Opium: Explorations of an Ambiguous Drug - Brill

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Opium:

Explorations of an Ambiguous Drug

Introduction

Since at least the 1960s, when increasing drug abuse became an issueof political and public concern in the West, the history of opium hasbeen of considerable interest. As in other areas of historicalinvestigation inspired by today’s problems, the focus tended to be onprecursor stages or roots of present phenomena, i.e., attention wasdevoted mainly to earlier perceptions of the drug’s psychotropic andaddictive properties, and to medical and social responses to this. Theby now classical study in this field was published in 1962/63 by GlennSonnedecker, who gave an overview of the development of the conceptof opiate addiction from the sixteenth to the twentieth century.Sonnedecker documented Western knowledge about the dangers ofhabitual consumption of the drug since the Renaissance, mainly fromreports of travellers to countries of the Near, Middle and Far East aboutindigenous opium-eaters. Yet he also pointed out that an awareness ofopium addiction as a serious medical or even social problem could notbe found in the West before the nineteenth century.1 This wasconfirmed by John C. Kramer in a brief survey of the medical uses andmisuses of opium in Western countries during the seventeenth andeighteenth centuries, and more recently in a comprehensive study ofthe history of opium addiction by Margit Kreutel.2

Accordingly most of the scholarly work on historical aspects ofopium has been devoted to developments from the late eighteenth orearly nineteenth century onwards, when the non-medical,recreational use of the drug became popular in the Western world.Alethea Hayter’s book on opium-eating writers of the Romanticperiod, such as Samuel Taylor Coleridge and Thomas De Quincey,3

was followed in the 1980s by detailed studies into the social historyof opium consumption in nineteenth- and twentieth-century Britainand North America by Virginia Berridge, Terry M. Parssinen, andDavid Courtwright. They elucidated changes in the publicperception of addiction and the beginnings of modern drug control.4

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The Chinese opium wars (1840-42 and 1856-58) have of coursefound their historians as well.5

Compared to this body of historical knowledge on issues related toopium addiction and recreational consumption, only a little disparatework has been done on the history of the therapeutic uses of the drugand on the develpoment of pharmacological knowledge about it. Theexisting studies into opium therapy have usually concentrated on somespecific aspect or period. Most recently, John Scarborough hasexamined the knowledge about opium in Hellenistic and Romanmedicine, especially as documented in the materia medica ofDioscorides. J. Worth Estes investigated the potency and contents ofseventeenth-century opium preparations on the basis of data publishedby the English physician John Jones in 1701. And Andreas NiklausBindler traced attitudes towards the use of opium as a painkiller asreflected in a number of German and Swiss medical inauguraldissertations of the seventeenth and eighteenth centuries. Luzius vonRechenberg and Huldrych M. Koelbing looked into the opium therapyof Christoph Wilhelm Hufeland, who introduced the term“Opiumsucht” (opium addiction) in 1829. The psychopharmacologicaluse of opium in nineteenth-century German psychiatry has beenreviewed by Matthias M. Weber. Finally, some insights into its moregeneral medical usage in the nineteenth century have been provided byJohn S. Haller Jr. on the basis of articles in Anglo-American medicaljournals.6

Studies of Brunonian therapeutics, such as those by Verena Jantzand Guenter B. Risse, have discussed opium, since John Brown andhis followers regarded it as the strongest stimulant and applied ittherefore frequently in so-called asthenic diseases. Recently ClaudiaWiesemann has argued that the genesis of the modern concept ofdrug addiction around 1800 was closely linked with Brownianism. 7

Finally, some historical accounts of concepts of pain have touchedupon opium as an analgesic.8

As for the history of the pharmacology of opium, some pertinenteighteenth-century experiments have been described and analysed inthe early 1960s by Melvin P. Earles, particularly those which dealtwith the question whether the drug acted directly on the nervoussystem or indirectly via absorption into the blood.9 After Earles’ workthis area attracted only scant interest of historians, however. In the1970s Rolf Winau reviewed some trials with opium in his account ofexperimental pharmacology and toxicology in the eighteenthcentury, and Claire Salomon-Bayet drew attention to auto-experiments with the drug by the seventeenth-century pharmacist

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Moyse Charas.10 Another survey by John C. Kramer, published in1980, dealt with the isolation of the opium alkaloids (especiallymorphine) in the early nineteenth century and the subsequentmedical use and abuse of opiates. This was followed by a short paperby Ronald K. Siegel and Ada E. Hirschman, in which they citedexcerpts from the extensive pharmacological self- and animalexperiments with opium, morphine, and narcotine carried out in1826 by the French physician Pierre-Alexandre Charvet.11 Onlyrecently has the topic been taken up again by the present author withan overview of experimental research on opium in the eighteenthcentury and a brief study into self-experiments in this field duringthe same period.12

This chapter aims at providing a more comprehensive picture andbetter understanding of early pharmacological experimentation withopium and its implications. In particular, it looks into thecontemporary leading questions in this area, the methods employedin answering them, the relevance of experimental results forpharmacological theories as well as for therapeutic practice, and alsointo some ethical considerations. The period under study begins inthe second half of the seventeenth century, when concerns amongdoctors about the safety of opium therapy were coupled with a stronginterest in the drug’s pharmacological properties, leading to firstexperiments. It ends in the early nineteenth century, when theisolation of morphine and other opium alkaloids gave new directionsboth to therapeutics and pharmacology.

The Medical Importance of Opium

Though well known as a powerful substance since antiquity, opiumbecame a very widely used remedy in the West only in theseventeenth century.13 Thomas Sydenham’s dictum that withoutopium medicine would be a “cripple” has often been referred to inthis context.14 This qualitative statement had its counterpart in thenumber of pertinent publications. In the part on plants (1787) in hisSystematisch-Literaerisches Handbuch der Naturgeschichte, GeorgRudolph Boehmer, “senior” of the University of Wittenberg, listedinternationally 76 monographs and 73 articles dealing specificallywith opium or poppy plants (papaver) since the early seventeenthcentury.15 In view of these numbers one may well agree with recentauthors, who have referred to an opium or opiology literature as agenre of medical writing.16 On the other hand, my systematic analysisof the Philosophical Transactions of the Royal Society of London, from1700 to 1800, and of the leading Edinburgh medical journals of this

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time, at first glance seems to arrive at a different result. ThePhilosophical Transactions had just one article (published in 1701)specifically on opium in the whole eighteenth century. Of theEdinburgh journals, Medical Essays and Observations (1733-44) andEssays and Observations, Physical and Literary (1754-71) eachpublished three, Medical (and Philosophical) Commentaries (1773-95)two, and Annals of Medicine (1796-1800) one such article during theperiods stated.17 These rather small numbers (compared to otherpharmacological and therapeutical topics, such as lithontriptics,mineral waters, and Peruvian bark) should not be taken, however, asrepresenting a relatively minor importance of opium in theeighteenth century. Some of the articles, such as those by theEdinburgh professors Charles Alston, Robert Whytt, and AlexanderMonro secundus, were major studies into the pharmacology of thedrug, that were quoted, translated, and discussed internationally.18

Other articles reported cases of poisoning or some unusualphenomenon or remarkable success in therapy with opium.19 Thismay in fact be seen as reflecting a widespread medical use of the drug,so that – apart from the scientific, experimental studies – only some“extraordinary” practical observations were published in thosejournals. Reports on contemporary efforts to produce opium inBritain (chiefly in order to solve the problem of varying strength andquality, which existed in the customary opium imported fromOriental countries) point in the same direction.20

While there is agreement in the secondary literature about themedical importance of opium during the seventeenth and eighteenthcenturies, different explanations have been given why it may havegained this prominence. In an essay published in 1971 RichardToellner argued that with Cartesian dualism pain was re-evaluated inthe seventeenth century. It was no longer seen as a God-given evil,following from the original sin, but as a corporeal symptom, whichcould be accepted as a useful warning sign in diseases, yet also befought and eliminated with bodily means.21 On this basis Andreas N.Bindler and Ulrich Tröhler have looked into the use of opium as apainkiller in the late seventeenth and early eighteenth centuries. Theysuggest a link between a liberal use of opium and an empiricalattitude in therapeutics (inclined to purely symptomatic treatment),which was combined with an anatomical understanding of disease.While they found this view reflected in medical dissertations at theUniversity of Basle, medical faculties still largely devoted to Galenichumoral pathology, such as Altdorf and Jena, appeared to bereluctant to give much space to opium in therapeutics. After all, it

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was hard to integrate into their therapeutic system. Opium was onlyin part an evacuant medicine: it was known to be a diaphoretic(sudorific), but on the other hand it stopped or diminisheddiarrhoea, vomiting, and cough (expectoration), thus being an anti-evacuant as well. Yet also the followers of either Friedrich Hoffmann’siatromechanical system or of Georg Ernst Stahl’s “animism” in Hallewere rather critical towards opium therapy, preferring – as Bindlerhas argued – intervention into the assumed causes of disease tosymptomatic measures.22

While Bindler and Tröhler made therapeutic empiricismresponsible for a more permissive medical use of opium since theseventeenth century, Kreutel emphasized from a pharmaceuticalperspective the contemporary belief in the ability to “correct” theharmful powers of the drug by admixing “contrary” substances. Inaddition, she linked the increase in the use of opium preparationswith the rise of the iatrochemical school, which advocated the use ofthe drug in the tradition of Paracelsus’ famous “laudanum” (thoughhis original recipe probably did not contain opium).23 In fact, thesame point had been made already at the beginning of the lastcentury by the medical historian Kurt Sprengel:

Incontestably the chemiatric school of the seventeenth century hasthe merit of having promoted and more generally recommended thisexcellent remedy {i.e. opium}, while it was decried by the Galenistsas a cooling agent, which thickens the humours.24

These historical interpretations lead us to the question of seventeenth-and eighteenth-century theories of the modus operandi of opium andtheir possible influence on therapeutic practice. In connection withthis we need to explore to which extent and how these theories wereshaped by experimental work with the drug – a topic, which has, withthe exception of Earles, virtually been left untouched in the secondaryliterature. The following sections are meant to provide some insightsinto these aspects of the history of opium.

Seventeenth-Century Views on the Pharmacology of Opium and Their Basis

As in other areas of medicine, such as anatomy and physiology,traditional, Galenic knowledge started to be questioned in themateria medica of the seventeenth century. This applied particularlyto opium. Traditional doctrine, going back to Dioscorides andGalen, taught that opium had a strongly cooling and drying effect,which led to a thickening of the humours, diminution or loss of

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sensitivity, and sleep.25 The inconsistencies of this view were nowsharply exposed by iatrochemists, most notably by van Helmont. Hepointed out that opium had, as everyone agreed, a bitter taste.According to the Galenic doctrine of qualities, however, bitterness asa secondary quality was a sign of excessive warmth as a primaryquality. In fact from the sixteenth century onwards some medicalauthors, such as Pierandrea Mattioli, Felix Platter, and MichaelDöring, had attributed a warm quality to opium.26 How then, askedvan Helmont, could this drug be hot and cold at the same time?27

Moreover, other anodynes (i.e. pain-relieving substances), such ashyoscyamus and mandrake, were not bitter, or were even sweet, e.g.“vitriol and sulphur” (i.e. probably ether). Some plants traditionallyregarded as having a cooling quality, such as nightshades (solanacea),made people “mad”, but they did not induce sleep.28 Even if opiumwas cooling, how could its cold drive narcotic vapours up to thehead? And if it could, how could these vapours penetrate the densesubstance of the brain and spinal marrow to reach the origins of thenerves and block their openings?29 Van Helmont concluded that thedoctrine of primary qualities in remedies (i.e. hot, cold, wet, dry) andthe old method of predicting the effects of a substance from its tastewere wrong, even “ridiculous”. Instead he suggested that opiumcontained a specific, hypnotic “bitter oil” or “sulphur”, combinedwith an “acrid, sudorific salt”.30

Whether these chemical characterizations had a material basis in adetailed chemical analysis of the drug, or whether they were usedmore symbolically in the language of the Paracelsians, cannot bedecided from the text.31 Also, van Helmont’s idea of the mode ofaction of opium was rather vague and only loosely connected with hischemical interpretation. In diseases caused by an enraged archeus (vanHelmont’s personified vital principle) opium helped by calming himdown. On the other hand van Helmont warned against using opiumto induce sleep, for it had not only a hypnotic but also a poisonouscomponent, which could cause “confusions and impetuousness”.32

Still, the importance of his critique lay in its demand for a new,chemical understanding of opium and other drugs. Writers on opiumin the second half of the seventeenth century followed his line,rejecting explanations with Galenic primary qualities. Likewise, theywould not accept any longer the doctrine of super-elementary, occultqualities in drugs and poisons, which also went back to Galen andhad been propagated recently by the Wittenberg professor DanielSennert (1572-1637).33 It was usually assumed now that opiumcontained a specific, effective chemical principle. In agreement with

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van Helmont it was also referred to as a volatile “fetid sulphur”combined with an “acrid salt”.34

Disagreement arose, however, over the precise nature of this activeprinciple and especially how it acted on the body. A commonspeculation was that it somehow hindered the flow of the spiritusanimales in the nervous system by binding, fixing, condensing,coagulating, or actually destroying them. Painlessness, sleep, and thestoppage of excretions were thought to result from this. Sweating wasseen as an indirect effect, following from relaxed, dilated pores.Actually this view was not too far away from the traditional Galenicidea of a cooling effect of opium. But it was couched in the terms ofcontemporary physiology and was held by prominent iatrochemists,such as Thomas Willis (1621-75) in Oxford, Franciscus de le Boë(1614-72) in Leyden, Michael Ettmüller (1644-83) in Leipzig, andGeorg Wolfgang Wedel (1645-1721) in Jena.35 Yet, in the lateseventeenth century some authors started to formulate differentconcepts of the modus operandi of opium, arguing that it had an effecton the blood as well, or that it acted even primarily on the blood.

A methodical precondition for these ideas had been thedevelopment of intravenous injection in the 1650s and 1660s.36 Infact some pioneers of this new technique had used opium solutionswhen trying it out on animals. In probably the first recordedexperiment of this kind, in 1656, Christopher Wren (1632-1723)and Robert Boyle (1627-91) injected a warm solution of opium intothe crural vein of a large dog. The animal soon “began to nod withhis head, and faulter and reel in his pace, and presently after appearedso stupified, that there were wagers offered his life could not besaved.”37 In animal experiments of the same kind, Thomas Willis andthe Germans Johann Daniel Major (1634-93) and Johann SigismundElsholtz (1623-88) induced drowsiness and sleep with injections ofopium. The latter convinced himself of the drug’s hypnotic andanalgesic effect with simple tests. His experimental animal being ahound, he tried to wake him up by shouting hunting commands,and occasionally he pricked the sleeping dog’s tongue or leg with aneedle. Less carefully, and as Willis had done before, WilliamCourten (1642-1702) beat and whipped a dog that had been putinto deep sleep with a high intravenous dose of opium.38 It should benoted, however, that these initial experiments had not beenperformed to explore the pharmacology of the drug. Rather they hadbeen concerned with the new method of application, and theobserved effects had been relevant insofar as they were principally thesame as those after oral administration (which were well-known from

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medical practice). Yet, towards the end of the seventeenth centuryintravenous injection became a tool for investigating the nature andmode of action of opium.

In 1693 the student Samuel Schroeer presented his thesis to themedical faculty of Erfurt. Though conventional in its title, De opiinatura et usu, it reported some original experiments. The student hadinjected half a drachm of “fetid oil of opium” into the jugular vein ofa dog. Dissecting the animal some hours later, he found the auriclesand ventricles of the heart filled with coagulated blood. Repetitionsof the trial on three more dogs, including injection of “fetid oil ofhorn” as a comparable substance, led to similar effects. The“sulphuric” parts, believed to be contained in both these oils, thusrather “placated and sedated” the movement of the blood thaninciting it, ran the conclusion.39 Additional in vitro tests led Schroeerto assume that the bitter taste of opium was due not to a “volatilesulphuric salt” (in the sense of van Helmont and his followers), butan “acid sulphuric principle”40: solutions of opium in water as well asin alcohol effervesced and precipitated when alkaline spirits wereadmixed, but not when acids were added. Also, a watery solution ofthe drug coagulated blood serum and milk like other acids.41 Goingone step further, he argued that the “acid-sulphuric particles” werethe actual narcotic agents in opium, adducing the indirect evidenceof more animal experiments. “Fetid oil of opium”, thought to lackthe acid component, caused vomiting and salivation, but failed toinduce sleep, when given orally to a cat, even in a sufficiently largequantity. A solution of the whole drug in water, however, given to thecat some days later in a smaller dose, made the animal sleep for anentire day, and this effect was confirmed in experiments on dogs.When mixed with spirit of wine (alcohol), a watery solution ofopium became even more effective – because of an increase in itsacidity, as Schroeer thought. Such a mixture injected into the cruralvein of a dog initially caused convulsions, followed quickly by a stateof narcosis, which ended – with respiration and heart action failingafter half an hour – in the animal’s death.42

On the basis of these chemical and pharmacological experimentsSchroeer formulated his own theory of the modus operandi of opium.Taken orally and dissolved by the acid gastric juice, its “sulphuricparticles” first “stifled and bound” the nutritive spiritus naturales,and then – because of the mutual connection between stomach andbrain – affected the whole nervous system. Meanwhile, however, theyalso coagulated the blood, and some particles of the drug were carriedwith the blood circulation to the head. They entered the ducts of the

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brain, slowed down and suppressed the cerebral circulation and thusput the spiritus animales to rest as well. “As a subject, on whichopium acts, we declare both the spiritus and the blood”, concludedSchroeer.43

In support of his thesis that the blood was equally affected helisted five “proofs”. The first was that his experiments withintravenous injection in dogs had produced the same effects as wereknown from oral taking in man, thus suggesting action on, or via, theblood. While this followed clearly from his experimental work, theother four “proofs” were given almost as afterthoughts. Whenhandling opium in distillation or preparation of solutions,“exhalations” had hurt and inflamed his eyes, and he had notedincreased diuresis in himself while occupied with this work. Thediaphoretic power of opium was well known, as he pointed out, andfinally, he had observed in three dogs that it killed their worms.According to contemporary understanding, all these effects could beexplained with one uniform cause, namely coagulation of the bloodand other humours, and they therefore strenghtened Schroeer’spoint. In a self-confident manner he thus finished his considerations:“In conclusion, opium not only acts on the spiritus, as Ettmüllerholds to have convinced himself so very well…”44

Yet, seen as a whole, Schroeer’s criticism of the conventionaliatrochemical view of opium was rather moderate. He had changedthe Helmontian chemical interpretation more in detail than inprinciple, and his pharmacological theory rather enlarged thanradically altered the previous ones of Ettmüller and others. After all,Schroeer’s experimental work and his arguments belonged to thesame intellectual framework: iatrochemistry. Less than ten years later,however, representatives of the iatromechanical school came forwardwith a new theory of opium, which in fact challenged and eventuallyreplaced the usual idea of spiritus being fixed or bound.

Iatromechanical Interpretations around 1700

The first in a small series of publications, offering a new, mechanicalunderstanding of the effects of opium, came from the school of theHalle professor of medicine Friedrich Hoffmann (1660-1742), themost prominent proponent of iatromechanics on the Continent atthe time.45 In his inaugural dissertation of 1700, Hoffmann’s pupilJacob Descazals critically discussed current pharmacological theoriesof the drug, such as the traditional notion of its cold quality, themodern views of Willis, Ettmüller, and Wedel on its interaction withthe spiritus animales, as well as the ideas of the Kreuznach physicus

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Johann Peter Gladbach (1647-1701) and the Cartesian TheodorCraanen (1620-90), who had suggested, similar to Schroeer,additional effects on the blood.46

Gladbach believed that the “volatile salt” and “thick oil” of opium“wrapped up” the spiritus vitales in the blood, so that less and thickerspiritus animales were produced in the brain, leading to obstructionof their flow in the nerves and slowing down of heart action. Craanenhad assumed that the “spirituous and volatile parts” of the drugcoagulated the blood, which would eventually cause sopor, and thatits “acrid volatile salt” further made the nerve fibres loose theirtension, resulting in a failure of sensation and thus painlessness.None of these theories, maintained Descazals, could sufficientlyexplain all the known effects of opium. For instance, the drug wasknown as an aphrodisiac, and according to the travellers, Orientalsoldiers took it to become alert and courageous in battle. Sucheffects, however, required rather excitement of the spiritus than theirextinction. Moreover, if it was the acid property of the “sulphur” inthe drug that fixed the spiritus and coagulated the blood (as Schroeerand others had suggested), why was it, asked Descazals, that strongacids, such as oil of vitriol, concentrated spirit of vinegar, and spiritusnitri, did not act as narcotics? And if it was a “volatile oily salt” thatwas the analgesic and diaphoretic principle, as for example CornelisBontekoe (1640-85) had stated, why was it that the small amountsof it contained in opium (as well as in mandrake and nightshade)were so effective, but not volatile oily salts in general, even if given inlarge doses? Similar to van Helmont, Descazals furthermore doubtedthat a “sulphuric vapour” could penetrate the brain and obstruct thepores of the nerves. If it really reached the origins of the nerves, heargued, it should rather be dissipated through their pores.47

Instead Descazals referred to some clinical observations of histeacher Hoffmann, which had obviously given the clues for a newtheory. In patients who had taken opium the vessels of the headappeared turgid and swollen, their faces turned red, and sometimesnosebleeds followed. Moreover, those who suffered from “ardent andinflammatory fevers”, became delirious even from small doses of thedrug, yet their delirium subsided after prolonged bleeding. Followingthe opinions of Hoffmann, Descazals suggested that opiumcontained a “resolvable and evaporable sulphur”. Absorbed into thecirculation, this fine “sulphur” was thought to increase the expansionof the blood, when the latter was exposed to air during its passagethrough the lungs. The unnaturally thin, “rarefied”, “inflated” bloodthen overfilled and distended the arterial vessels of the brain, leading

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to impeded or stagnating cerebral circulation. All effects of opium,maintained Hoffmann’s pupil, could be explained in this way.Extravasated serum caused sleep, and, in larger quantity, severeheadache, torpidity, loss of memory, and amentia. The remaining,thicker blood, stagnating in the cerebral vessels, could lead toturbulent and frightful phantasms and even furious insomnia.Diminished cerebral circulation meant that less spiritus animaleswere generated in the brain. A lesser flow of the spiritus through thenerves resulted in painlessness and in relaxation of muscular spasms.Relaxed pores in turn allowed sweating. The activitity of the heart(believed to depend on the inflow of spiritus animales) decreased,which accounted for the weaker and slower pulse that was observableafter taking opium. The aphrodisiac effect was explained by therarefied, slowly circulating blood, which, by expanding the “muscles”of the penis, led to a long lasting erection. Finally, Descazals quotedpathological observations in those who had died of narcoticremedies: the ventricles of the brain were found filled withcoagulated blood. Also this seemed to support the idea of stagnatingcerebral circulation.48

Hoffmann’s and Descazals’ “rarefaction theory” of opium (as onemay briefly call it) was thus to a great extent a iatromechanicalspeculation, which rested on some clinical and pathological findings.In this respect it was not principally different from the conventional“spiritus animales theory” favoured by the iatrochemists. IndeedDescazals was cautious or diplomatic enough to admit at the veryend of his thesis that opiates and other narcotics might notexclusively act on the blood, but in addition also affect the spiritusimmediately.49 Yet, support for Hoffmann’s theory was provided threeyears later on an experimental basis by his colleague at the nearbyUniversity of Wittenberg, the medical professor Johann GottfriedBerger (1659-1736). Dissecting cats which had been poisoned orallywith opium, Berger and his student Christoph Fimmler observedthat the animals’ blood was “never coagulated, but more dissolved,serous and fluid”. Likewise, in opening the skulls of dogs that werestupified from intravenous injections of the drug, they found thecerebral vessels “turgid and distended”. When cut, “florid, thin andserous blood” flowed out. The same observation was made in theblood of the heart and other vessels.50 These findings clearlycontradicted the experimental observations made ten years earlier bySchroeer in Erfurt.

Like the Halle researchers, Berger and Fimmler concluded thatopium “rarefied” the blood. The distended blood vessels, they

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speculated further, compressed the fibres of the brain and ofadjoining nerves, and this led to an intermission of sensation andmotion. As they believed, too, all effects of the drug could beexplained with this theory. Not doing without reference to modernauthorities, they pointed out that Ole Borch had found thin, fluidblood in his animal experiments with the drug as well, and that therenowned iatromathematician Archibald Pitcairne (1652-1713) hadtaught a theory of opium similar to their own in his Leyden lecturesin the early 1690s.51 Strongly declaring themselves for mechanicalexplanations, it is not surprising that Berger and Fimmler alsoreferred to Hoffmann’s work on opium, albeit only briefly.52

The “rarefaction theory” of opium was propagated at the sametime, yet without overt reference to the Continental work, in Englandas well. In his work Emmenologia (1st edn 1703) the iatromechanistOxford physician John Freind (1675-1728) discussed medicineswhich would promote or inhibit menstruation by rarefying orcoagulating the blood, respectively. His methods to ascertain eitherquality of a substance included examination of its “sensible effects”(taste, smell, obvious physiological changes, such as acceleration of thepulse or increased body heat and sweating), in vitro trials on freshlydrawn blood, testing for acidity or alkalinity by admixing syrup ofviolets, and intravenous injection in living animals.

In the case of opium everything pointed to its being an“emmenagogum”, i.e. a remedy that would bring forwardmenstruation by attenuating the blood. Firstly, the drug had an acridand bitter taste, indicating a rich content of “volatile salt”, which wouldthin the blood. Secondly, when Freind mixed fresh arterial blood froma dog with Sydenham’s Laudanum Liquidum (a solution of opium inwine) or Dr Jones’s Liquid Panacea of Opium (solution in water), theblood appeared thinner and kept its shining red colour. Similarly,human serum became thinner, and stayed like this for a day or two,after those opium solutions had been added. Thirdly, an aqueoussolution of the drug turned syrup of violets green, which meant that ithad an alkaline quality. Alkalies were known to dissolve coagulatedblood. Finally, in a dog killed by intravenous injection of a very highdose of the Panacea of Opium, the Vena cava, the ventricles of theheart, and the descending aorta were found to contain thin and brightred blood without a trace of coagulation, and the lungs appeared redfrom turgid blood vessels. These observations were confirmed inanother dog, which had been poisoned orally with laudanum.53

Freind did not leave it at this experimental characterization ofopium as an emmenagogum. Like Hoffmann and Berger, he

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developed a comprehensive theory of the drug’s action based on itsrarefaction of the blood. Freind distinguished between effects after a“moderate” dose, e.g. stimulation of the heart and increasedperspiration, and effects after an excessive dose. As in Berger’s theory,turgid blood vessels were believed to compress nerves and the brain,leading eventually to the more severe symptoms of opiumintoxication, such as somnolence and “quasi paralysis”.54

Almost simultaneously, Freind’s friend Richard Mead hadadopted a similar notion of the modus operandi of opium. Includedin the latter’s highly successful Mechanical Account of Poisons (1st edn1702, internationally at least sixteen editions until 1765), it becameprobably the best known iatromechanical interpretation of the drug’seffects in the eighteenth century.55 Having studied with Pitcairne inLeyden, Mead’s general concept in this work was to apply“mechanical considerations”, the “laws of motion”, and “geometricalreasoning” to the field of toxicology.56 His theory of opium consistedbasically of two parts: the first described the immediate effects of theorally taken drug on the stomach, and the second the effects after ithad passed the so-called primae viae (i.e. the gastrointestinal canal)and had entered the blood circulation. This second part resembledclosely the mechanical ideas of Pitcairne, Hoffmann, Berger, andFreind. Rarefied by opiate particles, the blood was believed to distendthe cerebral and other vessels, which pressed on the nervous “tubuli,or canals” and thus diminished the influx of “nervous fluid”containing the spiritus animales.57

In the first part of his theory, however, Mead suggested thatopium caused a “pleasant titillation” of the nervous coat of thestomach, leading to the feeling of “an agreeable plenitude”, which hecompared to that after a good meal. The mind, entertained by “ideasof satisfaction and delight”, would be distracted from sensations ofpain. Moreover, the fibres of the body were relaxed, and immoderatesecretions were stopped in this way.58 To some extent these notions,which were rather vitalistic than mechanistic, reflected the earlierHelmontian ideas about an effect on the archeus located in thestomach. But they were much more similar to a third theory ofopium (besides the spiritus animales and rarefaction theories), whichhad shortly before been published by the physician and chancellor ofthe diocese of Llandaff, John Jones (1645-1709). In his book TheMysteries of Opium Reveal’d (1st edn 1700) Jones had propagated hisview that all the known effects of the drug could be explained by itscausing a “pleasant Sensation”, which led to relaxation of all sensibleparts of the body.59

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At first glance it may appear surprising that Mead did not refer tothis work, which after all had been authored by a member of theRoyal College of Physicians in London and recommended forpublication by its president, Thomas Burwell. Mead’s silence maywell have had to do, however, with the book’s peculiar nature andstyle. Jones’ text was written in a proselytizing manner, replete withrepetitions and italicized emphasis characteristic of the pamphletliterature of the time. Repeatedly Jones thanked God for havingrevealed this new knowledge of opium to him and compared it withHarvey’s discovery of the blood circulation and Columbus’ ofAmerica, adding a triple “Amen”.60 The euphoric style of Jones’ booksuggests that it may actually have been written under the influence ofthe drug. In fact it contained quite detailed observations on theconsequences of habitual opium-taking.61 Considering this, one mayunderstand why Mead obviously omitted to mention Jones in hisown study, which being branded “mechanical” promised a rationalinquiry based on the most modern scientific, Newtonian principles.

Mead’s account of opium was not purely speculative, but hadexperimental components as well. He gave quantitative results of achemical analysis of the drug, which was found to contain “volatilealcaline spirit”, “foetid oil” and “coal, void of salt”, and he employedanimal experimentation, too. The latter, however, had a rathersubordinate role, compared to that in Berger and Freind. On the basisof his theory Mead predicted that a large quantity of opium wouldinflame the stomach and rarefy the blood so much that the vesselswould lose their tone, resulting in apoplectic symptoms. “To beconvinced of this” he performed just one experiment on a dog. Havingbeen poisoned orally with about two drachms of opium (i.e. ca. 120times the usual therapeutic dose of one grain in man), the animal diedunder convulsions within an hour. The post mortem examinationrevealed in fact “beginning inflammation” of the stomach, “very full”cerebral vessels, and coagulated blood in the Sinus longitudinalis of thebrain, “as is not uncommon in apoplectic carcases”.62

Seen as a whole, we can thus identify at the beginning of theeighteenth century two new pharmacological theories of opium, thatcompeted with the older view of “fixed” or “bound” animal spirits:rarefaction of the blood, indirectly and mechanically affecting thenervous system; and the “pleasant sensation” theory, which operatedmore in vitalistic or psychophysical terms. It is quite remarkable thatMead felt able to use both of them alongside, perhaps an earlyindication of his flexibility in theoretical explanations, which was tobecome obvious in later editions of his toxicological work.63 By

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contrast, referring to a German review of Jones’ Mysteries, Berger andFimmler condemned the notion of an “ideal” or “virtual” effect ofopium via “pleasant titillation of the stomach”. For them, this was“playing games with the very term of spiritus animales”. Theyscathingly compared such a mode of action with getting children tosleep by an old woman telling them fairytales, and addedsarcastically: if this were true, it was to be hoped that opium couldprocure death as suddenly as the children are caused to sleep.64

In fact it was rather the iatromechanical theory of rarefied bloodthan Jones’ ideas, that eventually replaced the notion of fixed animalspirits, as can be seen from later standard works in the field, such asEtienne-François Geoffroy’s Tractatus de materia medica (1741),William Lewis’ New Dispensatory (1753), George Young’s Treatise onOpium (1753), and Balthasar Ludwig Tralles’ Usus opii salubris etnoxius (1st edn 1757-1762).65 Yet by the middle of the eighteenthcentury the rarefaction theory had already come under attack itself.

Before we look into this and further developments in theories onopium, however, the question of therapeutic implications needs to beaddressed. What were the current opinions on opium therapy? Andmore specifically, which therapeutic conclusions were drawn fromthe new theories of opium in the late seventeenth and earlyeighteenth centuries?

Some Early Therapeutic Conclusions

Significantly, those new pharmacological theories were formulated ina period when concern about an all too liberal use of the drug intherapeutics became prominent. Opium was widely used and praisedfor its singular effectiveness as an analgesic, hypnotic, antitussive,sudorific, and antidiarrhoeal remedy, and it had also beenrecommended as an excellent cordial.66 Inevitably, it seems, lethalopiate intoxications during treatment were observed more frequently.The Marburg professor of medicine Johann Jakob Waldschmied(1644-87), writing in 1679, compared the problem with the damagethat was often caused by excessive use of purgatives. Opium, hepointed out, was like a double-edged sword or like a coin showing anangel’s face on one side and the devil’s on the other.67 Similar viewswere expressed by other medical writers of the time, for exampleWillis and Wedel.68 Like Willis, Waldschmied complained that“empirics, foolhardy medics, and anyone equipped for bloodsucking”savaged mankind by giving opiates indiscriminately in any kind ofdisease.69 Though their wish to restrict opium therapy to the learned,academic physicians may well be understood in terms of professional

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motives, it would probably go too far to doubt that their concernswere genuine.

Careful dosage, the obvious way to avoid intoxication, was notsufficient because of the greatly varying strength of the crude opium,which was imported chiefly from Turkey, Egypt, and East India.Though quality criteria, such as its colour, consistency, taste andsmell, and simple quality tests, such as colour changes when mixedwith saliva or burned in a flame, were known since Dioscorides, exactmethods of standardization were not developed until the nineteenthcentury. It was even controversial whether the imported “opium” wasreally the dried juice of slit poppy capsules, or whether it was theweaker “meconium”, i.e. the pressed and dried juice of the wholeplant or an extract of a decoction of it. Moreover, there weresuspicions that merchants adulterated opium with other drugs, suchas wild lettuce juice, to increase its quantity.70

Yet there were two other ways to counter the danger of iatrogenicopium poisoning. The traditional way, going back to antiquity, wasto “correct” the drug’s effect by combining it with other substances,which were believed to have a contrary quality. The theriac ofAndromachus (1st cent. A.D.), for example, had viper flesh amongits many ingredients, which was thought to be warm and dry andthus to compensate partly the cooling effect of opium contained inthe remedy.71 Pepper, cinnamon, saffron, castoreum, and other drugswith a warm quality were used as “correctives” of opium.72 With thequestioning of the Galenic primary qualities in the seventeenthcentury, however, the methods of pharmaceutical correction neededto be reconsidered as well. The second way was to define thosediseases or states of illness, in which the giving of opiates was harmfuland thus contraindicated. In these two areas, especially the latter,theories of opium became practically relevant.

An example of therapeutical conclusions drawn from theiatrochemical theory of opium binding or “fixing” the spiritusanimales was provided by Waldschmied. As he saw it, acrid and lethalexhalations of the drug “fixed” the “liquor animalis” (containing thespiritus) and caused it to degenerate into an acid. Consequentinhibition or failure of nutrition, blood circulation and nervousfunctions led to the known symptoms of opium poisoning, such as acold sweat and sopor.73 Against the background of this theoryWaldschmied discussed a long list of contraindications for the use ofopium, issued under the title of “Medical Admonitions” (Monitamedica circa opii et opiatorum usum) and publicly defended by one ofhis students at Marburg University.

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First of all, opiates should not be used in “soporous affections”,such as apoplexia, epilepsy, lethargy, paralysis, loss of memory, andvertigo, for they were characterized by a lack of active spiritusanimales. With reference to van Helmont he also warned againstcalming down states of “mania” or “amentia” with the drug, becauseit caused laborious, unpleasant sleep and had something “mad” initself, madness being “nothing but a daydream”. Since opium“darkened the light” of the animal spirits, it was not to be used inpeople with impaired sight (and hearing). Thickening pus and mucusand diminishing respiration, it accelerated death in patients withphthisis and put asthmatics into fear of suffocation. In angina,malignant, petechial and similar fevers, as in smallpox and measles,opiates would allow the disease to “nidate” even more profoundly inthe blood, because they “fixed” the vital spirits contained in the latterand bound the “active principles”. Moreover opium harmed thestomach, made constipation worse, put patients with haemorrhoidalor menstrual fluxes into a dangerous weakness, and might actuallykill someone with hydrops. In children and old people it shouldgenerally be avoided, because their spriritus animales were too weak.Finally, Waldschmied pointed to the dangers of habitual opiumconsumption: people became “inebriated and torpid” and “comatose,stupid, inconstant, saying ‘yes’ at one time and ‘no’ in the nextmoment”.74 These last observations, however, referred to “the Turks”,not to Western patients. Waldschmied relied here on the report ofone of the Oriental travellers of the sixteenth century.75 The fact thatthese consequences of chronic use of opium were mentioned at thevery end of his list of “admonitions” further indicates that they werenot yet regarded as a major problem. The main concern was aboutacute intoxications and harmful side effects in therapy.

As shown above, Waldschmied closely linked his theoretical,pharmacological considerations with his therapeutic warnings, theformer sometimes actually being the reason for the latter. In someinstances he also referred to cases of poisoning from the recentliterature or own clinical observations. But the important feature ofhis work was that he could rationally predict harm in certain diseasesor therapeutic situations on the basis of his pharmacological theory.

Waldschmied’s admonitions were soon adopted by other medicalauthors.76 Though the major contraindications for the use of opiumthus remained the same, the reasons given for them changed with thepharmacological theories. This is evident from the early adherents ofthe rarefaction theory of opium mentioned above. For example,Hoffmann and Descazals also warned about avoiding opium in “all

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diseases of the head”, such as apoplexia, vertigo, paralysis etc., butrather because of impeded cerebral circulation than a direct effect onthe spiritus animales.77 Likewise, Berger and Fimmler adoptedWaldschmied’s warning against giving opiates to children and theold, but the reason was now that their brains were too weak towithstand the pressure of distended blood vessels.78 A similar linkbetween theory and contraindications can be observed in Jones as therepresentative of the concept of “pleasant sensation”. Since the“pleasant sensation” led to general relaxation, he stated that opiatesshould not be given if parts of the body were unnaturally relaxed,paralysed, or ruptured, or if a “grievous sensation” was useful inpromoting the excretion of harmful matter.79

Occasionally the new theories led to new contraindications ordifferentiation in current indications. Mead, for instance, concludedthat opiates should be employed only in excessive secretions due toirritation, whereas in “colliquative diarrhoea”, in the course of hecticfevers, it would cause “real mischief, by relaxing the fibres, andheating and rarefying the fluids, already too thin and broken in theirtexture.”80 Probably the most important contraindication, emergingfrom the rarefaction theory, were acute inflammations. It appearedobvious that rarefied blood and distended blood vessels would makethem worse.81

The new theories of opium also induced some rethinking of thecurrent practices of preparing and “correcting” the drug. Schroeer,who, as mentioned above, believed to have identified an acidprinciple as the effective component of opium, suggested admixingalkaline substances, condemning simultaneously many of the moretraditional correctives.82 Similarly, Berger and Fimmler were highlycritical of the usual corrections, stating that most of them werefounded on “prejudiced opinions”. Someone who knows about themode of action of opium, they argued, should not have to be tooworried about corrective substances and should be able to use thecrude drug or simple preparations. As they saw it, in the classiccomplex composita, such as theriac, opium was not really corrected,but only given in very small doses (and therefore safely).83 Hoffmannand Descazals were more positive about corrections, however. On thebasis of their pharmacological theory they required that a correctivesubstance should promote the movement of the blood and animalspirits. Sudorifics, purgatives, aromatics, and diuretics appearedsuitable for this purpose. In principle, they admitted, thisrequirement had been fulfilled in traditional preparations, such astheriac and diascordium, as well as in more recent opium remedies,

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such as the “pillulae Wildegansii” (with added aloe) and “Starkey’s”or “Matthew’s pill” (with white hellebore).84

Yet the topic was obviously important enough for Hoffmann tomake another student of his, Friedrich Christian Muller, exploreexclusively the question of preparing and correcting opium. Aftertesting the efficacy of water and alcohol extracts of the drug (and oftheir residues) in animal experiments, and lengthy considerations,this student concluded that a simple extract of opium with distilledrainwater, as John Jones had recommended it, was the safest remedy.In the extracted gum, he explained, the active “sulphur” was sheathedby viscid, mucilaginous particles.85 Similarly Ole Borch, who hadtested various opium preparations in animals, had recommendedprescribing crude opium with little or no corrections; and Mullercould quote other recent authors, including the respected Wedel ofJena, who had also preferred simple extracts of the drug (with water,vinegar or alcohol) to any more complex preparations.86

Obviously there was a trend towards simple opiates in the lateseventeenth and early eighteenth centuries, which followed a generaltrend in the materia medica of the time, but was also founded uponnew theories of the drug’s mode of action and experimentalexperience.87 Safety of therapy with opium was aimed at by arestricted use in indicated cases rather than by complicatedpharmaceutical efforts in correcting the drug. Stating that the mostserious and frequent errors in contemporary medicine werecommitted in the use of opiates, Muller condensed therapeuticprecautions into seven rules, which probably reflected the teaching ofHoffmann: 1. to consider that some individuals might not toleratethe drug even in a very small dose because of a peculiarity in theirconstitution; 2. to give opium only if really necessary; 3. to preferweaker medicines if possible; 4. to avoid giving opiates in fevers,when the harmful “materia peccans” had to be excreted, and never togive them in the crisis of the disease; 5. not to use opium in“malignant” diseases, resulting from bad blood and humours; 6.likewise not in severe inflammations, gangrene, and in states ofplethora and “cacochymia”; and 7. not in “cold affections” of thebrain and nerves, chronic diseases, hydrops, and asthma. What wasleft as indications for the use of opium was mainly severe pain afterinjuries, in colics and stone disease, tooth- and earache,haemorrhoidal pain, and excessive coughing, vomiting, anddiarrhoea.88

Though this may seem a rather limited use, Hoffmann’sprofessorial colleague at the University of Halle, Georg Ernst Stahl

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(1660-1734), went even further in his therapeutic criticism. In 1707he matched Hoffmann’s initiatives with a thesis entitled De imposturaopii (“On the Imposture with Opium”), that was publicly defendedby his student Johann Georg Brunschwitz. The argument of thethesis was that treatment with opium betrayed both patients anddoctors, because it effected only a transient mitigiation of symptoms.Even worse, since salutary physical movements and powers, guidedby the soul, were “stupefied” and “dazed” by the drug, harmfulmatter (materia peccans) was not hindered in enhancing lesions andultimately destroying the patient’s body. If the primary affection of adisease could not be reached by therapeutic means, it was better tohope for help by “nature and time”.89 Evidently, Stahl’s animist theoryof health and disease played a major role in this almost completerejection of opiates.90 Yet Brunschwitz gave also some case historiesfrom his teacher’s practice to illustrate the negative effects anddeclared the usual corrections of the drug as “false” (i.e. ineffective).Opium should not be given except in cases where the symptoms“really urged” its use, ran the conclusion.91

As is clear from the examples discussed above, pharmacologicaltheories had some influence on therapeutic concepts, particularly bydefining and explaining contraindications for the use of opiates. Onthe other hand, there was certainly no simple, direct line from theoryto practice. Clinical experience of opium intoxications contributed totherapeutic caution as well, and some contraindications, onceintroduced into the literature by a respected medical writer, wereperpetuated probably on the grounds of authority alone. Nor was therea simple relation between pharmacological experimentation andtheory. Far from following strict Baconian induction, experiments were“embedded” in chemiatric, iatromechanist and vitalist speculation.Together with clinical observations and some simple chemical trials,animal experiments with opium could provide “arguments” towards atheory of the drug (as Freind put it), but they would not form itsfoundation.92 Neither were these pharmacological trials used as crucialtests for the truth of a particular theory. When Mead added an animalexperiment to his “mechanical account” of opium, this was not reallyfor verification or falsification of a hypothesis in the modern sense, butfor confirming a theory that he already believed in. Moreover,experimental observations were obviously moulded to fit the theory.Actually contrary findings in opium-poisoned animals, namelycoagulated blood (Schroeer, Mead) and thin, fluid, non-coagulatedblood (Berger, Freind), were both taken as a sign of impededcirculation – an assumption that had to be made in order to be able to

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account mechanically for the clinically known effects of high doses.However, despite these qualifications, one should note as a

characteristic of the examined early work on opium thatexperimentation, theory, and therapeutics were in fact linked witheach other, albeit not in a very stringent manner. With his late workPharmaceutice rationalis (1st edn 1674/75) Willis had made the bold,though not very successful attempt to build pharmacotherapy onpharmacological experiment and theory. And there is also theprogrammatic statement of the Essex pharmacist and licentiate ofmedicine Samuel Dale (1650-1739), in his Pharmacologia (1st edn1693), that the best way to investigate the medicinal properties ofnatural bodies was animal experimentation, as the Swiss physicianJohann Jakob Wepfer had demonstrated it on the water hemlock andother poisons.93 In fact a number of experimental studies on opiumwere performed in the course of the eighteenth century, whichbecame influential not only for pharmacological theory, but also forphysiology and for therapy. The following sections will analyse thiswork and its implications.

Opium and the Nervous System around 1750

In 1742, Charles Alston made a major contribution to theknowledge of opium by publishing a ‘Dissertation’ on the drug in theEdinburgh Medical Essays and Observations.94 With this work the“centre” of research on opium temporarily moved, as in the case oflithontriptics, from London to the young Edinburgh medical school(founded in 1726).95 As we shall see later on, a similar “move”happened on the Continent from the leading University of Halle(founded in 1694) to the University of Göttingen (founded in 1737).

Alston, trained by Herman Boerhaave in Leyden like all of thefirst professors in the Edinburgh medical faculty,96 was very critical ofthe contemporary state of pharmacological knowledge, and this wasparticularly true for the case of opium.97 As he stated in his lectureson the materia medica:

… some strenuously maintain that opium is cold in the fourthdegree; other that it is hot, yea caustic; some that it is an alcali, othersan acid; some that it rarifies the blood, other that it coagulates it;some think that its virtues are lodged in its sulphureous, and otherin its gummy parts, etc. each accounting for its effects from his ownopinions in their own way, though none of them are founded onexperience, and easily confuted.98

With respect to these “many Controversies”, which he also noted in

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his ‘Dissertation’, Alston put current views on opium to a systematictest by “Experiments and Observations”.99 In doing this he employeda spectrum of methods, which by far surpassed that of previousresearchers in this area: examination of the drug by taste and smell,various chemical tests and quantitative analysis, in vitro experimentson blood and serum, toxicological trials on frogs and dogs (applyingopium externally, perorally, and intravenously) includingmicroscopic observations and post mortem examinations, self-experimentation (external application and peroral taking), andinterpretation of one’s own therapeutic experiences as well as ofreported cases. As has been documented above, most of thesemethods as such had been used in studying the drug since the secondhalf of the seventeenth century, but not all of them in combination.In this respect Alston’s ‘Dissertation’ may be regarded as the first full-fledged pharmacological work (in the modern sense) on opium.

Remarkable is also the expert help that he was able to recruit.Andrew Plummer (c. 1698-1756), who held the Edinburgh chair ofmedicine and chemistry, put his laboratory to Alston’s disposal andassisted in chemical analysis; Alexander Monro primus (1697-1767),the professor of anatomy and surgery, contributed his manual skillsin performing an intravenous injection in a dog; and RobertFullarton, described as “a curious Gentleman, and very dextrous inMicroscopical Observations”, helped in performing some of theexperiments on frogs.100

In his testing of current opinions Alston began with the mostbasic issue, i.e. the question whether the imported “opium” was reallythe dried “tear” or “milk” of cut or scratched poppy capsules orwhether it was an extract of the whole plant, the weaker “meconium”.Medical travellers to Oriental countries could be quoted in supportof either view, e.g. Engelbert Kaempfer (1651-1716) for the former,Prosper Alpin (1553-1617) for the latter.101 The French chemistNicolas Lemery (1645-1715) had insisted in his authoritativeDictionaire ou Traité Universel des Drogues Simples (1st edn 1698) thatthe imported “opium” was nothing but meconium.102 To solve theproblem Alston produced his own opium from the heads of poppyplants grown by himself in Scotland. It closely resembled theimported “opium” in colour, taste, and smell, while self-mademeconium had a much less intense taste and smell. The imported“opium” was therefore “for the far greatest Part, the true Tear of thePoppy”, as Alston concluded, only “some part” of meconium mightbe admixed in “some Places”.103

His next step was to characterize the “virtues” or properties of the

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drug by tasting and smelling it, a classical method, which had beendeveloped into a fine art by his time. Nehemiah Grew (1641-1712),for example, had presented a highly differentiated system of tastes inplants to the Royal Society. Alston, who had adopted Grew’s system,taught his students to distinguish between sixteen kinds of simpleand six kinds of compound tastes, which were further differentiatedaccording to degrees of intensity, duration, increase and decrease, andplace of sensation within the mouth.104 From tasting and smellingopium, he felt able to infer that it was “an acrid, diaphoretic, nervine,and cathartic Medicine”. The last of these alleged properties,however, illustrated the limits of this method. Clinical experiencetaught that opium was not a cathartic or purgative substance, havingmostly the opposite effect of constipation. Faced with this apparentcontradiction, Alston distinguished between a sensible “stimulating”and an independent “narcotic” quality in the drug, foreshadowinglater debates on, and efforts to solve, this problem of seeminglycontradictory properties.105

This led to his chemical examination of the drug, which formedthe most extensive part of his work. Extraction trials with water,wine, vinegar, spirit of vinegar, brandy and rectified spirit of wine(alcohol) made him conclude that the gross constituents were a gum,a resin, and insoluble “terrestrial” matter in a proportion of 6:4:2.Self-experiments with the extracted resin showed it to be tasteless andsomniferous, without bad side effects. Alston disagreed at this pointwith John Jones, who had attributed the “mischiefs” caused by thedrug to this component. “The World is too cautious now”,commented the Edinburgh professor, “to believe implicitely everygeneral Assertion”.106 Numerous tests for acidity or alkalinity madehim also disagree with the Paris professor of medicine Etienne-François Geoffroy (1672-1731) and Friedrich Hoffmann, who (likeSchroeer) believed they had identified an acid “salt” or “sulphur” asthe drug’s active principle. According to Alston’s tests, the drug as awhole was rather alkaline, and further chemical experiments of hisindicated that also its “essential Salt” was “ammoniacal” (alkaline).Moreover, contrary to other chemical authors, evaporation anddistillation trials made him assume that the active principle in opiumwas rather fixed than volatile, which meant that the traditionalmethod of “correcting” the drug by roasting it was quite pointless.107

Assisted by Plummer, Alston then proceded to his quantitativeanalysis of the drug by way of chemical distillation, which gave aphlegm, spirit and oil, volatile salt, and caput mortuum (salt andearth). Further analysis of the spirit of opium revealed that it

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contained only very little volatile salt. Since the amount of volatilesalt obtained in the first process had also been very small, Alston wasreassured in his view that Hoffmann as well as Craanen had beenwrong in identifying this component as the effective principle in thedrug.108 Despite this quite detailed investigation, Alston went nofurther in his interpretation of the chemical results, being also hereaware of the limitations of the method. With chemical distillation, hewarned, the very same components had been found in deadlynightshade and in nutritious cabbage.109

Further-reaching conclusions were drawn, however, from his invitro and animal experiments with the drug. With the help ofFullarton he examined microscopically the blood flow in the webbedfeet of frogs, which had been given orally a solution of opium inwater. While the colour and consistency of the serum as well as thesize, form and colour of the red blood corpuscles remainedunchanged, the velocity of the blood stream slowed downconsiderably – a finding that could be confirmed in repeated trials ofthe same kind.110 Chiefly copying Freind’s and Mead’s experiments,Alston came further to different results. The post mortemexamination of a dog, that had been poisoned by Monro throughintravenous injections of an aqueous solution of opium, revealedsmall, white, and bloodless lungs, and the Vena cava, ventricles of theheart, and aorta contained clotted and coagulated blood. This clearlycontradicted Freind’s findings. Moreover, a small dog was givenorally the same dose of two drachms (120 grains) of opium as inMead’s experiment. Though it temporarily lost the power of its limbsand refused food and drink, it did not show the apoplexia-likesymptoms that had been described by the London doctor.111 Finally,in repeating Freind’s in vitro trials, Alston mixed solutions of opiumin water and alcohol with milk, serum, and fresh arterial and venousblood. Unlike Freind, he found rather coagulation and precipitationthan rarefaction.112

On the basis of these experimental observations Alston opposedthe “rarefaction theory” of opium, as it had been taught by Mead,Freind, and others, stating to the contrary that the drug “rathercoagulates or thickens, than dissolves or attenuates the Blood”.113 He didnot leave it at this conclusion, however, which would basically havebeen the older view of Craanen and Schroeer. At this point he movedforward to formulate a “new” theory of opium acting directly on thenervous system.

As Alston saw it, the analgesic and hypnotic effects of opium didnot depend on its direct action on the blood or the brain. Instead, it

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“first and principally” affected the nerves of the part to which it hadbeen applied, i.e. in the usual, oral case, the nerves terminating in thewalls of the stomach. The effect would then quickly be distributed overcommunicating nerves, and “by Consent”, or sympathy, the wholenervous system would soon be affected. The “primary effect” of the“narcotic Part” of opium (as distinguished earlier from the“stimulating” part) was believed to be a relaxation of the nervous fibres.This relaxation extended either directly or indirectly, via an impressionon the sensorium commune in the brain, to the “moving” muscle fibres.Depending on the dose of opium, this caused in a second step itsclinically known “good” secondary effects as an euphoristic, analgesic,cordial, sudorific, and hypnotic medicine, or – if overdosed –“Stagnations, Deliriums, Lethargies, Apoplexies, Death.”114

At first glance, Alston’s theory may appear quite similar to that ofJohn Jones or the first part of Mead’s, whom he quoted in thiscontext. Yet, judging from the reasons he gave for his theoreticalviews, the experimental work of Wepfer in the previous century andAlston’s own clinical experience with opiates played a greater role. Infact Alston did not really derive his pharmacological theory of opiumfrom his extensive experimental work, which, as we have seen above,rather served to evaluate and criticize the views of other authors.

Dissecting or vivisecting perorally poisoned animals, Wepfer hadfound that some “narcotic” plant poisons caused grave symptoms,although they had apparently not yet left the stomach and seemedunchanged. On this basis, and influenced by van Helmont’s idea ofthe archeus, the Swiss physician had suggested that these poisonsattacked primarily the nervous coats of the stomach. Per sympathiamthe Praeses systematis nervosi, i.e. the personified nervous, vitalprinciple, would be “enraged”, and in his efforts to subdue and expelthe poison, he caused the observable symptoms of intoxication. Thelatter were thus not, or at least not primarily, caused by an effect onthe blood. There was also indirect evidence for such a view, for earlyvomiting in his experimental animals, as well as in clinical poisoningcases, led often to recovery. It was to these observations of Wepferthat Alston referred, when he justified his theory. Yet Wepfer’sexperiments had not included opium or poppy. His theory restedmainly on his work on water hemlock and other toxic, fast actingplants and drugs, such as napellus, white hellebore, cocculi Indici,and nux vomica.115

In fact the speed with which the effects of opium and some otherdrugs showed after oral taking was Alston’s second argument tosupport his theory, and it was here that his clinical experience came

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in. A few drops of Liquid Laudanum (opium in alcohol) “in aMoment” ended violent tenesmus and stopped vomiting, eased pain,and induced sleep “almost as soon”.116 It was very unlikely in hisopinion that such instant effects were brought about by absorptionof the drug into the blood and transport to the brain. To understandthis view one has to consider the current doctrine of lymphaticabsorption in Alston’s time. An orally taken substance would have topass down to the guts, be absorbed by their chyle vessels and thentravel the long way up the thoracic duct before entering the blood ofthe subclavian vein to be distributed with the circulation.117

Alston’s theory of direct action on the nerves was the beginning ofanother shift in the pharmacological ideas on opium. Less importancewas placed on possible effects on the blood and circulation. Thenervous system became (again) the prime target of the drug.118 Moreexperimental “evidence” in support of this view was provided in 1745by the Dutch physician Abraham Kaau Boerhaave (1715-58), anephew of Herman Boerhaave. He basically applied Wepfer’s oldmethod of oral poisoning and vivisection to the study of opium. Thestomach of dogs that had been put to deep sleep by high doses stillcontained the drug after several hours, while the pylorus appearedperfectly closed, the intestines contracted and almost withoutperistaltic movement, and the (absorbent) chyle vessels empty. In oneexperiment Boerhaave had weighed the remaining amount of opiumin the stomach six hours after oral administration and found that theoriginal dose of 30 grains had been reduced by less than one grain.These findings seemed to speak against a primary effect of opium viaabsorption and the blood circulation. Consequently he concluded,like Alston, that it acted initially on the nerves of the stomach, fromwhich the effect spread per consensum to the central parts of thenervous system, leading to impaired sensation and motionthroughout the body. Turgid veins in the brain and elsewhere, whichBoerhaave (as Berger and others before) noted during his vivisections,were interpreted by him as a secondary effect, resulting fromdiminished motion of the heart and retarded blood circulation, afterthe nervous system had been affected.119 Though forming only a smallpart of a large theoretical work on the physiology of sympatheticaction, Boerhaave’s experiments seem to have had considerable impacton the development of pharmacological ideas on opium, beingrepeatedly quoted by later researchers.120 More important in thisrespect, however, became a series of trials in the 1750s by Alston’sEdinburgh colleague Robert Whytt.

Examining the question whether the blood circulation or the

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nervous system was more important in bringing forth the effects ofopium, Whytt compared the drug’s action on differently preparedfrogs with that on intact ones as controls. In some of the animals hepreviously either excised the heart or cut off the head and destroyedthe spinal marrow by pushing a wire down the vertebral column. Hethus used three “animal models” (as one would say today): one, inwhich the blood circulation had been interrupted, another, in whichthe central nervous system had been eliminated, and a third, inwhich both systems worked. Whytt’s experiments showed that asolution of opium in water, injected into the stomach and guts,destroyed sensibility and motion in a frog without blood circulatiomas soon as in an intact one. Moreover, when such a solution wasapplied to muscles or injected into the body cavities of frogs withoutcentral nervous systems, it reduced the heart rate much less quicklythan in the entire animal. Whytt concluded from these observationsthat opium produced its effects chiefly by direct action on thenervous system, not (or much less) via absorption and transport withthe circulating blood.121

This seemed to be supported by experiments on dogs, performedby his student Robert Ramsey. Opium solutions injected rectally orintraabdominally almost immediately led to paralysis and loss ofsensation in their hind legs, but not in the front part of their bodies– a phenomenon, which also made an effect via absorption andcirculation seem unlikely. Accordingly, Whytt endorsed Alston’stheory of a direct action on nerves spreading by sympathy andsimultaneously rejected the older idea of rarefied blood.122 Similar toBoerhaave, he explained the swollen blood vessels in opium-poisonedanimals with stagnating circulation. In Whytt’s physiological conceptof “vital and involuntary motions”, the heart needed to sense thestimulus of the returning blood to perform its contractions. Sinceopium caused “insensibility” of the heart, as it did in other parts ofthe body, cardiac motion necessarily slowed down and eventuallystopped. With regard to intravenous injection of opiates he suggestedthat they acted on nerves terminating at the inner surface of the heartand blood vessels or affected the cerebral medulla itself.123

Without doubt, Whytt’s animal experiments on opium had beenthe most sophisticated so far in this field of research. Not only hadhe compared the drug’s effects on specially prepared frogs with thoseon intact animals. In true control experiments he had also studied thephysiological changes caused by preparation alone (i.e. excision of theheart, decapitation and pithing), without administration of opium.124

Moreover, although his main experiments had been conducted on

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cold-blooded animals (frogs), he had sought confirmation of hisfindings in warm-blooded animals (dogs). Yet, despite thismethodical cautiousness, it was Whytt’s experimental design thatsoon became the target of criticism by expert colleagues: at home inEdinburgh by the anatomist Alexander Monro secundus (1733-1817), the son of Alston’s colleague, and on the Continent by therenowned Albrecht von Haller (1708-77). Though Haller’s critiquepredated that of Monro, we shall first look into the latter’s work andits consequences, because it was more closely concerned with thecontroversial question of opium’s effect on the nerves or on theblood.

In 1761 Monro presented the results of his own, extensiveexperimental work on this problem to the Philosophical Society ofEdinburgh. Whytt, he maintained here, had become victim of “anunlucky deception, in the chief of his experiments” by assumingimplicitly that absorption and circulation continued in frogs whosecentral nervous system had been eliminated. Monro had observedmicroscopically that the blood flow stagnated in the small vessels offrogs prepared in this way, and he had found experimentally thatabsorption became inconsiderable as the circulation ceased.Following his wrong supposition (explained Monro), Whytt hadattributed the slow effect of opium in decapitated and pithed frogsonly to the lack of a central nervous system, forgetting to considerdiminished absorption and circulation as well.125

Aware of these pitfalls, Monro used modified animal models, soto speak. In one group of frogs he either excised the heart orseparated one of the hind legs, leaving only the crural nerve as aconnection with the trunk. Applying subcutaneously a solution ofopium in water to the leg, he intended to study the effect mediatedsolely by nervous action in this way. In a second group he eitherdestroyed the lower spinal marrow or cut one hind leg so that itremained connected with the body only via its large blood vessels andconcomitant lymphatics. Again applying opium to the leg, theseanimals were supposed to show purely the effect through absorptionand transport with the blood and lymph. As Whytt had done it,intact frogs were used as controls, in which both the nervous andcirculatory system were unimpaired. Between these three groupsMonro compared the appearance and intensitity of typical effects ofopium intoxication, such as loss of sensitivity, diminished circulation(observed microscopically in the webbed feet after Alston’s method),paralysis, and convulsions. While they showed strongly in the modelsfor pure absorption, they appeared only locally in the hind legs, not

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throughout the body, in the models for pure nervous action. Notsurprisingly, the systemic symptoms of poisoning came up soonest inintact animals.

On the basis of these results Monro enlarged the current theoryof the modus operandi of opium. Its effects, he argued, were producedboth by way of direct action on nerves (in the sense of Alston andWhytt) and via absorption into the circulating blood.126 He was allthe more convinced of this broader concept, since he had found infurther animal experiments with alcohol and camphor that thesesubstances seemed to act even chiefly through absorption.127

Counterarguments suggested by the work of Kaau Boerhaave, i.e.that opium appeared to be effective while it was still in the stomachand hardly dissolved, were dismissed by Monro: the stomach hadlymphatic vessels capable of absorption like those of the guts, and theactive principle of opium probably formed only a small part of thewhole drug.128 Yet, even so, Monro did not radically depart fromWhytt’s theory. Like the latter he supposed that opium, once it hadbeen absorbed into the blood, would affect nerve endings at the innerside of the heart and blood vessels, which communicated their“sufferance” by sympathy. Instant convulsions in frogs afterintravenous or intraarterial injection of opium seemed to indicatethis mode of action. Rarefaction of the blood, however, if happeningat all, was in his view “so inconsiderable as scarcely to meritattention” and ought “not to be considered with Pitcairn, Friend{sic!}, and with the learned Dr Tralles, as the primary effect…, butonly as a secondary one.”129

While Monro thus stopped halfway in his critique of Whytt’s(and Alston’s) nerve theory, some twenty years later the well-knownItalian naturalist Felice Fontana rejected it altogether in favour of atheory of absorption. In a large series of experiments, involving notless than 300 frogs, Fontana had prepared the sciatic nerves on bothsides. On one side the nerve was then dipped into an aqueoussolution of opium, on the other side in pure water. Dividing the totalnumber of preparations into groups of thirty, the immersion timewas varied from ten to one hundred minutes in ten minute steps, andthe nerves of both sides were subsequently stimulated. Since theircapacity to conduct stimuli to the muscles of the hind legs decreasedequally and to the same degree on both sides, Fontana concluded thatopium had generally no direct effect on nerves.130 This meant that ithad to act via the blood circulation, a conclusion, which Fontanabelieved to have confirmed with a number of intravenous injectiontrials on rabbits. Depending on the dose of an injected aqueous

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solution of the drug, the animals quickly showed the usual symptomsof opium poisoning, such as deep sleep, paralysis, and convulsivemovements, sometimes ending in death.131

Since Fontana’s conclusion that opium acted primarily throughthe blood, and not through the nerves, was diametrically opposed tothat of Whytt, he repeated some of the latter’s crucial experimentswith slight modifications. In one group of frogs he destroyed thebrain and spinal marrow with a large needle inserted through a holein the skull and then compared the effects of orally given opium withthose in intact frogs. Examining their heart rates and stimulatingtheir crural nerves, Fontana could not confirm Whytt’s observationthat the drug’s effect was either weaker or appeared more slowly infrogs without a central nervous system.132 In another trial he gave theopium solution perorally to one group of frogs, in which heimmediately after excised the heart, and to another group, in whichhe only opened the thorax, leaving the heart in situ. Contrary toWhytt’s observations, the animals with heart showed signs of opiumpoisoning (loss of voluntary movement) much earlier than thosewithout, suggesting that an intact blood circulation was important inproducing the drug’s effects.133

Fontana’s experiments on opium in fact marked the beginning ofa final shift in the theories on its primary effect, moving away againfrom the idea of direct action on nerves towards a theory of absorptioninto the circulating blood. As Melvin P. Earles has shown, such a shifttook place generally in pharmacological and toxicological theories,action by way of absorption becoming eventually the acceptedconcept around the middle of the nineteenth century.134 Despite theimpressive numbers of trials performed by Fontana, however, theevidence he had produced for his theory was regarded as quite weakin his own time. It was criticized as methodically inadequate, forexample, that he had applied opium to the trunks of nerves, coveredby “thick, cellular” coats, while the natural places of sensation were thefine extremities of nerves or specially adapted nervous surfaces. It wastherefore wrong to conclude from the lacking effect here to a lack ofany direct nervous action of the drug.135 In fact this point had alreadybeen made before Fontana’s trials by Monro, who, however, in laterexperiments apparently ignored his own precautions and appliedopium solutions directly to the brain and spinal marrow of the frog,rabbit, and pig. Since this led to convulsions followed by paralysis,Monro actually felt confirmed in his view that opium – if it wasabsorbed into the blood – acted on nerves terminating at the heartand vessels and affected through these the whole nervous system.136

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Moreover, Fontana remained rather vague on the exact mode inwhich opium was supposed to act through the blood circulation. Hedid not seem to regard the blood as a mere transport medium for thedrug, but rather to assume that opium inhibited and diminished thecirculation, possibly by affecting the blood’s “living principle”.137 Alsothis assumption of a vital element in the blood, propagated at thetime most notably by John Hunter (1728-93), became a target ofcriticism, e.g. by the Irish physician Samuel Crumpe (1766-96), whoexperimented extensively with opium in the early 1790s.138 Crumperepeated also some of those of Monro’s experiments, which had inpart supported the theory of absorption. He applied subcutaneouslya solution of opium to frog legs that were left connected with thetrunk merely through the thigh bone and nerve. Compared tocontrol trials on intact frogs, death occurred equally fast in bothcases. Moreover, frogs only prepared in this way, but not given thedrug, survived clearly longer than the equally prepared animals thathad been given opium. As Crumpe saw it, these experimentsprovided decisive proof that opium acted only on the nervoussystem.139 The results of Fontana’s intravenous injections did notcount in his view, because “many substances friendly to the animalframe, or at least not poisonous, when injected in a similar manner,produce speedy death”.140 Likewise, changes of the blood observed inthe dissection of opium-poisoned animals, or in in vitro experimentsin the manner of Freind, said nothing about the drug’s real effect inthe body:

To me it appears pretty clear, that any conclusion deduced fromexperiments made on blood drawn from its vessels, in proof of its{i.e. opium’s} action thereon, are perfectly fallacious andinconclusive; and that the changes observed in it on dissection, havebeen rather the consequences of the previous state of the system, theaction of the vessels on their contents, and the effects of exposure tothe atmosphere, than to any immediate operation of the medicineitself on the fluids.141

Essential for the eventual change from the “nerve theory” to thetheory of absorption were, according to Earles, a number ofphysiological studies in the early nineteenth century, particularly byFrançois Magendie (1783-1855). They demonstrated thatabsorption was not only performed by lymphatic vessels, but alsodirectly (and thus quickly) by veins, and they showed the high speedof the circulation. New chemical methods, allowing poisons to bedetected in tissues of organs and the blood, helped further to

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discredit the theory of direct nervous action.142 The work of Monroand especially of Fontana, in response to Whytt, thus contributed tothe general change in pharmacological theory at a very early stage,when there was still strong opposition to the idea of effect byabsorption – an opposition, which was partly based, as has beenshown above, on experiments too.

Effects on the Heart and Irritability

The other main response to Whytt’s opium experiments, comingfrom Haller as mentioned above, was part of what is known tohistorians as the Haller-Whytt controversy over sensibility andirritability.143 In his famous paper on the “sensible and irritable parts”,given in 1752 to the Royal Society of Sciences in Göttingen, Hallerhad stated that opium diminished irritability (i.e. the contractility ofmuscle fibres) throughout the body, and in particular the peristalticmovements of the guts, but that it left the motions and force of theheart unimpaired.144 This assertion was founded on a number ofvivisections of opium-poisoned cold- and warm-blooded animals,that Haller had performed in the preceding year together with hisdoctoral student Johann Adrian Theodor Sproegel (1728-1807).145

A close reading of the findings in these experiments, which werefirst published in Sproegel’s dissertation and subsequently, withadditional trials, in Haller’s Mémoires sur la Nature Sensible etIrritable, des Parties du Corps Animal, indicates that the experimentalbasis for this view was rather thin and not completely unambiguous.Haller claimed to have observed in three opiated frogs that the heartstill retained its irritability, while the intestines had already lost it. Yet,in Sproegel’s account this was less clear in one of these three trials,and both reported one opium experiment on a cat, in which themovements of the guts actually survived those of the heart.146 Thelatter finding was apparently ignored by Haller in his conclusions,where he reiterated that “the irritability of the intestines is more easilydestroyed by opium, and less easily restored, than that of theheart”.147

Still, even with these uncertainties, Haller’s results sharplycontrasted with those of Whytt. In applying opium to frogs andvivisecting them, Whytt had found a considerable decrease of theirheart rate.148 Because of this discrepancy with Haller’s observations hehad conducted more experiments of this kind, which confirmed hisinitial observations. Moreover, excised frog hearts stopped beatingsooner if immersed in an aqueous solution of opium than if put inpure water. The deceleration of the heart rate was also noted in one

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of the opium trials on dogs performed by Whytt’s student Ramsey,mentioned above, and Alston and Kaau Boerhaave had described thisphenomenon in dogs, too.149 Accordingly, Whytt had emphasizedthat the irritability of the heart was not exempted from the effect ofopium, adding somewhat arrogantly that Haller’s “candor and love oftruth” would without doubt “make him readily acknowledge hismistake, as soon as he shall discover it.”150

As often in the eighteenth century, a scientific controversydeveloped. Haller quoted his and Sproegel’s experiments, questioningsimultaneously the validity of Whytt’s by emphasizing the problemof artefacts in the latter’s very invasive methods:

To open the abdomen of an animal, to cut off its head or spinalmarrow, in order to find out about the more or less slow effects of apoison, is surely not the way to learn the truth.151

Haller apparently ignored here the fact that Whytt had performedcontrol experiments and that his own trials, including vivisection ofthe poisoned animals, were open to the same criticism. Yet, on a lesspolemical level, he rightly pointed out that Whytt had not performedexperiments to confirm or refute his and Sproegel’s crucialobservation that the action of the heart survived the peristalticmovements of the guts. Moreover, he was able to quote experimentsof Fontana in his favour.152 Fontana, having examined the effect ofopium on the velocity and force of cardiac contractility in over ahundred trials, chiefly on frogs, actually remained undecided,because the results were too varied. But referring to experiments onwarm-blooded animals, he noted that a moderate dose intensified themovements of the heart, whereas high doses appeared to diminish itsforce, as it reduced the liveliness of the animals in general, weakeningtheir “vital force”. Fontana pointed out that a similar mode of actioncould be seen in man after oral taking of the drug. In most casescardiac movements were increased, and the few observations to thecontrary would not invalidate this general rule.153

In fact this was in keeping with the clinical testimony of GeorgeYoung and Tralles, who were both quoted by Haller. Young hadobserved that opium heated the body and augmented fever, implyinga stimulating effect on the blood circulation; and Tralles had clearlystated that the drug intensified and accelerated the pulse of the heartand arteries, and thus the whole of the circulation.154 Whytt, on theother hand, was subsequently supported by Monro in this questionof cardiac effect, on the basis of his own animal experiments.155

What at first glance may look like a quarrel about some rather

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minor aspect of the pharmacology of opium, had actually importantimplications for the general concept of sensibility and irritability, andthus for a central topic of eighteenth-century physiology. The vigourof Haller’s response to Whytt can be understood in this way. The twoopponents agreed that opium diminished sensibility. If this effect waslinked with a decrease of irritability throughout the body, includingthe heart, Whytt’s view was strengthened that irritability dependedon sensibility. If, however, the irritability of the heart was not reducedby the drug, this gave support to Haller’s doctrine, according towhich irritability was a distinct property of muscle fibres,independent of the sensibility of the nerves and able to endurewithout any nervous influence.156 We see here how a drug or poisonwas employed as a tool to investigate questions of physiology – amethod that was to be developed fully only in the nineteenth centuryby Claude Bernard (1813-78).157

Yet, also for the pharmacological theory of opium itself the effecton the heart had wider implications. Not only was the question atstake whether opium was a cordial, as Sydenham had affirmed soemphatically, but more generally, whether opium was basically astimulant or a sedative. Attracted by these problems, as by theprominence of Haller’s and Whytt’s names, several researchers in thesecond half of the eighteenth century tried to find a solution. Indoing this they went beyond the method of animal experimentation,performing also trials on themselves158 and other test persons.

In his Edinburgh medical dissertation of 1764 MaxwellGarthshore (1732-1812) had stated in line with Haller, Tralles, andthe lectures of William Cullen (1710-90), that opium first of allaccelerated the movement of the blood and increased body heat,referring also to “experiments conducted by myself”.159 Only a yearlater, however, another Edinburgh medical student, the youngAmerican Samuel Bard (1742-1821), challenged this view on thebasis of careful self-experimentation and other human trials.

On the day before his first experiment Bard registered a dayprofile of his pulse rate without the influence of the drug, takinghourly measurements and avoiding physical exercise. On thefollowing morning he then took orally one and a half grains ofopium, i.e. a usual therapeutic dose, and measured his pulse rate inintervals from half to one hour. In this way Bard found a significantdecrease of his pulse from 71 per minute (which corresponded to hismeasurements the previous day) to a minimum of 57 per minute.This effect set in about an hour after taking the drug and wascombined with a feeling of relaxation and loss of concentration,

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which increased to sleepiness. It wore off after about seven hours.Bard basically confirmed these observations in three repetitions ofthe experiment on himself, in three of his friends, and in sixconvalescent patients of the Edinburgh Royal Infirmary. The resultdid not change either when he modified the experiment on himselfby taking the one and a half grains of opium distributed into sixportions in half-hourly intervals. In addition Bard measured his bodytemperature with a Fahrenheit thermometer: it never went beyondhis usual temperature of 98 degrees.160

On the basis of these results Bard concluded in favour of Whytt,and against Haller and Tralles, that opium slowed down the heart rateand blood circulation and that it rather lowered the body temperaturethan increasing it. In his opinion this could be explained with ageneral diminution of both sensibility and irritability in all parts of thebody. His only concession to Haller’s view was that the heart, becauseof its exquisite irritability, was less affected than other parts.161

Yet, despite Bard’s circumspect experimentation, his findings didnot remain unchallenged either. The Münster physician Carl JosephWirtensohn (d. 1788), likewise stimulated by the Haller-Whyttcontroversy, also examined the effect of opium on the heart and pulseand published his results in his inaugural dissertation of 1775 at theUniversity of Harderwyk. Having swallowed each a grain of opium,he and a friend had measured their pulse rate: within half an hour ithad increased from 76 to 86, respectively 71 to 84, per minute. Onthe other hand, when Wirtensohn had repeated Whytt’s experimentswith opium on isolated frog hearts, he had also found that theirpulsations decelerated. If, however, the hearts of frogs were merelyexposed, being left in situ, the giving of opium actually acceleratedtheir contractions. Taking these seemingly discrepant observationstogether, Wirtensohn suggested a mechanical explanation, whichtried to reconcile the standpoints of Haller and Whytt. Opium, heargued in the sense of Whytt, weakened the force of the heart. Butsince irritability was diminished throughout the body, this meantthat the contractility of the arteries, and thus peripheral resistance,was reduced, too. Therefore the heart would initially beat faster, andthe speed of the blood circulation increased. This explained theobservations of Haller. Only in the later stages of opium poisoningwould the weakening effect on the heart become manifest.162

Haller kept his interest in the problem long after his move fromGöttingen to Berne in 1753. The dissertations of Garthshore andWirtensohn are in his library, as are, among other works on opiumand the poppy, the monographs of Young and Tralles, Descazals’

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thesis under Hoffmann, and the seventeenth century studies ofBorch and Waldschmied, discussed above.163 In 1776 and 1777,shortly before his death, Haller commented on the issue again, whenhe reported on his experiences as an opium-using patient over the lastfew years. Suffering from a chronic bladder disease during his lastillness, he had rather reluctantly followed the advice of his Britishcorrespondent Sir John Pringle (1707-82) and taken up a regular useof opium clysters.164 During this treatment Haller repeatedly notedthat his pulse rate increased as the clyster eased his pains, and that itdropped again as the drug effect wore off. The same stimulation ofthe “vital powers” could be observed after oral taking.165 In this wayHaller was reassured in his old opinion that irritability wasindependent of sensibility. As for the cardiac effect of opium, he nowwent even a step further than in his earlier experimental work. Basedon his own experience, and also with reference to Tralles’ work, hestated that a moderate dose actually increased, supported andrenewed the powers of the heart, accelerated the pulse, and warmedthe body. Only very high doses of the drug inhibited, and eventuallystopped, the action of the heart.166

Though not naming Whytt, but doubtlessly with the latter’sexperiments in mind, Haller argued anew that trials on animals withsuch high doses and including vivisection were not the right way tostudy pharmacological effects. In particular he argued that openingthe body cavities of a frog would make its pulse rate drop anyway,without having given opium. Instead of vivisection he advocatedcareful observation of the drug’s effects in the human patient,especially examination of the relation of loss of sensibility (analgesia)to changes in heart action, as he had done in his self-observations.167

This was also the opinion of Tralles, who a few years earlier hadresponded to Whytt’s experimental findings, too. Quoting Youngand Garthshore, he had pointed out that their experiences on theirown bodies supported his view of opium’s stimulating effect on theheart. Simultaneously, he had discarded the self-experiments of Bardas the work of someone whose only aim had been to prove that theviews of Whytt (who was then still living) were right, while his (i.e.Tralles’) were wrong. More importantly, Tralles had made clear thathe was not ready to give up his knowledge of the effects of opium,which was based on “thousands of experiences” in many years ofmedical practice, only because Whytt had found something differentin “marshy frogs”. Paraphrasing Erasmus, Tralles had written thatsomeone heading for “the better and more solid” was not distractedby the unpleasant croaking of frogs along his path.168

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Behind the overt polemic, a number of important questionsrelating both to the validity of pharmacological experimentation ingeneral and the ambiguous nature of opium had been brought up bythe Haller-Whytt controversy. Haller’s objection that Whytt’svivisectional trials created artificial conditions, and were thereforequestionable, was not without justification. Likewise, Tralles’criticism of Whytt’s frog experiments touched the problem oftransferability of results from animal to man, in this case accentuatedby the fact that a cold-blooded animal had been used. Bothobjections – artefacts and lack of transferability – were generallydiscussed around this time, especially also with respect to Haller’sdoctrine of sensibility and irritability.169 Such debates reflected agrowing awareness of the fallacies of animal experimentation. Thisawareness was not limited, however, to the camp of critics, but canbe found in the experimental researchers themselves. As mentionedabove, Whytt had performed control experiments, in which hestudied the effect of the vivisectional procedures alone, withoutgiving the drug. And though the majority of his trials had in factbeen performed on frogs, he had made the test on a warm-bloodedspecies (dog) as well. Alexander Monro was particularly aware of theobjection of a lack of transferability. While he admitted that “theeffects of a medicine may be much more speedy and violent on onespecies of animals, than on another”, he emphasized that the basicmode of action was the same, if the used species were “provided withlike systems of nerves and vessels”.170

Self- and human experiments were a way to avoid the problem oftransferability, yet here the possible influence of subjective factorsbecame apparent. When Samuel Bard in one of his trials had takenthe rather high dose of two and a half grains of opium, nausea andvomiting set in, and fearing an intoxication, his pulse rateaccelerated. Accordingly, this finding was not included in hisassessment of the drug’s cardiac effect.171 Similarly, Wirtensohninitially suspected that the increase of the pulse rate in himself andhis friend had rather to do with some emotion, or their expectationto see what would happen, than with the effect of opium itself. Onlyafter he had confirmed his findings repeatedly in the treatment ofpatients, did he regard the effect as authentic.172

Another difficulty was that of dosage. Both Haller and Fontanahad made clear that the effect of opium on the heart differed,depending on whether a “moderate” or a “high” dose had been taken.In the first case it consisted in stimulation, in the second ininhibition. Certainly this can be seen as a possible explanation for the

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discrepancy to Whytt’s observations. Yet Sproegel and Haller usedvery high doses in their animal experiments as well, such as ten grainsof opium in a frog, i.e. about ten times the usual dose in man.However, they do not seem to have had a clear notion of a ratio ofdose and body weight. Sproegel often gave some indication of thesize, breed, or general state of his experimental animals, such as “amiddle-sized, yet very robust dog”, “a yellow Molossian dog”, or “astrong tom cat”. But such descriptions rather had the purpose toprovide some idea of the resistance to poisoning that could beexpected in a particular animal. In fact Sproegel concluded from hisexperiments that animals generally tolerated much greater quantitiesof poisons than human beings, and Haller pointed out that heartaction was more resilient in cold-blooded than in warm-bloodedanimals. On the other hand Fontana, in his studies of viper venom,did explicitly relate the amount of poison to the weight of hisexperimental animals. For example, he extrapolated the lethal dose ofvenom in pigeons of six ounces weight to that which would kill a 750pound ox or a 150 pound man.173

A problem which may also have played a role was the variety inthe purity or quality of opium. Although this element of uncertaintywas in principle known (see above), it was not taken account of inthe debates surrounding the Haller-Whytt controversy. Typically,neither Haller or Sproegel, nor Whytt, nor one of the laterresearchers mentioned above, went into any detail about the sort andquality of opium they had used in their experiments.

Stimulant or Sedative?

Still, towards the end of the eighteenth century, an answer to theHaller-Whytt problem gained ground. Rather than different dosagealone, different stages of the action of opium were assumed to beresponsible for the observed differences in effects. In 1789, in a prizewinning essay for the medical faculty of Göttingen, the studentGeorg Christoph Siebold (1767-98), son of the renowned Würzburgprofessor of anatomy, surgery and obstetrics Carl Caspar Siebold,suggested such a theory. Based mainly on animal experimentationand some self-experiments, he proposed a first stage, in which opiumraised the pulse and respiration rates as well as body temperature,followed by a second stage, in which these parameters were lowered.Moreover, he observed that this first phase of stimulation lasted thelonger, the smaller the intake of opium had been.174 Probablyindependently of Siebold, Samuel Crumpe published similar views in1793. In experiments on himself, which were partly repeated on

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another healthy test person, Crumpe studied the effect of opium onthe pulse in the manner of Bard and Wirtensohn. After dosesbetween one and two and a half grains he measured the pulse everyfive minutes for one or two hours and noted accompanyingsymptoms. In doing this he found a fuller pulse and an increase ofthe pulse rate during the first half hour, which was followed by adecrease to the initial rate or below. While the phase of acceleratedpulse was linked with sweating, alertness and a bright mood, thephase of declining pulse was characterized by languor, headache,drowsiness, and nausea, followed by vertigo, trembling, vomiting,and a longer “stupid state”.175

Crumpe’s observations were relevant in two respects. Firstly, theyoffered an explanation for the discrepant observations of Bard andWirtensohn, and by extension for those of Haller and Whytt. Bardhad started to measure the pulse only half an hour after taking thedrug. He had therefore (as Crumpe pointed out) missed the initialincrease of the pulse rate and described only the second phase.176

Wirtensohn, on the other hand, had measured only up to thirtyminutes after the intake of opium and had therefore noted only theacceleration of the pulse in the first stage.177 Seen in this way, bothhad only in part been right. Secondly, Crumpe’s experimentalobservations provided support for the then widely discussed doctrineof excitability of John Brown (1735-88). As mentioned above, Brownregarded opium as the strongest stimulant, the powers of whichsurpassed those of ether, camphor, volatile alkali, musk, and alcohol.Though referring to trials with these drugs, his assessment of opiumseems to have been largely based on his own experience with it intreating his fits of gout. The instant and reliable success of the drugin this – in Brown’s understanding – asthenic disease (characterizedby weakness or lack of excitement) commended it has a highlyeffective stimulant medicine.178

Crumpe explained his two stages of the action of opium in termsof Brown’s system, acknowledging simultaneously the Scotsman’soriginality. The first stage was that of stimulation and excitement,which, as the body’s excitability became exhausted, turned into thesecond stage. This was characterized by insensibility to furtherstimuli, resulting in painlessness, slow movements of the heart andarteries etc., followed – if a very high dose had been given – by so-called indirect asthenia or weakness (due to over-excitement), thatsometimes ended with death.179

By the camp of Brunonian physicians Crumpe’s work was hailedas experimental proof of their therapeutic system. A positive review

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of the German edition (1796) of Crumpe’s book, in Melchior AdamWeikard’s (1742-1803) Magazin der verbesserten theoretischen undpraktischen Arzneikunst, stated:

By the experiments described in this work any doubt has beenremoved that opium is a stimulant. The mitigation of pain followsonly after a previous stimulus, an increase of pain etc. Thus opiumdiminishes sensibility, when it has induced indirect weakness…Almost everything fits together with Brownian doctrine.180

In fact Crumpe had made quite extensive trials to establish thestimulant power of opium. They included self-experiments in whicha watery solution of opium was applied to the eye, to excoriated skin,and into the urethra, always followed by pain or burning sensations.Powder of opium inhaled into the nose acted like weak snuff. Andvarious animal experiments also appeared to confirm the stimulanteffect of the drug.181

Support for a Brownian understanding of opium as a stimulantcame also from Alexander von Humboldt (1769-1859), whoincluded the drug among the various substances which he tested fortheir effect on the excitability of nerves and muscles. His trials wereperformed with alcoholic solutions of opium, which he applied tothe vagus nerve of a dog, the ischiadic nerve of a lamb, the axillar andcrural nerves of frogs, the forefoot of a rat, and isolated frog hearts.Humboldt claimed to have observed in these experiments an initialincrease in excitability (both spontaneously and after electricstimulation), followed by a state of atonia or lack of excitability,which he attributed to “over-stimulation”. On the basis of these trialshe objected to Fontana’s finding that opium did not act directly onnerves; and he sided with Whytt against Haller and his followers,asserting that opium did in fact quickly destroy cardiac pulsationafter a brief phase of stimulation.182 Most importantly, however, heconfirmed the views of Crumpe and Brown:

These facts and experiences now convince me completely thatopium … weakens, sedates, and acts as a narcotic only through over-stimulation. What I have observed in cold- and warm-bloodedanimals, in voluntary and involuntary muscles, confirms thedoctrines of the Brownian school…183

Speculating in the terminology of chemistry after Lavoisier,Humboldt thought that “carbon” and “hydrogen” contained inopium might attract “oxygen” from animal fibres as well as fromarterial blood, disturbing in this way the vital processes. Like other

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researchers of the time he applied opium solutions also to plants.Again he thought to have found here a decrease in “vital power”,expressed in their reduced absorption of fluid.184

On the other hand, those sceptical of, or in distance to, Brown’ssystem of excitability did not give much weight to Crumpe’s evidenceand conclusions. In fact his work became the prime target ofconservative medical men, who vigorously defended the view thatopium was a sedative. As the Critical Review pointed out, forinstance, pain after application to the eye was not a certain indicatorof a stimulant, because this effect could be evoked with “everyextraneous body”, and often pure water would do the same.Moreover, even if opium had some stimulant power (as the reviewerconceded for argument’s sake), it would not follow that its sedativeeffects resulted from previous stimulation. If this was true, thedegrees of stimulation and subsequent sedation should beproportional. Experience with increasing doses, however, taught thatthis was not the case, because they would eventually lead to sedationalone, without the first stage of stimulation.185

An extensive, devastating critique of Crumpe’s book waspublished in 1802 in the London Medical and Physical Journal byMichael Ward (1762-after 1831), surgeon to the ManchesterInfirmary.186 Ward had made himself known a few years before with“successful” external opium treatments, in which he had beensupported by his prominent medical colleague Thomas Percival.187 Insharp opposition to Crumpe’s and Brown’s understanding of thedrug’s mode of action, he now moved on to explain his own theory.For him, opium was clearly a sedative. Crumpe’s own human andanimal experiments, argued Ward, had shown this, since theydemonstrated a decrease of the heart rate and, in the animals, also analmost immediate loss of sensibility and motion. Crumpe hadtherefore been misguided by Brownian prejudice in hisinterpretation. His theory was “erroneous” and should be “consignedby all to merited oblivion”.188 As Ward saw it, it had been aparticularly serious mistake to conclude from the resemblance ofopium’s effects to those of wine and alcohol that it was a stimulant.Referring to Cullen, Ward regarded the latter two (as well as opium)as “narcotic sedatives”.189

He did not leave his criticism at this argumentative level. Usinghis sixteen-year-old house pupil as a test person, Ward examined thedrug’s effects experimentally, too. Having embrocated in two trialsthe boy’s legs and feet with a mixture of opium tincture, olive oil, andegg yolk, he noted that the pulse rate dropped considerably within

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ten to fifteen minutes. Moreover, the boy complained of feeling coldand drowsy, and his pulse appeared soft and weak, before – afterabout an hour – it started to return to normal again. Alsosubjectively, there was no indication of opium having a stimulanteffect. Rather it seemed to act as a powerful narcotic:

I now asked if he had felt exhilarated at all, either in this or the formerexperiment? He answered, No; and could not help smiling at thequestion, though he looked like one in the cold fit of an intermittent…On his saying he had often been very cold, but had never before foundthat sensation accompanied with such disagreeable symptoms, Imentioned the word Horror, and he said it conveyed the best idea ofwhat he had felt.190

Ward’s own theory of opium’s modus operandi was not only based onthis experimental evidence, but actually picked up on one ofCrumpe’s observations in animals. After injections of opiumsolutions into the abdominal cavity of animals, Crumpe had seenincreasead redness and apparent inflammation of their viscera, whichhe interpreted as a sign of the drug’s stimulant effect. For Ward,however, this showed that opium had made the blood vessels loosetheir “tone” and “action” – a view, which he believed to be alsosupported by Alston’s microscopical observation of a reducedcapillary blood flow in opiated frogs (see above).191 It actually was thestarting point in his pathophysiological explanations. Opium takenorally, wrote Ward, acted “directly as a sedative upon the vessels andcoats of the stomach and small intestines… retarding or interruptingTHE NATURAL FUNCTIONS OF THESE IMPORTANTORGANS”.192 The well-known alleviation of vomiting, diarrhoea,and tenesmus could easily be understood in this way. Furthermore,the reduced flow in the arteries of the stomach and intestines wouldlead to plethora in the aorta, which extended to the heart and thepulmonary, subclavian, and carotid arteries. Their contractionsconsequently increased in frequency and strength, resulting in atemporary acceleration of the blood circulation with its symptoms ofwarmth, liveliness, and alertness. Within an hour, however, the bloodwould also start to stagnate in the veins of the abdominal organs, theheart therefore receiving less venous blood. The arterial plethora wasnow quickly taken off, frequency and strength of the pulse werereduced below standard, and this led to languor, drowsiness,headache, nausea, and tremor. This, according to Ward, was theseries of changes after a moderate dose of opium. After a “large” dose,taken by an unaccustomed person, the second phase would come up

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immediately, resulting in a “state of suspension” of the physiologicalfunctions and often ending with death.193

Ward thus principally accepted the “two stages”-concept ofCrumpe, but for him also the first stage (increased circulation,alertness etc.) was indirectly explicable with a sedative effect ofopium. In comparing the rival theories of Crumpe and Ward, itbecomes clear that the crucial difference lay in their understanding ofthis first stage. For Crumpe (as for Humboldt) it was the essentialprerequisite for the second phase characterized by languor,drowsiness etc.: in the sense of Brown, stimulation exhaustedexcitability, thus leading to this latter stage. For Ward, however, thefirst phase was merely a transitory side effect of the directly sedatingaction of opium. It could be explained haemodynamically, and afterhigh doses it would not appear at all.

The Manchester surgeon’s attack on Crumpe’s theory of opium asa stimulant is only one – albeit a particularly elaborate – example forcontemporary discussions on the nature, and thus the therapeuticplace, of the drug. As Ward himself pointed out, not only Brown andCrumpe, but also Erasmus Darwin, in his Zoonomia, had called it apowerful stimulant. Cullen, on the other hand, in his Treatise of theMateria Medica, had ranked it as a sedative. Other authors had takenan intermediary position. George Young, in his still highly regardedTreatise on Opium, had described both exhilarating and cordialqualities and sedative effects. And Hooper’s Medical Dictionary listedthe drug both under sedatives and stimulants.194

The belief in the stimulant power of opium was actually acornerstone of Brown’s doctrine, and the debate over the drug’sstimulant or sedative property reflected the wider conflict betweenhis followers and adversaries. As Claudia Wiesemann has recentlyargued concerning Germany, where the debate on Brownianism wasparticulary intense around 1800, socio-political connotations gave aspecial edge to those exchanges: Brown’s new therapeutic system,with opium and alcohol as favorite stimulants, fitted the youngergeneration of doctors who were prone to Romantic ideas and showedrevolutionary zeal, both medically and socially. Anti-Brownians, onthe other hand, who saw a very liberal use of opium and alcohol as adanger to health, could be characterized as conservative, bourgeoisrepresentatives of late Enlightenment ideas, the prime example beingthe Prussian court physician and Berlin professor Christoph WilhelmHufeland (1762-1836).195 For Britain such a divide seems less clear,though Thomas Beddoes might be quoted as an example of theformer “type”.196

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To some extent the stimulant-sedative controversy over opiumcan also be seen as yet another edition of the old debate on the drug’sambiguous nature that went back to the seventeenth century, as hasbeen outlined above. With the beginning of the nineteenth centurypharmacological theories on opium had surely become morecomplex, as the example of Ward shows, being informed by thephysiological knowledge accumulated in the previous fifty years byHaller, Whytt, and others. But, three years before the isolation of thefirst opium alkaloid by Friedrich Wilhelm Sertürner (1805), thenature of the drug and its effects were still far from being clearlyunderstood, and there was no theory of its mode of action that wouldhave been unanimously accepted. To a great extent theories onopium had been a mirror of the changing general medical theoriesand systems of the eighteenth century. Aptly the medical historianKurt Sprengel observed in 1803:

How the spirit of the times has changed since one and a halfcenturies can hardly be seen more clearly than from a short survey ofthe different concepts of the effect of opium within this period.197

Before we turn to the (renewed) efforts in chemical analysis of thedrug after 1800, it will therefore be appropriate to pause and askwhat the string of pharmacological theories on opium since themidddle of the eighteenth century had meant in terms of therapeuticpractice. In this context, the views on the drug’s addictive propertiesalso need to be considered.

Pharmacology and Therapeutics

As has been shown above for the late seventeenth and earlyeighteenth centuries, a connection between experimental studies ofopium and recommendations for its therapeutic use existed from thebeginning, although they were not very stringent. A convenientstarting point for examining the further development of thisconnection is Charles Alston’s work of 1742 with its experiment-based rejection of the then current “rarefaction theory” of opium. ForAlston the replacement of this, in his view erroneous theory by hisconcept of direct action on nerves was not only a matter of scientificcorrectness, but of therapeutical importance. The theory that opiumrarefied the blood, he claimed, “might be of bad Consequence, andlead into dangerous Errors in Practice”.198 After an overdose ofopium, for example, venesection would be the measure of choice, ifrarefaction of the blood was assumed. There had been reports in theliterature, however, that the giving of a narcotic shortly after

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venesection had been lethal; and Alston was able to quote one case ofhis own experience in Edinburgh, in which an accidentalintoxication with opium a day after liberal bloodletting had led to thepatient’s death. Moreover, argued Alston, how could opium be founduseful in haemorrhages and smallpox, if it rarefied the blood(implying that bleeding should get worse and smallpox turnhaemorrhagic on this supposition).199

Apart from his warning of combining venesection and opium,Alston professed his belief in the usual indications for the drug, suchas violent pains, sleeplessness, excessive evacuations, “Choleras”,“Dysenteries”, various fevers, gravel, gout, cough, and consumption.He actually advocated a more liberal use of opium than hispredecessors in this subject about half a century earlier, stating thatopium was not absolutely contraindicated in infants, weak, plethoric,or aged persons, pregnant women, and malignant diseases.200 Alston’sindications for opiates included also “Disorders of the Nerves”,which strikes as following naturally from his theory of the drug’sdirect effect on the nervous system, though he did not furthercomment on this field of therapy. This link was fully elaborated,however, in the works of his Edinburgh colleague Robert Whytt, who– as shown above – strongly supported the “nerve theory” on thebasis of his numerous animal experiments.

These had convinced Whytt that opium acted directly on nervesterminating at the site of application and that its effect spread quicklythrough the whole nervous system by way of “sympathy” or “generalconsent”.201 On these grounds opium was one of the principalpalliative medicines in “nervous and hysterical people”, since itweakened the “sentient power of the nerves” and consequentlydiminished “those pains, irregular motions, or spasms which arisefrom any usual irritation”. The other main palliatives – camphor,castor oil, musk, and asa foetida (gum-resin of the root of Ferulaassafoetida) – were used as stimulants.202 Following thispharmacological scheme, Whytt recommended opium in fixedspasms, convulsions of muscles, of the stomach and intestines, intetanus, hydrophobia (characterized by convulsions of the gullet andstomach), pains without inflammation, weakness after a too greatflux of the menses, flatulent colics, spasmodic asthma, and“immoderate discharge of pale urine” in hysteric people (which heattributed to “an increased motion of the secretory vessels of thekidneys”).203 Together with asa foetida, opiates were further valued asa means to lessen “that restlessness, and those hot flushings and sickfits, which many hypochondriacal people are liable to”.204

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Like Alston, and unlike earlier authors, Whytt was prepared togive opium in plethoric patients. He advised here previousbloodletting to avoid “bad consequences” and to make the treatmentmore effective, apparently ignoring Alston’s warning of combiningvenesection and narcotics. Whytt was cautious, however, in givingopiates to “low-spirited” patients, arguing that their relief was onlytemporary and that they would become even more depressed, afterthe drug’s effects had worn off. Likewise he warned of administeringopium in large doses over a long time. Lessening the sensibility andvigour of the whole nervous system, it impaired not only physicalstrength, but also “the faculties of the mind”.205

As can be seen from the example of Whytt, the understanding ofopium as an immediately neurotropic agent, based to a great extent onanimal experimentation, opened up a whole field of indications underthe heading of nervous disorders. Furthermore, restraints in theopium treatment of plethoric patients, motivated by the earlier beliefin the drug’s expanding effect on blood and blood-vessels, seem tohave loosened. In this way the change in pharmacological theory mayhave had some impact on opium therapy, though its traditional mainindications were obviously kept (as can be seen from Alston).

This link between opium theory and therapy can be tracedfurther in relevant authors around the turn of the nineteenth century.As described above, Michael Ward argued that opium primarilydiminished the irritability and motility of the vessels and coats of thestomach, thus reducing gastrointestinal secretion. Announcing thathis new theory would be of “practical utility”, he was able to give anexample that must have been plausible at the time. In contemporaryunderstanding the proximate cause of diabetes (mellitus andinsipidus) was an increased secretion of gastric juice. Opium,reducing this secretion according to Ward’s theory, was thussuggested by him as a promising antidiabetic, all the more becausethe drug’s known diaphoretic effect would additionally reduce thepatients’ polyuria.206 To a much greater extent, however, theconnection between pharmacological theory and therapeuticrecommendations can be traced in the author who was so severelycriticized by Ward, Samuel Crumpe.

It has been outlined in previous sections how Crumpe –sympathetic to Brown’s doctrine – provided ample “proof ” of thelatter’s view that opium was a stimulant, drawing his arguments bothfrom animal and human trials, including self-experimentation. Aclose examination of Crumpe’s discussion of the drug’s therapeuticuses (which follows in his book of 1793 after the descriptions and

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interpretations of his experiments) reveals the impact of histheoretical understanding.

He saw two principal therapeutic uses of opium: as an anodyne(i.e. analgesic) by giving it “in large doses, and at considerableintervals”, and as a stimulant by giving it “in moderate dosesfrequently repeated”.207 While the former was the traditional use, thelatter, new use had a number of consequences for the treatment ofparticular diseases. In continued fevers, for example, Crumpedistinguished between a first, inflammatory stage, in which opium asa stimulant would make the condition worse and was thereforecontraindicated, and a second stage, characterized by debility, inwhich it showed very good effects exactly because of its stimulantpower.208 As he pointed out, these considerations were in keepingwith recent clinical observations of the Oxford professor andphysician Martin Wall (1747-1824), who had reported about hissuccesses with opium in treating so-called low fevers or typhus (i.e.“putrid” fevers, characterized by debility) and synochus (i.e. aninitially inflammatory fever changing to the debility of typhus).209

Moreover, Crumpe distinguished between “acute” and “passive”inflammations. The former, e.g. pneumonia, gastritis, and acuterheumatism, resulted from an increase in excitement, and the use ofopium as a stimulant medicine was therefore harmful in them.However, the latter, “passive” forms, including scrophulousinflammations, chronic rheumatism, and certain species of tonsillitisand ophthalmia, were seen as connected with debility and thereforebenefiting greatly from the drug’s stimulant effect.210

Along these lines a considerable list of other diseases orpathological conditions was discussed by Crumpe.211 His usualrationale was to identify their nature or stages in terms of theBrownian doctrine of excitement and then to outline the use ofopium on the new supposition that it was a stimulant. Sometimesthis would confirm the drug’s traditional use (e.g in intermittentfevers, going back to Galen), sometimes it would suggest change (e.g.contraindication for opium in measles, against Sydenham) ordifferentiation (e.g. in smallpox depending on their stage, partlyconfirming, partly departing from Sydenham).212 Acuteinflammations had largely been a contraindication for the use ofopium on the basis of the “rarefaction theory”. But now with opiumas a stimulant, and acute inflammation as a state of excessiveexcitement or sthenia, there were new reasons for not allowing its use.

Similar efforts to redefine opium therapy can be found someyears later in Germany as well. In 1803 the Braunschweig physician

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Adolph Henke (1775-1843) devoted a lenghty article to this subject,which was published in the Archiv für medizinische Erfahrung. Theeditor of this journal, Ernst Horn (1774-1848), formerly professor ofmedicine in Braunschweig and now in Wittenberg, dealt with thesame topic in a monograph in the following year. Both of themexpressed their belief in the stimulant power of opium, yet wereanxious to correct not only traditional therapy, but also therapeutic“misuse” or “abuse” of the drug by “crude Brownians”.213 Henkequoted Alexander von Humboldt’s animal experiments as proof ofthe view that opium was a stimulant, apart from the clinicalexperience of well-known Brownian physicians, such as Joseph Frank(1771-1832) and Andreas Röschlaub (1768-1835).214 Both Henkeand Horn generally warned of giving the drug in “hypersthenic”states, advocating simultaneously its circumspect, critical use inasthenic diseases.

Seen as a whole, these examples point to the conclusion thatpharmacological experiments with opium and the theories drawnfrom them, or at least connected with them, had in fact a distinct andconsiderable influence on therapeutics in the later eighteenth andearly nineteenth centuries. Though this may be said in general,contemporary resistance and opposition of doctors to the newpharmacological approach must not be overlooked, however.

The perhaps most influential critic was the Edinburgh medicalpractitioner George Young (1691-1757), whose Treatise on Opium,Founded upon Practical Observations (1753) was very frequentlyquoted in the second half of the eighteenth century and alsopublished in a German translation in 1760.215 Young rejected thechemical investigation of drugs, arguing that they revealed theirmedicinal properties in the human body, not in the retort or still.Likewise he did not accept in vitro experiments with opium or otherdrugs on freshly drawn blood, because such trials failed to considerthat the circulating blood was continually changed by absorption andsecretion. Neither would intravenous injections in living animalsteach anything about the therapeutic effects of substances, since evenharmless milk had acted as a deadly poison, when applied in this way.And the classic method of examining drugs by tasting and smellingthem could give no more than some first hints. For Young the onlyvalid method of finding out their medicinal qualities was to studytheir effects in the treatment of particular diseases and to deducefrom this “some general rules”.216 In other words, Young’s approachwas that of therapeutic empiricism. Accordingly he discussed indetail the use of opium in a great variety of symptoms, diseases, and

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conditions on the basis of his own practical and therapeuticexperiences.217 It has already been mentioned above that similarlydismissive remarks about experimental evidence were made by thecontemporary German authority on opium therapy, the Breslauphysician Balthasar Ludwig Tralles (1708-97).

The resistance of medical men to accept experimental results,especially if they did not conform with convential practice, canfurther be illustrated with the question of external, topical use ofopium. Opium-containing plasters and ointments had already beenused in Greco-Roman medicine.218 Yet since the seventeenth centurydoubts had been voiced concerning the analgesic efficacy of suchpreparations. As Alston noted, Wedel had stated that he had beenunable to observe a stupefying effect of externally applied opium.219

Following his general plan of examining open questionsexperimentally, Alston made a test on himself, putting opium plastersover night on his arm and little finger. Since neither stupefaction, norinflammation, nor any other effect occurred, he concluded:“Hence… Opium is not, properly speaking, narcotick externally; andthere may be Pains which it cannot remove as a Topick.”220 AlexanderMonro secundus took up the question as well, comparing the effectsof internally and externally applied opium solutions on frogs. Thesame symptoms of poisoning appeared in both cases, yet more slowlyafter external application, and Monro concluded that “in us, fromthe greater proportional hardness and compactness of the skin, thedifference will probably be still more considerable than in thefrog”.221 Accordingly he suggested that it was better to take opiuminwardly, even if pain or convulsions were local.222 John Leigh (before1755-after 1792), an American physician, who in the 1780s didsome experimental work on opium in Edinburgh, repeated Alston’sexperiment with opium plasters on two men, also without anynoticeable effect. Consequently he concluded “that the commonreceived opinion respecting the operation of opium, externallyapplied, must be erroneously founded”.223 Siebold, in his Göttingenprize essay of 1789, on the other hand, reported that he hadproduced polyuria, sleepiness and typical changes of the pulse byrubbing dogs with an opium ointment, and that he had killed a new-born rabbit by immersing its body in a strong solution of the drug.224

Yet, four years later Crumpe confirmed Alston’s and Leigh’s negativefindings on his own skin.225

There was thus a considerable body of experimental knowledgeon the efficacy of externally applied opium. It suggested that, whilesuch efficacy could be found in some animal trials, there was no

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experimental proof that opium acted as an analgesic, narcotic, or inany other way through human skin. But external opium therapycontinued, it seems, unabated. Characteristically a reader of Leigh’sstudy commented in the Critical Review in 1786:

Dr. Leigh found the external application of opium had little effect;yet, whoever has tried it in spasmodic pains of the side, in hystericaffections of the stomach, or… in a locked-jaw, will probably find itan useful remedy.226

True, Michael Ward, as mentioned above, apparently produced asedating effect with opium embrocations in two experiments on hishouse pupil.227 And – encouraged by Percival – he had reported casesof delirious patients, in which such external treatment had producedgood effects, a finding also described shortly before Ward by theFlorence physician Vincenzio Chiarugi (1759-1820).228 But suchevidence was probably not much needed to sustain the old practiceof external opium treatments. Hufeland, in his authoritative andinfluential manual of therapy Enchiridion medicum, first published in1836, still advocated this form of application. 229 Likewise itcontinued to be mentioned in medical dictionaries and encyclopediasof the first half of the nineteenth century.230

A certain lack of recognition of experimental studies in medicalpractice can also be traced in some other responses to the above-mentioned work of John Leigh. On the basis of chemical analysis andpharmacological trials – the latter made on animals, healthy testpersons (including self-experimentation), and patients – Leigh hadshown among others that the resin of opium was its most efficaciouscomponent, that a mixture of this resin with liquorice was most easilydissolved in the stomach, and that previous taking of acids lessened thedrug’s effects. Though his study had earned him the prize of theEdinburgh Harveian Society for the year 1785, reviewers were notimpressed at all.231 The critic of the Monthly Review thought that Leighhad not made any new observations and that his experiments, thoughnumerous, merely confirmed “the opinions concerning the propertiesand effects of this powerful medicine, which most writers on themateria medica have formerly delivered.”232 The above-mentionedreader writing in the Critical Review even characterized Leigh’sexperiments as “few, trifling, and inconclusive”. Variations in the drug’seffects on “differrent constitutions, and on the same at different times”required much more trials. But even this would only be a very first,small step. Diseases, argued this critic, changed the pharmacologicaleffects. Accordingly he rather referred to the experiences of “the more

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attentive practitioners” – no doubt with authors like Tralles in mind,whose work he had quoted earlier with approval.233

A more positive critique appeared in the German review journalMedicinische Bibliothek, edited by the Göttingen professor ofmedicine Johann Friedrich Blumenbach (1752-1840). Itacknowledged that Leigh’s animal and human experiments were“always interesting”, but they were

… on the whole, and particularly in comparison with the almostinnumerable, divergent and often contradictory trials of his manypredecessors, still not yet sufficient to draw certain generalconclusions. If only someone could be found, who had both the witand knowledge and the full time to perform a truly pragmaticrevision of all these hitherto published trials, to repeat himself themost decisive of them, to compare them etc., so that this until nowlargely dead capital might pay some practical interest at last.234

In other words, the considerable experimental knowledge on opium,which had been amassed until the late eighteenth century, still hadnot led to reliable guidelines for therapeutic practice, even in theassessment of a rather sympathetic reviewer.235 It is quite possible thatit was Blumenbach himself who had written these lines, for in thesame year, 1788, he initiated and put a prize question on the effectsof opium (compared with those of wine) to the medical students ofGöttingen. It was specified in the question that the drug’s effects hadto be studied in warm-blooded animals and that the use ofamphibians was permitted only for comparative purposes.236

Obviously there was concern about the transferability of results toman. Siebold’s essay was the only work that came in, yet it won theprize not for this reason alone. In their opinions the professors of themedical faculty said they were pleased with the variety of carefullyperformed experiments and the conclusions drawn from them.237

Blumenbach wrote a very friendly review in the Göttingische Anzeigenvon gelehrten Sachen, in which he emphasized Siebold’s findings ondose-effect relations and stated that the “useful practical conclusionsand applications” included in this essay gave an example of the“important, immediate beneficial use” that practical medicine gainedfrom theoretical inquiries of this kind.238 What he probably meantwas Siebold’s experimentally substantiated two-stages theory of theeffects of opium and their relation to dosage (see above). In fact thelatter had advised on these grounds giving small doses of opium, if apatient’s pulse and other vital functions had to be increased, and toadminister a larger quantity, if sedation was required.239

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As has been noted above, Crumpe later made a similar distinctionafter his own experiments, and it was also adopted by the moderateBrownian Adolph Henke.240 On the other hand, Crumpe’s animaland human experiments were simply dismissed in the Critical Reviewas adding “little to our knowledge”, and with reference to hischemical experiments with the drug the reviewer reminded that therewere “facts not to be learned in the elaboratory, but which must beobvious to every attentive practitioner”.241

Taken together, the examples of Leigh’s and Siebold’s prize essays,and the contemporary comments made on them and otherexperimental studies, allow three conclusions. Firstly they show thatthe medical élite of the time, in Edinburgh and Göttingen, was wellaware of the potential of practical, therapeutic conclusions frompharmacological experimentation and consequently encouraged suchwork; secondly, however, that there was a view that the requirementsof medical practice had so far not been sufficiently fulfilled in mostexperimental studies. Blumenbach’s praise of Siebold’s work, whichdid fulfil these requirements to some extent, indirectly confirms thispoint; and thirdly (if we consider also the question of external opiumtreatments) they indicate that practitioners resisted acceptingexperimental evidence, when it tended to discredit traditionaltherapeutic practice. Basic arguments against any investigation ofdrugs in animal and human experiments were the problems oftransferability from animal to man and from healthy test persons topatients. If the opinion was adopted that diseases actually changed theeffects of drugs, then therapeutic empiricism as exercised by GeorgeYoung was in fact the only way forward in pharmocotherapy.

Seen as a whole, it may be said from the case of opium that theconnection between experimental pharmacology and therapeuticswas strengthened in the course of the eighteenth century. But it wasstill a new and not yet well established relationship: experimentalistswere often rash in their conclusions, and practitioners may well beseen as having been rightly sceptical about this new approach.

Opium as a Habit-Forming Drug

In exploring the relations of pharmacology and therapeutic practice,one further aspect of opium needs to be discussed, which, thoughmuch less important to the eighteenth century than to our times, didnot go unmentioned: the drug’s potential to cause addiction.Detailed knowledge about habitual, non-medicinal taking of opiumin Oriental countries had been made available through the reports oftravellers since the sixteenth century.242 Such travel works were very

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popular throughout the seventeenth and eighteenth centuries, astheir multiple editions and translations indicate.243 They were alsoquoted in the pharmacological literature of the time, particularly asseveral of the travellers were medical men.244 The astonishingly highdoses of the drug consumed and tolerated by habituated opium-eaters were especially pointed out in the accounts of sixteenth-century travel authors, such as the Portuguese physician Garcia daOrta and the Dutchman Jan Huygen van Linschoten, who bothwrote on India, and the Italian doctor Prosper Alpin, who reportedon Egypt.245 This phenomenon was seen as remarkable, because it wasan impressive example of habituation to a substance that wasessentially considered a poison. As Alpin noted, Galen had alreadymentioned habituation with respect to another dangerous drug,hemlock.246 Apart from interest in particular properties of opium,such as its alleged aphrodisiac effect (discussed in detail by da Orta)and its euphoric and dream-inducing powers (a central topic inAlpin), the craving of opium-eaters and their dangerous symptomswhen failing to obtain a new dose were regularly described. Suchdrug dependence was not yet seen as a disease in the modern sense,however, as it was since the nineteenth century. Yet it wascircumscribed both in physiological and moral terms.

Alpin, for example, understood habituation to opium as a processin which human nature, being stronger than the poisonous drug,made the latter “in some way into a foodstuff ”. This explained forhim also the crisis in which opium-takers fell, if they were deprived ofthe drug. “Slavery” (servitus) was the term he used for thephenomenon of addiction.247 Yet not dependence as such wasconsidered harmful by the travel authors – such concern emergedonly, as Claudia Wiesemann has recently argued, in the earlynineteenth century.248 The problem was rather seen in the acutedanger to life in withdrawal situations and especially in the drug’slong-term toxicity. Da Orta and van Linschoten related that habitualopium-eaters appeared always sleepy and drowsy, and were known tobecome impotent. Alpin emphasized that they turned “comatose,lethargic, like frozen”, and that their personality changed. Becominginconstant, they would say “yes” in one moment and “no” in the next,so that people were on their guard against making deals with them.249

Concerns about the harm to physical and mental health throughhabitual consumption of the drug became more prominent in thedescriptions of later travellers, such as the French merchant JeanChardin (on Persia) in the late seventeenth century, and thephysicians Engelbert Kaempfer (Persia and India), Alexander Russell

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(Turkey), and Jakob Reinegg (Persia), and the Baron François de Tott(Turkey) in the eighteenth century.250 Their accounts now wentbeyond the scientific or medical interest, revealing also their personalattitude to opium-eaters. It reached from pity in Chardin and de Tottto outright disgust and moral condemnation in Reinegg. Russelldescribed them as “debauchees”, who looked “old and besotted, likesuch as in Europe have ruined their constitutions by harddrinking”.251 Kaempfer depicted them as emaciated, weakened, withgloomy and stupid minds, and he had been outraged by Indians whocommitted suicide by taking opium and then running amok.252

Reinegg described with abhorrence the initiation of a young man tohabitual opium-eating as well as the physical and moral decline of thehabituated.253 On the other hand it was acknowledged that someopium-takers, who suffered from their condition, made efforts tobreak their habit. Alpin had already observed that they tried tosubstitute the drug with plenty of seasoned Cretan wine, andKaempfer reported that they had often presented themselves to himand offered a high reward, if he could cure their craving withoutendangering their lives or damaging their health.254 Reinegg claimedto have met opium-eaters “who had freed themselves from thisplague by the frequent use of vinegar” and mentioned others whosubstituted the drug by the smoking of hashish.255

This knowledge conveyed with the travel literature, aboutopium-induced euphoria and dreams, habituation to and toleranceof the drug, about dependence, withdrawal symptoms, and long-term effects, has to be considered as a background to descriptionsalso of Western opium-eaters, that were given in medical works sincethe beginning of the eighteenth century. Detailed information bothabout the effects of habitual opium consumption and the acutesymptoms in withdrawal was given for example by John Jones in hisMysteries of Opium Reveal’d. He not only listed effects or symptoms,but gave also pathophysiological explanations for them, based on hisgeneral understanding of opium as a substance causing a “pleasantSensation” and general relaxation.256 Thus the physical weakness ofchronic opium-users was seen as contracted by “habitual over-relaxing” of their bodily parts, and their lacking in drive caused by“habitual Pleasure, Comfort, Promptitude, and Euphory” which madethe sensitive soul (i.e. the anima sensitiva in the Aristotelian sense)“lazy, listless, and averse to all Actions”. Jones compared the latterphenomenon with a man who is used to dance to excellent music andis then required to perform without any music at all.257 Likewise,because the sensitive soul was deprived of its usual comfort and

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pleasure in the state of withdrawal, intolerable distress, anxiety, anddepression would follow. In addition pain, contractions, anddiarrhoea set in, perhaps leading to death, because the soul was nolonger diverted through the opium-induced “pleasant Sensation”from the perception of irritations. Wine was recommended by Jonesas a substitute to get free of the habit, combined with a very slow,gradual reduction of the daily opium dose.258

It is not entirely clear how much Jones relied on the reports of theOrient travellers and to which extent he drew upon his knowledge ofEuropean opium-takers and possibly his own, personal experiencewith the drug. Yet he matched the travellers’ usual accounts ofOriental opium-eaters tolerating high doses with an extreme exampleof his own, writing he had been told of someone in Banbury(Oxfordshire), who was thought to take the enormous dose of twoounces per day. Moreover he referred to several other English peoplewho consumed daily doses between two and six drachms, some up toone ounce. It should be noted, however, that Jones did not mentionsuch cases to point out the extent of the practice of opium-eating inEngland in his time. His interest in them had rather to do withphysiology. He quoted these cases against the common opinion thatOriental people could generally stand larger doses of the drug, due todifferences in climate and their physical nature. In Jones’ view theopposite was true: Orientals, living in hot climates and having “softand flaccid Flesh”, actually tolerated less of the relaxing opium than“firm Fleshed Persons” in the cold north.259

This is not to say, however, that Jones had no moral concernsabout the English opium-eaters. An indicator is his remark that hecould give the names of these persons, but abstained from doing so,having “Reasons to the contrary”.260 In fact Jones, though fascinated ofthe drug’s powers, denounced its abuse in religious and moral terms,comparing it with immoderate drinking:

As an Excessive Dose of Opium is Intemperance for one time, so a longand lavish Use of it is an habitual Intemperance for a long time;therefore if you could not rationally expect good Effects in that Case,any more than from the best Wine taken suddenly in a vast Quantity,it follows, that you cannot expect good Effects from an habitualIntemperate Taking of it, any more than from a long and lavishDrinking of Wine… There is nothing so good, whereof anintemperate Use is not mischievous, God having so ordered it to deterfrom, and punish Intemperance , and the Abuse of his Creatures;Therefore ill Effects are not always to be imputed to the viciousness of

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the Things used, but frequently of the Person that imprudently usesthem.261

Despite this condemnation, it should be noted that Jones, like thetravellers to the Orient, did not criticize habitual use and ensuingdependence as such, but the self-inflicted physical and mental harmthrough the misuse of a substance. How Western people becamehabituated to the drug, and some further hints on moral and socialresponses to this, can be inferred from a number of case histories,which were published by George Young in his treatise on opium inthe middle of the eighteenth century. In all cases, patients gotaccustomed to the drug through its therapeutic use, for instance as anantitussive in pulmonary phthisis, as an analgesic in cancer, or as astimulant in states of weakness and melancholia.262 Young describedhabituation, tolerance, and dependence (becoming “slaves” toopium) rather as interesting pharmacological phenomena andtherapeutic problems than as matters of moral or social concern.There was in fact in Young’s time a simple mechanical explanationfor the development of tolerance to opium and the need forincreasing doses. As Etienne-François Geoffroy had speculated in histreatise on the materia medica, opium, by thinning the blood andinducing excessive sweating, eventually diminished the mass ofblood. Therefore increasingly higher doses were necessary to reachthe same degree of fluidity of the blood, which would (according tothe rarefaction theory) distend the arteries and – via compression ofneighbouring nerves – produce sleep.263 Though Young did notmention this aspect of the rarefaction theory, it is quite likely that heknew of it, since he quoted Geoffroy in another context.264 Young wasalso aware that the habitual use of opium by patients with advancedphthisis or with breast cancer probably shortened their remaininglifespan. He pointed out that the drug, though the only effectivepalliative in such cases, was actually harmful in those conditions.265

The moral and social dimension of the use of opium neverthelessbecomes apparent from some brief remarks in Young’s case histories.In part they stemmed from the patients themselves. In one case awoman, who had suffered from menorrhagia, weakness, and “adesponding mind”, had benefited greatly from taking the drug. Yet,as Young noted:

All her friends advised her to lay aside the use of opium, lest itshould by habit become necessary; but she whispered me privately,that she would rather lay aside her friends.266

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Even in a patient with incurable consumption:

Some advised her not to indulge herself in the use of opium. Sheanswered, that she would take it, tho’ she was certain it would hastenher death…267

The former case may be seen as pointing towards some actual fear ofdrug dependence as such, which would be unusual for the time. Yetthe friends’ concerns might well have simply been about the financialburden imposed through habitual opium-eating. The latter caseappears to indicate concern about the abuse of a drug leading tophysical harm and an early death – which would be in line with thecomments of Jones and some of the travel authors. Young’s ownposition shines through in his discussion of the use of opium as acough medicine and hypnotic in patients with phthisis. The poor,who could not afford to pay for the “sleepy draughts”, died “with easeboth of body and mind”, whereas the “people of rank” became“slaves” to the medicine, got confused, lost their memory, and died“delirious”.268 The common ideal to meet one’s Creator with a clearand prepared mind may have influenced this observation of Young.But also in a secular sense, the fear to lose one’s rationality could bea reason to abstain from opium even in painful and terminalconditions.

This worry was clearly expressed by Albrecht von Haller, who –as mentioned above – habitually took opium during his own finalillness and published his personal experience with it. Initially he hadbeen very reluctant to make use of the drug, fearing that his“intellectual power” might suffer. He referred to “the example of theTurks” and the “terrible weakness of mind through the use of opium,that was imposed on the Hindostan princes instead of death”.269 Onlyafter his correspondent Sir John Pringle had assured him that inEngland such a damage of intellect had not been described, Hallerwas ready to commence the regular taking of opium. Yet even thenhe was anxious to emphasize that it had so far not damaged hismental capacities, and that he would certainly give up the drug, if itshowed this effect on him only in the slightest degree.270 Again,Haller did not show concern about the habitual taking of the drug assuch, as long as no harmful effects were noted from it.271 But for aman of the Enlightenment, the “age of reason”, the prospect ofrisking a loss of rationality through opium must have been a seriousthreat indeed.

As Claudia Wiesemann has recently argued, the modern conceptof addiction emerged only at the end of the eighteenth and in the

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early nineteenth centuries, in connection with the debate on Brown’ssystem. Since both opium and alcohol were understood as stimulantsaccording to Brunonian doctrine, habitual consumers of thesesubstances were seen as persons getting accustomed to stimuli, whofell into a state of weakness (debility) when deprived of their drug.The regular taking of stimulants allowed them for some time a stateof “relative” or “deceptive health”, before harm, caused by exhaustionof the body’s excitability, became obvious.272

This new understanding of habituation and dependency wasreflected both in the contemporary literature on the consumption ofalcohol273 and pharmacology. The Erlangen physician Carl ChristianHeinrich Marc (1771-1841), for example, in a treatise on the effectsof poisons based on Brunonian doctrine, explained the phenomenonof drug tolerance in the new way. Patients suffering from chronicdiseases, who were treated with stimulants such as opium, benefitedfrom this only for some time, noted Marc, before therapy becameineffective and they got worse again. The reason for this was that thepatients’ excitability became “blunt” through a uniform stimulusover a long time, and that the then necessary higher doses eventuallyexhausted it.274 Ernst Horn, as mentioned above a moderateBrownian, stressed the necessity of stimulation for habituatedopium-eaters in order to enable themselves to cope with even simpledemands of daily life. He mentioned from his own experience “not afew” medical colleagues, a noblewoman, and “several young menstudying literature”, who had come to this state, and he warned thatthe latter ruined their prospects in life through this “perpetual andexcessive irritation and excitement of the vital flame”.275 As is wellknown, the period’s icon of the young, opium-consumingintellectual became the writer Thomas De Quincey (1785-1859). Heactually started his life-long habit in London in the same year, 1804,in which Horn’s work came out in Germany, and he later alsocharacterized the drug in Brownian terms as a stimulant.276

Comparisons between the effects of opium and alcohol (wine)had been for long a traditional topic of writers on the drug. Yet it wasonly in 1829 that Christoph Wilhelm Hufeland, who had stronglyargued against the spreading consumption of spirits at the beginningof the century, first compared alcoholism (“Trunksucht”) directlywith addiction to opium, actually coining the German term for thelatter: “Opiumsucht”. Though he was known as a critic of Brunoniantherapeutics, Hufeland nevertheless used the idea of stimulation inthis by now classic description:

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Spoiling. – In chronic illness one can at last get so accustomed to theuse of opium that it becomes a daily need, also if pains have beenremoved, in order to lift the general feeling to the point of well-being, of liveliness, of physical and mental usefulness, – just in thesame way as the drinker of spirits finally gets accustomed to spiritsand they become an indispensable need for him – but also with thesame consequence, the need for ever higher doses, – addiction toopium – completely in analogy to addiction to alcohol and its effects,ever increasing weakening of the nerves, trembling, destruction ofthe digestive and reproductive powers, in the end Delirium tremens,bluntness of the senses and the mind, haemorrhages, dissolution ofthe blood, Tabes.277

Opium addiction was thus eventually characterized as a disease of itsown, as had been alcoholism a decade earlier by the Moscowphysician Constantin von Brühl-Cramer.278

As can be seen from this brief view on the early knowledge aboutthe addictive property of opium, contemporary pharmacologicaltheories were occasionally applied in order to understand the clinicalphenomena. Jones’ concept of the opium-induced “pleasantsensation” offered some understanding of habituation, of withdrawalsymptoms, and of physical and mental changes in the habituated.The “rarefaction theory” of opium provided an explanation for theneed of ever higher doses to produce the desired effects. AndBrownian ideas about opium as a stimulant eventually formed thematrix for the modern understanding of addiction as a disease. Yet,on the whole the impact of the large amount of experiment-basedpharmacological knowledge, as described in detail above, was small.It may also seem striking at first sight that in the seventeenth andeighteenth centuries apparently no animal experiments were carriedout with opium to study habituation and tolerance any further. Likemost experiments with drugs and poisons in this period, opium wasgiven in “acute trials” only. The drug was occasionally applied to thesame experimental animal two or three times, yet this was done outof convenience for the researcher, or to increase the dose to the pointof intoxication, not in order to study long-term effects.

The method of chronic drug testing as such, however, was notunknown in the eighteenth century. The London physician BrowneLangrish, for example, had used it in the first half of the century inhis study of lithontriptic solutions on dogs in order to estimate theeffect of repeated injections into the bladder.279 Likewise he had madechronic trials with cherry laurel on dogs and a horse, giving it orally

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in small, yet slowly increasing doses for periods from one to over fourmonths. His interest in these trials, however, had rather been in thedrug’s effects on the blood and circulation than in the phenomenonof habituation.280 Also in the animal and self-experiments of theViennese clinician Anton Störck poisonous plants, such as hemlockand hyoscyamus, were tested in small doses for longer periods. Yetalso here the potential for intoxication was the main concern – inview of possible therapeutic uses.281

Habituation and tolerance became quite familiar phenomena, ashas been shown above, both from reports on Oriental opium-eatersand from accounts of opium use by Western patients. But they didnot constitute a specific field of experimental investigation. Therewere no attempts in the eighteenth century to produce addiction tothe drug in animals, for instance. Only one study, from thebeginning of the nineteenth century, has been found, in which theeffects of longer periods of taking opium were described on the basisof self-experimentation. F. Weber, a young surgeon at the ForeignGeneral Hospital at Lymington (Hantshire), mentioned his owntolerance to opium pills, which he constantly carried with him andtook “at all times”. He also described withdrawal symptoms onsudden discontinuation, such as exhaustion, stupor, lassitude, andviolent pain in the knee and hip joints. Weber matched these self-observations with similar phenomena in hospital patients, who hadbecome used to taking the drug for a long time. Yet, his observationsin this area were only a small part of a general study of the effects ofopium. Dealing mainly with dose-effect relations within a Brownianframework, it was not dissimilar to Crumpe’s work. Indeed Weber’saccount may well have been provoked by Ward’s critique of Crumpe,since it was published only a year later in the same periodical, theLondon Medical and Physical Journal.282

Likewise, eighteenth-century experimental studies on opiumdisplayed little interest in its psychopharmacological aspects.Certainly, the psychological effects of the drug were well known fromthe accounts of the Orient travellers. Moreover, John Jones hadeulogized them in his book. Opium, he wrote,

causes a brisk, gay and good Humour… Promptitude, Serentity,Alacrity, and Expediteness in Dispatching and Managing of Business…Assurance, Ovation of the Spirits, Courage, Contempt of Danger, andMagnanimity… prevents and takes away Grief, Fear, Anxieties,Peevishness, Fretfulness… causes Euphory, or easie undergoing allLabour, Journeys, &c…. lulls, sooths, and (as it were) charms the Mind

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with Satisfaction, Acquiescence, Contentation, Equanimity, &c.283

George Young, too, had noted such euphoric effects in some of hiscase histories.284 But, before De Quincey’s (non-medical)introspection, self-observations by doctors included psychologicaleffects only briefly, among a lot of physical phenomena. MoyseCharas in the late seventeenth century, for example, mentioned astrong tranquillizing effect and insomnia, yet his main interest was inthe gastrointestinal effects of the drug.285 Nearly a century later,Albrecht von Haller described this tranquillity as well, which, as heobserved, was combined with cheerfulness and a strong motivationto work.286 But again, this was not his central scientific interest, whichlay rather, as has been outlined above, in the effects on heart actionand irritability. Psychopharmacological aspects were still mentionedrather briefly, when medical men took opium in deliberate self-experiments to explore its effects. John Leigh, for instance, in hisprize-winning essay of 1786, quoted a report of such an experimentby his medical friend James Ramsay of Virginia. Similar to Haller,Ramsay first noted an enlivening effect, which enabled him tocontinue studying late at night but was followed by a state ofexhilaration and carelessness. Eventually forced through vertigo to goto bed, he lay “almost motionless” for several hours, while his“imagination was … distressed by the appearances of horridimages”.287 The author did not say, however, what these imagesshowed, nor did he try to give a pharmacological explanation.Likewise Weber, who was very detailed in his account of the physicaleffects of the drug, just spoke of “a strange chaos of happy anddisagreeable visions”, among many other symptoms.288 Thoughexaggerating, De Quincey was therefore principally right when hecriticized in his Confessions that, concerning opium, “most … even ofthose who have written professionally on the materia medica, make itevident, by the horror they express of it, that their experimentalknowledge of its action is none at all.”289

Reasons for what may now appear as a relative lack of interest in,or even neglect of, the psychological effects and the addictiveproperty of opium, can be found in contemporary modes of thedrug’s use, however. It was widely employed, it seems, for rather shortperiods as a medicine for acute symptoms, especially in strong painsand excessive diarrhoea. A danger of dependence developed mostly incases of serious chronic disease, such as pulmonary phthisis andbreast cancer, where opium was taken continuously as a palliative.290

Yet here prognosis was bleak anyway. The main concerns about

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opium in the seventeenth and eighteenth centuries were its potentialfor acute, dangerous intoxication through overdosage, and the risk ofmaking symptoms worse, if it had been given in the wrongcondition. Experimental research in this period, focusing on theintake of the substance into the body and its acute effects, reflectedthese concerns. For eighteenth-century authors, wide-spread habitualuse of opium in the West was at most a conceivable danger. It wasonly occasionally envisaged, for example by the Greenwichapothecary John Awsiter, in an essay on the toxicology of opium in1763 (later quoted by De Quincey).291 Most contemporaries, itseems, regarded non-medicinal opium-eating as a specific Orientalproblem that had its parallel in alcohol consumption in theOccident.

As for the psychic effects, it has been noted above that Alston andWhytt recommended opium in various “nervous disorders”; andYoung actually reported cases in which he had tried it in“melancholia”. But on the whole opium does not seem to have beenmuch employed in mental illness during the eighteenth century.Young himself confessed his disappointment about the effectivenessof the drug in melancholia and mentioned that it had “failed in otherpeoples hands” as well.292 The so-called “opium cures” for mentalpatients are largely a phenomenon of the nineteenth century.293

Considering this, the small psychopharmacological interest in theprevious century becomes understandable. In addition, the lack of amethodological basis may have played a role here. Whereaseighteenth-century, vivisectional physiology provided such a basis for“somatic” experimentation with opium, there were no specific toolsknown yet to examine the drug’s psychological effects. Onlygradually the very basic method of taking a defined dose of the drug,careful self-observation and recording of symptoms was used in amore systematic manner. An early example of this approach is thework of the Grenoble physician Pierre-Alexandre Charvet (1799-1879), whose Paris dissertation of 1826, De l’Action Comparée del’Opium, et de ses Principes Constituans sur l’Economie Animale, hasrecently been suggested to have been “the first book on modernexperimental psychopharmacology”.294 Other historians of thesubject have located its scientific beginnings only in Emil Kraepelin’sexperimental work of 1892 on “the influencing of simplepsychological processes through some medicines”. The substancesstudied in this way by Kraepelin were, among others, alcohol,paraldehyde, ether, amyl nitrite, and morphine.295

It was in fact only after the isolation of morphine in the early

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nineteenth century, and its gradual introduction both as a medicineand a “recreational” drug, that habituation, tolerance, and opiateaddiction became fields of scientific investigation. Hufeland’s notionof “Opiumsucht” – published more than twenty years afterSertürner’s discovery of “morphium”, yet also about twenty yearsbefore subcutaneous injections of morphine and other substanceswere introduced – was apparently an early perception without muchimmediate impact.296 Only after Eduard Levinstein’s clinical work on“morbid craving” for morphium had set the scene in the late 1870s,drug tolerance and withdrawal were studied experimentally,including trials with “dependent” animals.297

The Identification of Morphine

For the present historical case study, the isolation of morphine, andsubsequently of other opium alkaloids, can form an end.Experimental work increasingly concentrated rather on theproperties of these active constituents than on the whole drug.298 Yetin therapeutics the use of opium as a whole continued through thefirst half of the nineteenth century and beyond. Conservativepractitioners, most notably Hufeland, argued that the whole drugwas more than its parts, and thus therapeutically more valuable.299

But after the introduction of hypodermic injection in the 1850s,opium started to be replaced by morphine, at least as an analgesic.Though in psychiatry “cures” with Tinctura opii simplex kept theirplace into the 1950s (when they were quickly abandoned for the newtricyclic antidepressants), indications for opium were eventuallynarrowed down to its present, very limited medical use as a means tocheck hyperperistalsis.300

Seen in this way, Sertürner’s discovery of morphine marked a newdeparture, not only in the history of opium, but for the study ofplant drugs and poisons in general. In 1817, François Magendie andPierre Joseph Pelletier isolated emetine from ipecacuanha roots, andPierre Jean Robiquet extracted narcotine from opium. In 1818Pelletier and Joseph Bienaimé Caventou found strychnine as theactive principle of St. Ignatius beans and nux vomica. In the sameyear brucine was isolated from spurious angostura bark and veratrinefrom a species related to white hellebore. Codeine, the secondtherapeutically important opium alkaloid, was isolated in 1832,followed by thebaine in 1833 and papaverine in 1848.301

In retrospect the isolation of morphine by the young Paderbornapothecary’s assistant Friedrich Wilhelm Sertürner (1783-1841), firstpublished by him in 1805 and with important additions in 1817, is

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thus often regarded as a “breakthrough” in the history of plantchemistry and pharmacology, that opened up the study ofalkaloids.302 Though this view is on the whole right, it is moreaccurate to see Sertürner’s contribution also as one more small, yetdecisive step in the long search for the “true” nature of opium, whichwent back – as has been shown in this chapter – to the seventeenthcentury.

In 1804, the Berlin chemist Adolph Ferdinand Gehlen (1775-1815) published a review article on the “present state” of knowledgeof opium in the Medical and Physical Journal. The problems which heidentified were in principle not much different from those pointedout by Charles Alston more than sixty years earlier. It was still notsufficiently clear whether the Asian product “opium” was really theinspissated juice obtained by incisions of poppy capsules. Recentanalyses by the Rouen pharmacist-chemist Guillaume Dubuc (1764-1837) had again raised doubts on this question. They suggested thatthe pure juice was mixed with a fermented mass of squeezed poppyheads and leaves. Furthermore, opium had turned out to be a “verycompound substance” – a fact, which had made it increasinglydifficult to answer the old question of its active principle. Accordingto Gehlen’s stock-taking, the drug contained a “volatile narcoticprinciple”, extractive matter, mucilage, resin, oily matter, “acrystalline substance”, a kind of gluten, kaoutshouc, and diversevegetable particles. The quantitative proportions of thesecomponents appeared to vary, and it was not known whether all ofthem were actually present in all “sorts of opium”.303

Opinions were divided as to what was the true “narcotic”principle. The “volatile narcotic principle”, which was inferred fromthe drug’s smell, had recently been challenged by the Erfurtapothecary Christian Friedrich Bucholz (1770-1818), becauseconcentrated distilled water of opium had produced no deleteriouseffects on a dog. Earlier in the eighteenth century Caspar Neumann(1683-1737) of Berlin and Friedrich Hoffmann had held the viewthat an oily, non-volatile substance obtained from opium was itsnarcotic constituent, since it killed dogs already in doses of a fewgrains. But the French pharmacist Pierre Jossé (1745-99), on thebasis of his new analyses, had suggested a glutinous matter as thecarrier of the drug’s narcotic and excitant qualities.304 The latestcontribution in this field had been made in 1803 by the Parispharmacist Charles Louis Derosne (1780-1846). By way of alcoholextraction from pure opium, addition of alkalies, and repeatedwashings, he had obtained a white, crystalline substance, later known

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as the “sel de Derosne” or Derosne’s salt. It showed an alkalinereaction and could easily be dissolved in acids. These properties were,in Derosne’s view, apt to explain why acids, especially vinegar, wereknown to act as an “antidote” in opium poisoning. In fact he referredto experiments, in which he had “relieved and cured” dogs after sixto eighteen grains of opium by giving them vinegar.305 This, however,was directly contrary to Jossé’s opinion, who thought that acids, bydissolving the active components of the drug, made intoxicationswith opium even worse.306

Though Sertürner, in a postscript to his first relevant publicationof 1805, claimed not yet to have known about Derosne’s work,307 hisinvestigation has to be seen as part of those renewed efforts in theanalysis of opium and the ongoing search for the “narcotic principle”.He had first isolated an acid from opium, which he called“Mohnsäure” or “Opiumsäure”.308 While this opium acid (meconicacid), like any other acid, coloured both blue Litmus paper and theblue tincture of violets red, an aqueous extract of opium showed aweaker reaction with the former and merely discoloured the latter.From this difference in the reaction with blue plant pigmentsSertürner concluded “the presence of another substance” in theextract. In fact a greyish precipitate appeared, when he added potashor ammonia to the aqueous extract. This precipitate could becompletely dissolved by heating it in concentrated acetic acid andmade to fall out again by adding ammonia. Earlier researchers (e.g.Leigh, above) had assumed that the active principle was in the resinof opium, but Sertürner doubted this, since resin hardly dissolved inwater and yet aqueous extracts of the drug were known to beeffective. Instead he presumed that his greyish precipitate, obtainedfrom an aqueous extract, was the substance which contained this“effective factor”. Testing the substance on a dog, he actually foundthat the animal showed extreme sleepiness, followed by vomiting,trembling and convulsive movements. After various chemicalprocedures he subsequently obtained from this substance purecrystals. Given to a dog, they produced no vomiting, but to a greaterdegree sleepiness, trembling, and convulsions, ending in the animal’sdeath. By contrast, when the precipitate was removed from theopium extract by way of filtration, and the remaining fluid given toa dog, those symptoms could not be observed. On this basisSertürner was convinced that the narcotic effect of opium came fromits content of the “crystallizable body” that he had isolated and whichhe named “sleep-producing substance” or “Principiumsomniferum”.309

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The young apothecary’s conclusions were far-reaching. Not onlywould his “sleep-producing substance” act in the same way as, if notbetter than, the whole drug; doctors would at last be freed of theproblem of variations in quality and strength, that they had alwayshad to cope with in using the customary opium preparations.Moreover, Sertürner saw a new field opening up for the “practicalchemist”, who could now hope to isolate similarly the activesubstances from other plants and vegetable poisons.310 As outlinedabove, these visionary statements of 1805 in the long run actuallybecame true, but for several years Sertürner’s work was littleacknowledged. Johann Bartholomä Trommsdorf (1770-1837), theeditor of the Journal der Pharmacie, in which Sertürner’s article hadbeen published, cautioned in a note “not yet to regard the files asclosed” in this matter and suggested repeating the experiments withlarger quantities.311 Other researchers initially had difficulties induplicating Sertürner’s results.312

Naturally the question of priority arose in view of Derosne’s salt.There was, however, as Sertürner had already noted in the postscriptto his article of 1805, an important difference in the understandingof the alkaline quality of the crystalline substances that they had bothisolated. Derosne believed that it came from a small amount ofmineral alkali, added in the process of isolation, which wasinseparably bound to the salt. Sertürner asserted that it was aproperty of the newly found substance itself.313 It was actually thisinterpretation in which the German apothecary was proved “right”(plant alkaloids), and accordingly it was “pour avoir reconnu lanature alkaline de la morphine” that he was eventually awarded theMontyon prize of the Institut de France in 1831.314

Meanwhile Sertürner’s nowadays famous morphine article of1817 had attracted wide attention to his findings. He had furtherpurified his crystalline substance and renamed it “morphium” (afterthe god of sleep, Morpheus). Here he described also the step fromanimal to self- and human experimentation with the new substance,that is often mentioned in the historiography of pharmacology andmedicine in general.315 As a reason for this step he gave his opinionthat “experiments with animals lead to no real results”, probablyalluding to the then widely held view that pharmacological findingsfrom animal studies could not immediately be applied to the humanbody.316

Besides Sertürner, three young men – none of them older than 17years – swallowed initially half a grain (ca. 30 mg) of morphium.Blushing, reddening of the eyes, and a sense of general stimulation

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were the first symptoms. Having taken 30 minutes later a further halfgrain, nausea and “dumb headache with a stunned feeling” followed.A third half grain, taken only 15 minutes later, brought quickly moreintense symptoms: stomach pains and a heavily dazed state,bordering on faintings. Sertürner remembered that he fell into a“dreamlike state”, feeling twitches in his arms and legs accompanyinghis pulse beats. Fearing a serious intoxication, he gave vinegar, theknown “antidote”, to his three test persons, and took it himself. Aftervehement and lasting vomiting (which was then treated withmagnesium carbonate) and “heavy sleep” in the night, all fourrecovered, though they continued to suffer from daze, headache andabdominal pains, constipation and loss of appetite over the next fewdays.317 Sertürner concluded from this experience that morphiumacted as a “strong poison”, but simultaneously he assumed that it wasthe component of opium, on which its important medical effectsrested. In fact he was able to report from his own experience thatsevere toothache, which did not respond to opium, was immediatelyremoved by taking a solution of morphium in alcohol.318

As pointed out above, the discovery of morphine opened newpaths of research on opium, as well as of the drug’s use, in thenineteenth and twentieth centuries. One issue, however, whichbecomes particularly apparent in Sertürner’s rather dramatic accountof his human trials remains to be discussed: the ethical implicationsof such experimental investigations.

Ethical Aspects

It is evident from this case study that research on opium rested to agreat extent on animal and human experimentation. As I have shownelsewhere, animal experiments became a moral issue already in theseventeenth and eighteenth centuries.319 The sources on opiumexperiments also reflect this beginning moral awareness, yet to alesser extent than others, for one obvious reason: as a narcotic andanalgesic, opium mitigated the usual suffering of vivisected animals.One can actually find the occasional remark that an opiatedexperimental animal showed no or few signs of pain duringvivisection.320 Still, Haller’s pupil Sproegel, for example, includedsome utterances of compassion in the records of his experiments. Hespoke of “the poor dog” that had been poisoned with the drug,vivisected, and finally strangled; or he remarked that anotherpoisoned dog was “released” from its “tortures”. But this releasing wasactually death through vivisection.321 Siebold, in the preface to hisprize essay, noted that it was only “just” that he had experimented on

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himself as well, since he had “tortured” so many animals for hisstudy.322 Crumpe excused the “apparent inhumanity” of his animalexperiments by assuring that they were necessary in order toinvestigate “many points among the most interesting to mankind”.He abstained, however, from animal tests with highly concentratedextracts of opium, believing that such trials would have notherapeutic consequences.323 Remarks such as these were rathercommon among contemporary researchers. They reflected somecompassion with experimental animals, and thus a degree ofsensibility, yet no serious moral concern. In view of possible progressin medical knowledge and therapeutic improvements, the sufferingand death of animals were held to be easily excusable. Compassionwas generally no major obstacle to experiments on living animals.

In the contemporary accounts of human experiments with opiumthere are likewise some hints at ethical considerations. Since opiumwas a widely prescribed medicine, the transition from its therapeuticto its experimental use was often smooth or blurred. Yet the trialsmade by Leigh, Crumpe, and Sertürner indicate a certain concernnot to harm the test persons.324 The standards as to which effects wereseen as tolerable for the subjects in these experiments seem to havebeen rather low, however. Leigh, for instance, wrote that he “got twopatients in the same room”, a circumstance that offered him theopportunity to compare directly the effects of high doses of resin andgum of opium. The patient who had received the resin, a thirty-year-old man, got into “a kind of raving”, and the other, a twenty-five-year-old woman, who had been given the same amount of gum, wasthrown into “violent convulsions”. There is no indication that Leighhad a specific therapeutic reason to try these opium components inhigh doses (five grains, as compared to the usual one or two grains ofwhole opium) in these patients. In another record Leigh remarkedthat only with difficulty he prevailed on a healthy man to take somedrops of a presumedly very effective solution of oil of opium. Itproduced such vehement vomiting that Leigh was deterred frommaking any further trials of this kind.325

While such experiments may appear ethically questionable to themodern reader, one has to consider that most of those whoexperimented with opium on human beings included themselvesamong the subjects. This applied to Leigh, as it did to Bard,Wirtensohn, Crumpe, Weber, and Sertürner, as mentioned above.The case of the latter indicates that at least some of theexperimentalists were prepared to take the same risks as their subjects.The last quoted trial by Leigh moreover suggests that sometimes the

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benefits and dangers were discussed with the test person beforehand.Sertürner similarly wrote that he “persuaded” his three test persons totake the morphium.326 Such apparent consent is questionable,however, in Leigh’s experiment on the two patients, and one may alsowonder how voluntary Ward’s trial on his house pupil was.327

Contemporary sources briefly discussing experiments on hospitalpatients in general, such as the Thoughts on Hospitals (1771) by theyoung Manchester surgeon John Aikin (1747-1822) or the well-known Medical Ethics (1803) of the latter’s prominent physician-friend Thomas Percival (1740-1804), do not in fact mentioninformation or consent of the test persons. Aikin assured his readersthat all precautions were taken and that the subjects would be the firstto benefit from new forms of treatment.328 Percival thought itnecessary that a consultation with the other physicians and surgeonsof the hospital took place, before a trial was performed.329 The conceptof informed consent in the modern sense was clearly formulated onlyin the late nineteenth century – after abuses in experimentation onhospital patients had become a public issue.330 On the whole it can besaid that in both animal and human experimentation with opiumethical attitudes transpired. But neither compassion withexperimental animals nor a certain concern not to harm the testpersons prevented extensive and sometimes dangerous trials.

Conclusions

The history of opium from the seventeenth to the early nineteenthcentury, as discussed in this chapter, elucidates a number of issues incontemporary pharmacology and therapeutics. Perhaps most strikingis the change of theories of the drug’s mode of action during thisperiod. In the seventeenth century, the Galenic notion of a coolingeffect of opium was challenged by adherents of chemiatric concepts,such as Thomas Willis, Georg Wolfgang Wedel, and MichaelEttmüller, who replaced it with the speculation that the drug’s activechemical principle fixed or bound the spiritus animales in thenervous system. Around 1700 this view was questioned byiatromechanists, notably by Friedrich Hoffmann, Johann GottfriedBerger, John Freind, and Richard Mead. They concluded fromclinical and pathological observations, as well as from animalexperiments and in vitro trials, that opium acted by rarefying theblood. Effects on the nervous system were seen as indirect, followingfrom distended blood vessels, which pressed on the “tubuli” of thebrain and nerves and in this way obstructed the flow of the spiritus.About the same time a “vitalistic” interpretation, propagated by John

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Jones, assumed that the drug caused a “pleasant sensation” in thestomach, that led to general relaxation. Yet, this latter view gainedless ground than the “rarefaction theory”. In the middle of theeighteenth century, however, Charles Alston and Robert Whytt ofthe rising Edinburgh school of medicine, as well as Boerhaave’snephew Abraham Kaau, suggested that opium acted primarily anddirectly on nerves, its action being spread by “sympathy” from nerveends in the stomach walls throughout the whole nervous system.Their arguments in support of this view came also from clinicalobservations and animal experimentation. But further animalexperiments, both from within the Edinburgh school (AlexanderMonro secundus) and from without (Felice Fontana), pointed againto action via the blood, and a rival theory of opium’s effect throughthe circulatory system was put forward at the beginning of thenineteenth century by Michael Ward of Manchester.

These shifts in pharmacological theories of opium mirrored moregeneral changes and issues in the theory of medicine. The giving upof an explanation with the primary quality “cold” (or as some earlycritics wanted it, “heat”) was part of the general questioning ofGalenic doctrines in the seventeenth century. The dispute over direct,chemical action on the spiritus animales or their mechanicalobstruction by turgid blood vessels reflected the opposing conceptsof the body held by iatrochemists and iatromechanists. And theknown preoccupation with the nervous system of influentialEdinburgh teachers,331 such as Whytt, found its expression in thetheory of opium’s direct effect on nerves. Fontana’s criticism of thisview, in turn, was part of a wider experimental project of his, inwhich he showed that also fast-acting and powerful poisons, such asviper venom, curare, and cherry laurel, acted only after absorptioninto the blood. Experiments with opium were further an integral partof the controversy between Whytt and Albrecht von Haller over therelation between sensibility and irritability. Here the drug was used asa tool for the study of an important problem of contemporaryphysiology.

The present case study on opium has moreover revealed aremarkable degree of methodological awareness in eighteenth-century pharmacology. For instance, the question of artificialconditions through vivisectional procedures within pharmacologicalexperimentation was brought up by Haller against Whytt. That thelatter was aware of this difficulty, is clear from his controlexperiments, which involved vivisection, but not application of thedrug. Certainly, most researchers who performed trials with opium in

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vitro on blood, or in various species of animals, were rather quick toextrapolate their experimental results to the human body and thus tothe patient. Yet they did so amidst criticism by medical practitioners,such as George Young and Balthasar Ludwig Tralles, who denied thetransferability of such results and insisted on the supremacy oftherapeutic experience. Samuel Crumpe’s negative view of examiningthe effect of opium on blood shows that methodological criticism ofthis kind could also come from the experimentalists’ own camp. Self-experimentation was an answer to the problem of transferability,though subjective factors could distort findings – a problem, whichwas recognized by Samuel Bard and Carl Joseph Wirtensohn. Forthose, however, who believed that diseases changed drug effects, trialson one’s own body, or on any other healthy person, was no validsolution either. Therapeutic empiricism in the style of Young andTralles was then the only way to gain pharmacological knowledge.

This methodological awareness was matched by some degree ofethical concern, both in animal and human experimentation withopium. The suffering of experimental animals was mentioned by anumber of the researchers discussed in this chapter. And the dangerof poisoning was not concealed by those who performed humanexperiments with the drug or its preparations.

The example of opium has further shed light on the relationsbetween pharmacological experimentation, theory, and therapy. Ithas become clear that experiments were rather “embedded” inspeculation than used as crucial tests for hypotheses. Experimentalobservations also served only to a limited extent as a basis forpharmacological theory-building. They rather supplemented clinicalexperiences as additional “arguments” for a particular view of thedrug’s modus operandi. Likewise, there was not always astraightforward way from theory to therapy. Extensive therapeuticexperiences with opium counted more to eighteenth-century medicalpractitioners than the latest interpretations and explanations of itsactions. However, as the case of opium indicates, concretetherapeutical conclusions were increasingly drawn frompharmacological concepts. Johann Jakob Waldschmied in the lateseventeenth century, believing in the chemiatric “spiritus animalestheory” of the drug’s action, deduced contraindications from it, suchas apoplexia, epilepsy, lethargy, and paralysis. Alston, as a critic of the“rarefaction theory”, was less concerned about the dangers of givingopium to plethoric patients than the followers of this view.Conversely, he feared that they might endanger patients by orderingvenesection after an overdose on the wrong assumption that the

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blood had been thinned. Whytt, as an advocate of the theory ofopium’s direct action on nerves, used it consequently in the treatmentof various nervous disorders. And Crumpe differentiated his therapywith the drug, giving it either traditionally as a painkiller or in the“new” way as a stimulant. In fact, as has been shown, Brunoniansregarded his pharmacological characterization of opium as astimulant as proof of John Brown’s therapeutic system. On the wholeit can be concluded that – despite opposition of empiricist medicalpractitioners – the connection between the emerging experimentalpharmacology and therapeutics was strenghtened in the course of theeighteenth century.

The new theories of opium also contributed to the understandingof the phenomena of drug tolerance and habituation. The craving forever increasing doses of opium was explained, for example, withhabituation to the “pleasant sensation” (Jones) or the patient’sexcitability becoming “blunt” from perpetual stimulation (Carl C.H. Marc, Ernst Horn). As the comments by Jones, Young, Haller,and several Orient travellers on habitual opium-taking indicate,however, not drug dependence as such, but the prospect of physicaland mental harm through this habit caused concern. It has furtherbeen shown that interest in the psychopharmacological aspects ofopium was rather limited during the seventeenth and eighteenthcenturies. “Somatic” experimentation with the drug, benefiting fromthe methodology of contemporary physiological research, was clearlypredominant. By contrast, there was no specific methodology toassess the psychological effects of opium, which were merelymentioned by most experimentalists. This changed only with theconsiderable efforts in introspection by writers of the Romanticperiod, especially Thomas De Quincey.

As in the preceding case study, the young medical faculty of theUniversity of Edinburgh can be identified as a “centre” ofpharmacological research from about the middle of the eighteenthcentury – again through work of Alston and Whytt, which was heresupplemented by Monro secundus. Relevant experimentalinvestigations continued in Edinburgh with Bard and Leigh, whereasat the beginning of the century influential contributions had beenmade by Mead in London and Freind in Oxford. Such a “move” ofthe centre apparently happened in German work on opium as well.The important mechanist studies by Hoffmann in Halle and Bergerin neighbouring Wittenberg were followed by Haller’s, Sproegel’s,and later Siebold’s experiments at the new University of Göttingen.

The internationality of the contemporary pharmacological

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discourse is also evident from this case study, being perhaps bestillustrated by the Haller-Whytt controversy. It is likewise clear fromopium monographs, such as those by Young, Leigh, and Crumpe,which were translated from English into German within a few years,and from the critical adoption of John Brown’s use of opium as astimulant by German physicians, such as Henke and Horn.

Finally, as in the study on lithontriptics, the case of opiumillustrates the impact of improved chemical analysis with thebeginning of the nineteenth century. Friedrich Wilhelm Sertürner’sisolation of morphine not only permitted much more accuratedosage and effective treatment, but created the conceptualframework for the entire new research field of plant alkaloids.

Notes

1 G. Sonnedecker, ‘Emergence of the Concept of Opiate Addiction’,Journal Mondiale de Pharmacie, v (1962), 275-90, and vi (1963), 27-34; also in German: idem, ‘Die Opiumsucht: Wandlungen desBegriffs in historischer Sicht’, Pharmazeutische Zeitung, cviii (1963),835-40, 899-903.

2 J. C. Kramer, ‘Opium Rampant: Medical Use, Misuse and Abuse inBritain and the West in the 17th and 18th Centuries’, British Journalof Addiction, lxxiv (1979), 377-89; M. Kreutel, Die Opiumsucht(Stuttgart: Deutscher Apotheker Verlag, 1988). General culturalhistories of opium use are: J. M. Scott, The White Poppy: a History ofOpium (London: Heinemann, 1969); M. Seefelder, Opium: EineKulturgeschichte (Munich: Deutscher Taschenbuch Verlag, 1990); andP. Butel, L’Opium: Histoire d’une Fascination (Paris: Perrin, 1995).

3 A. Hayter, Opium and the Romantic Imagination (London: Faber andFaber, 1968). See also M. Lefebure, Samuel Taylor Coleridge, a Bondageof Opium (London: Gollancz, 1974), and G. Lindop, The Opium-Eater: a Life of Thomas de Quincey (London: J. M. Dent, 1981).

4 V. Berridge and G. Edwards, Opium and the People: Opiate Use inNineteenth-Century England (London: A. Lane, 1981); T. M.Parssinen, Secret Passions, Secret Remedies: Narcotic Drugs in BritishSociety, 1820-1930 (Philadelphia: Institute for the History ofHuman Issues, Manchester University Press, 1983); D. T.Courtwright, Dark Paradise: Opiate Addiction in America before 1940(Cambridge, Mass.: Harvard University Press, 1982). See also H. W.Morgan, Drugs in America: a Social History, 1800-1980 (Syracuse:Syracuse University Press, 1981), and D. Peters, ‘The BritishMedical Response to Opiate Addiction in the Nineteenth Century’,Journal of the History of Medicine and Allied Sciences, xxxvi (1981),

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455-88. For Germany, see P. Schendzielorz, ‘Die Anfänge derBetäubungsmittelgesetzgebung in Deutschland. Unter besondererBerücksichtigung der Opiumstelle Berlin und des PharmazeutenOtto Anselmino (1873-1955)’ (Pharm. Diss. FU Berlin, 1988). Fora collection of recent contributions to the historiography of drug useand abuse see Porter and Teich (eds), Drugs and Narcotics.

5 J. Beeching, The Chinese Opium Wars (London: Hutchinson, 1975);P. Ward Fay, The Opium War 1840-1842 (Chapel Hill: University ofNorth Carolina Press, 1975); B. Inglis, The Opium War (London:Hodder and Stoughton, 1976).

6 J. Scarborough, ‘The Opium Poppy in Hellenistic and Romanmedicine’, in Porter and Teich (eds), Drugs and Narcotics, 4-23; J. W.Estes, ‘John Jones’s Mysteries of Opium Reveal’d (1701): Key toHistorical Opiates’, Journal of the History of Medicine and AlliedSciences, xxxiv (1978), 200-9; L. von Rechenberg and H. M.Koelbing, ‘Hufelands Opiumtherapie im zeitgenössischen Vergleich’,Gesnerus, xlii (1985), 97-119; A. N. Bindler, ‘Schmerz undSchmerzbehandlung zwischen 1650 und 1760. Eine Untersuchunganhand von Dissertationen aus dem deutschen Sprachraum’ (Med.Diss. Basel, c. 1986); M. M. Weber, ‘Die “Opiumkur” in derPsychiatrie’, Sudhoffs Archiv, lxxi (1987), 31-61; J. S. Haller Jr.,‘Opium Usage in Nineteenth Century Therapeutics’, Bulletin of theNew York Academy of Medicine, lxv (1989), 591-607. A briefhistorical outline of therapy with opium is R. Schmitz, ‘Opium alsHeilmittel’, in G. Völger and K. von Welck (eds), Rausch undRealität: Drogen im Kulturvergleich, 2 vols (Hamburg: Rowohlt,1982), vol. ii, 651-61.

7 V. Jantz, ‘Pharmacologia Browniana: Pharmakotherapeutische Praxisdes Brownianismus aufgezeigt und interpretiert an den Modellenvon A. F. Marcus in Bamberg und J. Frank in Wien’ (Pharm. Diss.Marburg, 1974); G. B. Risse, ‘Brunonian Therapeutics: New Winein Old Bottles?’, in W. F. Bynum and R. Porter (eds), Brunonianismin Britain and Europe (London: Wellcome Institute for the Historyof Medicine, 1988), 46-62; C. Wiesemann, ‘Die heimlicheKrankheit. Zur Ideengeschichte des Suchtbegriffs in Deutschland im18. und 19. Jahrhundert’ (Med. Habil.-Schrift Erlangen, 1995).

8 U. Tröhler, ‘Pain: Historical Changes in Therapeutic Views andPhysiological Explanations of a Pathological Symptom’, in T. Ogawa(ed.), History of Pathology. Proceedings of the 8th InternationalSymposium on the Comparative History of Medicine – East and West(Osaka: The Taniguchi Foundation, 1986), 185-99; F. Schiller, ‘TheHistory of Algology, Algotherapy, and the Role of Inhibition’,

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History and Philosophy of the Life Sciences, xii (1990), 27-50; R. Rey,The History of Pain, transl. by L. Elliott Wallace, J. A. Cadden, andS. W. Cadden (Cambridge, Mass.: Harvard University Press, 1995).

9 Earles, ‘Early Theories’; idem, ‘Experiments with Drugs’, idem,‘Studies in the Development’.

10 Winau, ‘Experimentelle Pharmakologie und Toxikologie’; C.Salomon-Bayet, ‘Opiologia, Imposture et Célébration de l’Opium’,Revue d’Histoire des Sciences, xxv (1972), 125-50.

11 J. C. Kramer, ‘The Opiates: Two Centuries of Scientific Study’,Journal of Psychedelic Drugs, xii (1980), 89-103; R. K. Siegel and A.E. Hirschman, ‘Charvet and the First Psychopharmacological Studieson Opium: a Historical Note and Translation’, Journal of PsychoactiveDrugs, xv (1983), 323-9.

12 Maehle, ‘Pharmacological Experimentation’; idem, ‘Selbstversuche’.13 Kreutel, Opiumsucht; Kramer, ‘Opium Rampant’. See also F.-J.

Kuhlen, Zur Geschichte der Schmerz-, Schlaf- und Betäubungsmittel inMittelalter und früher Neuzeit (Stuttgart: Deutscher ApothekerVerlag, 1983), 373-5, who observes a shift in therapeutic practicefrom the use of nightshade plants (solanacea) to opiates around1600.

14 For example ibid., 378, and Kreutel, Opiumsucht, 134-5. T.Sydenham, ‘Medical Observations Concerning the History and Cureof Acute Diseases’, in The Works of Thomas Sydenham, M.D., transl.by R. G. Latham, 2 vols (London: Sydenham Society, 1848-50), vol.i, 173: “… I cannot but break out in praise of the great God, theGiver of all good things, who hath granted to the human race, as acomfort in their affections, no medicine of the value of opium,either in regard to the number of diseases that it can control, or itsefficiency in extirpating them… So necessary an instrument isopium in the hand of a skilful man, that medicine would be acripple without it; and whoever understands it well, will do morewith it alone than he could well hope to do from any singlemedicine.”

15 G. R. Boehmer, Systematisch-Literaerisches Handbuch derNaturgeschichte, Oeconomie und anderer damit verwandtenWissenschaften und Künste, 5 vols (Leipzig: J. F. Junius, 1785-89),vol. ii, 429-43.

16 Weber, ‘Die “Opiumkur”’, 31-2; Kreutel, Opiumsucht, 1. See alsothe anthology compiled by O. Zekert, Opiologia: Ein Beitrag zurGeschichte des Opiums und seiner Wirkstoffe (Vienna: HeilmittelwerkeWien, 1956).

17 See also chapter 1 above.

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18 C. Alston, ‘A Dissertation on Opium’, Medical Essays andObservations, v/1 (1742), 110-76; German transl.: ‘Eine Abhandlungvon dem Opio’, in Die medicinischen Versuche und Bemerkungen,welche von einer Gesellschaft in Edinburgh durchgesehen undherausgegeben werden, vol. v/1 (Altenburg: Druck und Verlag P. E.Richters, 1752), 125-214; R. Whytt, ‘An Account of SomeExperiments Made with Opium on Living and Dying Animals’,Essays and Observations, Physical and Literary, ii (1756), 280-316;German transl.: ‘Eine Nachricht von einigen Versuchen, die mitOpium an lebendigen und sterbenden Thieren gemacht wordensind’, in Neue Versuche und Bemerkungen aus der Arztneykunst undübrigen Gelehrsamkeit einer Gesellschaft zu Edinburg vorgelesen undvon ihr herausgegeben, vol. ii (Altenburg: Richterische Buchhandlung,1757), 316-58; French version: ‘Expériences faites avec l’Opium surdes Animaux Vivans’, Journal de Medecine, Chirurgie, Pharmacie, etc.,ix (1758), 25-44. A. Monro sec., ‘An Attempt to Determine byExperiments, How Far Some of the Most Powerful Medicines, viz.Opium, Ardent Spirits, and Essential Oils, Affect Animals by Actingon those Nerves to which they are Primarily Applied’, Essays andObservations, Physical and Literary, iii (1771), 292-365; reviewed inMedicinischchirurgische Bibliothek, iii/2 (1776), 132-7. For adiscussion of these works, see this chapter below.

19 J. Stedman, ‘The Bad Effects of Opium Given too Soon to Stop theOperation of Emeticks’, Medical Essays and Observations, iv (1737),37-8; D. Clerk, ‘The Effects of a Very Large Dose of Opium’, Essaysand Observations, Physical and Literary, iii (1771), 121-8; F. Willis, S.Flavell et al., ‘An Account of a Person who Took a Great Quantity ofOpium, without Causing Sleep’, Philosophical Transactions, xxii(1701), 999-1000; W. Chavasse, ‘History of a Case of TetanusSuccessfully Treated by the Use of Large Doses of Opium’, MedicalCommentaries, ix (1783/84), 374-9; T. Drummond, ‘Account of theSuccessful Employment of Laudanum in the Confluent Small-Pox’,ibid., xiv (1789), 300-1; J. Haxby, ‘Medical Histories… 1. A Case ofEpilepsy Terminating Favourably, under the Use of Musk andOpium…’, Annals of Medicine, iv (1799), 434-54.

20 T. Arnot, ‘A Method of Preparing the Extract and Syrup of Poppies’,Medical Essays and Observations, v/1 (1742), 105-9; Alston,‘Dissertation on Opium’, 116-9. See also Berridge and Edwards,Opium and the People, 11-17.

21 R. Toellner, ‘Die Umbewertung des Schmerzes im 17. Jahrhundertin ihren Voraussetzungen und Folgen’, Medizinhistorisches Journal, vi(1971), 36-44. See also R. Porter, ‘Pain and Suffering’, in Bynum

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and Porter (eds), Companion Encyclopedia , vol. ii, 1574-91.22 Bindler, ‘Schmerz und Schmerzbehandlung’; Tröhler, ‘Pain’.23 Kreutel, Opiumsucht, 104-10, 138, 259.24 Cf. K. Sprengel, Versuch einer pragmatischen Geschichte der

Arzneikunde. Fünfter Teil (Halle: J. J. Gebauer, 1803), 329.25 Riddle, Dioscorides, 38; Scarborough, ‘The Opium Poppy’, 7;

Zekert, Opiologia, 21-4; Kreutel, Opiumsucht, 24-8; G. Harig,Bestimmung der Intensität im medizinischen System Galens. Ein Beitragzur theoretischen Pharmakologie, Nosologie und Therapie in derGalenischen Medizin (Berlin: Akademie-Verlag, 1974), 130-1.

26 Ibid., 107; M. Döring, Mithridateiotechnia: hoc est, de mithridatilegitima constructione Nicolai Mutoni collectanea… cum auctariogemino: quorum prius exhibet acroama medico-philosophicum, de opiiusu, qualitate calefaciente, virtute narcotica, et ipsum corrigendi modo(Jena: J. Beitmann, 1620); F. Hoffmann sen., Clavis pharmaceuticaSchroederiana seu animadversiones cum annotationibus inpharmacopoejam Schroederianam, 2nd edn (Halle: Apud Viduam etHaeredes Mylianos, 1681), 593; Kreutel, Opiumsucht, 111.

27 J. B. van Helmont, Aufgang der Artzney-Kunst , 2 vols, transl. by C.Knorr von Rosenroth (Sulzbach: J. A. Endters Sel. Söhne, 1683;reprint Munich: Kösel-Verlag, 1971), vol. i, 220-1, vol. ii, 855,1112.

28 Ibid., vol. i, 512, vol. ii, 855.29 Ibid., vol. i, 566, vol. ii, 855-6. Nerves were thought to be hollow to

allow the flow of the spiritus animales as mediators of sensation andmotion.

30 Ibid., vol. i, 221, 515, vol. ii, 855. A “sulfur” as the effectiveprinciple of opium had also been assumed by the Paracelsian doctorJoseph Quercetanus (1521-1609), personal physician to Henri IV ofFrance. See Kreutel, Opiumsucht, 111, 122-5.

31 In Paracelsus’ terminology, “sulfur” meant an inflammable principleand “salt” the ash or residue after burning or heating. “Mercurius”,as the third principle, was fluid and evaporable. Cf. K. E.Rothschuh, Konzepte der Medizin in Vergangenheit und Gegenwart(Stuttgart: Hippokrates, 1978), 267.

32 Helmont, Aufgang, vol. i, 515, vol. ii, 1048.33 See for example M. Ettmüller and J. Acoluth, Virtutem opii

diaphoreticam examini publico exponunt (Leipzig: Brand, 1679),preface; J. J. Waldschmied and P. H. Chunon, Monita medica circaopii et opiatorum usum vulgo Schlaff-Tränck (Marburg: S. Schadewitz,1679), 6-8; S. Schroeer, Disputatio inauguralis de opii natura et usu(Erfurt: J. H. Kindler, 1693), 6-10. On the concept of occult

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qualities or powers of substances see J. Röhr, Der okkulte Kraftbegriffim Altertum (Leipzig: Dieterich, 1923), 96-133; M. Stolberg, ‘DasStaunen vor der Schöpfung: “Tota substantia”, “calidum innatum”,“generatio spontanea” und atomistische Formenlehre bei DanielSennert’, Gesnerus, l (1993), 48-65. For Sennert on opium seeKreutel, Opiumsucht, 133, 147.

34 Waldschmied, Monita medica, 8-9.35 T. Willis, Pharmaceutice rationalis: or, an Exercitation of the

Operations of Medicines in Humane Bodies, 2 parts (London: T.Dring, C. Harper, and J. Leigh, 1679), part i, 137-8; G. W. Wedel,Opiologia ad mentem Academiae Naturae Curiosorum (Jena: J. Fritsch,1674), 35-41; Ettmüller and Acoluth, Virtutem opii, chap. i-ii;Hoffmann sen., Clavis, 592; F. Hoffmann jun. and J. Descazals,Dissertatio inauguralis medica de opiatorum nova eaque mechanicaoperandi ratione (Halle: C. Henckel, 1700), 14-15; Kreutel,Opiumsucht, 148-53.

36 See H. Buess, Die historischen Grundlagen der intravenösen Injektion(Aarau: Sauerländer, 1946).

37 R. Boyle, ‘Some Considerations Touching the Usefulness ofExperimental Natural Philosophy’, in The Works of the HonourableRobert Boyle, 5 vols (London: A. Millar, 1744), vol. i, 420-554, on479.

38 Willis, Pharmaceutice rationalis, part i, 149-50; J. S. Elsholtz,Clysmatica nova, 2nd edn (Berlin, 1667, reprint Hildesheim: Olms,1966), 14-16; P. Scheel, Die Transfusion des Blutes und Einsprützungder Arzeneyen in die Adern (Copenhagen: F. Brummer, 1802), 206-8,211-2; H. Sloane, ‘Experiments and Observations of the Effects ofSeveral Sorts of Poisons upon Animals, etc. Made at Montpellier inthe Years 1678 and 1679, by the Late William Courten Esq.’,Philosophical Transactions, xxvii (1712), 485-500.

39 Schroeer, Disputatio, 7.40 Cf. ibid. Emphasis added.41 Ibid., 7, 10-11.42 Ibid., 8, 11.43 Ibid., 11-12.44 Ibid., 12. Cf. Ettmüller and Acoluth, Virtutem opii, chap. i,

paragraph xii.45 On Hoffmann’s iatromechanics see L. S. King, The Road to Medical

Enlightenment 1650-1695 (London: Macdonald 1970), 181-204;idem, The Philosophy of Medicine. The Early Eighteenth Century(Cambridge, Mass.: Harvard University Press, 1978), 234-6; K. E.Rothschuh, ‘Studien zu Friedrich Hoffmann (1660-1742)’, Sudhoffs

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Archiv, lx (1976), 163-93, 235-70; idem, ‘Therapia rationalissystematica bei Friedrich Hoffmann (1660-1742)’, in P. Dilg (ed.),Perspektiven der Pharmaziegeschichte. Festschrift für Rudolf Schmitzzum 65. Geburtstag (Graz: Akademische Druck- und Verlagsanstalt,1983), 269-80; Müller, Iatromechanische Theorie.

46 Hoffmann and Descazals, Dissertatio, 14-15.47 Ibid., 15-19.48 Ibid., 19-23.49 Ibid., 24.50 J. G. Berger and C. Fimmler, Dissertatio solennis de vi opii

rarefaciente, a qua, ostenditur, omnia illius effecta in homine proficisci(Wittenberg: Gerdesianus, 1703), 9-11.

51 Ibid., 10-23, 34, 38. Cf. O. Borch, De somno et somniferis maximepapavereis dissertatio (Copenhagen: D. Paulli, 1682), 25-8. Borch,however, still adhered to the older view that opium vapours(“nebulae”) pervaded the body and hindered the movement of thespiritus animales. Pitcairne believed that opium rarefied the blood inthe small cerebral arteries, which would “contract” adjacent nerves,leading to stoppage of their nervous fluid and thus to sleep. See A.Pitcairne, ‘A Dissertation upon the Circulation of the Blood in BornAnimals and Embryons’, in idem, The Works… Published by Himself,transl. by G. Sewell and J. T. Desaguliers, 3rd edn (London: F.Noble, 1740), 168-91, on 181-2. See also T. Brown, The MechanicalPhilosophy and the ‘Animal Oeconomy’ (New York: Arno Press, 1981),224.

52 Berger and Fimmler, Dissertatio, 2, 5, 38.53 J. Freind, Emmenologia: in qua fluxus muliebris menstrui phaenomena,

periodi, vitia cum medendi methodo, ad rationes mechanicas exiguntur(Rotterdam: J. Hofhout, 1711), 172-85.

54 Ibid., 166-9.55 Mead, Medical Works, vol. i, 125-37. For a brief summary of Mead’s

‘Mechanical Account’ see A. Zuckerman, ‘Dr. Richard Mead (1673-1754). A Biographical Study’ (Ph.D. thesis, University of Illinois,Urbana, 1965), 33-54. See also R. H. Meade, In the Sunshine of Life.A Biography of Dr. Richard Mead 1673-1754 (Philadelphia: Dorrance& Co., 1974), 16-17. Freind, publishing a year later than Mead, didnot refer to the latter’s theory of opium, however; nor did Meadmention Freind’s experiments, which had been performed early in1702. In 1703, Mead was appointed physician to St. Thomas’sHospital, London.

56 Mead, Medical Works, vol. i, 4-8.57 Ibid., vol. i, 133.

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58 Ibid., vol. i, 131-3.59 J. Jones, The Mysteries of Opium Reveal’d, 2nd edn (London: R.

Smith, 1701), 92-8, 209-27.60 Ibid., 98, 253, 370-1.61 See ibid., 31-3, and this chapter, below.62 Mead, Medical Works, vol. i, 131, 136-7. This result partly

contrasted with an earlier oral poisoning experiment reported byThomas Willis, in which a dog survived the same dose of 2 drachms(120 grains) of opium. Willis had attributed this outcome to the“acid Ferment” of the stomach, by which the “narcotick Sulphur”might have been “somewhat broken and overcome”. Cf. Willis,Pharmaceutice rationalis, part i, 149.

63 Especially concerning the viper venom, Mead changed his theoryfrom poisonous particles acting on the blood to an action on the“nervous fluid” comparable to electrical effects. Cf. R. Mead, AMechanical Account of Poisons in Several Essays, 1st edn (London: R.Smith, 1702) and 3rd edn (London: J. Brindley, 1745).

64 Berger and Fimmler, Dissertatio, 34-5.65 E.-F. Geoffroy, Tractatus de materia medica, sive de medicamentorum

simplicium historia, virtute, delectu et usu, 3 vols (Paris: J. Desaint,1741), vol. ii, 698-702; {W. Lewis}, The New Dispensatory…Intended as a Correction, and Improvement of Quincy (London: J.Nourse, 1753), 33-4; G. Young, A Treatise on Opium, Founded uponPractical Observations (London: A. Millar, 1753), 32, 140; B. L.Tralles, Usus opii salubris et noxius, in morborum medela, solidis etcertis principiis superstructus, Editio altera auctior, Sect. i-iii (Breslau:J. E. Meyer, 1774-82), Sect. i, 78-84. See also R. James, A MedicinalDictionary, 3 vols (London: T. Osborne, 1743-45), vol. iii, entry“Opium”. On Geoffroy’s and Tralles’ theories see also Kreutel,Opiumsucht, 183-9.

66 For example Sydenham, ‘Medical Observations’, 173: “To know it{i.e. opium} only as a means of procuring sleep, or of allaying pain,or of checking diarrhoea, is to know it only by halves. Like aDelphic sword, it can be used for many purposes besides. Ofcordials, it is the best that has hitherto been discovered in Nature. Ihad nearly said it was the only one.”

67 Waldschmied and Chunon, Monita medica, 3-4, 14, 22.68 See Willis, Pharmaceutice rationalis, part i, 144; Schroeer, Disputatio,

12-14; Hoffmann and Descazals, Dissertatio, 3-4; Berger andFimmler, Dissertatio, 5. See also Kreutel, Opiumsucht, 129. Onopium as a poison see W. Ramesey, Tractatus de venenis. Or, aTreatise of Poysons (London: D. Pakeman, 1661), 94-6.

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69 Waldschmied and Chunon, Monita medica, 4. Cf. Willis,Pharmaceutice rationalis, part i, 150-1.

70 Hoffmann sen., Clavis, 591; James, Medicinal Dictionary, entry“Opium”; J. H. Zedler, Grosses vollständiges Universal-Lexicon, vol.xxi (Leipzig: Zedler, 1739), entry “Mohn-Safft (Egyptischer) OpiumTebaicum”, cols. 848-58; Alston, ‘Dissertation on Opium’, 111-24;J. Reinegg, ‘Ueber das Opium und seine Würkungsart bey denMorgenländern’, Medicinische Bibliothek, ii (1785), 370-86; P.Scheel, ‘Zusätze und Anmerkungen des Uebersetzers’, in S. Crumpe,Auf Versuche gegründete Untersuchung der Natur und Eigenschaften desOpiums (Copenhagen: Proft and Storch, 1796), 193-216, on 194-5;Kreutel, Opiumsucht, 27, 34, 155; Scarborough, ‘The OpiumPoppy’, 16-17.

71 M. Charas, Histoire Naturelle des Animaux, des Plantes, et desMineraux, qui entrent dans la Composition de la Theriaqued’Andromachus (Paris: O. de Varennes, 1668), 29-56, 74-89. Watson,Theriac and Mithridatium, 45, 53, 73.

72 Willis, Pharmaceutice rationalis, part i, 150; F. Hoffmann and F. C.Muller dictus Wohlheimer, Dissertatio solennis, opii corrrectionemgenuinam et usum (Halle: C. Henckel, 1702), 22-4; Zedler, Universal-Lexicon, vol. xxv (1740), entry “Opium correctum”, cols. 1662-70.See also Kreutel, Opiumsucht, 125-6. Note, however, that Galenhimself intended to mitigate the cooling effects of opium in the bodyby adding warm substances, not to correct the quality and intensityof the drug itself; cf. Harig, Bestimmung der Intensität, 130-1.

73 Waldschmied and Chunon, Monita medica, 10-12.74 Ibid., 12-20.75 Though Waldschmied did not cite his source, it is evident that he

used the report by the French physician and botanist Pierre Belon (c.1517-64) on his travels in Asia Minor between 1546 and 1549. Cf.Sonnedecker, ‘Emergence of the Concept’, 281. Belon’s observationswere also mentioned (with reference) by Hoffmann and Descazals,Dissertatio, 10-11, and Berger and Fimmler, Dissertatio, 8.

76 Cf. the very similar contraindications, partly with reference toWaldschmied, in Schroeer, Disputatio, 13-14, and Hoffmann andDescazals, Dissertatio, 9-10.

77 Ibid., 22.78 Berger and Fimmler, Dissertatio, 26.79 Jones, Mysteries of Opium, 315-8.80 Mead, Medical Works, vol. i, 135.81 For example Young, Treatise on Opium, 140-3.82 Schroeer, Disputatio, 14-15.

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83 Berger and Fimmler, Dissertatio, 27-31.84 Hoffmann and Descazals, Dissertatio, 13. On current opium

preparations around 1700, their raw opium content and relativepotency see Estes, ‘John Jones’s Mysteries’.

85 Hoffmann and Muller, Dissertatio, 14-21.86 Ibid., 17; Borch, De somno, 25-7; M. B. Valentin, Historia literaria

S.R.I. Academiae Naturae Curiosorum (Gießen: H. Müller, 1708),72-4 (Review of Wedel’s Opiologia).

87 On the general trend, since the late seventeenth century, to simplifyand contract the materia medica see Earles, ‘Studies in theDevelopment’; Kühn, Untersuchungen zur Arzneischatzverringerung ;and chapter 1 above.

88 Hoffmann and Muller, Dissertatio, 29-31.89 G. E. Stahl and J. G. Brunschwitz, Dissertatio medica inauguralis, de

impostura opii (Halle: C. Henckel, 1707), 9-10, 36-8. See alsoBindler, ‘Schmerz und Schmerzbehandlung’, 18-20, 23-5.

90 On Stahl’s medical theory, its religious background, and itsdifferences to Hoffmann’s theory see J. Geyer-Kordesch, ‘GeorgErnst Stahl’s Radical Pietist Medicine and Its Influence on theGerman Enlightenment’, in Cunningham and French (eds), TheMedical Enlightenment, 67-87, and R. French, ‘Sickness and theSoul: Stahl, Hoffmann and Sauvages on Pathology’, ibid., 88-110.On Stahl’s therapeutics see Habrich, ‘Characteristic Features’.

91 Stahl and Brunschwitz, Dissertatio, 14-21, 39-40.92 Cf. Freind, Emmenologia, 172-3, 175, 192.93 Willis, Pharmaceutice rationalis; H. Isler, Thomas Willis 1621-1675.

Doctor and Scientist (New York: Hafner Publishing Company, 1968),182-5; S. Dale, Pharmacologia, seu manuductio ad materiammedicam, 3rd edn (London: W. Innys and R. Manby, 1737), 11;Wepfer, Cicutae aquaticae historia et noxae; Maehle, Johann JakobWepfer.

94 Alston, ‘Dissertation on Opium’.95 For historical analysis of the Edinburgh medical school see C.

Lawrence, ‘Medicine as Culture: Edinburgh and the ScottishEnlightenment’ (Ph.D. thesis, University of London, 1984); idem,‘Ornate Physicians and Learned Artisans: Edinburgh Medical Men,1726-1776’, in W. F. Bynum and R. Porter (eds), William Hunterand the Eighteenth-Century Medical World (Cambridge: CambridgeUniversity Press, 1985), 153-76. For Alston’s career see briefly E. A.Underwood, Boerhaave’s Men at Leyden and After (Edinburgh:Edinburgh University Press, 1977), 106-7, 120.

96 For possible reasons see A. Cunningham, ‘Medicine to Calm the

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Mind: Boerhaave’s Medical System, and Why It was Adopted inEdinburgh’, in Cunningham and French (eds), The MedicalEnlightenment, 40-66. See also Lawrence, ‘Early EdinburghMedicine: Theory and Practice’, in Anderson and Simpson (eds),Early Years of the Edinburgh Medical School, 81-94.

97 See Alston, Lectures, vol. i, 1-2, 25-7, 58-61, vol. ii, 583-4.98 Ibid., vol. i, 40.99 Alston, ‘Dissertation on Opium’, 110.

100 Ibid., 147, 153, 156.101 Ibid., 112-5. Cf. E. Kaempfer, Amoenitatum exoticarum politico-

physico-medicarum fasciculus V, quibus continentur variae relationes,observationes et descriptiones rerum Persicarum et Ulterioris Asiae multaattentione, in peregrinationibus per universum Orientem collectae(Lemgo: H. W. Meyer, 1712), 639-44; P. Alpin, La Médecine desEgyptiens, 2 vols, transl. from Latin and ed. by R. de Fenoyl (Cairo:Institut Français d’Archéologie Orientale, 1980), vol. ii, 341-2.

102 Alston, ‘Dissertation on Opium’, 115. Cf. N. Lemery, Dictionaire ouTraité Universel des Drogues Simples, 3rd edn (Amsterdam: AuxDépens de la Compagnie, 1716), 391-2. Pharmacologically Lemeryadhered to the “spiritus animales theory” of opium, teaching that itsviscous and sulphureous parts agglutinated the animal spirits in thechannels of the brain and thus caused sleep; see ibid.

103 Alston, ‘Dissertation on Opium’, 116-21. Also Albrecht von Hallerin Göttingen produced his own opium from poppy heads and foundit equally strong as the imported drug; A. von Haller, Enumeratiomethodica stirpium Helvetiae indigenarum, 2 vols (Göttingen: A.Vandenhoek, 1742), vol. i, 303-4; J. A. T. Sproegel, Dissertatioinauguralis medica sistens experimenta circa varia venena in vivisanimalibus instituta (Göttingen: P. C. Hager, 1753), 39-40.

104 N. Grew, ‘A Discourse of the Diversities and Causes of Tasts {sic!}Chiefly in Plants. Read before the Royal Society, March 25. 1675’,in idem, The Anatomy of Plants (London: W. Rawlins, 1682), 279-95; Alston, Lectures, vol. i, 33-6.

105 Idem, ‘Dissertation on Opium’, 135-6; and this chapter below. Onthe fallacies and limitations of examining substances by taste see alsoidem, Lectures, vol. i, 31.

106 Idem, ‘Dissertation on Opium’, 136-40. Jones thought that the resinstuck to the stomach, causing continuous harm, and that it shouldtherefore be separated from the crude opium. Cf. Jones, Mysteries ofOpium, 202-3, 309.

107 Alston, ‘Dissertation on Opium’, 141-7. Cf. Geoffroy, Tractatus demateria medica, vol. ii, 692; Hoffmann and Descazals, Dissertatio, 17.

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108 Alston, ‘Dissertation on Opium’, 147-9. Cf. Hoffmann andDescazals, Dissertatio, 15-16, 20.

109 Alston, ‘Dissertation on Opium’,147. See also idem, Lectures, vol. i,26. Note, however, the highly positive opinion of chemical analysis“by fire” in H. Pemberton (transl.), The Dispensatory of the RoyalCollege of Physicians, London (London: T. Longman, T. Shewell andJ. Nourse, 1746), 27-8: “… as heat is a primary agent in all naturaloperations, and fire one of the great dissolvents of bodies, no art ismore fitted for detecting the internal constitution of things. It hasalso furnished us with many of the most powerful remedies, as it hasput into our hand some of the active principles, by which thechanges in nature are wrought, less clogged and obstructed fromaction, than in the usual compound bodies, that come in our way.”

110 Alston, ‘Dissertation on Opium’, 153-5.111 Ibid., 156-8. Cf. Freind and Mead, above.112 Alston, ‘Dissertation on Opium’, 160-1. Cf. Freind, above.113 Alston, ‘Dissertation on Opium’, 160.114 Ibid., 168-70. On the roots of the concept of sympathy in antiquity

see Röhr, Der okkulte Kraftbegriff, 34-76.115 Maehle, Johann Jakob Wepfer, and idem, ‘Wepfers experimentelle

Toxikologie’.116 Alston, ‘Dissertation on Opium’, 165.117 N. Mani, ‘Darmresorption und Blutbildung im Lichte der

experimentellen Physiologie des 17. Jahrhunderts’, Gesnerus, xviii(1961), 85-146, and idem, Die historischen Grundlagen derLeberforschung, 2. Teil: Die Geschichte der Leberforschung von Galenbis Claude Bernard (Basel: Schwabe, 1967), 84-103.

118 See also Earles, ‘Early Theories’.119 A. Kaau Boerhaave, Impetum faciens dictum Hippocrati per corpus

consentiens philologice et physiologice illustratum observationibus etexperimentis passim firmatum (Leyden: S. Luchtmans & Fil., 1745),401-7.

120 For example Whytt, ‘An Account of Some Experiments’, 315;Monro, ‘An Attempt to Determine’, 298-9.

121 Whytt, ‘An Account of Some Experiments’. See also idem, ‘An Essayon the Vital and Other Involuntary Motions of Animals’, in idem,The Works, i-viii, 1-208, on 199-200.

122 Whytt, ‘An Account of Some Experiments’, 297-9, 307-9.123 Ibid., 303, 313; Whytt, ‘An Essay on the… Motions of Animals’,

195-8.124 Whytt, ‘An Account of Some Experiments’, 281-5.125 Monro, ‘An Attempt to Determine’, 299-302.

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126 Ibid., 337-8, 360.127 Ibid., 350, 357.128 Ibid., 339.129 Ibid., 330-3, 338, 363-4.130 Fontana, Traité sur le Vénin, vol. ii, 358-64; idem, Beobachtungen und

Versuche über die Natur der thierischen Körper… nebst einem Auszugaus dessen französischen Werke über das Viperngift, transl. by E. B. G.Hebenstreit (Leipzig: Weygandsche Buchhandlung, 1785), 251-3.See also Earles, ‘Studies in the Development’; Knoefel, FeliceFontana, 290-2.

131 Fontana, Beobachtungen, 253-4.132 Ibid., 257-8.133 Ibid., 260-1.134 On the resistance to Fontana’s theory and further experimental

efforts to answer the question of opium’s effect on nerves or via theblood see Earles, ‘Studies in the Development’, and idem, ‘EarlyTheories’.

135 G. C. Siebold, Commentatio de effectibus opii in corpus animalesanum maxime respectu habito ad eius analogiam cum vino(Göttingen: J. C. Dieterich, 1789), 82.

136 Monro, ‘An Attempt to Determine’, 325-6; idem, Experiments on theNervous System, with Opium and Metalline Substances; Made Chieflywith the View of Determining the Nature and Effects of AnimalElectricity (Edinburgh: A. Neill, 1793), 9-16.

137 Fontana, Beobachtungen, 256; Earles, ‘Early Theories’, 104.138 For John Hunter’s idea of a “living principle” in the blood see his A

Treatise on the Blood, Inflammation, and Gun-Shot Wounds, 2 vols(London: E. Cox, 1812), vol. i, 133-165. S. Crumpe, An Inquiryinto the Nature and Properties of Opium; wherein Its ComponentPrinciples, Mode of Operation, and Use or Abuse in Particular Diseases,are Experimentally Investigated; and the Opinions of Former Authors onthese Points Impartially Examined (London: G. G. and J. Robinson,1793), 104-25. Crumpe also criticized Fontana’s method of applyingsolutions of opium directly to nerves, arguing that “the nervousmatter must be organized in a peculiar manner, to enable it to receiveor be sensible of these impressions.” Ibid., 126.

139 Ibid., 137-9. Monro also tried to refute Fontana’s theory, pointingamong others to his earlier trials on frogs, which had indicated thatopium was still effective even if the circulation had been interruptedand the blood largely evacuated. See Monro, Experiments on theNervous System, 16, and idem, ‘An Attempt to Determine’, 318-9,331-2.

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140 Crumpe, An Inquiry into… Opium, 131.141 Ibid., 140-1.142 Earles, ‘Studies in the Development’. On the new chemical methods

for the identification of poisons in the body see N. G. Coley, ‘AlfredSwaine Taylor, MD, FRS (1806-1880): Forensic Toxicologist’,Medical History, xxxv (1991), 409-27.

143 For a summary of this controversy see Earles, ‘Studies in theDevelopment’. See also French, Robert Whytt, 52-3, 73.

144 A. von Haller, Von den empfindlichen und reizbaren Teilen desmenschlichen Körpers, ed. by K. Sudhoff (Leipzig: J. A. Barth, 1922),46.

145 Sproegel, Dissertatio, 25-39, 70-2.146 Ibid., 27-30; A. von Haller, Mémoires sur la Nature Sensible et

Irritable, des Parties du Corps Animal, 4 vols (Lausanne: M.-M.Bousquet & Ce. and S. D’Arnay, 1756-60), vol. i, 331, 371-2.

147 Ibid., 386.148 Whytt, ‘An Essay on the… Motions of Animals’, 197-8.149 Idem, Physiological Essays (Edinburgh: Hamilton, Balfour, and Neill,

1755), 204-13. See also idem, ‘An Account of Some Experiments’,282-306. Cf. Alston, ‘Dissertation on Opium’, 156; Boerhaave,Impetum faciens, 402.

150 Whytt, Physiological Essays, 212-3. See also idem, ‘An Account ofSome Experiments’, 305.

151 Cf. Haller, Mémoires, vol. iv, 131. See also idem, Elementaphysiologiae corporis humani, 8 vols (Lausanne: Bousquet, D’Arnayetc., 1757-66), vol. v, 609.

152 Haller, Mémoires, vol. iv, 130-1.153 Fontana, Beobachtungen, 261-2.154 Haller, Mémoires, vol. iv, 128. Cf. Young, Treatise on Opium, 161;

Tralles, Usus opii, Sect. i, 56, 58-9. See also Haller, Elementaphysiologiae, vol. v, 609-10.

155 Monro, ‘An Attempt to Determine’, 320-1, 332.156 Whytt, Physiological Essays, 188-9, 204; Haller, Mémoires, vol. iv,

117-8, 127-8.157 See M. D. Grmek, Raisonnement Expérimental et Recherches

Toxicologiques chez Claude Bernard (Geneva: Librairie Droz, 1973).158 See also Maehle, ‘Selbstversuche’.159 M. Garthshore, Dissertatio medica inauguralis, de papaveris usu, tam

noxio, quam salutari, in paturientibus, ac puerperis (Edinburgh: TypisAcademicis, 1764), 4.

160 S. Bard, Tentamen medicum inaugurale, de viribus opii (Edinburgh:A. Donaldson and J. Reid, 1765), 14-20, 25-6.

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161 Ibid., 26-8.162 C. J. Wirtensohn, Dissertatio medica inauguralis, demonstrans opium

vires fibrarum cordis debilitare, et motum tamen sanguinis augere, 2ndedn (Münster: P. H. Perrenon, 1775), 9-14, 21-6. See also idem,Abhandlung vom Mohnsafte, welche erweiset, daß er die bewegendenKräfte des Herzens vermindert, und dennoch die Bewegung des Blutesvermehret, transl. by G. J. Fehr (Kassel: J. J. Cramer, 1778). Forsummaries of both Wirtensohn’s and Bard’s dissertation see J. C.Tode, Medicinischchirurgische Bibliothek, vol. iv (Copenhagen: J. G.Rothen, 1777), 243-50.

163 M. T. Monti, Catalogo del Fondo Haller della Biblioteca NazionaleBraidense di Milano, 12 vols (Milan: F. Angeli, 1983-94).

164 A. von Haller, Abhandlung über die Wirkung des Opiums auf denmenschlichen Körper, transl. and ed. by E. Hintzsche and J. H. Wolf(Berne: Verlag P. Haupt, 1962), 11.

165 Ibid., 16-17.166 Ibid., 5, 17.167 Ibid., 5-8.168 B. L. Tralles, Ad illustri viri Christiani Gottlieb Ludwigii Facult. Med.

Lipsiensis Decani etc. disquisitionem de vi opii cardiaca adversariismedico-practicis insertam humanissima responsio (Breslau: J. E. Meyer,1771), 23-5.

169 See Maehle, Kritik und Verteidigung des Tierversuchs, 15-56.170 Monro, ‘An Attempt to Determine’, 294-5.171 Bard, Tentamen medicum, 18.172 Wirtensohn, Dissertatio, 10.173 Sproegel, Dissertatio, 24-41; Haller, Mémoires, vol. i, 371, 385-6;

Knoefel, ‘Felice Fontana on Poisons’.174 Siebold, Commentatio, 7-9, 48-53.175 Crumpe, An Inquiry into… Opium, 33-6.176 Ibid., 36. Cf. Bard, Tentamen medicum, 15, 19.177 Wirtensohn, Dissertatio, 10.178 {J. Brown}, The Elements of Medicine; or a Translation of the Elementa

Medicinae Brunonis. With Large Notes, Illustrations and Comments. Bythe Author of the Original Work, 2 vols (London: J. Johnson, 1788),vol. i, ix-xii, 103-4. See also Wiesemann, ‘Die heimliche Krankheit’,62-6.

179 Crumpe, An Inquiry into… Opium, 98-9, 184-5, 192-3.180 Cf. Magazin der verbesserten theoretischen und praktischen

Arzneikunst, i/3 (1796), 166-7. Weikard, in 1795, had edited thefirst German translation of Brown’s Elementa medicinae.

181 Crumpe, An Inquiry into… Opium.

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182 F. A. von Humboldt, Versuche über die gereizte Muskel- undNervenfaser nebst Vermuthungen über den chemischen Process des Lebensin der Thier- und Pflanzenwelt, 2 vols (Posen: Decker undCompagnie, 1797), vol. ii, 407-14.

183 Cf. ibid., vol. ii, 408.184 Ibid., vol. ii, 414-7.185 Critical Review, n. s. xi (1794), 66-70.186 M. Ward, ‘Observations on the Modus Operandi of Opium’,

Medical and Physical Journal, vi (1801), 478-86; vii (1802), 124-37,341-60, 497-506; viii (1802), 325-48, 388-94.

187 See this chapter, below.188 Ward, ‘Observations on the Modus Operandi’, vol. viii, 347.189 Ibid., vol. vii, 127. Cullen classified opium as a narcotic and

described its mode of action as “diminishing the mobility, and in acertain manner suspending the motion, of the nervous fluid”. W.Cullen, A Treatise of the Materia Medica, 2 vols (Edinburgh: C.Elliot, 1789), vol. ii, 224-5.

190 Ward, ‘Observations on the Modus Operandi’, vol. vii, 137.191 Ibid., vol. vii, 346-7, 359-60.192 Ibid., vol. viii, 325. Emphasis in the original.193 Ibid., vol. vii, 497-506, vol. viii, 325-9.194 As quoted ibid., vol. vii, 126.195 C. Wiesemann, ‘Brownianism and the German Medical

Establishment: a Case Study on “Orthodoxy” and Malpractice’(typescript, Erlangen, 1994).

196 See ibid., and Porter, Doctor of Society.197 Cf. Sprengel, Versuch, 329.198 Alston, ‘Dissertation on Opium’, 171.199 Ibid., 161-2, 171. Note that in the seventeenth century

Waldschmied (see above) had opposed the use of opium in smallpoxand haemorrhoidal and menstrual fluxes, though on differentgrounds.

200 Alston, ‘Dissertation on Opium’, 172, 176. Cf. the contraindicationsof Waldschmied, Berger and Fimmler, and Hoffmann and Muller,mentioned above.

201 Whytt, The Works, 494.202 Ibid., 646-9, 680-1.203 Ibid., 643-4, 679-80, 693-701, 707.204 Ibid., 644.205 Ibid.206 Ward, ‘Observations on the Modus Operandi’, vol. vii, 504-5.207 Crumpe, An Inquiry into… Opium, 218. For the antispasmodic

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treatment of tetanus large and often repeated opium doses weregiven; see for example T. Conyns Cole, ‘Case of Tetanus SuccessfullyTreated by the Exhibition of Opium’, Medical and Physical Journal,vii (1802), 55-7.

208 Crumpe, An Inquiry into… Opium, 225-6.209 See M. Wall, The Use of Opium in Low Fevers, and in the Synochus;

Illustrated by Cases, 2nd edn (Oxford: Clarendon Press, 1786), whichcontains 17 case histories, including three unsuccessful treatments.Though inspired by the “Pupils of Dr. Brown” to try opium in thosefevers, Wall regarded the drug traditionally as a cordial and sedativerather than as a stimulant. See ibid., xiii, 12, 17, 37, 60-1.

210 Crumpe, An Inquiry into… Opium, 248-63.211 See ibid., 247-8, 265-300, for his discussion of the use of opium in

intermittent fevers, gout, smallpox, measles, haemorrhagies, phthisis,dysentery, tetanus, chorea, epilepsy, asthma, pyrosis, colic, cholera,diarrhoea, hysteria, hydrophobia, mania, and syphilis.

212 Ibid., 247-8, 269-72, 276-7.213 A. C. H. Henke, ‘Abhandlung über die Wirkungsart und klinische

Anwendung des Mohnsaftes, mit Hinsicht auf die Meinungen derälteren, neueren und neuesten Zeit über diesen Gegenstand’, Archivfür medizinische Erfahrung, iv/2 (1803), 765-839; E. Horn, De opiiabusu tam respectu veteris quam novae medicorum doctrinae(Wittenberg: S. G. Zimmermann, 1804). For Brunonianism inGermany see Jantz, ‘Pharmacologia Browniana’; N. Tsouyopoulos,‘The Influence of John Brown’s Ideas in Germany’, in Bynum andPorter (eds), Brunonianism, 63-74. Wiesemann, ‘Die heimlicheKrankheit’; U. Wiesing, Kunst oder Wissenschaft? Konzeptionen derMedizin in der deutschen Romantik (Stuttgart-Bad Cannstatt:fromann-holzboog, 1995).

214 Henke, ‘Abhandlung über die Wirkungsart’, 780-2. On Frank andRöschlaub see Jantz, ‘Pharmacologia Browniana’, and Tsouyopoulos,‘The Influence’.

215 G. Young, Abhandlung vom Opio, oder Mohnsafte, auf PraktischeBemerkungen gegründet. Aus dem Englischen übersetzt (Bayreuth:Verlag J. A. Lübecks, 1760).

216 Young, Treatise on Opium, 4-13.217 See ibid., 28-168, for his discussion of opium use in cough and

catarrh (including observations on himself ), diarrhoea and vomiting,diarrhoea in weaning-illness of infants, rickets, and scrophula, indysentery, tenesmus, nephritis, pregnancy, labour-pains, milk-fever,weed, lochia, flux of the menses, spasms, haemorrhoids, rheumatism,operations in surgery, fractures, phthisis pulmonalis, lowness of

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spirits, melancholia and mania, great fatigue, hysteries and nervousdisorders, nervous asthma, rickets and scrophula, toothache, cancer,kidney stone, lethargy and other sleepy diseases, asthma senile,peripneumonia notha of old men, internal inflammations, smallpox,measles, salivation, and fevers.

218 See Scarborough, ‘The Opium Poppy’.219 Alston, ‘Dissertation on Opium’, 159.220 Ibid.221 Monro, ‘An Attempt to Determine’, 303-6.222 Ibid., 308.223 J. Leigh, An Experimental Inquiry into the Properties of Opium, and its

Effects on Living Subjects: with Observations on Its History,Preparations and Uses (Edinburgh: C. Elliot, 1786), 96-8. AlsoGerman transl., idem, Erfahrungsmäßige Untersuchung derEigenschaften des Opiums und seiner Wirkungen bei lebendigenGeschöpfen (Leipzig: J. F. Junius, 1787), 72-3.

224 Siebold, Commentatio, 37-8.225 Crumpe, An Inquiry into… Opium, 27-8.226 Critical Review, lxii (1786), 130-2, on 132.227 Ward, ‘Observations on the Modus Operandi’, vol. vii, 135-7.228 idem, ‘Facts and Observations Relative to the External Application of

Opium by Friction, so as to be Absorbed by the Lymphatics’,Medical and Physical Journal, i (1799), 441-449; ii (1799), 6-9. Alsoin German: idem, ‘Über den äusserlichen Gebrauch des Mohnsaftes’and idem, ‘Neuere Bemerkungen über den äusserlichen Gebrauchdes Mohnsaftes’, Sammlung auserlesener Abhandlungen zumGebrauche praktischer Aerzte, xix/2 (1800), 275-98. For a review ofChiarugi’s publication see {anonymous}, ‘Letter on the External Useof Opium, to Dr L. Frank, from Vincenzio Chiarugi… Florence,1797’, Annals of Medicine, iii (1798), 194-6. Henke, in 1803, agreedwith Ward and recommended opium externally as a useful treatmentof “asthenic pains in all kinds of diseases” and several otherconditions; see his ‘Abhandlung über die Wirkungsart’, 835-6.

229 C. W. Hufeland, Enchiridion medicum oder Anleitung zurmedizinischen Praxis. Vermächtnis einer funfzigjährigen Erfahrung, 2ndenlarged edn (Berlin: Jonas, 1836), 828. See also Rechenberg andKoelbing, ‘Hufelands Opiumtherapie’, 109.

230 See ibid., 110-5.231 The Harveian Society had been founded in 1782 by Andrew

Duncan senior. On the history of the Harveian Society and its prizeessays see Sir D’Arcy Power (ed.), British Medical Societies (London:The Medical Press and Circular, 1939), 45-52; Jenkinson, Scottish

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Medical Societies, 139-140.232 Monthly Review, lxxvi (1787), 258.233 Critical Review, lxii (1786), 130-2.234 Cf. Medicinische Bibliothek, iii/1 (1788), 54-6, on 56.235 A similar tendency can be identified in a review of Leigh’s study in

the Allgemeine Deutsche Bibliothek, supplement to vols liii-lxxxvi {noyear}, part i, 395-6. Its author acknowledged Leigh’s chemical andpharmacological work, writing that it could provide usefulknowledge for some doctors, who either over- or underestimated thepowers of opium. But he criticized that “clearly too little” had beensaid by Leigh on the therapeutic use of the drug.

236 Universitätsarchiv Göttingen, Medizinische Fakultät. Dekanats- undPromotionsvorgänge und -urkunden for the year 1788, letters by J.F. Blumenbach dated 3 May and 9 May 1788.

237 Ibid., Dekanats- und Promotionsvorgänge und -urkunden for theyear 1789, including opinions on Siebold’s essay by the DeanHeinrich August Wrisberg (2 May 1789) and professors JohannAndreas Murray (3 May 1789) and Johann Friedrich Gmelin (5 May1789), with notes of agreement by professors Richter andBlumenbach.

238 J. F. Blumenbach, Göttingische Anzeigen von gelehrten Sachen, xxix(1790), 281-3.

239 Siebold, Commentatio, 11.240 Henke, ‘Abhandlung von der Wirkungsart’.241 Critical Review, xi (1794), 66-70.242 See also Sonnedecker, ‘Emergence of the Concept’.243 For recent studies into this literary genre see K. Parker, ‘Telling Tales:

Early Modern English Voyagers and the Cape of Good Hope’, TheSeventeenth Century, x (1995), 121-49.

244 For the scientific reception of travellers’ reports on opium see forexample Alston, ‘Dissertation on Opium’, 112-6, 122-3, 163-4;Siebold, Commentatio, 9, 37, 63; Crumpe, An Inquiry into…Opium, 177-9.

245 G. da Orta, Colloquies on the Simples and Drugs of India, new edn(Lisbon 1895), ed. and annotated by the Conde de Ficalho, transl.with an introd. and index by Sir Clements Markham (London: H.Sotheran and Co., 1913), 330-4; A. Coke Burnell and P. A. Tiele(eds), The Voyage of John Huygen van Linschoten to the East Indies, 2vols, from the old English transl. of 1598 (London: Hakluyt Society,1885; reprint New Delhi: Asian Educational Services, 1988), vol. ii,112-114; P. Alpin, La Médecine des Egyptiens, vol. ii, 332-46.

246 Ibid., vol. ii, 333.

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247 Ibid., vol. ii, 334.248 See Wiesemann, ‘Die heimliche Krankheit’.249 Alpin, La Médecine des Egyptiens, vol. ii, 341. See also Waldschmied,

above.250 J. Chardin, Travels in Persia, reprint of the Engl. edn of 1720, with

an introd. by Sir Percy Sykes (London: Argonaut Press, 1927), 243-6; E. Kaempfer, Amoenitatum exoticarum… fasciculus, 644-5, 649-50; A. Russell, The Natural History of Aleppo, and Parts Adjacent(London: A. Millar, 1856 {1756}), 83-4; Reinegg, ‘Ueber dasOpium’; F. de Tott, Mémoires sur les Turcs et les Tartares, 4 vols(Amsterdam, 1784), vol. i, 158-61, vol. ii, 290-3.

251 Russell, Natural History of Aleppo, 83-4.252 Kaempfer, Amoenitatum exoticarum… fasciculus, 645, 649-50.253 Reinegg, ‘Ueber das Opium’, 373-80.254 Alpin, La Médecine des Egyptiens, vol. ii, 334; Kaempfer,

Amoentitatum exoticarum… fasciculus, 645.255 Reinegg, ‘Ueber das Opium’, 380-1.256 See this chapter, above.257 Jones, Mysteries of Opium, 31, 245-6.258 Ibid., 32, 249-50 305-6.259 Ibid., 32-3, 307-8.260 Ibid., 307.261 Ibid., 245. Emphasis in the original.262 Young, Treatise on Opium, 77-8, 97-105, 124-6.263 Kreutel, Opiumsucht, 183-4.264 Young, Treatise on Opium, 4-5, where he criticizes E.-F. Geoffroy’s

approach of studying the properties of opium and other drugs withchemical analysis.

265 Ibid., 94-103, 124-9.266 Ibid., 77.267 Ibid., 102.268 Ibid., 98-9.269 Haller, Abhandlung über die Wirkung, 11. Haller’s source here is not

known, yet Chardin mentioned an infusion made from poppy seeds,hempseed, and nux vomica, and commented that the “Indians use itwith their State-Criminals, when they wont {? won’t} take their Lifeaway, in order to deprive them of their Senses; and with the King’sChildren, when they intend to Incapacitate them for Reigning.”Chardin, Travels in Persia, 245-6.

270 Haller, Abhandlung über die Wirkung, 11, 20-1.271 See also Wiesemann, ‘Die heimliche Krankheit’, 107-9.272 Ibid., 112-23.

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273 Wiesemann, ibid., quotes among others Christoph WilhelmHufeland’s Ueber die Vergiftung durch Branntwein (1802) andThomas Trotter’s Essay on Drunkenness (1804).

274 C. C. H. Marc, Allgemeine Bemerkungen über die Gifte und ihreWirkungen im menschlichen Körper. Nach Brownischem Systemedargestellt (Erlangen: J. J. Palm, 1795), 271.

275 Horn, De opii abusu, 60-3.276 T. De Quincey, Confessions of an English Opium-Eater. Now First

Carefully Revised by the Author, and Greatly Enlarged, 2nd edn(Edinburgh: J. Hogg, 1856), 203: “… the primary effects of opiumare always, and in the highest degree, to excite and stimulate thesystem.” The Confessions were first published in a shorter version in1821, in the London Magazine. On De Quincey’s experience withthe drug and its relevance for his literary work see Hayter, Opiumand the Romantic Imagination, and Lindop, The Opium-Eater.

277 Cf. Hufeland, Enchiridion medicum, 854. The quotation is part of achapter, respectively essay, on opium, which Hufeland first publishedin his Journal der Practischen Arzneykunde und Wundarzneykunst,lxix/1 (1829), 7-69. See also Rechenberg and Koelbing, ‘HufelandsOpiumtherapie’; Kreutel, Opiumsucht, 204-9; Wiesemann, ‘Dieheimliche Krankheit’, 117-121. On Hufeland’s campaign againstspirits see H. Spode, Die Macht der Trunkenheit. Kultur- undSozialgeschichte des Alkohols in Deutschland (Opladen: Leske &Budrich, 1993), 124-5, 155-6.

278 See ibid., 127-8; Wiesemann, ‘Die heimliche Krankheit’, 124-6.Hufeland had written the preface to the German edition of Brühl-Cramer’s work in 1819.

279 See chapter 2 above.280 Langrish, Physical Experiments upon Brutes, 74-108.281 See Winau, ‘Experimentelle Pharmakologie und Toxikologie’, 74-82,

and chapter 1 above.282 F. Weber, ‘Observations on the Effects of Opium on the Human

Body’, Medical and Physical Journal, viii (1803), 435-43, 501-16. Seealso Kramer, ‘The Opiates’, 90-1.

283 Jones, Mysteries of Opium, 21-2. Emphasis in the original.284 Young, Treatise on Opium, 101-5285 See Salomon-Bayet, ‘Opiologia’.286 Haller, Abhandlung über die Wirkung, 11-15.287 Leigh, An Experimental Inquiry, 113-7.288 Weber, ‘Observations on the Effects of Opium’, 436.289 De Quincey, Confessions, 199-200.290 See the cases of Young, above.

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291 J. Awsiter, An Essay on the Effects of Opium. Considered as a Poison.With the Most Rational Method of Cure, Deduced from Experience(London: G. Kearly, 1763), 5: “… there are many Properties in it{i.e. opium}, if universally known, that would habituate the Use, andmake it more in Request with us than the Turks themselves, theResult of which Knowledge must prove a general Misfortune.” Seealso De Quincey, Confessions, viii.

292 Young, Treatise on Opium, 106-8.293 See Weber, ‘Die “Opiumkur”’.294 Siegel and Hirschman, ‘Charvet’.295 Holmstedt and Liljestrand, Readings in Pharmacology, 202-3; Stille,

Der Weg der Arznei, 270.296 Cf. Kreutel, Opiumsucht, 209, 259-262.297 See Kramer, ‘The Opiates’.298 See ibid.299 Hufeland, Enchiridion medicum, 830. On the reluctance of English

physicians, up to the 1830s, to use morphine instead of traditionalopium preparations, see Morson, Operative Chymist, 101-2.

300 Weber, ‘Die “Opiumkur”’; Haller Jr., ‘Opium Usage’.301 Kramer, ‘The Opiates’, 91; Stille, Der Weg der Arznei, 43-5; Lesch,

Science and Medicine in France, 136-42; Müller-Jahncke andFriedrich, Geschichte der Arzneimitteltherapie , 79-81.

302 F. Krömeke (ed.), Friedrich Wilh. Sertürner, der Entdecker desMorphiums. Lebensbild und Neudruck der Original-Morphiumarbeiten(Jena: Verlag von G. Fischer, 1925), 16-17, 26; Lesch, ‘ConceptualChange’; R. Schmitz, ‘Friedrich Wilhelm Sertürner and theDiscovery of Morphine’, Pharmacy in History, xxvii/2 (1985), 61-74;P. Kurzweil and L. Pittrow, ‘Die Alkaloide des Schlafmohns (Papaversomniferum) im Licht der Pharmaziegeschichte. Teil 1: Von derEntdeckung des Morphins bis zum Heroin’, Geschichte derPharmazie, xlvii/4 (1995), 55-60.

303 A. F. Gehlen, ‘On the Present State of Our Knowledge of Opium’,Medical and Physical Journal, xii (1804), 38-44, 117-22.

304 Cf. ibid., 42-3. See also the review {anonymous}, ‘Mémoire surl’Opium. Par Jossé…1796’, Annals of Medicine, iii (1798), 259-65.

305 Cf. Gehlen, ‘On the Present State’, 118-9. See also Krömeke (ed.),Sertürner, 5-6.

306 Gehlen, ‘On the Present State’, 43, 119. On acids, especially vinegar,as antidotes to opium and the treatment of opium poisoning ingeneral see Awsiter, An Essay on the Effects, 38-52. See also idem, ‘AnAccount of the Effects of Opium as a Poison; with the Method ofCure; and Proper Directions What to Do, when Medical Assistance

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is Not at Hand’, Gentleman’s Magazine, xxxiii (1763), 51-4.307 F. W. Sertürner, ‘Darstellung der reinen Mohnsäure (Opiumsäure)

nebst einer chemischen Untersuchung des Opiums mit vorzüglicherHinsicht auf einen darin neu entdeckten Stoff und die dahingehörigen Bemerkungen’, Journal der Pharmacie, xiv (1805), republ.in Krömeke (ed.), Sertürner, 33-57, on 56.

308 F. W. Sertürner, ‘Säure im Opium’ and ‘Nachtrag zur Charakteristikder Säure im Opium’, Journal der Pharmacie, xiii (1805), republ. inKrömeke (ed.), Sertürner, 29-92.

309 Cf. Sertürner, ‘Darstellung der reinen Mohnsäure’.310 Ibid., 55-6.311 Ibid., 57.312 F. W. Sertürner, ‘Ueber das Opium und dessen krystallisirbare

Substanz’, Journal der Pharmacie, xx (1811), republ. in Krömeke(ed.), Sertürner, 58-60.

313 Sertürner, ‘Darstellung der reinen Mohnsäure’, 56-7.314 Krömeke (ed.), Sertürner, 19.315 F. W. Sertürner, ‘Ueber das Morphium, eine neue salzfähige

Grundlage, und die Mekonsäure, als Hauptbestandtheile desOpiums’, Annalen der Physik, xxv (1817), republ. in Krömeke (ed.),Sertürner, 61-81. See also Kramer, ‘The Opiates’, 90; L. K. Altman,Who Goes First? The Story of Self-Experimentation in Medicine(Wellingborough: Equation, 1988), 89-90.

316 Sertürner, ‘Ueber das Morphium’, 68. On the problem oftransferability in contemporary pharmacology see Maehle, Kritik undVerteidigung des Tierversuchs, 37-44.

317 Sertürner, ‘Ueber das Morphium’, 68-9.318 Ibid., 69-70. See also A.-H. Maehle, ‘Neue Mittel der

Schmerzbekämpfung. Vom Morphium zur Narkose’, in H. Schott(ed.), Meilensteine der Medizin (Dortmund: Harenberg Verlag,1996), 297-303; for a recent discussion of the historicaldevelopment of anaesthesia and its consequences for surgery see P.Ridder, Chirurgie und Anästhesie: Vom Handwerk zur Wissenschaft(Stuttgart: S. Hirzel, 1993). On the manufacture and sale ofmorphine in the nineteenth century, see Morson, Operative Chymist,83-121.

319 See Maehle, Kritik und Verteidigung des Tierversuchs ; idem, ‘TheEthical Discourse’.

320 Sproegel, Dissertatio, 26, 29, 35, 37; Whytt, ‘An Account of SomeExperiments’, 299.

321 Sproegel, Dissertatio, 31, 35.322 Siebold, Commentatio, 4.

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323 Crumpe, An Inquiry into… Opium, 54, 77.324 Leigh, An Experimental Inquiry, 57; Crumpe, An Inquiry into…

Opium, 77; Sertürner, ‘Ueber das Morphium’, 69.325 Leigh, An Experimental Inquiry, 56-7, 110-2.326 Sertürner, ‘Ueber das Morphium’, 68.327 See this chapter, above.328 J. Aikin, Thoughts on Hospitals. With a Letter to the Author, by

Thomas Percival, MD FRS (London: J. Johnson, 1771), 76-82.329 T. Percival, ‘Medical Ethics, or, a Code of Institutes and Precepts,

Adapted to the Professional Conduct of Physicians and Surgeons’, inidem, The Works, Literary, Moral, and Medical, 4 vols (Bath: R.Cruttwell, 1807), vol. ii, 377-8.

330 See B. Elkeles, Der moralische Diskurs über das medizinischeMenschenexperiment im 19. Jahrhundert (Stuttgart: G. Fischer Verlag,1996); S. E. Lederer, Subjected to Science: Human Experimentation inAmerica before the Second World War (Baltimore: Johns HopkinsUniversity Press, 1995); R. Faden, T. L. Beauchamp and N. M. P.King, A History and Theory of Informed Consent (New York: OxfordUniversity Press, 1986).

331 See C. Lawrence, ‘The Nervous System and Society in the ScottishEnlightenment’, in B. Barnes and S. Shapin (eds), Natural Order:Historical Studies of Scientific Culture (Beverly Hills: SagePublications, 1979), 19-40.

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Opium: Explorations of an Ambiguous Drug - Brill

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