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The technical term placebo is precisely applied in the specialized medical domains of pharmacology, nosology, and aetiology to denote the pharmacologically inert, dummy simulator of an "active" drug that serves as a scientific control in clinical trials designed to determine the clinical efficacy of that particular drug. In the past, there was tendency for American authors to speak of all controls as placebos, whilst British authors tended to speak of dummy drugs, placebo therapies, and sham procedures.

In particular, these clinical trials are conducted in order to determine whether a drug's supposedly active ingredients affect the subject through direct physiochemical processes or through mind-mediation.Wampold, Minami, Tierney, Baskin & Bhati (2005), p.836.

Inertness

Although placebos are generally characterized as pharmacologically inert substances, sham treatments, or inactive procedures, they are only inert, sham, 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.

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.

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 mg capsules of sacchari lactis href="http://articles.gourt.com/en/milk sugar">milk sugar, QID 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)

Applications of the term placebo

Whilst it is universally accepted that the Latin word placebo means "I shall please", the precise meaning of the English technical term placebo is not always immediately clear.

In the strictest sense, the technical term placebo denotes the inert, dummy simulator of an "active" drug that serves as a control in the clinical trials of drug efficacy, that are conducted to determine whether a drug's supposedly active ingredients affect its recipients through direct physiochemical processes or through mind-mediation.

However, some such as Gaddum (1954, p.197) have taken the position that -- by contrast with the "counterfeit objects" that are genuinely "dummy drugs" (which "cannot be distinguished from the real treatment" and are "indistinguishable in appearance, taste and smell from the real *" and, by definition, "have no effect", and "are sometimes called placebos" -- only those "counterfeit objects" that really do have some biochemical, physiological, behavioural, emotional and/or cognitive effect on a subject, and produce that effect through a psychological (rather than pharmacological) mechanism, can truly be called placebos.

A placebo is something which is intended to act through a psychological mechanism. It is an aid to therapeutic suggestion, but the effect which it produces may be either psychological or physical. It may make the patient feel better without any obvious justification, or it may produce actual changes in such things as gastric secretion. Dummy tablets may, of course, act as placebos, but, if they do, they lose some of their value as dummy * tablets. They have two real functions, one of which is to distinguish pharmacological effects from the effects of suggestion, and the other is to obtain an unbiased assessment of the result of the experiment. (p.197)

In a far more general sense, the term placebo is also sometimes used to denote the pharmacologically inert, but subjectively soothing "sugar pill", electuary, or pharmaceutical syrup that a doctor might give a patient in order to gratify their need for treatment.

The term placebo may also be used pejoratively to mean a treatment or remedy that has no demonstrated efficacy whatsoever; and it is most often used to describe earlier forms of treatment to which some level of therapeutic efficacy had once been actively misattributed.

In everyday English, the word placebo is also used to denote a pharmacologically active drug, treatment or surgical procedure that has a positive, beneficial, desirable or pleasant outcome. The negative counterpart of this sort of placebo -- an active drug, treatment or procedure that has an injurious, undesirable or unpleasant outcome -- is called a nocebo.

…a therapy may be used with or without knowledge that it is a placebo. It would include treatments given in the belief that they were not placebos, but which actually are placebos by objective evaluation. The placebo may be inert or active and may include, therefore, all medical treatment no matter how potentially specific or how administered. It may take the form of oral and parenteral medication, topical preparations, inhalants, and all mechanical, surgical, psychotherapeutic, and other therapeutic techniques. It would include a treatment that produced symptoms or side effects which were not specific for that treatment. A placebo may or may not result in a placebo effect, and the effect may be favorable or unfavorable — that is, positive or negative. Shapiro (1968), p.682

In the absence of contextual evidence -- and, in particular, in the absence of any direct knowledge of the theoretical orientation of the individual who is using the term -- it may be quite impossible to accurately and unequivocally identify its meaning in a particular case, due to the extremely wide range of different (and possibly mutually exclusive) meanings to which the term may be applied.

Uses of the term placebo

Homonymy vs. polysemy

This confusion and ambiguity within the term's application, to a large extent is due to the complex nature of the English word. For, rather than there being an extended range of linked polysemous meanings of a single term (i.e., placebo) that have multiplied, over time, from a single original source,Such as, for example, the word net, an openwork meshed fabric, a fishing net, cricket practice held in "the nets", a tennis net, a tennis shot that hits the net cord, etc. many of the applications of the term placebo emanate from quite different sources.

Consequently, the range of different usages of the term placebo are homonymous (rather than polysemous) usages; with significantly different concepts sharing the same spelling (as with the homonyms ear, bank, sound, corn, and scale).This may be due to the fact that the term placebo, in certain of its applications, is far more of an "English" word (i.e., simulator), and in others is far more of a Latin word (i.e., a "pleaser"). This phenomenon is well known across English; e.g., the term index, as in index of a book, is an established English word (because we speak of the indexes of books), but the term index, as in mathematical index, is a Latin loan-word (because we speak of mathematical indices).

Origins of placebo (the simulator)

By the 8th century the Roman Catholic Church had established the final form and content of its Office of the Dead ritual.

This ceremony was designed to bring solace to the living just as much as comfort to the dead. As part of the ritual, the celebrant would recite certain extended passages from scripture (mainly from the Psalms). At the end of each recited passage, the congregation would make a specific response (antiphon) to each recitation. The celebrant’s first recitation was Psalm 116:1-9http://www.biblegateway.com/passage/?book_id=23&chapter=116&version=9 -- or, Psalm 114:1-9 in Septuagint versionSee Composition of the Book of Psalms -- and the congregation’s first responding antiphon was verse 9 of that Psalm.http://www.hebrewoldtestament.com/B19C116.htm#V9 or Green (1997), p.502.

The Roman Catholic Church had chosen Jerome’s first (circa 384) Greek-to-Latin version of the Vulgate as the source of the celebrant’s text, rather than his third (circa 405) Hebrew-to-Latin version.

The Psalms in his first version were translated directly into Latin from the Septuagint’s Greek text. The Psalms in his third version had been translated directly from the Hebrew text of his day into Latin.The Septuagint had been translated from Hebrew into Greek, some seven centuries earlier, specifically for lodgement into the Library of Alexandria. The numbers of the Psalms are different in each of Jerome’s version, because they were numbered differently in his Septuagint and Hebrew sources. See Composition of the Book of Psalms

There is a significant difference in the Septuagint Psalm’s 114:9’s* Rahlfs (1935), p.128. Latin translation, "placebo Domino in regione vivorum"http://www.drbo.org/lvb/chapter/21114.htm ("I will please the Lord in the land of the living"), and the Hebrew Psalm's 116:9’shttp://www.hebrewoldtestament.com/B19C116.htm#V9 Latin translation, "ambulabo coram Domino in regione vivorum" ("I will walk before the Lord in the land of the living"Colunga & Turrado (1965), p.553 displays both the Greek to Latin version of the Septuagint’s Psalm 114, and the Hebrew to Latin version of Psalm 116 side by side. Scholars are divided on whether the Septuagint translators were attempting to provide a more poetic translation, or whether, in using ευαρεστισω ("I shall be well pleased") instead of περιπετει ("I shall walk") they have provided a translation of an entirely different Hebrew text from the text that is accepted as the standard today. For example, the Christian scholar John Chrysostom (347 - 407) understood the Septuagint verse to mean that "those who had departed this life accompanied by good deeds . . . * abide forever in high honor" -- and it was from this perspective that he chose to read the Septuagint as saying "I shall be pleasing in the sight of the Lord in the land of the living" (Hill, 1998, p.87). See also Popper (1945), Shapiro (1968), Lasagna (1986), Aronson (1999), Jacobs (2000), and Walach (2003). -- which also matches the English of the King James Versionhttp://www.biblegateway.com/passage/?book_id=23&chapter=116&version=9) and the English version of the Islamic Zabur 116:9.http://www.al-kitab.org/al-kitab/zabur/Zabur_116.htm

In France, it was the custom for the mourning family to distribute largesse to the congregation immediately following the Office of the Dead ritual. As a consequence, distant relatives and other unrelated parasites would attend the ceremony, simulating great anguish and grief -- in the hope of, at least, being given a meal and something to drink.

This practice was so widespread that these parasites were soon recognized as the personification of all things useless; and were considered to be archetypical simulators. Because the grief simulators' first collective act was to chant "placebo Domino in regione vivorum" they were collectively labelled (in French) as either "Placebo Singers" or "Singers of Placebo"; and they were so labelled because they sang the word "placebo", not because they were "choral placaters", using their song to please.

In the light of all of the subsequent terminological confusion it is significant that, if Jerome’s third version of the Vulgate had been selected for the ritual’s text instead of the first -- or if the Septuagint’s translators had translated an entirely different Hebrew text -- the congregation’s first response would have been "ambulabo coram Domino in regione vivorum". As a consequence, the simulators would have been "Ambulabo Singers" or "Singers of Ambulabo".

By the time of Chaucer’s Canterbury Tales (circa 1386), the disparaging English expression placebo-singer, meaning a parasite or a sycophant, was well established in the English language.In Chaucer’s Parson’s Tale, for example, the Parson speaks of how flatterers -- those who continuously "sing Placebo" -- are "the Devil’s Chaplains". (Perhaps Charles Darwin had Chaucer’s Parson in mind when he wrote: “What a book a Devil's Chaplain might write on the clumsy, wasteful, blundering low and horridly cruel works of nature.”)

The English word placebo also denoted a sycophant, Chaucer’s Merchant’s Tale, which contains a character called Placebo, also includes other significantly named characters: January, the old, blind knight, with hair as white as snow; May, his beautiful, lusty, and extremely young wife (and, thus, a January-May marriage); Justinus (the noble man), his correct and thoughtful brother, who strongly advised against the marriage of January to May (which also involved a considerable transfer of money, land, and wealth to the young woman); and Placebo (the “Yes man”), his sycophantic, flattering brother, who never once raised objection to any of January’s thoughts, and actively supports January’s proposal. and it was this application of the word placebo that seems to have oriented those unaware of the term’s origins, over time, to the irrelevant fact that the Latin word placebo means "I shall please".

However, the first English meaning of "placebo" is simulator; and it denotes any thing that simulates any other thing (thus, A is a placebo, or simulator of B).

…for Distinction Sake, a Deceiving by Words, is commonly called a Lye, and a Deceiving by Actions, Gestures, or Behavior, is called Simulation… Robert South (1643-1716)South, 1697, p.525. Samuel Johnson thought so highly of South's definition, that he used it in the entry for simulation in his Dictionary of the English Language.

South was speaking of the differences between a falsehood and an honestly mistaken statement. The difference being that, in order for the statement to be a lie, the truth must be known -- and the opposite of that truth must have been knowingly uttered -- and, from this, to the extent to which a lie involves uttering deceptive words, a simulation involves the performance of deceptive actions, deceptive gestures, or deceptive behavior.

Thus, if a simulation is genuinely false, the real truth must be known in order for some other thing (i.e., other than the truth) to be presented in its stead; otherwise, one would not know what to offer up in simulation.Roger Bacon’s (1214-1294) essay Of Simulation and Dissimulation expresses somewhat similar views.

Origins of placebo (the morale-booster)

Hooper’s (1811) Quincy’s Lexicon-Medicum defines placebo as "an epithet given to any medicine adapted more to please than benefit the patient".

In the practice of medicine it had been long understood that, as Ambroise Paré (1510–1590) had expressed it, the physician’s duty was to "cure occasionally, relieve often, console always".i.e., "Guérir quelquefois, soulager souvent, consoler toujours".

According to Jewson, eighteenth century English medicine was gradually moving away from the patient having a considerable interaction with the physician -- and, through this consultative relationship, having an equal influence on the construction of the physician’s therapeutic approach -- and it was gradually moving towards that of the patient being the recipient of a far more standard form of intervention that was determined by the prevailing opinions of the medical profession of the day.Jewson (1974 & 1976).

Jewson characterizes this as parallel to the changes that were taking place in the manner in which medical knowledge was being produced;For more on the effect of the development of various types of medical technology see the effect of technology on the importance of medical signs. namely, a transition all the way from "bedside medicine", through "hospital medicine", to "laboratory medicine".Jewson (1976), p.227.

From this point of view, the last vestiges of the consoling approach to treatment are to be found in the administration -- often without any sort of adequate history being taken, or any sort of appropriate physical examination being madeCarter (1953), p.823. -- of the morale-boosting and pleasing remedies, such as the "sugar pill", electuary or pharmaceutical syrup;Cooper (1823, p.259), speaking of the application of "the compound decoction of the sarsaparilla" in cases of "irritable ulcer", noted that "some think it placebo; others have a very high opinion of its efficacy" and goes on to remark that when it is used "after the use of mercury, it diminishes the irritability of the constitution, and soon soothes the system into peace" (p.259, emphasis added). all of which had no known pharmacodynamic action.Shapiro (1968, p.656) expresses the view that this application of the term placebo was a form of positioning: "Introduction of the word placebo to describe a class of treatments not previously specified was an important development in the history of methodology and medicine."

Those doctors who provided their patients with these sorts of morale-boosting therapies -- which, whilst having no pharmacologically active ingredients, provided reassurance and comfort -- did so either to reassure their patients whilst the vis medicatrix naturæ (i.e., "the healing power of nature") performed its normalizing task of restoring them to health, or to gratify their patients’ need for an active treatment.Handfield-Jones (1953) expressed the view that "some patients are so unintelligent, neurotic, or inadequate as to be incurable, and life is made easier for them by placebo"; and, in the view of Platt (1947, p.307), "the frequency with which placebos are used varies inversely with the combined intellligence of the doctor and his patient".

To argue with a man, and especially with a woman, that there is little the matter with them might be thought injudicious, and to advise them to return at a more convenient occasion requires more time and resolution than writing out a prescription or administering a placebo. (Steele, 1891)Steele (1891), pp.277-278.

By contrast, Shapiro (1968) reports that many of his respondents expressed the opinion that, in cases such as these, it was wrong to think of the medication as inert:

If a placebo is prescribed by a physician because it is thought that it will help the patient, then it is a specific and therefore not a placebo [at all.Shapiro (1968), p.679.

An editorial in the British Medical Journal of 19 January 1952 warns that any failure of the placebo to affect the disorder for which the patient has presented for treatment may only serve to reinforce the patient's belief that they have a serious disease:

But it is a fallacy to suppose that an inactive medicine can do no harm. If prescribed in a perfunctory way for a patient needing explanation and reassurance it may increase faith in his disease rather than in the remedy, and a doctor who gives a placebo in the wrong spirit may harm the patient. (Anon, 1952, p.150)

More than sixty years ago, Pepper noted the significant fact that "there may be a time when during the carrying out of diagnostic tests it is undesirable to give potent medicine lest it interfere with the tests and yet the patient must be encouraged by treatment" (1945, p.411). He had this to say about the application of placebos in routine medical practice:

…there is a certain amount of skill in the choice and administration of a placebo. In the first place, it must be nothing more than what the name implies a medicine without any pharmacologic action whatever. Even a mild sedative is not a true placebo. Secondly, its name must be unknown to even the most inveterate patient who knows most drugs by name and is always quick to read the prescription. If the medicines named are familiar the type of patient who needs a placebo will promptly exclaim that this or that drug had been tried and "had not helped me" or "had upset my stomach". It is well if the drug have a Latin and polysyllabic name; it is wise if it be prescribed with some assurance and emphasis for psychotherapeutic effect. The older physicians each had his favorite placeboic prescriptions -- one chose Tincture of Condurango, another the Fluidextract * of Cimificuga nigra. Certainly this latter by its Latin name might be expected to have more supratentorial action than if one merely wrote for the Black Cohosh, and Condurango would be more efficacious than sugar of milk. Pepper (1945), p.411. Pepper's assertion that a placebo "must be nothing more than what the name implies" -- namely that it must be "a medicine without any pharmacologic action whatever" -- in order for it to be called a placebo, is most significant.

In 1953, Findley expressed the view that, provided the placebo was not "used as an instrument of deception, but as a technique for cementing the emotional bond which must attach doctor to patient if any form of treatment is to be really successful… was the most important weapon the physician has";Findley (1953), p.1826. specifically because "in proportion as this bond is firm, the [patient's need for drugs will likely diminish".Findley (1953), p.1824.

1n 1954, Leslie lamented the fact that physicians were losing their skill in applying placebos:

Because medicine has been so concerned with its scientific growth too little attention has been paid to advancing the art of medicine, to which therapy with placebos belongs, and consequently knowledge of the use of placebos has not progressed significantly.Leslie (1954), p.854. Also, Carruthers, Hoffman, Melmon & Nierenberg (2000):
In clinical practice, where a majority of patient visits are for conditions that cannot be explained on a pathophysiologic basis of for which no specific treatment is available, it is essential that physicians understand the concepts and principles of placebos and placebo effects and, when appropriate, use them correctly. (p.1268)

Origins of placebo (the useless)

"Heroic medicine" had begun to fall from favour long before research scientists such as Robert Koch, Louis Pasteur, Frederick Hopkins and Casimir Funk demonstrated that the presence or the absence of specific agents could cause specific diseases, and long before the chemical laboratory orientation of Abraham Flexner’s 1910 Flexner Report had evolved into the evidence-based medicine of the 1970s.

As the earliest precursors of modern, scientific, conventional medicine began to emerge, medical scholars began to routinely question:

In many cases, active agents were identified within supposedly efficacious treatments; such as salicylic acid within decoctions of willow bark, which eventually led to the production of the drug aspirin.

However, it was also apparent that certain other treatments, such as the treatment of syphilis with salves made from mercury, had no efficacy whatsoever; and, regardless of the level of their acceptance within the medical profession, or the curative intentions associated with their administration, they were medically useless.Many, such as Pepper (1945) would strongly argue that, prior to the Countess of Chinchón's learning of the medicinal properties of cinchona bark -- perhaps the first occasion upon which a real active ingredient had been isolated and identified -- that "there was * basis for terming anything a placebo" (p.410).

It was these sorts of useless decoctions, drugs, treatments, remedies and procedures that were given the pejorative label placebo -- the second edition of Motherby’s (1785) New Medical Dictionary defines placebo as "a common place method or medicine".N.B.: not "a common place method of medicine" as is often misquoted.

Because this usage does not appear in English -- or in any English, French, German, Italian, or Portuguese dictionary -- prior to Motherby’s 1785 edition, Shapiro (1968, pp.656-657) is certain that this pejorative use of placebo was actually coined by Motherby.The fact that Samuel Johnson's 1755 Dictionary of the English Language has no entry for placebo, or for placebo-singer, or for singer of placebo, strongly supports Shapiro's contention.

Origins of placebo (the simulator in a clinical trial)

The aim of a clinical trial is to determine what treatments, delivered in what circumstances, to which patients, in what conditions, are the most efficacious;Gaddum (1953):

The first object of a therapeutic trial is to discover whether the patients who receive the treatment under investigation are cured more rapidly, more completely or more frequently, than they would have been without it. (p.195) as well to obtain objective evidence of what treatments are efficacious and specific (i.e., rather than just being efficacious),Chambless & Hollon (1998) or are intentionally efficacious and specific (i.e., rather than being just intentionally efficacious or inadvertently efficacious)Lohr, Olatunji, Parker & DeMaio (2005).

In pursuit of these goals, 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), or simply serendipitous effects of treatment (i.e., effects of the subject just being "in therapy").Perlman (2001). In discussing the "unrecognized serendipitous effects of being in therapy", Perlman (p.283) suggests the following as examples: the "organizing effects of the therapeutic structure", "inadvertent role modeling", "outside knowledge of the therapist", "chance remarks or encounters", and "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 1747, James Lind (1716-1794), the Naval Surgeon on HMAS Salisbury, conducted what was most likely the first-ever clinical trial when he investigated the efficacy of citrus fruit in cases of scurvy.

He randomly divided twelve scurvy patients, whose "cases were as similar as I could have them", into six pairs. Each pair was given a different remedy.According to Lind’s 1753 Treatise on the Scurvy in Three Parts Containing an Inquiry into the Nature, Causes, and Cure of the Disease, Together with a Critical and Chronological View of what has been Published of the Subject, the remedies were: (a) one quart of cider per day, (b) twenty-five drops of elixir vitriol (aromatic sulphuric acid) three times a day, (c) two spoonfuls of vinegar three times a day, (d) a course of sea-water (half a pint every day), (e) two oranges and one lemon each day, and (f) an electuary (Dunn, 1997, p.F65). According to Gaddum (1954, p.196) the electuary had been recommended to Lind by a hospital surgeon, and it contained garlic, mustard, balsam of Peru, and myrrh. He noted that the pair who had been given the citrus were so restored to health within six days of treatment that one of them returned to duty, and the other was well enough to attend the rest of the sick.Dunn (1997), p.F65. Lind’s approach can still be seen in the way that the comparative efficacy of various treatments for particular sorts of cancer are determined, by examining and comparing the five year survival rates of those who have been treated with each of the different interventions.

In 1784, the French Royal Commission into the existence of animal magnetismNote that using the (conventional) English term animal magnetism to translate Mesmer's magnétism animal is extremely misleading for three reasons:

1. Mesmer chose his term to clearly distinguish his variant of magnetic force from those which were referred to, at that time, as mineral magnetism, cosmic magnetism and planetary magnetism.
2. Mesmer felt that this particular force/power only resided in the bodies of humans and animals.
3. Mesmer chose the word "animal", for its root meaning (from latin animus = "breath") specifically to identify his force/power as a quality that belonged to all creatures with breath; viz., the animate beings: humans and animals. investigated the practices of Charles d’Eslon (1739-1786);It did not examine the practices of Franz Mesmer. It examined the significantly different practices of his associate Charles d’Eslon. and compared the effects of his allegedly magnetized water with that of plain water.Gauld (1992), p.28.

In 1799, John Haygarth investigated the efficacy of Perkins tractors -- they were called "tractors" because they were drawn across the skin -- by comparing the results from dummy wooden tractors with a set of allegedly "active" metal tractors. Green, (2002); Haygarth (1801).

It was not until 1863 that Austin Flint (1812–1886) conducted the first-ever trial that directly compared the efficacy of a dummy simulator with that of an active treatment; although Flint's examination did not compare the two against each other in the same trial. Even so, this was a significant departure from the (then) customary practice of contrasting the consequences of an active treatment with what Flint described as "the natural history of untreated disease".Flint (1863), p.18.

Flint’s paper is the first time that either of the terms "placebo" or "placeboic remedy" were ever used to refer to a dummy simulator in a clinical trial.

…to secure the moral effect of a remedy given specially for the disease, the patients were placed on the use of a placebo which consisted, in nearly all of the cases, of the tincture of quassia, very largely diluted. This was given regularly, and became well known in my wards as the placeboic remedy for rheumatism.Flint (1863), p.21. Flint treated 13 hospital inmates that had rheumatic fever; 11 were "acute", and 2 were "sub-acute". He then compared the results of his dummy "placeboic remedy" with that of the active treatment’s already well-understood results (Flint had previously tested, and reported on, the active treatment’s efficacy). There was no significant difference between the results of the active treatment and his "placeboic remedy" in 12 of the cases in terms of disease duration, duration of convalescence, number of joints affected, and emergence of complications (pp.32-34). In the thirteenth case, Flint expressed some doubt as to whether the particular complications that had emerged -- namely, pericarditis, endocarditis, and pneumonia -- would have been prevented if that subject had been immediately given the "active treatment" (p.36).

Origins of placebo (the benefactor)

Origins of the "placebo effect"

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".Graves (1920) p.1135.

In 1933 (Evans and Hoyle) and in 1937 (Gold, Kwit and Otto), two studies were published which compared the outcomes from the administration of an active drug and a dummy simulator (which both research groups explicitly called a placebo) in the same trial.Evans & Hoyle's (1933) study involved 90 subjects. Gold, Kwit & Otto's (1937) study involved 700 subjjects.

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. However, in accounting for the fact that 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.Gold, Kwit & Otto (1937), p.2177.

In 1938, Diehl, Baker and Cowan reported the results of a two year study that they had conducted over a two year period into the efficacy of injected vaccines in prevention of colds.

Whilst their experimental group showed a significant reduction in the number of colds per person per year, the placebo control group reported the same magnitude of reduction as the vaccinated group.Diehl, Baker, & Cowan, D.W. (1938), p.1171.

This finding was significant, because they also found that their observed level of reduction in the number of colds per person per year matched that of other "uncontrolled studies"; which, given the demonstrated level of placebo responses, meant that "there is no evidence in this study… that vaccines reduce the complications of colds… in a cold-susceptiible group".Diehl, Baker, & Cowan, D.W. (1938), p.1173.

By 1948, the term placebo effect was so widely established that an Egyptian physician could write to The Lancet, reporting that:

The success achieved in 83% of cases cannot by any means be ascribed to suggestion or to a placebo effect.Ayad (1948), p.305.

In 1949, Wolf conducted a series of investigations into the "measurable "drug effects" that are not attributable to the chemical properties of the agents administered".Wolf (1950), p.100. Wolf contrasting what he called drug effects with what he called placebo effects.

He noted the extent to which the ""placebo" actions depended for their force on the conviction of the patient that this or that effect would result".Wolf (1950), p.106. He drew attention to the impressive frequency and magnitude of these placebo actions and placebo effects and how they could mimic, mask, potentiate or prevent beneficial responses to the active drugs. He also stressed that all of these placebo actions and placebo effects, "which * inert agents with potency" were associated with real and substantial physiological changes; and, therefore, they were not imaginary. His study also revealed that the action of a drug could be nullified or, even, reversed in the presence of emotional states such as anger, hostility or resentment.

He also observed that "these effects at times more potent than the pharmacologic action customarily attributed to the Wolf (1950), pp.108-109. and spoke of the well-established understanding "that the mechanisms of the body are capable of reacting not only to direct physical and chemical stimulation but also to symbolic stimuli, words and events which have somehow acquired special meaning for the individual",Wolf (1950), p.108. in the hope that, "in the future drugs will be assessed not only with reference to their pharmacologic action but also to the other [psychodynamic" target="_blank" >* forces at play and to the circumstances surrounding their administration".Wolf (1950), p.100.

Origins of placebo response/reaction

In 1946, the Yale biostatistician and physiologist E. Morton Jellinek was the first to speak of either a "placebo reaction" or a "placebo response".Jellinek (1946) 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. It is also significant that, despite the fact that Beecher's 1955 paper The Powerful Placebo does speak of placebo effects on, perhaps, five occasions -- and, on each of these occasions, these placebo effects are specifically contrasted with drug effects -- his paper constantly speaks of "placebo reactors" and "placebo non-reactors". Also, 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".

In post-World War II 1946, pharmaceutical chemicals were in short supply. One U.S. headache remedy manufacturer sold a drug that was comprised of three different ingredients: a, b, and c. Chemical b was in short supply.

Jellinek was asked to test whether or not the headache drug's overall efficacy would be reduced if ingredient b was missing.

Jellinek set up a complex trial involving 199 subjects, all of whom suffered from "frequent headaches".Originally there were 200 subjects, but one did not complete the trial. The subjects were randomly divided into four test groups. He prepared four test drugs, involving various permutations of the three drug constituents, with a placebo as a scientific control. The structure of this trial is significant because, in those days, the only time placebos were ever used "was to express the efficacy or non-efficacy of a drug in terms of "how much better" the drug was than the "placebo".Jellinek (1946), p.88. Note that the trial conducted by Austin Flint is an example of such a drug efficacy vs. placebo efficacy trial. The four test drugs were identical in shape, size, colour and taste:

  • Drug A: contained a, b, and c.
  • Drug B: contained a and c.
  • Drug C: contained a and b.
  • Drug D: a simulator', contained "ordinary lactate".

Each time a subject had a headache, they took their group’s designated test drug, and recorded whether their headache had been relieved (or not).Despite the fact that "some subjects had only three headaches in the course of a two-week period while others had up to ten attacks in the same period", the data showed a "great consistency" across all subjects (Jellinek, 1946, p.88) Every two weeks the groups’ drugs were changed; so that by the end of eight weeks, all groups had tested all the drugs.The stipulated drug (i.e., A, B, C, or D) was taken as often as necessary over each two-week period, and the two week sequences were:

(1) A, B, C, D; (2) B, A, D, C; (3) C, D, A, B; and (4) D, C, B, A.

Each group took a test remedy for two weeks. The trial lasted eight weeks, and by the end of the trial all groups had taken each test drug for two weeks (although each group had taken them in a different sequence). Over the entire population of 199 subjects, 120 of the subjects responded to the placebo, and 79 did not; i.e., there were 120 "subjects reacting to placebo" and 79 "subjects not reacting to placebo".Jellinek (1946), p.89.

At first glance there was no difference between the self-reported "success rates" of Drugs A, B, and C (84%, 80%, and 80% respectively);The "success rate" of the simulating, placebo Drug D was 52%. and, from this, it appeared that ingredient b was completely unnecessary. However, in quite a remarkable way, the trial eventually did demonstrate that the chemical in question did make a significant contribution to the remedy’s efficacy.

Examining his data more closely, Jellinek discovered that there was a very significant difference in responses between the 120 placebo-responders and the 79 non-responders. The 79 non-responders' reports showed that if they were considered as an entirely separate group, there was a significant difference the "success rates" of Drugs A, B, and C: viz., 88%, 67%, and 77%, respectively. And because this significant difference in relief from the test drugs could only be attributed to the presence or absence of ingredient b, he concluded that ingredient b was essential (thus contradicting his initial conclusion, derived from the comparison between the "success rates" for all test subjects, that Drugs A, B, and C were equally efficacious).

There were two further repercussions from this trial:

  • Jellinek (p.90), having identified 120 "placebo reactors", went on to suppose that all of them may have been suffering from either "psychological headaches"With or without attendant "hypochondriasis" (p.90). or "true physiological headaches were accessible to suggestion". Thus, according to this view, the degree to which a "placebo response" is present tends to be an index of the psychogenic origins of the condition in question.Lasagna, Mosteller, von Felsinger & Beecher (1954), p.777.

  • It indicated that, whilst any given placebo was inert, a responder to that particular placebo may responding for a wide number of reasons unconnected with the drug's active ingredients; and, from this, it could be important to pre-screen potential test populations, and treat those manifesting a placebo-response as a special group, or remove them altogether from the test population.

Origins of the "psychoactive placebo"

In his account of his 1962 Marsh Chapel Experiment in his unpublished Ph.D. dissertation,Drugs and Mysticism: An Analysis of the Relationship between Psychedelic Drugs and the Mystical Consciousness, submitted in 1963, for his Ph.D. in Religion and Society at Harvard University. Timothy Leary was the principal academic advisor for his dissertation. Walter Pahnke speaks of administering capsules that contained 30mg of psilocybin extracted from psychoactive mushrooms, and contrasting their effects with those of psychoactive placebos.

These "psychoactive placebos" 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, in fact, received the psychoactive drug. Although the term "psychoactive placebo" is rare in the literature, it always denotes a placebo of this type.For example, "Neither the experienced investigator nor the naive * is easily foooled 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)

Origins of the "placebo ritual"

Ambiguity of medical usage

Ambiguity of anthropological usage

See also

Notes

References

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