Scopolamine A Potent Chemical Weapon Domlnlck A. Labianca Department of Chemistry and William J. Reeves Department of English Brooklyn College of The City University of New York, Brooklyn, NY 11210 Since the fall of 1979 numerous patients have been brought to emergency departments in New York City after being poisoned with an alcoholic beverage. On admission to the emergency services, they were noted to manifest significant anticbolinergietoxicity. An analysis of the case histories, clinical presentations, and laboratory data suggests that scopolamine eyedrops were deliberately used ta poison these patients. This statement was made quite recently by Dr. Lewis Goldfrank, Director of Emergency Services a t New York City's Bellevue Hospital, and his team of chemical/medical detectives in their technical account of how they identified the mast likely cause of what they termed "an epidemic of anticholinergic poisonings. . .presently occurring in the New York City area" (1). The widespread concern generated by this epidemic also prompted the publication of accounts in the popular New York ( 2 )and Time (3)magazines entitled "Psycho-drops-A New Epidemic" and "The Mickey Finn Updated," respectively. Scopolamine has played a role in many instances of ahnormal behavior that have occurred in the fictional world of literature and film and the real world of crime and drug abuse. In this article, the key characteristics and effects of scopolamine are exemplified in a number of situations from these two worlds, including the case solved by Goldfrank and his coworkers. Characteristics and Effects (4) Scopolamine (I) is one of the alkaloids, a class of organic, nitrogenous bases that are usually characterized by heterocyclic structures, occur naturally in plants, and have potent physiological effects. Specifically, scopolamine--and its noted structural and pharmacological analog, atropine (11)-is one of the alkaloids found in the Solanaceae family of plants. Among the members of this family is the well-known Datura stramonium, which is commonly referred to by a variety of names, including apple of Peru, Jimson weed, Jamestown weed, devil's apple, thorn apple, stinkweed, and loco seeds or weed.
In terms of its drug classification, scopolamine is considered one of the two classic anticholinergic drugs (atropine is the other). In this capacity, scopolamine opposes the actions of acetylcholine (ACh), a vital neurotransmitter, or "chemical messenger," in the two major functional components of the nervous system: the central nervous system (CNS), which encompasses all the neurons, or nerve cells, within the skull and the spine, and the peripheral nervous system (PNS), which consists of all the neurons outside the skull and spine (5). The term cholinergic is used to describe neurons that liherate ACh (6). Once released, ACh acts a t cholinoceptive sites of effedor cells: these sites are those in the cells of organs and glands that are activated hy this transmitter and that include, for example, the heart, lungs, salivary and sweat glands, stomach, and intestine, all of which act involuntarily (7). Sco~olamineand ACh are both capable of binding to cholinoceptive sites; thus, scopolamme ran eflect its anti. rholinerric action hv complexinn these s i b , thereby hlwklnl: ; of scopolamine has their incraction with A C ~~. h i property allowed it to be used as a preanesthetic medication for surgical patients-it reduces various bodily secretions, such as those of the mucous glands, which can accumulate and interfere with normal respiration-and as a component of ophthalmic solutions that are applied topically to the eye to produce pupillary dilatation (mydriasis) and paralysis of accommodation, or loss of power in the ciliary muscle of the eye (cycloplegia). Ophthalmologists utilize these effects to facilitate various diagnostic procedures as well as to treat some inflammatory disorders (8). As with so many drugs that have been used positively by the medical profession, scopolamine is capable of severe toxic effects when its use is not carefully regulated. These have been summarized in terms of CNS and PNS effects. Among the former which relate to the cases involving toxicity to he considered in this article are anxiety, agitation, delirium, hyperactivity, amnesia, disorientation, confusion, stupor, behavioral instability, and hallucinations; among the latter are mydriasis, hyperpyrexia (high fever), intense drying of mouth and intense thirst, dry skin, urinary retention, and tachycardia (rapid heart action). Toxic Incidents Although scopolamine was discovered in 1888 by E. Schmidt (9),the ill effects produced by consumption of Datura stramonium were recognized long before this date. There have been references to its toxic pruperties inChinese and Sanskrit writines and in Homer's Illad 110) and Od~ssr., (11). The plant wa;used by Cleopatra to woo Caesar, and it caused stupor, confusion, and mortality among Marc Anthony's trwps who consumed the plant as they retreated from Parthia in 38 A.D. (4c). A particularly interesting account concerned with the plant--in terms ofdepictingsnme of the physiological effects, such as agitation, disnrientarim, hallucinations, and amnesia, that can he attril~uted,in part, at least, to the scopolamine contained in the Datura plant-is
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a portion of the h i s w y associated with the Jamestown weed. In 1676,damestown. Virginia, was the site of an uprising called Rawn's Rebcllion. The Britishmldiers who had h e n in\'olved in suouressine the rebellion consumed a salad which they had .. prepared from certain plants. Robert Beverley's historicdescrintiun uf the incident was first nublished in 1705 and is rep;oduced here (12): ~
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All over the Country, is interspers'd here and there, a surprizing Variety of curious Plants and Flowers. . . . The James-Town Weed (which resembles the Thorny Apple of Peru, and I take to be the Plant so call'd) is supposed to he one of the greatest Coolers in the World. This being an early Plant, was gather'd very young for a boil'd Salad,by some of the Soldiers sent thither, to pacifie the Troubles of Bacon: and same of them eat plentifully of it, the Effect of which was a very pleasant Comedy; far they turn'd natoral Fools upon it for several Days: One would hlow up a Feather in the Air; another wou'd dart Straws at it with much Fury; and another stark naked was sitting up in a Corner, like a Monkey, grinning and making Mows at them; a Fourth would fondly kiss, and paw his Companions,and snear in their Faces, with a Countenancemore antick, than any in aDutch Droll. In thisfrantickcondition they were confined,lest they should in their Folly destroy themselves; though it was observed. that all their Actions were full of Innocence and good Nature. indeed. thev were not verv cleanlv: for thev would have . ~~~~~~~~, ~~~~, wallow'd in their own Excrements, ;f they had not be& prevcnrcd. A Thousand suchsimple'l'rickr they plafd.and after Elcven I)ays. return'd to themselves again, not remembring any thing that had pass'd. [nterestingly, the ability of scopolamine todisturh mpmory and todisorient the individual may constitute a basis for the often hmiliar reference to thedrugasa "truth serum." Some douht has been cast upon thissupposed pruperty uf the drug hy a recent study in which human subjects who were given scopolamine exhibited signiticant impairment of retrieval uf information from "old memory store" (13). Nevertheless, a consideration of a classic fictional portrayal of the "truth serum" character of scopolamine is noteworthy. I n Carl Foreman's celebrated 1961 production of "The Guns of Navarone," based on the 1956 novel by Alistair MacLean, actor Anthony Quayle plays Major Franklin, a British officer and member of a six-man team of saboteurs that undertakes the task of destroying two large radar-controlled guns on the island of Navarone, which effectively block Allied access to the Aegean Sea. During the course of this mission, Franklin is severely injured, captured by the Germans, and given scopolamine in order to extract information from him. Franklin provides the information, but it is incorrect. Another member of his team, Captain Mallory, played by Gregory Peck, had given Franklin false information prior to his capture. Mallory had expected Franklin's capture and bad predicted t h a t t h e Germans would "shoot him full of scopolamine." Franklin's experience with scopolamine while in captivity can he contrasted with that of Philip Marlowe, the detective hero of "Farewell, My Lovely," which has been regarded as Raymond Chandler's best hook and as one of the greatest detective stories ever written. One of the truly intriguing segments of the novel is Chapter 25 in which Marlowe presents his recoverv from sconolamine donine. This s e m e n t has been novel. Dick Powell in preserved i n the film versions 2 "Murder, My Sweet" (1944) and Robert Mitchum in "Farewell, My Lovely" (1975) bring to film the terrifying conditions nroduced hv this drua. - T h e most effective presentation, however, remains Chandler's prose version. Chapter 25 is a five-page chapter which details Marlowe's battle with the hallucinatory effects of scopolamine. T h e hallucinations are suggested by a metaphor of smoke, which Marlowe sees filling the room a i d which he fights toremove. He describes the retreat of the smoke from a situation in which he is overwhelmed by i t (nearly immersed in it) to a point where he can dismiss i t as "just something back of my eyes" (14). The condition of hallucination is then followed by a description of stupor. Marlowe says that "I was dull, without
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thought" (15). The stupor gives way to behavioral instability: "That made me laugh. I didn't know what was funny, but I began to laugh. I lay there on the bed and laughed. I didn't like the sound of the laugh. It was the laugh of a nut" (15). Interspersed with this madness is the problem of delirium: the smoke becomes a weh woven by thoisands of spiders and then comes hack to smoke. Marlowe's rnernur) is impaired. He is unable to construct a chronological account of the events leading to his current situation. He then starts to walk and immediatelv becomes aware of another effect of sconolamine intake-extreme thirst. In addition to the scopolkine, he has been "shot full of dope to be kent auiet" (14). In Marlowe's case, this "quieting" dope, no doudt a depressant such as morphine, potentiates another of scopolamine's effects, namely its ability to depress the CNS, and makes sleep his most dreaded antagonist. While the above fictional episode is quite fascinating hecause of the scientific accuracy that characterizes its presentation, the nonfictional episodes involving toxic responses to sco~olamineremain the most disturbing hecause thev are real. T h k e that are particularly significant--hecause they rrllrct two of the critical problems that currently plague our society, namely crime anddrug abuse-are describedbelow. The first of these cases happens all too frequently and is aptly summarized in the following passage (4c): The 15-year-old was agitated and actively communicating with an invisible girl friend. He presented with the classic signs and symptoms of anticholinergicpoisoning: mydriasis, vasodilation, hyperpyreria, tachycardia, decreased intestinal motility, urinary retention, decreased salivation, amnesia, agitation, and Lilliputian hallucinations. This 15-year-old youth was one of four adolescents, ranging in age from 12 to 17, who had been drinking a tea made from "locoweed" to achieve a "high" while a t a beach party. The events that initiated the second case are a s follows (16): In the early evening of October 16,1973,an attractive young woman entered a local jewelry store (inFlorida) and approached the manager and his twoemployeesstating that she was conducting an orange juice taste survey. After agreeing to participate in the "survey" three individuals were each given two 3-in. plastic cups of juice to taste. Approximately 15 min after ingestion all three persons experienced dizziness, blurred vision, muscular weakness, and difficulty in maintaining their equilibria.
These three victims were later transported to a hospital, where thev exhibited svmntoms of mvdriasis. aeitation. delirium. stupor, disorieniatibn, and incoherent'sieech. ~ h b s e ~ u e n t analysis of the gastric lavages of all three patients utilizing thin-layer and gas-liquid chromatographic techniques confirmed scopolamine as the culprit. Scopolamine was also confirmed as the toxic agent in similar incidents involving fifteen other Floridians. T h e final case returns us to the incident described a t the beginning of this article. The patients who were treated by Dr. Goldfrank had been robbed of cash, jewelry, and furs after having consumed drinks offered them by casual acquaintances. They exhibited the classic toxic symptoms of scopolamine wisoniw, some of which were vividlv described in connection k i t h a n&e victim by Linda ~ o l f e i her n New York article (2):
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(He)was in Bellevue's emereencv " .rwm.,his heart noundine. ~ ~hir ~eves " - . wild, his mouth hone dr). his arms flailing at on arm" of terrif+g 1.illiputlans who kept trying to grab him. I'olice had i o u d him hallucinating on a curl, in Iron1 of the Sheraton, tielrn, ~aIIetI~.ss, his sample case gone, his shirt unbuttoned and draped loosely over his shoulders.. . .He had total amnesia for all that had happened.. . . ~~
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The crucial analysis t h a t finally led to the pinpointing of cause of these toxic reactions was thin-layer chromatography of some liquid found in a wine glass from the apartment of one of the victims. The specimen possessed a chromatographic assay identical to that of scopolamine. After ruling out other anticholinergics, Goldfrank and his co-workers concluded that readily available and quite potent ophthalmologic scornlaminepreparations were being "slipped into the drinks of ;nwittingvi&ims. (Two preparations that are currently available are Alcon Laboratories' "Isopto Hyoscine," each milliliter of which contains 0.25% scopolamine hydrobromide, and Muro Pharmaceutical's "Murocoll-2 Solution" which contains 0.3% scopolamine hydrobromide (86). It should also be noted that there have been a number of cases involving accidental poisoning with scopolamine eyedrops (17) and that as little as 4 drops of a 0.25% scopolamine solution, which would be equivalent to 0.45 mg of scopolamine, have caused acute toxic psychosis (I).)The conclusion of Goldfrank et al. is supported by the following addendum to their paper: the
In a recent case reported by the police to the New Yark City Poison Center, an antieholinergie robbery victim was brought to another hospital and a presumed perpetrator was apprehended with a bottle of scopolamine eyedrops. The police had heen alerted to this possibility by a Health Department warning pertaining to the ease cited in this paper.
Conclusion There are manv other substances that have been used as --~.-. chemical weapons. These include cyanide (18), "knockout drons" (19). ,~., thallium (20). muscarine (21). and laudanum (22). In terms of its length;; history and the scope of its toxic manifestations, however, perhaps scopolamine can be regarded as one of the chemical weapons that has achieved a particularly significant status. ~
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Literature Cited (11 Goldfrank,L., Flomonbaum,N.,Lewin. N., Wcisman.R, Howknd, M.A..and Balk~Ishena,K, Clin Torieol., 19.17 (19821.
(71 Ref. (61, pp. U 1 . (81 (a)Shader,Rl..andGmblatt.D.JDDii"PByehiatritriC~pLi~Bom~fMediealD~." IShader. R. I.. Editor).Raw" Pram. New York. 1972.~. 112:lb) "1982 Phvaieland Desk Refim& for 0phthalmology.'i 10thed.,~edieal~hnomies Co., ~ne.,~~rsdell, NJ, 1981.pp.M. 115. (9) Adriani, J., "The Pharmamlogy of Aocathetic Drugs: A Syllabus for Students aod Clinieisna,"5th od.. CharlaC.Thoma8,Puhlisher.Sprin%leld, IL.1977,p. 171. 1101 Jenninzs. R. E . . J Pediot.6.657 119351.
"*,. (14) Chsndb, Ravmond,"Faraell,My Lavely..'Ballantine.NewYork. 1974p. 142. (151 Ref (14),p.139. (16) Ksp1an.M. M., Register.D.C.,Bierman,A. H.,and Rkcher.R L., CIin TozMI,7, G r n ,,O"*,
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and R&. R.s.. j. 0 p h t h ~ 1 ~ 0 1 . ; 71136 ~ . (1911). (181 See,for example,(a) Chandler,Raymond, "The Big Sleep." 193%(b) Asimov, h a o , "A Whiff of Death."1958;(el Labiama, D. A,, J. CHEM. EDUC., 57,198119791. (191 See, for example,(a1 Hammetf,Dashiell,'"ThoMsltoseFsleon."1925; lb) the filmof the same title (1941):(el Lshiancs,0. A,, J. CHEM EDUC.,52.101 (1975). 1231 See,for example, (s)Christie,Agatha. "The Pale Horse."l962;(bl Daily New8 (New Ymk), June 24,1977,~. 4; (c) Time,July17,1972,p. 31; Id1 Lahianes,D.A.,Seieneo Edue..62,491(1978). (21) See,for ersmplc, 1s)Sayera,Domthy, and Eustaee, Robert,"The Dauments in the Case." 193%(b) Hart, H., J. CHW. EDUC., 52,444 (1975);(el Sevcro, R., TheNam
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(1975);Id1 Blumenthal,R., The New Yark Times, hiar. 29,'1974,p. 37
