Mithridates VI, also known as Mithridates the Great, was the ruler of the Kingdom of Pontus, a region of northern Anatolia in what is now modern-day Turkey, from 120 to 63 BC. In 120 BC Mithridates’ father, Mithridates V, was assassinated by poison, allegedly as part of a conspiracy lead by his wife, Queen Laodice VI. Throughout his life, the younger Mithridates lived in fear of being poisoned, and began taking small non-lethal doses of various poisons in order to build up an immunity. After a series of wars against the Roman Empire, in 66 BC Mirthridates was defeated by Roman general Pompey at the Battle of Lycus and forced to retreat to the city of Panticapaeum on the Black Sea. There he hoped to gather another army to fight the Romans, but the local population rebelled against his rule and he was forced to commit suicide. At first Mithridates attempted to drink poison, but as he had already built up an immunity this had no effect, and he instead had to ask his bodyguard, Bituitus, to run him through with his sword. Ever since, this practice, known as mithridatism, has appeared in countless works of fiction, perhaps most memorably in the 1987 film The Princess Bride. But is it really possible to immunize yourself against poison by taking tiny doses over time, just like the Dread Pirate Roberts?

Well yes and no. The body’s ability to tolerate a given poison depends on its ability to metabolize or break down said poison into a less toxic form, a task largely performed by enzymes in the liver. Thus the poisons one can build immunity to tend to be larger organic molecules. One common example of this is ordinary grain alcohol, or ethanol, which is toxic if consumed in large quantities. The body actually has two lines of defence against ethanol: the stomach and the liver. The stomach secretes small quantities of an enzyme called alcohol dehydrogenase, which converts ethanol into less toxic acetaldehyde. This mechanism exists to counter the small amounts of ethanol – around 3g per day – generated naturally by the fermentation of food in the stomach. However, this small amount of dehydrogenase is easily overwhelmed by most alcoholic beverages, so most of the alcohol we consume is metabolized in the liver. Here, as in the stomach, ethanol is converted into acetaldehyde by alcohol dehydrogenase. However, as acetaldehyde is also toxic it must then be acted upon by another enzyme called acetaldehyde dehydrogenase, which converts it into harmless acetic acid, the main ingredient in white vinegar. Acetic acid is further broken down into carbon dioxide and water, which can then be expelled by the lungs and kidneys.

When a person drinks heavily and often, it can stimulate the liver to produce larger quantities of alcohol and acetaldehyde dehydrogenase, accelerating the metabolic process and gradually building a tolerance to alcohol. However, this process can only go so far. An excess of alcohol dehydrogenase can lead to a buildup of toxic acetaldehyde, which can cause alcoholic fatty liver disease – a common affliction among those with chronic alcoholism. This is particularly dangerous for certain individuals – including around 50% of those of Northern Asian descent – who thanks to a mutated gene produce a less efficient version of the acetaldehyde dehydrogenase enzyme. This leads to the rapid onset of acetaldehyde poisoning symptoms – including skin flushing, sweating, increased heart rate, and nausea – after even mild alcohol consumption. Increased levels of alcohol dehydrogenase can also accelerate the metabolism of other substances, such as the barbiturates in sleeping pills, leading the user to take larger amounts and risk overdosing. The rapid breakdown of acetaminophen, a common painkiller, also produces a number of substances toxic to the liver, making this drug potentially dangerous to those with chronic alcoholism.

These defence mechanisms can also backfire in other ways, such as when a person consumes methanol. Methanol, or wood alcohol, smells and tastes nearly identical to ethanol but when ingested can be deadly. This is because when acted upon by alcohol dehydrogenase, methanol breaks down into formaldehyde, the chemical used to embalm corpses and preserve biological specimens. Acetaldehyde dehydrogenase further breaks down formaldehyde into formic acid, a highly toxic substance that immediately attacks the optic nerve, causing one of the first symptoms of methanol poisoning: permanent blindness. Formic acid and formaldehyde are also cellular poisons and in high quantities cause the victim’s body to slip into a coma and shut down. During Prohibition in the 1920s, the United States Government added methanol to industrial ethanol – a process known as denaturing –  in order to prevent it from being diverted for human consumption. But vast quantities of this denatured alcohol still made it onto the black market, leading to the deaths of an estimated 10,000 people.

Another type of poison to which humans can become at least partially immune is the venom of snakes. While composition varies from species to species, snake venom generally contains a combination of complex enzymes such as proteases to dissolve tissues, nucleases to break down DNA, cholinesterase inhibitors to impede nerve function, ATPases to rob cells of their energy, and anticoagulants to encourage bleeding –  all of which ensures that whatever creatures the snake bites is guaranteed to have a very bad day. Yet despite snaked possessing this seemingly overpowered cocktail of death, many animals are effectively immune to their bite, including the Mongoose, Secretary Bird, Garden Dormouse, Hedgehog, Wood Rat, Opossum, California Ground Squirrel, and yes, everyone’s favourite furry badass, the Honey Badger. The biological mechanisms which confer this immunity vary widely: Opossum blood contains a peptide that breaks down snake venom proteins, while the proteins of Mongoose cell membranes feature a mutation that protects them from venom proteases.

While humans have no such natural protection, it is possible for us to build up a tolerance to snake venom. In fact, inoculation against snakes and other venomous animals is one of the oldest forms of vaccination, with cultures throughout history such as the Pakokku snake cult of Myanmar injecting or tattooing their skin with small doses of venom in order to gain immunity. Unlike with alcohol tolerance, protection is conferred not via metabolic enzymes but rather the immune system, with each exposure generating antibodies to that specific venom. If the inoculated person is bitten again, these antibodies will recognize and latch onto the venom proteins, allowing the immune cells to neutralize them.

In more recent years, researchers such as Charles Tanner, Herschel Flowers, and Joel la Rocque have confirmed the effectiveness of the practice by injecting themselves with pure or dried venom. This research lead to the development of the first effective antivenins, which are traditionally manufactured by injecting horses with venom, collecting their blood, and purifying the resulting antibodies. However, there have been numerous incidents where the immune systems of snakebite victims have rejected the horse proteins, leading a number of scientists continue self-experimentation in order to make a safer antivenin. Among the most extreme of these is Tim Friede, a self-taught immunologist from Wisconsin, who over the last 17 years has endured over 200 bites from some of the world’s deadliest snakes. And the results speak for themselves: a bite from an African Black Mamba usually results in an agonizing death within 15 minutes, but for Friede its effects are, according to him, no worse than a handful of bee stings. Working with Dr. Brian Hanley, a microbiologist at University of California and founder of gene therapy startup Butterfly Sciences, Friede hopes that his blood will lead to the development of a universal antivenin for all Old World snakes.

Another strange case is that of British rock musician Steve Ludwin, who has been injecting himself with snake venom for the past 40 years. Ludwin’s first encounter with snake venom came at the age of 10 when he visited legendary reptile handler Bill Haast’s Serpentarium in Florida:

“Bill Haast came out and draped an indigo snake around my neck. I was aware that he had been injecting himself with snake venom and I just thought it was the wildest thing I had ever heard.

 When I was 17, I knew I was going to inject snake venom in the future. I felt like Richard Dreyfuss in Close Encounters of the Third Kind, when he had that feeling ‘this means something’.

 But you know I’ve always loved snakes. I had no idea what it would do to me, but I knew it’d been done before and was curious to see if it was possible to become immune to snake venom.”

Ludwin began injecting snake venom in October 1988, slowly working his way up through larger doses and more venomous species. One day in 1991 he injected himself with a mixture drawn from the Pacific Rattlesnake, Eyelash Viper, and Green Tree Viper, only to realize that he had gone too far:

“My arm was all red and doughy with a sack of liquid hanging from it and I could see the blood vessels appear. It was like something out of Evil Dead.”

Ludwin finally decided to go to the hospital, where the emergency room doctors, who had never treated a snakebite before, administered  the common rattlesnake antivenin CroFab. But after spending three days in intensive care without improvement, Ludwin decided to discharge himself from hospital. Incredibly, despite the doctors’ warnings that he would either die or lose his hand, within a week his arm had returned to normal – a recovery Ludwin attributes to his immunization regimen. Today, Ludwin frequently travels to Denmark to have his blood drawn by researchers from the University of Copenhagen and the biotech startup VenomAB. Like Tim Friede, Ludwin hopes that his unique antibodies will eventually lead to a universal antidote for all snakebites, which according to the World Health Organization kill 125,000 people worldwide every year.

When it comes to simpler, inorganic poisons, however, the prospective mithridatist is unfortunately out of luck. The majority of these poisons either can’t be broken down by the body or break down into even more toxic substances. Heavy metals like lead, antimony, or cadmium are cumulative poisons, meaning that rather than being metabolized or flushed out of the body, they slowly accumulate within tissues, their toxic effect only growing over time. Certain metals like plutonium, strontium, or radium can be mistaken by the body for calcium or phosphorus and used in its place in forming bones, making it extremely difficult to remove. In addition to being conventionally toxic these metals are also radioactive, and can lead to the development of bone cancer or leukaemia. Another common accumulative metal is Mercury, which tends to collect in the brain. Indeed, this is the origin of the term “mad as a hatter” as milliners would often use various mercury compounds to soften the felt used in making hats, eventually developing chronic mercury poisoning and psychosis.

One seeming exception to this rule is Arsenic, to which people can actually develop a certain tolerance. In 2012, researchers from Lund and Uppsala Universities in Sweden conducted a study on the residents of the small Argentinian town of San Antonio de los Cobres in the Andes, where, thanks to natural mineral deposits and centuries of copper mining, the groundwater contains extremely elevated levels of Arsenic. They found that a large proportion of the town’s population possesses a gene called AS3MT, which allows the body to expel arsenic more efficiently. However, this ability was gained not through individual exposure but collectively through natural selection over the past thousand years; it is not possible for an individual to consume small quantities of Arsenic and become immune.

Another partial exception is Cyanide, which the liver can metabolize in small quantities using the enzyme rhodanese, converting it into less-toxic thiocyanate. This allows the body to tolerate the small amounts of cyanide found in foods such as apple seeds or almonds. However, unlike alcohol, it is not possible to stimulate the liver to more quickly metabolize cyanide. While the liver can produce more rhodanese, the reaction also depends on the compound thiosulfate, whose supply in the body is limited and cannot be increased.

Yet throughout history there have been individuals who appeared to be completely immune to cyanide poisoning. One such person was Grigori Rasputin, the Russian mystic who held great sway over the court of Tsar Nicholas II. In 1916, a group of noblemen lead by Prince Yusupov plotted to assassinate Rasputin, inviting him to Yusupov’s home in St. Petersburg where they offered him wine and cakes laced with cyanide. While Rasputin initially refused, he eventually relented and ate the food seemingly without ill effect. This forced Yusupov and his co-conspirators to shoot Rasputin, wrap him in a carpet, and dump him in the frozen Neva river. Rasputin’s immunity to poison is often attributed to his mystical powers, but the actual explanation is likely far more mundane. The poison the conspirators fed him was likely either potassium or sodium cyanide, which cannot be directly absorbed into the bloodstream. Instead, it must first react with the hydrochloric acid in the stomach, producing hydrogen cyanide gas which can then be absorbed through the stomach wall. Due to a variety of factors including genetics or various diseases, certain individuals cannot produce stomach acid, a condition known as Hypochlorohydria. If Rasputin was such a person, then the cyanide would simply have sat harmlessly in his stomach, making him appear to be immune.

So unless your enemies plan to attack you with poisonous snakes – and if so then your life must be awesome – unfortunately mithraditism appears to be largely the stuff of fiction. However, we at Today I Found Out believe in being prepared, and not wanting to fall victims to one of the classic blunders, have spent the last few years building up an immunity to Iocane Powder.

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