ons are a popular literary plot device due to their versatility. In a fictional universe, you can create a poison that fits every need - fast or slow acting, undetectable, come in a variety of forms… you get the idea. It’s no surprise that a Game of Thrones poison has been used by villains several times to kill off their victims. Most notably are “The Strangler” (used to kill Joffrey Baratheon) and “The Long Farewell” (used to dramatically murder Mycella Baratheon and possibly the last Dornish Sand Snake). How do these poisons work? Are they based on real-life poisons? Love is a poison. A sweet poison, yes, but it will kill you all the same. -Cersei Lannister SPOILER WARNING: If you haven’t seen the show or read the books, be warned that there are some spoilers below. WHAT IS A POISON? DEFINITION The word ‘Poison’ can have a few different meanings based on context. In biology, we typically label substances as poisonous if they negatively disturb the normal physiology of an organism. Unfortunately, this is a very broad definition and in medicine we’re all about confusing lingo. For example, the word ‘toxungen’ refers to a poison that is delivered to the body surface without creating a wound (much like the spitting Dilophasaurus in Jurrasic Park). For the purposes of our Game of Thrones poison discussion, we will think about poisons as a substance that you have to touch, eat, drink, or inhale in order to be affected. We will also include both biological and non-biological compounds. THE DOSE MAKES THE POISON As we said before, almost anything can be a poison. Fun fact: ingesting too much licorice can kill you, and is called glycyrrhism (don’t worry, Red Vines and Twizzlers don’t actually have any licorice in them). The key to any poison in the dose. You probably ingest teeny-tiny concentrations of many deadly poisons every day. Some fruit seeds contain arsenic. Your water contains chlorine. The list goes on… The dose-lethality relationship is what makes many health headlines so ridiculous. The most common anti-vaccination arguments revolve around toxins that are added to the vaccine, usually in order to provoke an immune response (which is required for them to function) or to increase shelf life. It’s important to note that while these compounds seem scary, they exist in too small of a dose to actually affect you. Sure, consuming 4 pounds of aluminum hydroxide (a common vaccine adjuvant) in one day will likely harm you. But so will drinking 4-gallons of water, or eating 1,800 cups of rice. None of these things are dangerous, or even remotely harmful in the quantities consumed. But we’re here to talk about the most lethal of substances. The greatest of toxic tinctures. A badass blight. The most malicious miasma. The stuff so bad, that even Walter White is too afraid to use it. So enough about science rejecting crackpots and onto the good stuff. WHAT MAKES A GOOD POISON? We’re using “good” in the evilest sense here. Think of Cersei at her best. As in: what characteristics would make a poison the perfect murder weapon? There was a little debate to this question. Wouldn’t some villains want their poisons to cause long periods of suffering while others want a swifter course? Should it be reversible (in case someone uses it on you) or should it cause death in everyone it touches? Do you even want the victim to die? Anyways, we ultimately had to decide what would make for the perfect Game of Thrones poison. We assumed that in Westeros, the best poisons were: 1) Lethal in very small doses; 2) Reversible (all the better to get someone else if you can ingest it too); and 3) Undetectable, or made to look like some other disease process. THE “BEST” GAME OF THRONES POISON Several high profile poisonings have occurred throughout the show. Many were successful, including: King Joffrey, princess Mycella, a hand of the king Lord Arryn, and a maester Cressen (who poisoned himself trying to kill Melisandre). Although there are several specific compounds listed in the books, we are going to focus on the two most successful poisons used in the TV show. THE STRANGLER As possibly the most infamous GoT poison, The Strangler has been used for two very dramatic killings. It was first used in Season 2, when Stannis Baratheon’s maester attempts to murder the fire priestess Melisandre, and again in Season 4 when King Joffrey is assassinated at his own wedding. But what makes this poison so effective? SYMPTOMS/EFFECTS: In both of the televised uses of The Strangler we see a similar pattern: the victim appears to choke and quickly develops difficulty breathing, followed by bleeding out of the nostrils and discoloration of the face (maybe that is why it was called the “purple” wedding?). Death typically results within several minutes of ingestion, giving very little time to administer an antidote (if one exists). ROUTE OF ADMINISTRATION: INGESTION It seems that the most popular route of administering this particular Game of Thrones poison involves dissolving a small amount of it into wine. There may be several reasons why this method is favored. First, we see that the poison can be disguised as a light blue colored crystal by the way it was fashioned into Sansa Stark’s necklace. We have no way of knowing if The Strangler has any strong flavor, but we assume that dissolving it into a dark wine disguised both the color and flavor of the poison. Secondly, having the victim drink the concoction may help target the poison to where it seems to be the most effective: the upper airway (or the throat). Toxins that have to enter the bloodstream by passing through the intestines can take hours to be fully distributed throughout the body. Finally, having the victim drink the poison makes it more stealthy than using a dart or any object that pierces the body (hats off to you, Mr.Jaqen H’ghar). Not that anyone would question that the person was poisoned with how purple they become. WHAT’S REALLY GOING ON? The Strangler appears to be more of a toxic irritant than a nuanced poison. One of the most telling signs is that unlike other, slower poisons, this one works extremely rapidly. This suggests that it works locally - probably by damaging the surface tissue of the throat and airway causing it to swell. We see these features in burn injuries and smoke inhalation. The heat or chemical burns cause edema (fluid build-up from inflammation) in the upper airway, which can get so swollen that air cannot pass through. When patients come in with severe burns or throat injuries they are almost always intubated (insertion of an breathing tube) right away to prevent this from happening. Choking or coughing can push the poison further into the airway or even up into the nasal cavity/sinus. The nosebleeds seen in these victims may be a result of the poison damaging the nasal passage after one of the choking/coughing fits. However, in the books blood also oozes from the mouth (which would be expected from a burn) and the skin. Direct damage from the poison does not explain bleeding from the skin, and thus another mechanism must be at play. We cannot know for certain what is exactly going on, but it is possible that a severe coagulation (blood clotting) problem is at play here. Warfarin is a rodent poison that causes blood to lose its ability to clot. It is also used as a medication in humans to prevent blood clotting in the lungs, hear, or legs, and is sold under the name Coumadin. People or animals who ingest too much warfarin bleed profusely, and even the smallest cuts can bleed for hours. Another explanation for these bleeds may be from a temporary increase in blood pressure. Many different activities can cause a forced increase in pressure inside of your body. For instance, “bearing-down” (as in trying to forcefully poop) can cause blood vessels in the eyes to burst. It is possible that the strain of choking would cause the pressure inside of the victim’s abdomen would lead to an increase in blood pressure. This acute pressure increase can lead to a burst vessel in the nostril and explain the nose bleeds. Finally, victims who are choked to death often have discoloration of the face and burst vessels in the eyes and other parts of the head. The purple coloration seen most vividly at Joffrey’s death may be caused by a similar way. THE LONG FAREWELL This poison is one of the favorite weapons used by the Dornish Sand Snakes. Remember that scene where Myrcella Lannister dies in Jaime’s arms on her way back home? Yea, she was poisoned with The Long Farewell. SYMPTOMS/EFFECTS: As the name implies, The Long Farewell kills much more slowly than The Strangler. The exact details of the symptoms have not been completely revealed, but we do get an idea in the TV show when Bronn is poisoned and experiences blurred vision and nausea. Again, it appears that nosebleeds also play a prominent role. The Long Farewell is also the only notable poison that has a rapid acting antidote that has been used successfully. It seems that exactly how long it takes before the poison takes effect varies from person to person. Bronn was poisoned when one of the Sand Snakes cut him with her blade, and it took over a day (and significant taunting) before it began to take effect. Myrcella, on the other hand, died within only a few hours of being exposed through the mouth. ROUTE OF ADMINISTRATION: CONTACT The preferred method of delivery of this poison seems to be via kiss. Well, more specifically - direct contact involving the oral cavity. It’s hard for us to pin down exactly how The Long Farewell is transmitted. The delay in symptoms (at least when compared to The Strangler) lends some evidence that the poison must be distributed throughout the body and is more likely to be absorbed through the intestines. This would also help explain why it would take different times for different individuals: the speed of digestion varies based on the types of food you eat and how recently you’ve eaten. However, the poison itself appears to be deadly in extremely small quantities. Just a touch of the lips is enough to doom a person to an early grave. The oral mucosa (all the skin inside your mouth) if known to allow for very rapid absorption into the bloodstream. By this mechanism certain medications are given under the tongue, and can act immediately. If The Long Farewell were able to be absorbed by contact with the mouth, it would explain why only a very small dosage is required to lethal. In the end, we decided that this was most likely spread by contact and not digestion. The variance in timing in the TV show may be for dramatic effect, or based on the body weight of the victim. WHAT’S REALLY GOING ON? Unfortunately, we have less detail about this Game of Thrones poison than we’d like. Myrcella’s death was rather simple, and she showed very few signs of poisoning other than a pretty significant nose bleed. Using the assumptions we’ve made on the method of transmission, we can continue to make educated guesses on The Long Farewell’s mechanism. Bleeding is again a prominent feature of this poison. Similar to The Strangler, the frequent bleeding makes it seem like this poison interrupts the body’s ability to clot properly. In fact, blood thinner overdose (including Warfarin described above) is a very common cause of bleeding. Additional symptoms described in the books could also be explained by a disruptions of normal blood clotting. Internal bleeding has been known to cause vague symptoms, and can explain both the nausea and blurred vision. Large amounts of blood (actually almost all of your blood) can empty into the stomach/intestines, which would lead to dizziness, nausea, and ultimately death. Some of the modern blood thinners also have reversal agents (aka antidotes). The Long Farewell is the only major Game of Thrones poison to have an antidote, which further leads us to believe it would fit into this category. Finally, due to it’s similarity to a particular venom (see below), we are going to go ahead and wager that The Long Farewell does in fact interrupt the clotting cascade. MODERN EQUIVALENTS TO A GAME OF THRONES POISON? You would be hard pressed to find anything like the two poisons we’ve described above. There just doesn’t seem to be many things that are stable enough to handle, but cause such assured and specific symptoms. But we’re no quitters, so here’s a few that are at least close to what we’ve talked about above. CYANIDE First used as a chemical weapon in 1916 by the French, and later in the Holocaust gas chambers, Hydrogen Cyanide is an effectively brutal poison. Cyanide works by preventing your cells from using oxygen. [In case you’re interested, it directly inhibits a mitochondrial enzyme called Cytochrome C oxidase. This enzyme is the very last step required to utilize oxygen and create ATP]. Solid Sodium Cyanide Briquettes Without the ability to generate energy, your body quickly shuts down. The highest energy consuming tissues that are near the poison would die first. If inhaled, the lung tissue would begin to fail almost immediately. However, since inhaled substances enter the blood stream very quickly, your brain would follow soon after. GAME OF THRONES POISON EQUIVALENT: THE STRANGLER Some of the properties and symptoms of cyanide poisoning align with those seen in its fictional counterpart. First, if cyanide is inhaled it can cause the victim to stop breathing and die within a few seconds to one minute. Sound familiar? However, unlike the Strangler, many other visible symptoms occur with cyanide poisoning. After acute inhalation victims often experience convulsions, seizures, and cardiac arrest. Cyanide can also cause several changes in skin color. Classically, cyanide victims have been described as having a cheery-red appearance similar to carbon monoxide poisoning. This occurs due to have too much oxygen within the blood. By stopping the use of oxygen in the tissues, the blood is unable to exchange its oxygen stores for carbon dioxide. Despite the similarity in the names, Cyanide poisoning does not directly cause cyanosis – a bluish/purple discoloration of the skin. If cyanosis is present, we usually attribute it to shock or look for another cause. Joffrey’s facial discoloration looks more purple/blue than red to us, but it may in fact be caused by the oxygen over saturation described above. While cyanide can be formed into several compounds, I was not able to find any instances of it forming a blue crystal. Most often it is described as a clear crystalline structure (Potassium cyanide) a white solid (Sodium cyanide), or a gas (hydrogen cyanide). VIPER VENOM True to their name, the Sand Snakes seem to prefer a poison that is most similar to snake venom. Snake venom has been found to contain special proteins that shut down the coagulation cascade, rupture red blood cells, interrupt your nervous system, destroy your kidneys and cause your heart to go into cardiac arrest. Sounds delightful, right? By Uajith (Own work) [CC BY-SA 3.0 (http://creativecommons.org/licenses/by-sa/3.0)], via Wikimedia Commons Snake venom has several destructive mechanisms that all vary depending on the type of protein and the viper species. This is a very interesting topic deserving of its own write-up, so it would be impossible to give a decent overview here. However, we will give a (very brief) description of the most applicable mechanism. Viper venom, in particular, is known for containing hemotoxins – proteins that cause your red blood cells to burst and can dramatically affect the blood’s ability to clot. While this process is painful, it does not cause death right away. Whole limbs can die within a few minutes by the destructive nature of the injected hemotoxin alone. Initially, the blood becomes hypercoaguable, which means that is clots too much. But, the rapid clotting uses up all the proteins and other substances needed in this process, and your blood boomerangs back down to not being able to clot at all. Interestingly, contemporary medicine takes advantage of what we know about viper venom in some pretty cool ways! Because we know that the venom can affect the bloods ability to clot, we can use it to study other clotting disorders. For example, one specific venom type is used to test how quickly diseased blood will clot when the venom is added. Genetic diseases, or diseases that produce antibodies such lupus, have been studied using this approach. GAME OF THRONES POISON EQUIVALENT: THE LONG FAREWELL It makes a kind of awesome sense that the Sand Snakes would use some sort of venom in their assassinations. Since we only get brief descriptions in the show and books, we can only guess at any real-life equivalents. Bleeding was the only major symptom displayed by Myrcella as she was dying in front of Jamie. Our venom hypothesis does a pretty good job accounting for this, but we’re not exactly sure what else is going on. Additionally, much like viper venom, The Long Farewell doesn’t kill right away. Dizziness and nausea could be explained by the victim going into shock as the venom damages blood vessels and internal organs. The antidote to The Long Farewell Most types of venom also have an antidote in the manner of anti-venom. Antivenom is usually a type of antibody against the toxic portion of the protein, or another form of metalloproteinase inhibitor. All that to say that these substances bind to the toxin and prevent it from working. Unfortunately, we cannot account for several other aspects of the poison. Most venom has to be injected into the body to do damage. While a topical contact may cause skin irritation, it would not lead to devastating damage or death. Applying the stuff to your lips would be a very ineffective way to kill someone, and would probably just leave you with a numb and sore mouth. The Long Farewell sounds very unpleasant, but in truth if the dizziness and passing out comes before the rest of the symptoms the person may be gone before the horrors really take effect. Truth be told, there are very few perfect poisons in the world. Most take hours to take effect,or are easily identified. Some of the more popular ones in modern history (such as Ricin for all you Walter White wannabes) would not be available to someone in Westeros due to advanced chemical processing or unstable handling processes. We wanted to cover only those poisons that make sense to the era. Also, we wanted to look into what kind of poison Lady Olenna received at the end of the last episode. Maybe this week we’ll see if she shows any symptoms. Let us know what other topics you would like to hear about in our TV and medicine write ups in the comments!