Lithium Salts and Mania: Cade's 1949 Discovery

On 3 September 1949 the Medical Journal of Australia printed a four-page paper by a little-known Melbourne psychiatrist, John Cade, under the title “Lithium salts in the treatment of psychotic excitement.” It described ten patients with mania who had calmed, within days to a couple of weeks, after being given lithium citrate or lithium carbonate — and who became excited again when the lithium was stopped. The work had been done with almost no equipment in a disused pantry at the Repatriation Mental Hospital at Bundoora, starting from an idea about a poison in the urine and passing through a series of experiments on guinea pigs. The paper is now counted as one of the founding documents of modern psychiatric drug treatment, and lithium, a simple salt of a light metal found in rocks, springs and seawater, is still in use more than seventy-five years later.

This page tells the story of the discovery itself: the hypothesis Cade started from, what he did with the guinea pigs and why he reached for lithium, his decision to take it himself first, the first patient (known only by his initials, W.B.), what the 1949 paper actually reported, the quiet response, the death of W.B. from lithium poisoning and the American salt-substitute poisonings of the same year, the later argument over what the guinea pigs really showed, and the debate over whether Cade discovered lithium treatment or rediscovered it. The doses Cade used are part of the historical record but are not repeated here; nothing on this page is guidance on taking lithium. Cade’s own life is told on John Cade: Life and Career, and what happened after 1949 on From Cade to Schou.

Table of Contents

  1. A Toxin in the Urine? The Hypothesis
  2. Guinea Pigs, Urea and Uric Acid
  3. Lithium Urate and the Calm Guinea Pigs
  4. Testing It on Himself
  5. W.B. and the First Patients (1948)
  6. Ten Manic Patients: What the 1949 Paper Reported
  7. A Quiet Reception
  8. The Salt-Substitute Poisonings and W.B.’s Death
  9. Were the Guinea Pigs Calm or Poisoned?
  10. Discovery or Rediscovery?
  11. Key Research Papers
  12. Connections

1. A Toxin in the Urine? The Hypothesis

When Cade came home from the war and took up his post at Bundoora in 1946, the major mental illnesses had almost no specific treatments. Psychiatric hospitals relied on sedatives, on confinement, and on physical methods such as electroconvulsive therapy (ECT). Cade’s starting point was an old idea in medicine, sometimes called auto-intoxication: that some illnesses are caused by the body’s own chemistry going wrong and producing, or failing to clear, a substance that poisons it.

Cade reasoned that mania might be caused by a normal product of the body’s own metabolism circulating in excess — not a foreign poison, but an ordinary substance present in the wrong amount. As the historian Johan Schioldann reconstructs Cade’s reasoning from his later lectures and writings, the hypothesis was a metabolic one: if a substance were present in excess in the blood of manic patients, some of it would be passed in their urine, and that urine might prove more poisonous than urine from other people.

The psychiatrists G.D. Burrows and J.W. Tiller, writing for the fiftieth anniversary in 1999, describe the discovery as a progression in exactly these steps: from a metabolic hypothesis of mania, through animal studies, to patients.

Cade’s biographers have suggested that his three and a half years as a prisoner of war in Changi, where he ran a psychiatric section and saw the illnesses of malnutrition — beriberi from lack of vitamin B1 and pellagra from lack of niacin — shaped his habit of looking for a chemical cause behind a mental disturbance. A frequently repeated story that the urine idea itself came to him in the camp has not been found in a verifiable source, so it is not stated here as fact.

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2. Guinea Pigs, Urea and Uric Acid

Bundoora had no research laboratory. According to the Nature review of Walter Brown’s 2019 biography, Cade worked in an abandoned pantry on the hospital grounds, without sophisticated chemical analysis, keeping guinea pigs for his tests. He collected urine from patients with mania, schizophrenia and melancholia and from healthy people, concentrated it, and injected it into the abdomens of guinea pigs to compare how poisonous each sample was.

The result, as Schioldann quotes Cade’s account, was that any concentrated urine in a large enough quantity killed a guinea pig, but that urine from manic patients “often killed much more readily.” Cade took this as a sign that he was on the right track and set out to find which part of urine did the killing.

Urine contains many dissolved substances, and he tested the main nitrogen-containing ones:

If creatinine protected and uric acid enhanced, then the balance of these substances in a patient’s urine might change how toxic the urea was — and uric acid became the candidate to study further. To test it, Cade needed to give the guinea pigs uric acid in solution.

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3. Lithium Urate and the Calm Guinea Pigs

Here chemistry pushed the experiment in an unexpected direction. Uric acid barely dissolves in water, which is exactly why it forms crystals in the joints in gout. To get enough of it into a solution for injection, Cade used its most soluble salt, lithium urate. This was not an exotic choice: lithium had been used in the nineteenth century precisely because its urate dissolves better than any other, a fact Cade himself reviewed in the 1949 paper.

The lithium urate did not behave as he expected. Instead of making urea more deadly, as Schioldann quotes Cade, its toxicity “was far less than expected” — the mixture seemed to protect the animals. Cade wondered whether the lithium itself might be responsible, and so he turned to lithium salts on their own, giving the guinea pigs injections of lithium carbonate solution.

What he saw next became the most famous image of the story. In the words of his 1949 paper, quoted by Schioldann, after about two hours the animals, “although fully conscious, … extremely lethargic and unresponsive to stimuli for one to two hours.” In a later retelling, written in 1970, Cade said that the guinea pigs could be turned onto their backs and that they merely lay there and gazed placidly back at him.

For Cade this was the bridge from animal to patient: a substance that quietened a lively animal without putting it to sleep might quieten a manic person. In the 1949 paper he proposed trying lithium in mania, for what he called its sedative effect, and also in epilepsy, for a possible anticonvulsant action. According to Schioldann, the epilepsy trial never took place. Whether the guinea pigs were really calmed, or simply ill, became a matter of argument decades later (section 9).

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4. Testing It on Himself

Lithium salts were not unknown in medicine, but Cade had no modern safety data and no way of measuring lithium in the blood. By his own later accounts, written in 1967 and 1970 and summarised by Schioldann and by the Nature review of Brown’s biography, he took both lithium citrate and lithium carbonate himself over a period before giving them to any patient, and noticed no ill effects.

Self-experimentation has a long history in medicine, and Cade’s was in that tradition: a check that the salt could be swallowed by a person without obvious harm. It could not tell him what would happen at the larger amounts, given for longer, to a sick and agitated patient whose eating, drinking and kidney function might be very different from his own. That gap, between what one healthy man could tolerate and what was safe in patients, would matter a great deal within two years.

Cade described himself, in a 1951 lecture quoted by Schioldann, as “an enthusiastic amateur, full of curiosity, with fair determination, golden opportunities, inadequate knowledge and woeful technique.” The self-test was characteristic of that self-portrait.

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5. W.B. and the First Patients (1948)

Cade’s first patient is known in the medical literature only by the initials he used, W.B. His case notes, quoted by Schioldann, show that on 6 March 1948 Cade recorded “Chronic mania. This extremely high blood uric acid result is suspect” — a sign that he was still testing his uric-acid idea on patients. Lithium treatment of W.B. began at Bundoora on 29 March 1948.

W.B. had been severely ill for a long time. The Newtown Review of Books’ account of the 2016 biography Finding Sanity says he had been in a state of mania for five years and had already had nine ECT treatments; the Nature review of Brown’s biography speaks of a much longer history of manic-depressive illness. The two accounts can both be true, one describing the current episode and the other the whole illness. Patients in such a state might be sleepless, restless, constantly talking, destructive or impossible to nurse, and many spent years on locked wards.

According to these accounts, W.B. improved within days, and after a few weeks Cade extended the treatment — a striking change in a man who had been severely ill for years.

Over the following months Cade gave lithium to more patients at Bundoora: others with mania, and, to see whether the effect was specific, patients with schizophrenia and with chronic melancholia as well. Cade worked without a control group and without blinding; the design was a clinical series of the kind common at the time, judged by the observing doctor.

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6. Ten Manic Patients: What the 1949 Paper Reported

The paper appeared in the Medical Journal of Australia on 3 September 1949 (volume 2, pages 349–352). As Schioldann summarises it, it reported on 19 patients:

The pattern was the striking part: lithium seemed to act on mania specifically, not on mental illness in general. Cade judged the effect “purely sedative,” with “no apparent hypnotic effect” (Schioldann’s quotations) — that is, it calmed without sending the patients to sleep, unlike the barbiturates and bromides then used. The relapses when lithium stopped suggested to him that it was controlling the illness rather than curing it.

The paper also contained a theory. Since lithium seemed to correct mania, Cade speculated that mania might involve a deficiency of lithium ions in the body. He wrote that lithium “may well be an essential trace element,” noting that it is “widely distributed,” detected in sea-water and in many spring and river waters, in the ash of many plants, and in animal ash. That idea of lithium as a natural trace mineral is followed up on Lithium: The Mineral.

The numbers in the paper are often misquoted. A later account by Samuel Gershon referred to six manic patients; Schioldann, reading the original, treats the figure of ten manic, six schizophrenic and three melancholic patients as correct. The Nature review of Brown’s biography adds that five of the manic patients improved enough to go home.

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7. A Quiet Reception

A discovery that would later be called a turning point in psychiatry arrived almost without notice. Cade was a hospital psychiatrist in Melbourne, not a university researcher; the paper was short, uncontrolled and published in a national journal far from the centres of psychiatric research in Europe and the United States. According to the Nature review of Brown’s biography, it went largely unnoticed at first.

Cade himself kept experimenting. He tried salts of other elements — rubidium, cerium and strontium — on patients. None of them showed a therapeutic effect like lithium’s.

In Australia there was some follow-up. Burrows and Tiller record further reports on lithium in the Medical Journal of Australia in 1950 and 1951. In 1951 C.H. Noack and E.M. Trautner, in Melbourne, published “The lithium treatment of maniacal psychosis” in the same journal, describing their own series of patients. Trautner’s group went on to study how the body absorbs and excretes lithium, early steps toward the blood-level monitoring that would eventually make lithium manageable. That later work, and the Danish trial of 1954 that brought lithium to the world’s attention, are told on From Cade to Schou.

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8. The Salt-Substitute Poisonings and W.B.’s Death

By an unfortunate coincidence, 1949 was also the year lithium became notorious as a poison. In the United States, people with heart disease were placed on low-sodium diets, and lithium chloride, which tastes salty, was sold as a table-salt substitute. In March 1949 the Journal of the American Medical Association published reports of lithium poisoning among patients using these substitutes, including deaths: one by A.C. Corcoran, R.D. Taylor and Irvine Page titled “Lithium poisoning from the use of salt substitutes,” and one by L.W. Hanlon and M. Romaine on observations of the toxicity of lithium chloride used in place of sodium chloride in the diet.

The American cases illustrated a point of pharmacology that would shape the rest of lithium’s history: the body handles lithium partly like sodium, and in people eating little salt, or with weak kidneys or heart failure, lithium can build up to toxic levels. The gap between an amount that has an effect and an amount that poisons is narrow.

Cade’s own first patient became an example of that narrow margin. According to the Nature review of Brown’s biography and the Newtown Review of Books’ account of Finding Sanity, W.B. died of lithium poisoning in 1950, as the coroner’s records show. There was then no routine way to measure lithium in the blood. Following W.B.’s death, the same accounts say, Cade abandoned lithium treatment.

The combination of the American poisonings and the death of the first patient goes a long way toward explaining why a positive report from Melbourne did not spread quickly. Lithium would only become widely usable once doctors could measure blood levels and keep them within a range, work that began in Melbourne and Denmark in the 1950s.

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9. Were the Guinea Pigs Calm or Poisoned?

Cade’s story of the placid guinea pigs was repeated for decades as the classic example of an animal experiment leading to a new drug. Later researchers were less sure it meant what he thought.

Schioldann devotes a chapter of his history of lithium to the attempts to replicate Cade’s observations. Mogens Schou, the Danish psychiatrist whose controlled trials established lithium, reviewed the biology of the lithium ion in 1957 and, with his colleagues at Risskov, could not reproduce a specific calming effect in animals. Schou’s view, as quoted by Schioldann, was that apathy in animals given lithium may simply reflect general intoxication, and that Cade’s guinea pigs were lethargic because they had been given toxic amounts. Others who looked at the question, including Smith and Samuel Gershon, reached a similar view, and in 1999 the Australian psychiatrist Philip Mitchell wrote that the guinea pigs were probably lethargic because of lithium toxicity.

Schou did not take this as diminishing Cade. In a much-quoted remark from 2001, reproduced by Schioldann, he wrote: “To make therapeutic discoveries on the basis of misinterpreted experiments requires curiosity, daring, luck and compassion for patients!”

Two points stand side by side in the record. Cade’s own account is that the animals were fully conscious but calm. The later critique is that what he observed was an early sign of poisoning, not a specific calming effect. Either way, the guinea-pig result is not treated today as established pharmacology; what established lithium was the response of patients, later tested in controlled trials.

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10. Discovery or Rediscovery?

Lithium had a medical history long before Cade. In the mid-nineteenth century the London physician Alfred Baring Garrod introduced lithium salts for gout, because lithium urate dissolves so readily (see the history of gout). Through the late nineteenth and early twentieth centuries lithium salts and “lithia” tablets and waters were taken for a long list of complaints, until reports of toxicity accumulated, a story told by Strobusch and Jefferson in their 1980 paper “The checkered history of lithium in medicine.”

Cade knew at least part of this. His 1949 paper, as Schioldann summarises it, reviewed Garrod’s use of lithium for gout, the popularity of lithia tablets, the toxic reports in the medical press of 1907 and 1909, and an older textbook remark that the waters of certain wells were believed to help in mental illness. Cade wrote that it was “very likely that their supposed efficacy was a real efficacy and directly proportional to the lithium content of the waters.”

There was also an earlier psychiatric use. The historian Edward Shorter writes that lithium’s use in psychiatry goes back to the mid-nineteenth century, after which it was forgotten, and that Cade is credited with reintroducing it in 1949. Schioldann names the Danes Carl and Fritz Lange among those earlier users, and argues that Cade probably knew the old gout and uric-acid literature that ran through his own experiments.

Not everyone accepts the “rediscovery” label. N. Cole and G. Parker, writing in 2012 under the title “the prospector who found a gold nugget,” argue against the idea that Cade simply rediscovered lithium, pointing to his observational skill and to the experimental path that led him to it. Cade himself, in a 1967 editorial quoted by Schioldann, rejected the idea of luck as well, calling the finding “not an accidental discovery” but “the inevitable though unforeseen product of a hypothesis and of a series of experiments.”

What is not in dispute is that it was Cade’s 1949 paper, with its specific effect in mania and its relapses on withdrawal, that started the line of research leading to lithium’s place in the modern treatment of bipolar disorder. The anniversary articles of 1999 by Mitchell and Hadzi-Pavlovic, Burrows and Tiller, and Schioldann all mark it as that starting point.

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Key Research Papers

  1. Cade JF. Lithium salts in the treatment of psychotic excitement. Med J Aust. 1949;2(10):349-52. — PubMed PMID: 18142718
  2. Schioldann J. From guinea pigs to manic patients: Cade's 'story of lithium'. Aust N Z J Psychiatry. 2013;47(5):484-6. — PubMed PMID: 23508681
  3. Schioldann J. John Cade's seminal lithium paper turns fifty. Acta Psychiatr Scand. 1999;100(6):403-5. — PubMed PMID: 10626917
  4. Mitchell PB, Hadzi-Pavlovic D. John Cade and the discovery of lithium treatment for manic depressive illness. Med J Aust. 1999;171(5):262-4. — PubMed PMID: 10495760
  5. Mitchell PB. On the 50th anniversary of John Cade's discovery of the anti-manic effect of lithium. Aust N Z J Psychiatry. 1999;33(5):623-8. — PubMed PMID: 10544984
  6. Burrows GD, Tiller JW. Cade's observation of the antimanic effect of lithium and early Australian research. Aust N Z J Psychiatry. 1999;33 Suppl:S27-31. — PubMed PMID: 10622176
  7. Cole N, Parker G. Cade's identification of lithium for manic-depressive illness--the prospector who found a gold nugget. J Nerv Ment Dis. 2012;200(12):1101-4. — PubMed PMID: 23197126
  8. Noack CH, Trautner EM. The lithium treatment of maniacal psychosis. Med J Aust. 1951;2(7):219-22. — PubMed PMID: 14881840
  9. Corcoran AC, Taylor RD, Page IH. Lithium poisoning from the use of salt substitutes. J Am Med Assoc. 1949;139(11):685-8. — PubMed PMID: 18110875
  10. Hanlon LW, Romaine M 3rd. Lithium chloride as a substitute for sodium chloride in the diet; observations on its toxicity. J Am Med Assoc. 1949;139(11):688-92. — PubMed PMID: 18128981
  11. Schou M. Biology and pharmacology of the lithium ion. Pharmacol Rev. 1957;9(1):17-58. — PubMed PMID: 13431415
  12. Shorter E. The history of lithium therapy. Bipolar Disord. 2009;11 Suppl 2:4-9. — PubMed PMID: 19538681
  13. Strobusch AD, Jefferson JW. The checkered history of lithium in medicine. Pharm Hist. 1980;22(2):72-6. — PubMed PMID: 11610717
  14. Draaisma D. Lithium: the gripping history of a psychiatric success story. Nature. 2019;572:584-585. — DOI: 10.1038/d41586-019-02480-0

PubMed Topic Searches

  1. https://pubmed.ncbi.nlm.nih.gov/?term=John+Cade+lithium+history
  2. https://pubmed.ncbi.nlm.nih.gov/?term=history+of+lithium+therapy+mania
  3. https://pubmed.ncbi.nlm.nih.gov/?term=lithium+salt+substitute+poisoning+1949
  4. https://pubmed.ncbi.nlm.nih.gov/?term=lithium+guinea+pig+Cade

Further Reading

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Connections