From Artificial Hibernation to Psychiatry: The Discovery of Chlorpromazine

Chlorpromazine, the first drug that reliably calmed the agitation of severe mental illness, was not discovered by a psychiatrist. It came out of an operating theatre. Its route into medicine ran through a French naval surgeon, Henri Laborit, who in the late 1940s was trying to understand why badly injured patients went into shock and died even when their wounds could be repaired. His answer — that the body’s own alarm reaction was part of the problem — led him to antihistamines, to drug “cocktails” that damped the nervous system before surgery, to the cooling technique he called “artificial hibernation”, and finally to a new molecule made for him by a French drug company’s chemists in December 1950.

This page tells that story in order: the shock theory, the antihistamine experiments of 1950, the lytic cocktail and potentiated anaesthesia worked out with the anaesthetist Pierre Huguenard, artificial hibernation in 1951, the synthesis and screening of the compound coded RP 4560, Laborit’s February 1952 paper on a “new vegetative stabilizer”, the first psychiatric patient treated at the Val-de-Grâce military hospital, the trials of Jean Delay and Pierre Deniker at the Sainte-Anne hospital, the drug’s arrival in North America through Heinz Lehmann, and finally the long-running question of who deserves the credit. The chemistry of the phenothiazine family and the drug’s later history and side effects each have their own page in this wing.

Table of Contents

  1. 1. Surgical Shock and the Body’s Own Defences
  2. 2. Antihistamines in the Operating Theatre
  3. 3. The Lytic Cocktail and Potentiated Anaesthesia
  4. 4. Artificial Hibernation (1951)
  5. 5. RP 4560: A New Molecule from December 1950
  6. 6. ‘A New Vegetative Stabilizer’ (February 1952)
  7. 7. The First Psychiatric Patient at the Val-de-Grâce
  8. 8. Delay and Deniker at Sainte-Anne
  9. 9. Across the Atlantic: Lehmann in Montreal
  10. 10. Who Discovered Chlorpromazine? The Question of Credit
  11. Key Research Papers
  12. Connections
  13. Featured Videos

1. Surgical Shock and the Body’s Own Defences

“Shock” in the surgical sense is not fright. It is the collapse of the circulation that can follow a severe injury, heavy bleeding or a long operation: blood pressure falls, the skin turns cold and pale, the pulse races, and the organs begin to starve of oxygen. In the first half of the twentieth century it was one of the commonest ways for a surgical or battlefield patient to die, and surgeons argued for decades about what drove it. The surgeon-historian T. S. Helling has traced these competing theories from the French physiologist Claude Bernard in the nineteenth century to Laborit in the twentieth.

Laborit came to the problem as a navy doctor who had turned to surgery. The idea he developed in the late 1940s was that the body’s defensive reaction to injury — the surge of nervous and hormonal signals that tightens blood vessels, speeds the heart and mobilises the body’s reserves — was not only a protection. Pushed too far and kept up too long, the same reaction could itself do harm. In his view, much of what killed a patient in shock was the patient’s own over-reaction rather than the injury alone.

If that was right, the logical step was a drug that could damp the reaction: a way to quieten the autonomic nervous system (the part that runs the heart, blood vessels, gut and glands without conscious control) and the hormone responses that went with it, so that the patient could ride out the operation in a calmer physiological state. This was the problem Laborit set himself, and it is the thread that runs through every later step of the chlorpromazine story.

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2. Antihistamines in the Operating Theatre

The drugs Laborit reached for were antihistamines. Histamine is one of the body’s chemical alarm signals, released by mast cells in allergy and injury; it widens small blood vessels and makes them leak. In the 1930s and 1940s French pharmacology was a world centre of antihistamine research. Work associated with Daniel Bovet, Bernard Halpern and their colleagues produced a series of synthetic antihistamines, and several of the most useful belonged to a chemical family called the phenothiazines. One of these, promethazine, was synthesised in 1947 by the chemists of the French firm Rhône-Poulenc.

Laborit tried these antihistamines on his surgical patients and noticed something that went beyond blocking histamine. Promethazine in particular had marked effects on the central nervous system: patients became calm and drowsy and seemed less troubled by what was happening around them, while the drug also blunted some of the autonomic responses to the operation. He published his observations in 1950 in a French hospital weekly under the title “Synthetic antihistamines in surgery”.

That observation pointed in a new direction. If an antihistamine could calm the brain as well as the blood vessels, perhaps a related molecule with an even stronger central action could do more of the work Laborit wanted — damping the defensive reaction at its source.

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3. The Lytic Cocktail and Potentiated Anaesthesia

Laborit did not work alone. His closest collaborator was the anaesthetist Pierre Huguenard, and together they developed what they called “potentiated anaesthesia”. The idea was to prepare the patient with a combination of drugs that each blocked a different part of the body’s alarm system, so that a lighter general anaesthetic would be enough and the patient’s nervous system would react less violently to surgery.

The combinations became known as the “lytic cocktail” (from the Greek for “loosening”, in the sense of dissolving the reaction). E. Kunz, in a 2014 biographical article on Laborit, lists its main ingredients as promethazine and the synthetic painkiller pethidine, with chlorpromazine joining them once it existed. Accounts of the period describe Laborit and Huguenard experimenting with several other agents as well, including local anaesthetics and nerve-blocking drugs; the mixtures changed as they learned. The point of the cocktail was never to put the patient to sleep on its own, but to “disconnect” the reflexes that drove shock.

The historians F. López-Muñoz and colleagues, in their detailed history of chlorpromazine’s discovery, place these lytic cocktails at the centre of the story: it was in the search for better ingredients for them that the decisive molecule was asked for and made.

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4. Artificial Hibernation (1951)

Laborit and Huguenard took the idea one step further. Hibernating animals survive the winter by lowering their body temperature and slowing their metabolism; their tissues need far less oxygen. Laborit reasoned that a patient whose autonomic reactions had been blocked by drugs could then be cooled by physical means without the shivering and blood-vessel spasm that normally fight against cold. The combination of a pharmacological block and physical cooling would lower the body’s metabolic demand during shock and major surgery.

They called this “artificial hibernation” (hibernation artificielle) and described it in two papers in 1951: “Artificial hibernation by pharmacodynamical and physical means” in La Presse Médicale, and a fuller surgical account, “Artificial hibernation by pharmacodynamic and physical means, in surgery”, in the Journal de Chirurgie. The technique attracted wide attention in France in the early 1950s.

The body’s temperature control is itself a nervous reflex run from the hypothalamus at the base of the brain; part of what made artificial hibernation possible was that the drugs in the cocktail weakened that reflex. As the next sections show, this effect on temperature regulation was one of the first things Laborit noticed about chlorpromazine.

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5. RP 4560: A New Molecule from December 1950

Laborit asked Rhône-Poulenc whether its chemists could produce a phenothiazine with a stronger action on the brain than promethazine. The company’s chemist Paul Charpentier made a new phenothiazine carrying a chlorine atom on its ring system. It was given the laboratory code RP 4560.

The date of the synthesis is usually given as December 1950. López-Muñoz and colleagues give that date, and Kunz writes “the end of 1950”. The historian Thomas Ban, in his 2007 review, gives December 1951 — a date that conflicts with the rest of the record, since the compound was already being tested on patients during 1951 and Laborit published on it in February 1952. (Why the chlorine atom changed the drug’s behaviour is explained on the wing’s page on phenothiazines.)

The pharmacologist Simone Courvoisier then ran the animal screening. Her tests confirmed that the new compound acted strongly on the central nervous system. The company passed samples to clinicians, and according to the history of the drug summarised in reference works, physicians tested it between about April and August 1951. Laborit used it at the Val-de-Grâce in Paris as a potentiator of anaesthesia — a new ingredient in the lytic cocktail — and noted its effect in lowering body temperature, which fitted neatly into artificial hibernation. He went on describing its surgical use for several years, for example in a 1954 paper on ganglion-blocking agents in surgery.

Chlorpromazine has no plant ancestor. It is a fully synthetic molecule, descended from the coal-tar dye chemistry of the nineteenth century through methylene blue and the phenothiazine antihistamines.

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6. ‘A New Vegetative Stabilizer’ (February 1952)

On 13 February 1952 Laborit, Huguenard and their colleague R. Alluaume published a short paper in La Presse Médicale: “Un nouveau stabilisateur végétatif (le 4560 RP)” — “A new vegetative stabilizer (4560 RP)”. “Vegetative” was the French term for the autonomic nervous system, and “stabilizer” described exactly what Laborit had been hoping for: a drug that steadied the body’s automatic reactions during surgery.

The paper is now remembered mainly for its description of the drug’s mental effect. In Thomas Ban’s English rendering, the authors reported that it produced “disinterest without loss of consciousness and with only a slight tendency to sleep”. Patients were awake and could answer, but they seemed detached and unconcerned about their surroundings and about the coming operation.

That quality — calm without stupor — was what set RP 4560 apart from the sedatives then in use. Barbiturates and similar drugs quietened a disturbed patient mainly by making him sleep. Here was a drug that seemed to quieten the emotional reaction itself while leaving the person conscious.

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7. The First Psychiatric Patient at the Val-de-Grâce

Laborit encouraged the psychiatrists at his own hospital, the Val-de-Grâce military hospital in Paris, to try the drug on their patients. According to Ban’s account, the military psychiatrists Joseph Hamon, Jean Paraire and Jean Velluz gave it on 19 January 1952 to a 24-year-old man with mania, a state of extreme excitement and overactivity. He received it together with other agents, in keeping with the cocktail approach of the time. Ban reports that after 20 days of treatment the patient was discharged in remission.

Hamon, Paraire and Velluz reported the case in 1952 in the Annales Médico-Psychologiques, the journal of the French psychiatric society, under the title “Remarques sur l’action du 4560 RP sur l’agitation maniaque” (“Remarks on the action of 4560 RP on manic agitation”). This report is not indexed in PubMed and is listed under Further Reading below; it is described in the histories by Ban and by López-Muñoz and colleagues.

The patient’s name has circulated in some accounts; this page leaves it out. What matters historically is the date: the first psychiatric use of chlorpromazine took place at a military hospital in January 1952, at a surgeon’s suggestion, several months before the drug became famous in civilian psychiatry.

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8. Delay and Deniker at Sainte-Anne

The trials that made chlorpromazine known to the world took place a few kilometres away, at the Sainte-Anne psychiatric hospital in Paris, under the professor of psychiatry Jean Delay and his younger colleague Pierre Deniker. Their crucial change was to give chlorpromazine on its own — without the barbiturates and other drugs of the cocktail, and without cooling the patient — so that its effect could be seen clearly.

Delay and Deniker presented their first results in late May 1952 at the centenary meeting of the Société Médico-Psychologique (Ban gives 25 May; other accounts give 26 May). Ban counts six papers from the Sainte-Anne group within six months. Two of the earliest, both written with J. M. Harl and published in the Annales Médico-Psychologiques in 1952, carry titles that show how the drug was still understood through Laborit’s work: “Therapeutic use in psychiatry of phenothiazine of central elective action (4560 RP)” and “Therapeutic method derived from hiberno-therapy in excitation and agitation states”.

The results were striking to psychiatrists of the time. Patients in states of agitation and excitement, who until then could be managed only with heavy sedation, restraint, or treatments such as insulin coma and electroconvulsive therapy, became calm and approachable. Rhône-Poulenc put the drug on sale in France in November 1952 under the name Largactil — from “large action”, a reference to the very wide range of effects its developers had found. (Reference works sometimes give 1953; Ban gives November 1952.)

In 1955 Delay and Deniker gave the new class of drugs a name. In papers such as “Neuroleptic effects of chlorpromazine in therapeutics of neuropsychiatry” they called them neuroleptics, from the Greek for “taking hold of the nerves”. The word is still used, alongside the later term “antipsychotics”. Decades later Deniker wrote his own short history of the neuroleptics, “From chlorpromazine to tardive dyskinesia”, which traced the story from these first trials to the movement side effects that later became the drug’s best-known drawback.

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9. Across the Atlantic: Lehmann in Montreal

Chlorpromazine reached North America through Canada. Heinz Lehmann, a psychiatrist at the Verdun Protestant Hospital in Montreal, learned of the French reports and tried the drug with his colleague Gorman Hanrahan. Their paper, “Chlorpromazine; new inhibiting agent for psychomotor excitement and manic states”, appeared in February 1954 in the AMA Archives of Neurology and Psychiatry. Ban describes it as a paper of major impact, and it was among the first North American publications on the drug in 1954.

In the United States the drug’s reception was slower at first. López-Muñoz and colleagues note that American psychiatry of the early 1950s was strongly shaped by the psychoanalytic tradition, which looked for psychological rather than chemical explanations of mental illness; a drug that calmed symptoms did not fit easily into that framework. Once the clinical results became known, however, use spread quickly, and by 1955 neuroleptic therapy was, in López-Muñoz’s word, consolidated.

Lehmann later wrote his own account, “The introduction of chlorpromazine to North America”, published in 1989 alongside Deniker’s history in the same journal issue. How chlorpromazine spread through the world’s hospitals, and what it changed, is told on the wing’s legacy page.

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10. Who Discovered Chlorpromazine? The Question of Credit

Because the drug passed through so many hands in such a short time — Laborit and Huguenard in surgery, Charpentier and Courvoisier in the laboratory, Hamon, Paraire and Velluz at the Val-de-Grâce, Delay and Deniker at Sainte-Anne, Lehmann in Montreal — there has never been a single agreed answer to the question of who discovered it as a psychiatric medicine.

Historians record what López-Muñoz and colleagues call “initial discrepancies” between the Val-de-Grâce group and the Sainte-Anne group over who first used the drug in psychiatry and who first understood its importance. The Val-de-Grâce case came first in time, in January 1952; the Sainte-Anne trials were the first to give the drug alone and the first to be widely reported. In a 1998 letter titled “The discoverers of the therapeutic effect of chlorpromazine in psychiatry: qui étaient les vrais premiers praticiens?” (“who were the real first practitioners?”), W. W. Shen and M. C. Giesler revisited the question. A 1991 French paper by J. Postel and E. Farjon drew attention to yet another figure, the physician Philippe Decourt, and his part in recognising the drug’s psychoactive effects.

Recognition followed the same uneven lines. The 1957 Albert Lasker Clinical Medical Research Award for chlorpromazine went to Henri Laborit, Pierre Deniker and Heinz Lehmann; the Lasker Foundation’s citation for that award reads “For the development of chlorpromazine as a therapeutic agent in schizophrenia.” Jean Delay was not among the laureates. The same year Nathan Kline and the American psychiatrist Robert H. Noce were honoured for reserpine, the plant-derived drug from Rauwolfia that entered psychiatry at the same moment. No Nobel Prize was awarded for chlorpromazine; Laborit’s own life and recognition are covered on the wing’s Life and Career page.

Most modern histories describe the discovery as a chain rather than a single moment: a surgeon’s theory of shock created the demand for the molecule, industrial chemists and pharmacologists made and screened it, military psychiatrists tried it first, and university psychiatrists established how to use it alone and made it known. Thomas Ban, writing on the drug’s fiftieth anniversary, credits chlorpromazine with founding the field of neuropsychopharmacology.

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Key Research Papers

  1. Laborit H. Synthetic antihistamines in surgery. Sem Hop. 1950;26(69):3646-9. PubMed PMID: 14781932
  2. Laborit H, Huguenard P. Artificial hibernation by pharmacodynamical and physical means. Presse Med. 1951;59(64):1329. PubMed PMID: 14891672
  3. Laborit H, Huguenard P. Artificial hibernation by pharmacodynamic and physical means, in surgery. J Chir (Paris). 1951;67(8-9):631-41. PubMed PMID: 14880599
  4. Laborit H, Huguenard P, Alluaume R. A new vegetative stabilizer; 4560 R.P. Presse Med. 1952;60(10):206-8. PubMed PMID: 14957790
  5. Delay J, Deniker P, Harl JM. Therapeutic use in psychiatry of phenothiazine of central elective action (4560 RP). Ann Med Psychol (Paris). 1952;110(2:1):112-7. PubMed PMID: 12986408
  6. Delay J, Deniker P, Harl JM. Therapeutic method derived from hiberno-therapy in excitation and agitation states. Ann Med Psychol (Paris). 1952;110(2:2):267-73. PubMed PMID: 13008201
  7. Lehmann HE, Hanrahan GE. Chlorpromazine; new inhibiting agent for psychomotor excitement and manic states. AMA Arch Neurol Psychiatry. 1954;71(2):227-37. PubMed PMID: 13123588
  8. Laborit H. Ganglion blocking agents in surgery; R. P. 4560. Anaesthesist. 1954;3(1):20-5. PubMed PMID: 13148585
  9. Delay J, Deniker P. Neuroleptic effects of chlorpromazine in therapeutics of neuropsychiatry. J Clin Exp Psychopathol. 1955;16(2):104-12. PubMed PMID: 14392209
  10. Deniker P. From chlorpromazine to tardive dyskinesia (brief history of the neuroleptics). Psychiatr J Univ Ott. 1989;14(1):253-9. PubMed PMID: 2566183
  11. Lehmann H. The introduction of chlorpromazine to North America. Psychiatr J Univ Ott. 1989;14(1):263-5. PubMed PMID: 2654980
  12. Postel J, Farjon E. Philippe Decourt (1902-1990) and the discovery of psychoactive effects of chlorpromazine. Hist Sci Med. 1991;25(2):97-100. PubMed PMID: 11629904
  13. Shen WW, Giesler MC. The discoverers of the therapeutic effect of chlorpromazine in psychiatry: qui étaient les vrais premiers praticiens? Can J Psychiatry. 1998;43(4):423-4. PubMed PMID: 9598287
  14. López-Muñoz F, Alamo C, Cuenca E, Shen WW, Clervoy P, Rubio G. History of the discovery and clinical introduction of chlorpromazine. Ann Clin Psychiatry. 2005;17(3):113-35. PubMed PMID: 16433053
  15. Ban TA. Fifty years chlorpromazine: a historical perspective. Neuropsychiatr Dis Treat. 2007;3(4):495-500. PubMed PMID: 19300578
  16. Kunz E. Henri Laborit and the inhibition of action. Dialogues Clin Neurosci. 2014;16(1):113-7. PubMed PMID: 24733976
  17. Helling TS. “A cold and drowsy humor”: Theories of traumatic shock from Bernard to Laborit. J Trauma Acute Care Surg. 2020;89(3):e41-e47. PubMed PMID: 32618959

PubMed Topic Searches

  1. Chlorpromazine — history of the discovery
  2. Papers by Henri Laborit
  3. Artificial hibernation and the lytic cocktail
  4. History of traumatic shock theories

Further Reading

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Connections