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The show "The Wonder Pill" will premiered February 18, 2003.

				A Different Way to Heal Historians of medicine explain why people sought medical help long before the science caught up to the art of healing.
		Select text to jump ahead in the clip: Imagine a scene like this: You come into your doctor's office with a problem that won't go away. And you've had the usual round of blood tests and maybe some expensive scans. And finally the doctor is ready to prescribe some medicine for you, and she gives you a choice: some heavy-hitting drug with risks of side effects, or this: a pill which she says is proven effective in some one-third to one-half of patients taking it. It's been in use for years, and it's been through thousands of clinical trials and has minimal side effects. No one's quite sure how it works, although some new research has been coming up with interesting ideas about how it affects the brain. Oh, and one more thing-- and, you know, she... she sort of slips this in there-- it doesn't actually contain any active drug. So what do you think? Would you give it a try? The pill you were offered was a placebo, a sugar pill. Placebos are a hot topic in medicine right now. The placebo effect is the often positive response that patients get to a sham medical treatment-- not just a fake pill, but in some cases even a fake surgical procedure. Recently, researchers have discovered that in some cases, the placebos cause physical changes in the brains of people taking them. This has led to surge of interest in understanding the placebo effect. And while your doctor may never offer you a sugar pill instead of the real drug, there's real interest now in trying to turn the placebo effect into a useful therapeutic tool. Which is why we're starting our show here, among the graves of people who died-- often very young-- from diseases that pre-scientific medicine was unable to cure. This is the grave of Dr. Harriot Hunt, one of the first women physicians in the country. What was it that Harriet Hunt and her mostly male colleagues in the healing profession were able to offer their patients? The short answer-- obvious in the gravestones here at Mount Auburn Cemetery in Cambridge, Massachusetts-- is "not much." There are hundreds of graves of children, and many of the adults died in their 30s and 40s. Most of these deaths were from infectious diseases like cholera and tuberculosis that medicine was once helpless against. But as long as people have been getting sick, there have been people who claimed to be able to cure them. Inspire them to look beyond where... ALDA: We invited Anne Harrington and Charles Rosenberg, both of nearby Harvard University, to help us understand what kept doctors in business. Over the centuries, what have people actually been given to make them feel better? Well, lots of different things, but I think that there is a real continuity: people always expected, if they were sick, to take a drug. This book was published in 1656, and it was a very, very popular English book called The English Physician Enlarged. With 369 medicines "made of English herbs that were not in any impression until this." This is an herb called Alheal. It was also called Hercules Alheal and Hercules Wound-Wort. "It is under the dominion of Mars; hot, biting and choleric. "It kills the worms, "helps the gout, cramp and convulsion; "provokes urine and helps all joint aches. "It helps a cold grief of the head, the vertigo, "falling sickness and lethargy; "the wind colic; obstructions of the liver and spleen. "It is excellent good for the grief of the sinews, itch, sores and toothaches." "Grief of the sinews"? That would mean probably arthritis or something like that. Pains in the joints. But you know what's wonderful about this? Is that it's, uh, so... authoritative. It tells you about the planets that govern it and... It's a lot like saying... "proven in clinical trials." That's right. ALDA: Some of these herbal remedies may have had consequences-- acting as a diuretic, say, or making your pulse race-- but it's unlikely they actually cured many diseases. ALDA: Was there anything that worked, a hundred, a hundred and fifty years ago? Well, the issue is "worked," because that's not... It sounds like a simple word, but it's a complicated word. Because when we say "worked," we put a kind of physiological, modern kind of notion: Does it have a physiological effect? Can it make a disease change its course? Make the body operate differently? But if you think about "worked" as having a patient feel differently or have the patient feel that someone was taking care of them, well, then, medicines worked in a different kind of way. ALDA: This "different kind of way" is what our show is about-- the mysterious chemistry brewed up between doctor and patient that works even when the medicine is what today we'd call a placebo-- an inert substance masquerading as medicine. While most doctors in the past would certainly not have thought of their remedies as placebos, there was a time, right before the advent of modern medicines, when placebos had an acknowledged place in the physician's medical cabinet. HARRINGTON: Back in the '30s and '40s, when we lived in a more paternalistic culture, doctors would keep bottles of placebos on their shelves. And in fact, they had these mail-order catalogs that advertised placebos of different sizes and shapes and colors. And there were professional conversations about the yellow ones that were particularly good for patients who were suffering from one kind of thing. Blue would be... help... be good for sleeping pills. Red were for pick-you-uppers. Because these things have a symbolic logic that doctors were aware of. And doctors were prepared to give these pills to patients in the 1930s and '40s because it wasn't... It was felt, in a sense, that doctor knows best. Patients didn't need to have full... consent and information about what was going on. We live in a different kind of society today. ALDA: It's a society where house calls have been replaced by the ten-minute HMO appointment, robbing the doctor-- and so his patient-- of the very thing that was once medicine's most effective treatment. HARRINGTON: I sometimes think of it as the "white- feather effect." You know, in the Disney film, Dumbo needs a white feather in order to fly, and he believes the white feather is the... You don't... haven't seen this film, have you? Uh, yeah, I haven't seen it since I was five. So... so you're looking at a blank face here, I'm sorry. Well, the... in... in the animated Disney film, Dumbo was an elephant with gigantic ears. And he flaps his ears and he can fly. He believes he can fly only when he carries a white feather in his trunk. Yeah, well, that's true for me, too. And one day the white feather falls from his trunk and he realizes he was doing it all along. So the placebo is the trick that enables us to open up things inside ourselves in... through mechanisms that aren't well understood, but are beginning now to be elucidated perhaps somewhat in... in the laboratory. But we do it ourselves... to our ourselves. ALDA: In this show we are going in search of Anne Harrington's "white feather," trying to rediscover the trick that allowed 19th-century physicians like Harriot Hunt to turn a placebo into a wonder pill-- and that even in the medicine of the 21st century can perhaps still cast its spell.

				Brainwaves Lift the Blues A researcher measures physical changes in the brains of depressed people taking sugar pills to treat their illness.
		Select text to jump ahead in the clip: ALDA: Of my two companions here at the University of California in Los Angeles, one succumbed spectacularly to the spell of the placebo effect while the other decidedly did not. They each answered an ad recruiting people suffering from severe depression for a study of antidepressant medications. As is usual for such studies, some of the patients were assigned to a control group receiving placebo pills çDinstead of the real thing. ALDA: CxThey told you that you might be on the medication or you might be on a placebo. WOMAN: Mm-hmm, mm-hmm. And you assumed you were on the medication. I certainly did. At... at... when did you make the transition from thinking, "Well, I wonder what I'm taking." You must have thought that, right? Or did you? No, I never did. Oh. ( laughing ) It sounds like they didn't have to give you anything. No, no, no. Because I was feeling so much better, I was convinced I was on the medication. Are these the pills that the patients take? These are the pills, the study material. Which pills are these? Well, we don't know. Oh, so they all look exactly the same. They all look exactly the same. Okay. Of course they would. ALDA: The physician running the study is Dr. Andrew Leuchter. LEUCHTER: When somebody comes to this big, imposing research institution and they see a warm and caring nurse in a white coat, they're... they have an expectation they're going to get better. They believe they're going to get helped. And since we're conditioned to believe that sugar pills can't possibly get you better, we tend to think those are real medicine. ALDA: Janis Schonfeld had never taken antidepressants before. LfBut Frank Strauss had-- and to be eligible for the UCLA study, he had had to stop taking his old medication a couple of weeks before the trial began. STRAUSS: When I get depressed, it's debilitating. I mean, I can't see to walk downstairs. I have to hold on to the, you know, railings. I can hardly leave my apartment. I... I get zero sleep because my heart beats all night long, you know? And I just lay there and watch the sun come up, which I... and it'ís çñ;like, the worst. How did you feel when you knew it was a placebo? You know, I thought it was a really cruel joke, is what I thought. You know, I thought, here's my whole life in the balance, and they're giving me something that, you know, all of a sudden I'm, like, getting screwier by the moment, you know? And, uh, I was angry to say the least. It never even entered my mind that they would give me a placebo, because I'm, like, "Here's this basket case. You can't possibly give me a placebo," you know? ( Alda and Schonfeld laughing ) You know, it's like... "What are you thinking?" And, uh... ( chuckling ) ALDA: Frank may not have responded, but many studies have shown that some 40% of patients with depression feel better on placebo-- and in this respect, the UCLA trial was typical. Have you seen people markew-dly çimprove on the placebo? Yes. We've seen complete cessation of depression on the placebo. LEUCHTER: The patients who got better on placebo, and the patients who got better on medication, couldn't be distinguished. At the end of eight weeks, we told everybody what they were getting. So at the end of eight weeks, they knew they'd been getting either placebo or medication. The patients who got placebo, almost all of them, within a month of the end of the study, had relapsed. Because as soon as they knew they were on placebo, most of them said, "You know, maybe I'm not feeling that good." "Maybe I don't feel that good." Yeah, exactly. "Maybe I'm still depressed." ALDA: But while Andrew Leuchter's study was unremarkable in finding that many patients like Janis responded to placebo, it was pioneering in what it found out about her brain. Like the other subjects in the study, including those taking real antidepressants, Janis came in for regular EEGs. Leuchter was trying to see if he could spot early changes in the brain waves of patients on medication. Often patients don't get any benefit from an antidepressant for several weeks, and Leuchter was hoping to find a brain wave signature that will predict if an antidepressant is going to help. Early results looked promising. Depressed patients usually have less activity than normal in the front of their brain, and in the UCLA trial, antidepressants that worked lowered the activity still further. A puzzling finding, perhaps, but still potentially a useful predictor of an effective treatment. TECHNICIAN: Try to think about something that keeps you alert. ALDA: But the big surprise came in the brain waves of patients like Janis Schonfeld, who felt better even though they were on placebo. LEUCHTER: What we found was that in patients who got placebo, when they got better, this same region of the brain here actually showed an increase in activity. It was the opposite pattern. It took a little bit longer to come on, but over the span of eight weeks of treatment, there was this augmentation of activity in the front of the brain in patients who felt better on placebo. Now, wait, this is a little hard to get. That... they take the antidepressant pill, the real pill... Right. And... they feel better and they get, uh, lower activity in that part of the brain. That's correct. Then they're given the placebo and they feel better, but they get heightened activity in that part of the brain. Yes. Now, originally I would imagine you would have thought that the lowered activity was related to feeling better. So how is it that-- never mind that they took a placebo-- how is it that they have this heightened activity here, but they feel better? How could that take place? What do you think is going on there? As you yourself said, the brain is extraordinarily complex. I think what it all gets down to is that there are multiple pathways to improvement. There's not just one way to get better. Now, it may not be as robust an improvement as a lot of patients would get with medication, and we don't think it lasts as long. We think it's a more fragile kind of improvement. But it's important because there is this other way to feel better that some patients are able to activate. SCHONFELD: My mood lightened, definitely. And if you've ever suffered from depression-- and I had been diagnosed with clinical depression beforehand-- there is such a weight that you carry. It feels like it's on your shoulders and in your head, that, um, to have that lifted, it almost feels like you can run... you could run a marathon or you could run quickly. And that's... that's how I was feeling. That's amazing. And yet it was a sugar pill. Yes. ALDA: Andrew Leuchter's discovery that placebos can actually change the brains of people who feel better is dramatic confirmation of the fact that while it may all be in the mind, the placebo effect is real and measurable. LEUCHTER: The importance of this work, from my perspective, is we can help figure out what leads to healing. That's really what this is all about, is healing. There's something that some patients are able to activate just by coming into treatment, getting inert treatment, taking a placebo pill. Some patients are able to feel better. What is it that is leading to that placebo effect? Is it a stronger bond between those patients and their doctors? Is it that they have more positive expectations, that they come in really believing they're going to get better? If we can distill that out and apply it more broadly, maybe we can help all treatments be more effective. And that's really one of the goals of this is to tease out something about the placebo effect that we could apply more broadly. ALDA: Leuchter's hunch is that this something-- the essence of the placebo effect-- lies in that most ancient of a doctor's skills: the healing power that flows from a caring physician to a receptive patient. Hi, I'm Dr. Leuchter. ( quietly ): Oh, hi. ALDA: Which is why I'm in his consulting room, acting the role of a patient with depression. So how are you doing today? Uh... well, I feel a little low. ALDA: Leuchter is shortly to begin a new study, in which-- as well as getting either a real antidepressant or a placebo-- patients will also be randomly assigned to either a detached and businesslike physician or, as Leuchter is presenting himself here, a warmer and more empathic one. I, um, wake up and then I can't go back to sleep. I'm sorry to hear that. Okay. Are you having problems sleeping every night? ( quietly ): Yeah. Yeah, every night. Okay. I'm going to go down just a list of some questions that I have to ask you here to see how you're doing. ( quietly ): Mm-hmm. Would you say that you feel the depression every day? Oh, yeah. Yeah. Okay, okay, um... Yeah, you know... you know, I wake up with it. You know, wake up. Right. Is there any time of day that it's worse than other times of day? Uh... ALDA: I'm doing my best to act depressed, while Leuchter is doing his best to act empathetic. Do you feel that the treatment has been helping you? ALDA: Later, I'll still pretend to be depressed but he'll change to a different persona. I'm going to jot down a couple of notes here for a second, if that's all right. Yeah, sure. Okay, um... ALDA: In his "Old Doc Brown" persona, the doctor in the new study will strive to build a bond with the patient, asking open-ended questions, maintaining eye contact, even when making notes, and generally being as supportive as possible. ÑñÑñÑññññññññññÑÑ98sOhzzssss, okay.ppppppppp It doesn't seem to be working. I'm sorry to hear that. Sometimes people do feel that way. It's important to remember that sometimes the medication can take a little while to work. So you might not notice the effect right away, but you may notice over the next week that you start to feel a little bit better. Yeah, but you know, it feels like nothing helps. Let me just ask you a couple more questions here before we close. Um, how has your appetite been? Uh, well, I eat when I'm depressed. Okay. I also eat when I'm feeling good. ( chuckles ): Okay. You still have some sense of humor. Yeah, yeah. Well, I, you know... Okay. I think that you should stick with this. I think that, you know, this is something that can help you. I hope you're willing to continue and give it more time and see if, in fact, this treatment can help you. Well, if you think so. I think it's worth it. Okay. Okay. I feel better already. ( laughs ) Okay. ( laughs ) ALDA: In his brisk HMO doc persona, the doctor in the new study will still be polite. Hi, I'm Dr. Leuchter. Hello. Hi. Good to see you. I've got a few questions for you today. Just have to take some notes and see how you're doing. ALDA: But this doctor will be focused on getting the clinical information he needs, rather than trying to discover the needs and concerns of his patient. He'll make less eye contact. Uh, so your mood's been down, depressed? Yeah, yeah. Okay. I feel like nothing, you know, like nothing matters. It doesn't make any difference... ALDA: His questions will be more pointed. Appetite? Well, I eat but I'm just not.... ALDA: Over the course of the study, patients will have their brain waves measured to see if there's a difference between the brains of patients who get the warm doctor and those who get the cooler one. Okay. Uh, sleep? Yeah, I don't sleep... I don't sleep well. ALDA: Andrew Leuchter is the first to acknowledge that a study like this is fraught with problems, not the least of which is that the doctor-patient relationship is a two-way street. For instance, for whatever reason, I find myself slightly preferring this more detached doctor than the one who was supposed to be warm and fuzzy. Well, I think that, you know, taking this medicine is an important part of your recovery. I think that, uh, it can help you stay well, so we need to continue with what we're doing right now. ALDA: But what's most fascinating about Leuchter's planned study is that it will be one of the first to try to bring the tools of research medicine to the study of medicine's art, to try to quantify what has always been regarded as mysterious and beyond quantification. Thanks for coming in. Okay. I don't know, what do think? You think the other guy was better? ALDA: When the original UCLA study was over, patients on the placebo were offered a real antidepressant, free of charge. Janis Schonfeld took up the offer and made a full recovery from her depression. Frank Strauss never made it beyond the first few days on placebo. STRAUSS: I always say this, sort of in jest, but that I was too screwy to even stay with the study, so they sent me down the road to another place, you know, and said, "We can't help this guy. Go down here." And, uh, so I went down... ALDA: I just want to get a positive ending to this. You finally did get on a medication that helped you. I did, yeah, ñwright-- down at another organization. And finally they balanced it out and I've had, like, the best years of my life since then. And, um, it's amazing what all has happened. My life just totally changed. So it sounds like you have two different testimonials to make about placebos. Yours isn't so bad, but you don't seem to be a fan of placebos. You know, it's kind of like, you know, being in the desert and thinking you're getting water and you get a bottle of sand or something, you know? It almost sounds like, really, one of the things that affects your reaction is your expectation going into it. OoDon't you think? I mean, you had a different /owwneed and want than I did. Yeah, I was interested in finding something that would be a little better than the ones I was taking. So I thought this new, you know, whatever it was would be the miracle drug that would fix me up. n,o,n-n,nYou know, and all of a sudden I'd, you know, get rich and find the girl of my dreams. ñó7( all laugh ) All over night, you know. They have a pill for that? Really. I was looking for it, you know.

				Expectation Pays Scientists find a placebo drug can lessen the symtoms associated with Parkinson's disease.
		Select text to jump ahead in the clip: ALDA: We're in Vancouver, British Columbia, where Sedric Bell is renewing a love affair with the latest version of a car he first drove over 40 years ago. Back in his native England in the 1960s, Sedric had great success racing Minis on some of Britain's major circuits. He emigrated to Canada 20 years ago. But then Parkinson's disease struck, stiffening his limbs and making movement difficult. Now it takes 16 to 20 pills a day to give him control over his body, and the dosage has to be tuned precisely. BELL: If it cuts in good, I'm as fit and agile as anyone; I can run, jump, uh... anything like that. But when you're stiff, you're just as stiff as a board, and if you're a little bit over, my head's flopping all over. There's no control over my muscles. Um... people say, you know, relax. I can't relax. There's no connection. My head can't tell my arm and leg to relax. It's just locked solid until the medication works through. Just relax your head. Let it go loose. Okay, very good. Now just open and close your hands, would you please? ALDA: Sedric was recently one of the Parkinson's patients volunteering for a study conducted by Jon Stoessl and his colleagues at the University of British Columbia Hospital. Now open and close your left hand. ALDA: Like Andrew Leuchter at UCLA, Jon Stoessl planned a study of real drugs, but he ended up instead with startling new evidence about how placebos affect the brain. Legs go loose here. ALDA: The tests Sedric's going through are standard for assessing the severity of a patient's impairment due to Parkinson's. His right side is more affected than the left, showing up mostly in his slow and difficult movements, but also especially when he's stressed-- in the tremor most of us associate with Parkinson's. STOESSL: The tremor is often not a prominent feature. Even though it's a very common feature, it's often not the most prominent feature for people and, in fact, it is very uncommon for it to be the disabling feature of Parkinson's. The disabling feature is the poverty of movement, the slowness of movement. It's rare that I shake. See? It's very rare. The only time I notice it is on the transition of the medications when it's coming on and going off. I may get a little bit of... a little... a wee bit of that. It could be any other part of the body. And then it just settles down when it goes in, and generally I should be good for three hours with the medication I take. ALDA: The medication is levodopa, which, in Sedric's brain, helps replace dopamine: one of the brain's communication chemicals and essential for controlling movement. STOESSL: When we start treatment for Parkinson's, people get a good response for several years. But after a few years, they get into trouble often with the benefit of the medication wearing off before the next dose is due. So we were doing studies to try and better understand why that might occur, and those studies involved looking at the amount of dopamine that's actually available to the nerve cell. ALDA: Measuring how much dopamine is released in response to medication involves a trip to the hospital basement. Here we are at Positron Emission Tomography. Yes. ALDA: Where Sedric has spent long hours lying in the PET scanner. The bed knows me. It does, yes. ALDA: During this time, his head must be perfectly still. A mask that's flexible when warm, and can be molded to his face, dries into a rigid head restraint. And as it cools, it's going to harden to the shape of your face. This one's hardening quick. So keep your eyes closed. ALDA: Parkinson's is one of those conditions, like depression, that in many patients can be alleviated, at least for a while, by a placebo. So it was especially important to include in the trial of active dopamine-releasing drugs a placebo control. STOESSL: They were told explicitly that they would be receiving three or four injections of drug, one of which would be an inert substance. They were not told in which order those injections were to be given. ALDA: As expected, the PET scan showed an increase in dopamine release in the brains of subjects receiving an active drug. But what was not expected was that there was just as big a dopamine release in the brains of some patients, like Sedric Bell, when the injection was of an inert placebo, a saline solution. It was, initially, certainly a big surprise and then when we stopped to think about it, it became somewhat less of a surprise in that it's been recognized for many years that dopamine is somehow involved in reward mechanisms in the brain. So when we have things that we enjoy or that we look forward to... Drug addicts, for instance, get their reward related to dopamine release. And so if you think about it, the placebo effect has everything to do with the expectation of benefit and that, I think, could be very analogous to reward. Okay, we're going to bring you out now. You did well. ALDA: Making the Vancouver study even more remarkable was the fact that the placebo resulted in dopamine being released in precisely the same place in the brain as the real drugs release dopamine-- just where it's needed to activate the pathway that controls movement. You did really well. WOMAN: Thank you. WOMAN: Let's have a look. ALDA: And to top it off, volunteers like Sedric, whose PET scans revealed dopamine release in response to the placebo, also improved when run through the standard test battery. Big, powerful movements. ALDA: Again, just as you'd expect if he'd received active medication. So you're a little better than you were earlier. Yes, a little bit better. What about this one? STOESSL: I think this is really a tremendous example of the mind controlling the body. I mean, those of us who work in neuroscience regard these as closely linked. We don't really think that there's something different about the mind. But this is really the classic example of how your expectation of something, your attitude toward something can materially affect the physical outcome, that it's not just loosely how you think about whether or not you responded, that there is actually a physical explanation. It's like trickery, you know. They tell you they've given you whisky, but they haven't. ( laughs ) Um... It's quite surprising that things turned out like that. You know, for... to take something that activates your dopamine cells, and it isn't supposed to do anything like that at all is truly amazing.

				Snuffing the Sniffles A cold researcher untangles the relationship between how one feels and how one thinks one should feel.
		Select text to jump ahead in the clip: ALDA: We've seen how the expectations aroused by placebos can affect the brain. Those same expectations can make drug research an often very messy business. These volunteers, whose noses are being rinsed out with a saline solution, are being paid to catch a cold. If you wash his nostrils out, he'll have a better chance of catching cold? Mm-hmm, because his nostril will be nice and clean. This is a horrible thing to learn first thing in the morning. ( chuckling ) Okay, go ahead. I mean, I would have thought that getting your nose clean-- you know, like they say, "Keep your nose clean"-- I would think that would help. ALDA: The man dispensing the colds is Ronald Turner. What he's carefully placing up the nostrils of his volunteer subjects here in Charleston, South Carolina, is a strain of rhinovirus, one of the commonest causes of the common cold. Now, you already had one of these? WOMAN: I had one. I had one already. So how many do you give? Two. We just go around twice. You really want to make sure you make these poor people sick. That's right. ALDA: Actually, Ron Turner is hoping some of his volunteers won't get sick, because for the last two weeks, some of them have been taking twice-daily doses of one of those herbal extracts that a lot of us believe help fend off or shorten a cold. Some of them are getting active medication, some are getting placebo. But everybody gets the virus. Now, do you know what... Are you aware of who's getting the placebo and who's getting the medication? No, no. We're all blinded. You don't have any idea. Uh-uh. MAN: This is what they look like. ALDA: The famous jujube medication. ( chuckles ) So what do you think is in there? I'm really not sure. Hopefully some medication that will take care of me. But, um, for all I know, it could just be sugar pills. ALDA: This need to ensure that no one knows who's getting what is absolutely critical in a trial like this. It's especially important that the volunteers aren't picking up any clues from how the pills taste or make them feel. Do you think you were getting the active medication or the inactive medication? I think I was getting the inactive. I have no idea. I really don't. I had no side effects, no symptoms of any kind either way, so... Okay, if you were to give me a guess. Active. Inactive. I think I was getting inactive. Active. And why? I don't know, it's just that Ñwhuenever I took it I felt, like, fuller. I would have to say the active medication. Why would you say that? Um... it'd kind of depress me if I was having the other medication, so... ( chuckling ): Okay. I would say the inactive. RESEARCHER: And why would you say that? Just because I didn't feel any difference. Do you think it matters whether or not you believe you're taking ç>ñthe active ingredient? @q Yeah. I think if I thought I was on it, I would definitely experience a placebo effect and feel better than maybe I should. And thinking that I'm not on the medication I might be more inclined to feel the symptoms more severely. ALDA: Lindsey's right. If people are able to figure out what they're getting, then it could dramatically influence the results of the trial. I'll go with active. RESEARCHER: Why do you say that? I'm hopeful. No difference between... They couldn't tell. And, for some reason... ALDA: In fact, in Ron Turner's opinion, the placebo effect-- and in particular, the difficulty of eliminating it-- is why we're all so confused about popular cold remedies like echinacea or vitamin C. Take one of my favorites, for example, zinc lozenges. Is it true that even when you're not in a study, when you're just sick and taking this lozenge, the fact that it tastes funny might have... might increase the placebo effect for you and may help you feel better sooner? Is that possible? Yeah, I think that's the old, "It's got to taste bad to be good" concept. You know, good medicine has got to be, in some way, onerous. There's got to be some penalty for getting better faster. If we in fact believe that on some deep level, then it might, you know, be a self-fulfilling prophecy. Is that right? Is that the way it might work? Sure. I think clearly that's a possibility. And, in fact, you might say, "Well, so what?" If that's the benefit you get, that's good. Okay, I'm desperate now. What did you put in the study today? Maybe I can take that. I mean, even before you find out in your study that it's no good, I'll have a couple of colds that I can use it on and get the placebo effect. Definitely have the cold... I have it. I don't feel ill at all. If I'm supposed to be ill, I'm not. I have the cold. ALDA: Three days have passed since our volunteers were infected with the cold virus. They've been reporting in every morning since. It's been 72 hours since the inoculation. Do you think you received a cold? Yeah, I do-- I definitely had it yesterday. Okay, I want you to rate your symptoms this morning based on the severity since your last visit. Any symptoms of sneezing? I'd say about a two. Okay, runny nose? One. Nasal stuffiness or obstruction? Uh, two. ALDA: There are a dozen symptoms on the list-- enough to get a pretty objective measure of the severity of the cold. One. Definitely getting worse, huh? Yes. You can go back and get your nasal wash. ALDA: The nasal wash will reveal how strongly the virus took hold. WOMAN: Good morning. Good morning. ALDA: Meanwhile, we wondered how our volunteers feel now about whether they are on the test medication or the placebo. WOMAN: I think I'm receiving just a placebo. I think it kind of got better because I was taking... I'm not sure whether I was taking that medication or not, but I think I did. I believe I had the inactive medicine. Because otherwise I think I probably wouldn't have gotten the cold or it wouldn't have been as severe. Based on how mild my symptoms are I think maybe I did get the active. Oh, yeah, I'm really glad I got it. Because I'd be walking around with tissues hanging out of every pocket and just not a pretty sight. I think I got the inactive medicine, because I've been getting worse as the days go on. I guess I got the active medication because all I've had is a runny nose and that's it. ALDA: Not surprisingly, most of those with the worst colds thought they were on the placebo while most subjects with mild colds guessed they had had the medication. But in fact, it was all in their heads. Later, when who got what was matched up with the severity of their infections, there was no difference between those who got the herbal substance and those who got placebo. That's right. The mystery herbal ingredient in those big brown pills did no better and no worse than the placebo-- a judgment Ron Turner also makes about most other popular cold remedies. You know what's funny about this? And this is just... totally personal. I'm going to keep taking this stuff because I haven't got any other... any other feeling of control over the cold. And for me, getting a cold-- because I have to use my voice in my work-- it's something that I'll... I'll clutch at straws over. How does that strike you as a scientist? Well, I guess I don't have any problem with that. As I said, my job here is to try to figure out whether there is a biologic effect. Whether people choose to use that information or whether they get some benefit-- whether it's psychological or mental-- that's fine. You know, the saying is, of course, that if you take this medicine you'll get over your cold in seven days and if you don't it will take a week. ( chuckles ): So... That's the best you can come up with after all these years? Well, I think we're doing better than that. I've heard that joke. I think we're doing better than that.

				Healing Rituals A doctor trained in Chinese medicine attempts to quantify how much of healing is science and how much is art.
		Select text to jump ahead in the clip: ALDA: One of the most mysterious of medical treatments is acupuncture. Thousands of years old, still practiced widely in China, in recent years, it's edged into mainstream medicine even here in the United States. ALDA: Acupuncture's growing popularity comes despite its striking contrast to conventional Western medicine. Its theoretical underpinnings, involving the manipulation of a force called Qi through energy channels in the body, has no known basis in how Western medicine believes the body to work. People go to acupuncturists for one good reason-- many feel better as a result. But while some scientific studies suggest acupuncture may relieve pain by releasing natural painkillers in the brain, the power of acupuncture to heal some people of some conditions remains mysterious. Mysterious, exotic and tantalizingly different from establishment medicine-- just the formula to entice a 1960s student radical to China to study traditional Chinese medicine. Ted Kaptchuk spent several years there, returning to the United States skilled in herbal medicines as well as acupuncture, which he practiced here with a success that surprised even him. KAPTCHUK: I said to myself, "I'm not as good a practitioner, I'm not as good an acupuncturist as my teachers." But I kept seeing people get better much quicker than I saw in clinics where I worked in China. And it occurred to me that maybe the exotic-ness, the ritual, the complexity, talking about mysterious forces may indeed elicit a ritual response, or elicit a kind of magical capacity for self-healing that's actually greater. ALDA: Now firmly back in the medical establishment at Harvard Medical School, Ted Kaptchuk wondered if this magical capacity for self-healing has more to do with the placebo effect than with Qi. So he's designed an elaborate study of RSI-- repetitive strain injury, or carpal tunnel syndrome-- the pain many people experience after hours spent at a keyboard. Some of the patients in the study will get a pill-- either a real drug or a look-alike placebo. Others will get acupuncture-- either real or a placebo, sham acupuncture. What Kaptchuk really wants to find out is how the two placebo treatments stack up against each other. Is the placebo effect of sham acupuncture, with all its rituals and mystery intact, more effective than the placebo effect of simply popping a pill? That's what's unusual about this particular experiment. It's saying, no longer do we take the placebo effect and just throw it in the wastepaper basket. But let's look at these placebo effects as a major question, a major component of medicine, a major consequence in health care. To what extent does the ritual, one particular ritual-- in this case the ritual of acupuncture versus the ritual of taking a pill... Those rituals are different. What's the consequences of those rituals in terms of people feeling better, in terms of people feeling more intact, being able to work better? How do those rituals... Do those rituals elicit different healing? In this study, you... you... you replicate the experience of acupuncture without actually giving acupuncture. How do you do that? The basic idea is that the needle... It's a magic sword... principle. When you have a magic sword, you stick it in, but instead of the shaft of the sword going into the person, it goes up the handle, so it retracts. So basically this is a needle that looks like it goes in, it feels like it goes in, you see it go in, but in fact it goes up the shaft. And in fact, the first time it was done to me, I was sure that they had made a mistake and given me the real needle. Okay, don't make any mistake and try it on me. Okay, I actually have a little inflammation in this finger. So would you stick me someplace where it would help that finger? Sure, and I'll cure it for you. Thank you. By the way, even when I know it's a placebo, it cures me, so this will be fine. So basically we do this to both the real needle and the fake needle. The needle is indistinguishable. It's a real needle. There's no way you could tell this is not a regular needle. I feel it, yeah. I felt it. That's the way a real needle would look and that's the way our placebo works. This is also the way it would happen if the producer was tricking me into getting a real needle because I don't want any real needles in my hand, and this is exactly the way it would happen. We'll have to see, make sure it's the placebo needle, and then pull it out. Should I pull it out? And that's it. And then we take this away, and... and that's it. Now, does it cure your hand? It's only a little worse. It's going to get much better in five minutes. Okay, five minutes. Let me assure you. MAN: Kathleen, how much pain are you in, in terms of your right arm? Would you say mild, moderate or severe? Um, moderate. Moderate. How bothersome... ALDA: Joe Kay is one of several licensed acupuncturists who are lending their services for the trial. And how much does the pain interfere with your life? Would you say mildly, moderately or severely? Moderately. ALDA: So that the sham needles won't simply fall out, he'll be using the disks and tape on all the subjects in the trial. People will come to you as part of the study who have had acupuncture before. Are there people like that? Yes. So when you suddenly put the disk and the tape on them, do they say, "What's this? I never had acupuncture like this before"? Many times, but the thing is with acupuncture, there's many different styles of acupuncture. You know, it's been around for a couple thousand years, so there's many different techniques that are used, and I just explain to people that this is just one technique that's used in order to make sure that we get the exact point. KAY: Okay, did that feel okay? ALDA: Now, the patient doesn't know if these are an actual application of acupuncture needles or a sham procedure. Even if the patient has had acupuncture someplace else, they really don't have any idea. And neither do I know if it's real or not. No, keep going. I want to see if I can guess. Okay. Uh... Would it... would it spoil things for me to say what I think it is? No. I think it's the real thing. Okay. There's something about the way you... you had to... you had to get it in there. It didn't seem like, uh, like... like the fake needle. You could be right. So... so... so let me... let me just get this part of it straight. This is sort of a placebo event we're doing here. Kathleen, you're not really a patient. No, I'm not. This is just demonstrating the way the study works. So... but do you know what kind of a needle was going in you? Honestly I thought I'd be able to tell. I really... I'm going to have to ask Joe. I really don't know what I had. I really don't. What was it, actually? What were you putting in her? I actually used the placebo needles. The placebo needles. And you couldn't tell. I thought I was getting a real treatment. I thought Joe was going to tell me later he really used the needles. I'm surprised. I really am. ALDA: Kathleen wasn't the only subject to be fooled by the fake procedure. I had one participant in this study who I was using the, um, sham needles on, and it was someone who had had RSI for many years, and after about four treatments, it was completely gone. After four treatments the person was okay? They were okay. And... and had they had any kind of acupuncture treatment before that? No, they'd never had acupuncture before-- ever. And so they got better from the sham needles. Right. Wow. How did that make you feel? Uh, well, from the standpoint of being an acupuncturist, it made me feel great because the person was better. But on the other end, it's like, "Well, gee, what happened there?" So... Well, I wonder if those 20 years of treating people has given you a sense of authority in relation to the patient that... that's curative in and of itself. Do you know what I mean? If they come in, they get a treatment by you. They think, "This person clearly knows what he's doing. I'm going to get better here." That's not to say that... I mean, that must be part of doctoring. Yeah, yeah. I mean, ultimately, if that's the case, then that's fine. As long as a person gets better, that's what my goal is. Now, this... raises... I really am interested to know why... why are you taking part in this project? Because what if it's found out in the course of this study that it's really not the insertion of a needle in the right place that... that... that does it-- that has a positive effect-- it's just the ritual surrounding it-- that the... that the sham needles are just as good as the real needles? I mean, what would that do to your practice? Um, I don't think it would do much to my practice. I mean, there's a placebo aspect to any sort of medicine. I mean, even in conventional Western medicine as we know it, there's a placebo factor that's in there. And I really feel pretty strongly that, you know, once the data has actually all been crunched, that we'll find out that the real acupuncture is the real thing. You know, if it doesn't and I'm proven wrong, I don't think it's going to, um, necessarily disappoint me or make me, um, change professions or whatever. But it might make you change your needles. I mean, you... Yes, I would change my needles. ALDA: But remember, the real focus of this study, which Ted Kaptchuk is still running, isn't to find out whether placebo acupuncture is as good as the real thing. It's to see if the placebo effect is greater when there's more ritual surrounding a treatment, as in acupuncture, than when the treatment is nothing more elaborate than swallowing a pill. Unless we begin to address those questions, a big part-- a big, big part-- of what medicine's about gets left behind, gets put in the trash basket. And one of the things that is exciting about the new development in placebo research is we're saying some of what's in that trash basket is precious. It's an important ingredient of what makes people healthy. It's an important ingredient of what makes people feel better, and we have to bring it onto the table. ALDA: In the shadow of the Alps, the city of Turin has become well known among researchers exploring the placebo effect. ( man speaking Italian ) Fabrizio Benedetti and his colleagues, including Antonella Pollo, have in the last several years conducted a series of startling experiments here in the pain clinics of some of the city's largest hospitals. Today Luama Collosa is the volunteer subject for one of these experiments. The Turin group is studying placebo analgesia-- the relief from pain that many people experience when they believe they're getting a painkiller but in fact they're not. ( speaking Italian ) ALDA: In this series of experiments, the Italian researchers will rely not just on Luama's reports of the pain she experiences but they'll also be measuring her body's reactions. This is for, uh, EKG-- electrocardiogram. Electrocardiogram, uh, because we want to see whether or not there is an increase or decrease in heart rate during, uh... the induction of pain-- the experimental pain. These two leads are to, uh, measure skin conductance, and this is to, uh, measure respiratory rate. It goes up and down with the respiration and it comes up as a signal on the screen. ALDA: Luama's blood pressure is also being monitored, as well as heart rate, breathing rate and skin conductance-- a measure of how she's sweating. ( pumping ) The pain she'll experience is induced by inflating a blood pressure cuff, cutting off the blood supply to her arm and hand. In a scale from zero, which means no pain, to, uh, ten, which means unbearable pain, she will experience, uh, around usually after ten minutes, about, uh, six, seven. ALDA: On this day Luama is getting no treatment, either real or placebo. The goal is to see how her body reacts to get baseline measures of its response to the pain in her arm. Sí. She said that she experienced on a scale from zero to ten, a pain of six in the arm. ALDA: The next day the setup is the same, except that now she's receiving an injection for the pain. No one in the room knows what she's getting. ( speaking Italian ) She knows that she can receive either a placebo or a painkiller. ALDA: In previous experiments, the Turin team has shown that when a placebo injection lowers the subject's experience of pain, there's an increase in the brain of natural painkillers-- morphinelike substances called endogenous opioids. What's more, giving a drug that blocks these opioids cancels out the pain relief caused by placebos. So this means that there is a close correlation-- a tight correlation-- between activation of endogenous opioids and analgesia-- placebo analgesia. ALDA: These new experiments are revealing that the body's response to pain actually changes during placebo analgesia. So the placebo effect is much more than in the mind, although the mind must be where it begins, in the expectations of the patient... triggered, as all the new research we've seen in this show confirms, by the still mysterious chemistry between a hopeful patient and a caring doctor. BENEDETTI: They should smile. They should talk to their patients. They should interact a lot with their patients, because there is a very strong, uh, indication that all these mechanisms-- for example, the endogenous opioids, the endogenous painkillers-- are released when the patient feels safe, feels comfortable with, uh, with the doctor. KAPTCHUK: Ultimately the way a single human being reacts to a single human being is going to be part of the art of medicine. And I think we can learn a lot about it through research. Do I think science will take all the mystery out of healing? I don't believe so. I think that there's going to be an element of the shaman residing at the core. My effort to do research in placebo is to acknowledge that core, not to destroy that core, because I don't think it can be destroyed.

Take a look at these related stories from the Frontiers Archive:

				Needles and Nerves Studies find acupuncture can reduce blood pressure, but how?
		Select text to jump ahead in the clip: ALDA: China International Medical University is a small company that offers an increasingly popular service: acupuncture. Dr. Jiang, who trained in China, will treat this young man for insomnia. ALDA: She measures down to the two Hsinshu, or heart back points. She inserts fine needles no thicker than a human hair and then uses an up-and-down movement to "tonify the heart Chi." Chi, in Chinese medicine, is the body's basic life energy. Now she moves down to the Kanshu, or liver back points, where she will relieve "stagnation of the liver Chi." The patient later reported his insomnia cleared up. Of all the alternative medical practices, acupuncture is probably the most widely accepted. It's often covered by insurers. In America, interest in acupuncture really took off after Nixon went to China in 1971. A New York Times reporter, James Reston, had been in Beijing during Henry Kissinger's preparatory visit. Reston had to have his appendix out, and after conventional surgery at the Anti-Imperialist Hospital, he was given acupuncture for post-surgical pain. He ended his glowing account of the experience by writing that the hospital... RESTON ( dramatized ): ...like everything else in China these days is on its way toward some different combination of the very old and the very new. ALDA: Acupuncture is very old. The first descriptions date back 4,000 years. These illustrations are about 1,500 years old, but the dense maps of meridian lines and acupuncture points that you see nowadays are from the 19th century. Depending on who you ask, there are up to a thousand usable points on the body. Bill Stroud gets acupuncture from Dr. Jiang every two weeks. Bill's got heart problems and diabetes, and he says these visits help. What science says right now is maybe. It says there could be something happening, but it's not clear what. STROUD: When they hit the mark, I get a tingle. ALDA: What do you mean, hitting the mark? STROUD: When she hits the nerve. After it reaches a certain depth and it gets to the nerve, that's when you feel a tingle? That's it. Then it goes down to my fingertips. Yeah. And my toes. Is it similar to the pins and needles you feel when your foot goes to sleep? No. What about, is it like... I'm trying to try out some feelings that I'm aware of. Is it like a little electric shock? Yeah, that's more like it. Yeah, it's a little shock. ALDA: We're observing Bill's treatment with a cardiologist who's a leading acupuncture researcher. Okay, so the Neikuan is right here. This is along the so-called pericardial meridian. That's what Bill is getting now? Yes, yeah. They're stimulating here, Neikuan, and then up here, at the Hsimen. This corresponds to a nerve identified by Western medicine that's actually in everybody's arm. What we've found is this, is that most meridians overlie major neural pathways. Most of them do. Not 100%, but most of them do. And then the acupuncture points would be sticking the median nerve at various different levels. ALDA: The central belief in acupuncture is that stimulating specific points can affect particular body functions. One of the few scientific demonstrations of this came when colleagues of John Longhurst used a brain scan to detect activity while stimulating a traditional, vision-related point on the toe. LONGHURST: They showed that the visual cortex up in the brain lit up. So that's kind of provocative. And that has been considered for centuries by the Chinese as a way to affect vision. Exactly. ALDA: Bill's Hsimen point is stimulated in order to help his heart Chi. It's not language scientists understand, but that doesn't mean nothing's happening. DR. JIANG: Heavy thrusting, light lifting. This is to build up the heart Chi. How do you know you've got the heart Chi? How do you know you've got the right spot for that? I feel some heaviness under my fingers. I feel the chi. I feel I've... You feel some resistance? Yeah, I've captured the chi. I see, so you're responding to the chi in his body, and that's how you know you've got it. ALDA: Twenty minutes later, and Bill's happy. How you doing, Bill? Fine. Yeah? Mm-hmm, real good. Do you feel relaxed? You said you often feel relaxed. Real relaxed, yeah. Why don't you... I think I almost dropped off to sleep while you fellas were talking. ( both chuckle ) ALDA: We're going to look at oneof John Longhurst's experiments involving blood pressure. ALDA: Does the act ofmeasuring somebody's blood pressure alone have an effect on the blood pressure? LONGHURST: Mm-hmm, and if you wear a white coat, it increases it even more. ALDA: The background to this experiment is some key results John Longhurst has found in animals. Stimulating the Hsimen and the Neikuan heart points released natural opiates in the brain. These opiates were able to reduce the animal's response to stress, suppressing blood pressure. He's sure this is real. He could stop the effect when he blocked the opiates, and animals, of course, don't have any ideas or beliefs about acupuncture. Were you surprised when you came across this confirmation that it stimulates the body's opiates? Let me just say that I, like most Western scientists and Western physicians, had absolutely no belief that acupuncture had any validity to it. I didn't believe it worked. It was only after I read the literature and started to do my own studies that I started to believe in it. But I did not come at this from the viewpoint that, a priori, that it worked. ALDA: Eric, our experimental subject, is having his Hsimen and Neikuan points located by Peng Li, Longhurst's Chinese collaborator. Any feeling now? ERIC: A little. When you leave here after one of these trials, do you feel any different from the way you did when you came in? I don't feel much different, and that's not normal after a workout like what I'm going to be doing. ALDA: They're going to use electric acupuncture to stimulate the nerves because it's more controllable than the manual method. Switch on. ALDA: The twitching shows Eric's median nerve, which runs from neck to fingertips, is being stimulated. Eric, we're going to shut the light, okay? Okay. ALDA: Eric gets 30 minutes of acupuncture in a low-stress setting which won't elevate his blood pressure. For comparison, other subjects get the same thing but without the acupuncture. Now the test. Eric has to pedal until he can pedal no more. At that point, his blood pressure will be at its peak. 105/70. ALDA: It's the first numbethat matters. 120/65. 128/68. 140/60. 148/60. 150/58. Uncle. Okay, let me get a last blood pressure. ALDA: You do want to gethis blood pressure before he's lying on the floor, right? Yes, I do. You can do it, Eric. 158/55. TECHNICIAN: Thank you. ALDA: The results of the study were a surprise. Subjects who got acupuncture at the Hsimen and Neikuan heart points, as expected, showed significantly lower peak blood pressure, compared to the no-acupuncture group. But as an additional control, another group received acupuncture at the Hoku point, which is supposed to affect the intestines, not the heart. And that point turned out to be just as good at lowering blood pressure. LONGHURST: We found that that was as potent as our cardiovascular active one. For a cardiovascular response? For the cardiovascular response to exercise, exactly. So now what will you do? You'll have to pick another spot. Exactly, so we do have another comparison, and that is no acupuncture whatsoever. And there, both of them seem to be better than no acupuncture whatsoever. But at the moment, that seems to indicate that if you stick a pin in a person anyplace, you're liable to get this cardiovascular response. At least in two places. At least in two places. ALDA: So acupuncture has effects, but not in the way Chinese theory describes. That's where John Longhurst's research stands right now, but his conclusion that acupuncture stimulates the body's own opiate system opens up some intriguing ideas. Scientists are now coming to believe that most alternative therapies, where they have any effect, operate through that same opiate system. There's another name for this. It's the "placebo effect," and it can be triggered by many things-- belief, expectation, habit, discussion, touch. Acupuncture, therefore, would be a kind of double dose of placebo. LONGHURST: Some of my colleagues in alternative medicine would not like me saying this, but almost any sort of alternative medicine that is being used today-- a significant portion of its effect is through a placebo. Whether you're talking about healing touch or aromatherapy or herbal medications or acupuncture-- just any of these things-- transcendental meditation, any of them, there is a potential for a placebo effect. But I will go one further step and say that I think despite this, I think that some of these alternative therapies, including acupuncture, there is a real effect over and above placebo. It's just that the window between what is placebo and what is real is somewhat narrow. What dyou look forward to finding out as time goes on? What are you really trying to... what do you want just to narrow down to? I would like to see it-- acupuncture and complementary therapies that have proven to be beneficial-- to be taught in medical schools today, because certainly when I went to medical school, we didn't even talk about this form of therapy. Yet we know that as many people see an acupuncturist or a physician who is going to give some form of complementary therapy, as see primary-care physicians today. And most people don't realize that so many patients are accessing this other form of therapy. So don't we need to know something about it? Don't our physicians need to be able to ask questions?

				Cold Comfort Some cold remedies may be all in your head.
		Select text to jump ahead in the clip: or the suddenly scratchy throat we wonder, "How did I catch it this time? "How bad is it going to be? "Should I take some vitamin C, suck a lozenge drink some herbal tea? " And then there's the big one. If scientists can send a man to the moon or invent the Internet or peer at distant galaxies, why can't they cure the common cold? Well, I've come here to Charleston, South Carolina, to find out. Because Charleston is about to experience a sudden mini-epidemic, an outbreak of runny noses and stuffy heads that could take us one step closer to an answer. What's unusual about this outbreak of colds is that it didn't just happen. WOMAN: Okay, put it in the cup. ALDA: These volunteers, whose noses are being rinsed out with a saline solution are being paid to catch a cold. If you wash his nostrils out he'll have a better chance of catching cold? Mm-hmm, because the nose will be nice and clean. This is a horrible thing to learn first thing in the morning. Okay, go ahead. ( chuckling ) I mean, I would have thought that getting your nose clean-- you know, like they say "Keep your nose clean"-- I would think that would help. ALDA: The man dispensing the colds is Ronald Turner an old hand at conducting studies on candidates for cures. What he's carefully placing up the nostrils of his volunteer subjects is a strain of rhinovirus one of the commonest causes of the common cold. Now you already had one of these? WOMAN: I had one-- I had one already. So how many do you give? Two-- we just go around twice. You really want to make sure you make these poor people sick. All right, this is the same as before, okay? ALDA: Actually, Ron Turner is hoping some of his volunteers won't get sick. Because for the last two weeks some of them have been taking twice-daily doses of one of those herbal extracts that a lot of us believe helps fend off or shorten a cold. Some of them are getting active medication some are getting placebo, but everybody gets the virus. Do you know, are you aware of who's getting the placebo and who's getting the medication? No, no, we're all blinded. You don't have any idea? Uh-uh. MAN: This is what they look like. ALDA: The famous Jujube medication. MAN ( laughing ): Yeah. So what do you think is in there? I'm really not sure. Hopefully some medication that will take care of me. But... for all I know it could just be sugar pills. ALDA: This need to ensure that no one knows who's getting what is absolutely critical in a trial like this. These are your pills for the next five days. ALDA: It's especially important that the volunteers aren't picking up any clues from how the pills taste or make them feel. Do you think you were getting the active medication or the inactive medication? I think I was getting the inactive. I have no idea, I really don't. No, I had no side effects no symptoms of any kind either way, so... WOMAN: Okay, if you had to give me a guess? Active. Inactive. I think I was getting inactive. Active. WOMAN: And why? I don't know-- It was just that whenever I took it I felt, like, fuller. I'll have to say the active medication. WOMAN: Why would you say that? It'd kind of depress me if I was having the other medication. I would say the inactive. WOMAN: Why would you say that? Just because I didn't feel any difference. Do you think it matters whether or not you believe you're taking the active ingredient? Yes. I think if I thought I was on it I would definitely experience a placebo effect and feel better than maybe I should. And thinking that I'm not on the medication I might be more inclined to feel the symptoms more severely. ALDA: Lindsey's right. If people are able to figure out what they're getting then it could dramatically influence the results of the trial. I'll go with active. WOMAN: Why do you say that? I'm hopeful. ALDA: In fact, in Ron Turner's opinion many of the clinical trials of popular cold remedies are fatally flawed by this very problem. His list includes even that old stand-by, vitamin C +and, distressingly, two of my personal favorites-- zinc lozenges and Echinacea. He's tested both in carefully controlled trials like his current one and found they don't work. All right, I've got one left. ( both laughing ) If you kill this, I'm never going to be able to fight off a cold again. Vitamin E. Well, vitamin E is interesting and we actually have looked at vitamin E as well. There's some biologic rationale for vitamin E and for vitamin C, for that matter in the sense that they are both antioxidants, and we do think that oxidative stress in the cell has something to do with production of the symptoms of the cold. And so we did a study of vitamin E where we gave vitamin E supplements for a couple of weeks to a group of volunteers. We drew blood from them. We showed that the vitamin E levels in their blood were substantially higher than in the placebo group and then we challenged them in our model with our virus and had absolutely no effect. So it... it was no good as a prophylactic, but... Or as a treatment. Or as a treatment either? Right. I'm dead. ( Turner laughs ) That's it, I've got nothing left. Well, the good news is that you'll get over your cold anyway. Definitely have the cold... I have it. I don't feel ill at all. If I'm supposed to be ill, I'm not. I have the cold. ALDA: Three days have passed since our volunteers were infected with the cold virus. They've been reporting in every morning since. WOMAN: It's been about 72 hours since the inoculation. Do you think you received a cold? Yeah, I do-- I definitely had it yesterday. Okay, I want you to rate your symptoms this morning based on the severity since your last visit. Any symptoms of sneezing? I'd say about a two. Okay, runny nose? One. Nasal stuffiness or obstruction? Ah, two. Cough? One. ALDA: There are a dozen symptoms on the list-- enough to get a pretty objective measure of the severity of the cold. Definitely getting a little worse, huh? Yes. You can go back and get your nasal wash. ALDA: The nasal wash will reveal how strongly the virus took hold. WOMAN: Good morning. Good morning. ALDA: Meanwhile, we wondered how our volunteers feel now about whether they are on the test medication or the placebo. YOUNG WOMAN: I think I'm receiving just a placebo. I think it kind of got better because I was taking... I'm not sure whether I was taking that medication or not but I think I did. I believe I had the inactive medicine. Because otherwise I think I probably wouldn't have gotten the cold or it wouldn't have been as severe. Based on how mild my symptoms are I think maybe I did get the active. Oh, yeah, I'm really glad I got it. Because I'd be walking around with tissues hanging out of every pocket and just not a pretty sight. I think I got the inactive medicine because I've been getting worse as the days go on. I guess I got the active medication because all I've had is a runny nose and that's it. ALDA: Perhaps not surprisingly most of those with the worst colds thought they were on the placebo while most subjects with mild colds guessed they had the medication. But in fact, it was all in their heads. Later, when who got what was matched up with the severity of their infections there was no difference between those who got the test substance and those who didn't. That's right. The mystery herbal ingredient in those big brown pills did nothing in Ron Turner's study-- joining on his hit list Echinacea, zinc lozenges and vitamin E. You know what's funny about this? And this is just... totally personal. I'm going to keep taking this stuff because I haven't got any other... any other feeling of control over the cold. And for me, getting a cold-- because I have to use my voice in my work-- it's something that I'll... I'll clutch at straws over. How does that strike you as a scientist? Well, I guess I don't have any problem with that. As I said, my job here is to try to figure out whether there is a biologic effect. Whether people choose to use that information or whether they get some benefit-- whether it's psychological or mental-- that's fine. You know, the saying is, of course that if you take this medicine you'll get over your cold in seven days and if you don't it will take a week. ( chuckles ): So... That's the best you can come up with after all these years? Well, I think we're doing better than that. I've heard that joke. I think we're doing better than that. ALDA: One way in which science may at last be doing better is in attacking cold viruses themselves. A big reason the common cold hasn't been cured in the past is that so many different viruses can cause it. And for many, many years people thought that that was going to make it impossible to develop therapy for the common cold. ALDA: Yeah, that's what I've read, constantly is that there are too many colds to be able, too many viruses to be able to find something common in all of them. Right, and I remember when I first started on this project somebody who I, that I was good friends with in college who... we diverged slightly-- he went into medicine and I went into basic biochemistry-- I told him I was working on this and he laughed his head off at me and he said, there are over a hundred serotypes. No one will ever do that. Now your friend is giving out antihistamines and you're solving the common cold. Probably, yeah. ALDA: Steve Worland's company, Agouron is trying to attack the commonest group of cold viruses the rhinoviruses. Their target is actually a protein called protease that all rhinoviruses use to make copies of themselves. The company started by making tiny crystals of this crucial protease then used an X-ray crystallography machine to get a precise three- dimensional picture of it. MAN: ... you can actually look down and you can see the tip of the loop. The crystal is very small only a couple of tenths of a millimeter. What we're seeing here is an electronic image of the, uh... ALDA: Now, there are moments when we're making Frontiers when we get just a little out of our depth. ALDA: What do you do, roughly to get a three-dimensional picture from those dots? Well, basically what we do is we use computers to carry out a three-dimensional Fourier summation uh... and the individual coefficients in that Fourier series are related to the intensities that we're measuring here. And that's the rough version. ALDA: Okay, well, once they did that, this was the result: a 3-D image of the protease the virus needs in order to replicate itself in our nose cells. WORLAND: That was enough to say that there are regions where the protein goes in rather than comes out where we could then plug in, if you will, our drug molecule. Now, the reason you want to plug your drug molecule in is if you don't do that this is going to be a place where the protease is going to hook up with what it needs to hook up with to do its work and help the virus replicate. That's precisely right. ALDA: The drug molecule Agouron designed which nestles neatly into the critical protein successfully stops the virus from replicating in a test tube. The next step was to try it in noses. Good morning, everybody. ALDA: In a clinical trial very similar to the one Ron Turner ran the antiviral drug was tested on college students at the University of Virginia-- except that here, the subjects got to stay in a hotel. 24 hours after getting infected they received several daily doses of the experimental drug in a nasal spray. Here, too, some of the subjects got a placebo spray instead of the real thing. Do you feel generally bad? I feel like I got a cold. Okay, that's what I need to know. ALDA: The severity of their colds was judged by questionnaire by measuring the virus directly and by weighing the tissues they used. And the results were promising-- a significant reduction in cold symptoms among those on the drug. How you feeling this morning? I'm feeling fine. No cough, no sore throat, no nothing? Nothing. All right, that sounds good. ALDA: Even though the drug seems to work getting it to market will be far from easy. It will have to be cheap, it will have to work fast and, as Steve Worland knows only too well it will have to be completely safe. It's a real drag to have a cold, but it's not life-threatening. In that case, we're even more concerned about a safety burden because we're not treating something like cancer or HIV where a certain degree of side effects traded for saving somebody's life that person would almost always say, "I'll take it. " It's not worth trading a serious side effect to get rid of a cold. So this really has to be a compound that has virtually no side effects or people are just going to elect not to choose it. If you tell people, "Well, you know you're going to feel numbness in your hands" for, just as a hypothetical example "but your cold will go away" most people will say, "I'll take the cold.