Sometimes the history of medicine is very, very surreal. For example, consider that in 1927, a physician named Julius Wagner-Jauregg received the Nobel Prize in medicine, for...deliberately infecting his patients with malaria. As a treatment for psychosis. 

This often worked

Well, it did kill around 15% of the patients, but it was nonetheless seen as a miracle cure. 

General paralysis of the insane was first identified and described as a distinct disease in the early 19th century. It was initially thought to be caused by an ‘​​inherent weakness of character’. The initial symptoms were of mental deterioration and personality changes; patients suffered a loss of social inhibitions, gradual impairment of judgment, concentration and short-term memory. They might experience euphoria, mania, depression, or apathy. Delusions were common, including “ideas of great wealth, immortality, thousands of lovers, and unfathomable power” – or, on the more negative side, nihilism, self-guilt, and self-blame. 

It was a progressive disease, and nearly always a death sentence. As the condition advanced, the patient would develop worsening dementia, motor and reflex abnormalities, and often seizures; death usually took 3 to 5 years from the initial symptoms. In the 19th century, cases of general paralysis could account for up to 25% of admissions to asylums. 

Some physicians were drawing a connection between general paralysis and syphilis infection as early as the 1850s; however, it took until much later for this explanation to be generally accepted within the medical community, and full confirmation via pathology examinations of the brains of patients who had died of the disease would have to wait until 1913. 

In 1909, an antisyphilitic drug compound was discovered via a process of trialing hundreds of newly synthesized organic arsenical chemicals, looking for one that would have anti-microbial activity but not kill the human patient; this was the first research team effort to optimize biological effects of a promising chemical, which is now the basis of a huge amount of pharmaceuticals research. Unfortunately, arsphenamine, also known as Salvarsan or “606”, was difficult to prepare and administer, and was still fairly toxic to the human patient as well as the syphilis. 

Julius Wagner-Jauregg was a Viennese psychiatrist, but a psychiatrist with a particular interest in experimental pathology, and in brains. Already in the mid-1880s, he was noticing an odd pattern; many of his psychiatric patients were showing improvements in their mental condition after recovering from bouts of other illnesses that resulted in fever. 

Wagner-Jauregg formed two hypotheses. One, some cases of insanity had ‘organic’, biological causes and were related to physical dysfunctions in the brain; two, one disease could be fought by another. He tried deliberately inducing fevers in his patients, by injecting them with tuberculin, a sterile protein extract from cultures of the tubercle bacillus responsible for tuberculosis. However, this was inconsistent at producing a fever, and the results were disappointing. 

In 1917, a soldier ill with malaria was admitted to Wagner-Jauregg’s ward. No, I am not at all sure why a malaria patient was being treated in a psychiatric ward! And, apparently, neither was Wagner-Jauregg:

“Should he be given quinine?” [my assistant Dr. Alfred Fuchs] asked. I immediately said: “No.” This I regarded as a sign of destiny. Because soldiers with malaria were usually not admitted to my wards, which accepted only cases suffering from a psychosis or patients with injuries to the central nervous system.

Wagner-Jauregg would have known that malaria is especially likely to cause repeated, intermittent paroxysms of high fever. Also, unlike with general paralysis, quinine was available as a treatment and reasonably safe. Since general paralysis was still mostly incurable, he must have felt that there wasn’t much to lose. He made the bold choice to draw blood from the sick soldier and inject it into nine of his psychiatric patients diagnosed with general paralysis. It is deeply unclear from sources on this whether he bothered to obtain consent from any of the patients involved. Six of the nine saw improvements in their psychiatric condition, and only one patient is reported to have died of the fever. 

(Unfortunately, but perhaps unsurprisingly given his predilection for mad science, Wagner-Jauregg was later a proponent of eugenics, and backed a proposal for a law that would ban "people with mental diseases and people with criminal genes" from reproducing. His application to join the Nazi party was, apparently, rejected on the basis that his first wife was Jewish.) 

In 1921, Wagner-Jauregg published a report claiming therapeutic success in treating GPI patients with malaria, and this became the standard treatment until the discovery of penicillin in the 1940s. Tens of thousands of patients were treated with deliberate malaria infections. Special psychiatric clinics were opened for this purpose. There were various attempts to produce fevers in safer ways, mostly via hot baths, electric blankets, or “fever cabinets” but sometimes via injection of toxic sulfur compounds; none were as successful as malaria. 

According to a historical cohort study, despite the high risk of this treatment – between 5% and 20% of patients would die from the ‘cure’ – patients treated with malariotherapy did have significantly better chances than they would otherwise. 70% were alive a year after admission, compared to 48% of untreated cases; at 5 years, 28% of malaria-treated patients were alive versus only 8% at baseline. Patients who had only recently contracted syphilis – and thus presumably had less irreversible neurological damage – could be cured entirely, especially if the malarial fever was followed by Salvarsan treatments. 

Graph of survival after admission

It wasn’t a great treatment, and it was obviously far from safe, but given the prognosis for general paralysis and the lack of other good options, it’s not surprising that it was seen as revolutionary.

Even now, it’s not fully understood how the fever resulted in a cure; it’s unlikely that the patients’ body temperatures were high enough for a prolonged enough period to directly kill the spirochetes responsible for syphilis infection. Another hypothesis is that the infection stimulated the patient’s immune system to a higher level of activity, which also boosted the body’s defenses against the syphilis infection.  

Even once penicillin was discovered, the treatment wasn’t immediately accepted, and was often given in combination with malariotherapy; this was done in the United States and in the Netherlands up to the mid-1960s, and in the United Kingdom until the 1970s. 

The popularity of pyrotherapy during this period resulted in significantly more research effort going toward the biological study of malaria, including its mode of transmission and treatment. The first permanent laboratory colonies of mosquitoes, and the isolation of various malaria strains, were both established during this time period. Testing of synthetic drugs for malaria treatment was another related advance. It seems likely that malaria is much better understood now than it would be if this historical interlude had never happened. 

Wagner-Jauregg’s work here also pioneered the field of ‘stress therapies’ for psychiatric illnesses, including induced insulin coma therapy for schizophrenia. Electroconvulsive therapy, also popularized during this time period, is still used as a treatment for refractory depression today. 





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8 comments, sorted by Click to highlight new comments since: Today at 11:34 PM

Curated. Despite the topic being horrible diseases, there's something refreshing about the ingenuity past innovators brought to problems, as though they weren't constrained in nearly the ways we are in our problem-solving today.  Without commenting on the correctness/morality of everything past doctors did, it's amazing that they were actually able to make hard tradeoffs. Nothing like the modern Western world and its IRBs from which we suffer now.

This puts me in mind of how the Soviet Union deployed phage therapy, because they weren't as good at pharmaceutical development as the US. I understand the idea is making a comeback in the face of antibiotic resistant strains; it seems human trials for phage therapy in the US were approved in 2019.

This further makes me wonder if we could develop something that attacked or fed on prions, via some method of targeting the fold in the protein. Is that a thing? Do any microscopic organisms hunt via geometry?

The world is a complicated and chaotic place. Anything could interact with everything, and some of these are good. This post describes that general paralysis of the insane can be cured with malaria. At least if they do not die during the treatment.

If late-stage syphilis (general paralysis) isn't treated, then they probably die 3-5 years with progressively worse symptoms each year. So even when 5-20% of the died immediately when the treatment started, they still had better survival rates in one and five years. A morbid example of an expected value choice: waiting for a certain long death vs taking a chance at a short or longer possible lifetime.

If they were allowed to choose at all, where the "they" means the patients. The post mentions that Wagner-Jauregg maybe hasn't asked for consent when he tried his experiments. But this is on par for the age, early XX. century hasn't considered mentally ill patients human. Anyway, at this point, I disagree with the tone of the post, which may support human experimentation without consent. I mean, the guy just tried a bunch of diseases on terminally ill because of a fight-fire-with-fire theory and randomly found one which somewhat works.

He got a Nobel for this discovery, and a few years later he supported eugenics and anti-Semitism. Nowadays we don't use it because somebody else discovered penicillin and half of medicine was solved. We know a bit more about malaria. We don't know why this therapy worked and other high-temperature methods don't. The guy got a few places named after him in Austria.

The article is well-researched. Does it carve reality at its joints? I don't feel like it describes a reliable and ethical scientific process. But maybe sometimes you just can't, because the world is a complicated and chaotic place.

I remember reading about this years ago and wondering, if it was the heat that killed the syphilis, why they couldn't just use total immersion in hot baths to raise core temperature (more) safely and in a more controlled manner. 

It sounds like it was tried, any idea why it didn't work?

Just guessing, but I wonder if this has something to do with the physics of heating something from the inside vs the outside - perhaps to get to a high enough deep internal temperature in a heat bath either takes too long or requires such a high temperature as to hurt the skin and outer body.


  • Maybe they didn't try that (hot baths*).
  • Out in versus inside out
  • It's not safe to do at those temperatures, or not feasible over the necessary periods of time. (Fever round the clock, versus a long bath.* Difference in time. (A more elaborate hypothesis including biological rhythms might make sense as well.))


If the body heats up in order to fight something, and that's the body doing something, then maybe it's being handled by systems for that purpose.

  • The different diseases have effects on each other. It's weird to think about, but, in an abstract way, fighting off another infection is a good move if it improves what you're trying to do - improve host survival, not wipe out populations (so you can spread, etc.)
  • They were also trying stuff like arsenic. For comparison maybe 'arsenic' does not 'try to keep you alive'.

*(A bath for a lot of people might be hard to pull off - especially if this is treatment at a central facility. Control over temperature or widespread stuff or that might not be present, safe or cheap.) Also, you can try to keep people hot via insulation. I'm not sure whether adding water/humidity has effects other than making heating (someone up) easier.

Wait, but isn't this after the invention of arsenic treatment, one of the big drugs of the early 1900s? How big was arsenic vs. malaria (really not the two forces you want to choose between) for syphilis treatment, do you know?

This is a great post, however the title says 'insanity', and could slightly more precise if it said 'psychosis'.