The Amazonian Arrow Poison that Revolutionized Medicine
Somewhere deep in the Amazon, a monkey leaps nimbly through the rainforest canopy, blissfully unaware that it is being hunted. Down below on the forest floor, the hunter lurks patiently in the shadows, stalking its prey, waiting for the perfect moment to strike. When the moment comes, the hunter raises his long bamboo blowgun, places it to his lips, and blows hard, launching a small poison-tipped dart into the canopy. The dart strikes home, causing the monkey to flee in panic. But it lasts only a few minutes before collapsing and plummeting to the ground, dead. The hunter returns to his village with his prey slung over his shoulder, having once again exploited the deadly power of the Amazon’s most infamous poison. Once the source of countless myths and legends among early European explorers, in more recent years this substance has made a surprising transformation from deadly arrow poison to miracle drug, helping to unlock many of the mysteries of the human nervous system and make modern surgery safer and more effective. This is the fascinating story of curare [“Koo-rah-ree”].
Curare is manufactured and used by dozens of indigenous tribes across Central and South America and the Caribbean, from the Island Caribs of the Lesser Antilles to the Macusi of Guyana and the Yagua of Columbia and Peru. The term “curare” refers not to a single substance but rather a whole family of similar arrow poisons, and is derived from the Macusi word uirary meaning “it kills birds.” Over the centuries there have been numerous attempts by Western researchers to transliterate this word, leading to the substance being variously dubbed “Woorari”, “Woorara”, “Woorali”, “Ourari,” and finally “Curare”. In its traditional form, curare consist of a dark brown, sticky, resin-like paste which can easily adhere to the tips of arrows and blowgun darts. Due to the relative rarity of its ingredients and the significant time involved in its manufacture, curare is largely considered too valuable for use in warfare and is employed almost exclusively in the hunting of game. As most of the animals hunted using curare live high up in the dense rainforest canopy, great care is taken to maximize the potency of the poison so that prey animals cannot flee out of visual range before dropping to the ground. This potency is typically evaluated using animal tests – for example, by pricking a frog with a poison-tipped dark and counting the number of hops it makes before dying. For the most potent curare recipes, time to death ranges from 1-2 minutes for birds, 10 minutes for small mammals like monkeys, and up to 20 minutes for large mammals like Tapirs. As you might imagine, the process for making curare is very complex and often a closely-guarded secret, allowing certain tribes to establish local monopolies and grow wealthy on its manufacture and trade.
While it is not known exactly when curare was first discovered – or by whom – the poison first came to the attention of the Western world in the 16th Century as European explorers began pushing deeper into the South American continent. One of the first descriptions of curare comes from Pietro Martir d’Anghiera – better known as Peter Martyr – an Italian-Spanish historian who in 1530 compiled numerous accounts of South American exploration in a book titled On the New World. In the book, d’Anghiera describes battles between Spanish conquistadores and indigenous tribes in which soldiers and horses were struck by poisoned arrows and appeared to become paralyzed before eventually dying. This detail would be the first hint as to how this mysterious poison actually worked. d’Anghiera goes on to describe how curare was exclusively manufactured by “old criminal women” who were locked up in cramped huts and forced to produce the poison from various toxic plants. When these women were overcome by the toxic fumes and passed out, the poison was deemed to be ready for use. In reality, however, this account turned out to be a complete fabrication, for as later explorers and anthropologists would discover, most South American tribes believe women to be too ritually unclean to participate in the sacred rite of curare production. Indeed, allowing a woman anywhere near the manufacturing process would diminish the magical powers and thus the potency of the poison.
Another early description of curare comes courtesy of English adventurer Sir Walter Raleigh, who in 1595 travelled up the Orinoco River in modern-day Guyana in search of El Dorado, the legendary lost city of gold. But Raleigh’s account is no less fanciful than d’Anghiera’s. In his 1596 chronicle of the expedition, The Discovery of the Large Rich and Beautiful Empire of Guiana, claims that garlic, salt, sugar, or tobacco are effective antidotes to curare poisoning – claims which are known to be laughably false.
Thanks to such rampant exaggeration and confabulation – not to mention extreme secrecy on the part of indigenous tribes – for nearly two centuries the true nature of curare remained a total mystery, the substance passing into myth and legend as one of the many exotic dangers that lurked in the Amazon jungle. It would not be until the 18th century that explorers and scientists began to shed some light on this mysterious poison.
One of the first Westerners to acquire and study a sample of curare was French explorer and mathematician Charles Marie de la Condamine. Perhaps most famous for teaming up with philosopher Voltaire to exploit a loophole in the French National Lottery in 1729, in 1735 Condamine was sent to South America on a surveying mission to measure the length of one degree of latitude. However, Condamine was more interested in finding and bringing back examples of the Cinchona tree, whose bark was the source of the antimalarial drug Quinine. To this end, he travelled widely across the continent for nearly a decade, making many valuable discoveries along the way. For example, he was the first European to encounter and describe caoutchouc or natural latex rubber, identified valuable platinum ores, and brought back seeds of several exotic plants including cacao, vanilla, and sarsaparilla. During his travels he also encountered an indigenous tribe called the Yameos, from whom he acquired a large sample of black curare resin. Upon returning to Europe, Condamine teamed up with Dutch physicians Herman Boerhaave and Gerard van Swieten and anatomist Bernhardus Albinus at the University of Leyden in the Netherlands to investigate the properties of this legendary poison. By injecting various doses into a cat, the four scientists were able to confirm that curare works by paralyzing the muscles. To their surprise, however, they discovered that the cat’s heart continued beating for up to two hours following its apparent death.
Today, we know that curare works by interfering with the function of motor neurons – that is, nerves which command the muscles to contract. At the junction between two nerves or between a nerve and a muscle or organ lies a tiny gap known as a synapse. When a nerve impulse reaches a synapse, it triggers the release of special signalling chemicals known as neurotransmitters, which cross the gap and bind to receptors on the other side, transmitting the impulse across the synapse. In motor neurons, the primary neurotransmitter is acetylcholine. Curare works by binding to the acetylcholine receptor sites, preventing the neurotransmitter molecules from transmitting nerve impulses across the synapse and resulting in the flaccid paralysis of the victim’s entire body. The first muscles to be affected are usually those of the eyes, meaning that the first signs of curare poisoning are fatigue, double vision, and difficulty keeping your eyes open. Next to go are your tongue and throat muscles, making it difficult for you to swallow or speak, followed by your limbs and all other voluntary muscles. But while this in itself sounds bad enough, unfortunately it gets worse. For you see, curare only works on the voluntary and semi-voluntary muscles, meaning that your heart will be unaffected and continue to beat. However, curare does paralyze the diaphragm and intercostal muscles responsible for breathing, meaning your death will be a slow and agonizing one by asphyxiation. Even more horrifying, curare has no effect on human consciousness, meaning you will be fully awake – but unable to move or even call out for help – as you slowly suffocate. Lovely. About the only good news is that, as we shall see, it is now possible to survive curare poisoning thanks to advances in medical technology.
In addition to discovering that curare does not affect the heart, Condamine and his colleagues also found that the poison is harmless when swallowed and must be injected through the skin in order to take effect. Indeed, Western explorers reported that Amazonian tribes readily ate the meat of animals killed with curare with no special preparation. In the 1850s, famous French physiologist Claude Bernard would conduct even more detailed experiments on curare’s effects and mechanism of action, establishing much of what we now know about the poison.
The Leyden team’s research was next taken up by English botanist Edward Bancroft, who in his travels throughout South America became the first European to discover the botanical source of curare and witness its manufacture. This process was also recorded by German naturalist Alexander von Humboldt, who travelled widely throughout the Americas between 1799 and 1804. While recipes vary from region to region, the main ingredient in curare is typically the vine Strychnos toxifera, first identified and classified by German explorers and brothers Robert and Richard Schomburgk in the 1850s. This, along with other plants including Chondrodendron tomentosum and Sciadotenia toxifera – and sometimes even ant or snake venom – are crushed and boiled in water for up to two days, until the residue boils down to a black, sticky substance resembling pitch or molasses. Then, slivers of the Cokarito palm are dipped into the mixture and used to smear it on the tips of arrows and blowgun darts. While the alkaloids responsible for curare’s toxicity mainly come from the Strychnos toxifera vine, the other ingredients act as adjuvants to increase its effectiveness – for example, by accelerating its absorption into the bloodstream or preventing the blood around the arrow or dart wound from clotting. In 1895, German Pharmacologist Rudolf Böhm attempted to classify the different types of curare by the type of container they were stored in, identifying three main categories: tube curare, stored in sections of bamboo, pot curare, stored in terracotta pots, and calabash curare, stored in hollow gourds. This system, however, was later found to have little factual basis. In reality, different tribes simply have different recipes for curare and different containers in which they typically store the finished product, the two being unrelated to one another.
In 1811, English surgeon Benjamin Brodie repeated Condamine, Boerhaave, van Swieten, and Albinus’s experiments, confirming that curare paralyzes the breathing muscles while leaving the heart unaffected. Crucially, however, he postulated that if the victim’s lungs could be kept mechanically ventilated using bellows, then life could be sustained until the poison wore off, allowing them to make a complete recovery. This hypothesis was confirmed in 1825 by fellow Englishman Charles Waterton, in a series of now-classic experiments conducted on a female donkey. Waterton, who had made his name as a South American explorer by – among other things – wrestling an alligator and a boa constrictor, first applied a tourniquet to one of the donkey’s legs to cut off blood flow before injecting the leg with curare. The donkey suffered no ill effects. But when Waterton removed the tourniquet, allowing blood from the leg to recirculate into the donkey’s body, the animal collapsed and stopped breathing within minutes, confirming that curare does not act locally and must be carried throughout the body to be effective. Once the donkey had collapsed, Waterton proceeded to insert bellows into its windpipe and artificially ventilate the animal for two hours until the poison wore off. The donkey made a full recovery with no lingering effects and lived for another 25 years, having been put to pasture as reward for her medical contributions. Waterton might not have known it at the time, but a century later this remarkable achievement would form the basis of a revolution in surgical science.
Based on these experiments, Waterton began to wonder whether curare might have medical applications. Observing that the action of curare appeared to be the exact opposite of tetanus, rabies, and strychnine poisoning, he suggested it be used in the treatment of these afflictions. Waterton had a particular interest in rabies, having been bitten by a dog as a child. Unfortunately, he never had the chance to test these theories. The closest he got was in 1839 when one Mr. Isaac Phelps, a police inspector for the city of Nottingham, was bitten by a rabid dog he was attempting to rescue from a deep hole. The wound healed and for a while Phelps appeared well, but seven weeks later he began displaying the classic symptoms of rabies – then known as hydrophobia – and was admitted to hospital. One doctor, who had read of Waterton’s theories, called for him at his home 80 kilometres away. Unfortunately, by the time Waterton arrived with his curare preparation, Phelps had already died. While Scottish physician George Harley would later prove that Waterton was correct about curare’s usefulness in treating tetanus and strychnine poisoning, the poison is unfortunately useless against rabies, which directly attacks the central nervous system.
It would be another 100 years before curare finally found a place in the pharmacopeia. In the meantime, however, the poison would play a vital role in solving a medical mystery and expanding our understanding of the human nervous system. In 1900, Austrian physiologist Jacob Pal was conducting experiments on digestive function using dogs. By this time, curare was commonly used to paralyze laboratory animals so that their automatic physiological responses to various drugs and treatments could be more easily observed. On one occasion, Pal injected a paralyzed dog with the toxin physostigmine, extracted from Physostigma venenosum – better known as the Calabar Bean. To his shock, the dog suddenly resumed breathing on its own. Pal had accidentally discovered the first known substance which could counter the effects of curare, unearthing a vital clue as to how the poison actually worked. This discovery in turn led to another dramatic medical breakthrough 35 years later. In 1935, Dr. Mary Walker at St. Alfege’s Hospital in Greenwich, England was studying a rare neurological disorder known as Myasthenia gravis, which causes profound and sustained muscle weakness and fatigue. After observing that patients with the disease were uniquely sensitive to small doses of curare, Walker hypothesized that the affliction was caused by a curare-like substance produced by the patient’s own body. Having read about Jacob Pal’s discovery three decades before, Walker decided to try injecting her patients with physostigmine. The results were dramatic – so dramatic, in fact, that the sudden and seemingly complete recovery of her patients is now widely known as the “Miracle at St. Alfeges.” It is now known that Myasthenia gravis is not, in fact, caused by a natural curare-like substance but rather by an auto-immune disorder that attacks the acetylcholine receptors in the motor neuron synapses. Physostigmine, meanwhile, acts as a cholinesterase inhibitor, interfering with the enzymes that break down acetylcholine molecules after a nerve impulse is sent, effectively resetting the nerve for the next impulse. This increases the amount of neurotransmitters in the synapses, allowing the nerves to overcome the effects of the disease.
Nonetheless, Walker’s discovery led to the discovery of acetylcholine’s role in motor nerve transmission, which had been hypothesized by English pharmacologist Sir Henry Dale in 1914. After two decades of research, Dale, along with German psychobiologist Otto Lowei, finally confirmed the function of acetylcholine, the two men sharing the 1936 Nobel Prize in Physiology or Medicine for their groundbreaking discoveries.
A year earlier, the composition of curare was finally worked out by English chemist Harold King, who determined that the most active toxins in the sticky mixture were the alkaloids curarine and tubocurarine. This attracted the attention of pharmaceutical company E.R. Squibb & Sons, who, intrigued by the potential medical uses for the poison, began purifying and selling small amounts of d-tubocurarine to medical researchers under the brand name intocostrin.
In 1939, curare finally saw its first medical application when American psychiatrist Abram Elting Bennett used it to paralyze patients undergoing metrazol-induced convulsive therapy. The precursor to electroconvulsive or shock therapy, this procedure was used to treat various psychiatric disorders including depression and schizophrenia and involved inducing seizures using a drug called Metrazol or Cardiazol. The problem was, the convulsions induced by this drug were so severe that patients often ended up injuring themselves. By paralyzing the patient with curare first, the procedure was rendered much safer – and for more on how this bizarre treatment came to be, please check out our previous video Who Invented Shock Therapy and Does it Actually Work?
But it was not until 1942 that curare would finally find its most prominent medical application. It was in that year that anesthesiologist Dr. Harold R. Griffith and resident Enid Johnson of Montreal’s Homeopathic Hospital, first experimented with the use of intocostrin in surgery. While surgical anaesthesia had been around since 1946 and was well-established a century later, it still wasn’t a perfect technology. While early general anaesthetics like ether, chloroform, and cyclopropane quickly and efficiently rendered patients unconscious, they did not completely inhibit their automatic responses, meaning patients could still twitch and move about on the operating table, with sometimes tragic results. And while such movements could be eliminated by administering more anaesthetic, this risked inducing respiratory arrest and other deadly side effects – especially in patients with severe medical conditions or bad hearts. Griffith and Johnson’s solution was to administer intocostrin in combination with the anaesthetic, inducing complete paralysis with none of the side effects and allowing less anaesthetic to be used. As he later recalled in 1944:
In June, 1939, Dr. L.H. Wright, of E.R. Squibb & Sons of New York, told me of this new work with curare and remarked how nice it would be if we could use some of it in anaesthesia to relax the muscles of our patients when they got a little too tense. I agreed that such an effect is often to be desired but was too horrified at the old poisonous reputation of curare to be seriously interested. I met Dr. Wright again in October, 1941, and asked him how he was getting on with curare in anaesthesia. He said he still thought the idea was sound, but that so far as he knew no one had tried it. I thought I had better not pass up a good thing any longer, so Dr. Wright kindly sent me some ampoules of intocostrin and in January, 1942, we began using it in the operating room of the Homeopathic Hospital in Montreal. We administered the drug intravenously to patients under general anaesthesia, and found that it acts quickly, producing in less than a minute a dramatic and complete relaxation of the skeletal muscles. Even under the most favourable circumstances, and with every general anaesthetic agent, occasions do arise when it seems impossible to get the patient sufficiently relaxed to make abdominal exploration or to close a friable peritoneum. To have a drug at hand which will give the patient at these critical moments complete relaxation, uniformly, quickly and harmlessly, has seemed to us a blessing to both surgeon and anaesthetist.”
So groundbreaking was this development that anesthesiologists often divide the history of surgery into “before Griffith” and “after Griffith”. Of course, the use of curare and its derivatives in this fashion also paralyses the patient’s lungs, requiring them to be artificially ventilated throughout the surgery. While this was initially done using a hand-pumped rubber bulb, in the late 1940s and early 1950s inventors like John Emerson and Forrest Bird developed mechanical ventilators which used electric or pneumatic motors to automatically breathe for the patient. These twin developments revolutionized surgery, allowing increasingly complex procedures to be performed more safely and with fewer side effects and postoperative complications. While curare derivatives like intocostrin have since been supplanted by safer but related paralytics like pancuronium, the basic procedure remains relatively unchanged since Griffith’s pioneering experiments. Like botox, digitalis, and other poisons-turned-medicines, curare has certainly come a long way from its deadly Amazonian origins.
Of course, as you might expect from a deadly poison, curare also has its darker uses. Indeed, pancuronium bromide is one of three drugs used combination for medical euthanasia and lethal injection – the official method of execution in 28 U.S. states. The other two drugs are sodium thiopental to induce unconsciousness and potassium chloride to stop the heart. While this method is intended to be quick and painless, as previously mentioned, paralytics like pancuronium have no effect on consciousness, meaning that it is impossible to tell whether a person is conscious during the procedure. This has led to speculation that many prisoners may actually experience severe pain during their executions, especially if an inadequate dosage of barbiturates is administered. Such fears have led eleven U.S. states to switch to a single-drug lethal injection method wherein death is induced via an overdose of sodium thiopental.
And if any murder mystery fans in the audience are wondering if curare has even been used in a crime, it most certainly has. Pancuronium was the lethal agent of choice of Efren Saldivar, a serial killer who is estimated to have killed up to 200 patients between 1988 and 1998 while working as a respiratory therapist at Adventist Medical Centre in Glendale, California. The drug was also used by four paramedics nicknamed the “Skin Hunters” to kill five elderly hospital patients in the Polish city of Lodz- the personal details of whom the killers sold to competing funeral homes. And finally, more than a century ago, curare was at the centre of a now long-forgotten assassination attempt. In 1916, a group of socialists and pacifists known as the Adullamites plotted to assassinate British Prime Minister David Lloyd George and Paymaster General Arthur Henderson in the hopes of ending the First World War. At the heart of the conspiracy was Alice Wheeldon, a women’s suffrage and anti-war activist who ran a chemist’s shop in Southampton – along with her two daughters and son-in-law. But before the plot could be carried out, Wheeldon’s group was infiltrated by one ‘Alex Gordon’, an agent for British Military Intelligence. When Gordon informed his handlers of the plot, they sent another agent, Herbert Booth, to gather more information. Booth must have been one hell of an actor, for he soon ingratiated himself to the conspirators to the point that they selected him as Lloyd George’s assassin! Given an air pistol and pellets dipped in curare, Booth was instructed to hide out on Walton Heath Golf Course in Surrey, and there ambush the Prime Minister. Instead, Booth betrayed the plot to his handlers and the conspirators were arrested and charged with treason. Five were put on trial and three found guilty, with Alice Wheeldon being sentenced to ten years in prison and her daughter and son-in-law seven and five years, respectively. A potentially disastrous wartime assassination was thwarted, and Lloyd George doubtless breathed a great – and thankfully non-paralyzed – sigh of relief.
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Birmingham, A.T, Waterton and Wouralia, British Journal of Pharmacology, April 1999, https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1565951/\
Gray, T. Cecil, The Use of D-Tubocurarine Chloride in Anaesthesia, Royal College of Surgeons of England, April 17, 1947, https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1940167/?page=1
From Arrow Poison to Surgical Muscle Relaxant, Ye Olde Log, https://web.archive.org/web/20080509154855/http://www.yeoldelog.com/medicinal/curare.shtml
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