Henri Laborit: Chlorpromazine and the Birth of Psychopharmacology

Henri Laborit (1914–1995) was a French navy surgeon who set out to solve a problem of the operating theatre and ended up changing psychiatry. Working on surgical shock in the late 1940s, he came to believe that the body’s own violent defensive reaction to injury could itself do harm, and he looked for drugs that would calm it. Antihistamines from the French phenothiazine family seemed to help, and they had striking effects on the brain. At his request, chemists produced a new phenothiazine with a stronger central action in December 1950. Its laboratory code was RP 4560; its generic name became chlorpromazine.

In February 1952 Laborit and his colleagues described the new compound as “a new vegetative stabilizer” that, in the historian Thomas Ban’s translation, produced disinterest without loss of consciousness. Psychiatrists at the Val-de-Grâce military hospital had already given it to a patient with mania in January 1952, and within months Jean Delay and Pierre Deniker at Sainte-Anne hospital in Paris were giving it to patients with mania and psychosis. Historians describe chlorpromazine as the drug that opened the era of modern psychopharmacology, the treatment of severe mental illness with specific medicines. This wing tells the story in four deep-dive articles; the overview below gives it on one page.

Table of Contents

  1. Deep-Dive Articles
  2. 1. Who Henri Laborit Was
  3. 2. The Discovery on One Page
  4. 3. The Source: A Dye, Not a Plant
  5. 4. Timeline at a Glance
  6. 5. Later Significance
  7. 6. The Side-Effect Record
  8. Key Research Papers
  9. Connections
  10. Featured Videos

Deep-Dive Articles

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Henri Laborit: Life and Career

A colonial doctor’s son born in Hanoi, a navy surgeon who survived the sinking of his ship at Dunkirk, the founder of an independent laboratory in Paris, and a writer whose ideas reached the cinema.

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From Artificial Hibernation to Psychiatry: The Discovery of Chlorpromazine

Surgical shock, the lytic cocktail and artificial hibernation, the new molecule RP 4560, the first psychiatric patients in 1952, and the long question of who deserves the credit.

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Phenothiazines: From Coal-Tar Dyes to Chlorpromazine

How a ring of atoms from the nineteenth-century dye industry led through methylene blue, antimalarials and antihistamines to chlorpromazine, and how the dopamine discovery explained what it does.

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Chlorpromazine’s Legacy: Side Effects, Later Research and Laborit’s Later Drugs

The spread from Paris to the world’s hospitals, what historians say about the “revolution”, the side effects found over fifty years, modern trial evidence, and the drugs Laborit studied afterwards.

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1. Who Henri Laborit Was

Henri Laborit was born on 21 November 1914 in Hanoi, in French Indochina, the son of a medical officer in the French colonial troops. His father died of tetanus in 1920, when Henri was five, and the boy himself contracted tuberculosis at about the age of twelve. After secondary school in Paris he entered the naval medical school at Bordeaux at about twenty, qualified in medicine, served as a navy doctor and then turned to surgery. On 31 May 1940, during the evacuation of Dunkirk, he was the medical officer aboard the French torpedo boat Siroco when it was sunk; he was among the survivors and was awarded the Croix de guerre.

After postings that included Dakar, he was by about 1949–1951 a surgeon at the Val-de-Grâce military hospital in Paris, where the chlorpromazine work took place. In 1958 he founded the Laboratoire d’Eutonologie at the Hôpital Boucicaut in Paris and directed it until his death, funding it largely through patents on molecules rather than through the universities. He edited the journal Agressologie until 1983, belonged to the interdisciplinary “Groupe des Dix” from 1969 to 1976, and was a visiting professor at the Université du Québec from 1978 to 1983. The psychiatrist Edward Kunz, in his 2014 portrait, counts 624 Medline-listed publications, almost all in French, and over fifteen books, among them Éloge de la fuite (1976). In 1980 he appeared as himself in Alain Resnais’s film Mon oncle d’Amérique. He died in Paris on 18 May 1995, aged 80. The full story is in Henri Laborit: Life and Career.

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2. The Discovery on One Page

Laborit’s starting point was shock after surgery and injury. He came to view the body’s autonomic and hormonal defence reaction as harmful in its own right, and in 1950 he published on synthetic antihistamines in surgery, having found that these drugs, especially promethazine, had marked effects on the central nervous system. With the anaesthetist Pierre Huguenard he developed “potentiated anaesthesia” and the “lytic cocktail” — according to Kunz, promethazine and pethidine, later joined by chlorpromazine — and in 1951 the two men described “artificial hibernation”: a drug-induced damping of the body’s autonomic reactions combined with physical cooling, aimed at lowering the body’s demands during shock.

Laborit asked the French drug maker Rhône-Poulenc for a phenothiazine with a stronger central action. The chemist Paul Charpentier synthesised RP 4560 in December 1950, and the pharmacologist Simone Courvoisier screened its effects in animals. Laborit used it at the Val-de-Grâce as an anaesthetic aid and reported its calming effect in the Presse Médicale on 13 February 1952. He encouraged the hospital’s military psychiatrists Joseph Hamon, Jean Paraire and Jean Velluz to try it; on 19 January 1952 they gave it, with other agents, to a 24-year-old man with mania, who according to Ban was discharged in remission about three weeks later. Jean Delay and Pierre Deniker at Sainte-Anne hospital then gave chlorpromazine on its own, without barbiturates or cooling, and presented their results in late May 1952. The drug was available on prescription in France in November 1952 under the name Largactil (“large action”), and in February 1954 Heinz Lehmann and Gorman Hanrahan in Montreal published the North American report that Ban describes as of major impact. Historians record “initial discrepancies” over credit between the Val-de-Grâce and Sainte-Anne groups. The full account is in From Artificial Hibernation to Psychiatry: The Discovery of Chlorpromazine.

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3. The Source: A Dye, Not a Plant

Unlike aspirin, morphine or quinine, chlorpromazine has no plant source. It is a fully synthetic molecule. Its natural-history thread runs instead through chemistry: the phenothiazine ring at its core came out of the German coal-tar dye industry of the late nineteenth century, through the work of chemists such as Graebe, Liebermann and Bernthsen. The phenothiazine dye methylene blue was used by Paul Ehrlich to stain malaria parasites, and from 1891 he investigated its effect against malaria itself. Up to about 1940, López-Muñoz and colleagues write, phenothiazines were used as antiseptics, anthelmintics (worm treatments) and antimalarials, and in the 1940s French researchers working in the tradition of Daniel Bovet turned the ring into antihistamines such as promethazine.

A plant medicine did enter psychiatry at the same moment. Reserpine, from the Rauwolfia plant, was being tested alongside chlorpromazine in the mid-1950s; Delay and Deniker compared the two in 1955, and Nathan Kline and Robert Noce received 1957 Lasker Awards for reserpine in the same year Laborit was honoured for chlorpromazine. How chlorpromazine acts was explained later: in 1963 Carlsson and Lindqvist reported its effect on dopamine metabolites in mouse brain, interpreted as receptor blockade, and binding studies in 1975 and 1976 showed that antipsychotic potency tracks dopamine-receptor blockade. The chemistry is told in Phenothiazines: From Coal-Tar Dyes to Chlorpromazine.

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4. Timeline at a Glance

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5. Later Significance

Thomas Ban wrote on the drug’s fiftieth anniversary that chlorpromazine transformed disturbed wards, that its commercial success stimulated the development of other psychotropic drugs, and that it was instrumental in founding neuropsychopharmacology. López-Muñoz and colleagues called its introduction one of the greatest advances of twentieth-century medicine and the start of the “psychopharmacological revolution.” Other historians qualify that picture: Caponi (2021) questions the revolution thesis, and Pieters and Majerus (2011) found that in Belgium and the Netherlands chlorpromazine first entered psychiatry as an addition to older treatments. Kirkby (2005) and Boyd-Kimball and colleagues (2019) link the antipsychotics to the shift from the asylum to community care in the 1960s and 1970s.

Laborit did not receive a Nobel Prize, unlike Daniel Bovet, whose antihistamine work lay upstream of chlorpromazine. His own research moved on: around 1960 he studied sodium 4-hydroxybutyrate (gamma-hydroxybutyrate, which he called “gamma-OH”) pharmacologically, reviewed it in 1964, and, according to Kunz, also worked on minaprine and clomethiazole. His later theory of the “inhibition of action” held that being unable either to fight or to flee is a source of stress-related illness. The full account is in Chlorpromazine’s Legacy: Side Effects, Later Research and Laborit’s Later Drugs.

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6. The Side-Effect Record

The hazards of chlorpromazine appeared in the medical literature within a few years. Laborit himself published on precautions in chlorpromazine therapy in 1954. The same year the psychiatrist H. Steck described an extrapyramidal syndrome, a parkinsonism-like movement disorder, in patients given chlorpromazine or reserpine. Jaundice after chlorpromazine was reported in the New England Journal of Medicine in 1955, and agranulocytosis, a dangerous fall in white blood cells, in 1956. Later decades added tardive dyskinesia, the involuntary movements that can persist after long-term use, and neuroleptic malignant syndrome.

Modern reviews put numbers to both benefit and harm. A 2005 Cochrane review by Adams and colleagues, pooling 50 randomised trials from 1955 to 2000 with 5,276 participants, found that chlorpromazine improved global state compared with placebo (about seven people treated for one to benefit), with a considerable placebo response, and more sedation, movement disorders, low blood pressure with dizziness and dry mouth; the authors concluded that its place on the WHO essential-medicines list was understandable. A 2017 meta-analysis by Carbon and colleagues reported tardive dyskinesia in 30.0% of people currently taking first-generation antipsychotics, against 20.7% with second-generation drugs. These are findings from the research record; this site gives no guidance on antipsychotic use.

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Key Research Papers

  1. Laborit H, Huguenard P, Alluaume R. A new vegetative stabilizer; 4560 R.P. Presse Med. 1952;60(10):206-8. PubMed PMID: 14957790
  2. Laborit H, Huguenard P. Artificial hibernation by pharmacodynamical and physical means. Presse Med. 1951;59(64):1329. PubMed PMID: 14891672
  3. Laborit H. Synthetic antihistamines in surgery. Sem Hop. 1950;26(69):3646-9. PubMed PMID: 14781932
  4. 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
  5. 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
  6. 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
  7. Ban TA. Fifty years chlorpromazine: a historical perspective. Neuropsychiatr Dis Treat. 2007;3(4):495-500. PubMed PMID: 19300578
  8. Kunz E. Henri Laborit and the inhibition of action. Dialogues Clin Neurosci. 2014;16(1):113-7. PubMed PMID: 24733976
  9. Ohlow MJ, Moosmann B. Phenothiazine: the seven lives of pharmacology’s first lead structure. Drug Discov Today. 2011;16(3-4):119-31. PubMed PMID: 21237283
  10. Carlsson A, Lindqvist M. Effect of chlorpromazine or haloperidol on formation of 3methoxytyramine and normetanephrine in mouse brain. Acta Pharmacol Toxicol (Copenh). 1963;20:140-4. PubMed PMID: 14060771
  11. Adams CE, Rathbone J, Thornley B, Clarke M, Borrill J, Wahlbeck K, Awad AG. Chlorpromazine for schizophrenia: a Cochrane systematic review of 50 years of randomised controlled trials. BMC Med. 2005;3:15. PubMed PMID: 16229742
  12. Carbon M, Hsieh CH, Kane JM, Correll CU. Tardive Dyskinesia Prevalence in the Period of Second-Generation Antipsychotic Use: A Meta-Analysis. J Clin Psychiatry. 2017;78(3):e264-e278. PubMed PMID: 28146614

PubMed Topic Searches

  1. Henri Laborit — papers by author
  2. Chlorpromazine — history
  3. Artificial hibernation and the lytic cocktail
  4. Phenothiazines and methylene blue — history

Further Reading

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Connections