Season 2 • Episode 15
We’ve known about the placebo effects for over 200 years. That’s where doctors give you a pill containing no actual medicine, but you still get better.
Recent studies have uncovered a broader range of benefits from the including alleviated pain, nausea, heart rate, hay fever, allergies, insomnia, depression, anxiety, fatigue, and even symptoms of Parkinson’s.
Weirder yet, the characteristics of the pill — color, size, and shape — influence their effectiveness.. Fake capsules work better than fake pills, and fake injections work best of all. The question is: Just how far can fake treatments go?
Episode transcript
Intro
Theme begins.
The placebo effect is when someone sick gets better by taking a fake pill, that contains no actual medicine. Or they get fake injections. Or even fake surgery. The effect is not in your head; the results are scientific and measurable. That already sounds crazy—but it gets a lot crazier.
Robson: [00:01:03] /we have these expectation effects that go kind of beyond the medical setting and to things like how easily you can perform a workout, you know, how well you can get fit, the effects of sleep loss. / even the effects of your mindset on aging and how quickly you age. These are all expectation effects that go way beyond what we once knew about the placebo effect.
I’m David Pogue, and you’re about to hear some very strange “Unsung Science.”
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Season 2 Episode 15: What if Placebos ARE the Medicine?
Battlefield sounds.
Every modern army employs medics to treat the wounded soldiers. And in World War II, anesthesiologist Henry Beecher was one of them.
Robson: And what he found was that when he was treating soldiers, he found that often—you know, they seemed to kind of not need pain relief when they came off the battlefield. And this got him kind of wondering whether it was just the pure relief of having been saved from the battlefield that was kind of producing its own euphoria that was then reducing the kind of pain that they were feeling.
So they actually refused to have morphine when they were offered it. Which is incredible. And this was quite a high percentage of people. So that suggested there was some way that kind of the psychology of the soldier could influence the pain they were feeling.
This is David Robson, author of “The Expectation Effect: How Your Mindset Can Transform Your Life.”
Robson: Now there’s this other story that says that he actually ran out of his drugs at one point. And so his nurse started injecting a salt solution instead of morphine.
And what they found was that a lot of these soldiers really did experience that kind of pain relief. And it seemed to be quite profound. And then, you know, he studied this in later more controlled experiments and found that that was indeed the case.
Every year, the pharmaceutical industry tests thousands of new drugs. And in clinical trials, to see if they actually work, they usually test each drug candidate against pills that look identical, but don’t actually contain any medicine. They’re just sugar pills. They’re called placebos.
The idea is not to compare the candidate drug with doing nothing. That would be a bad study, because even if the medicine doesn’t do anything, some people will get better because of the placebo effect. The researchers might think that the medicine works, when it actually doesn’t.
No, the point of comparing the test medicine against the placebo to subtract out what’s called the placebo response. For example: If 75% of patients get better with the actual medicine, and 50% of them get better taking the placebo, you know that the actual medicine’s effect is…25%.
Keep in mind that the people who got the fake pills might be showing improvement because they just got better over time, or saw a fluctuation in their symptoms. Either way, you now have a better idea of what effect the actual medicine candidate produces.
The best studies are double-blind, meaning that neither the researcher nor the patient knows which pills are which. That’s to make sure that the researcher’s own words and attitudes don’t somehow give away whether a patient is getting the good stuff or the sugar pill, which they worry could skew the results.
But in the last couple of decades, scientists have started to realize: Well, wait a minute. Why are we subtracting out the placebo effect? If it’s producing positive outcomes in patients, maybe we should consider treating them with placebos.
Robson: Like if it’s providing relief, could we actually harness that effect as well—you know, potentially reducing the doses of drugs that we give to people?
What’s crazy is that the placebo effect is not just some woo-woo, “if you dream it, it will come true” kind of thing. There are measurable biological effects. There’s been one study after another. Most of them have to do with pain.
Robson: One of my favorites was that if you give people morphine and you give it through the IV drip, so it’s kind of surreptitiously delivered, that produces much less pain relief than if you give morphine in front of the patient with the doctor telling them what they’re doing.
In one study, researchers at Columbia and Stanford gave students free bottles of a new energy drink that contained 200 milligrams of caffeine, 2.5 times as much as what’s in a Red Bull. Or at least that’s what they told the students.
Robson: I mean, it was just a bottle of pure water, but it was turned into a placebo. But this kind of energy drink that was meant to leave you feeling more alert and, you know, kind of energized. And that’s indeed what they found actually produced a change in blood pressure and, you know, feelings of alertness that just didn’t come obviously, when you just drink a glass of tap water.
Pogue: Wait. Blood pressure? See, that’s another one of those examples where it crosses over from the woo-woo into the physiological.
Robson: Yeah, exactly. / in all these ways there are objective, measurable changes. It’s not just the patient self-reporting.
And it’s not just fake medicines, by the way. There’ve even been tests of fake surgery.
Pogue: You mentioned one study in the book where doctors would go in to put a stent in during heart surgery but not actually put one.
[define stent]
Robson: Yeah, that’s right. The surgeon did actually kind of make a cut in their skin and, you know, like perform the actions as if they were delivering the stent. It’s just there was no stent attached to the catheter that they were inserting. The patient fully believed they were they could have been receiving the stent. It was quite a big group sample of patients, a couple of hundred.
They found no statistically significant difference in their symptoms.
And I should—I should emphasize actually, that this was a very particular use of the stent. So it was for treating angina. So, you know, pain in the chest. I’m not saying that doctors don’t need to use stents at all. But for the treatment of angina, it certainly seemed that there was no benefit of having the stent over just having the placebo surgery.
Pogue: Wow. Well, the whole thing starts to make you wonder how much of real medicine and surgery is benefiting from the placebo effect. Like when we—when we buy Advil or something, I wonder if the fact that we expect we’ll get better from it is boosting its actual medical effect.
Robson: Yeah, I think it is. And actually, you know, the drug’s marketing is really important in the size of the placebo effect. You can find all kinds of painkillers. Some of them, you know, like with bright packaging and, you know, telling you it will produce, like, ten times greater pain relief than the average painkiller. And you know, what we know is that when you have all of that positive reinforcement of the positive expectation, then that it really is more powerful.
Pogue: And you’re saying, comparing a drug that has 200 milligrams of ibuprofen versus a generic one that also has 200 milligrams of ibuprofen?
Robson: That’s exactly it. Yeah, you’re getting the exact same chemical. It’s just the way it’s presented.
It gets even weirder. It turns out that bigger fake pills produce a more dramatic effect than smaller fake pills. And even the color matters.
Robson: All kinds of these things seem to make a difference. If, say, you’re trying to—um, receive like a kind of tranquilizing drug to reduce anxiety, that actually blue pills seem to be more effective in that case than if you have a red pill, because we associate blue with a kind of calmness.
Pogue: That’s crazy. Do you think modern pharmaceutical companies know that as they decide how to design their pills?
Robson: I expect they probably do. And, you know, that alone is enough reason for them to change the color of the pill.
We also know that fake capsules have a stronger beneficial effect than fake pills, and fake injections have the biggest effect of all.
Now, to be clear, this stuff isn’t magic. Placebos work on some ailments much better than others. They’re amazing for pain, and do a good job on insomnia, depression, anxiety, and problems with peeing and pooping.
But they can’t shrink tumors. They don’t lower cholesterol. They don’t bring down high blood pressure. They can’t cure malaria. They can’t make a wound heal faster.
Ted: The placebo effect is primarily reducing symptoms. People say, you know, “well, medicine’s really into the underlying pathophysiology. We get rid of this chemical, fix this organ that has a disrepair, trauma,” but actually, for patients, symptoms are really important.
Ted Kaptchuk is a professor of medicine at Harvard, where he’s the director of the Program in Placebo Studies. And what do they do there?
Kaptchuk: We do nothing but placebo research. You know, we’ve tried to find out how we can amplify placebos, make them smaller, make them higher, make the effects higher or smaller.
Few people have been working as hard, for such a long time, to advance the idea of placebos as treatment.
Ted: So let me tell you a very simple example of a placebo effect. I could pick headaches, I could pick irritable bowel syndrome, chronic pains in the belly, but let’s start with lower back pain.
You fall down, hurt yourself, get an injury, trauma in your back. You’re hurt.
You’re hurt, so the doctor prescribes aspirin or Advil, maybe try some physical therapy. And in time, the injury heals, and the pain stops. For most people.
Ted: But for many people, 50 to 100 million Americans, their brain doesn’t shut off the signal. It keeps firing in the brain. That’s what most chronic pain is. Your nerves change their function and structure and they keep firing, telling you you’re in pain.
Because we do know that when you respond to placebos, endorphins, dopamine, cannabinoids are released. Drugs hijack those same pathways. And the drugs that try to treat it, like opioids, use the same pathways as the placebo effect.
Pogue: So, you’re saying that the symptom of pain continues long after the actual injury.
Ted: Right. Tthe brain is misfiring. It’s a false alarm. That’s very, very common. 15 to 20% of every medical kind of specialty has patients coming in saying, “You gave me this drug, I did the surgery, and I’m still in the same pain.” And doctors, what they do, they send them to psychologists. And it’s not a psychological problem, most of the time. It’s a question of how the nerves work. A lot of people haven’t caught up to that explanation.
What Kaptchuk has discovered after 30 years of research is that there’s a lot more to the placebo effect than the pill itself.
Ted: Well, first of all, it’s not a pill, the effect of a pill, because it has no effect. It’s everything that surrounds the pill: the rituals, the symbols, the acts of kindness, the smells, the bells and whistles, of a clinical interaction. That’s really an incredible, important drama of every person that seriously wants to get healing.
If you need any proof that the doctor’s attention really makes a difference, consider one of Kaptchuk’s most famous studies. It was a study of 262 people with irritable bowel syndrome (IBS). It’s like a perpetual stomach ache, accompanied by various pooping problems.
Ted: It’s a really nice study. It’s one of my more well-known studies, but it was published in British Medical Journal in 2008.
He divided these people into three groups—or, as they call these groupings in the clinical-trial biz, arms. Three arms.
Ted: We randomized 260 patients to three arms. One was, no treatment control. The second arm was, it’s a needle that looks like an acupuncture—it is an acupuncture needle. It goes in and the patient feels it. It stands there straight up. But in fact, it’s a magic sword. The needle goes up the shaft and you, you can’t tell the difference between it and real acupuncture.
Pogue: Oh, man.
Ted: Fake acupuncture.
This second group had no doctor-patient relationship at all. An acupuncturist breezed in, asked if the patient was comfortable, and breezed out.
But then there was the third group.
Ted: They also got the fake needle. But then the doctor, the acupuncturist, would say, “So I’ve read your chart. I have a good idea what’s going on. But I want to hear in your own words, what is going on? How does this affect you? What symptoms are the worst, what makes it better? How does it make you feel? What things can you do that you still can do? What things you can’t do? What do you think is the cause?”
Real schmaltzy relationship, or a little probably over the top.
Pogue: The article about the study that I read, it said that in the third group, “practitioners were required to touch the hands or shoulders of members of their group, and spend at least 20 seconds lost in thoughtful silence.”
Ted: You know, it was great. We went over the top.
And we got this incredible result, as good as it can get, where the intense doctor-patient relationship, 60% of people got better.
If they had only the paraphernalia, fake acupuncture, 40% got better. And those people who are no treatment control, they had 27% improvement. Time heals.
And I would say that it’s clear that the patient-doctor relationship can modulate placebo effects from that study.
Pogue: That is— so mind blowing! By a third, by a third better.
Ted: It’s really amazing.
Pogue: Yeah. And so, so, so this seems like a valid study. The numbers were big enough. It was well-designed. Why didn’t that instantly translate into a universe of doctors who do not rush you through the office?
Ted: Two reasons. The evidence wasn’t good enough. But the real evidence is doctors don’t mostly care about placebo effect. I teach in a medical school, we get taught, the students get taught, that if it’s not more than a placebo, it’s worthless, right? The placebo is junk. I mean, that’s what you get taught when you’re studying development of pharmaceuticals and devices and surgery. So it’s, it’s, it’s always been tending to be marginalized, placebo.
But the other reason that doctors don’t care about it, is that placebos are tainted with deception and trickery, that you had to conceal or deceive the patient and make them think it was a real drug or real intervention. So, you know, I studied with the greats, and the people that were my predecessors, my teachers and everyone believed that.
And here’s where things get really nuts. Ted Kaptchuk is the first man who ever ran a study to answer the question, “Would a placebo still work if you knew you were getting a placebo?”
After the ad break, I’ll tell you how he tracked the answer down.
Ad Break
We’ve been talking to Ted Kaptchuk, who runs a Harvard group dedicated to turning the placebo effect into an actual medical treatment.
But remember: Most doctors have encountered placebos only in the context of studies, where you’re giving half the patients real medicine, and the other half a fake pill that has no active ingredients. And in those double-blind studies, they tell you that you may be getting a placebo.
You could never give a placebo pill to a sick person and pretend that it’s medicine. You can’t lie to them. “First, do no harm,” right? Informed consent, and all that stuff? That would be really unethical. And so, as a result, few doctors give a placebo to patients and claim that it’s real medicine. Well, few doctors admit to it.
So Kaptchuk had what may sound like the craziest idea in all of crazy placebology. What would happen if we gave patients a placebo—and told them it was a placebo?
TED: I said, “Let’s try this. Let’s do an experiment where we tell people it’s placebo. We have to try it.”
He approached the gastroenterologist he’d worked with on a recent experiment.
TED: And I said, “Tony, I got to do this. I got to do this. I want to give patients placebos and tell them it’s placebos.”
And he was great. He said, “Ted, that’s the craziest thing I’ve heard, I’m on board.”
And I said, “we have to get a grant.” And he said, “You’re never going to get a grant!” And he said, “Ted, can you recruit the patients and pay for parking? “
I said, “Yeah, I’ll do the work for free, and we’ll sneak into the research part of the hospital and not have to pay the fine.”
And it came out that it actually worked pretty good. 60% of people got better on the open-label plus usual care, 30% got better without extra treatment.
That blew us all away. I don’t know. It’s really hard to believe.
In other words, compared with the people who got no treatment at all, twice as many people got better when they’d taken a placebo that they knew had no active ingredients, what Kaptchuk calls an open-label placebo or honest placebo.
But what about people who got an honest placebo versus people who got…dishonest placebos? Pills that they thought might contain actual medicine, in those double-blind trials?
Ted: Yeah, we’ve compared them directly many times. Several times. There’s no difference.
Pogue: There’s no difference!
Ted: I’ve published great studies with 300 people and irritable bowel, and there’s no difference between double-blind and open-label.
Pogue: It’s so hard to believe.
Ted: There have been now over a thousand patients randomized to this kind of thing in different conditions, like low back pain, migraine headache, knee osteoarthritis, all kinds of pain conditions, and also lots of non-pain conditions. Cancer-related fatigue, it’s been done three times now. Perimenopausal hot flashes. So there’s a lot of evidence for it. It’s hard to believe, but I—
Pogue: Yes.
Ted: It’s because the nerves are in a context of healing. It happens automatically. It’s like the rituals, the bells and whistles, the doctor. It’s not a mind cure. It’s actually the nervous system regulates itself. It’s much smarter than the mind. The non-conscious world of our being is what’s doing it. And that’s really a breakthrough.
Pogue: But it occurs to me that there would be no side effects, either.
Ted: No. If a person is honestly told it’s a placebo, there’s no side effects.
Pogue: When I was a kid, and I found out placebo effects about the same time I found out about this effect, that the placebo effect still works if you know it’s a placebo.
Ted: Yeah.
Pogue: You’re the guy who figured that out?!
Ted: Yeah, that’s my first experiment, and I’ve done 15 of them since then.
Pogue: That was you?! That, that has been a cornerstone of my cocktail party conversations—
Ted: I really want to take that taint out of placebo. The idea that you need deception. In some ways, healing rituals tricks our minds to turn down the amplified pain sensation. It turns down the false alarm.
Pogue: Absolutely incredible. So do we have any idea what the physiological explanation is for that?
Ted: Oh, thank you. Thank you. Thank you. It’s a really important question to ask.
We don’t 100% know everything what’s going on there. But, the simplest explanation is that the nervous system amplifies symptoms, not only pain. And sometimes it gets stuck there, and up in the brain, the pathways that make the pain light up, the false alarms, are the same pathways that placebo sometimes, in some people, turn down.
We know from—for a long time, that for double-blind placebos and deceptive placebos, neurotransmitters were involved. Like, like endorphins—if you respond to placebo, the release of maybe endorphins, cannabinoids, dopamine. And what we now know, recent experiments tell us, that even when it’s open-label, you get the endorphins involved, right?
So we know that, in many cases, after you take a fake pill, your brain releases real chemicals, which produce genuine improvements in your symptoms. We know that the placebo effect gets magnified if you get a lot of attention from the doctor. Schmaltz, as Kaptchuk calls it.
Pogue: Okay, so in three groups in general: a group that gets no care might get less pain over time, just because it fades. Placebo effects with no schmaltz does better than that.
Ted: Right.
Pogue: But a placebo pill plus schmaltz—
Ted: —will get a bigger placebo effect. Yeah, yeah.
Now, remember our author friend, David Robson?
Robson: I’m David Robson. I’m 35 years old. I’m the author of “The Expectation Effect.”
There’re actually only two chapters in his book about the placebo effect. To him, the placebo effect is only one form of the expectation effect. Placebos are a subset of the effect that expectations can have on your life.
Robson: One of the best examples concerns exercise. They gave these students a genetic test for a variant that’s known to affect your kind of capacity for endurance exercise. So if you have one variant of the CREB-1 gene, it seems that you are a bit, you know, better able to do endurance exercise. And that’s reflected in physiological measures like the gas exchange within the lungs.
So they gave these students this genetic test, but then they gave them sham feedback. So the students didn’t initially find out, you know, what variant they had.
And what the researchers found was that those expectations alone, independent of the genes they were carrying, influenced their performance in this endurance exercise. And in some cases, the influence of the expectations was actually greater than the influence of that gene. So for the gas exchange within the lungs, the expectations were a bit more powerful.
Pogue: So if I told you, “oh, lucky you, you’ve got the gene, you’ll—you’ll run better, longer”—you believe it and you do?
Robson: Yeah, exactly. That’s what they found. And, you know, it also affected feelings of how hard they were working out. If you thought you had the good gene, you could be really like going for it on the treadmill, but it didn’t feel like so exhausting.
So I think it speaks more broadly to, you know, the narratives we carry around us. Like, if you’ve always just assumed that you just aren’t cut out for exercise, maybe because of—you know, what you see in your family members, maybe because of, you know, memories from high school of not really enjoying gym class—well, that is actually going to have a similar kind of expectation effect on you.
And then there’s the aging study, performed in 2002 by Becca Levy at Yale.
Robson: So that’s the one that really blew my mind. She found that people—people’s kind of self-reported expectations of aging, you know, at midlife seem to predict their longevity by seven and a half years.
So if they thought that things would get better with age, they lived longer. If they expected that things would automatically get worse with age, they lived seven and a half years less than the other people. So a huge effect.
That includes getting the various diseases you can get when you’re older, too. Here’s Becca Levy herself, in an American Medical Association video:
Levy: We were able to look at people who had the riskyou gene for developing dementia. And we were able to look at people who were free of dementia at baseline, and then we followed them over six years to see whether they developed dementia. And we found that even in this high-risk genetic group, if they take in more positive age beliefs, they actually had, we found, they had a 40% reduced risk of developing dementia. Their risk of developing dementia was as low as people who were not who are not born with that risky gene.
Robson: There’s a really big body of evidence that’s built up over the last 20 years that shows this to be the case. So the big question is, well, how could that happen?
Well, one explanation is that if you think things get better with age, you take better care of yourself. But Robson says there’s more to it than that; the expectation effect messes with your release of damaging stress hormones.
Robson: So what you see is that people who have the negative expectations of aging, they start to feel a lot more vulnerable and they’re going to see the challenges around them. Even something like going to post a letter, you know, going to the store to get your groceries, you’re going to start worrying about, you know, losing your way or having a fall. And that sense of vulnerability increases the kind of stress that they’re feeling.
So you see for these people, a steady rise in the stress hormone cortisol. And again, that then causes a steady rise in inflammation, which we know causes kind of bodily wear and tear.
And over time, you know that the consequences add up, and it just puts you at a higher risk of all of these different illnesses associated with aging, and eventually your mortality.
Pogue: Well, what should we do with that information? Should medical science at every checkup tell you getting older is nothing to worry about?
Robson: Right. I think we do need to take action. And, you know, Becca Levy in her first paper was like if we found that there was some kind of virus that was reducing people’s longevity by seven and a half years, we would be taking action. But actually, what she argued is that, you know, the ageism that permeates our culture is, you know, is a pathogen that is having that effect.
We as a society—we should be fighting ageism a lot more fervently than we do at the moment. We need to stop reinforcing this message that as you get older, it’s automatically a time of vulnerability and decline.
So I think that’s a no-brainer, really, is that we have to kind of, you know, be a bit more careful about kind of what messages we’re sending to other people and ultimately what messages we’re internalizing ourselves.
You know…I watched a couple of Becca Levy’s videos. At one point she suggests keeping an ageism journal.
BECCA: What that involves is, for one week, writing down all the messages about aging that you encounter, whether it be in social media, whether it be in a magazine, seen advertisements, whether it be, you know, talking to a relative or overhearing a conversation in the coffee shop. Write it down, and then write it down whether it’s positive or negative. And if it’s negative, take a moment and think, “could there have been a different portrayal of that older person?”
You know? It’s true. Think about it: It’s no longer cool to make fun of people’s looks, or race, or disabilities. But for some reason, making fun of old people is still fair game.
Dyer: The conversations I had with my dad at the end of his life were the same ones we had when I was about six; the roles just flip around. We would go out to eat, walk into a restaurant, I’d look at my dad and go, “Listen, sit right here. Don’t touch anything, don’t talk to anyone. I’ll be back in a minute, all right? Where are your shoes?”
That’s comedian David Dyer on YouTube. Sure makes me look forward to getting old.
Anyway.
So what have we learned? The placebo effect is real, it’s measurable, it produces physical changes in your body, and it’s freaking weird. Placebos even work when you know you’re getting them. Even though you know they can’t work on you, they work on you.
If you ask Harvard’s Ted Kaptchuk, modern medicine is just ignoring a vast realm of potential treatments that could be helping people—right now. He believes that placebos shouldn’t just be a nuisance variable in medical trials; placebos should be considered treatments in their own right. They work!
But making them mainstream will be an uphill battle.
Ted: But it hasn’t caught on. And I ask many of my colleagues who’ve been doctors in my, in my studies, I say, “Why don’t you use it when you’ve got these great results?” They say, “it’s not standard of care, Ted.” You didn’t get trained in medical school to give placebos, you’re trained not to give placebos. I give them a break. And it’s going to take a shift.
But, you know, I never stop fighting. So let’s see where it goes.
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