If you’re in the market for a favorite historical figure then look no further than Mithridates VI Eupator, king of Pontus from 120 to 63 BCE and arguably the most cunning adversary ever encountered by the Roman Empire. Like a comic book supervillain, the legendary monarch is said to have made himself immune to the effects of poison by obsessively training his body on small doses of lethal substances. His enemies, on the other hand, were very much susceptible to toxins, and it was Mithridates’ tendency to exploit this fact that earned him the nickname "The Poison King". 

To this day, the practice of incrementally building up a tolerance to poisons is known as mithridatism. And while the idea of microdosing on deadly chemicals may not appeal to many, a few brave scientists are now following in the footsteps of the ancient Pontic ruler in the hopes of developing a universal anti-venom for snake bites. 

The Poison King

Like Simba in The Lion King, Mithridates fled into the wild as a young prince following the murder of his father, only to return years later to take his rightful place on the throne. Lacking a problem-free philosophy, however, Mithridates spent the intervening period paranoid that he too would be the target of assassins, and therefore used this time to build up his biological defenses.

According to legend, the young prince used to feed poisonous plants to ducks before drinking the blood of those that survived. In doing so, he was able to ingest non-lethal doses of all manner of deadly substances and slowly increase his tolerance to the various weapons in a Pontic assassin’s chemical arsenal. He is also said to have created an infallible anti-venom known as Mithridatium, although the ingredients that make up this fabled invincibility potion have been lost to history.

With no worries for the rest of his days, the poison-proof Mithridates returned to Pontus and ascended the throne before going on to prove himself as one of the most ingenious military leaders the ancient world had ever seen. Thrice was his kingdom assailed by the mighty Roman Empire, and it was during these skirmishes – known as the Mithridatic Wars – that Mithridates demonstrated his flare for biological warfare.

Single-handedly writing the book of dirty tricks, the invulnerable ruler repeatedly slaughtered the invading enemy using poisoned arrows, venomous animals, and chemical weapons made from naphtha. However, while the advance of the Roman army could be slowed, it could not be stopped, and Mithridates was eventually captured and defeated. 

In a final ironic twist, Mithridates is said to have attempted suicide by poisoning following his arrest, yet was unable to achieve a lethal dose. In the event, he was forced to seek a cruder death, asking his bodyguard to deliver a mortal blow with his sword. Hakuna matata, as they say.

Mithridates the myth?

While the story of Mithridates is most likely a blend of fact and fiction, it’s not beyond the realms of scientific possibility to become immune to certain poisons. However, before you start microdosing on polonium, bear in mind that different toxins affect the body in different ways, and mithridatism will only work for some of these – so choose your poison wisely.

Heavy metals, for instance, accumulate in the body, which means that taking multiple small doses eventually adds up to a big dose. Regularly ingesting tiny amounts of lead, mercury, cadmium, or other heavy elements will not, therefore, confer tolerance, but can severely damage the body’s vital organs.

Then there are toxins that are processed by the liver. In theory, a gradual increase in exposure to such substances can train the liver to produce more of the enzymes required to metabolize them, thus resulting in a degree of tolerance. 

The most obvious example here is alcohol, which is broken down by dehydrogenase enzymes. In heavy drinkers, the liver may become accustomed to churning out these catalysts, which is why it takes a lot more booze to start feeling drunk. However, while such a person can be said to be somewhat tolerant to the effects of alcohol, some of the metabolites created by this process are themselves toxic and can accumulate in the liver.

Acetaldehyde, for instance, is a by-product of alcohol metabolism and is a major contributor to fatty liver disease. Overall, then, booze probably isn’t the ideal material for the budding mithridatist.

Far more suitable are those poisons that activate the immune system, with snake venom being the perfect mithridatic matter. Unlike mongeese, opossums, and honey badgers, humans aren’t born with any immunity to snake bites, which is why a nip from a cobra or a black mamba can be so deadly. However, when exposed to a sub-lethal dose of serpentine toxin, we can develop antibodies to protect us against future bites.

In fact, some of the oldest vaccinations ever created were against snake venom. Traditionally, these were manufactured by injecting horses with the relevant toxins before extracting the antibodies from their blood. However, there are numerous examples of humans directly exposing themselves to snake venom in order to produce their own antibodies.

The Pakokku Snake Clan, for instance, is a small tribe in Burma that is renowned for its so-called protection tattoos. Clan members capture dangerous cobras and vipers by hand before mixing the snakes’ venom with ink which they use to tattoo their entire bodies. Supposedly, this inoculates members against the wrath of these deadly animals, and the practice is credited with ensuring that none have ever died from a snake bite.

Modern mithridatism

It’s been more than 2,000 years since Mithridates’ failed suicide attempt, and while we’ve moved on from drinking the blood of Pontic ducks, researchers are still using themselves as guinea pigs in the quest for poison immunity. Back in the 1960s, for instance, US Army veterinarian Herschel Flowers repeatedly injected himself with snake venom in an attempt to create a vaccine that would protect soldiers fighting in the snake-infested jungles of Vietnam. Documenting his efforts, he revealed that he was able to withstand a cobra bite with no ill effects after taking repeated doses of various toxins.

If ever there was an heir to Mithridates himself, though, it would have to be Tim Friede, director of herpetology at a company called Centivax, which is currently developing a universal anti-venom against the bite of every dangerous snake on the planet. The starting material for this elixir is Friede’s blood, which is loaded with antibodies as a result of 756 deliberate exposures to snake venom between 2001 and 2018.

“Immunizations included mambas, cobras, rattlesnakes, water cobras, taipans, as well as M. fulvius (coral snake), B. caeruleus (common krait), B. multicinctus (banded krait), N. scutatus (tiger snake), and P. textilis (eastern brown snake),” explain Friede and his colleagues in an as-yet unpublished study on the effectiveness of their vaccine.

Speaking to IFLScience, Friede says that at the peak of his self-experimentation in the early 2000s, “I had more specific antibodies in my blood that are directed towards snake venom than most humans just have in their blood – period.”

“That's when I was hitting it really hard. I was doing pure black mamba venom, pure green venom,” he explains. “So my titer levels were so high because I was doing pure lethal injections.”

Naturally, such extreme levels of tolerance are not reached overnight, and Friede says it generally requires 24 venomous injections of increasing concentration, spread over four months, to attain full immunity to a given toxin. “You have to start with small dilutions and build your way up to pure venom,” he says. “But in that four-month range, if you can hit pure venom, you’re gonna be crazy immune. And then you can just do maintenance doses.”

Unlike Mithridates, of course, Friede isn’t motivated by a fear of assassins, but puts his body on the line in the hopes of saving lives in countries where snakes still pose a significant threat to humans. “The anti-venom shortage right now is so bad that hopefully, our product in the future is going to save a lot of lives,” he explains.

In their latest pre-print, researchers from Centivax reveal that the vaccine created from Friede’s blood neutralizes the effects of 3-finger toxins (3FTXs), the dominant neurotoxin found in the elapid family of snakes. Incredibly, rodents that were inoculated with the product were able to withstand pure venom from cobras, king cobras, and black mambas.

Given that elapids make up roughly 60 percent of venomous snakes, this is a highly encouraging start. However, Friede insists that “we want the whole package complete for every single snake,” which means there’s plenty more work to do.

“The results of our paper are just from one antibody, called D09.  That's the most powerful antibody to nicotinic long neurotoxins,” he says. “But that’s just elapids. Now we have to deal with vipers and pit vipers, and they don't have alpha toxins so D09 will not apply to them.”

Not wishing to make guinea pigs out of any unconsenting horses, Friede has painstakingly bolstered his own personal army of antibodies in the quest to create a panacea that will neutralize the bite of any snake. It’s been quite a slog and there have been a few close calls along the way, but at the end of it all, he says “It feels good to know that there’s a kid somewhere 8,000 miles [12,800 kilometers] away that I'll never meet or never talk to, but I’ll hopefully save his life.”

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The content of this article is not intended to be a substitute for professional medical advice, diagnosis, or treatment. Always seek the advice of qualified health providers with questions you may have regarding medical conditions.