0:33 Intro. [Recording date: December 17, 2018.] Russ Roberts: My guest is psychotherapist and author Gary Greenberg. He first appeared on EconTalk way in September, 2010, when we talked about his books The Noble Lie and Manufacturing Depression.... Our topic for today comes from a recent article of yours in the New York Times Sunday Magazine that we'll link to entitled "What if the Placebo Effect Isn't a Trick?" Let's start by defining what the placebo effect is. Gary Greenberg: Well, you are going to start in a really hard spot, because nobody has a really good definition of the placebo effect. Let me give you two that will show you the extent of the problem. One version of the definition of a placebo effect is: Any effect of a medication that isn't due to the medication. Which is simple and straightforward. But there are problems with that definition. And, the other definition is: Anything that happens in a clinical trial that isn't related to the effect of the medicine. Or, to put it another way: Everything that happens in a clinical trial except for the medication effect. Russ Roberts: And why are those different? Gary Greenberg: Well, the difference is the placebo effect as we think of it now is almost entirely an artifact of the process of trying to experiment and find out which treatments--mostly medications, but to some extent other medical treatments--work. And which don't. So, to limit it, to define it by means of the clinical trial, which is the method by which the Food and Drug Administration [FDA] requires makers of drugs and devices to prove that they work--to define it in those terms is to give an idea of how the placebo effect really functions in medicine. It's the stalking horse against which all of the other horses have to race in order to show that they deserve to not be put out to pasture. And so, what that tells you is that the placebo effect is really just the flip side of medicine. It's like the evil opposite twin from the medical point of view--the evil opposite twin of the medication--because it also has a healing effect that nobody very well understands or control. Russ Roberts: And in those clinical trials, the way this manifests itself is that a population will be split in half. One half will get the real medicine, so to speak; and the other will get--typically what? A sugar pill? Gary Greenberg: Yes. Some formulation that looks and tastes and in every other way is exactly the same as the study drug. The only difference is that it is inert. It would be made of dextrose or something like that. Russ Roberts: And I know this sounds like a stupid question, but after I read your article I realized it's not really a stupid question at all: The people who--the participants in these clinical trials have no idea which they are getting. They just get a pill. Gary Greenberg: Generally, that's the case. It's called the double-blind, placebo-controlled method. So, what that means is that neither the experimenter nor the subject knows whether they are getting drug or placebo. And that, in turn, reflects the hope that they've managed to make the two treatments exactly equivalent with the exception of the molecule that's in the active drug. Russ Roberts: Yeah. It's a strange test when you think about it, because, if it weren't for the so-called placebo effect, you wouldn't have to give anybody the sugar pill. Right? You'd just say, 'You're not on the trial. We're going to see how your health goes over the--you're not getting the medicine.' Or, 'You're getting a sugar pill, and we're just doing that just to kind of have you kind of come in and go through the same kind of stuff that the other people are going through. But, by the way, you've got a sugar pill.' That's not what they do, typically. Gary Greenberg: No. And the reason is that--well, there are a couple of reasons for that. One is that the idea, the general received wisdom about placebo is that it works somehow or other by deception. That is to say: If you know that you are getting a placebo, somehow that's going to diminish its effect. Or change its effect. And so, telling people that they are getting a placebo theoretically would reduce the placebo effect. Now, interestingly, to the extent that that question has been researched, it doesn't necessarily prove out. So, the ongoing use of the placebo in the clinical trial is really just there to reassure everybody that they are actually seeing the work of the drug and not the work of treatment in general--not simply the work of being exposed to a healer or to the medical industry in any way.

5:57 Russ Roberts: One of the things I took away from your article is that that's something of an illusion: That they are only getting the medicine. And, of course, the part that--I don't think you wrote about this, but it's got to be an issue--it also means the way we conduct clinical trials that the people who get the "real medicine," the people who are getting the molecule that purports or trying to figure out whether it helps or not--those people have some awareness they might have a placebo. Gary Greenberg: Well, part of the process of being in a clinical trial is being informed that you have a 50% chance of getting a placebo. So, presumably everybody in a clinical trial that's placebo-controlled knows that that's a possibility. They just don't know whether or not they've got the drug. Russ Roberts: So, if I told half the group, 'Oh, you've got the placebo,' and I told the other half, 'You've got the real drug,' you'd think you'd get--from what I've learned--you'd get a different result than if everybody thought it was a 50-50. Because some of the people getting the real drug are thinking, 'This might not be the real drug.' And that's psychological awareness, perhaps, has a negative impact, just like the people who get the placebo are sometimes getting an improvement in the trial at all just from the possibility that they might have the real drug. Gary Greenberg: That's right. And so, what you are really getting at there is the fact that every clinical trial has a placebo group--virtually, every one--and therefore is a study of the placebo effect as well as of the drug, there hasn't been a whole lot of inquiry into the placebo effect itself. So, the scenario that you just described--you could actually find that out fairly easily. You would have to have a group that you tell you are giving a placebo, but give them the real drug; and another group that you tell that to but you are honest; and then the same with the drug--a group that gets it thinking they are getting it and a group that gets it thinking they are not getting it. And that would really answer a lot of questions, once you crunched the numbers. The problem with that is, a). Who are you going to get to pay for that? And, b). Even if you get somebody to pay for it, you have to deceive your subjects. And, while that's not impossible, that's a higher bar to cross than most researchers are willing to go in order to get the research approved by the government funders or the university or whoever is providing the funding for the study.

8:26 Russ Roberts: It's a serious ethical question, obviously. And we're going to come back to it, I think, more than once. Especially when I'm talking to the author of a book called The Noble Lie. In which these issues that are raised by the placebo effect reminded me of your book. We all--most of us would say--'Well deception is wrong.' But if I deceive you and improve your health, it's a strange moral conundrum. And, the point I want to make--and, actually, I'll re-quote from the article. You say the following: Give people a sugar pill, they have shown, and those patients—especially if they have one of the chronic, stress-related conditions that register the strongest placebo effects and if the treatment is delivered by someone in whom they have confidence—will improve. Tell someone a normal milkshake is a diet beverage, and his gut will respond as if the drink were low fat. Take athletes to the top of the Alps, put them on exercise machines and hook them to an oxygen tank, and they will perform better than when they are breathing room air—even if room air is all that's in the tank. Wake a patient from surgery and tell him you've done an arthroscopic repair, and his knee gets better even if all you did was knock him out and put a couple of incisions in his skin. Give a drug a fancy name, and it works better than if you don't. Now, these are the--just various examples of the placebo effect in action. The willingness of our--of something to happen that is not related to what we think is the therapeutic treatment. So, tell us what we know about how the heck that's possible. Gary Greenberg: Very little. You know, it's widely observed; it's been widely observed for many years. And, let's remember that prior to, say, 1860 at the earliest, almost all medical treatment was, worked by, well, relied on the placebo effect. Or, another way of saying that is: Most of it didn't work by the mechanism that it was thought to work. And, in general, there was no reason for it to work at all. There are a few exceptions. Aspirin is an ancient remedy. Some of the, you know--Pepto-Bismol has an ingredient in it that has been around for a long time. But, for the most part, we are--if you go back in history, all the treatments were placebo treatments. So, the fact is that, it defies in so many ways the standard model of understanding about healing, about illness, about how to study these things, that it's been very difficult to pin it down. But, let me say one thing about that list, which you prefaced by talking essentially about deception. There are some pretty strong studies that show that if you just tell people that they are getting a placebo, they get better. That has to be in certain conditions. And with certain medical conditions and under certain treatment conditions. But, deception may not be as central to it as we think.

11:34 Russ Roberts: So there are two pieces to your article that I was fascinated by. One is the possibility that the placebo effect is related to the level of empathy or the style in which the placebo is delivered; and the second is a possible genetic difference among people in having a stronger versus a weaker placebo effect--and that genetic difference is not stupidity. It's not somebody saying, 'Oh, I'm going to say a magic word here and your cancer is going to be cured.' It's rather that, literally, some of the placebo effects observed in at least clinical trials vary by genetic markers. So, let's start with the empathy question. Gary Greenberg: So, there's a theory out there is that what's happening in the healing encounter is that the healer--the physician--is, in order to do his or her work, has to try to understand the patient's situation from the inside. Now, we know that there are many, especially as you get into rarified, specialties that the stereotype is exactly the opposite. That, the subspecialist is more interested in the particular disease or the symptom or the surgery or whatever it is that the person needs than he or she is in the whole person. But, at the level of primary care for sure, medical care involves being empathic with somebody who is suffering. And the idea there is that, when you do that, you set off a series of events that--and this is real preliminary--but that may modulate the body's own healing abilities. So, for instance, there's research we know from other areas in which, we know there's something called mirror neurons. And, mirror neurons are networks of brain cells that respond to watching somebody do something that you're familiar with as if you yourself were doing it. So, somebody having an experience like sadness that you yourself are familiar with, your brain actually looks like the brain of the person who is sad. And that's thought to be related to empathy. I would go so far as to say it's the cause of it. But it may be the signature of it in the brain, loosely speaking. And so there's research that's emerging--it's in the very early stages--which shows that when there's a successful therapeutic alliance between a healer and a patient is that one of the things that's going on is that their mirror neuron networks are being activated. And so that's very suggestive that if there is what they call brain concordance between a healer and a patient, that that may help the healing process. Which isn't to say that whatever the treatment is isn't also part of it. But that in a way the treatment is the occasion for this expression of empathy or care or concern or whatever you want to call it. And that that isn't just window dressing, and that isn't just their making you feel good for a moment. It's somehow related to the fact of healing. You know, we can look at, I don't know, an antibiotic eat a bacteria in a test-tube; and that will tell us that antibiotics eat, you know, eat bacteria. But nobody with an infectious disease can say exactly why that treatment is what makes you feel better. Or get better. We're pretty close to being able to state it as a fact, but if you think about it, there's still a little bit of a gap even in that most objective kind of medicine, of, say, giving somebody penicillin for an infection. There's still a little bit of a gap there that we just don't fully understand. And it's possible that that placebo effect is part of what's in that gap. Russ Roberts: We had David Meltzer on here a few months back, and he's looking at--he's looking at a few things, but one thing he's looking at I would think of as empathy or more wholistic approach--this is my memory of the moment that you are reminding me of, where doctors interact more conversationally with patients rather than making sure they fill out all the right checkboxes and medical record data. Instead, they chat with the patients. They give them a lot more one-on-one time. And that also originated, by the way, as a story in the New York Times Sunday Magazine. In that article the author talked about Meltzer's physicians in these trials that they're doing learned things about the patient that they might not otherwise have known. They find out they were playing poker last night, ate a lot of French fries, and therefore maybe that's why their cholesterol spiked. That kind of fuller picture, or anxieties from their daily life, you wouldn't otherwise know about that might explain some of their conditions. But, hearing you talk, it makes me think maybe a lot of what they're doing is just a placebo effect. It's the emotional--and Meltzer may have talked about this, so I'll have to go back to the episode--but a lot of it may just be the emotional comfort, the body being in a healthier situation, that someone's listening to them and seems to care at least, or maybe actually does care, even better. So, that's the first thing I want to mention. The second thing I want to mention is Lynne Kiesling, economist, has looked at mirror neurons and the correspondence to Adam Smith's work in The Theory of Moral Sentiments; and as listeners know, I'm a big fan of that book. We'll link to that article as well--this question of what's exactly going on. And the fact that you raised this issue--when people are perhaps responding to a doctor's care--but this idea that we don't even understand fully--you say we're close. I wonder how close we really are in understanding the power of antibiotics or chemotherapy. It would seem, as an amateur, novice, layperson with no real knowledge, I always thought, 'Well, we know how these pathways work.' So, if we don't--if some of it is the unleashing of the body's own anti-immune system, I mean immune system; and also the body's ability to fight various infections automatically, which probably is just the English phrase for immune system. It's crazy. It's crazy to think that through emotion and the feeling that you are being taken care of or the idea that something you are putting in your body is going to help you--just the idea of it--could focus those inner strengths and stratagems that your body already has. Gary Greenberg: Yeah. I would say that--'crazy' is an interesting word. To me-- Russ Roberts: Wrong word. For talking to a psychotherapist, maybe. Gary Greenberg: Yeah. Maybe so. Unless you want a diagnosis. Um, it is a little crazy-making though. If you--if the definition of illness and healing is limited to the actions of molecules upon molecules--you know, an antibiotic on a bacterium--then it is a little crazy-making, because it makes it hard to talk about all this other stuff. So, even the little--even the things that you were saying just a minute ago, a doctor would hear that, could hear that and begin to really worry that you are about to tell people that, you know, vaccines don't really work. I know you're not. But, you know--there's such a strong set of beliefs that the way medicine works is objective: It works despite who you are. Russ Roberts: It's science. Gary Greenberg: It's science. Yeah. And science has been construed as this way of knowing that provides certainty. And doesn't, you know, sort of rules out the random. It rules out the subjective. And, I'm not--I think that there's some truth to that. But I also think that, when it comes to medical treatment, we underestimate the extent to which our experience, our expectations, our understandings about healing and illness are indebted to historical accidents. For instance, the first advances that really start modern medicine were advances that recognize germs as the cause of disease. The discovery of anthrax, of smallpox, of cholera--all of those 19th century--syphilis. Nineteenth century discoveries of these bugs that were creating illness. Russ Roberts: They are real bugs. Gary Greenberg: They are real bugs. They really exist. And really when you do something to not exist, or not so much, you end up feeling better. Or being better. Or surviving. You know. And this is--you know, I don't want to underestimate this at all. This is revolutionary. The fact that--it changed everything. I mean, look at the fact, what it means to know as a parent, today, that if your kid gets strep throat, 99.9% of the time you can give him some drugs and he's going to be just fine. A hundred and fifty years ago, that kid probably could have died. And that would be a real possibility. Or get scarlet fever and end up maimed for life. That was a real possibility. So, I don't want to underestimate this. But, because those were the early discoveries, this is our idea of medicine. It's a magic bullet model. You find the cause in the body and you aim your bullets at it and you kill it. And, while that works for some things, it doesn't work for others. And, more to the point, we may be, I don't know, mistaking the basic mechanism. We may not really understand the basic mechanism. You don't really have to. You know? If it works, it works. But, when you then go to branch out to other, more mysterious, more complicated illnesses, you find that it doesn't work quite so well; and in fact it's possible the low-hanging fruit has been picked. And that with the proliferation of immunological diseases, autoimmune diseases, or complex cancers, and so on, we may be looking at the kinds of illnesses that simply aren't going to respond to that model. And among those conditions, I think are some conditions that do respond strongly to placebo treatments: chronic fatigue syndrome, chronic pain, irritable bowel syndrome. And there's others. All are illnesses that modern medicine does a relatively poor job with. And that placebo seems to be--well, more effective than you would expect it to be.

23:18 Russ Roberts: So, I mean, pain, we know, is a peculiar thing because we know people can have pain from phantom limbs. So, obviously pain is weird. Pain is somewhat in your head. Of course, everything is in your head. So, it's a little bit tricky. But, you know, somebody who has chronic pain--you'd like to say, 'Well, so here's a painkiller; but actually don't take that because actually they may be addictive. So, instead I'm going to give you a sugar pill. Just think of it as a painkiller.' And that is not good medical practice, in general. Or, to tell people to "think positively," or whatever else. But there's a sense in which this research is heading in this direction, in some degree. Right? Gary Greenberg: Yes. And what you just got at is--it's a double-edged sword. On the one hand, there's great evidence that techniques related to mindfulness can be very helpful with chronic illness, particularly with the pain component of it. At the same time, you know, you can end up with--you can end up blaming the victim: where the patient feels pain and he or she has been told that that's, his mindfulness could control it, and it doesn't. Like he's failed. And that, you know, that's also a function of what we expect medicine to do in the first place. It's all supposed to happen without us. You know, you could be asleep and we give you the drugs and you are better. So, to introduce human agency--we don't really know how to do that yet; and we certainly have to be aware of the fact that in doing it, you could introduce things like victim-blaming and unnecessary guilt and all sorts of things that could go wrong with that formulation. Russ Roberts: And unnecessary doubts, for people who think they can avoid some challenge, health challenge by just thinking their way through it or meditating over it. I mean, if you read the Walter Isaacson biography of Steve Jobs, there are some strange things he did to himself when he was suffering from cancer that I feel--I worry, I feel sadly--that, you know, he was rejecting some--he was accepting some alternative treatments that probably didn't help him. So, as you said earlier, I want to make it clear: Nothing we're saying here is anti-science or anti- the many--it appears to be the many wonderful successes of what we might call Western medicine: the purely objective, scientific method for intervening in the body. But, there are just some mysteries here that we don't fully understand. And I have to tell a story--I've told it before, but it's so appropriate. I heard it told about Niels Bohr, I think. It's not really, I think, about Niels Bohr; I think it's been told about many people, Einstein and others. The student goes into Bohr's office, and, as he's leaving after chatting about some homework problem notices a horseshoe over the door. And the student says, 'Oh, well, Professor Bohr, you don't believe in that, do you?' And Niels Bohr answers, 'Well, of course not. But they say it works even if you don't believe in it.' It's the same kind of crazy, unscientific, unobjective, impossible result--that something magical is happening. Gary Greenberg: Yeah. And actually, that's--that happens in real medicine, too, right? Because, why--you look at a pill. A pill is tiny. Right? It's just this little thing. And it has no taste. And you swallow it, and all of a sudden, something--or maybe not so suddenly, but eventually, something really quasi-miraculous happens. I mean, where's the--there's magic in that, too. Russ Roberts: It's true.

27:10 Russ Roberts: So, I'm going to tell a story. I don't think I've told this before. But, I'll let you react to it because it's perfect for your article and this conversation. I had some shoulder pain. So, I went in to get a steroid shot. And one of the things that--I had a tear in my rotator cuff, despite my lack of baseball experience. And I--this happened 5, 4 years ago maybe: I'm 60 years old; I'm laying on the table; and it's a really cool thing. They've got a--of course, I'm not paying for it, so it's not perhaps as cool as it should--I should probably feel some pain about this, but I don't. I'm enjoying watching the fact that the doctor gets to put the needle exactly where she wants to put it. Because she's watching my shoulder on some kind of scanner. And I can see it, too. Which, of course, is a perfect placebo effect: I can actually see, 'Oh, the needle is going right where it's supposed to go.' And of course, my shoulder got better, either because of the steroids or the placebo effect. But while I was waiting for the doctor, I was chatting with the nurse; and I said, 'What's the coolest thing you've seen in this office?' And she said, 'Oh, it's this amazing thing. These people come in with back pain, and we put this cement in their joints. And it--it's magical. Their pain just totally disappears.' And I said, 'Well, that's very cool.' Which was restrained on my part, because a week or few, maybe a month before, I had at some point recently interviewed Adam Cifu, EconTalk guest, about his book, Reversing--I may get the title wrong but we'll put a link to it [Ending Medical Reversal--Econlib Ed.]. And basically what they find when they actually do clinical trials of this technique, which is called vernoproblastia [vertebroplasty?--Econlib Ed.]--I don't know how to pronounce it, but where they put cement into your vertebrae to get rid of back pain from osteoporosis--there is no difference between doing the treatment, where you actually go into this person's back and inject cement, versus laying him down, opening this cement so they can smell it, and then injecting saline into their vertebrae. And, of course, in a certain dimension--so, what did we learn from that? So, I kept my mouth shut. I didn't say, 'Did you know that doesn't work?' And now that I've read your article--the doctors in that office are particularly empathetic. They are wonderful people. They are great listeners. Maybe that's why their vertebroplasty does have a big placebo effect. But, what do you learn from that? You can't say to people, 'Well, you've got back pain, so what we're going to do,' you really don't want to inject the cement, 'we're just going to let you sniff this glue; and we'll inject some saline.' That's not a viable alternative. So, in what dimension is this placebo effect a horse that has to be beaten, a real horse? It's not even a real horse. It's strange. Gary Greenberg: Well, yeah. It's because--you say with some certainty, and I'm not disagreeing with you, that you can't just tell people, 'This is what we're going to do.' But, in part, that's because we're pretty well socialized to expect a certain kind of treatment; and the kind of treatment we are led to expect is not, you know, of saline injection accompanied by a lot of really nice people. However, medical treatment, no matter what it is, is a ritual. And so, what we could learn from that is what we learn from all of these studies. And, by the way, that lower back study that you mentioned is one of a number of studies that show that lower back pain in general is one of the most responsive of troubles to the placebo effect--to placebo treatments. So, what we learn is that, in addition to that there's more things under heaven and earth than you've dreamt of, is that the ritual is very, very important to the outcome. That, especially in a certain group of people, and this gets back to your second point about genetics, especially in a certain group of people with a certain group of illnesses, the ritual part of the treatment becomes very important. Russ Roberts: That book is called Ending Medical Reversal, by Adam Cifu, and it's co-authored with Vinayak K. Prasad. So, the ritual is important. And that's challenging to our view of that science. Gary Greenberg: Well, you know, the very word 'ritual'--it's like myth. It gets people's--if you are a scientist or a physician, married to the scientific method, you start to feel like somebody's trying to say something bad about you, if they say it's a ritual. I actually don't think so. I mean, I'm a psychotherapist: I believe what I do is I practice-- Russ Roberts: A lot of ritual-- Gary Greenberg: Well, yeah. I believe I deliver a placebo treatment. I think I do a really good job of it. For the most part. But, I couldn't tell you what the active ingredient is in psychotherapy. And I think that to some extent, that goes on in all medical treatment. So, we have our rituals. And, by the way, one of the interesting things that's happening in placebo research is that there is a mystery as to why the placebo effect is getting stronger as time goes on, at least with respect to clinical trials. In other words, as time goes on, each clinical trial is more likely to show a stronger placebo effect than they used to. And this has become a problem, because if the drug can't beat the placebo, the drug can't get approved. And so many companies get their drugs as far as the Phase 3 Trials, which is where the rubber meets the road; and they find out that it doesn't really beat the placebo, and it's withdrawn from the market, as if that means it doesn't work. But, what it may also mean is that people have come to--that the placebo effect has been augmented, maybe by advertising or by expectation. Yeah. And, it may be that the clinical trial setting--if you've ever been in a clinical trial, which I have, you get treated like royalty. They are never late. And if they are, you know, 5 minutes late, they apologize. They love you. You are worth money to them. And they treat you really, really well. You get the undivided attention of many physicians and nurses. For many weeks. And it could be that that is one of the reasons it's increasing, not because the treatment itself is increased but because while that's been going on, the rest of our lives in the medical industry have been getting worse. The doctors are more harried, the treatment is more fragmented, etc. Russ Roberts: It's also, I think, people increasingly, whether it's legitimate or not, think that doctors are saving the world and that everything works; and we've had a guest on here and I've talked to my own friends who are doctors--every patient assumes, and every family member assumes there's a cure for everything. You go in and the doctor starts describing why the patient is in very bad shape and people need to start getting their relationships in order and their affairs in order; and the family member says, 'So, what do we do next?' And the answer is, 'There's nothing to do. It's time to say goodbye.' Which we as human beings find infinitely painful. But we find it now intellectually perplexing, because of course we've figured out "everything"--almost everything. Surely there's another treatment to try, another drug to take in. And I think what you're saying is that would enhance the placebo effect. Bizarre. Gary Greenberg: Yes. That level, that set of expectations I'm sure is related. And, you know, the rituals there are immensely important. Think about the patients that spend their last two weeks in the intensive care unit. Now, you know, a lot of times that is primarily treating--I mean, obviously, they are doing things. But who are they really treating? Are they treating the patient or are they treating the family, when nobody will say that it's a lost cause? So, it's only tangentially related to the placebo effect, but it shows you the extent to which we grant authority to these rituals.

36:24 Russ Roberts: Yeah. I'm thinking about pediatrics for a minute. I'll tell you why: I remember when we had our first kids, we were getting advice on doctors, and people recommended a particular doctor, and they'd say, 'Well, he's not very warm and he's not good socially, but he really knows his stuff.' And, in my mind, that's the kind of doctor I want. 'I want the doctor who knows his stuff. I want the doctor who has got the best training, who has seen the most cases, has the best hard drive--mental hard drive, this is slightly pre-internet, 'Right? I want them to be able to pull on all that knowledge. That empathy thing? It's just gravy. It's just--I don't need that. I'm not even willing to pay for that.' And I suspect--I suspect--we've been talking a little bit about how doctors find this alarming or puzzling or troubling--I suspect there are a lot of doctors out there, and maybe some of them are listening and I'd like to hear from them, who believe in this overwhelmingly. Who very much believe that their bedside manner and their level of empathy makes a difference. And some of that's self-deception, of course, and confirmation bias. But I think a lot of doctors believe that. And of course they're the ones who have the best bedside manner. The ones who don't, probably think it doesn't matter much at all. But, I'm thinking them about pediatrics where, I wonder--that would be an interesting place to look. Right? For this effect. Because, kids are going to, infants are going to respond at an incredibly visceral level--I'm not sure what the word 'visceral' means in that sentence, but, a primitive, non-rational level to emotional care. And we know infants respond to that. So it would be interesting to see if, free of all the baggage or knowledge we would still respond to some kind of placebo. Gary Greenberg: Yeah. Right. These are all interesting ideas about how to study it. Of course, that's not getting done because there's no money in it. Russ Roberts: There might be.

38:30 Russ Roberts: Let's talk about the genetic thing. We didn't get to that. What's the genetic recent findings, that suggestion, that have something to do with this? Gary Greenberg: Well, there are findings that show, there are some studies, as I mentioned before, that have been done with open-label placebo--in other words, you tell people they are getting a placebo. And you compare their response to people for whom you literally do nothing. And you also compare the responses of people told they are given placebo to people who are told with a great amount of detail and attention and warmth. And what you find is what you might expect: the no-treatment people do worse; the placebo-receiving people--people receiving placebo with some explanation--do better; and the people that receive a lot of attention and care along with their placebo and explanation do the best. It's small studies; they are with irritable bowel syndrome. But if you then take the people who do the best on the placebo and you look at their DNA [deoxyribonucleic acid], what you find is that they vary in a predictable way. People who have one particular variant of a snippet of the genome are more likely to have a strong placebo effect than people who have the different variant of that same snippet of the genome. And so, what you find--and this finding has been, not exactly replicated but at least supported by large-scale studies that show--you know, one study that has 40,000 participants followed for 10 years--showing that the same set, the same area of the genome which produces a particular enzyme is related to the response to placebo. And this isn't for irritable bowel syndrome. This is the response to placebo for the prevention of heart disease and also, I think--this study will be emerging soon--for the prevention of cancer. That, there is a relationship between taking a placebo and avoiding those diseases--the placebo, people were taking placebo Vitamin E or aspirin. And there's a relationship between taking the placebo and not getting those or being prevented, having prevention from those diseases. And, the indication is that when you have a certain kind of genetic makeup, you are more able to make use of the placebo effect. Or, conversely, if you have a different genetic makeup, you not only can't use it, but in some ways it looks like it might affect you negatively, to be taking a placebo. Which is a very strange idea. In the absence of side-effects--you know, a placebo that somehow creates side-effects--it's very odd to think that the placebo could actually make things worse. And, the explanation for this is that all of these effects are modulated on the same neural pathways, which is a neural pathway that has to do with dopamine. And that, what the body--what we're really looking at is the body's ability to detect disruptions to homeostasis, and then to restore homeostasis. Not just in psychological disorder, but in physical disorder. So, there's this long chain of reasoning that is increasingly getting empirical support indicating that the reason that there's a placebo effect is because we've been misunderstanding healing all along--that there is this neural aspect to healing which is about more than just, you know, antibiotics eating bacteria or cancer chemotherapy agents eating cancer cells. That, it actually has to do with some healing process that is modulated by the central nervous system. And these findings are very suggestive. They are very early stages. But, when you really look into it, it doesn't seem all that implausible. And, one of the effects of this is that it indicates that the whole model of the clinical trial might be wrong, because it assumes that the placebo effect is part of the drug effect. Or that--sorry--that the overall effect is the outcome of the placebo effect plus the drug effect. It doesn't take into the consideration the possibility that they might interfere with each other. It doesn't take into account the possibility that a placebo might actually stop a drug from working. Or might make a person worse off to start with. Or vice versa. And this is a real challenge to the clinical trial model. But, it's really basic. Nobody has stopped to ask, 'Wait a minute. Are they really additive? Is the placebo effect plus the drug effect really the healing effect?' Nobody ever proved that. They just assumed it. Russ Roberts: And I like to think of the body as a complex system-- Gary Greenberg: Yeah. Yeah, I guess that's an interesting-- Russ Roberts: well, [?]--well, for me, it brings a lot of baggage with it. It means I see it as an emergent system; it's something like the economy; it's prone to unintended consequences. The policy interventions are not always as straightforward as we think. We have to ask the question, 'And then what?' And actually what you are saying, in so many words, you are saying that, 'We don't fully understand the underlying complexity; and if we don't, we don't understand then what we are actually doing when we intervene in these particular ways.'

44:21 Russ Roberts: I want to take us down a path that you only allude to in the article, which is weight loss. We had Gary Taubes on here, a long time ago, a couple of times. And many listeners have told me they've lost tens of pounds--30, 40 pounds. It changed their life. And, I remember telling this to a friend of mine, and he said, 'Oh, no. That's all nonsense. The China Study shows that what we really need to be doing is x, y, z.' I've looked at the China Study; it doesn't seem to be a very reliable study. But my friend lost an immense amount of weight following a very different paradigm than the Taubes more Paleo approach, of low-carb and not worrying about fat. And, I've said this on the program--I've said it in humor, but it's always crossed my mind that if you believe in the diet you are going to lose weight even if there is no "science" behind it. And that's a joke, I've always thought. But maybe it's not such a joke. In which case, listeners who lost 30 and 40 pounds, probably shouldn't be listening to this next part. Because, I don't want to spoil it. But, I mean, that's where this kind of starts to get crazy--I'm going to say 'crazy' again. Weird, Ouroboros-y. I don't know. Circular. Non-stable. Gary Greenberg: Yeah. I think that's right. I think the connection there is that--I mean, aside from the fact that maybe the weight loss is not a simple matter of metabolism. Right?-- Russ Roberts: okay-- Gary Greenberg: of what you eat and what you don't eat and so on, and how much you exercise. But that it also has to do with how you are, what your mind is doing. And there is--as you read that paragraph from the article, there is good research at Stanford that shows that the gut response--I mean, our gut is fully--people are now talking about the gut-brain, right? That there's so much neural activity in the gut. So, it's possible that the placebo effect could be related to weight loss. I just don't--aside from the studies showing the secretion of peptides is related to the expectation of the person who is taking them--which is a pretty astounding finding, really--you take, you know, if you give somebody a milkshake and you tell them it's diet that their gut behaves one way; and you tell them it's just a regular old milkshake, their gut responds another way--that shouldn't happen. But it does. Russ Roberts: It also raises the question of how you clinically test dieting. Right? Because, it may matter a lot about what you tell people, and what you do to their expectations. I used to have this--I don't remember who first told me the joke, but, you know, somebody offers me a brownie, and I say, 'I'm trying to lose some weight,' and they say, 'Oh, don't worry. All the calories are in the last one.' And if I could just believe that, maybe it would be true. I mean, this is just--it's a terrifying--I don't believe that, by the way. I don't think that that would work. But you're suggesting there is something to that. Gary Greenberg: Well, there might be. Yeah. If this research proves out, maybe you just order yourself 16 brownies and only eat 15 and you'll be fine. Russ Roberts: Heh, heh, heh.

47:38 Russ Roberts: I think, to get serious again--not that that's not serious-- Gary Greenberg: Oh, come on. Russ Roberts: There's some seriousness there about the psychological expectations part. But, you know, when you said there's no money in it: It would seem to me to be there's an immense amount of money in this, in fully understanding. It's not money you might be able to capture. But, you would think that foundations, and possibly the NIH [National Institutes of Health], would be deeply interested in getting a fuller understanding of the pathways of healing that we don't fully understand. Gary Greenberg: Well, here's the sad part of that story. Everybody knows that--well, first of all, the reason I said so glibly there's no money in it, is because, in the end, the money to bring something to market--whatever that might be--is generally provided by private industry. But as I'm sure you know, they are essentially helping themselves to taxpayer-funded research all the time. So, what I really meant by 'there's no money,' is that the drug companies can't figure how to make money off of it. But, I agree with you. But, the sad part of the story is that, um, the NIH has had a Center for Complementary and Alternative medicine, for many years now. And it's run by good people. The fellow who I think was its first director, is no longer, he's retired. But, and some of the people I interviewed for the Magazine article are active and get a lot of their money from that Center. But, so far, anyway, they have been unable to come up with very strong results about anything. Whether it's complementary medicine like homeopathy or chiropractic or studying the placebo effect. Or, what happens is: The more you increase the population of your study--or, let's say you do a lot of studies and then somebody does what's called the meta-analysis, to do a study of studies--the placebo effect begins to recede. Because this contradicts everything we've been saying to the last 45 minutes, or whatever. Because it begins to look like well, maybe the thing doesn't exist after all. But, what has happened is that, we have not been able to detect a strong-enough signal to know in what direction to move, in order to exploit the placebo effect in the standard way that we exploit other medical knowledge. I think--this is part of what I was trying to write about in this article--that that may be because the placebo effect has never been something that we could study very well with the instruments of medical science. Bearing in mind, that the placebo effect was really first identified in an attempt to discover whether or not the claims of a, a guy named Mesmer, famous for being Mesmerist, of the whole hypnotic thing-- Russ Roberts: It's mesmerizing-- Gary Greenberg: It's mesmerizing. Russ Roberts: That's where the word comes from, I assume. Gary Greenberg: Yes. That's exactly right. And he's practicing this kind of weird, séance-like treatment in Paris in the late 18th century. Which was very effective. It was having very powerful effects on people with fatigue and malaise and odd paralyses and stuff like this. But, the King decided to investigate this, and appointed a panel of leading scientists, including Benjamin Franklin. And determined that the placebo[?]--I'm sorry--that the hyp[?] mesmerism wasn't really doing anything. That it was all in the imagination. And that, in fact, the only thing worth looking at were the things that happened when the imagination wasn't engaged--what they were calling imagination. And that's actually the birth of the placebo effect. That's when placebo was separated off from the rest of medicine. And it was in the century later--the subsequent, the 19th century and then the 20th century, that we became accustomed to looking at medicine the way we do, and developing the instruments and the techniques and the methods for answering questions about health and illness. And so, there's a mismatch that's built in from the beginning from how we investigate illness and healing on the one hand, and placebo effects on the other. And it could be that what's going on is that looking for the placebo effect for those instruments is like looking for feathers with a magnet. It's like, just because you magnet doesn't find the feathers doesn't mean the feathers aren't there. It just means that you haven't quite figured out how to find them yet. So, yes. There's probably money in it. But, that money would have to be, at least at first, based on a new paradigm for even understanding healing in the first place. Russ Roberts: It seems we ought to think about it. You know, I'm not a doctor. And I'm not a medical philosopher. But, it seems like there is something there.