The Alkaloid Revolution and Morphine in Medicine

When Friedrich Sertürner published his 1817 paper on morphium, he did more than explain why opium makes people sleep. He showed that a plant medicine could be taken apart in a pharmacy laboratory and that its power lay in one pure, nitrogen-containing “plant base” — an alkaloid — that could be weighed, crystallised and compared from batch to batch. Chemists of his day had denied that such plant bases could exist at all. Within a few years pharmacists across Europe were applying the same reasoning to other famous plant remedies, and the bark, roots and seeds of the old herbal tradition began to yield their active compounds one after another.

This page follows what came after the discovery: the cascade of alkaloids from medicinal plants (quinine from cinchona bark, codeine from opium), the move from the pharmacy bench to factory production, Alexander Wood’s 1855 injections and the hypodermic syringe, the vast opium supplies of the American Civil War, the nineteenth-century recognition of addiction and the first United States narcotics laws, heroin’s brief career as a supposedly safer substitute, the discovery of the body’s own opioid receptors and enkephalins in the 1970s, and what modern research reports about morphine and long-term opioid therapy. Everything here is history and research findings; it contains no guidance on the use of any of these substances. The story of Sertürner himself, of the isolation experiments and of the opium poppy is told on the wing’s other pages, linked under Connections.

Table of Contents

  1. A Cascade of Plant Alkaloids
  2. Quinine from Cinchona Bark, 1820
  3. Codeine and the Other Opium Alkaloids
  4. From Pharmacy Bench to Factory
  5. The Hypodermic Syringe and Alexander Wood
  6. Morphine in Nineteenth-Century Wars and Homes
  7. Addiction Findings and the First Narcotics Laws
  8. Heroin: A Substitute That Was Not Safer
  9. Opioid Receptors and the Body’s Own Enkephalins
  10. Morphine Today: Reference Analgesic and Long-Term Risks
  11. Key Research Papers
  12. Connections
  13. Featured Videos

1. A Cascade of Plant Alkaloids

Before Sertürner, a pharmacist’s idea of what made a medicinal plant work was shaped by the great Swedish chemist Carl Wilhelm Scheele, who had isolated a series of acids from plants. Sertürner himself first expected opium’s active principle to be an acid. What he found instead was a substance that behaved like an alkali: it neutralised acids and formed salts with them. The Hungarian alkaloid chemist S. Hosztafi, in his review of the discovery of the alkaloids, describes how firmly the chemists of the time held that bases of this kind could not come from plants, and how the recognition of morphine as a salt-forming plant alkali broke that dogma.

Once the idea was accepted, the method spread quickly. The approach was the same each time: take a plant remedy that physicians already valued, extract it with water, alcohol or acid, add an alkali to free the base, and crystallise the product until it was pure. Hosztafi’s review traces how, within roughly two decades of Sertürner’s 1817 paper, pharmacists and chemists isolated a whole run of alkaloids from medicinal plants, and how disputes about who had been first for several of them continued long afterwards. The German national biography (Neue Deutsche Biographie) credits Sertürner’s discovery with setting off this broader alkaloid research.

The natural-medicine thread is direct. Each of the new compounds came out of a plant that had a long history in folk and learned medicine: the poppy, the Peruvian “fever bark”, and many others. The alkaloid revolution did not replace those plants so much as explain them, by identifying the single molecule that carried most of the effect. That made it possible, for the first time, to give the same amount of active substance every time — something Klockgether-Radke, writing on the 200th anniversary of the discovery, identifies as the chief practical change: before the nineteenth century the compounds in opium were unknown, which made exact dosing almost impossible.

Why a pure compound mattered

Brook, Bennett and Desai, in their chemical history of morphine, describe the problem the alkaloids solved. Opium preparations varied from batch to batch, and their potency could be neither predicted nor controlled. A crystalline alkaloid, by contrast, could be weighed. This made pharmacology as an experimental science possible: an investigator could give a known amount of a single substance to an animal and record what happened, and different laboratories could compare their results.

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2. Quinine from Cinchona Bark, 1820

The most consequential alkaloid after morphine came from the bark of the South American cinchona tree, which had been used against intermittent fevers — malaria — since the seventeenth century. In 1820 two Paris pharmacists, Pierre Joseph Pelletier and Joseph Bienaimé Caventou, isolated, named and extracted quinine from cinchona bark. Achan and colleagues record that isolation in their review of quinine’s place in malaria treatment.

Pelletier and Caventou were already experienced plant chemists. Govindjee and colleagues, writing about their earlier papers, note that the same pair gave chlorophyll its name in papers of 1817 and 1818, a reminder that these early alkaloid hunters were working across the whole chemistry of plants, not only on drugs.

The isolation of quinine changed how the bark was used. Instead of powdered bark of uncertain strength, physicians could now obtain a crystalline salt. Quinine went on to become one of the most widely used medicines of the nineteenth century and, as Achan and colleagues review, it still has a role in the treatment of severe malaria in parts of the world today. The site’s history of malaria follows that story further, and the Tu Youyou wing tells how a later anti-malarial, artemisinin, was found in another traditional plant remedy, sweet wormwood.

The two discoveries, morphine and quinine, set the template for a century of drug discovery: start from a plant that traditional medicine already trusted, and find the molecule inside it.

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3. Codeine and the Other Opium Alkaloids

Opium itself turned out to hold more than one alkaloid. In 1832 the French chemist Pierre-Jean Robiquet isolated and characterised codeine. According to Anna Maria Papini’s history of the opioids, he found it while examining a method for extracting morphine that had been proposed by William Gregory of Edinburgh. Codeine is chemically very close to morphine — it is morphine with one extra methyl group — but it is considerably weaker.

Over the following decades chemists identified a family of related compounds in the poppy’s dried latex. Beaudoin and Facchini, reviewing the biochemistry of the opium poppy, list morphine and codeine together with thebaine, papaverine and noscapine among its alkaloids, and note that the poppy remains the only commercial source of morphine and codeine. The chemistry of these compounds, and how the plant builds them, is covered on the wing’s page on the opium poppy and the chemistry of morphine.

The recognition that opium was a mixture of several active substances also explained something physicians had long observed. Harold Kalant’s review of opium describes it as a variable mixture whose effects are essentially those of morphine, but whose exact composition differs from sample to sample. A pure alkaloid removed that variability.

Codeine and the genes

Much later, pharmacologists found that codeine acts largely after the body converts part of it into morphine, through a liver enzyme whose activity differs widely between people because of inherited gene variants. That modern finding is described on the site’s pharmacogenomics page.

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4. From Pharmacy Bench to Factory

Sertürner made his morphine in the back room of a provincial pharmacy. Within a generation, the production of alkaloids had moved into dedicated manufacturing works. The Neue Deutsche Biographie describes his discovery as a starting point not only for alkaloid research but for the rise of the chemical-pharmaceutical factories. In the 1820s and 1830s the extraction of alkaloids began to move from single pharmacies to manufacturing on a much larger scale.

Papini records that MacFarlane was preparing morphine on a commercial scale in 1833. The quantities involved soon dwarfed anything a single pharmacist could make, and the extraction of alkaloids became one of the foundations of the modern pharmaceutical industry. The same process was repeated for quinine, whose demand in malarial regions created a large trade in cinchona bark and, later, in plantation-grown trees.

Industrial production had two consequences that shaped the rest of the century. First, pure alkaloids became cheap and widely available, no longer confined to physicians’ dispensaries. Second, a standardised product made it far easier to give much stronger doses than opium itself had ever delivered. Both facts matter for what followed: the spread of morphine by injection and the recognition of addiction.

From the apothecary to the laboratory

Goerig and Schulte am Esch, in their study of Sertürner, count him among the co-founders of alkaloid chemistry and see the discovery as part of pharmacy’s move from alchemy to science. The shift is visible in the factories: a craft based on recipes and experience gave way to a chemical industry based on analysis, purity testing and reproducible manufacture.

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5. The Hypodermic Syringe and Alexander Wood

For several decades after its isolation, morphine was mostly given by mouth. Hamilton and Baskett, in their history of morphine for postoperative pain relief, note that its use became widespread only after the hypodermic needle and syringe arrived, nearly fifty years after Sertürner’s first work.

The Edinburgh physician Alexander Wood published one of the landmark early reports in 1855, in the Edinburgh Medical and Surgical Journal, under the title “New method of treating neuralgia by the direct application of opiates to the painful points.” As the title says, Wood’s idea was that injecting an opiate close to a painful nerve would act locally. Later physicians found that injected morphine works throughout the body wherever it is given, because it travels in the bloodstream to the brain and spinal cord. The local theory was wrong, but the method stuck.

Injection changed morphine’s pharmacology in practice. A dose given under the skin or into a muscle acts faster and more completely than the same amount swallowed, because it bypasses the first pass through the liver. For surgeons and for patients with severe pain, this was a major change. For the history of addiction, as the next sections describe, it was a turning point too.

Morphine and anaesthesia

Hamilton and Baskett trace how injected morphine became part of surgical practice in the second half of the nineteenth century, given before operations and afterwards for pain relief, and how it became the standard against which every later pain-relieving opioid was measured.

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6. Morphine in Nineteenth-Century Wars and Homes

The wars of the mid-nineteenth century put opium and morphine into the hands of military surgeons on a scale never seen before. Papini records that during the American Civil War (1861–1865) the Union Army used about 2.8 million ounces of opium tincture and powder and about 500,000 opium pills. Opium preparations were used for the pain of wounds and amputations and for the illnesses of camp life.

At home, opium and morphine were sold with few restrictions for much of the century. Opium-based syrups and tinctures were sold for coughs, sleeplessness, diarrhoea and the pains of ordinary life, and the new pure alkaloid was available from pharmacists. Norn, Kruse and Kruse, in their history of the opium poppy and morphine, describe how widely opium and its alkaloid were woven into nineteenth-century medicine and everyday life.

The same feature that made morphine so valuable — a reliable, powerful effect from a small, measured amount — also made long-term use easy. Patients given repeated injections for chronic pain, and people who bought opium preparations freely, were the groups in whom physicians of the period began to describe dependence.

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7. Addiction Findings and the First Narcotics Laws

By the middle of the nineteenth century, Buchanan and colleagues write in their review of narcotic analgesics, opium and opioid products had become a source of major addiction in the United States and, to some extent, in Britain. Physicians described a recognisable pattern: tolerance, so that larger amounts were needed for the same effect; a severe withdrawal illness when the drug was stopped; and a craving that drew people back to it.

Kalant’s review of opium compares the relative risks of different forms of use. He reports that the addiction risk of opium smoking appears somewhat less than that of injected heroin, but appreciably greater than that of alcohol. The general finding from this literature is that the speed and strength with which the drug reaches the brain are closely tied to its addictive power — one reason the hypodermic syringe mattered so much in this history.

The first United States laws

Legal controls followed. Papini lists the first federal measures in the United States: the Smoking Opium Exclusion Act of 1909, which banned the import of opium for smoking, and the Harrison Narcotics Act, passed in 1914 and in force from 1915, which brought opium, morphine and coca products under federal registration and taxation. These laws turned the pure alkaloids, once freely sold, into controlled substances obtainable only through physicians and pharmacists.

Norn and colleagues note a thread that runs from these years to the present: chemists synthesised many morphine-like compounds in the hope of keeping the pain relief while reducing the adverse effects and the potential for abuse, yet the goal of a non-addictive opiate has remained elusive.

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8. Heroin: A Substitute That Was Not Safer

One of the most striking episodes in that search was heroin. Diacetylmorphine — morphine with two acetyl groups attached — was first made by the chemist C. R. A. Wright and was made again in 1897. Papini records that from 1898 it was sold by a German pharmaceutical company as a cough medicine and as a supposedly non-addictive substitute for morphine, before its addictiveness was recognised.

The belief that heroin was safer turned out to be wrong. The body converts heroin into morphine, and because heroin reaches the brain faster than morphine, it proved at least as addictive. Kalant’s comparison of risks places injected heroin at the high end of the scale. Within two decades heroin had gone from a pharmacy product to a controlled drug, and it later became the centre of the illicit opioid trade.

The heroin story is closely connected to the history of aspirin, which came out of the same laboratory in the same years. That connection is told on the Felix Hoffmann wing’s page on the 1897 synthesis of aspirin, which covers the heroin episode in more detail.

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9. Opioid Receptors and the Body’s Own Enkephalins

For more than 150 years after Sertürner, nobody knew exactly how morphine acted. The answer came in the 1970s. In 1973 Candace Pert and Solomon Snyder at Johns Hopkins reported in Science that radioactively labelled naloxone, a drug that blocks the effects of opiates, bound to a specific opiate receptor in nervous tissue. Their experiments showed that the binding was selective and that it paralleled the drugs’ known effects, evidence that morphine acts on a dedicated receptor rather than by some general effect on cells.

A receptor for a plant molecule raised an obvious question: why would the brain have one at all? In 1975 John Hughes, Hans Kosterlitz and colleagues in Aberdeen answered it in Nature. They identified two related pentapeptides — chains of five amino acids — from the brain with potent opiate-like activity. These were the enkephalins, the first of the body’s own opioid substances.

Michael Brownstein’s brief history of opiates, opioid peptides and opioid receptors summarises what followed: further families of opioid peptides, including the endorphins, and several types of opioid receptor were described in the following years. Papini’s review traces the same line, from Sertürner’s crystals to the endogenous opioid peptides.

Closing the circle

These discoveries closed a circle that began in the poppy field. The molecule Sertürner extracted works because it imitates signals the human body makes for itself, in pain-control pathways of the brain, spinal cord and gut. The natural plant compound turned out to be a key fitting a lock built for the body’s own messengers.

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10. Morphine Today: Reference Analgesic and Long-Term Risks

Two centuries after its isolation, morphine still occupies a special place in pharmacology. Klockgether-Radke describes it as the first pure opioid that allowed pain to be treated with a single, defined compound. Hamilton and Baskett, writing in 2000, report that morphine remained the most widely used analgesic for postoperative pain and the standard against which new opioids were compared. Devereaux, Mercer and Cunningham, in their 2018 review, trace morphine from the 1804 isolation to the modern opioid crisis.

What the research on long-term use found

The use of opioids for chronic pain that is not caused by cancer has been studied closely. In 2015, Chou and colleagues published a systematic review for a National Institutes of Health Pathways to Prevention workshop. They found that the evidence was insufficient to determine whether long-term opioid therapy is effective for improving chronic pain and function. They also found that the evidence supported a dose-dependent risk of serious harms, including overdose, opioid abuse, fractures and heart attack (myocardial infarction).

Volkow and McLellan, writing in the New England Journal of Medicine in 2016, reviewed common misconceptions about opioid abuse among people with chronic pain and the approaches studied for reducing it. The site’s pages on opioids for chronic non-cancer pain and on opioid overdose report this modern research in more detail.

The legacy

The story that began with a pharmacist’s curiosity about why opium preparations varied in strength thus led to quinine, codeine and dozens of other plant alkaloids, to the modern pharmaceutical industry, to the hypodermic syringe, to the first drug laws, and finally to the discovery of the body’s own pain-control system. Morphine remains both one of the most important pain-relieving medicines known and the clearest example of how a powerful plant compound carries serious risks alongside its benefits.

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Key Research Papers

  1. Hosztafi S. The discovery of alkaloids. Pharmazie. 1997;52(7):546-50. PubMed PMID: 9266593
  2. Klockgether-Radke AP. [F. W. Sertürner and the discovery of morphine. 200 years of pain therapy with opioids]. Anasthesiol Intensivmed Notfallmed Schmerzther. 2002;37(5):244-9. PubMed PMID: 12015680
  3. Goerig M, Schulte am Esch J. [Friedrich Wilhelm Adam Sertürner--the discoverer of morphine]. Anasthesiol Intensivmed Notfallmed Schmerzther. 1991;26(8):492-8. PubMed PMID: 1786314
  4. Brook K, Bennett J, Desai SP. The Chemical History of Morphine: An 8000-year Journey, from Resin to de-novo Synthesis. J Anesth Hist. 2017;3(2):50-55. PubMed PMID: 28641826
  5. Achan J, Talisuna AO, Erhart A, Yeka A, Tibenderana JK, Baliraine FN, Rosenthal PJ, D’Alessandro U. Quinine, an old anti-malarial drug in a modern world: role in the treatment of malaria. Malar J. 2011;10:144. PubMed PMID: 21609473
  6. Govindjee G, Stirbet A, Lindsey JS, Scheer H. On the Pelletier and Caventou (1817, 1818) papers on chlorophyll and beyond. Photosynth Res. 2024;160(1):55-60. PubMed PMID: 38488941
  7. Papini AM. From morphine to endogenous opioid peptides, e.g., endorphins: the endless quest for the perfect painkiller. Substantia. 2018;2(2):81-91. DOI: 10.13128/substantia-63
  8. Beaudoin GA, Facchini PJ. Benzylisoquinoline alkaloid biosynthesis in opium poppy. Planta. 2014;240(1):19-32. PubMed PMID: 24671624
  9. Kalant H. Opium revisited: a brief review of its nature, composition, non-medical use and relative risks. Addiction. 1997;92(3):267-77. PubMed PMID: 9219389
  10. Hamilton GR, Baskett TF. In the arms of Morpheus the development of morphine for postoperative pain relief. Can J Anaesth. 2000;47(4):367-74. PubMed PMID: 10764185
  11. Wood A. New Method of Treating Neuralgia by the Direct Application of Opiates to the Painful Points. Edinb Med Surg J. 1855;82(203):265-281. PubMed PMID: 30332200
  12. Norn S, Kruse PR, Kruse E. [History of opium poppy and morphine]. Dan Medicinhist Arbog. 2005;33:171-84. PubMed PMID: 17152761
  13. Buchanan WW, Rainsford KD, Kean CA, Kean WF. Narcotic analgesics. Inflammopharmacology. 2024;32(1):23-28. PubMed PMID: 37515654
  14. Pert CB, Snyder SH. Opiate receptor: demonstration in nervous tissue. Science. 1973;179(4077):1011-4. PubMed PMID: 4687585
  15. Hughes J, Smith TW, Kosterlitz HW, Fothergill LA, Morgan BA, Morris HR. Identification of two related pentapeptides from the brain with potent opiate agonist activity. Nature. 1975;258(5536):577-80. PubMed PMID: 1207728
  16. Brownstein MJ. A brief history of opiates, opioid peptides, and opioid receptors. Proc Natl Acad Sci U S A. 1993;90(12):5391-3. PubMed PMID: 8390660
  17. Devereaux AL, Mercer SL, Cunningham CW. DARK Classics in Chemical Neuroscience: Morphine. ACS Chem Neurosci. 2018;9(10):2395-2407. PubMed PMID: 29757600
  18. Chou R, Turner JA, Devine EB, Hansen RN, Sullivan SD, Blazina I, Dana T, Bougatsos C, Deyo RA. The effectiveness and risks of long-term opioid therapy for chronic pain: a systematic review for a National Institutes of Health Pathways to Prevention Workshop. Ann Intern Med. 2015;162(4):276-86. PubMed PMID: 25581257
  19. Volkow ND, McLellan AT. Opioid Abuse in Chronic Pain--Misconceptions and Mitigation Strategies. N Engl J Med. 2016;374(13):1253-63. PubMed PMID: 27028915

PubMed Topic Searches

  1. Alkaloids — history of discovery
  2. Morphine — history
  3. Quinine and cinchona — history
  4. Opioid receptors — history
  5. Long-term opioid therapy for chronic pain — systematic reviews

Further Reading

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Connections