In 1969, researchers proposed the strange behavior of the monarch who reigned during the American Revolution resulted from a rare hereditary blood disorder called porphyria.
However, a study this week in The Lancet medical journal found high concentrations of arsenic in the king's hair and contends the severity and duration of his episodes of illness may have been caused by the toxic substance.
The 18th-century king, under whose reign Britain mastered the oceans, defeated Napoleon and expanded its empire to superpower dimensions, was best remembered for the humiliating loss of the American colonies and for the periods when he lost his mind.
While on the throne, George had five episodes of prolonged and profound mental derangement. At the time, his malady was thought to be a psychiatric disorder.
But in 1969, psychiatrists investigating his documented symptoms such as lameness, acute abdominal pain, red urine and temporary mental disturbance, proposed he suffered from porphyria. Subsequent studies that examined records of his ancestors, descendants and other relatives refined the diagnosis to a certain type of porphyria.
However, the research did not explain the unusual persistence, severity and late onset of attacks.
"People can have the faulty gene which makes them susceptible to attacks, but in about 80 percent of cases they never have any symptoms," said Martin Warren, a professor of biosciences at the University of Kent in England who led the latest study.
"If you are unfortunate enough to get them, porphyric attacks can be deadly and some patients die from their first one, but in many cases the attacks tend to be much less severe, and certainly not for the same duration that George III had," he said.
Warren and his team set out to examine a sample of the king's hair on display at London's Science Museum for traces of mercury or lead, metals known to make porphyria worse.
"What surprised us was there were very high levels of arsenic. Arsenic is also known to push porphyric patients into a worse state," Warren said. The semi-metallic element was found to be at 17 parts per million in the hair. Levels are normally found at less than one part per million.
Arsenic interferes with the production of heme, a key element of blood and the central problem of porphyria. The blood then gets toxic, which can cause mental disturbance and severe pain.
However, John Henry, a toxicologist at Imperial College in London, said he was cautious about interpreting the findings.
"He may have accumulated significant amounts in the last few months of his life, but that doesn't prove it caused his illness all his life," Henry said. "It's a nice theory, but it's just that — a theory."
Museums sometimes spray artifacts with arsenic to preserve them, but the arsenic was evenly distributed along the whole length of the hair, which is consistent with the toxin being within the hair rather than dusted on it.
Wig powder and skin ointment were other possibilities, but the levels were too high for that to be a plausible explanation, Warren said.
The king's medical records revealed he had been consistently given a medicine containing antimony, a mineral often found in the ground with arsenic.
"The way antimony was extracted 200 years ago means that it was often quite contaminated with arsenic," Warren said. "The king was given large doses of antimony for his abdominal pains and that was probably the source of the arsenic."