The poison in the cup Hemlock plant, Conium maculatum. Illustration by Jim M’Guinness. 26 The Pharos/Spring2011 Horton A. Johnson, MD The author (AΩA, Tulane University 1979), was formerly activeingredientcouldbeisolated,howitfunctionedphysi- director of Pathology, St. Luke’s/Roosevelt Hospital and ologically,andwhetheritmightbeanotherplantalkaloidlike Professor of Pathology, Columbia University College of morphine, strychnine, and quinine, which had just recently Physicians and Surgeons. A previous contributor to The beenisolated.Thewinneroftheprize,AugustLudwigGieseke Pharos, he is a docent at The Metropolitan Museum of Art. (Giseke),hadreceivedfromacolleagueanamplequantityof seedsofthespottedhemlockanddecidedtousethatasthe robablythebest-knownimageofthedeathofSocrates subjectofhisinvestigations. is the painting by Jacques-Louis David now in the His report of his work3 recalls the fact that it took place Metropolitan Museum of Art. David followed, more justthirty-sixyearsafterLavoisier’sTraitéhadgivenbirthto Por less, the eyewitness account of Phaedo as recorded by moderninorganicchemistry.Organicchemistrywasstillinits Plato.1Socrates,inprison,shacklesremoved,discoursingon infancy, just emerging from the shadowy worlds of alchemy theafter-life,isabouttoacceptthepoison.Havingfollowed andherbalism.Thelitmustestwasavailablefromthealche- Zeus’s command in a dream to “make music and work at mists, but otherwise organic substances were characterized it,”hislyreisathisside.Critoclutcheshismaster’slegand chiefly by odor and taste. Gieseke had no thought of atoms Apollodorosweeps.InthebackgroundSocrates’swifeisbeing ormolecules. ledawayathisrequest.Atthefootofthecouch,facingaway Giesekeplannedtoseparatevariousfractionsofthehem- fromSocratesandthegrief-strickendisciples,sitstheghost lockjuiceonthebasisofvolatility,solubility,andcrystalliza- of Plato, a gray figure, head bowed in thought, scroll, pen, tion.Thevariouscomponentswouldthenbetestedinrabbits andinkathisside.Platowas,byhisownadmission,absent todeterminewhichcontainedtheactiveprinciple,thepoison. becauseofillness,butDavidhasplacedhimthereinspirit. HewouldfollowcloselyontheworkoftheSwissapothecary Thecenterpieceofthepaintingisthecupofpoison,offered chemistJacquesPeschier,whoin1821hadseparatedthejuice bythedistraughtjailerandcalmlyacceptedbySocratesashe of the hemlock into several components. One of these, ob- continueshisdiscourse.Ithasbeenassumedthatthepoison tainedaftertreatmentwithmagnesiumhydroxideandether wasthejuiceofthespottedhemlock,Conium maculatum L, extraction,yieldedamereone-halfgramofanalkalinemate- amemberoftheparsleyfamilyandunrelatedtothehemlock rial,notenoughforfurtherinvestigation.Peschierhadnamed tree.TheGreekshadaspecificwordforthepoisonoushem- thesubstanceconiineaftertheLatinforhemlock.3 lock,κώνειον(hencetheLatinconium),butPlatonevercalled Gieseke’s first attempt failed rather badly. He began by it that. Instead he used the general term, φάρμακον, simply mashinghemlockseedsinwinespirits(ethylalcohol)andfil- meaningadrugorpoison.Sincethejuiceofhemlockleavesor teringoutthesolidmaterial.Hethenevaporatedthealcohol seedswas,atthattime,commonlyusedtoexecutecriminals, anddissolvedtheresidueinwater.FollowingPeschier’slead, andsinceitwasrepeatedlyreferencedbyancientauthorsin theaqueoussolutionwasheatedandmixedwithmagnesium connectionwiththedeathofSocrates,andgivenPhaedo’sde- hydroxide.Ashedidthis,anintolerableodorspreadnotonly scriptionofthemodeofdeath,itseemsreasonabletoassume through his laboratory but throughout the entire building. thatSocratesdid,infact,drinkjuiceofhemlock.2Onewon- Fearingforhishealthandthatofothers,hequicklybrought ders,then,justwhatwasthepoisonoussubstanceinthatcup? theproceduretoanend. Starting over, he heated the aqueous hemlock extract In 1824 the medical faculty of the University of Halle, with magnesium hydroxide again, but this time in a retort, Germany, offered a prize for the investigation of any of the capturingthenoxiousfumesbycondensingthemalongwith localpoisonousplants.Thestudywastodeterminehowthe the steam in the neck of the retort. The residual material The Pharos/Spring2011 27 The poison in the cup PhaedorecalledthatSocrates’sjailer,whomusthavewit- nessedmanydeathsbyhemlockpoisoning,saidthata“cold- ness[lifelessness?]andcongealing”wouldtravelfromthelegs up the body until it reached the heart, causing death. The experiencedexecutionertestedtheprogressbypinchinghard firstthefeet,thencalves,andsoon.Althoughheappearedto betestingforsensoryloss,itmayhavebeenformotorloss, lossofpain-withdrawalreflex.Ifthecupreallycontainedthe juice of Conium maculatum, a flaccid paralysis moved up Socrates’s body until it affected the muscles of respiration, causingasphyxia.Intheory,hecouldhavebeensavedbyarti- ficialrespirationuntiltheeffectsofthepoisonworeoff. Gieseke made several speculations that would be proven correct.Hesuggestedthatanybasicsubstance,notjustmag- nesium hydroxide, might somehow drive the poison out of The coniine molecule. the hot water solution and that addition of any acid might drawitbackintosolution.Actually,coniine,themostimpor- remaining in the retort was saved and further separated to tantofseveralalkaloidsinthehemlockplant,waspresentin maketwofractionsthatwouldeventuallyprovetobeinnocu- theformofstable,water-soluble,acidsalts.Asheheatedthe ous to the rabbits. The distillate, a slightly yellow, turbid, crude aqueous extract and made it basic by adding magne- aqueous solution, had oily droplets floating on its surface. siumhydroxide,Giesekewasliberatingthefree,basic,poorly It had a very bitter, ammonia-like taste, an odor much like soluble, and volatile coniine from its acid salts and into the thespiritsofhartshorn,andastronglyalkalinereactionwith atmosphere.Acenturyandahalfbeforethescourgeof“crack litmus.Itwasneutralizedwithsulfuricacidandthenevapo- cocaine,” Gieseke was “free-basing” another plant alkaloid, rated to obtain needle-like crystals. These were dissolved coniine. Adding acid reversed the process, recapturing the in alcohol to produce a fraction that was lethal to rabbits. coniineintoacidsalts. Gieseke had, with this simple procedure, isolated from the Asheworkedwiththepoison,therewasalwaysasmellof crudehemlockextracttheactiveprincipleofhemlockinpure ammoniaabout.Hespeculatedthattracesofammoniawere crystallineform,probablyasconiinesulfate.Interestingly,he beingreleasedfromthepoisonitself,thatammoniamightbe neverusedPeschier’sterm,coniine,butsimplyreferredtoit apartofthepoison.Coniinecan,infact,bereducedtorelease asSchierlinggift,hemlockpoison. ammonia, leaving a straight carbon chain, ordinary octane. Thedriedmaterialwasdissolvedinwaterandgiven(route Giesekesuggested,ashadothersbeforehim,thatitmightbe notspecified,probablybymouth)totwoyoungrabbits,one an ammonia component that gave the plant alkaloids their grain(65mg)tooneand5grainstotheother.Therabbitgiven basicoralkaloidcharacter.Itisindeedthenitrogenatomwith thelargerdosediedwithintwominutes.Theother,however, itslonepairofelectronsthatmakesconiine“alkaloid.” diedslowly,allowingGieseketodescribewhatwouldbecome Alkaloid chemistry moved ahead swiftly in the following known as the typical syndrome of hemlock poisoning: as- years.In1881,thegreatA. W. Hofmanndeterminedtheem- cendingflaccidparalysis,notunlikethedeathofSocratesas piricalformulaofconiine,C8H17N,anddeduceditsstructural describedbyPhaedo.Withinfifteenminutestheanimalbegan formula,apiperidineringwithapropylgroupatthe2posi- tohoparoundanxiously.Soonthehindlegsbecameparalyzed tion.4 By century’s end, dozens of plant alkaloids had been andstretchedoutonthetable.Theanimalstruggledtosup- isolated and characterized, including morphine, codeine, portitselfuprightwithitsforelegs.Aftertwentyminutesthe nicotine,atropine,cocaine,quinine,strychnine,andcaffeine.5 forelegscollapsed,andtheanimaltriedtosupportitselfoffthe Coniine,thesimplestofalltheplantalkaloids,wasthefirst tablewithitshead.Afterthirtyminutesitlaydownonitsside. tobesynthesizedin1885byLadenberg6who,inhiscompre- Clonicspasmsbegan.Eyesbecamefixed.Afterfifty-fivemin- hensiveHistory of the Development of Chemistry,7madeno utestheanimalwasdead.Autopsiesoftheseanimalsshowed mentionofGiesekeandhisprimitiveexperiments. nosignificantpathologicalchanges. It has since been shown that coniine blocks the neuro- TheMetropolitanMuseumofArtboughtDavid’spainting muscularjunctionsofskeletalmuscles,butGieseke,knowing in1931.Withinafewyearsmillionsofvisitorstothemuseum nothingofneuromuscularjunctionsorlowermotorneurons, had witnessed Socrates accepting the cup of hemlock with attributed the deaths to poisoning of the spinal cord and itsconiine.ThosewhoknewthestorycouldforeseeSocrates brain.Hisrabbitsactuallydiedofparalysisofthemusclesof drinkingthepoisoncheerfullyandarisingtowalkaboutuntil respiration. hefeltaheavinessinhislegs.Theywouldrememberhowhe 28 The Pharos/Spring2011 Jacques-Louis David (French, 1748-1825), The Death of Socrates, 1887, oil on canvas, 51 x 77¼ in. The Metropolitan Museum of Art, Catharine Lorillard Wolfe Collection, Wolfe Fund, 1932(31.45). Image © The Metropolitan Museum of Art. layonhisbackasthechillofdeathtraveledupwardtoward DidPlatoTelltheTruth?In:TheTrialandExecutionofSocrates: his abdomen, and how he spoke his last words, “Crito, we SourcesandControversies.BrickhouseTC,SmithND,editors.New oweacocktoAsclepius.Payit,anddonotneglectit.”Aftera York:OxfordPress;2002:255–76. whilehemovedabit.Thenhiseyesbecamefixed.Critoclosed 3. GiesekeAL.ÜberdiewirksamePrincipdesSchierlings,Co- hiseyesandmouth.“Suchwastheend,”saidPhaedo,“ofour niummaculatum.ArchPharm1827;20:97–111.