effect is real, and it’s not just about people’s expectations. Fine. But why on earth does the effect still work when you tell patients the drug isn’t real? That it’s just sugar?

Ted Kaptchuk

First of all, I have no idea.

Brian Resnick

That’s actually a refreshing answer.

Ted Kaptchuk

Ultimately, it’s very peculiar. Our patients tell us it’s nuts and crazy. The doctors think it’s nuts. And we just do it. And we’ve been getting good results.

I don’t know if this is going to keep working [in clinical studies]. It’s really novel and new, in infancy. This needs to be replicated. We need to test it over time, too.

It doesn’t work in everyone — that’s clear. And we don’t know what makes it work, exactly. But we do know with double-blind studies with placebo — deceptive studies with placebo — that [neuro]chemicals are activated, regions of the brain are engaged that are specific and relevant — there’s something going on. And I don’t think it’s belief.

How open-label placebos could be put to actual use



Brian Resnick

How could you imagine using open-label placebos in a clinical setting?

Ted Kaptchuk

[In the example of back pain], basically you give people medication — there’s no reason not to give them medication — if you have an effective medication. But we know people with back pain that after a while try another medication, and that’s not good and doesn’t work. Another that has side effects. The thing about open label is there’s no side effects. And I could imagine a doctor saying, “We’ve tried everything. Let’s see if the placebo effect can work for you. Try it out for three weeks.” That’s one scenario.

Another scenario is doctors are routinely giving people drugs they know are not effective. Because they just want to give a patient something because they are being driven nuts. For example, if someone complains of fatigue, and doctors do tests and can’t find anything, they’ll say, “Why don’t you take some vitamins?” They know that’s not going to do anything. So that’s a kind of deception that’s routinely used. That could be a place to use it.

Brian Resnick

If you find a way to bring this to patients, do you worry about them becoming complacent with placebo? That they’ll be on it, feeling a bit better, but actually let some very real physical ailment fester?

Ted Kaptchuk

Oh, absolutely. This is not about taking care of yourself by taking pills and seeing what happens. This needs to be engaged with a physician, or with some kind of professional.

If someone has stomach pain, they need to go to a doctor. There are good drugs for that. But sometimes they might need an open label to deal with some of the symptoms like pain or nausea. This is something that should be deliberately done, carefully done.

Brian Resnick

Would you also worry that open-label placebos, if they work, dissuade doctors from looking for a root biological cause of their patients’ symptoms?

Ted Kaptchuk

No. Doctors, they’re trained like hound dogs to find the root biology. The real problem is that doctors hate the placebo effect. Because that’s what they’ve heard in their training from day one: “It’s nothing but a placebo.”

But there is a danger.

Brian Resnick

I get the sense that the take-home conclusion here is: “The placebo effect is weirder and more potentially useful than we have realized.”

Ted Kaptchuk

It’s disruptive. And what it is disrupting is all the theories about placebo. That this is deeper than, “I think I’m going to get better so I get better.”

This open-label placebo is really just one piece of how we harness placebos clinically. It really shakes the paradigm. You don’t have to give a drug that’s more than placebo; the placebo effect itself is something. And we don’t know if a good [doctor-patient] relationship without that pill would work also. But I don’t think so. I think it’s taking home the pill, and that connection is important.

I would like to see if we can get open label used in practical ways with real patients who are having a real hard time and need more improvement.

That’s a lot of work. We need to do more research. We need to see how long it lasts. We have to find the optimal way of doing it. There’s education of providers who don’t like the idea of giving placebos and are uncomfortable with it. That would be one goal.

I would like to see the bottom line of my research change the art of medicine into the science of medicine. Is there a way to quantify what are usually intangible items concretely into: How does this affect illness or health?


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