Placebo

Assessment | Biopsychology | Comparative | Cognitive | Developmental | Language | Individual differences | Personality | Philosophy | Social |
Methods | Statistics | Clinical | Educational | Industrial | Professional items | World psychology |

Statistics: Scientific method · Research methods · Experimental design · Undergraduate statistics courses · Statistical tests · Game theory · Decision theory

---

The placebo effect (Latin placebo, "I shall please"), also known as non-specific effects and the subject-expectancy effect, is the phenomenon that a patient's symptoms can be alleviated by an otherwise ineffective treatment, since the individual expects or believes that it will work. Some people consider this to be a remarkable aspect of human physiology; others consider it to be an illusion arising from the way medical experiments were conducted.

In the opposite effect, a patient who disbelieves in a treatment may experience a worsening of symptoms. This nocebo effect (nocebo translates from Latin as "I shall harm") can be measured in the same way as the placebo effect, e.g., when members of a control group receiving an inert substance report a worsening of symptoms. The recipients of the inert substance may nullify the placebo effect intended by simply having a negative attitude towards the effectiveness of the substance prescribed, which often leads to a nocebo effect, which is not caused by the substance itself, but more the patient's mentality towards her or his ability to get well.

The concept of placebo

The placebo effect is the term applied by medical science to the therapeutical and healing effects of inert medicines and/or ritualistic or faith healing manipulations. . When referring to medicines, placebo is a preparation which is pharmacologically inert but which may have a therapeutical effect based solely on the power of suggestion. It may be administered in any of the ways in which pharmaceutical products are administered. An active placebo is a placebo that mimics the side effects of the drug under investigation but which lacks the therapeutic effect. They are important in drug trials where the tested drug produces sidef effects that could act as clues to participants as to whether they were in the control or experimental group.

Sometimes known as non-specific effects or subject-expectancy effects, a so-called placebo effect occurs when a patient's symptoms are altered in some way (i.e., alleviated or exacerbated) by an otherwise inert treatment, due to the individual expecting or believing that it will work. Some people consider this to be a remarkable aspect of human physiology; others consider it to be an illusion arising from the way medical experiments are conducted.

The placebo effect occurs when a patient takes an inert substance (a "sugar pill") in conjunction with the suggestion from an authority figure that the pill will aid in healing and the patient’s condition improves. This effect has been known for years.

The word "placebo" has been used in many somewhat varying meanings; see below.

Methodology of administration

Placebos are things like sugar pills, that look like real treatments but in fact have no physical effect. They are used to create "blind" trials in which the participants do not know whether they are getting the active treatment or not, so that physical effects can be measured independently of the participants' expectations. There are various effects of expectations, and blind trials control all of these together by making whatever expectations there are equal for all cases. Placebos are not the only possible technique for creating "blindness" (= unawareness of the treatment): to test the effectiveness of prayer by others, you just don't tell the participants who has and has not had prayers said for them. To test the effect of changing the frequency of fluorescent lights on headaches, you just change the light fittings at night in the absence of the office workers (this is a real case).

Related to this is the widespread opinion that placebo effects exist, where belief in the presence of a promising treatment (even though it is in fact an inert placebo) creates a real result e.g. recovery from disease. Placebos as a technique for "blinding" will remain important even if there is no placebo effect, but obviously it is in itself interesting to discover whether placebo effects exist, how common they are, and how large they are. After all, if they cure people then we probably want to employ them for that.

Claims that placebo effects are large and widespread go back to at least Beecher (1955). However Kienle and Kiene (1997) did a reanalysis of his reported work, and concluded his claims had no basis in his evidence. Beecher misinterpreted his data. Also, Beecher's methodology was very questionable. Then Hrobjartsson & Gotzsche (2001) did a meta-analysis or review of the evidence, and concluded that most of these claims have no basis in the clinical trials published to date. This opinion is widely spread in the placebo literature. The chief points of their skeptical argument are:

• Only trials that compare a group that gets no treatment with another group that gets a placebo can test the effect.
• Most claims are based on looking at the size of the improvement measured in placebo groups in trials comparing only placebo and experimental (active) treatments. This is misleading since (for instance) most diseases have a substantial clearup rate with no treatment: seeing improvements does not mean the placebo had an effect. (Put more technically, comparing with the baseline (pretest measure) is vulnerable to regression to the mean.)

Nevertheless, even they conclude that there is a real placebo effect for pain (not surprising since this is partly understood theoretically: Wall, 1999)); and for some other continuously-valued subjectively-assessed effects. A recent experimental demonstration was reported: Zubieta et al. (2005) "Endogenous Opiates and the Placebo Effect" The journal of neuroscience vol.25 no.34 p.7754-7762

This seems to show that the psychological cause (belief that the placebo treatment might be effective in reducing pain) causes opioid release in the brain, which then presumably operates in an analogous way to externally administered morphine.

A recent and more extensive review of the overall dispute is: M. Nimmo (2005) Placebo: Real, Imagined or Expected? A Critical Experimental Exploration Final year undergraduate Critical Review, Dept. of Psychology, University of Glasgow. PDF copy.

It has been observed often enough, yet still frequently overlooked, that the notion of placebo as it occurs in modern clinical discourse is not a rigorous concept, and despite many attempts, it has not been possible to provide a coherent definition. The most cited one is probably that of Arthur Shapiro, which together with others in the same vein, makes use of the idea of "non-specific" therapeutic effects, and thus merely shifts the explanatory burden to this equally undefined concept. In addition, as Moerman has pointed out, such definitions assert at the same time that placebos are inert and that they produce the placebo effect, which is self-contradictory. In a detailed critique of Shapiro's approach, Grunbaum attempted to formulate a logically consistent definition, but this in turn has been criticized on the grounds that it is uninformative in respect of the phenomenon itself – that is, the behaviour in a clinical setting of patients, bodies, physicians, and therapeutic maneuvers. In the view of Moerman and others, clinical science has burdened itself with a pseudo-concept, more confusing than useful, the correction of which will entail a revision of some foundational thinking in clinical medicine.

Recent studies published in Proceedings of the National Academy of Sciences using advances in neuroscience (PET scans) have shown that placebos can demonstrably reduce pain in humans. Researchers at Columbia and Michigan University have shown that the brains of volunteers who believed that what they were taking was pain medication were shown to be spontaneously releasing opioids, or natural pain relief. According to that ABC report the Food and Drug Administration contends that as many as 75 percent of patients have had responses to sugar pills. It pointed out that all major clinical trials use placebo groups because the effect is significant and to be expected.

This effect has been known for years. Generally, one third of a control group taking a placebo shows improvement and Harvard’s Herbert Benson says that the placebo effect yields beneficial clinical results in 60–90% of diseases, including angina pectoris, bronchial asthma, herpes simplex, and duodenal ulcers.

The following are some of the issues pointing to a fundamental problem:

• Ever since Beecher's 1955 study appeared, it has been claimed that about one third of the therapeutic effect observed in a typical trial is attributable to the placebo effect. But this is not what Beecher showed at all. In the "meta-analytic" section of his paper he gave the proportion of subjects across 15 trials deemed to have "been satisfactorily relieved by placebo" as 35.2% +/- 2.2%. This, if anything, is an estimate of the frequency of 'placebo-responders' in the aggregate trial group, but says nothing about the magnitude of the effect.
• Beecher, intentionally or otherwise, gave currency to the idea that the placebo effects were roughly constant at around 35%, and that the term could be usefully applied to all those variables otherwise called "non-specific" contributors to therapeutic outcomes - the natural (and unknowable) course of diseases, regression to the mean, expectation effects, changes in effect and other unquantifiable psycho-somatic features of illness, beliefs and therapeutic communication, etc. If anything is clear from subsequent studies, it is that the placebo effect is not constant, but strikingly variable. Placebo response rates all the way from zero to 100% have been reported in virtually every clinical condition studied (the variation in Beecher's own series was 15-58%). The so-called effect appears to be both universal and utterly unpredictable.
• Beecher, who was concerned to promote the use of Randomised controlled trials (RCTs) in clinical research, made an unjustified assumption which is almost certainly false - that placebo effects in the intervention and control arms of a trial will be identical, or nearly so, and independent of the therapeutic effects. In the rationalization of RCTs which followed, this claim has never been rigorously defended, and in specific instances, can be easily refuted.
• The original 1955 article of Beecher "The Powerful Placebo" claimed a 35% placebo effect in 15 studies. The original article was in 1997 re-analysed and "no evidence was found of any placebo effect in any of the studies" used by Beecher. The claimed "effects" were produced by spontaneous improvement, fluctuation of symptoms, regression to the mean, additional treatment, conditional switching of placebo treatment, scaling bias, irrelevant response variables, answers of politeness, experimental subordination, conditioned answers, neurotic or psychotic misjudgment, psychosomatic phenomena, misquotation, etc.
• Kaptchuk has shown that both the name and the concept of placebo were transferred from at least 200 years of use in clinical practice, in the decade following the second world war, to a new role required by the methodology of what was then the new discipline of 'clinical research'. Earlier usage corresponded to its Latin etymology - a harmless pill or potion given knowingly to patients who were either hard to please or hard to cure. The first clear example cited in the OED is from 1811. But during the post-war therapeutic revolution, it became the trashcan into which all the confounding factors that disturb therapeutic assessments were tipped. In Beecher's terms, it became a powerful if enigmatic distraction to researchers, whose results would be contaminated without rigorous procedures for its exclusion. Its modern use is therefore quite recent, and closely related to the adoption of the RCT as the methodological gold standard for trials of therapy.
• A considerable body of work has attempted to elucidate the 'mechanism' of the placebo effect - but without much success. Proposals ranging from 'suggestibility' and various other psychological hypotheses, to neuro-endocrine studies, and attribution of the effect to statistical artefacts, have turned out to be flawed in various ways, so that clinical researchers have no more idea of what is really going on in the control arms of their trials than did Hippocrates. It seems unlikely that this deeply unsatisfactory situation will be resolved by a new attempt to answer the old question; instead, as has been suggested by some of the most thoughtful students, we should expect to find that some part of the conceptual landscape in which this problematic entity resides must be reconstructed before it will come into focus. This view commends itself specially to those scholars who bring to the problem a perspective from outside the clinic - from medical anthropology, history of medicine, philosophy, and statistics.

Inertness

Although placebos are generally characterized as pharmacologically inert substances or formulations, sham treatments, or inactive procedures, they are only inert, sham, ineffective, or inactive in the particular sense that they have no known cause and effect relationship with any of the pre-designated, biochemical, physiological, behavioural, emotional and/or cognitive outcomes of the pharmacologically active and known-to-be-efficacious intervention that might have otherwise been applied (see below).

Placebos are inactive or ineffective treatments or formulations; however a patient may experience either a positive or negative clinical effect while taking one. When a placebo is administered to mimic a previously administered drug, it may also incur the same side effects as the prior authentic drug. Most of these effects are thought to be psychological in nature or due to other unrelated factors. Not all placebos are equally effective. A placebo that involves ingestion, injection, or incision is often more powerful than a non-invasive technique. Placebos administered by authority figures such as general practitioners and other experts may also be more powerful than when this psychological authority effect is absent.

They are, however, not inert, sham, or inactive in any other manner of speaking; and they may well, in and of themselves, generate considerable change within any given subject, at any given time, under any given circumstances. According to Shapiro:

Actually the question of inert versus active placebo is academic, because there is no such thing as an inactive substance. For example, distilled water injections can cause hemolysis and water intoxication. Ingestion of two 5-grain [325 mg] capsules of sacchari lactis [milk sugar], QID [quater in die, "four times a day"], for 30 years, can result in a weight gain of 30 pounds, so that even sugar can hardly be considered harmless, indifferent, or inert.

— Shapiro, 1968, p.675

Etymology

The word placebo is Latin for "I will please". It is in Latin text in the Bible (Psalm 114:1-9, Vulgate version), from where it became familiar to the public via the Office of the Dead church service (see Placebo (at funeral) for details).

Whenever a placebo is requested in a medical prescription it may imply a statement by the prescribing doctor that "This patient has come to me pleading for a treatment which does not exist or which I cannot or will not supply; I will please him by giving him something ineffectual and claiming that it is effectual." It could also indicate a belief that the effect was due to a subconscious desire of the patient to please the doctor. Since the placebo effect is in the patient not the doctor this may be more self-consistent. Early usage of the term does not indicate why it was chosen.

Obecalp

Sometimes a doctor who does this, says that the fake medicine is `Obecalp', which is "placebo" spelled backwards. [1] [2] (and many other links)

Early use of placebos

Main article: History of the placebo

File:AntiBiliousBitters.jpg

Anti-bilious bitters and other early placebos

Originally, a placebo was a substance that a well-meaning doctor would give to a patient, telling him that it was a powerful drug (e.g., a painkiller), when in fact it was nothing more than a sugar pill. Thus, Hooper's medical dictionary of 1811 says placebo is "an epithet given to any medicine adapted more to please than benefit the patient." The subsequent reduction of the patient's symptoms was attributed to the patient's faith in his doctor and hence his belief in the drug. (This category, particularly before the first Medicines Act was passed, may merge into fake medicines.)

Modern clinical application

Experimenters typically use placebos in the context of a clinical trial, in which a "test group" of patients receives the therapy being tested, and a "control group" receives the placebo. It can then be determined if results from the "test" group exceed those due to the placebo effect. If they do, the therapy or pill given to the "test group" is assumed to have had an effect.

Origin of term "placebo effect" (1920)

Perhaps Graves (1920) was the first to speak of the placebo effect, when he spoke of "the placebo effects of drugs" being manifested in those cases where "a real psychotherapeutic effect appears to have been produced".

In 1933 (Evans and Hoyle) (using 90 subjects) and in 1937 (Gold, Kwit and Otto) (using 700 subjects) each published a study which compared the outcomes from the administration of an active drug and a dummy simulator (which both research groups called a placebo) in the same trial. Neither experiment displayed any significant difference between drug treatment and placebo treatment; leading the researchers to conclude that the drug exerted no specific effects in relation to the conditions being treated.

In 1946, the Yale biostatistician and physiologist E. Morton Jellinek was the first to speak of either a "placebo reaction" or a "placebo response". He speaks of a "response to placebo" (p.88), those who "responded to placebo" (p.88), a "reaction to placebo" (p.89), and of "reactors to placebo" (p.90). From this, it is obvious that, to Jellinek, the terms "placebo response" and "placebo reaction" -- or the terms "placebo responder" and "placebo reactor" -- were identical and interchangeable.

The general literature commonly misattributes the term "placebo effect" to Henry K. Beecher's 1955 paper The Powerful Placebo, where, however, he only speaks of placebo effects when he is contrasting them with drug effects; otherwise, he always speaks of "placebo reactors" and "placebo non-reactors".

Beecher (1952), Beecher, Keats, Mosteller, and Lasagna (1953), Beecher (1959), consistently speak of "placebo reactors" and "placebo non-reactors"; they never speak of any "placebo effect". Beecher (1970) simply speaks of "placebos".

Isolation of causation

According to Kleijnen and his colleagues, healing is an interactive process between three influences:

• (1) the self-healing properties of the subject.

(Here, they are referring to an inherent self-healing force (such as that which naturally staunches a bleeding cut) similar to that of the élan vital (“life force”) or the vis medicatrix naturae (“healing power of nature”), per medium of which the patient recovers entirely without the physician’s intervention, rather than to some sort of active, intentional, purposeful arousal of a subject’s optimal physiological, psychosomatic and somatopsychic healing resources by the therapist)

• (2) the non-specific effects induced by the presence of the therapist and the therapeutic setting.

(The term "non-specific effects" has many advantages; e.g., psychopharmacological research that Hankoff (1999) conducted with colleagues in the 1950s, led them to conclude that “it is best to think of a range of nonspecific factors to account for the response to a medication (which can be both positive and negative), rather than speaking of a placebo reaction or a placebo reactor as an explanation” (p.199). Roberts, et al. (2001) describes these non-specific effects as “the nonpharmacologic benfits of the protocol involvement and of participants’ beliefs that they may be taking an active medication” (p.887))

• (3) the specific effects of the physical or pharmacological therapeutic interventions.

These effects are not isolated mutually-exclusive effects and, rather than just adding, they may help or hinder each other to various degrees. Also, Hyland (2003, p.348) notes that, in cases where “contextual factors contribute to a strong placebo response”, due to “the potentiating or adjunctive effect of the placebo response”, placebos can be used “potentiate the effect of an active treatment” that would have otherwise been far less efficacious.

From this notion that a “drug” has a specific treatment effect (i.e., the effect for which it has been administered), Perlman (2001, p.283) draws attention to three other treatment effects:

1. non-specific effects: these are the side effects (“which are usually considered deleterious”);
2. unintended effects: these are the placebo effects (“which… are still considered to be for the most part uncontrolled and unscientific”); and
3. serendipitous effects: these are the “serendipitous effects of being in therapy, such as [the] organizing effects of the therapeutic structure, inadvertent role modelling, outside knowledge of the therapist, chance remarks or encounters, and the influence of auxiliary personnel”.

In pursuit of establishing causation, the question “Who does what, with which, and to whom?” is central to task of identifying what are:

• specific effects (those for which the treatment was administered),
• non-specific effects (predictable "side effects"),
• unintended effects (i.e., the placebo responses),
• serendipitous effects of treatment (i.e., effects of the subject just being "in therapy"); Perlman (2001)(p.283) in discussing this suggests these as examples:
  • the "organizing effects of the therapeutic structure",
  • "inadvertent role modeling",
  • "outside knowledge of the therapist",
  • "chance remarks or encounters",
  • "the influence of auxiliary personnel" ("this category includes doormen, receptionists, cashiers, secretaries, security guards, janitors, and child care attendants", p.287).

Gaddum (1954) also recognizes that "changes in the incidence or severity of diseases in a hospital may be due to changes in the diet or changes in the nurses, which happen to coincide with the introduction of a new treatment" (pp.195-196).

In experiments with the common cold by Gold, Kwit & Otto (1937), in accounting for why those who received the placebo drug often experienced considerable benefit, Gold and his colleagues supposed that other, non-drug-related factors may have made a significant contribution to the apparent efficacy of the supposedly active drug, such as:

1. Spontaneous variations in the course of the pain.
2. Change in the weather.
3. Change of occupation or amount of work.
4. Change of diet.
5. Change in eating habits with increase in the amount of rest before and after meals.
6. Condition of the bowels.
7. Emotional stress.
8. Change in domestic affairs.
9. Confidence aroused in the treatment.
10. Encouragement afforded by any new procedure.
11. A change of the medical adviser.

Also, due to the difficulty in ascribing causation, many phenomena overlap with, and are thus misattributed to, subjects' placebo responses (the phenomena are known as "confounders" or "lurking variables", such as:

• Natural termination of the disease process.
• Regression to the mean.
• Cyclical presentation of the disease.
• Errant diagnosis or prognosis.
• Temporary improvement confused with cure.

Preventing subjects recognizing placebo

Appropriate use of a placebo in a clinical trial often requires or at least benefits from a double-blind study design, which means that neither the experimenters nor the subjects know which subjects are in the "test group" and which are in the "control group".

Adherence to placebo

The Coronary Drug Project was intended to study the safety and effectiveness of safety of drugs for long-term treatment of coronary heart disease in men. Those in the placebo group who adhered to the placebo treatment (took the placebo regularly as instructed) showed nearly half the mortality rate as those who were not adherent. A similar study of women similarly found survival was nearly 2.5 times greater for those who adhered to their placebo. This apparent placebo effect may be caused by:

• The psychological effect of adhering to the protocol, i.e. genuine placebo effect.
• Being healthy enough to follow the protocol.
• Compliant people being more diligent and scrupulous in all aspects of their lives.

Need for psychoactive placebo

Because a belief that one has received the active drug can produce a markedly heightened placebo effect, it is often necessary to use a psychoactive placebo in clinical trials; i.e., a drug that produces enough physical effects to encourage the belief in the control and experimental groups that they have received the active drug.

A psychoactive placebo was used in the Marsh Chapel Experiment: a double-blind study, in which the experimental group received psilocybin while the control group received a large dose of niacin, a substance that produces noticeable physical effects.

Walter Pahnke in 1962 described his Marsh Chapel Experiment in his unpublished Ph.D. dissertation "Drugs and Mysticism: An Analysis of the Relationship between Psychedelic Drugs and the Mystical Consciousness, and submitted it in 1963, for his Ph.D. in Religion and Society at Harvard University; Timothy Leary was the principal academic advisor for his dissertation. In it, Pahnke wrote of administering capsules that contained 30mg of psilocybin extracted from psychoactive mushrooms, and contrasting their effects with those of psychoactive placebos, which contained the chemical niacin in such a dosage that it produced very significant physiological responses. It was intended that these responses would lead the control subjects to believe they had received the psychoactive drug.

The term "psychoactive placebo" is rare in the literature; but, when it is used, it always denotes a placebo of this type. For example, "Neither the experienced investigator nor the naive [subject] is easily fooled on the matter of whether he has received a psychedelic substance or merely a psychoactive placebo such as amphetamine." (Harman, McKim, Mogar, Fadiman & Stolaroff, 1966, p.215)

Placebos in clinical trials

Placebo simulators are a standard control component of most clinical trials which attempt to make some sort of quantitative assessment of the efficacy of new medicinal drugs; It is a view held by many "that placebo-controlled studies often are designed in such a way that disadvantages the placebo condition" and, generally speaking, for a drug to be put on the market, it must be significantly more effective than its placebo counterpart.

According to Yoshioka (1998), the first-ever randomized clinical trial was the trial conducted by the Medical Research Council (1948) into the efficacy of streptomycin in the treatment of pulmonary tuberculosis.There were two test groups in this trial

1. those "treated by streptomycin and bed-rest", and
2. those "[treated] by bed-rest alone" (the control group).

What made this trial exceptional was that the subjects were randomly allocated to their test groups. The up-to-that-time practice was to allocate subjects alternately to each group, based on the order in which they presented for treatment. This practice was considered to be extremely biased, because those admitting each patient knew to which group that patient would be allocated (and it was considered that the decision to admit or not admit a specific patient might be influenced by the experimenter's knowledge of the nature of their illness, and their knowledge of the group to which the alternate allocation demanded they would occupy).

In recent times, the practice of using an additional natural history group as the trial's so-called "third arm" has emerged; and trials are conducted using three randomly-selected equally-matched trial groups, David (1949, p.28) wrote: "... it is necessary to remember the adjective ‘random’ [in the term ‘random sample’] should apply to the method of drawing the sample and not to the sample itself.".

1. The Active drug group (A): who receive the active test drug.
2. The Placebo drug group (P): who receive a placebo drug that simulates the active drug.
3. The Natural history group (NH): who receive no treatment of any kind (and whose condition, therefore, is allowed to run its natural course).

The outcomes within each group are observed, and compared with each other, allowing us to measure:

1. The efficacy of the active drug's treatment: the difference between A and NH (i.e., A-NH).
2. The efficacy of the entire treatment process alone: the difference between P and NH (i.e., P-NH).
3. The efficacy of the active drug's active ingredient: the difference between A and P (i.e., A-P).
4. The magnitude of the placebo response: the difference between P and NH (i.e., P-NH).

Note that, depending upon the focus of your interest, the value of P-NH can either indicate the efficacy of the entire treatment process or the magnitude of the "placebo response".

The results of these comparisons then determine whether or not a particular drug is considered efficacious.

In recent times, as the demands for the scientific validation of the various claims that are made for the efficacy of various so-called "talking therapies" (such as hypnotherapy, psychotherapy, counselling, and non-drug psychiatry) has significantly increased, there is continuing controversy over what might or might not be an appropriate placebo for such therapeutic treatments.

In 2005, the Journal of Clinical Psychology, an eminent peer-reviewed journal (founded in 1945), devoted an entire issue to the question of "The Placebo Concept in Psychotherapy", and contained a wide range of articles that made many valuable contributions to this overall discussion.

The placebo response as an index

In certain clinical trials of particular drugs, it may happen that the level of the "placebo responses" manifested by the trial's subjects are either considerably higher or lower (in relation to the "active" drug's effects) than one would expect from other trials of similar drugs. In these cases, with all other things being equal, it is entirely reasonable to conclude that:

• the degree to which there is a considerably higher level of "placebo response" than one would expect is an index of the degree to which the drug's active ingredient is not efficacious.
• the degree to which there is a considerably lower level of "placebo response" than one would expect is an index of the degree to which, in some particular way, the placebo is not simulating the active drug in an appropriate way.

However, in particular cases such as the use of Cimetidine to treat ulcers (see below), a significant level of placebo response can also prove to be an index of how much the treatment has been directed at a wrong target.

Placebo-controlled studies

Beecher (1955) reported that about a quarter of patients who were administered a placebo, e.g. against back pain, reported a relief or diminution of pain. Remarkably, not only did the patients report improvement, but the improvements themselves were often objectively measurable, and the same improvements were typically not observed in patients who did not receive the placebo.

Because of this effect, government regulatory agencies approve new drugs only after tests establish not only that patients respond to them, but also that their effect is greater than that of a placebo (by way of affecting more patients, by affecting responders more strongly or both). Such a test or clinical trial is called a placebo-controlled study. Because a doctor's belief in the value of a treatment can affect his or her behaviour, and thus what his or her patient believes, such trials are usually conducted in "double-blind" fashion: that is, not only are the patients made unaware when they are receiving a placebo, the doctors are made unaware too. Recently, it has even been shown that "mock" surgery can have similar effects, and so some surgical techniques must be studied with placebo controls (rarely double blind, for obvious reasons). To merit approval, the group receiving the experimental treatment must experience a greater benefit than the placebo group.

Nearly all studies conducted this way show some benefit in the placebo group. For example, Kahn published a meta-analysis of studies of investigational antidepressants and found a 30% reduction in suicide and attempted suicide in the placebo groups and a 40% reduction in the treated groups. However, studies generally do not include an untreated group, so determining the actual size of the placebo effect, compared to totally untreated patients, is difficult.

Notable placebo effect absences

In psychological treatment, two disorders are known to have very low placebo effects: schizophrenia, and obsessive compulsive disorder.

Placebo and pain

Careful studies have shown that the placebo effect can alleviate pain, although the effect is more pronounced with pre-existing pain than with experimentally-induced pain. People can be [Conditioning|conditioned]] to expect analgesia in certain situations. For example see Wager (2004). When those conditions are provided to the patient, the brain responds by generating a pattern of neural activity that produces objectively quantifiable analgesia.

Evans (2004) argues that the placebo effect works through a suppression of the acute phase response, and as a result does not work in medical conditions that do not feature this. The acute phase response consists of inflammation and sickness behaviour:

• Four classic signs of ‘inflammation’: tumor, rubor, calor and dolor – swelling, redness, heat and pain.
• Sickness behaviour: lethargy, apathy, loss of appetite and increased sensitivity to pain.

Placebo and depression

A brain-imaging study by Leuchter (2002) found that depressed patients who responded to the placebo effect showed changes in cerebral blood flow, which were different to the changes in brain function seen in patients who responded to anti-depressant medication. Other studies such as Khan (2000) argue that up to 75% of the effectiveness of anti-depressant medication is due to the placebo-effect rather than the treatment itself.

Endogenous Opiates

Endogenous opiates are chemicals produced by the brain that suppress pain and produce analgesia and a sense of well-being. Opium and drugs derived from it (opiates) produce their "highs" by triggering the same brain receptors used by natural opiates. Increased release of endogenous opiates like endorphin is associated with pleasant experiences like excercise (the runner's high) and sex. The placebo effect can be blocked by naloxone, a drug that blocks the effects of opiates, suggesting that the placebo effect may be partly due to the release of natural opiates.

Withdrawal symptoms on discontinuance of placebo

The Women's Health Initiative study of hormone replacement therapy for menopause was discontinued after participants still in the program had been taking either hormones or placebo for an average of 5.7 years. Moderate or severe withdrawal symptoms were reported by 40.5% of those on placebo compared to 63.3% of those on hormone replacement. Pain and stiffness (musculoskeletal symptoms) were the most frequently reported symptoms in both the placebo group (22.2%) and the hormone group (36.8%), exceeding other symptoms by more than 10%. Of those reporting pain and stiffness, 54.7% in the hormone group and 38.3% in the placebo group had these symptoms at the onset of therapy. Tiredness was the second most frequently reported withdrawal symptom (21.3% hormone, 11.6% placebo) and hot flashes/night sweats the third (21.2% hormone, 4.8% placebo). Only the vasomotor symptoms (hot flashes/night sweats) were acknowledged to be verified effects of menopause by a 2005 National Institutes of Health panel.

These results may indicate some learned response concerning which withdrawal symptoms appear in a placebo group as well as in the subjects who received therapy, with a greater effect on pain and tiredness than on vasomotor symptoms.

Objective or subjective effects?

An alternate opinion attributes the false perception of a placebo effect to the fact that patients who have been given a placebo report improvement earlier and more eagerly in order to please and thank the care giver. These patients may even do this when there is no real physical improvement attained. One quoted figure is that about one third of patients improve on a placebo, but a recent study has called that number into question. Hróbjartsson and Götzsche reported in 2001 that the placebo effect is much smaller than previously thought, if it exists at all. The 30 percent figure derives from a paper by Henry Beecher, published in 1955 (H. Beecher, 1955). Beecher was one of the leading advocates of the need to evaluate treatments by means of double-blind trials and this helps to explain why it has been so widely quoted.

The Hróbjartsson & Götzsche study demonstrated that in many studies where a control group was used that did not get any treatment at all, the effects in the no-treatment group were almost equal to the effects in the placebo group for studies with binary outcomes (e.g. well treated or poorly treated). The authors concluded that the placebo effect does not have "powerful clinical effects," and conceded that placebos have "possible small benefits in studies with continuous subjective outcomes and for the treatment of pain." They therefore concluded that there was no justification for its use outside of clinical trials.

In a follow-up study in 2004, the same authors were able to confirm their previous results and concluded: "We found no evidence of a generally large effect of placebo interventions. A possible small effect on patient-reported continuous outcomes, especially pain, could not be clearly distinguished from bias".

If their conclusions are correct, the placebo effect is reduced to a subjective placebo illusion, while retaining its importance as a statistical research tool. As such it is imperative to use it in research, but unethical to use it in normal clinical treatment of patients.

These conclusions contradict what some would now consider to be a great deal of folklore that has evolved around the whole idea of the placebo effect. That folklore has evolved in a "research vacuum" of ignorance about the true nature of the placebo effect.

What is new about these conclusions is an emphasis on the key words "subjective" and "pain". This explains the well-established fact that the placebo effect is most "effective" in conditions where subjective factors are very prominent or significant parts of the problem. Some of these conditions are: headache, stomach ache, asthma, allergy, tension, and especially the most subjective of them all - pain, which is a significant part of most serious (and many mild) illnesses.

It also explains why there is no conclusive documentation for placebos causing significant healing effects in serious biological pathologies.

How the placebo effect works

It is universally accepted that, for a placebo response to occur, the subject must believe an effective medication (or other treatment) has been administered to them, but must not know it is an ineffective placebo. This is quite different from the case of an "active drug", where the drug response is generated even in the case of covert administration, in other words regardless of whether the patient knows or doesn't know they have received any medication.

The question of just how and why placebo responses are generated is not an abstract theoretical issue; it has wide implications for both clinical practice and the experimental evaluation of therapeutic interventions.

In recent times, three different hypotheses have been offered to account for these placebo responses — i.e., "expectancy theory" and 'classical conditioning" and motivation — which, whilst emphasizing different factors, are not mutually exclusive and, in fact, overlap to a certain extent.

Expectancy Effect

The subject-expectancy effect attributes the placebo effect to conscious or unconscious manipulation by patients in reporting improvement. Hrobjartsson and Götzsche argued in their article, "Most patients are polite and prone to please the investigators by reporting improvement, even when no improvement was felt." Subjective bias can also be unconscious, where the patient believes he is improving as a result of the attention and care he has received.

Conditioning

Classical conditioning is a type of associative learning where the subject learns to associate a particular stimulus with a particular response. In this case the stimulant is the substance perceived as medicine but is the placebo, and the response is the relief of symptoms. It is difficult to tell the difference between conditioning and the expectancy effect when the outcome is subjective and reported by the patient. However, conditioning can result in measurable biological changes similar to the changes seen with the real treatment or drug. For example, studies showing that placebo treatments result in changes in brain function similar to the real drug are probably examples of conditioning resulting in objectively measurable results. (Sauro 2005, Wager 2004, Arnaldo 2002)

Motivation

Motivational explanations of the placebo effect have typically considered the placebo effect to be an outcome of one’s desire to feel better, reduce anxiety, or cooperate with an experimenter or health care professional (Price et al. 1999, Margo 1999). The motivational perspective is supported by recent research showing that nonconscious goals for cooperation can be satisfied by confirming expectations about a treatment (Geers et al. 2005).

Role of endogenous opiates

The discovery in 1975 of Endogenous opiates alias endorphins (substances like opiates but naturally produced in the body) have changed matters in investing placebo effect. When patients who claimed to experience pain relief after receiving a placebo were injected with naloxone (a drug that blocks the effects of opiates), their pain returned, suggesting that the placebo effect may be partly due to psychological reaction causing release of natural opiates. (Sauro 2005)

Biological substrates of the placebo response

A "placebo response" can amplify, diminish, nullify, reverse or, even, divert the action of an "active" drug.

Because a "placebo response" is just as significant in the case of an "active" drug as it is in the case of an "inert" dummy drug, the more that we can discover about the mechanisms that produce "placebo responses", the more that we can enhance their effectiveness and convert their potential efficacy into actual relief, healing and cure.

Recent research strongly indicates that a "placebo response" is a complex psychobiological phenomenon, contingent upon the psychosocial context of the subject, that may be due to a wide range of neurobiological mechanisms (with the specific response mechanism differing from circumstance to circumstance). The very existence of these "placebo responses" strongly suggest that "we must broaden our conception of the limits of endogenous human control"; and, in recent times, researchers in a number of different areas have demonstrated the presence of biological substrates, unique brain processes, and neurological correlates for the "placebo response":

• 2001: de la Fuente-Fernández and colleagues reported their PET scan findings on test subjects with Parkinson's disease.
• 2002: Petrovic and colleagues reported their PET scan findings on test subjects in a trial of opioid analgesia.
• 2002: Mayberg and colleagues reported their PET scan findings on test subjects with unipolar depression.
• 2004: Wager and colleagues reported their fMRI scan findings on test subjects in a trial of placebo analgesia.
• 2004: Lieberman and colleagues reported their PET scan findings on test subjects with Irritable bowel syndrome.
• 2006: Bingel and colleagues reported their fMRI scan findings on test subjects in a trial of placebo analgesia.
• 2006: Zubieta and colleagues reported their PET scan findings on test subjects in a trial of placebo analgesia.
• 2006: Sarinopoulos and colleagues reported their fMRI scan findings on test subjects in a trial neural responses to a highly aversive bitter taste.

A complex fMRI-centred study by McClure, et al. (2004) on the brain responses of subjects who had previously expressed a preference for one or other of the similar soft drinks Pepsi and Coca-Cola, demonstrated that "brand information", which "significantly influences subjects’ expressed preferences", is processed in an entirely different brain area from the area activated in blind taste tests (when their "preferences are determined solely from sensory information"). This supports the claim that there are unconscious brain processes that activate the "placebo response".

Ethical challenges and concerns

Bioethicists have raised diverse concerns on the use of placebos in modern medicine and research. These have been largely incorporated into modern rules for the use of placebos in research but some issues remain subject to debate. The ethics of prescribing placebos in medical practice is highly debated. Some practitioners argue that the use of placebos is sometimes justified because it will do no harm and may do some good. With the publication of studies by Hróbjartsson and Götzsche and others, the proposition that placebos may do some good is under fire.

• Disclosure. Rules that govern modern clinical trials insist on full disclosure to subjects who take part. Today, subjects are told that they may receive the drug being tested or they may receive the placebo.
• Balancing Treatment vs. Research Objectives. Ethicists have also raised concerns on the use of placebos in those circumstances in which a standard treatment exists unless there are genuine doubts of the effectivity of such standard treatment. If standard treatments exist for the disease being studied in clinical trials, a standard treatment is always used in place of a placebo for serious diseases. In research experimental studies, the method of establishing a proper control group to eliminate the placebo effect has also been difficult, particularly for surgical and therapy interventions that are not pharmaceutical in nature. Notably, there has been much debate of whether to use a placebo pill or conduct a sham procedure as a control.

Most of these concerns have been addressed in the modern conventions for the use of placebos in research; however, some issues remain subject to debate.

From the time of the Hippocratic Oath questions of the ethics of medical practice have been widely discussed, and codes of practice have been gradually developed as a response to advances in scientific medicine.

The Nuremberg Code, which was issued in August 1947, as a consequence of the so-called Doctors' Trial which examined the outrageous human experimentation conducted by Nazi doctors during World War II, offers ten principles for legitimate medical research, including informed consent, absence of coercion, and beneficence towards experiment participants.

In 1964, the World Medical Association issued the Declaration of Helsinki,[3] which specifically limited its directives to health research by physicians, and emphasized a number of additional conditions in circumstances where "medical research is combined with medical care".

The significant difference between the 1947 Nuremberg Code and the 1964 Declaration of Helsinki is that the first was a set of principles that was suggested to the medical profession by the "Doctors’ Trial" judges, whilst the second was imposed by the medical profession upon itself.

Paragraph 29 of the Declaration makes specific mention of placebos:

29. The benefits, risks, burdens and effectiveness of a new method should be tested against those of the best current prophylactic, diagnostic, and therapeutic methods. This does not exclude the use of placebo, or no treatment, in studies where no proven prophylactic, diagnostic or therapeutic method exists.

In 2002, World Medical Association issued the following elaborative announcement:

Note of clarification on paragraph 29 of the WMA Declaration of Helsinki

The WMA hereby reaffirms its position that extreme care must be taken in making use of a placebo-controlled trial and that in general this methodology should only be used in the absence of existing proven therapy. However, a placebo-controlled trial may be ethically acceptable, even if proven therapy is available, under the following circumstances:

— Where for compelling and scientifically sound methodological reasons its use is necessary to determine the efficacy or safety of a prophylactic, diagnostic or therapeutic method; or

— Where a prophylactic, diagnostic or therapeutic method is being investigated for a minor condition and the patients who receive placebo will not be subject to any additional risk of serious or irreversible harm.

All other provisions of the Declaration of Helsinki must be adhered to, especially the need for appropriate ethical and scientific review.

In addition to the requirement for informed consent from all drug-trial participants, it is also standard practice to inform all test subjects that they may receive the drug being tested or that they may receive the placebo.

A Danish study of placebos

A study of Danish general practitioners found that 48% had prescribed a placebo at least 10 times in the past year. The most frequently prescribed placebos were antibiotics for viral infections, and vitamins for fatigue. Specialists and hospital-based physicians reported much lower rates of placebo use. (Hrobjartsson 2003) A 2004 study in the British Medical Journal of physicians in Israel found that 60% used placebos in their medical practice, most commonly to "fend off" requests for unjustified medications or to calm a patient. Of the physicians who reported using placebos, only 15% told their patients they were receiving placebos or non-specific medications. (Nitzan 2004) An accompanying editorial stated,

The placebo effect, thought of as the result of the inert pill, can be better understood as an effect of the relationship between doctor and patient. Adding the doctor's caring to medical care affects the patient's experience of treatment, reduces pain, and may affect outcome. This survey makes it clear that doctors continue to use placebos, and most think they help.

The editorial suggested there were problems with Hróbjartsson and Götzsche's methods and argued that their results show that placebos can't cure everything, but don't prove that the placebo effect cures nothing. The editorial concluded, "We cannot afford to dispense with any treatment that works, even if we are not certain how it does." (Spiegel 2004)

The editorial prompted responses on both sides of the issue.

• Critics of the practice responded that it is unethical to prescribe treatments that don't work, and that telling a patient that a placebo is a real medication is deceptive and harms the doctor-patient relationship in the long run. Critics also argued that using placebos can delay the proper diagnosis and treatment of serious medical conditions.
• Defenders of the use of placebos suggested that placebos do not work in clinical trials because the subjects know they might be getting a placebo, but do work in medical practice where the patient believes he or she is getting an active drug. Other writers pointed to the empirical data showing that placebos can have measurable biological effects, especially in pain relief (see above), or argued that the use of a placebo to "please the patient" fosters real healing as part of a caring doctor-patient relationship. (Barfod 2005, Di Blasi 2005)

BMJ posted a series of responses to Dr. Spiegel's editorial online in their rapid response section. Selected responses were published in later issues of the Journal.

In addition, there are the impracticalities of placebos:

• Roughly only 30% of the population seems susceptible to placebo effects, and it is not possible to determine ahead of time for whom a placebo will work and for whom it will not.
• All placebo effects eventually wear off, thus making the placebo effect impractical for long term or chronic medical matters.
• Patients rightfully want immediate relief or improvement from their illness or symptoms. A non-placebo can often provide that, while a placebo might not.
• Legitimate doctors and pharmicists could open themselves up to charges of fraud since sugar pills would cost pennies or cents for a bottle, but the price for a "real" medication would be have to be charged to avoid making the patient suspicious.
• Unscrupulous medical practitioners could swindle patients with fake surgeries and sugar pills, then later claim that they only meant to help their patients by using "placebos".

About 25% of physicians in both the Danish and Israeli studies used placebos as a diagnostic tool to determine if a patient's symptoms were real, or if the patient was malingering. Both the critics and defenders of the medical use of placebos agreed that this was unethical. The British Medical Journal editorial said, "That a patient gets pain relief from a placebo does not imply that the pain is not real or organic in origin...the use of the placebo for 'diagnosis' of whether or not pain is real is misguided."

The placebo administration may prove to be a useful treatment in some specific cases where recommended drugs can not be used. For example, burn patients who are experiencing respiratory problems cannot often be prescribed opioid (morphine) or opioid derivatives (pethidine), as these can cause further respiratory depression. In such cases placebo injections (normal saline, etc.) are of use in providing real pain relief to burn patients if they (those not in delirium) are told that are being given a powerful dose of painkiller.

There is general agreement that placebo control groups are an important tool for controlling for several types of possible bias, including the placebo effect, in double blind clinical trials.

The placebo effect is an active area of research and discussion and it is possible that a clear consensus regarding the use of placebos in medical practice will emerge in the future.

Practical implications and consequences

According to these findings, a placebo can make you think you are better, and even temporarily feel that you are better, but it can't actually make you any better. It will not cause any significant physiological change in a serious disease. In short, it will fool you (which is its intended function in double blind experiments).

To most scientists, these conclusions aren't revolutionary, since they have been using placebos in research for years, based on assumptions that this was the case. If they had believed otherwise, they would have been acting against better knowledge.

Much quackery achieves temporary "success" by a conscious or unconscious misuse of this placebo illusion. To the patient, such misuse of placebos can be expensive and ultimately fatal. To the quack, it will fool the patient long enough to keep the scam rolling.

Placebo control groups will continue to be a vital part of double blind clinical trials for the foreseeable future. Even if the placebo effect is not a useful method for treating illness, its effects are observed in clinical studies and are real enough to interfere with efforts to determine the usefullness of new drugs and therapeutic procedures, unless they are properly controlled for.

Confounders mistaken for placebo effect

Due to the difficulty in ascribing causation, many phenomena overlap with - and can thus mistakenly be included in - statistics on the placebo effect.

• Natural termination of the disease process.
• Cyclical presentation of the disease.
• Errant diagnosis or prognosis.
• Temporary improvement confused with cure.

Neurobiology of the placebo effect

• Nucleus accumbens

See also

• Autosuggestion
• Belief
• Charm
• Clinical trial
• Confounding factor
• Culture-specific syndrome
• E. Morton Jellinek
• Efficacy
• Expectation
• Experimental design
• Flexner Report
• Hawthorne effect
• Homeopathy
• Hypnotic susceptibility
• Iatrogenesis
• Intention
• Medication
• Nocebo
• Observer-expectancy effect
• Optimism
• Pessimism
• Pharmacology
• Post hoc ergo propter hoc
• Psychiatry
• Psychosomatic illness
• Pygmalion effect
• Scientific control
• Scientific method
• Self-fulfilling prophecy
• Simulation
• Simulator
• Stigmata
• Subject-expectancy effect
• Therapeutic effect
• Thomas theorem
• Unintended consequence

Additional references

• Anon, "The Bottle of Medicine" [Editorial], British Medical Journal, No.4750, (19 January 1952), pp.149-150.
• Andrews G (2001) Placebo response in depression:bane to research boon to therapy. British journal of Psychiatry,178, 192-194. Full text
• Aronson, J., "When I use a word . . . Please, please me", British Medical Journal, Vol.318, No.7185, (13 March 1999), p.716.
• Ayad, H., "Khellin in Angina Pectoris", The Lancet, Vol.251, No.6495, (21 February 1948), Page 305.
• Bacon, R., Of Simulation and Dissimulation, 1597.
• Barfod TS. 2005. Placebos in medicine: placebo use is well known, placebo effect is not. BMJ. 330:45. PMID 15626817.
• Beecher, H. K. (1955) "The powerful placebo" Journal of the American Medical Association 159 pp.1602-1606 [Original article, most cited one, claiming a widespread placebo effect]
• Beecher, H.K., "Experimental Pharmacology and Measurement of the Subjective Response", Science, Vol.116, No.3007, (15 August 1952), pp.157-162.
• Beecher, H.K., "The Powerful Placebo", Journal of the American Medical Association, Vol.159, No.17, (24 December 1955), pp.1602-1606.
• Beecher, H.K., Measurement of Subjective Responses: Quantitative Effects of Drugs, Oxford University Press, (New York), 1959.
• Beecher, H.K., Research and the Individual: Human Studies, Little, Brown, (Boston), 1970. [ISBN 0-7000-0168-9]
• Beecher, H.K., Keats, A.S., Mosteller, F. & Lasagna, L., "The Effectiveness of Oral Analgesics (Morphine, Codeine, Acetylsalicylic Acid) and the Problem of Placebo "Reactors" and "Non-Reactors"", Journal of Pharmacology and Experimental Therapeutics, Vol.109, No.4, (December 1953), pp.393-400.
• Benedetti F, Pollo A et al. Conscious expectation and unconscious conditioning in analgesic, motor, and hormonal placebo/nocebo responses. J Neurosci. 23:4315-4323. PMID 12764120
• Bernheim, H. (trans. by Herter C.A. from Second, revised French Edition of 1887), Suggestive Therapeutics: A Treatise on the Nature and Uses of Hypnotism, G.P. Putnam's Sons, (New York), 1889.
• Carroll, Robert Todd (2001?) The Placebo Effect Accessed on 2004-05-19. [Part of the Skeptics Dictionary. Useful categorization of possible types of mechanism for the placebo effect if it exists.]
• Carruthers, S.G., Hoffman, B.B., Melmon, K.L. & Nierenberg, D.W. (eds.), Melmon and Morrelli's Clinical Pharmacology: Basic Principles in Therapeutics (Fourth Edition), McGraw-Hill, (London), 2000.
• Carter, A.B., "The Placebo: Its Use and Abuse", The Lancet, Vol.262, No.6790, (17 October 1953), p.823.
• Chambless, D.L. & Hollon, S.D., "Defining Empirically Supported Therapies", Journal of Consulting and Clinical Psychology, Vol.66, No.1, (February 1998), pp.7-18.
• Charcot, J.M., "The Faith-Cure", The New Review, Vol.VIII, (January 1893), pp.18-31.
• Colunga, A. & Turrado, L. (eds.), Biblia sacra iuxta Vulgatam Clementinam nova editio Logis partitionibus aliisque subsidiis ornata a A. Colunga et L. Turrado, Biblioteca de autores cristianos, (Madrid), 1965.
• Cooper, A., "Surgical Lectures", The Lancet, Vol.1, No.8, (23 November 1823), pp.253-260.
• Di Blasi Z, Reilly D. 2005. Placebos in medicine: medical paradoxes need disentangling. BMJ. 330:45. PMID 15626818.
• Di Blasi, Z., Harkness, E., Edzard, E., Georgiou, A. & Kleijnen, J., "Influence of Context Effects on Health Outcomes: A Systematic Review", The Lancet, Vol.357, No.9258, (10 March 2001), pp.757-762.
• Diehl, H.S., Baker, A.B. & Cowan, D.W., " Cold Vaccines: An Evaluation Based on a Controlled Study", Journal of the American Medical Association, Vol.111, No.13, (24 September 1938), pp.1168-1173.
• Dodes, John E. (2001?) The Mysterious Placebo Accessed on 2001-01-19. Originally published in the January/February 1997 issue of Skeptical Inquirer. A nice overview of the placebo effect and how it influences the study of alternative medicines.
• Ernst, E. & Resch, K.L., "Concept of True and Perceived Placebo Effects", British Medical Journal, (26 August 1995), Vol.311, No.7004, pp.551-553.
• Evans D. 2004. Placebo: Mind over Matter in Modern Medicine. HarperCollins (UK) / Oxford University Press (US). ISBN 0-19-522054-4.
• Evans D. 2005. Suppression of the acute-phase response as a biological mechanism for the placebo effect. Med Hypotheses. 64:1-7. PMID 15533601.
• Evans M. 2000. Justified deception? The single blind placebo in drug research. J Med Ethics. 26:188-193. PMID 10860211.
• Evans, W. & Hoyle, C., "The Comparative Value of Drugs Used in the Continuous Treatment of Angina Pectoris", Quarterly Journal of Medicine, No.7 (Vol.2, No.4), (July 1933), pp.311-338.
• Findley, T., "The Placebo and the Physician", Medical Clinics of North America, Vol.37, (November 1953), pp.1821-1826.
• Flexner, A., Medical Education in the United States and Canada: A Report to the Carnegie Foundation for the Advancement of Teaching (Bulletin Number Four), The Merrymont Press, (Boston), 1910. [4]
• Flint, A., "A Contribution Toward the Natural History of Articular Rheumatism, Consisting of a Report of Thirteen Cases Treated Solely with Palliative Measures", American Journal of Medical Science, Vol.46, (July 1863), pp.17-36.
• Gaddum, F.M., "Walter Ernest Dixon Memorial Lecture: Clinical Pharmacology", Proceedings of the Royal Society of Medicine, Vol.47, No.3, (March 1954), pp.195-204.
• Gauld, A., A History of Hypnotism, Cambridge University Press, (Cambridge), 1992.
• Geers AL et al. 2005. Goal activation, expectations, and the placebo effect. J Pers Soc Psychol. 89:143-159. PMID 16162050.
• Goddard, H.H., "The Effects of Mind on Body as Evidenced by Faith Cures", American Journal of Psychology, Vol.10, No.3, (April 1899), pp.431-502.
• Gold, H., Kwit, N.T. & Otto H., "The Xanthines (Theobromine and Aminophyllin) in the Treatment of Cardiac Pain", Journal of the American Medical Association, Vol.108, No.26, (26 June 1937), pp.2173-2179.
• Graves, T.C., "Commentary on a Case of Hystero-Epilepsy with Delayed Puberty: Treated with Testicular Extract", The Lancet, Vol.196, No.5075, (4 December 1920), pp.1134-1135.
• Green, J.P. (ed. & trans.), Interlinear Bible: Hebrew/Greek/English, With Strong's Concordance Numbers Above Each Word, Sovereign Grace Publishers, (Lafayette) 1997.
• Green, S.A., "The Origins of Modern Clinical Research", Clinical Orthopaedics and Related Research, Vol.405, (December 2002), pp.311-319.
• Handfield-Jones, R.P.C., "A Bottle of Medicine from the Doctor", The Lancet, Vol.262, No.6790, (17 October 1953), pp.823-825.
• Harman, W.W., McKim, R.H., Mogar, R.E., Fadiman, J. & Stolaroff, M.J., "Psychedelic Agents in Creative Problem-Solving: A Pilot Study, Psychological Reports, Vol.19, No.1, (August 1966), pp.211-227.
• Hahn, R.A. & Kleinman, A, "Belief as Pathogen, Belief as Medicine: "Voodoo Death" and the "Placebo Phenomenon" in Anthropological Perspective", Medical Anthropology Quarterly, Vol.14, No.4, (August 1983), pp.3, 16-19.
• Harrington, Anne, ed. 1997. The Placebo Effect: An Interdisciplinary Exploration. Cambridge: Harvard University Press. ISBN 067466986X
• Houston, W.R., "The Doctor Himself as a Therapeutic Agent", Annals of Internal Medicine, Vol.11, No.8, (February 1938), pp.1416-1425.
• Haygarth, J., Of the Imagination, as a Cause and as a Cure of Disorders of the Body; Exemplified by Fictitious Tractors, and Epidemical Convulsions (New Edition, with Additional Remarks), Crutwell, (Bath), 1801.
• Hill, R.C. (trans.), St. John Chrysostom: Commentary on the Psalms, Volume Two, Holy Cross Orthodox Press, (Brookline), 1998.
• Hrobjartsson, Asbjorn; Gotzsche, Peter C. (2001) "Is the Placebo Powerless? An Analysis of Clinical Trials Comparing Placebo with No Treatment" New England Journal of Medicine 344 (21) May 2001 pp.1594-1602 [Meta-analysis, destroying most but not all of the belief that there is evidence for a placebo effect.]
• Hyland, M. E. (2003). Using the placebo response in clinical practice. Clinical Medicine (London, England), 3, 347-350.
• Jacobs, B., "Biblical Origins of Placebo", Journal of the Royal Society of Medicine, Vol.93, No.4, (April 2000), pp.213–214.
• Jellinek, E. M. "Clinical Tests on Comparative Effectiveness of Analgesic Drugs", Biometrics Bulletin, Vol.2, No.5, (October 1946), pp.87-91.
• Jewson, N.D., "Medical Knowledge and the Patronage System in 18th Century England", Sociology, Vol.8, No.3, (1974), pp.369-385.
• Jewson, N.D., "The Disappearance of the Sick Man from Medical Cosmology, 1770-1870", Sociology, Vol.10, No.2, (1976), pp.225-244.
• Kaptchuk, T.J., "Intentional Ignorance: a History of Blind Assessment and Placebo Controls in Medicine", Bulletin of the History of Medicine, Vol.72, No.3, (Fall 1998), pp.389-433.
• Khan A, Warner HA, and Brown WA. 2000. Symptom reduction and suicide risk in patients treated with placebo in antidepressant clinical trials: an analysis of the Food and Drug Administration database. Arch Gen Psychiatry 57:311-317. PMID 10768687
• Kienle G. S., Kiene H. (1997) "The powerful placebo effect: fact or fiction?" Journal of Clinical Epidemiology. 50 (12) pp.1311-8. [Destroys Beecher's original article]
• Kirsch, I., "Response Expectancy as a Determinant of Experience and Behavior", American Psychologist, Vol.40, No.11, (November 1985), pp.1189-1202.
• Kirsch, I., "Response Expectancy Theory and Application: A Decennial Review", Applied and Preventive Psychology, Vol.6, No.2, (Spring 1997), pp.69-79.
• Lasagna, L., "The Placebo Effect", The Journal of Allergy and Clinical Immunology, Vol.78, No.1, Pt.2, (July 1986), pp.161-165.
• Lasagna, L., Mosteller, F., von Felsinger, J.M. & Beecher, H.K., "A Study of the Placebo Response", American Journal of Medicine, Vol.16, No.6, (June 1954), pp.770-779.
• Leslie, A., "Ethics and Practice of Placebo Therapy", American Journal of Medicine, Vol.16, No.6, (June 1954), pp.854-862.
• Leuchter AF, Cook IA et al. Changes in brain function of depressed subjects during treatment with placebo. Am J Psychiatry. 159:122-129. PMID 11772700.
• Leslie, A., "Ethics and Practice of Placebo Therapy", American Journal of Medicine, Vol.16, No.6, (June 1954), pp.854-862.
• Lohr, J.M., Olatunji, B.O., Parker, L. & DeMaio, C., "Experimental Analysis of Specific Treatment Factors: Efficacy and Practice Implications", Journal of Clinical Psychology, Vol.61, No.7, (July 2005), pp.819-834.
• Lorenz, J., Hauck, M., Paura, R.C., Nakamura, Y., Zimmermann, R., Bromm, B. & Engela, A.K., "Cortical Correlates of False Expectations During Pain Intensity Judgments — A Possible Manifestation of Placebo/Nocebo Cognitions", Brain, Behavior, and Immunity, Vol.19, No.4, (July 2005), pp.283-295.
• Margo CE. 1999. The placebo effect. Surv Ophthalmol. 44:31-44. PMID 10466586.
• McDonald CJ, McCabe GP. 1989. How much of the placebo 'effect' is really statistical regression? Stat Med. 2:417-27. PMID 2814076.
• McDonald C. J., Mazzuca S. A., McCabe G. P., Jr. "How much of the placebo 'effect' is really statistical regression?" Statistics in Medicine 2(4):417-27 (1983).
• McGlashan, T.H., Evans, F.J. & Orne, M.T., "The Nature of Hypnotic Analgesia and Placebo Response to Experimental Pain", Psychosomatic Medicine, Vol.31, No.3, (May-June 1969), pp.227-246.
• McMahon, C.E., "The 'Placebo Effect' in Renaissance Medicine", Journal of the American Society of Psychosomatic Dentistry and Medicine, Vol.22, No.1, (1975), pp.3-9.
• McMahon, C.E., "The Role of Imagination in the Disease Process: Pre-Cartesian History", Psychological Medicine, Vol.6, No.2, (May 1976), pp.179-184.
• McMahon, C.E. & Hastrup, J.L., "The Role of Imagination in the Disease Process: Post-Cartesian History", Journal of Behavioral Medicine, Vol.3, No.2, (June 1980), pp.205-217.
• Merton, R.K., "The Unanticipated Consequences of Purposive Social Action", American Sociological Review, Vol.1, No.6, (December 1936), pp.894-904. [5]
• Miller, F.G., "Sham Surgery: An Ethical Analysis", The American Journal of Bioethics, Vol.3, No.4, (Fall 2003), pp.41-48.
• Miller, F.G., "William James, Faith, and the Placebo Effect", Perspectives in Biology and Medicine, Vol.48, No.2, (Spring 2005), pp.273-281.
• Nitzan U, Lichtenberg P. 2004. Questionnaire survey on use of placebo. BMJ 329:944-946. PMID 15377572.
• Nordenberg, Tamar (2000) "The Healing Power of Placebos" FDA Consumer magazine
• Pepper, O.H.P., "A Note on the Placebo", American Journal of Pharmacy, Vol.117, (November 1945), pp.409-412.
• Perlman, L, "Nonspecific, Unintended, and Serendipitous Effects in Psychotherapy", Professional Psychology: Research and Practice, Vol.32, No.3, (June 2001), pp.283–288.
• Platt, R., "Two Essays on the Practice of Medicine", The Lancet, Vol.250, No.6470, (30 August 1947), pp.305-307.
• Price DD et al. 1999. An analysis of factors that contribute to the magnitude of placebo analgesia in an experimental paradigm. Pain. 83:147-156. PMID 10534585.
• Pyysiäinen, I., "Mind and Miracles", Zygon, Vol.37, No.3, (September 2002), pp.729-740.
• Rahlfs, A. (ed.), Septuaginta: Volumen II: Libri poetici et prophetici, Deutsche Bibelgesellschaft Stuttgart, (Stuttgart), 1935.
• Rajagopal, S., "The placebo effect". Psychiatric Bulletin, Vol.30, (2006), pp.185-188.
• Sauro MD. 2005. Endogenous opiates and the placebo effect: a meta-analytic review. J Psychosom Res. 58:115-120. PMID 15820838.
• Senn SJ. 1988. How much of the placebo 'effect' is really statistical regression? [letter] Stat Med. 7:1203. PMID 3201046.
• Senn SJ. 1992. The ignoble lie [letter; comment]. J Clin Epidemiol. 45:1338-40.
• Senn SJ. 1996. A personal view of some controversies in allocating treatment to patients in clinical trials. Stat Med. 14:2661-74. PMID 8614742.
• Senn SJ. 1997. Are placebo run ins justified? [letter] BMJ 314:1191-3. PMID 9146400.
• Senn SJ. 2001. The Misunderstood Placebo. Applied Clinical Trials 10:40-46.
• Senn SJ. 2002. Ethical considerations concerning treatment allocation in drug development trials. Statistical Methods in Medical Research volume 11, pp.403-411.
• Senn SJ. 2003. Dicing with Death: Chance, Risk and Health (Cambridge University Press: Cambridge, UK. ISBN 0-521-54023-2.
• Shapiro, A.K., "A Contribution to a History of the Placebo Effect", Behavioral Science, Vol.5, No.2 (April 1960) pp.109-135.*Senn S. J. (2003) Dicing with death (CUP: Cambridge)
• Shapiro, A.K., "Semantics of the Placebo", Psychiatric Quarterly, Vol.42, No.4, (December 1968), pp.653-695.
• Simon, Steve (2003) Ethics of a placebo group
• Spiegel D. 2004. Placebos in practice. BMJ. 329:927-928. PMID 15499085.
• Staats, P., Hekmatb, H. & Staats, A., "Suggestion/Placebo Effects on Pain: Negative as Well as Positive", Journal of Pain and Symptom Management, Vol.15, No.4, (April 1998), pp.235-243.
• Stam, H.J. & Spanos, N., "Hypnotic Analgesia, Placebo Analgesia, and Ischemic Pain: The Effects of Contextual Variables", Journal of Abnormal Psychology, Vol.96, No.4, (November 1987), pp.313–320.
• Stam, H.J., Hypnotic Analgesia and the Placebo Effect: Controlling Ischemic Pain, (Ph.D. Dissertation), Carleton University, (Ottawa, Canada), 1984.
• Steele, Dr., "The Charitable Aspects of Medical Relief", Journal of the Royal Statistical Society, Vol.54, No.2, (June 1891), pp.263-310.
• Stewart-Williams, S. & Podd, J., "The Placebo Effect: Dissolving the Expectancy Versus Conditioning Debate", Psychological Bulletin, Vol.130, No.2, (March 2004), pp.324-340.
• Wager TD, Rilling JK, Smith EE et al. 2004. Placebo-induced changes in FMRI in the anticipation and experience of pain. Science. 303:1162-1167. PMID 14976306
• Walach, H., "Placebo and Placebo Effects – A Concise Review", Focus on Alternative and Complementary Therapies, Vol.8, No.2, (June 2003), pp.178-187.
• Wampold, B.E., Minami, T., Tierney, S.C., Baskin, T.W. & Bhati, K.S., "The Placebo is Powerful: Estimating Placebo Effects in Medicine and Psychotherapy from Randomized Clinical Trials", Journal of Clinical Psychology, Vol.61, No.7, (July 2005), pp.835-854.
• Wilson, I., The Bleeding Mind: An Investigation into the Mysterious Phenomenon of Stigmata, Paladin, (London), 1991.
• Wolf, S., "Effects of Suggestion and Conditioning on the Action of Chemical Agents in Human Subjects; The Pharmacology of Placebos", Journal of Clinical Investigation, Vol.29, No.1, (January 1950), pp.100-109.
• New Scientist Space. March 19, 2005. 13 Things that do not make sense. URL accessed May 8, 2006.
• Zubieta et al. (2005) "Endogenous Opiates and the Placebo Effect" The Journal of Neuroscience 25(34) p.7754-7762

Further reading

• Bausell, R. Barker (2007), Snake Oil Science: The Truth About Complementary and Alternative Medicine, Oxford University Press, ISBN 978-0-19-531368-0  Has several chapters on the placebo effect.
• McQuay HJ, Moore RA (2005) Placebo. Postgrad Med J. 2005 Mar;81(953):155-60. PMID 15749790 [6]

External links

• "Placebo Effect: Harnessing Your Mind's Power To Heal" ScienceDaily, 2003-12-31
• Desonie, Dana "The Placebo Effect: Real or Imagined?"
• The Placebo Effect at the Skeptic's Dictionary
• "Mystery Painkiller" at sciencentral.com (includes a short video.)