Gather round and I shall tell you a tale! A tale of a mistaken assumption that started a weird, long science odyssey that included urine, steak, and guinea pigs, and ended in a miracle drug.

Our story begins in 1859, when a doctor named Alfred Garrod discovered high uric acid levels in the blood of people afflicted with gout. Gout is an inflammation of the joints caused by a build-up of the uric acid that the body uses to digest certain foods, mainly meat and alcohol. It was known as the “disease of kings,” because it affected rich people who could afford rich food.

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Often doctors would prescribe treatments like drinking plenty of healthful wine, and staying in bed all day. Both of these exacerbate the condition instead of treating it, so Garrod’s discovery was a big deal. People knew what they were fighting, and they knew they could dissolve uric acid with lithium carbonate. The treatment was wonderful. It not only cleared up gout, it also cleared up two attendant symptoms of gout; depression and mania.

Eventually, gout dropped out of the equation, and uric acid itself came to be seen as the cause of mania and depression. Lithium carbonate was used, on and off, to clear up these episodes. Unfortunately, lithium can be very dangerous if people ingest too much. Lithium carbonate treatments, though tried on and off to treat uric acid mania, were often abandoned when patients were overdosed.

While we know that people with bipolar disorder have been known to have increased uric acid during manic episodes, uric acid doesn’t automatically cause mania. An injection of uric acid does put people out of sorts, though, at least if the behavior of guinea pigs is anything to go on. John Cade found this out in the 1940s, when he injected guinea pigs with urine and observed their subsequent erratic behavior. A shot of lithium carbonate calmed them down to the point of lethargy, and Cade thought he’d proved that uric acid does cause mania.

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Except none of the other uric acid solvents worked. Oh sure, they broke down the uric acid in the various animal subjects they were injected into, but they didn’t make the subjects any more calm and reasonable. Only lithium carbonate did. Cade worked out that he was doing the right thing using the wrong assumption. Uric acid didn’t cause mania, and dissolving it didn’t treat mania. It was something in lithium that managed to treat the disease.

Lithium became an amazing drug, used to help cases of bipolar disorder that otherwise would have been considered untreatable. As a drug, it has had a remarkably long life. Although there are alternatives, it hasn’t been discredited or supplanted. And while doctors have gotten much better at monitoring the amount of lithium a patient gets, we still don’t entirely know why it works. The latest revelation, made in 2011, is that lithium seems to alter the brain structure. People with untreated bipolar disorder had, compared to neurotypical people, increased volume in the right lateral ventricular, left temporal lobe, and right putamen areas of the brain, but decreased volume of the cerebrum and the hippocampus. Bipolar patients on lithium had dramatically increased volume in the cerebrum and hippocampus, so it’s possible that lithium alters the proportions of the brain and that relieves the disorder.

[Sources: Lithium: Discovered, Forgotten, and Rediscovered, Shrinks.]

Guinea Pig Image: GDFL, Gout Image: Wellcome Images.