BioSocieties (2006), 1, 181193 London School of Economics and Political Science doi:10.

1017/S1745855206050216

The Many Meanings of the Placebo Effect: Where They Came From, Why They Matter
Anne Harrington Department of the History of Science, Harvard University, Science Center 371, Cambridge, MA 02138, USA E-mail: aharring@fas.harvard.edu

Abstract The placebo effect is variously vilified as a basis for unethical medical practice, dismissed as the ephemeral product of gullible imaginations, sanctioned as key to the clinical trials process, and romanticized as evidence of the minds quasi-miraculous power to heal the body. These many meanings of the placebo effect exist for a reason: they are products of multiple histories whose legacies continue to be upheld by various stakeholders in debates in which placebos and their effects figure today. Keywords Clinical trial, Endorphin, Imagination, Mindbody medicine, Placebo effect, Positive thinking, Suggestion

I begin, so to speak, interactively, by inviting my readers to answer what might look like a rather straightforward multiple choice question: what is the placebo effect?1 (choose one) (a) a short-term and illusory impression of improved health that some patients experience when they take an inert substance that looks like real medicine (e.g. a sugar pill); (b) the non-specific effects of medical treatment that, in clinical trials, must be controlled in order for researchers to assess the specific effects of new interventions, especially drugs; (c) a powerful mindbody phenomenon with a specific real biology all its own, one that medicine should study and exploit.
Anne Harrington is Harvard College Professor and Professor for the History of Science at Harvard University, and Visiting Professor in Medical History at the London School of Economics. She was formerly director of Harvards interfaculty initiative on Mind, Brain, Behavior, and a consultant for the MacArthur Foundation on themes around medical understandings of mindbody interactions, including the placebo effect. Specializing broadly in developments in the mind and brain sciences from the nineteenth century to the present, she is the author of two books, Medicine, mind and the double brain (1987) and Reenchanted science (1996), with a third, on the making of American mindbody medicine, Stories under the skin, to be published soon (by W.W. Norton). Her newest project analyzes the intellectual and cultural significance of a new narrative genre of writing about the brain that is concerned with the so-called inner world of brain disorderabout what it is like to be a person with a damaged or differently wired brain. 1 These remarks, lightly edited for publication, were originally delivered in January 2005, as the opening address to an interdisciplinary seminar series on the placebo effect, jointly sponsored by the BIOS Centre at the LSE and the Institute of Psychiatry, University of London, and funded by a grant from the Nuffield Foundation.

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What I expect to find with such an exercise is a decisive preponderance of votes for (c)the definition of the placebo effect as a real phenomenon with real biology and potentially significant therapeutic implications. Certainly, (c) is the answer that intrigues our generation the most. Answers (a) and (b), however, are by no means defunct: (b) is still the working definition of the placebo effect assumed in the high-powered world of pharmacology, while (a) is the working definition assumed in bioethical discussions about placebo use, as well as explanations as to why biochemically ineffective treatments like homeopathy (or over-the-counter cough syrup!) might nevertheless command a large and loyal customer base. What this teaches us is that the placebo effect is a phenomenon with at least three distinct definitions, each thoroughly incompatible with the others, and each nevertheless enjoying some authority in our society today. No wonder we have trouble bringing this phenomenon into focus for ourselves! We believe in the placebo effect, or we dont believe in it; we hold its use to be problematic or we consider it to be greatly underutilized; we turn to it to protect us from the contaminating influence of the psychological in our medical trials; or we hope that it will illuminate important facts about the role of the mind in processes of recovery from illness. Indeed, one suspicion we may have from a tabulation like this is that more than one wemore than one community of scholars, researchers or consumersis likely to be in play here; and that each may have its own reasons for favoring one definition of the placebo effect some other. The period of time between 2000 and 2001 was doubtless remarkable for many things, but one of these was the way in which it put this instability in our thinking on public display to an extent certainly that I had never seen before. First there was a cover story in the New York Times Magazine with the hard-hitting title: Astonishing medical fact: Placebos work! So why not use them as medicine? (Talbot, 2000). The article was largely organized around a story about patients who had experienced dramatic improvement in pain and mobility after undergoing knee surgery that consisted of all the paraphernalia and theatre of a real operation but was actually (in the articles words) an exercise in just pretend, that simply involved opening up and closing the knee without cutting, scraping or changing the insides at all. All the patients were later debriefed as to whether they had received real or placebo surgery, but, even after they were, none were displeased with the results. They could walk again, sleep soundly again, mow the lawn again. Whatever the placebo surgery was or wasnt, it worked for them. In the words of one of the patients (who had received placebo surgery): I was very impressed with him, especially when I heard he was the team doctor with the Rockets [a US basketball team]. So, sure, I went ahead and signed up for this new thing he was doing.. . . The surgery was two years ago and the knee never has bothered me since. Its just like my other knee now. I give a whole lot of credit to Dr. Moseley. Whenever I see him on the TV during a basketball game, I call the wife in and say, Hey, theres the doctor that fixed my knee! The New York Times article generated an enormous amount of both public interest and further journalistic efforts on the same theme, many of which began to suggest that the amazing power of the placebo effect demonstrated the inadequacies of biomedicines understanding of the nature of healing, while raising the prospect of new kinds of

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treatments that harnessed its powers. Having edited an academic book myself on the placebo effect a year or two prior to the publication of all this new journalistic interest in the phenomenon, I found myself now modestly caught up in what had suddenly become a very public discussion. In one of the most personally poignant moments from that time, I received the following email, not from a journalist wanting a quote or two for yet another article about the amazing placebo, but from an ordinary person with other concerns on his mind (I have deleted the authors name to protect his privacy): My name is. . .. I live in Cali, Colombia. A few days ago I listened [to a talk] about the placebo effect. My father has cancer, and I believe a placebo can help him. I need to know where I can get the sugars pills or saline injections, and how I must to give them to him. My fathers doctors have said that his cancer is very bad, and its so difficult to treat. He has been following a treatment for 8 years, but he always falls ill again. I think the placebo effect is his last hope. If you can help me, Ill be grateful all my life. The year 2000 gave way to 2001, and in that year another article on the placebo effect was published, this time in the New England Journal of Medicine. The article was called Is the placebo powerless? and its answer basically was: yes (Hrobjartsson and Gotzsche, 2001). The media had been misled and the public had been deceived. In fact, the authors insisted, the evidence strongly suggested that much, if not all, of the improvement seen in the placebo arm of many clinical trials has nothing to do directly with the placebo treatmentwith the sugar pills, etc.but rather was due to spontaneous tendencies for people to get better (natural history of disease), or for their state of health to revert over time towards more normative levels (regression to the mean). The authors based this claim on their meta-analysis of a cluster of clinical trials where the decision had been made to include, not just a placebo control but also a so-called no-treatment control. In such socalled three-arm trials, they said, the patients in the no-treatment group generallythere were exceptionsshowed levels of improvement that were almost indistinguishable from the levels seen in the placebo group. It is true that the New England Journal of Medicine piece was attacked almost immediately by a whole slew of workers in the field for methodological flaws and flaws in interpretation (Moerman and Jonas, 2002; Spiegel et al., 2001). At the same time, the same media that had, literally just weeks before, been romancing the placebo effect, now embraced a new knowing skepticism (e.g. Kolata, 2001). The placebo effect had been exposed and debunked, unmasked as nothing more than an updated version of what one pundit called the Dale Carnegie school of medicinegrounded in the optimistic philosophy that if you believe in yourself, then all things are possible (Dalrymple, 2001). Very few in the media seem to have read the critiques; at least they largely failed to report on these. There is evidence that many didnt even read the technical article itself, but simply responded to and further amplified the Schadenfreude of the editorial that the New England Journal of Medicine published alongside the article. It was called: The powerful placebo and the Wizard of Oz (2001). The idea of the powerful placebo, the editor wrote, was an appealing myth, but we must now grow up, put away our childish ideas and admit that it is without any basis in reality. The placebo effect, he concluded, could be compared to the Wizard of Oz, who was

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powerful because others thought he was powerfuluntil they found that the curtain hid a very ordinary man. A man, in fact, who is forced to admitwhen he is caught in the actthat he is nothing but a humbug (New England Journal of Medicine, 2001) The dramatic flip-flop in public and professional conviction, all on the basis of one article is striking. How does it come about, we must ask, that we can be so readily persuaded of perspectives that are effectively the opposite of those that we had been happy to accept, just weeks or months earlier? Why is our commitment to any specific understanding of, or approach to the placebo effect so shallow? And, as we vacillate and argue, why do emotions run so high? To make sense of this, we could do worse than pay attention to history. As an historian, I would of course think that, but let me see if I can also demonstrate the usefulness of my proposed approach by leading us through three distinct historical excursions that I believe have independently produced the three main definitions of the placebo effect with which we must contend todaythe three definition with which I began these remarks. Along the way, I hope well discover something else: that each of these definitions is powerfully connected to larger values and agendas that are social, political, ethical and philosophical in nature. To recognize this is to understand why debates over the real nature of the placebo effect invariably feel so fraught and also so strangely important. There is a lot more at stake in the outcome of the struggle over definitions than at first meets the eye.

Historical excursion one: the placebo effect as medical humbug

The Wizard of Oz, the humbug definition of the placebo effect, is the oldest. Its origins lie in eighteenth-century European skeptical and rationalistic sensibilities, and an associated deep suspicion of an unreliable part of the human mind called fancy or sometimes the imagination. The imagination, as historian Jan Goldstein among others has taught us, was a smear word in educated eighteenth-century European society (in England, the equivalent smear word was enthusiasm). A potential source of madness, religious manias, political unrest and more, it was the least protected part of the mental apparatus . . . the principal entryway for error and disorder, the potential site for the capture of the will and the consequent loss of self-control (Goldstein, 1998). One of the chief qualities of the imagination that contributed to its perceived dangerousness was the way in which it made people believe that they were seeing, feeling and experiencing things that werent really there. Armed with this understanding, we can begin to understand the rationale behind the famous eighteenth-century debunking of mesmerismanimal magnetismby a group of prominent French scientists plus the American scientist Benjamin Franklin. This was an investigation that included what one student of the era, Ted Kaptchuk, has called the first placebo controlled trial (Kaptchuk, 1998a). The test involved blindfolding a young boy and telling him that one of the trees on the estate had been magnetized. He was then led up to four trees in succession. At the first tree, he began to sweat, tremors commenced by the second tree and, by the time he was brought to the fourth tree, he had collapsed into convulsions. In fact, at no time had he been near

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any tree that had actually been magnetized. The investigators had tricked the boy, and he had responded as he would have done if the situation had been as he had been led to believe it was. The conclusion the investigators drew from all this? They had been asked to determine whether the dramatic effects of mesmerism were due to the presence of some kind of magnetic fluid and they had determined that they were not. Neither, however, were they exactly fraudulentat least not in the sense that the boy was trying to trick the commissioners (if anything, it was the other way around). The boy had also really convulsed, really sweated and really trembledthere was nothing made up about any of that. Nevertheless, because all those experiences were produced by the boys own imagination, they were not what they seemed. In this sense, they were self-deceiving, and scientific methods were required, not to make sense of them, but to unmask them for the fancies they were. The most important legacy to come out of the debunking of mesmerism was a style of skepticism towards subjective experiences of healing (and testimonies about the same) that has persisted into our own time. Since Mesmer, medicine has learned that, when it comes to getting better, what you see is not always what you get: the mind can play tricks, the body can be deceived. Historicallyand still todayone of the prime arenas in which medicine has tended to employ this kind of skeptical critique is the world of alternative or (as it used to be called) irregular medicine. Despite the fact that many such therapies have loyal followings of patients numbering in their thousands and even millions, for over a century non-orthodox practitioners have been challenged by the mainstream to prove the efficacy of their treatments by subjecting patients to placebo or fake versions of the treatment to see whether they respond just as well as they would to the real thing. Initiallyand tellinglyit was not felt necessary until much more recently that orthodox, mainstream medicine subject itself to similar tests. This teaches us something important: that initially the entities we would call placebos were tools designed to expose fraud; not to clarify efficacy, as would later come to be the case. Before the conditions for new definitions could come into being, however, one further thing needs to be noted about this style of skepticism towards the imagination and the subjective that would come to inform one important definition of the placebo effect in our time: namely, that epistemological concerns came to be overlaid with moral ones. More precisely, people concluded that the imagination was actually most likely to play tricks on the body under conditions (such as hypnosis) when a weak and impressionable mind (i.e. the patients) came under the thrall of a strong and persuasive personality (i.e. the doctors or healers). In the larger culture, this vision found its climax in the best-selling book of the nineteenth century (the first blockbuster of all time), Trilby, by the Anglo-French author George du Maurier. Trilby told the story of an evil-minded hypnotist who turns a beautiful, unsuspecting young girl into a singing automaton and his sex slaveand gave the world a new word: Svengali (du Maurier, 1895; Pick, 2000). The conditions for the making of the idea of the placebo effect came about when the two levels of concernepistemological and moralmerged into a single new technical concept: suggestion. The term (defined as the capacity to transform an idea directly and automatically into a sensation or movement) was invoked by the French physician

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Hippolyte Bernheim in part as a way of making sense of the bodily symptoms of hysteria that his rival, Jean-Martin Charcot, had wanted to see as symptoms of objective neurological damage. Bernheims view was that such objective symptoms did not exist; that Charcot, through the force of his charismatic personality, had instead compelled his hypnotized patients, through a range of suggestive cues, to produce the array and ordering of symptoms he then convinced himself he was simply observing (Ellenberger, 1970). In a sense, we might say today that Charcot had unwittingly turned himself into a kind of living placebo for an entire population of patientsand this unintended intervention of his person into their physiologies proved to be his professional downfall! With Charcots career on the rocks, discussions about suggestion were quite quickly expanded to frame or otherwise give expression to more general anxieties about hypnosis as a phenomenon in which subjects dance helplessly to the will of the hypnotist. Stage hypnotists in the twentieth century exploited this understanding to the hilt. Sigmund Freud used those same understandings as a starting point for his own reinterpretation of hysteria and the ways in which transferencethe powerful role played by the analyst in the patients imaginationfunctions in first exacerbating and then dissolving neurotic symptoms (Freud, 1915, 1921). Suggestion also became a way of thinking afresh about a long-standing and widespread practice in mainstream medicine, and why it might be an effective practice. I am talking about the practice in mainstream medicine of giving patients placebos: fake pills or powders with no known active ingredients, but which the patients themselves often seemed to find quite satisfactory. The word placebo has a history that conveys its own independent sense of moral ambiguity. Derived from the Latin word placebo, which means I shall please, it is the opening word of the Catholic Vespers for the Dead (Placebo domino in regione vivorumI shall please the Lord in the land of the living). Placebo came to be associated with unsavory moral practices from the fact that, in medieval times, the Vespers for the Dead was often sung by hired mourners, people who sold their services as professional grievers. These people, therefore, were usually seen as sycophants, flatterers who stood in for the truly grieving family members (if any such really existed), weeping crocodile tears. In medicine, placebo thus became little offerings that doctors gave to patients to mollify them; offerings that stood in for truly effective medication. Doctors were understood to make such offerings especially when they were dealing with patients whom they couldnt really help, orequally commonly with patients whom they believed didnt really have anything wrong with them, but who wouldnt stop complaining and go away unless given something that appeared to address their complaints. In 1903, Harvard Medical School professor Richard Cabot admitted that: I was brought up, as I suppose every physician is, to use placebos, bread pills, water subcutaneously, and other devices.. . . I used to give them by the bushel. (Cabot, 1903) Cabot admitted this in part because he was now committed to stamping out placebo use, had become persuaded that giving placebos turned orthodox medical practitioners into quacksno better than the snake-oil and patent medicine salesmen that the American Medical Association was in those years trying to stamp out.

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Every placebo is a lie, and in the long run the lie is found out. We give a placebo with one meaning; the patient receives it with quite another. We mean him to suppose that the drugs acts directly on his body, not through his mind. . .. If the patient finds out what we are doing, he laughs at it or is rightly angry with us. I have seen both the laughter and the angerat our expense. Placebo giving is quackery. (Cabot, 1906) Cabots exhortations did little to change clinical practice immediately, though they almost certainly contributed to tendencies within the profession to become more circumspect about their continuing use of placebos. Nevertheless, the use of placebos, if anything, became rather commercialized: by the 1940s, a physician could order them from mail order catalogues. At the same time, the secret shame felt about this face of medical practice is shown by the fact that, when an article about placebo use was published in a medical journal in 1945, its author, O.H. Perry Pepper, said he believed his was the first article on the topic to appear in the published medical literature. In choosing to speak out at this stage, Perry Peppers goal was to suggest that the profession take a pragmatic and compassionate view of its placebo use. They were not an alternative to real treatment, but sometimes they were all that might work for a patient, and why should a doctor withhold any comfort that was his to offer? The human mind is still open to suggestion, even in these modern and disillusioned days. The sympathetic physician will want to use every help for these pathetic patients and if the placebo can help, he will not neglect it. It cannot harm and may comfort and avoid the too quick extinction of opiate efficacy. (Perry Pepper, 1945) Nevertheless, talk of this sort was already sounding like the wisdom of a fading generation of practitioners. By 1945, medicine was on the verge of changing, transforming itself into a practice rooted in laboratory practice and science; it was also in the first stages of claiming for itself a whole new arsenal of pharmaceutical interventions that it believed to be effective, from new analgesics to penicillin. And these larger social and intellectual changes would produce conditions that would eventually lead to the development of a new definition of the placebo effect.

Historical excursion two: placebo effect as a scientific confound

Ive noted that, since at least the nineteenth century, there had been repeated calls for placebo-controlled tests of unorthodox treatments as a way of exposing their supposed true uselessness. There had been no consensus, however, that orthodox medicine needed to subject its own treatments to placebo trials or other controls and checks. Indeed, imposing such checks would have been deemed insulting. A reputable physician, it was felt, should be free to use all his clinical observational skills to decide what worked and what didnt. The processes of then pooling observations and discussing discrepancies in the service of consensus would be the means people argued by which the field would progress. By the middle of the twentieth century, however, it was no longer clear that such gentlemanly strategies were still going to be good enough. Clinical impression was far too subjective and imprecise a measure for the rising proponents of the new evidence-based

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medicine, and tensions between the old guard and the new began to grow. In this context, old ideas about the suggestive powers of placebos were revisited, but this time not to praise them as a source of consolation in the clinic, but to condemn them as a source of bias in the testing situation, bias that could infect both physicians and patients. A 1955 paper by Henry Beecher, The powerful placebo, both catalyzed and embodied the sea-change here. The paper had two goals. On the one hand, it wanted to argue for a new understanding of placebos and their effects. They were not harmless humbugs, little decoys that one gives patients whom one cannot otherwise help or who have nothing really wrong with them. Using meta-analytic techniques on 15 clinical trials that used placebo controls, Beecher had determined that the effect of these inert tablets was profoundon average, he said, they affected a third of the patients in the placebo group (though there was great variability across the trials), and in some instances they seemed to produce bodily changes that exceed[ed] those attributable to potent pharmacological action. Recognizing the power of the effects produced by placebos, however, did not warrant the further conclusion that these entities could be therapeutically useful. The old Enlightenment suspicions still prevailed: we were still dealing with a vision of these effects as a kind of biological lie, an intrusion of mind into physiology that could, if not properly accounted for, undermine the honest efforts of science-minded physicians to determine the specific efficacy of real new treatments. And here Beecher came to the second goal of his paper: a political goal. In the emerging new age of pharmaceuticals, medical research could no longer afford to muddle along unprotected. It needed to defend itself against the powerful placebo by adopting a cutting-edge methodology that would come to be called the randomized controlled trial (RCT). The method in question involved first randomizing the patients in ones study into two groups, in part so that there would be roughly equal numbers of placebo responders in each. One of the groups was then offered a placeboa dummyversion of a new active medication; the other was offered the real medication. Because the subjects have been randomized, it was supposed that placebo effects would operate in both groups at approximately the same levels. If the new drug turned out to be effective, however, the active treatment group would show evidence of added benefit. The specific effectiveness of the new drug could then be quantified as anything above the common level of placebo effect supposed to be working in both groups. The eventual enshrining of the randomized, placebo-control trial as the methodological gold standard of clinical research is a story that warrants its own paper (cf. Kaptchuk, 1998b). What is worth simply noting here is the confused, even incoherent understanding of the placebo effect left behind by these developments. The placebo effect was still plainly a sham effect, but one possessed with a powerful physiology. Patients responded to placebos with a range of striking bodily responses (cf. Lasagna et al., 1954, 1958), but nevertheless none of this was judged to be of clinical relevance; on the contrary, these phenomena were deemed to be an obstruction to the development of effective therapeutics.

Historical excursion three: placebo effects as a powerful mindbody intervention

So let us ask now: how and when did this second understanding change? When did placebos and their effects begin to be seen as therapeutically interesting, and what enabled them to be so seen?

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The answer to this question takes us back to yet another set of historical events, largely based in the United States and, initially, at least, remote from the concerns of mainstream medicine. I am speaking of the rise of certain Protestant-based religious movements that emerged in the United States in the late nineteenth century, and that focused on healing as one of the promised fruits of faith. By adopting the right mental attitude of faith, these groups claimed, one could command Gods healing power. These Protestant religious movements sometimes called themselves mind cure, sometimes new thought, sometimes Christian science and sometimes practical Christianity. Most people today, at least those of a certain age, are familiar with Norman Vincent Peales advocacy of the healing power of positive thinking. Earlier in these remarks, I made reference to Dale Carnegie, the American motivational speaker who exhorted people to believe that you will succeed and you will. In fact, both Carnegie and Peale were directly influenced by these nineteenth-century Protestant healing movements, though they expanded the remit and promised not just health, but also wealth, happiness and business success as fruits of positive thinking (Harrington, 2005). Health remained, however, a continuing concern and goal of the positive thinking movement and, by the 1950s, we had arrived in a situation in which the publiceven those who would not have considered themselves religious and had never heard of new thought or mind curebelieved widely in the healing power of positive thinking. Medicine proper, however, had not paid the idea much attention, and probably would have considered a proposal to weigh in on the healing power of faithlet alone explain itas beneath its dignity. It had, in any event, bigger fish to fry at that point in time. A generation later, however, in the early 1970s, the confidence of medicine was beginning to be shaken as patients became less compliant and more consumer-oriented, and its practices came under increasing attack as technocratic, impersonal and disempowering. These were the years that saw the rise of movements, in both the United States and Europe, that aimed to reorient medicine towards more holistic ways of practice, ways that would result in patients being empowered rather than patronized. In this context, the importance of the doctorpatient relationship was emphasized, but not the patronizing relationship of old: in the 1970s vision of holistic medicine, doctors and patients would work as partners in the healing process. In this context, the social conditions were ripe to take a fresh look at the placebo effect and all the things it was known (or believed) to do. A key catalyst for this new evaluative moment came in 1976 when Norman Cousins the prominent editor of the Saturday Reviewpublished a paper in the New England Journal of Medicine called Anatomy of an illness (as perceived by the patient). The paper described Cousins own journey in self-healing. Diagnosed with a rare degenerative disorder (ankylosing spondylitis) over which his doctors had despaired, he had decided to turn his back on the quick-fix high-tech medicine of his time, and subject himself to generous doses of laughter, vitamin C and a positive attitude. The article ended with images of Cousins standing in the surf in Puerto Rico, jogging on the beach and then, finally, back at work full-time editing his magazine (Cousins, 1976). Cousins story became a cultural phenomenon, the talk of the town; but it also served as an occasion for the placebo effect to make its first serious outing in a new guise: as something both powerful and positive; a vehicle by which the power of positive thinking could work real and lasting healing effects. In this way, also, Cousins in his 1976 article did

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something at once intoxicating and heretical: he proposed that medical science take the claims of religious communities seriously. Faith did heal, but not because God rewarded the faithful by making miracles. It was because faith itself set into motion healing powers in the body that medicine had long dismissed as mere placebo effects, but that actually did pack a true physiological punch: It is quite possible that . . . everything I did . . . was a demonstration of the placebo effect. If so, it would be . . . important to probe into the nature of this psychosomatic phenomenon. At this point, of course, we are opening a very wide door, perhaps even a Pandoras box. The vaunted miracle cures that abound in the literature of all the great religions, or the speculations of Charcot and Freud about conversion hysteria, or the Lourdes phenomenaall say something about the ability of the patient, properly motivated or stimulated, to participate actively in extraordinary reversals of disease and disabilities. (Cousins, 1976). In the 1970s, its authority with the public no longer as certain as it had been, the medical profession proved more willing to listen to ideas like these than it would have been a generation before. Cousins reported receiving literally thousands of letters from physicians praising him for his courage in speaking out the way he did, and making reference to the larger professional and clinical benefits that all now agreed would come from integrating mindbody healing effects into clinical practice. But this growing sense of a need for reform and a new openness to funky ideas in medicine was only part of the larger context that made it possible to think about the placebo effect in a new way. New ways of thinking about the placebo effect also became possible because of a series of changes in the sciences deemed important to understanding human behavior. More specifically, the late 1970s saw the beginning of a decisive sidelining of the old psychoanalytic perspectives in psychiatry (that had largely acted to encourage older ways of thinking about the placebo effect) and the rise of various kinds of neuroscientific perspectives to take their place. I will just mention two events in particular that were decisive specifically to our concern with the emergence of new ways of conceiving the placebo effect. The first was an outgrowth of the discovery in the early 1970s of endorphins: substances in the brain that are chemically similar to opioids, and that therefore appeared to be the brains own natural painkillers. In 1978, a report was published that suggested that placebo treatments for pain were mediated, at least in part, by those biochemical substances. When you blocked the bodys opioid receptors using an opioid-blocker called naloxone (without telling patients you were doing this), placebo responders stopped reporting relief of pain. Cousins dream that science could get to the bottomeven to the biochemistry of positive thinking and faith healing thus seemed to some to be on the way to being realized (Levine et al., 1978). The second event from the 1970s that began to change the fortunes of the placebo effect is closely linked to the rise of the new field of psychoneuroimmunologythe growing evidence that the immune system could be affected by input from the nervous system and, in this way, from the mind. In 1975, the psychologist Robert Ader at the University of Rochester put a powerful immune-suppressing drug, cyclophosphamide in saccharine water and fed it to rats. They grew ill and began to die. Then he took away the drug and just continued

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to feed them saccharine waterand they continued to grow ill and die. He had conditioned their immune systems to act as if they were being bombarded with a powerful drug (Ader and Cohen, 1975). The results had not been expected, but, faced with them, he began to ask: hadnt he effectively just created a placebo version of the drug and shown that it was truly potent, capable even of affecting the immune systems of these rats and killing them? Between Aders work and the naloxone work, research on placebo effects seemed more compatible with the hard science posture of the science of the day than ever before. And that perception of compatibility has, if anything, grown in our own time. Today, research on the placebo effect focuses overwhelmingly on the perceived hardware or mechanisms underlying the effect. A new favored direction for studies, for example, uses new brain imaging technologies in order to compare the brain activation patterns of people who have been given placebo versions of treatments with those of people who have received active medication. Interesting differencesif not wholly consistent across studieshave indeed been found (cf. Petrovic et al., 2002). What I think is most important for our purposes here is the extent to which all this apparently hard-nosed biochemistry and neuroscience would, quite quickly, become a critical resource for the critics of technocratic medicine, the advocates for patient empowerment, the celebrants of holistic medicine. For them, the new material reality of the placebo effect has allowed it to emerge as a verified mindbody treatment that can be used, not deceptively but in a way that empowers patients to work as partners with doctors in their own healing. I could give many examples of this trend, but Ill choose one by a patient (who makes a point of the fact that she also has a PhD), Lolette Kuby, author of a book called Faith and the placebo effect: An argument for self-healing: The placebo effect is the good news of our time. It says, You have been cured by nothing but yourself. (Kuby, 2003). So a phenomenon that began as an impediment to rational scientific inquiry is now increasingly accepted by mainstream medicine as a legitimate and productive object of scientific inquiry. A phenomenon that began as quackery, deception and domination is now embraced by various counterculture strains in our society as a means of healing and personal empowerment. Neverthelesscoming back to where I began my remarksnone of this is as digested or resolved as it might seem. The placebo effect, as a phenomenon, concept, research agenda and practice, remains very much informed still by unfinished business from the past. I indicated, when I began my remarks, that a great deal was at stake for us in this unfinished business. Let us see if we are now in some better position to take stock of some of those stakes. They include, at minimum:
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Philosophical and methodological concerns to protect rational empirical inquiry in medicine from being misled by the tendency of the human mind, especially when under the influence of imagination or suggestion, to make things up; human subjective experience, for this reason, is an inherently unreliable source of knowledge. Political zeal within mainstream medicine to expose the humbug at the heart of nonorthodox forms of medicine (including the quacks of the past) by showing that their apparent efficacy is due to nothing but placebo effects (suggestion, the imagination). Ethical ambivalence by clinicians about the use of placebos in mainstream medicine; is it sometimes a useful and necessary form of consolation or a cheap means of deception that always degrades medicine?

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Economic and commercial concerns (especially within the pharmaceutical industry) to find a way to test the objective and specific efficacy of new drugs, and avoid being misled by confounding data produced by placebo reactors. Social dissatisfaction (popular and professional) with the technocratic impersonality of modern medicine; the placebo effect proves that the warm and fuzzy side of clinical practice (the bedside manner, the doctorpatient relationship) really matters. The relative authority and power of neuroscientific perspectives over the softer perspectives of classical psychology or psychoanalysis. If the biostatistics warrant it, orbetterthe brain scans show there is a discernible biology in play, then this effect can be taken seriously by the biomedical community. Populist ideologies of self-help, positive thinking and patient empowerment that see in the rehabilitated placebo effect a new way of talking about long-standing beliefs in the untapped (and sometimes quasi-miraculous) healing powers within each of us.

With so much in play, and so much at stake, it seems unlikely that we will be seeing a consensus on the real meaning of the placebo effect very soon.

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