Reflections

Science in the cultural context

The Isolation o
of

First Principles in
Science and Ethics

Within the infant rind of this small flower Poison hath residence, medicine power…
Shakespeare, Romeo and Juliet
TABLE 1. ISOLATION
T he isolation of morphine from opium—the first isolation of a OF ALKALOIDS
natural product—was a seminal event in the development of Year Compound Investigator
pharmacology as an independent discipline. The purification 1817 Narcotine Robiquet
kick-started natural product chemistry and quickly led to the 1818 Strychnine Caventou & Pelletier
isolation of a host of other alkaloids (Table 1). Within a few 1818 Veratrine Meissner & Caventou
years, in 1827, Heinrich Emanuel Merck of Darmstadt began 1819 Colchicine Meissner & Caventou
selling morphine, resulting in the development of the 1820 Caffeine Runge; Caventou & Pelletier
eponymous company. 1820 Quinine Caventou & Pelletier
A young German pharmacist, Friedrich Wilhelm Adam 1822 Emetine Pelletier & Magendie
Sertürner, achieved the purification of morphine. Sertürner was 1827 Coniine Giesecke; Geiger & Hess
born in Neuhaus, near Paderborn, on June 19, 1783, and died 1828 Nicotine Posselt & Reimann
in Hameln on February 20, 1841. His work on opium 1831 Aconitine Mein; Geiger & Hess
developed over many years, resulting in some confusion as to 1832 Codeine Robiquet
the dates of his discovery. The first edition of Goodman & 1833 Atropine Geiger & Hess
Gilman (1), for example, reports, “In 1805, a young German 1833 Thebaine Pelletier & Dumas
pharmacist in Hanover named Sertürner isolated and described 1842 Theobromine Woskresenky
morphine. This epochal finding went unnoticed until his later 1848 Papaverine Merck
publication in 1816. Sertürner almost lost his life by 1851 Choline Babo & Hirschbrunn
experimenting with morphine on himself.” The second edition 1860 Cocaine Niemann
(2) states, “In 1803, a young German pharmacist in Paderborn 1870 Muscarine Schmiedeberg & Koppe
named Sertürner isolated and described morphine,” and in the
seventh edition (3) we read, “In 1806, Sertürner reported the
isolation of a pure substance in opium that he named prepared an aqueous alcoholic extraction of opium that had a
morphine, after Morpheus, the Greek god of dreams.” “sleep-inducing principle.” The extract was tested on four dogs
Sertürner did, in fact, begin publishing on opium in and a mouse that he found wandering in the laboratory. He
Paderborn in 1805 (4), and claims to have begun work before gave 6 grains to a dog, followed an hour later by another 6
a paper on opium by Derosne had appeared in 1804. This grains. The total dose, therefore, was around 780 milligrams.
claim has been interpreted to mean that Sertürner began work The dogs vomited, had convulsions, and were drowsy, but did
in 1803. However, his earlier work fixated on acid constituents not sleep. One “gentle little dog” died. Because these doses of
of opium. Thus, his 1806 paper (5) is mainly concerned with his extract did not cause sleep, we can conclude that the
the constituent we now know as meconic acid. He also material was highly impure.

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Volume 1, Issue 4 189
 Reflections
Sertürner moved to Einbeck, just north of Göttingen, in
1806. It was only in 1817, while there, that he unequivocally
reported the isolation of pure morphine (6). He prepared it by
extracting opium with hot water and precipitating morphine
with ammonia. He obtained colorless crystals, poorly soluble in
water, but soluble in acids and alcohol.
In order to establish that his crystals carried the
pharmacological activity of raw opium, Sertürner tested them
on himself and three boys, “none older than seventeen.” It was
a near-catastrophe. He writes:
In order to test my earlier experiments strictly, I
encouraged three persons, none older than seventeen
years, to take morphine with me simultaneously.
Warned by the previous effects, however, I merely
administered half a grain dissolved in half a drachma
of alcohol and diluted with several ounces of distilled
water.1 This produced a generalized redness of cheeks
and eyes [perhaps due to the alcohol] and the vital
functions appeared generally enhanced. After half an
hour, another half-grain was taken; the condition was
aggravated markedly, while a transient tendency to
vomiting and a dull pain in the head with narcosis was felt.
After another 15 minutes, we swallowed another
half-grain of morphium, undissolved, as a coarse
powder, with 10 drops of alcohol and a half-ounce of
water. The outcome with the three young men was
decidedly rapid and extreme. It presented as pain in the
region of the stomach, exhaustion, and severe narcosis
that came close to fainting. I also was subject to the
same fate. Being in the supine position, I fell into a
dream-like state and sensed in the extremities,
particularly the arms, a slight twitching which
accompanied the pulse beats. These distinct symptoms
of true intoxication, particularly the frail condition of the
three 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 others
do the same. This led to such severe vomiting that,
several hours later, one who was of a particularly
delicate constitution and whose stomach had already
been emptied completely, found himself in a continuous
state of a most painful and highly alarming retching. In
this condition, I gave him carbonated magnesia, upon
which the vomiting subsided instantly. The night passed
under deep sleep. Although the vomiting recurred in the
morning, it immediately subsided after a strong dose of
magnesia. Lack of opening of the body, loss of appetite,
1
In other words, he gave about 32 milligrams of material,
comparable to a 60-milligram average oral adult dose of a
morphine salt (7).
190
narcosis, and pain in the head and body disappeared
only after several days. Judging from these highly
unpleasant experiences, I deduce that morphine, even
in small quantities, acts as a strong poison. . . . As none
of the other components of opium possesses effects such
as those described here, the important medicinal
properties of opium probably result from pure
morphine, which I have to leave to the physicians to test.
In this and other experiments, Sertürner showed that his
crystalline material had the pharmacological actions of opium
by testing it both on animals and humans. Importantly, he also
demonstrated that other preparations from opium were devoid
of 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 replace
opium.
We are left feeling uneasy about the experiment on the
teenaged boys. Although scientifically important, the
experiment is ethically dubious. Sertürner was not a physician
and also took part in the experiment, with a near-disastrous
loss of judgment as a result. A modern Human Subjects
Committee would not approve. Indeed, such an experiment
today would open the investigator to criminal prosecution.
Was Sertürner’s experiment acceptable by 1817
standards? There should perhaps have been a physician
present who was not an experimental subject. If the experiment
was morally or ethically reprehensible, the transgression is
insignificant compared to the slaughters being wrought by
Napoleon. One has only to think of the 200 amputations
carried out (without anesthesia) in one day by the French army
surgeon, Larrey, at the battle of Borodino, to place Sertürner’s
experiments in context. However, other experiments on humans
in Germany, a century or more in the future, would reach back
to shadow reflections on Sertürner’s achievement.
Claims of priority in the discovery of morphine have been
made 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 he
called “sel de Derosne.” Derosne’s alkaloidal fraction lacked
narcotic properties, and was probably largely narcotine (also
known as noscapine), perhaps with meconic acid, both
abundant in opium. Armand Seguin read a paper to the
Institute of France in 1804, but only published it in 1814 (9).
He described the isolation of a principle, but did not report any
animal or human experiments.
The relationship between toxicity and therapy was an
ancient concept. Walter Raleigh wrote, in 1614 (10), “The
skillful and learned chemist could draw helpful medicines out of
poison, as poison out of the most helpful herbs and plants.”
Shakespeare refers to the same principle more poetically in
Henry IV, part 2: “[I]n poison there is physic.” However,
Sertürner helped establish the relationship as an experimental
principle, thereby stimulating an era of chemical and
pharmacological progress. He explicitly recognized that an
extract of opium would have a purity and reproducibility of
effect not obtainable with raw opium. He generalized the
principle that other “so-called poisonous plants” would contain
extractable materials with potential therapeutic activities.
Sertürner initiated the development of natural product
chemistry, and he stimulated the evolution of synthetic and
degradative chemistry for the structural elucidation of complex
crystalline chemicals isolated from plants. Initially, the emphasis
was on alkaloid isolation, because of the ease of acid
extraction of alkaloid salts and the ease of purification by
organic extraction of lipophilic free alkaloids from basified
medium. Winterstein and Trier (11) write that alkaloid chemistry
began in 1817. Hanzlik (12) comments, “The isolation of
morphine was a comparatively humble achievement. It required
no munificent grant, no extensive laboratory equipment, no
highly organized institute or factory.”
In view of its dream-inducing properties, Sertürner named
his crystalline material “morphium,” derived from “Morpheus,”
the Latin name that Ovid (43 BC - 17 AD) used for the god of
dreams (Metamorphoses, Book XI). Morpheus was the son of
Somnus, the god of sleep. Ovid derived the word from the
Greek morphe, or form, because the god of dreams gives airy
nothings their form and fashion (13):
King Sleep was father of a thousand sons–
indeed a tribe – and of them all, the one
he chose was Morpheus, who had such skill
in miming any human form at will.
Despite the derivation, Morpheus is a Roman invention,
and not Greek. (In Hesiod, dreams were the daughters, and not
the sons, of Night.) It was Joseph Louis Gay-Lussac who
introduced the form “morphine,” against the objections of
Sertürner (14). The Oxford English Dictionary has the first
citation in English in 1828: “morphine is the narcotic principle
of opium.”
Ryan J. Huxtable
Department of Pharmacology
College of Medicine
University of Arizona
Tucson, Arizona 85724-5050
Stephan K. W. Schwarz
Centre for Anesthesia & Analgesia
Dept. of Pharmacology & Therapeutics
and
Dept. of Anesthesia
Faculty of Medicine
The University of British Columbia
Vancouver, B.C. Canada V6T 1Z3
Acknowledgment
We thank Marion Huxtable for help with translations from the German.
REFERENCES
1. 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. New
York: The Macmillan Co., 1958, p. 216.
3. Gilman, A.G., Goodman, L.S., Rall, T.W., and Murad, F. The Pharmacological
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229-243, 1805.
5. Sertürner. Darstellung der reinen Mohnsäure (Opiumsäure) nebst einer
Chemischen Untersuchung des Opiums mit vorzüglicher Hinsicht auf einen
darin neu entdeckten Stoff und die dahin gehörigen Bemerkungen. Journal
der Pharmacie fuer Aerzte und Apotheker 14: 47-93, 1806.
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Mekonsäure, als Hauptbestandtheile des Opiums. Annalen der Physik 55:
56-89, 1817.
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14. Sertuerner, F.W. Ueber eins der fürchterlichsten Gifte der Pflanzenwelt, als ein
Nachtrag zu seiner Abhandlung über die Mekonsäure und das Morphium;
mit Bemerkungen, den aciden Extractivstoff des Opiums und seine
Verbindungen betreffend. Annalen der Physik 57: 183-202, 1817.
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