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The isolation of morphine from opium—the first isolation of anatural product—was a seminal event in the development of

pharmacology as an independent discipline. The purificationkick-started natural product chemistry and quickly led to theisolation of a host of other alkaloids (Table 1). Within a fewyears, in 1827, Heinrich Emanuel Merck of Darmstadt beganselling morphine, resulting in the development of theeponymous company.

A young German pharmacist, Friedrich Wilhelm AdamSertürner, achieved the purification of morphine. Sertürner wasborn in Neuhaus, near Paderborn, on June 19, 1783, and diedin Hameln on February 20, 1841. His work on opiumdeveloped over many years, resulting in some confusion as tothe dates of his discovery. The first edition of Goodman &Gilman (1), for example, reports, “In 1805, a young Germanpharmacist in Hanover named Sertürner isolated and describedmorphine. This epochal finding went unnoticed until his laterpublication in 1816. Sertürner almost lost his life byexperimenting with morphine on himself.” The second edition(2) states, “In 1803, a young German pharmacist in Paderbornnamed Sertürner isolated and described morphine,” and in theseventh edition (3) we read, “In 1806, Sertürner reported theisolation of a pure substance in opium that he namedmorphine, after Morpheus, the Greek god of dreams.”

Sertürner did, in fact, begin publishing on opium inPaderborn in 1805 (4), and claims to have begun work beforea paper on opium by Derosne had appeared in 1804. Thisclaim has been interpreted to mean that Sertürner began workin 1803. However, his earlier work fixated on acid constituentsof opium. Thus, his 1806 paper (5) is mainly concerned withthe constituent we now know as meconic acid. He also

prepared an aqueous alcoholic extraction of opium that had a“sleep-inducing principle.” The extract was tested on four dogsand a mouse that he found wandering in the laboratory. Hegave 6 grains to a dog, followed an hour later by another 6grains. The total dose, therefore, was around 780 milligrams.The dogs vomited, had convulsions, and were drowsy, but didnot sleep. One “gentle little dog” died. Because these doses ofhis extract did not cause sleep, we can conclude that thematerial was highly impure.

ReflectionsScience in the cultural context

First Principles inScience and Ethics

The Isolation ofoThe Isolation o

Within the infant rind of this small flower Poison hath residence, medicine power…

Shakespeare, Romeo and Juliet

TABLE 1. ISOLATION OF ALKALOIDS

Year Compound Investigator1817 Narcotine Robiquet1818 Strychnine Caventou & Pelletier1818 Veratrine Meissner & Caventou1819 Colchicine Meissner & Caventou1820 Caffeine Runge; Caventou & Pelletier1820 Quinine Caventou & Pelletier1822 Emetine Pelletier & Magendie1827 Coniine Giesecke; Geiger & Hess1828 Nicotine Posselt & Reimann1831 Aconitine Mein; Geiger & Hess1832 Codeine Robiquet1833 Atropine Geiger & Hess1833 Thebaine Pelletier & Dumas1842 Theobromine Woskresenky1848 Papaverine Merck1851 Choline Babo & Hirschbrunn1860 Cocaine Niemann1870 Muscarine Schmiedeberg & Koppe

Reflections

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Sertürner moved to Einbeck, just north of Göttingen, in1806. It was only in 1817, while there, that he unequivocallyreported the isolation of pure morphine (6). He prepared it byextracting opium with hot water and precipitating morphinewith ammonia. He obtained colorless crystals, poorly soluble inwater, but soluble in acids and alcohol.

In order to establish that his crystals carried thepharmacological activity of raw opium, Sertürner tested themon himself and three boys, “none older than seventeen.” It wasa near-catastrophe. He writes:

In order to test my earlier experiments strictly, Iencouraged three persons, none older than seventeenyears, to take morphine with me simultaneously.Warned by the previous effects, however, I merelyadministered half a grain dissolved in half a drachmaof alcohol and diluted with several ounces of distilledwater.1 This produced a generalized redness of cheeksand eyes [perhaps due to the alcohol] and the vitalfunctions appeared generally enhanced. After half anhour, another half-grain was taken; the condition wasaggravated markedly, while a transient tendency tovomiting and a dull pain in the head with narcosis was felt.

After another 15 minutes, we swallowed anotherhalf-grain of morphium, undissolved, as a coarsepowder, with 10 drops of alcohol and a half-ounce ofwater. The outcome with the three young men wasdecidedly rapid and extreme. It presented as pain in theregion of the stomach, exhaustion, and severe narcosisthat came close to fainting. I also was subject to thesame fate. Being in the supine position, I fell into adream-like state and sensed in the extremities,particularly the arms, a slight twitching whichaccompanied the pulse beats. These distinct symptomsof true intoxication, particularly the frail condition of thethree young men, caused me so much concern that I,half unconscious, drank more than a quarter of a bottle(6 to 8 ounces) of strong vinegar and also had the othersdo the same. This led to such severe vomiting that,several hours later, one who was of a particularlydelicate constitution and whose stomach had alreadybeen emptied completely, found himself in a continuousstate of a most painful and highly alarming retching. Inthis condition, I gave him carbonated magnesia, uponwhich the vomiting subsided instantly. The night passedunder deep sleep. Although the vomiting recurred in themorning, it immediately subsided after a strong dose ofmagnesia. Lack of opening of the body, loss of appetite,

narcosis, and pain in the head and body disappearedonly after several days. Judging from these highlyunpleasant experiences, I deduce that morphine, evenin small quantities, acts as a strong poison. . . . As noneof the other components of opium possesses effects suchas those described here, the important medicinalproperties of opium probably result from puremorphine, which I have to leave to the physicians to test.

In this and other experiments, Sertürner showed that hiscrystalline material had the pharmacological actions of opiumby testing it both on animals and humans. Importantly, he alsodemonstrated that other preparations from opium were devoidof activity. As a consequence of his studies, Sertürner estab-lished the principle that plants contain active substances that,on isolation, carry the therapeutic properties of the plant.Sertürner further concluded that morphine would soon replaceopium.

We are left feeling uneasy about the experiment on theteenaged boys. Although scientifically important, theexperiment is ethically dubious. Sertürner was not a physicianand also took part in the experiment, with a near-disastrousloss of judgment as a result. A modern Human SubjectsCommittee would not approve. Indeed, such an experimenttoday would open the investigator to criminal prosecution.

Was Sertürner’s experiment acceptable by 1817standards? There should perhaps have been a physicianpresent who was not an experimental subject. If the experimentwas morally or ethically reprehensible, the transgression isinsignificant compared to the slaughters being wrought byNapoleon. One has only to think of the 200 amputationscarried out (without anesthesia) in one day by the French armysurgeon, Larrey, at the battle of Borodino, to place Sertürner’sexperiments in context. However, other experiments on humansin Germany, a century or more in the future, would reach backto shadow reflections on Sertürner’s achievement.

Claims of priority in the discovery of morphine have beenmade for two other investigators. Jean-Francois Derosne (8)prepared a crude extract of opium (with alcohol and water),and obtained, by potassium carbonate precipitation, what hecalled “sel de Derosne.” Derosne’s alkaloidal fraction lackednarcotic properties, and was probably largely narcotine (alsoknown as noscapine), perhaps with meconic acid, bothabundant in opium. Armand Seguin read a paper to theInstitute of France in 1804, but only published it in 1814 (9).He described the isolation of a principle, but did not report anyanimal or human experiments.

The relationship between toxicity and therapy was anancient concept. Walter Raleigh wrote, in 1614 (10), “Theskillful and learned chemist could draw helpful medicines out ofpoison, as poison out of the most helpful herbs and plants.”Shakespeare refers to the same principle more poetically in

1In other words, he gave about 32 milligrams of material,comparable to a 60-milligram average oral adult dose of amorphine salt (7).

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Henry IV, part 2: “[I]n poison there is physic.” However,Sertürner helped establish the relationship as an experimentalprinciple, thereby stimulating an era of chemical andpharmacological progress. He explicitly recognized that anextract of opium would have a purity and reproducibility ofeffect not obtainable with raw opium. He generalized theprinciple that other “so-called poisonous plants” would containextractable materials with potential therapeutic activities.

Sertürner initiated the development of natural productchemistry, and he stimulated the evolution of synthetic anddegradative chemistry for the structural elucidation of complexcrystalline chemicals isolated from plants. Initially, the emphasiswas on alkaloid isolation, because of the ease of acidextraction of alkaloid salts and the ease of purification byorganic extraction of lipophilic free alkaloids from basifiedmedium. Winterstein and Trier (11) write that alkaloid chemistrybegan in 1817. Hanzlik (12) comments, “The isolation ofmorphine was a comparatively humble achievement. It requiredno munificent grant, no extensive laboratory equipment, nohighly organized institute or factory.”

In view of its dream-inducing properties, Sertürner namedhis crystalline material “morphium,” derived from “Morpheus,”the Latin name that Ovid (43 BC - 17 AD) used for the god ofdreams (Metamorphoses, Book XI). Morpheus was the son ofSomnus, the god of sleep. Ovid derived the word from theGreek morphe, or form, because the god of dreams gives airynothings their form and fashion (13):

King Sleep was father of a thousand sons–indeed a tribe – and of them all, the onehe chose was Morpheus, who had such skillin miming any human form at will.

Despite the derivation, Morpheus is a Roman invention,and not Greek. (In Hesiod, dreams were the daughters, and notthe sons, of Night.) It was Joseph Louis Gay-Lussac whointroduced the form “morphine,” against the objections ofSertürner (14). The Oxford English Dictionary has the firstcitation in English in 1828: “morphine is the narcotic principleof opium.”

Ryan J. HuxtableDepartment of PharmacologyCollege of MedicineUniversity of ArizonaTucson, Arizona 85724-5050

Stephan K. W. SchwarzCentre for Anesthesia & AnalgesiaDept. of Pharmacology & TherapeuticsandDept. of AnesthesiaFaculty of MedicineThe University of British ColumbiaVancouver, B.C. Canada V6T 1Z3

AcknowledgmentWe thank Marion Huxtable for help with translations from the German.

REFERENCES1. Goodman, L. and Gilman, A. The Pharmacological Basis of Therapeutics. New

York: The Macmillan Co., 1941, p. 186.

2. Goodman, L. and Gilman, A. The Pharmacological Basis of Therapeutics. NewYork: The Macmillan Co., 1958, p. 216.

3. Gilman, A.G., Goodman, L.S., Rall, T.W., and Murad, F. The PharmacologicalBasis of Therapeutics. New York: MacMillan Publishing Co., 1985, p. 491.

4. Sertürner, F. [No title]. Journal der Pharmacie fuer Aerzte und Apotheker 13:229-243, 1805.

5. Sertürner. Darstellung der reinen Mohnsäure (Opiumsäure) nebst einerChemischen Untersuchung des Opiums mit vorzüglicher Hinsicht auf einendarin neu entdeckten Stoff und die dahin gehörigen Bemerkungen. Journalder Pharmacie fuer Aerzte und Apotheker 14: 47-93, 1806.

6. Sertuerner. Ueber das Morphium, eine neue salzfähige Grundlage, und dieMekonsäure, als Hauptbestandtheile des Opiums. Annalen der Physik 55:56-89, 1817.

7. Hardman, J.G., Limbird, L.E., Molinoff, P.B., Ruddon, R.W., and Gilman, A.G.Goodman & Gilman’s The Pharmacological Basis of Therapeutics. New York:McGraw Hill, 1995,

8. Derosne, C.L. Mémoire sur l’opium. Ann.Chim. 45: 257-285, 1803.

9. Seguin, M.A. Premier memoire sur l’opium. Annales de Chimie 92: 225-245,1814.

10. Raleigh, W. The History of the World I I Chap. 7, p71. London: 1614.

11. Winterstein, E. and Trier, G. Die Alkaloide. Berlin: Borntraeger Press, 1910.

12. Hanzlik, P.J. 125th Anniversary of the discovery of morphine by Sertürner. J.Am. Pharm. A. 18: 375-384, 1929.

13. Mandelbaum, A. The Metamorphoses of Ovid. New York: Harcourt Brace andCo., 1993.

14. Sertuerner, F.W. Ueber eins der fürchterlichsten Gifte der Pflanzenwelt, als einNachtrag zu seiner Abhandlung über die Mekonsäure und das Morphium;mit Bemerkungen, den aciden Extractivstoff des Opiums und seineVerbindungen betreffend. Annalen der Physik 57: 183-202, 1817.