Scopolamine and the Murder of King Hamlet

ORIGINAL ARTICLE Scopolamine and the Murder of King Hamlet

Basilio Aristidis Kotsias, MD, PhD

he events narrated by Shakespeare in his tragedy Hamlet1 are the following: King Ham- let of Denmark dies suddenly and his brother Claudius a few weeks later marries the widow, his sister-in-law, Queen Gertrude; according to the official explanation, a snake- bite was the cause of his death. The ghost of the king appears before his son, Prince THamlet, and tells him that his own brother, now his converted stepfather, has killed him, pouring into his ear the contents of an ampoule of henbane (Act I, scene 5). I cite the ghost’s account in full: Sleeping within mine orchard, effect and at the same time describes My custom always in the afternoon, what may be considered the blood circu- Upon my secure hour thy uncle stole, lation. Readers may be interested to With juice of cursed hebona [henbane] in a vial, know that, although Shakespeare and And in the porches of mine ears did pour Harvey were contemporaries, Hamlet was The leperous distilment; whose effect Holds such as enmity with blood of man published in 1603, 25 years before The That swift as quicksilver it courses through Motu Cordis. The natural gates and alleys of the body, Henbane or hebona is extracted from And with a sudden vigour it doth posset the seeds and leaves of Hyoscyamus niger And curd, like eager droppings into milk, and Scopolia carniolica, plants belonging The thin and wholesome blood: so dit it mine: to the Solanaceae family that also in- And a most instant tetter bark’d about, cludes common foods such as tomatoes, Most lazar-like, with vile and loathsome crust, potatoes, eggplant, peppers, and to- All my smooth body. bacco. Hyoscyamus and Scopolia contain In this article I attempt to analyze and dis- the active ingredients scopolamine (or hyo- cuss in the light of present medical infor- scine) and hyoscyamine,7,8 whereas atro- mation this scene of Hamlet. How did pine is extracted from other plants of the Shakespeare come to this singular idea? same family. All these substances have no Could the venom extracted from a nar- known function in the plants in which they cotic plant with beautiful leaves, a foul odor, are found. yellow flowers above and purple below, have Scopolamine and atropine are anti- been responsible for the death of King Ham- cholinergic drugs that block the acetylcho- let? If it is accepted that the extracted hen- line muscarinic receptors in a competitive bane was of good quality, could the man- and nonspecific manner, preventing a close ner chosen by the fratricide have been interaction between the ligand and lipo- effective? I conclude that it was possible to philic sites on the receptor.7,9,10 Musca- accomplish the murder as it was written in rinic receptors are G protein–coupled re- the tragedy. ceptors and mediate their inhibitory or Incidentally, we recall that although excitatory responses by activating a cas- this subject in Hamlet had received atten- cade of intracellular pathways rather than tion in the past,2-6 it has an additional in- the direct opening of an ion channel as with terest because the ghost in Shakespeare’s nicotinic receptors. Molecular cloning tech- play speaks of the rapidity of the toxic niques identified 5 different subtypes of muscarinic receptors that share common From the Instituto de Investigaciones Me´dicas A. Lanari, University of Buenos Aires, features, including specificity of binding for Buenos Aires, Argentina. the agonists and the classic antagonists. M1,

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©2002 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/25/2021 M3, and M5 receptors are associated with an increase in ditory canal; however, it is reduced to a fine layer of epi- the production of inositol triphosphate, while M2 and M4 dermis and is less fit for rapid drug absorption. The subtypes decrease the levels of cyclic adenosine mono- possibility of a murder via auris was known to occur in 16th- phosphate by inhibiting adenosine cyclase. The tissue dis- century Italy,5 and it was based on the knowledge of that tribution differs for each subtype. M1 receptors are found time about the direct absorption of some substances from in the forebrain, especially in the hippocampus and cere- the ear. Pliny in his Natural History (Book 25.4.17), pub- bral cortex. M2 receptors are found in the heart and brain- lished in English in 1601, recommended pouring oil of hen- stem, while M3 receptors are found in smooth muscle, exo- bane into the ears for use in earache, though he warns that crine glands, and the cerebral cortex. M4 receptors are found it may cause mental disorder. Henbane was an official drug in the neostriatum and M5 receptor mRNA is found in the mentioned in old English pharmacopeias and dispensato- substantia nigra.9 ries and it was used as well as the cannabis extract in the The absorption of scopolamine through the skin is form of eardrops in the treatment of earache.5,17 Many years limited, although a preparation in the form of transder- ago, Macht2 demonstrated with experiments in animals that mal patches placed over the mastoid region of the neck certain poisons, including scopolamine, can be absorbed is used for the prevention of motion sickness.7 The rela- through the intact ear and often likewise skin eruptions and tive ease with which scopolamine crosses the blood- shorten the coagulation time of blood.(quoted in 3) It is hard, brain barrier makes its effects on the central nervous sys- however, to accept that, in this way, such a quick poison- tem more important than other anticholinergic drugs. For ing would take place. On the other hand, the tympanic this reason, it is used not only in the inhibition of para- membrane can be perforated and the highly vascularized sympathetic function, but also in experimental studies middle ear is connected to the pharynx by the eustachian involving memory.11 The half-life of scopolamine in tube. Something similar happens with intoxication by plasma is 3 hours and its use in toxic doses (about 10 atropine contained in eyedrops, where the drug passes by mg) is accompanied by a rapid and weak pulse, paraly- way of the lacrimal duct toward the nose and is eventually sis of the iris, blurred vision, dry, warm, and reddish skin, swallowed.7 Chronic otorrhea was not uncommon in decreased intestinal peristalsis and motility, ataxia, hal- Shakespeare’s times4 and there are indications that physi- lucinations, and eventually coma and death.7,12 cians of that time might have known that fluids in the middle Both atropine and scopolamine have a long history ear could pass into the pharynx and that a substance in- involving witchcraft and the analgesic and anaesthetic stilled into an ear with a tympanic perforation could find actions of these drugs, isolated or in combination with its way to the pharynx and be swallowed. The work of Bar- opioids and stramonium, have been known for centu- tolommeo Eustachio (ca 1520-1574) was known. His de- ries13 and related by Dioscorides in the first century BC, tailed description, the Opuscula Anatomica, published in Cervantes (Don Quixote, part I, chapter 18), and Cal- Venice in 1563, includes the differences between the bony deroń de La Barca (La Vida Es Suenõ, second episode). and cartilaginous portions of the tube, a description of the For centuries, the Roman spongia somnifera, remem- nasopharyngeal opening, and a description of the tensor bered today for the association it had with the punish- tympani muscle.(quoted in 4,5) The effective concentration in ment of crucifixion, was used as vector of several types plasma of scopolamine is very low: 40 pg/mL is necessary of drugs, including henbane among others.8,14,15 for its therapeutic effects, and up until a few years ago, 0.5 Shakespeare may well have been influenced by con- mg was injected during preanesthesia.2 The proportion of temporary events or other authors chosing this finesse in alkaloid in dried leaves and seeds of henbane is relatively the administration of a “mixture rank, of midnight weeds high, ranging from 0.045% to 0.6%.18 Although we do not collected.” In 1560, the surgeon A. Pare´ was accused of hav- know either the concentration used by the murderer or the ing poisoned Francis II, King of France, by blowing ve- rate of absorption of the drug, a few milligrams of the drug nous powders into his ear (a white powder was found in instilled into the ear may reach toxic levels in the blood. one of his caps).3,16 In 1538, Francisco Marıá I, Duke of Ur- Thus, the ampoule containing the henbane that Claudius bino, was murdered in Pe´saro. The crime was attributed poured into King Hamlet’s ear could very well have con- to some Luigi Gonzaga, who might have bribed the bar- tained sufficiently high enough amounts of scopolamine ber and surgeon of the noble to introduce the venom into so as to fulfill his lethal mission. his ear. It is possible that Shakespeare was aware of these We ask ourselves if King Hamlet suffered a tym- episodes and used the last one in the scene of the play within panic membrane perforation causing an associated hear- the play (Act III, scene 2). The actors perform “The Mur- ing loss and had word of this gotten around to the am- der of Gonzago” in which the name of the murderer is ex- bitious Claudius. Perhaps this drove “that adulterate, that changed for that of the victim, slightly altered,14,16 whereas incestuous beast” to easily enter the garden during the a murderer in Marlowe’s play Eduard II (Act V, scene 4) placid nap to empty the fatal preparation of henbane in uses poisonous powders introduced into the ear with the his brother’s ear, depriving him of his life, crown, and help of a feather. queen. Could the liquid, filling the 2.5-cm3 capacity of The skin lining the ear canal is rigidly adhered to the the external auditory canal, have awoken the king? The underlying bone and cartilage and is very vulnerable to me- author does not say, maybe the the ampoule was warmed chanical damage, such as a scratch; it can become in- or the king was taking a nap after a good meal and hav- flamed and the vasodilation or neovascularization pro- ing drunk much beer, as was the custom in those days. voked by the inflammation makes it more capable of There are other explanations that fit the crime in absorbing drugs. The poorly vascularized tympanic mem- question, such as a reflex provoked by vestibular stimu- brane is covered by skin similar to that of the external au- lation with consequences in higher centers associated with

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©2002 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/25/2021 autonomic functions or a tachycardiac effect on a dis- 4. Eden AR, Opland J. Bartolommeo Eustachio’s De Auditus Organis and the unique eased heart. Finally, there exists the possibility that murder plot in Shakespeare’s Hamlet. N Engl J Med. 1982;307:259-261. 5. Pellant A. Otorhinolaryngeal diseases in old age and in famous persons. Acta everything related to the apparition of the ghost on the Medica (Hradec Kralove). 1996;39:81-85. platform before the castle of Elsinore was a product of 6. Kotsias BA. Hamlet, el belenõ y los canales iońicos. Medicina (B Aires). 1998; Shakespeare’s fantasy, as well as the death of the melan- 58:433-438. cholic prince, wounded by the poisoned sword (with what 7. Hardman JG, Limbird LE, Goodman Gilman A, eds. Goodman & Gilman’s The Phar- macological Basis of Therapeutics. 8th ed. New York, NY: McGraw Hill Co; 1996. venom?) that Laertes held. If this were true, our inter- 8. Carter AJ. Narcosis and nightshade. BMJ. 1996;313:1630-1632. pretation would result in pure fiction. 9. Caulfield M, Birdsall NMJ. Classification of muscarinic acetylcholine receptors. Pharmacol Rev. 1998;50:279-290. Accepted for publication November 30, 2001. 10. Tucek S, Proska J. Allosteric modulation of muscarinic acetylcholine receptors. I thank Susie Kestner, J. A. Barcat, L. O. Aiello, and Trends Pharmacol Sci. 1995;16:205-212. 11. Ohno M, Watanabe S. Blockade of 5-HT1A receptors compensates loss of hip- both reviewers for their valuable help with the manuscript. pocampal cholinergic neurotransmission involved in working memory of rats. Corresponding author and reprints: Basilio Aristidis Brain Res. 1996;736:180-188. Kotsias, MD, PhD, Instituto de Investigaciones Me´dicas A. 12. Norton S. The basic science of poisons: toxic effects of plants. In: Klaasen CD, Lanari, University of Buenos Aires, C. de Malvinas 3150, ed. Casarett & Doull’s Toxicology. 5th ed. New York, NY: McGraw Hill Co; 1996: 1427 Buenos Aires-Argentina (e-mail: [email protected]). 841-853. 13. Diccionario Enciclope´dico Hispano-Americano. Barcelona, Spain: Montaner y Simoń; 1923. REFERENCES 14. Hoeniger FD. Medicine and Shakespeare in the English Renaissance. Cranbury: New Jersey Associated University Press; 1992. 15. Bellucci G. The hope of anaesthesia. Lancet. 1999;sIV:5. 1. Shakespeare W. Hamlet, Prince of Denmark. In: The Tragedies of Shakespeare. 16. Bullough G, ed. Narrative and Dramatic Sources of Shakespeare. Vol 7. New York, Vol 2. New York, NY: Modern Library. NY: Columbia University Press; 1973. 2. Macht DI. A pharmacological appreciation of Shakespeare’s Hamlet : on instil- 17. Kabelı´k J. Treatment with cannabis in ancient, folk and official medicine up to lation of poisons into the ear. Johns Hopkins Bull. 1918;329:165-170. the beginning of the twentieth century. Available at: http://www.undcp.org 3. Huizinga E. Murder through the ear. Pract Otorhinolaryngol (Basel). 1971;33: /bulletin/bulletin_1960-01-01_3_page003.html. Accessed August 8, 2001. 361-365. 18. Grieve M. A Modern Herbal. New York, NY: Barnes & Noble; 1996:402-403.

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