Was Alexander the Great really poisoned? Science sheds new light on an age-old question.

National Geographic

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The sick Alexander (Alessandro infermo), by Domenico Induno, 19th Century, oil on canvas. Alexander drinks from a cup to show his trust in the doctor who gave it to him and condemns Parmenione who told him he would be poisoned. This event was said to take place in 333 B.C., 10 years prior to Alexander's death. Photograph by Sergio Anelli / Mondadori Portfolio, Getty Images
The young conqueror fell suddenly and fatally ill at an all-night feast. Now, a Stanford historian has found a potential culprit.
In June 323 BCE, in the palace of King Nebuchadnezzar II in Babylon, the most powerful man in the world died. Just 13 days earlier, Alexander the Great—the greatest conqueror the world had seen—had been drinking at one of his many all-night banquets when he suddenly cried out in pain. He was sent to bed suffering from abdominal pain and a fever, and over the following days his condition deteriorated. He suffered from weakness, thirst, possible convulsion, pain, partial paralysis and dozed in and out of consciousness. Towards the end he slipped into a death-like state and was unable to speak or move.
For six days after his death, the body of Alexander the Great showed no signs of decomposition. To the ancient Greeks it was a sign that Alexander was more god than man. To everyone else, for more than 2,000 years, the cause of his death and his body's preservation has been a mystery. Despite numerous theories, and a great deal of speculation, the death of the 32-year-old Alexander has been one of history's greatest cold cases. Fragment from the "Alexander Mosaic" showing Alexander the Great in battle against Persian King Darius III. (From a Roman copy of a Hellenistic painting.) Photograph by Universal History Archive, Getty Images
Even in antiquity people debated the cause of Alexander's death. Some thought it was caused by illness or infection, but throughout the ages, many historians from Pliny to Voltaire suspected foul play. The conspiracy to murder Alexander, wrote Diodorus, 'was suppressed by the power of Alexander's successors.'
Those who suspected poisoning even claimed to know the toxin at work: Roman intellectual Pausanias (2nd century CE) wrote of the 'lethal power' of the River Styx and added that he had heard it said that water from the Styx 'was the poison that killed Alexander.' Others, including Plutarch a biographer of Alexander, even claimed that it was Alexander's former teacher, the philosopher Aristotle, who provided the fatal dose. Apparently, Aristotle feared the man that Alexander had become. (Whatever else happened Aristotle is undeniably innocent—he was in Athens at the time of Alexander's death).
(How suspicion and intrigue eroded Alexander the Great's empire)
It is here that history appears to bleed into mythology. To moderns, the River Styx is best known from legends about the underworld. According to numerous ancient myths, the souls (or shades) of the deceased have to cross the River Styx on their way to Hades. But the Styx was not only a portal to the underworld, it was also a real place. Based on ancient accounts and modern investigation, the Styx has been securely identified as the Mavroneri (Black Water), a tributary of the Karathis River that empties into the Corinthian Gulf.
Why would people think that the waters of the Styx were poisonous and that this poison was used to assassinate Alexander the Great? In a new article, published in Geoheritage, Adrienne Mayor, a renowned research scholar in Classics and History of Science at Stanford, decided to investigate. Bulgaria's cultural capital
Many people in antiquity recognized the noxious properties of the River Styx. Plato refers to the 'fearful powers' of the Styx, the geographer Strabo described it as 'deadly water,' and the natural historian Pliny said that 'drinking [the water] causes immediate death.' The waters of the Styx were even thought to corrode metals and ceramic containers. As late as the 1860, when famed German naturalist Alexander von Humboldt commented on the Styx, he remarked that the stream has an 'evil reputation' among the 'present inhabitants' of the region. Even in the twentieth century locals avoided drinking from the stream and complained that it corrupted clay vessels.
Poisonous waters were well known in antiquity—one mentioned in the Bible was used as part of a truth trial for potentially adulterous women—but this fact alone does not explain the Styx's dark and persistent reputation.
(Were Alexander the Great and Hephaestion more than friends?)
Mayor, a historian of ancient science, wanted to understand how the mythology of the Styx's waters had developed. She told National Geographic that the project was years in the making. As someone who has specialized in unearthing the genuine natural knowledge embedded in ancient legends, the project was something of a natural fit. Fifteen years ago, in 2010, Antoinette Hayes, a pharmaceutical toxicologist, told Mayor about the possibility of a toxic crust that forms on limestone, and a recent report on the mass death of an elk herd after eating toxic lichen that piqued Mayor's imagination.
Together with the assistance of geologists, chemists, toxicologists and other scientists, Mayor began to investigate the possibility that in antiquity the Styx harbored naturally occurring toxins. In the resulting article and her forthcoming book Mythopedia: A Brief Compendium of Natural History Lore, Mayor argues that the limestone-lined pools of the Styx are 'ideal for harboring two extremely lethal natural substances, both only recently discovered by science: calicheamicin and toxic lichen.'
(Alexander the Great's warrior mother wielded unprecedented power) Calicheamicin from limestone
Calicheamicin is a crusty deposit that precipitates out of limestone, particularly in places where water drips, pools, and evaporates. As Mayor notes in her article, 'These are the conditions described by ancient observers of the rock-ringed pool by the Styx/Mavroneri waterfall. The water that flows through limestone is charged with calcium carbonate, which deposits hardened caliche crusts on rock surfaces, moss, and lichen' It can also form crusts on metal or clay (which might explain the myths about corroding vessels).
A number of organisms are known to colonize the surface of caliche. Some, like algae, are comparatively harmless. Others, like cyanobacteria, are 'neurotoxic, hepatotoxic, cytotoxic, and endotoxic at levels very dangerous to humans and animals.' In the 1980s a toxicologist collected a sample of caliche in Texas that led to the discovery of calicheamicin, a toxic substance that has been used to develop potent antibody-targeted chemotherapy but in its original form has a 'cellular lethality greater than that of ricin.' We cannot say for certain if it was present in antiquity at the limestone rimmed pool of the Styx. A great deal depends on the presence—in antiquity—of the proper nutrients and soil conditions for its growth. Depending on the dose, mortality from a substance like this would 'probably take days or weeks due to the toxic mechanisms of DNA destruction.' This process would ultimately have led to multiple organ failure. Because it dissolves in alcohol it would have been the perfect poison to slip into Alexander's drinking vessel at a banquet.
(Alexander the Great had daddy issues) Oxalic acid from lichen
Mayor also posits a second soil-based toxin that may have been collected from the limestone rock ledges and pools of the Styx. Many fungi, molds and lichens produce toxic mycotoxin. While the harmful effects of certain species of mushrooms have been well known for centuries, until relatively recently lichen were thought to be benign. A recent study noted by Mayor discovered that 'one in eight species of lichens contain…poisons [microcystins] that cause liver damage.' Because ancient people did not recognize lichen as distinct from host trees and rocks, they were not identifiable as a source of poisoning. If goats died at the River Styx, as the ancient geographer Pausanias says that they did, 'water,' writes Mayor, 'might be logically identified as the culprit, rather than the rocks on the banks.'
The most common lichen forming fungi on limestone in this region, Mayor writes, are 'black meristematic aureobasidium-like and Penicillium-like species, which can be highly toxic when ingested by animals and humans.' The fact that lichenizing fungi produce a black patina on rocks recalls the use of the adjective 'black' in description of the Styx. These fungi also excrete toxic oxalic acid, which is highly corrosive. This, too, might explain the rumors that the waters of the Styx destroyed metal. Today, oxalic acid used to dissolve rust. The roots of a legend
'The results of ingesting [either of these] these substances,' Mayor says, 'would have been observed and remembered over generations.' Even if only a few animals and people died, the memory of the events would have added to the ancient lore surrounding a river already saturated with myths about the underworld.
In the aftermath of Alexander the Great's death, says Mayor, 'I think it was reasonable for Alexander's companions to believe that he had been poisoned—many in his circle had motives and opportunities. And his detailed symptoms match those long associated with Styx water.' Mayor stressed that her study does not solve the debate over the death of Alexander the Great. For that, she noted, we need a time machine and a toxicological autopsy.
The problem is ultimately unsolvable. Scientists could test the waters of the Styx/Mavroneri today for calicheamicin and lichen but their findings—whether positive or negative—would not tell us if these poisons were present in the stream in antiquity.
What Mayor's study does explain is why people thought Alexander had ingested the waters of the Styx. Once members of his circle decided that Alexander had been poisoned, they identified the poison with the River Styx because, like Alexander, the River Styx was the stuff of legend. After the association was made, people began to narrate his death with this idea in mind.