Penny le Couteur & Jay Burreson

by Napoleon's Buttons: How 17 Molecules Changed History

  Mandrake, deadly nightshade, and henbane all contain a number of very similar alkaloids. The two main ones, hyoscyamine and hyoscine, are found in all three plants in varying proportions. One form of hyoscyamine is known as atropine and is still valued today, in very dilute solutions, to dilate the pupil of the eye for ophthalmic examinations. Large concentrations produce blurry vision, agitation, and even delirium. One of the first symptoms of atropine poisoning is the drying up of bodily fluids. This property is taken advantage of in prescribing atropine, where excess saliva or mucus secretion may interfere with surgery. Hyoscine, also known as scopolamine, has gained a probably undeserved reputation as a truth serum.

  Combined with morphine, scopolamine is used as the anesthetic known as “twilight sleep,” but whether one babbles the truth under its effect or just babbles is not clear. Still, writers of detective novels have always liked the thought of a truth serum, and it will probably continue to be quoted as such. Scopolamine, like atropine, has antisecretory and euphoric properties. In small amounts it combats travel sickness. U.S. astronauts use scopolamine as a treatment for motion sickness in space.

  As bizarre as it might seem, the poisonous compound atropine acts as an antidote for groups of even more toxic compounds. Nerve gases such as sarin—released by terrorists in the Tokyo subway in April of 1995—and organophosphate insecticides, such as parathion, act by preventing the normal removal of a messenger molecule that transmits a signal across a nerve junction. When this messenger molecule is not removed, nerve endings are continuously stimulated, which leads to convulsions and, if the heart or lungs are affected, to death. Atropine blocks the production of this messenger molecule, so provided the right dosage is given, it is an effective remedy for sarin or parathion.

  What is now known about the two alkaloids atropine and scopolamine, and was obviously known by the witches of Europe, is that neither is particularly soluble in water. As well, they would have recognized that swallowing these compounds might lead to death rather than the euphoric and intoxicating sensations they wanted. Hence extracts of mandrake, belladonna, and henbane were dissolved in fats or oils, and these greases were applied to the skin. Absorption through the skin—transdermal delivery—is a standard method of taking certain medications today. The nicotine patch for those trying to quit smoking and some travel sickness remedies and hormonal replacement therapies use this route.

  As the records of witches’ flying salves show, the technique was known hundreds of years ago as well. Today we know that the most efficient absorption is where the skin is the thinnest and blood vessels lie just under the surface; thus vaginal and rectal suppositories are used to ensure rapid absorption of medications. Witches must also have known this fact of anatomy, as flying ointments were said to be smeared all over the body or rubbed under the arms and, coyly, “in other hairy places.” Some reports said witches applied the grease to the long handle of a broom and, sitting astride, rubbed the atropine-and-scopolamine-containing mixture onto the genital membranes. The sexual connotations of these accounts are obvious, as are the early engravings of naked or partially clothed witches astride broomsticks, applying salves and dancing around cauldrons.

  The chemical explanation is, of course, that the supposed witches did not fly on broomsticks to sabbats. The flights were ones of fancy, illusions brought on by the hallucinatory alkaloids. Modern accounts of hallucinogenic states from scopolamine and atropine sound remarkably like the midnight adventures of witches: the sensation of flying or falling, distorted vision, euphoria, hysteria, a feeling of leaving the body, swirling surroundings, and encounters with beasts. The final stage of the process is a deep, almost comalike sleep.

  It is not difficult to imagine how, in a time steeped in sorcery and superstition, users of flying ointments really did believe they had flown through the night sky and taken part in wild dancing and wilder revelries. The hallucinations from atropine and scopolamine have been described as particularly vivid. A witch would have no reason to believe the effects of her flying ointment were solely in her mind. It is also not difficult to imagine how the knowledge of this wonderful secret was passed on—and it would have been considered a wonderful secret. Life for most women in these times was hard. Work was never ending, disease and poverty ever present, and a woman’s control over her own destiny unheard of. A few hours of freedom, riding the skies to a gathering where one’s sexual fantasies were played out, then waking up safely in one’s own bed must have been a great temptation. But unfortunately the temporary escape from reality created by the molecules of atropine and scopolamine often proved fatal, as women accused of witchcraft who confessed to such imagined midnight exploits were burned at the stake.

  Along with mandrake, deadly nightshade, and henbane, other plants were included in flying ointments: foxglove, parsley, monkshood, hemlock, and thorn apple are listed in historical accounts. There are toxic alkaloids in monkshood and hemlock, toxic glycosides in foxglove, hallucinogenic myristicin in parsley, and atropine and scopolamine in thorn apple. Thorn apple is a Datura; devil’s apple, angel’s trumpet, stinkweed, and jimsonweed are some of the other plants in this genus. Now widely distributed in the warmer parts of the world, Datura furnished alkaloids for witches in Europe as well as for initiation rites and other ceremonial occasions in Asia and the Americas. Folklore associated with Datura usage in these countries reveals hallucinations involving animals, a very common aspect of witches’ flights. In parts of Asia and Africa Datura seeds are included in mixtures to be smoked. Absorption into the bloodstream through the lungs is a very rapid method of obtaining a “hit” from an alkaloid, as European tobacco smokers later discovered in the sixteenth century. Cases of atropine poisoning are still reported today, with thrill-seekers using flowers, leaves, or seeds of Datura to pursue a high.

  A number of plants from the nightshade family were introduced into Europe from the New World soon after the journeys of Columbus. Some that contained alkaloids—tobacco (Nicotiana) and peppers (Capsicum )—gained immediate acceptance, but surprisingly, other members of this family—tomatoes and potatoes—were initially regarded with great suspicion.

  Other alkaloids that are chemically similar to atropine are found in the leaves of several species of Erythroxylon, the coca tree, native to parts of South America. The coca tree is not a member of the nightshade family—an unusual situation, as related chemicals are normally found in related species. But historically plants were classified on morphological features. Revisions now consider chemical components and DNA evidence.

  The main alkaloid in the coca tree is cocaine. Coca leaves have been used as a stimulant for hundreds of years in the highland areas of Peru, Ecuador, and Bolivia. The leaves are mixed with a paste of lime, then tucked between the gum and the cheek, where the alkaloids, released slowly, help counter fatigue, hunger, and thirst. It has been estimated that the amount of cocaine absorbed this way is less than half a gram daily, which is not addictive. This traditional method of coca alkaloid use is similar to our use of the alkaloid caffeine in coffee and tea. But cocaine, extracted and purified, is a different matter.

  Isolated in the 1880s, cocaine was considered to be a wonder drug. It had amazingly effective local anesthetic properties. Psychiatrist Sigmund Freud considered cocaine a medical panacea and prescribed it for its stimulating properties. He also used it to treat morphine addiction. But it soon became obvious that cocaine itself was extremely addictive, as addictive as any other known substance. It produces a rapid and extreme euphoria, followed by an equally extreme depression, leaving the user craving another euphoric high. The disastrous consequences on human health and modern society of abuse of cocaine are well known. The cocaine structure is, however, the basis for a number of extremely useful molecules developed as topical and local anesthetics. Benzocaine, novocaine, and lidocaine are compounds that mimic the pain-destroying action of cocaine by blocking transmission of nerve impulses, but they lack cocaine’s ability to stimulate the nervous system or d
isrupt heart rhythm. Many of us have thankfully experienced the numbing effect of these compounds in the dentist’s chair or the hospital emergency room.

  THE ERGOT ALKALOID S

  Another group of alkaloids of quite different structure was probably, although indirectly, responsible for thousands of witch burnings in Europe. But these compounds were not used in hallucinogenic ointments. The effects of some of the alkaloid molecules from this group can be so devastating that whole communities, afflicted with horrendous suffering, assumed that the catastrophe was the result of an evil spell cast by local witches. This group of alkaloids is found in the ergot fungus, Claviceps purpurea, that infects many cereal grains but especially rye. Ergotism or ergot poisoning was until fairly recently the next-largest microbial killer after bacteria and viruses. One of these alkaloids, ergotamine, causes blood vessels to constrict; another, ergonovine, induces spontaneous abortions in humans and livestock; while others cause neurological disturbances. Symptoms of ergotism vary depending on the amount of the different ergot alkaloids present but can include convulsions, seizures, diarrhea, lethargy, manic behavior, hallucinations, distortion of the limbs, vomiting, twitching, a crawling sensation on the skin, numbness in the hands and feet, and a burning sensation becoming excruciatingly painful as gangrene from decreased circulation eventually sets in. In medieval times this disease was known by various names: holy fire, Saint Anthony’s fire, occult fire, and Saint Vitus’ dance. The reference to fire relates to the terrible searing pain and blackened extremities caused by the progression of gangrene. Often there was loss of hands, feet, or genitals. Saint Anthony was considered to have special powers against fire, infection, and epilepsy, making him the saint to appeal to for relief from ergotism. The “dance” of Saint Vitus’ dance refers to twitching and convulsive contortions due to the neurological effects of some of the ergot alkaloids.

  It is not hard to envisage a situation where a large number of villagers or townsfolk were struck by ergotism. A particularly rainy period just before harvest would encourage fungus growth on rye; poor storage of the cereal in damp conditions would promote further growth. Only a small percent of ergot in flour is needed to cause ergot poisoning. As more and more of a town’s inhabitants displayed the dreaded symptoms, people might start to wonder why their community had been singled out for disaster, especially as adjacent towns had no sign of the disease. It could have seemed quite plausible that their village had been bewitched. As in many natural disasters, the blame was often placed on the innocent head of an elderly woman, someone who was no longer useful for childbearing and who may have had no family support. Such women often lived on the outskirts of the community, perhaps surviving on their skills as herbalists and unable to afford even the modest sum required to purchase flour from the miller in town. This level of poverty would have saved a woman from ergotism but ironically, as maybe the only person untouched by the ergot poisons, she became even more vulnerable to the accusation of witchcraft.

  Ergotism has been known for a long time. Its cause was hinted at in reports from as early as 600 B.C., when the Assyrians noted “a noxious pustule in the ear of grain.” That ergot alkaloids from “noxious grasses” could cause miscarriages in cattle was recorded in Persia around 400 B.C. In Europe the knowledge that fungus or mold on grains was the cause of the problem seems to have been lost—if it was ever known— during the Middle Ages. With damp winters and improper storage, mold and fungus flourished. In the face of famine, infected grain would have been used rather than discarded.

  The first recorded occurrence of ergotism in Europe, in A.D. 857, is from Germany’s Rhine valley. Documented reports of forty thousand deaths in France in the year 994 are now attributed to ergotism, as are another twelve thousand in 1129. Periodic outbreaks occurred throughout the centuries and continued into the twentieth century. In 1926-1927 more than eleven thousand people were afflicted with ergotism in an area of Russia near the Ural Mountains. Two hundred cases were reported in England in 1927. In Provence, France, in 1951, four died and hundreds more became ill from ergotism after ergot-infected rye was milled and the flour sold to a baker, although the farmer, miller, and baker were supposedly all aware of the problem.

  There are at least four occasions when ergot alkaloids are claimed to have played a role in history. During a campaign in Gaul, in the first century B.C., an epidemic of ergotism among Julius Caesar’s legions caused great suffering, reduced the effectiveness of his army, and possibly curtailed Caesar’s ambitions to enlarge the Roman Empire. In the summer of 1722 Peter the Great’s Cossacks camped at Astrakhan, at the mouth of the Volga River on the Caspian Sea. Both the soldiers and their horses ate contaminated rye. The resulting ergotism supposedly killed twenty thousand troops and so crippled the tsar’s army that his planned campaign against the Turks was aborted. Thus Russia’s goal of a southern port on the Black Sea was stopped by ergot alkaloids.

  In France, in July 1789, thousands of peasants rioted against wealthy landowners. There is evidence that this episode, termed La Grande Peur (the Great Fear), was more than just civil unrest associated with the French Revolution. Records attribute the destructive spree to a bout of insanity in the peasant population and cite “bad flour” as a possible cause. The spring and summer of 1789 in northern France had been abnormally wet and warm—perfect conditions for the growth of the ergot fungus. Was ergotism, much more prevalent among the poor, who ate moldy bread out of necessity, a key factor in the French Revolution? Ergotism was also reported to be rife in Napoleon’s army during its journey across the Russian plains in the fall of 1812. So maybe the ergot alkaloids, along with the tin in uniform buttons, share some responsibility for the Grande Armée’s collapse on the retreat from Moscow.

  A number of experts have concluded that ergot poisoning was ultimately responsible for the accusations of witchcraft against some 250 people (mainly women) during 1692 in Salem, Massachusetts. The evidence does indicate an involvement of the ergot alkaloids. Rye was grown in the area in the late seventeenth century; records show warm, rainy weather during the spring and summer of 1691; and the village of Salem was located close to swampy meadows. All of these facts point to the possibility of fungal infestation of the grain used for the community’s flour. The symptoms displayed by the victims were consistent with ergotism, particularly convulsive ergotism: diarrhea, vomiting, convulsions, hallucinations, seizures, babbling, bizarre distortions of the limbs, tingling sensations, and acute sensory disturbances.

  It seems probable that, at least initially, ergotism may have been the cause of the Salem witch-hunts; almost all the thirty victims who claimed to be bewitched were girls or young women, and young people are known to be more susceptible to the effects of the ergot alkaloids. Later events, however, including the trials of the alleged witches and an increasing number of accusations, often of people outside the community, point more to hysteria or just plain malice.

  Symptoms of ergot poisoning cannot be turned off and on. The common phenomenon in the trials—victims throwing a convulsive fit when confronted by the accused witch—is not consistent with ergotism. No doubt relishing the attention and realizing the power they wielded, the so-called victims would denounce neighbors they knew and townsfolk they had scarcely heard of. The suffering of the real victims of the Salem witch-hunts—the nineteen hanged (and one pressed to death by a pile of rocks), those tortured and imprisoned, the families destroyed—may be traced to ergot molecules, but human frailty must bear ultimate responsibility.

  Like cocaine, ergot alkaloids, although toxic and dangerous, have had a long history of therapeutic use, and ergot derivatives still play a role in medicine. For centuries herbalists, midwives, and doctors used extracts of ergot to hasten childbirth or produce abortions. Today ergot alkaloids or chemical modifications of these compounds are used as vasoconstrictors for migraine headaches, to treat postpartum bleeding, and as stimulants for uterine contractions in childbirth.

  The alkaloids of ergot all have the
same common chemical feature; they are derivatives of a molecule known as lysergic acid. The OH group (indicated with an arrow, below) of lysergic acid is replaced by a larger side group, as shown in the ergotamine molecule (used to treat severe migraine headaches) and the ergovine molecule (used to treat postpartum hemorrhages). In these two molecules the lysergic acid portion is circled.

  In 1938, having already prepared a number of synthetic derivatives of lysergic acid of which some had proved useful, Albert Hofmann, a chemist working in the research laboratories of the Swiss pharmaceutical company Sandoz, in Basel, prepared another derivative. It was the twenty-fifth derivative he had made, so he called lysergic acid diethylamide LSD-25, now known, of course, as just LSD. Nothing exceptional was noted about the properties of LSD.

  Lysergic acid diethylamide (LSD-25), or LSD as it was to become known. The lysergic acid part is circled.

  It was not until 1943, when Hofmann again made this derivative, that he inadvertently experienced the first of what was to become known in the 1960s as an acid trip. LSD is not absorbed through the skin, so Hofmann probably transferred LSD from his fingers to his mouth. Even a slight trace would have produced what he described as an experience of “an uninterrupted stream of fantastic pictures, extraordinary shapes with intense kaleidoscope play of colors.”

  Hofmann decided to deliberately take LSD to test his assumption that this was the compound producing the hallucinations. The medical dosage for lysergic acid derivatives such as ergotamine was at least a few milligrams. Thinking, no doubt, that he was being cautious, he swallowed only a quarter of a milligram, an amount at least five times that needed to produce the now well-known hallucinogenic effects. LSD is ten thousand times more potent as a hallucinogen than naturally occurring mescaline, found in the peyote cactus of Texas and northern Mexico and used for centuries by native Americans in their religious ceremonies.