[PAGE 1]
Aa 0JI Study on the

SAIGE01C. EOTOAL STSEPCCANOB (OF LISERGIC ACSO DESTZYINUDC (MED-25)

: NÓTICE

Thís pobüeatics has beea prepared in Cta/Si as an ald to lntellgr dee ansiyss an v2h the subject ratter preaented. leview Las been mlnimized-in créer on o: Gea paforaation.

30 Augaust 1555

CENTRAL INTELLIGENCE AGENCY

OFGCE OF SCIENTIFIC INTELGENCE

[PAGE 2]
STRATEGIC NEPICAL SIGRFICAHCE OF LYSERGIC ACID DIETAYLANIDE (ISP-25)

Distributicn Limited to:

iií

[PAGE 3]
PRETACE

Vp to this this. there tas been no evaluation of the cicnifleancu ef eurrent knoaledre ebout )yrercie aeid dietglanide, called LSb-25, end related drugs. Kuoalçdze or the vneonventioral, as vell as dha therapeutic uae to vhieh this vost vacncal drug migàs te put, both offensively as zell as dofensively, is of considerable strategte sirnificance. The brcad odjsctive of this study, therefore, is to revicv, aralyze, and evaluate bicchenical-and phanrncological research on LSb-25 and other poyehogonic árugs.

Avrendix y. the Clobal Availcbility of Ergot, the natural scuree of lysrrgic acid, indicetes the areas of its grovth, both naturally and, by caltivation; the approzirsto cnouots obtainable frcn eash coratry isvgiven for relativa cczparison of Soviot Rlce pnd Vestern capabilitiss to proîuce ergot end its derivasives.

A partial list of scze kno:m rescarch installetions and versoncel currently ergageá in ressareh on ergot and ergot alkaloids is sttacitod as appendi: C. It shovs the videspread interest in these products, ans the geographical distribution of this vork. It is coneeivable that they represont poteutial prodvcors of the chozical substance, LSD-25. At prosent, tho only kacm foroigo source, of LSb-25 is Sandoz, Ltd., Switzerland.

In the U.S. the total syuthesis of lyseraic acid ves ecccrplished in Septerber l95h by Eli Lilly, Research Laboratories, Insianapolis.

Fornl research of this ptugy vas elosed l Pebruary 1955, hovover any pertinent. insorzation recçiyed up. to. the. date, of publisation. has becn inclxded.

[PAGE 4]
COENTS

43.1

[PAGE 5]
Trade in Ergot and Eegol. Altaloids..... 40
Possibility of stockpiling Ergét... 4.9

APPRIDIX C.--Tustallaticns and Persons Associated vith Recearch on Ergot... 50

APPEDTX D.-Clossary of Scientifie Ters............. 57

: TABLES

I. Alkaloids of Ergot.. 8
II. Honspocific Cozpounds Found in Rrgo 13
Ii.. Peptide-like, partially Synthstic. Derivatives of Lyserzic Acie, Isclysergic Acid, and Dihydrolysergic Acid.... 21
IV. Hiuimunn Aetien Valve of Cerobral Agents in luran Therapy...... 23 V.. Coxparative Effeets of LSD-25 and Nescaline.. 2

FICURES

1. Lafe Cyéle of Ergot, Souree of Igsergie Acià.. 5556 2. Effect of LSD-25 on Eandriting.
3. Bfect of LSD-25 on Praving Dosts.
h. The Effect o2 LSD-25 on the Euan Eectreencophalograph.
5. Effcetof LSD-25 o2 the Blcctrceorticograph.or the
Rabbit... 65

6. lhe Rorsctach Eest fcr the Erccet of LSD-25 on the Mind......... 65

- viii

[PAGE 6]
7. Effeet o LSn-25 on Uhe Blgod Aárenadino level.

8. Mental. enl Ruseulne Disoréer Resulting fren-Large

9. Effects of LS and LSD-25 on the lovements of the

10. The Effect of LSD-25 on a Spider'sWeavire Ability.......

Follovia

[PAGE 7]
PROMM

To deteraino the strategie udical. nicaificance of lyscrçie esi
diethylasice (isn-a5) throvgh a reviov èrd en cvaluation of sko cozs
biochenical esl piraracological research cs this psychogeuic crus.. 【

CORCLUSIONS

2. LSD-2"15 the rost potent psychochosical ecent available ts the prepent tize. Trace qeantitiss of Lod-25 create norisus Leatai confusioa of tho ranie cad szbizopkrenic,tpe sná rcnder the mied tomporarily cusseptible touggestion.

yot insvfriczont dsta to ccniirs or dany its uscfuluass for alicitir "trte and cccurets statamsuts, froz sudjects upder its jutluence.

3. Becavse LSD-25 is colorless, oáorloss snd tasteless, it coui: possibly be usod cleudestipely for the contasination cf zcoà ard water althovgh tzs data on its stability in solution are conrlictiss.

4. Since the effoct of this érug is ter the fatal rorve egeots, thore are its use,i2.certais ópore

5. Although no Cefinito conolusions can be drava as to the diaguostic nnd therepeutie valre of LD-25, it -Cces cppeer to bava the potentinl or beiug a valuzble idjunct ia tha troatasnt er ceriais Eental discases. lathylone blue cnd puouothiaziss Carivativco, Auçluding chlcrprcrasize, eppaar roth to rodify cud inhibis Lch-25 psychosis. Tho gatza isomer of zeratranalsospoas to blcck the psychie effects-of L3n-25.

6. or the othar kmowa psychogenie drugs, rzrealino producas reactions that are tho zost sinilar to thoso of LsD-a5.

7. Sufficiently Cetailod daperiptiots of tho rethodo of ptttrat: of both lysergic neia and LD3-25 cre aveilable in the oçen litorature : make possible its production by an intoreoted country. Purthor, tho

2

[PAGE 8]
Eothonl or preparatioe, except that of syathesis, dozs uot appear to be extrczely ecapke.

8. Although no Soviet eata ere availeblo os JSb-25, it rast be assured that tho seioutirts of thé usa cre thoroeghly cogaisrnt of tho strategis imporzares ol this povorãul drug aud oro capable of protucirg it nt ary tine.

piscussIoN

LSD-25, tho giethyleuide derivative of lyscrçic acia (frca ergot), is a relatively rev chemcal. egent vhich effccts tho humau rind. To date, osly very small quantitzes c2 LsD-25 have been prepared. Hore vidaspread use o LSD-25 cez nov bo expected as it has recently been syathesizod.

Data ou the stability of ISD-25 in solution are at varianoe with oue another. Publisted mothees of preparatica, in Coneral, do not indictte the conditions unéer vhieh the solution was yrepered or stored. Consistent resuits vill. capens, other thiogs being cqual, on the edoptioa of iacstical procedvres. Thís has apparently not boen considored by all vorkers.

Rescarch on the physicochezical end toxicolcgical properties as vell es the rochaviex of ectics of LSD-25 cortainiy varrants further considoratioz, insszvch as little is actually knova.

Thare coss not szes to te cood agreoxent as to the dosage to be used for clinieal trials, Further investigatica would unteubtcdly estáblish nore cecurately the linitias dosagas for racimus therapeutic efficieney.

.A relation seens to exist emoes sueh érugs as LsD-25, bulbocapaine, mascnline, hashish, and etropine. Additional rosoarch is necessary to determive vhether the rclation is duo to a similcrity in tho reohanisu of acticn or to pcns coplotely nov physiolcgieal efrcot not previcusly considered.

To date little vork has boen reported on tha ccnbiled use of ISp-25 vith othor érugo. Rescareh in this araa Micht indicate the substances Whiel, vhon adainistered prior to or ccncvrrently vith LED-25'or other poychogenic drugs, Higat carance, Nodizy, or diuieins tsi effcets.

Roletively little has bacn publiched on the thoravoutic use of LSp-25 for xental disordors or cveu as a diagnostic aid for thoár elnscificatioa.

[PAGE 9]
Data on tvo derivatives of LsD-25 have been publishoa. A. mathos seareh for other derivatives nicht bo very fruitful.

I LSD-25 is to he used rore exteusively in the futurve, 2 reliable counternçons rust be daveloped. At present phenocarbital and a bronine derivative or LsD-25 ara only slightly esricacicus fer this purpcsa. Eovever, prorising results hava been reported with mothyleno blue aud chlorprczasine, but thoy vill have to be verifiad. The acninistrutien ef the gza-iscner of raratran, "Frerquel," repert blocks the psychic erfects of LSD-25 vhen civen orally as a premedication. lo ore patient iniravocous injection abruptly torainatas the effects ol LSD-25.

Sinee minute quzntities of LSD-25 are effective, a repis nicrebiological or niercchenical mathod of detcction should be cevelorad. At prosunt neither is available, although vory linited rathods e detection asj icantificaticn arc lnosn, sueh as fluoresecuce, staining vith ninnyarin and spectrcpkotozetry.

3

[PAGE 10]
SULTTUY

lile ergot poisonizg has been knoun for mny husdreds of years, the paront substanco, lycergie seià, froa which all erzot éerivatives are rade, was isolatnd only 20 years ago. Teo diethylaside derivative of lysertic ecid (LsD-25), a potertul psyehogeuic érug, uas first prepared in l9h3 by Eandoz, Lèd., Suitrerland, and vas fully deseribed in a Sauzoz patdnt euplication in lghh. Othor derivatives or ergot (lysercic acić) have teon syathesized which possess sympathicolytic and oxytocic prepertios.

Iysergic acid eiothylanide (LsD-25), a partially synthetic dorivative of lysergic acis vhich is ostained iron extractions of ergot, is prodcced both sy straight syathesis and by reacting the asices of d- or dl-lysergic or isolysergic acid vith diethylanine. The production and more exteusive use of iSD-25 ean nov be expected since the total syuthesis has boen acccplished. Other derivatives of lysergic ecia heve been prepared by reaction vith azino acids, dipeptides, and tripeptides.

The use of ISD-25 is relatively safe because of the wide margin of safoty betveen an erfective and a lethal dose. In goneral, LSD-25. is adainistered erally to hurans, elshcvgh in anirals it is usually administered subcutajcously or intravenously. The norl cose is l: garma" por kilogran of veiges; hovever, it is active in a total cose as small es lo gara. Froz stuñies carrica ous on anirals, the lethal intravenous cose yas ceterzined. to be 65 milligrars or 65,c00 gaa per kilogran og weight, and the lathal subeutaneous cose vas 205 villigrans or 285,00o saa per kiloa or, veiact. Dy extrapolatins the datn, on rinals to homnps, the lochsl cose: is 50 percent of human cases is calculate6 to no h;550,0c0 gaa or 4,550 nilligraes. Antidotes 2or ISD-25 have receptly hean sugcstod in the for of inhibitors. such as metlylone blue, chlorpreaazise, and "Frençuel" (gaza icozsr of zeratran).

ISD-25 usualiy procuces physiological clangós in the centrnl nervous systen, blood piessure, diceneivs systen, liver, respiration, vrogenital systen, terperature, salivary, ceerotion, lachrynal secretion, cyes, blood picture, and dlced susar, It also intorreres with cartohydrate metabolisui hovever, thore crsoots can-be pertially counteracted by barbituratés. and by inpravonous injection of clucose.

APPEIDE A

#1 cca = 1 micregran.00l nilligran

[PAGE 11]
LSb-25 exerts a uterotonie effect in rabbits andi iahflit. the actioo of the so called "valtaiuz nlee." Esbs voven by spiders uae the iaflveacs of the drus are ncre symsretrical than those produsea by norral spidere.

LSb-25 dees not produce a uaiforn psyehic reaction but tuo nain types are distinguirhabie, the sehisophnrenic tnd the Lanie. The synptças produced by isp-25 are exprossioas o ceute exegetic psyahc. analogous to those prodecet ty aleohol, cccaine, hashish, monealine, and the enphetunines. The characteristic signs observed in ISD-25 intoxieation pre: chznges in thiskius and speoch ans, disturtamees of bohaviór. Coneral syeptens reported are: clanges in emotion, nood, effeet; subjeetive feelings; norbid idens and sensory exporier end disturbancos of porception. LSD-25 creates a cosdition c eir sehisophrenis, cnd it is hoped that a solution to this foru of zzutal diseuso ray be dovelcyed sines soze indications exist that tho kmnn organisn pey proiuee toxius sizilar to LSD-25 vhich ray actually Lo t cause of reutal diseascs.

In nost cases of dzorossion so fer studied, LSD-25 doss act nee to have a sicaificant theropeutic-adventage over other árugs. Hisete it did appsar to de valuable as an adjuvant in a eertain nuzter c cases. The disaivantages or using LSn-25 are that it inoreasos an already prosent anxiety, anorexia, terdency tovards aremia, and inscr Like all intoxicants, it discloses pethological tendencies, whieh pernit coajocture of the nazrer in vhich a, person my becczo psyehoti:

LSD-25 aias psychiatry dy feoilitating the contact apprszch tr pationt and physicien. As a therapeutic shock agent, it prcduces ros: similer ta. other types- of: shock Lethods.

Other. drugs vhich night bo operationally used and which yredvee reactions somowhat sinilar to those of ISD-25 are scopolamine, scii amytal, pertitin, sktedron,-atropine, bulbocapniñe, ená-rescaline. Kescaline: is. by far the closest in actica to LSD-25.

Mescaline and LSD-25 produce the saze psychic phenemena alikou they varyin ths quality of their efzects, and rescaline must te adninistered in larger amounts.

Historical Acccut er Erget and LSD-25

Ergot, vtich has been knoun to countloss civilisatiens, esnssr the dried sclerctiun of Claviceps purpurea-vhich infoets cereal rost. freqtently developiug cn ts imlcrescence of rye plants. Kothers vho have borefited curing. chilabirt effcrts producad by the alkaloidal coostitutents of trgat pe the greatest approciation for the developzont and-gevth or this fungus selerotins. Eut to the ron and woron vho in earlier tizes fron "ergot discase," as tho resvlt of eating-ergotizod cereal. criiao

[PAGE 12]
Ue word tas signilied pain end dath. Since Uhe Gth century, the ery "ergotirn" has eassed feer enì leas rtressed the nead for proeautious in gatherieá grain erops. Parrers shose fielda have beeota infested vith fençes knot of the daruce it víll. cauze to erops. Taus, this drug fuugos during ile advert of mun'a uzo of plits for,food anà nodicino has played doth a userul and a destructive rolo.

Knowledçe concerning ergot mnd its rediciral virtuzs his rapidly accumlated sinee the carly 19th cantury. Frca 500 A.D. to 1600 A.D., accounts cr the sighisicanee of ergot and ergotized host plants vary cossiderably and are linited ia regard to ths early redicinal importstee of ergotised grains. Ergotized creins are reported to have been uzed ty the Chineze mihvirery at an early date and similarly by Arabian nedicine. Taere is also evicence among the recorás of the Noorish physician, Avicerna, which indicate that the fungus vas used redicinally during the l0th contury.

Tho greatest historical significance of ergot and ergotised grains up to the 2oth contury sas the disosse, ergotisu. Te dicease ves characterised by the dovelopzent of gangrene in the lines of the victin due to the cevere vascccnstricticn ans pressor acticus of the ergot alkaloids. Such ections vcula eventuzlly causc a nuzsness and shrinkage o2 the appendages, which finally separated and dropped off. According to the deseription ia the "Aunales Xantenses" of S57 A.D., "a great plague cr swollen blisters consurod the pecple by a loathsoms rot, so that their lirbs vere loosened and fell off before doath." This disease proved Patal to thousands during the enénzic end pancomia plaguos of Europo and Russis durins the l0:, llth, and l2th centurios vhan the peasant classes ingasted ergotised crains. The great ergot plagues of the midale asse, daich sere kndia as "Holy Fire," "St. Anthony's Fire, 11 and "So. lartial's Fire," cere all asscciated with ergotin s trains of ze. In additien, ergot coisonins plagued vhole populaticns in all parts of the vorld. 1/. 2/

It vas not until l93h that rescareh on ergot yiolded.the cavsative agent of the xental dorangomant. vaich invariabiy acconpanied ergot intoxication. Iysergic Acić was fouad to re that poztion or tho ergot alkaloics vhich is responsible for the pharrasological action en the nivd.

Hedical interest vas aroused vhen De. lofmanp of Sandos, Ltd., Switzerlana, sufsered psychie aisturbanees Vhile exqorireuting vith LsD-25. Arthur Stoll or Sandos, Lod., and his co-vorkers are respoasible for nost of tho knevledge of this porerul agent, as vell as for ito partial aynthesis. W. A. Stoll studied extensively its psychological effccts. 6/ 39/

.6

[PAGE 13]
Gources of tep-es

Ergot 1s'heearartly the sole soorze of raterial. fres vhteh lb-2; 1s provmed. All the elkaloiés. o2 crcet contain cithar lyrarrie aic or isolyoetnio aeld es the srineital énd charasteriotle eososiivtont er the uoleculo. Tha tahaloiós or the ergotaziae and ergotezire greuça are polvapstidas, the lvserele or faotycerçlc acad cegant deirç joíred to etrr énnso neics. c8/ s5/ Tho alkaloíds of the ergozovino Eroup are tatceo,, the lyacrgie aeid teivg joiaad to en aiuo aleolol.

Thoae frons cezsrise 12 alaloiés shiah aro reçarded as 6 paira of optieal isczrs. In adiitlop, ergot costaies an uasually larãa nuder of pharcasoiyzanically cetive substances.

The reccet vork of xosszar (o/end Stoll 35/ yoizts out that tho ergot anloids soa to classiriad rirst into two Lecad grovps ruely, poptice cnd aréda ecspouzis or lysorgis aeid. A socond clessificatica Splioates the exastenze of three otter carsçories hased on pharazolozie: activity. They are callzd (ho crcotaate (Groop I), ths erzoreyies (Groop I), ard the ctgosorise (Groop J). Is Table 1, the chouianl ecrpositiocs or the l2 dcozerio ergot alkaloids end the Tesponsiblo invcotigators ero pointod out. In Crovy l, tho difference tsiuees tho 2 alkaloidr is dse to the presosce of ooly l tino asid, eitzer l-phenylslazize or l-ieueits. Te scparatios of Ceoep I fzem Gro I is tassd co tho presonce of pyruvis cois in the forzer avd direthyipymris eeid an the latter. Rovever, tho eiiferonce bateon the 3 alialoics vithis Grouy I is aue to the exolusive, presonce er 1 o2 3 enino ceids, l-ptsvylalavaze,.l-valiss.or l-leueice. Finslly, Group all asirert tren Grops I and Il in that tho lyscrzio aoad is cczoinad vith é-czanopropszot to for as aniss derivative rathir thap c peptide coazound.ss in the fiist tro groups., Goly ore ceme pound ás kzo to exast ia Geog Ji. (See Sable l). i

The Tirst rertçvi of caah of the atove psirs ceaurs ergot and is as aide of of each pair is an anzde ca are not idcatisal 27 nirror iñsges cr cash comi ataticn ef coth rezber J3 óce alkaloids of evgoo are éerived, is usuelly rouzd to posscss coly atoat 1 perccns op tke activity of tho rirst, its sacurally cscurring

Iu additice, ergot contains variovs primry anlics, espcainlly histraine, sscuglssina, end tyrosine, as vell as ths quatererry dares, choline end acetylcholise. It is vot ouupaisios, thererore, thas tho

7

[PAGE 14]
A. Fepties Alkaloids of Ergot

\- Ergosristire " Iysergic Acid • l-phenylalavine ) (C35H39051is)

Prcsucis of Fyérolyois e\* Not yat introduccá into lodicine

TAULI. Altelcids o? Eecot

1 fungas vith ell ito rell-ccntredictory drugs has becn en Iutriguing mterial for pharracole,teal receareh. 1

8

[PAGE 15]
n. kealde Alkeloics of Ergot

Croun Jir - Loccsovine Coumerr

Yo (forula). Chenical CermositicrEs

Prgonorive = Lysergic Acid • d-cninopropanol ) (019=2332-3)

Ergosorinine: itolysorgic Acid  d-eainoproperol) (C19H23023)

«x» Knon in Eziena ás Frgozetrine end in Suitzerlard as Ergobasite xx.Proáucto.of Syarolycis

Chonical Prcparation asd Frcoerties of Iysrrsic Asid and Ien-25

Since the parczt coxpound of all the ergot cospounds is lyscngic or isolysorgio acid,. tha preparetion of IsD-25 is depandont Apon the availability of lysergie acid, a snebouad wich ccss not occur raturally. Jecoss nnd Graia,. 5/ woskias vith the dearedatios peodhots of crsot, 2irst prepared lysergic asia in l93e by the rsstion or ergotibine (srgosrissine) and nethyl alsoholis potassiun mydroxide. The alschol vas removad by yecuua distallation. The residue vas tresied vith adelsional potasaius hydroxids asd letted os a dford tsth, dorirg wch tra à stroei or pitroges Geo vas paosed throozh ths flssk. After ccollns, the naterisl Nas acidifiod Lad considorasle zaterial crystallized cut. This suspeusios vas extraoted wiih cther and the reralaing aqueous suspoesion filtored. Ehe riltzate was evaporated to eryness uocer redured Posoure. To pemove, celored havritdes, the resiáus vaa digested brisrly with a Ssall qucutity of rethyl alcchol. After cooliue, the vsatssoived crystais vere collested. Tao yield vas £6 rersent. Uades uliravaolet rays, lysergie aoid has a dsstist blse fluerescence. l03

Lysergic aeid, bast erystellized froa vater, eppanrs as slightly colored, vary thin hezasesal learlets vaich contuia ose molg, of vator of erystallization. In resetion, it is smohoterie, that io, it behaves like an acid suvá also a base. It is solubic in soàiua asd potassiuz

TABLE I -- Cont Inued

Discoveroy DUMIEY and KOM IJIAVASCE LECNUIT EIOLL avá BURCRIRT TOMPEN (1)

[PAGE 16]
hydrozkce, collua cz:lonate end hydveche:la ecid. In rast of the naukr.l ortnie solvcats, it is cpariaz)y solubie, hat in pyriálne it is quite rolublc.

Jycergie aeid etetlylaside, 1c9-25, prapéred in 1043 by Stoll cnd Nofrana, é/ is a partially syuthztio éerivntivo cotsined ty reseting the asides og à-. er dl-lysrrgic or icolyeergic aeid vith diettyiezine. In ordar to obtain tho forar, sepsrutioa is cffected Ly a chrcuatographie celrra. This rothod o preperation.9/ is ceseribed in Pateat No. 579,4Sh iosueù to Candos Co., Ltd. o2 fasel, Soicsorland. Hovever, in thisppatent no zenticn is raée of the rzthod of proparation of lysergie tcid, the parent zterial of Lob-25. Like the navural alkaleiés c2 ergot, their chier ccmponent, lyscrgic tuid, is also a sensitive suhstaree. Spocial, nild mathoás ione thereforo necessery in order to cosvare lyserzie ecid into e derivative suitablo for chanical reacticns; such a éerivative vas fcud to to the ezics ce Jysergie acid. Tho strreture o2 lysergie acid vas elucidated in l933 by A. Stoll, and the steces involved in the preparaticn or LsD-25, accoréirg to Rothlin, h0/ere listed belov.

10

[PAGE 17]
Aceordin; to theze forzalen, tha folocius tromings À ateei my te recognieed in the Ipergte oeid iolceulea: an lucote crotes (rire s A aaa B), " maphthalere syaten (rlaga A and C), and a quinolite syatea (riags C énd D).

Previoos attcepts at tho blosynthosis et crgot in Stoll's laboratery in Switserlrnd vere uucuseessrul. 3/ The hiosynthesis is, hosever, eurrontly leing cttersted ,in East Cerrany ia the lstoratory of Prer. De. K. Nothas cad R. Silcer or tho Yesourch Iastiiute for Caltivoted plants, Germa Aeadery of Eeiences, Catersleren, do Vast Cenauy by Rocheleoyer, I 23/ 1n Trepee by kadaze Vialazd 1ca/ and in Japan by Ab. 82/

The total crgezic syathesis of lysorgls aaid, iuelvding tho ácuble bond in ring n, remained vuazeoslistsà until Oecoben 195h 67/. This first total syottcsis was zcported ty the Lilly Rascareh Laboraporios, Indianapolis, Izdiaza. Soe of the steps iovolved in the synthesis of lysergie asid ere as follovs:

11

[PAGE 18]
Lsp-25 is tdorloss, colorlocs, aud tastolesa. The tartrate salt is readily soluble in cater and decoxposes at 2o degrees ceutigraãe. In stroog aquoous solatiod it is fairly stable. 5/ 23/ For oral yse the solutica shcula ta pde up aná'storeà in a dark class bottle and uot used teyoad the third éay after preparation. loo/

Reccnt rescareh: ll7/ bas shoun that lysergie acid reacts with pdinethyl-aninctgusalaShyde in an acid rediva. Wien an oxident, such as hyárogen peroziãa or forrie chloride is adzed, a blue color is Cormed. This renction is ccnsicered usoful for the quantitative detormnination of ergot alkaloids.

Derivatives of Ergot and LSD-25

5ho hydrolytie products of polypoptide alkaloids of ergot vere found to ccntain lysergic acid, succiuic acid, anino acids, and amonia. The close relationship of the reptide serront o the nolcculo to tho anino acids end the ketonie acić vas roadily, resogaizad by research vorkors of the Sandoz, Ltd. Thus, the total synthosis cf. ergot alkaloids has beccre "a possibility. As a rasult or this research, peptido-liko derivatives of LSD-25 vere proparod by partial synthosis through tho transformatiod of 6 ariuo acids, including tryptophane, 2 di- and 2 tripeptices, all of vhich ere knoum as normal links ip the retabolisz of nan.

Ergotanine, originally telieved,to be'a theoretical copound vhich did not exist in pure state, vas actually disccyared by Stoll in 19l8. 22/ Ergotanino. tartrate is the rost ixportant c2 the ergotanine salts. It is rolatively stable and çuite readily sclvblo is vater. It is also knou as Cnergen, and is cne cocponent of thewoll-kuoa proparatinn bellergall.. It is officially recegnized in theipharacopoéias of both Switzcrlznd-aud the United States.

As. far as the treatmazt :of certaia types of migraire and vasomotor headache is concerned, Krayenbuhl l9/ pointes out that thoro can bo so doubt that ergot preparabicns - errctsmino tartrate, "dihydrcergotanire, aud cafergot (a cozbination cr angotaains und-catfeire)- eliuiuate the pain phase of-the ettack ty inereasins vascular temus and reducing the anplitude of pulsations. Io a stuéy en a lprge nunser or pationts, it yas shoun that prolenged oral treatzent vith dibydrcorgotanine-Sandos or. vith hydergine exerted e, favcrahle. effect onnigraine aad vascnoter headcches,

The drus hydorgine, tecauseof its efficacy in the trehtmont o peripheral vascular diseases, ineludins-troneh foot and frostbite, nighs be very useful in Aretic cperaticss, A stoskpile of this drus vould te ixportant for husen protection. 21/ Eydergine ccutains tho

12

[PAGE 19]
retnuzsuhiaetes of afhgütecvgoeeunite, dibydrezrgoeriatdre and dilydroaraekrtino in cuat parts. Theae Uace sebssanees are obtained by tha partial hyárvreration of the cetrespoeding natvrai ellalotés of cgot ead vara sirat prerared by Etoll. aed Rofzanu áu 19h3 in tho Saudoa Rescarch Latorátories. 32/

Recent vork has tzan cencueted on the syapathicolytic and oztoeio proparties ef syashetic, derivatives of ergot. 22/

In tho psareh for the troe active prinoisles ef ergot, various investigators curing the sovrse or tho past 50 years hava isolated fren the drug a jane nuter ef cezscuaáa, dezssatrating iyreosively tho pover of sytkesis vhieh ray be poasessed by a fongus sueh as Claviocos porourea. ln scsitien to the speeifie ergot alralciss, ethar Isveressing ecapcueds are roued is crgot. Rothlis h/.csmiled a list of Lonapooific cozpsuèds vhich is presestes as Table 1. In contzast to the ergot alkalolds, hovever, these cospcusds are uoiquitously distributed in nature.

TADLE I

Honspeoifie Cimdounds Found in Ergot

Tyranice Clavize Histanite Tyrosine Agratine (deita-Guaniöyl-butylanine) Histidino Putresciue Pryptopbeve Cadaverire Ergothioroine Isoarylegile Prgotiuic aciá Trimsthylcnite Ergosisrin (Ercosterol) Choline Vitamip D. Betaine

5 The kaovloögs of the shsziaal stvstoreof the ergot altaloids vbish accooliszed by Stoll cnd covorkers, has boer gaired as a tesult it possible to attampt Uhle end Jacotà aod others. In jsis tzd dei egradatica has aloo r ystheres wase for tha scplave tyat 1953-54, Vale cczpleteà 12 c2 the 12 As ináiaatcd esrlsor, is steps vhieh le couszderad nezessary Soptaner 195h Kondelá aeà other staifvor U23 cf laboratordes,
lyeeraie aoid eaa tre ercet aioie Laborator Indianspolis, Ind. vork verd Galversi Weodvard ef the Converas Nurotial
'synthosos are of creat siga canee hs ramufasture ofethe knows, nuturally cecurriss active yrinsiplcs aoa closely relateddarivativas.

.13.

[PAGE 20]
Banthzses tae also dasired for tho preparntio) of ecepeands, vhteh eay postfbly te ctrentr ás ation, less tasily d.toctatle, ara loager Jasting in effeet than lSo-£5, for sastance, pná yáich nápit elso open the hiná Lo the pover or' sagsestionto a cegtce never hitherto dreered posoible. In vicw o tizce pessibliities, the stretegie uzo of suth synthetie cczpounds is self-evident.

Recout vork on tho preparation of partially synthetic dorivatives of lycergie ceid had led vo cezpounés vhich already boar a cloce reseuiblcnce to the datvral elkaloids of crgot, havius a peptico-liko ctrusture. Teble Hl, a list or the derivatives cr lysergic acid vhich have co fer leon prepared, irdicates the great varicty of possibilities for preparing rev ccrpounds.

TADLE III

Peptide-like. Partially Smthotie Derivativos\* of Ixserrie Acid Isolyserris Asid ena hiaydrelvaetgae Aeis

Freperèà by Reastion With

Peptice-like Partially Synthetic Derivatives

amino zoido.

L-alavise
L-lcvcine
a-muinotutyric acid
Lephopylalasine
L-tryptcphane
L-histidine

l. Iysorgic écia:

2. Isolysergic qcid:

glyeyl-clyeine zlyeyl-L-levaine . L-seryl-L-lsucine

diglyeyl-6-yeino J-seryl-L-icueyl-Dproliuo

«jno-eczacunás. dasozábad by Rothlio-havo toco terzad "partially
cynthetic" becsuse thoy-havo beop obtzinsd by chezical- reastioas-with
Jysergic ecid vhich vas derived zrcz natural alkaloids of evgot, 5

24

[PAGE 21]
A synthzsls of 3-sulctitried quiaolthrs vas doveloped by Ule nad Jacots. hh/ This work has tde possible the eynthesis or a derivative called diiydro-dl-lysergic ecid.

Mheeler und ottors h5/ réported Uo syithesis of four nov inaole derivatives vhich have cürtain structures vhich are olco contsinod iu lysergie acid. Hovever, attempts to prepare substituted cside derivatives by various rothods vere unsucccssful.

Lysergic peid moncathylmido, á derivative called LA3 has heen rentioned by Rbthlin ara Cerletti. 58/ Lov doses (0.5-0.75 =3) of LAE produce, according to Solns lo5y, a schizcphreuie-like conditicn in nornl people and a sedative-like eficct in schizophrenics.

As of l953, it vas reperted that Sandoz Ltd. was ectively searehing tor an anticote for LSD-25 Ooe copouni, a Bros-LSD-£5, is availabla, which scors to check the action of LSD-£5 in the "valtzing mice." As en antidote in ran, its erfeet is unknoum. 2/

Fischer 107/ attezpted to prevent an LSD-caused psychosis by previous acninistration cf a competitive inhibitcr. Scitable compcunds vere found in the phenothiazino series: rethylene blue, l-(2-dicthylauinen-propyl)-phenothiazine, 3-chloro-l0-(-3-dizethylazinopropyi) phenothiacine, and B-diethylanirccthyi-N-phenothiazize vhich display gradually inereasing affinity for vool protein as vell as nodify and inhibit the psyohotic expsrience otherwiss caused by LSD. Prelininary experiments sugsest that a Gradual inerease in affinity for vool of a compouad might be asscciated vith a more complete inhibition or the experirental psychosis. Tness inhibitors also displsy.e gradually increasing.adrenolytic action.

Most recently Fabirg l20/ observed thet the ama isozer or reratran, when, siven orally as a preredication, blocked the psychic etsact: due to LSD-25. Bhen aceinistercd ictravenously, it atsoptly torinated the psvchotic reactions due to LSD-25.

Pharmcolczical Ersects of ISn-25

Effects of ISD-25 on Han. -- Althcugh the fornela for lysorgic aeid vas estarlished in lsju aud tne substanee vas preparod in the sone yeer, LSD-25. was. nct diseovered until 1943. It vas Hofmann 22/ vho, vhiie vorking yith the cnice cerivative of lyscrsie acid, -encerienced tae psychogcnic errects of the drug. He felt that it vás pacossary to leave his work because of dizziness and markcd umrest. At houe ho fell into a state o2 dicagreeable intoxication vhich lnsted for hours, during vhich he expericcced visual hallucinatious. In erder to vorify

15

[PAGE 22]
the effect, Hoftrun leter cualloved C30 cm, e quartity thay considared too tral). to bo cffcetive. acter ho rtaates vegeiatise erdas toponred, aud a violent daliricus paychosis daveloped. lie discontimued raking notus in the latoratory rocord took beeaudo ho could no lon;xr cive seasihle ansvers. A pbysieian lad to to surzoned. Six hours laíer there ves a cpontanoous uproveront, and efter a uight of slcep, the chomiot felt ecapletely vell again, althongh still tired.

Studies with 1SD-25 vore carried cut by Forrerend Goldrer 13/ in an effort to clavsy tho physiologieal aud poychic rosponses attensant on aosinistratico of this drus is sohizophonie pationts. Tho Crug produced a slight increase in blosù pressure, slicht inereaso in pulse rate, no cssontial chaogo in resniratzoa, increase in salivation and lacrivatiou. dilstion of the pupils, increase in daep reflexes, end alich. ataxia. · Oral adzinistration predused pupillary dilation of Earked'cogree, vhereas tepizal eéninistration preduoed very slight dilatiou. The totsl vhite blooi coll couut was inereassd during the ties of nction of the druz. Urinary coustitutonts, the nooprotein nitrogon level, the clectroencephalcgren, cophalin-cholestorol flceculaticn, vaight, and terperature vore not effocted by the adsinistratiou of this drvg ln dsses up to 6 carza per kilogren. Io viow of these data LSD-25 Ecems to bo.a suiteblo substance for further therapeutic investigation or the psychoses.

DaShon and others investigated the effeet of LSl-25 on the cerebrocpiral and eutonomic rervous systens. .17/ Dysarthvia, vhich occurred in five experircuts, ccnsisted or a transiant stuzbling over vords and vas never msked. Isvoluatary sniling, sizslios, and lavghing vore céssicored in the rature cr "risus sadonieus" vhese the pubject Soscribed these phonczssa as oseurrins without or egainst his vill. Ono subject stated, for cxaple, thzt, in a soile, he felt as if his faciel muscles vere liko plsstic war tetus roved by soze inexorable forceEquilibretory icscoielsation, subjoetively -exporievsod cy scne subjcets, covld naver cbjootively do ascertsineê. Disturbasees in tosts of haudsritins, raading, 8ois, statica, pupils, nonoqkilibratcry coordisaticn, deep tendou reflezes, abd Eusele-pover in thd aras vore rot observed. . Ths autonrsie nirvous cysten cppeared to bo rore affected thaa tho cerebrospinal. Fluchizs, sacatins, shivering and chills vith goose-piples oesurred mny tires. Taehypusa, salivation, pellor, sighing, end vrgeney of nicturition vore seattored oboorvatiqds. Chances in polse vote bed a Tise do both syotolée ard diaotolic blooi prcssure or l0-2d millimtors of morcury obourred in l bour and 30 ninutes arter aéninistration of lSD-25. Striking changes in handvriting vere also recorded. 54/

26

[PAGE 23]
Other effects of LSn-25 on the boJy are lieted as folloum:

CARDiovApcuLa Srsjii - mlqod pressure slightly inareares, vithin the phgsiolàgteal. liits, or not rodicied; leas froqyeutly it ves clighely daereased. Iwo pattents doveloyed prtfcund sireulatory depressien. liasrt rats iucrcased in soue, decreased in 'others, not podificd in, cne case.

DIGESTIVE SYSTEH - Anorexiaj sonetixs naucea with occasicaal voniting; alto isolated cases of lycorexia.

HEPATIC FUTCTIorS - Oaly slight changes were observed. Kevever, subjocts in vhoa cven slight Louification of hepatic function is preren such as tho protracted seguelne of infectious hepatitis, have a vory marked respouse to LSD-25.

RESPRRATIOii - Usually not changed, although occasicnally deeper and slover.

URIlT StSTE- lo changes in ccnposition of urire. Diuresis sometines-increases. In isolated cases retenticn of urino follcved by polyuria was present when the erfects of LSD-25 had vorn off.

REPROPJOTIVE SYTEM - Uterive ereps in isolated cases.

TEPiTURE - No change;. io xeeptionel cases, it ineroesed 17.

SALIVARY SECRETION - Often increased.

… SWEAT SECRSSICn- Often increased.

LACHRYIAL SECRETION-Sonetines inérèasel

EYEs - Generally dilatation of the pupils; scmotime irmairment of the reaction to. light; rydriasis less prosounced when LSD-25 is instilied into the ccnjunctival sac.

MLOOD PICTURE - Tenporary inorease in the total vhite coll found vithout modisicatiop in the differeutial count or rolative ;neutrophilia. Slizht increaso in potassiun blood valves but no chango in calciw blocd levels. Some teniency tovarós ancnia appeared durins prolonged treatment.

BIOOD SUGAR - Slighs rise vithin physiological lisits; less froquently a fell;. slignt transitory ineroase in the glicose and hexose monophosphate bleod levels; othervise, carbohydrate cetabolian not affceted.

…

17

[PAGE 24]
Accordin: to Wthl 5/, th: septees espezieaced by 32 subjects vere wydrianis, uauron, aftor-eifects, aerosyancsss, elecpleacams, leadache, fatiguo and other paina, lacinrytritien, suellinc, iuereaseá pulse rate, und sniivary secretiou in tte deseetding order of occurrenee.

Mectreoneeyhalopraphic studiés yere perñorezed by Gastaut and others 61/ on 12 noreal, subjeeia who hed taken a single oral dose o2 h0-60 gatza of LSD-25. In theso studies it was fonnd that the alpha rhyUls vas increased by 0.5 to 4.O.cyelos per szcoad. In half of the cases thz central tuta rhrytiu vas inisiated, or if already present, uas accentuated. Stinulation ty raaps of a flickering light caused an inereese in occipital potentials in seven cuses. Other vorkers have reported sinilar findirgs. 101/

Efects of ISD-25 oc Aninls. -- In certain respects LSD-25 resemblos ergonvvine. It exarts a uteroconze cffcct on the ratbit, vhich in situ is 70 percent that of ergenovine. In contrast to the alkaloids of .the ergotonine and ergonovine groups LSD-25 exerts no edrenosytpathicolytic effect. 27/

However, LSD-25 roy be clearly éistinguished fron all mentinned ergot alkaloids so Tar invostigated in other respects. The injection, of small coses of LSD-25 into the anesthetized rabhit produces motor excitatiou. In tho dos the first appareni effects of LSD-25 are of a vegetative (sympathetic) nature, e.g., copious salivation, vithout any sigaificant change in affective behavior. High doses of LSD-25, like bulbocapnine, cause motor rigidity in uan, dog aud cat, a condition reninisceut of a catatonic state. In the nornal nouse, LSD-25 has a vaak exéitatory action which eprcars cnly at subtoxio levels.Mice vith an heroditary anoualy, the so-callod "valtzing nico," are nore sensisive to this èrug. 59/, 105/

Kayer-Cross et al. llo/studied the efcects. of IsD-25 on the retatolion o isolated brain and liver. tissus of guinea pigs. As a result, it was concluded that Lsn-25 exerted e sparing efsect ou the hexosenonephosphata tetetolisn vhieh is, greater.in brain than in liver tissue, at the sare tire stimaletiog the respiration c the train. It vould therefore seen justifiablo to relate ths psychological aotion of the drus to these effects ou retabolisa. Norever, in in vivo exporirents no such relatipnship between psychelogienl and rotabolie cienges was noted.

[PAGE 25]
Th valtainr vith thr slate,

r’erte of toth LSb-25 and L (yaargie aetd roasthylla ) . ree have teen studteà. 53/ Iastead of sedatioa as aypaa) of hédergize, there vs an irerease in the ceneval. eseltet: uith simraltanecys suppressjon of tha valtzing rovement.

carotld tracing: dosac ar 600 there w to the c'

of ho garas per kilograa injected intravenovslg or into the tery of a rabbit cansed marked or corplete flatlening of tha Llie: electrocorticororma. The effeet vas clear-cut crer after l as l8-20 gama per kilegrean after massive doses (30- frtr kilograc), the effeet vas idontical. In eddition, imuttaneous marked roter hyperexeitability 27/ 23/ l05/due ct of this LSD-25.

LSI prevent the berr cortica' acid, J' effect game F In anin

à inlibitod the spentaneous rhythais activity. It did not remponso to eleetrical stinolation, tho cpileptic spikes, or of rapid spikes proäveed by the barbiturates, or by cumx. Of the vasocilator substances investigates, nicotinis uniue, hexozathcaius, priscol, and alcohol dis not medisy the D-.5. Acetyleholine, riven intravencusly, in dcsas of 2o-lo .tlcgran, caused ths reappenresee of bursts of tasal rithn. exporireuts LSD-25 is usually adzinistored intravenously. 23/

LSt systen to drue instiva the wee influer effcct - differc spidorr. ful in influer.

5 har also beon tested for its effecàs on the contral. nervous syldors. 16/ 57/ It was found that nommliy spidors exoses Tecting their central rervous systons lose soze of their ahility. This was particularly noticeable in tha aase c s of spicor vebs. The vobs voven by spiñers uder the sueh druzs are asyumetrical and slcppily construetad. Ths sD-5 on the instinet behavior of spicors is, hovever, coite it was discovored that inder the inluence of this árus, adle to veave vebs vhich are rore srzatrical and rora bezvt w Way than the vecs they are able to veave while under the any other érugs.

spidert LSD-25. systen voven veb pa: trace c howeve:

reeent verk, 53/ supplemented by photegraphs of vobs veven ly ler the inrluezce cf cafeire, chlcral hydrete, porvitin and arly shows -the effocts of theso drugs on the contral nervous te spider. It vas felt that beeavse of the charneteristio ilavs ueder ths inrlvance of certain specisic drugo; theve-may bo esed to ičeutily ths presonce of miuate aui evan cins of unknon árugs. Ona disadvansase or this techsiçue that it appears te vork only curing the swrer months. 57

Antion of ISD-25 wrgh chenical and phannacological. investigations of the

19

[PAGE 26]
ercot altaloide vhtch bve tscn cnrled cut dueinz tbe iast 3o yecra have revcated jntrestia relationhivs texep chraieal saveture aud pharzacoloice). actioa. It has ios been estsblished ho/ that (he Puuderental ceuce of tis aatioo reciczs in tìs d-lyaerzie ceid pat of ths rolecul?. Ga ths citer lnd, otrer ecustitutents or the noleeulo which ere cocplel vith lyaerzle eeid cre respcasible for tre - differentietion in the pharmacological actioa.

The netion of tho ergot, elkaloids is inflvenced to a very larce extent ty "éhs deuble beud in the D-ring" of lyzergic ezid which is assrmed to to id tho 9, l0 yosition. I this boad is saturated by eatalytie hyarcgenaticn, all the ratural ergot alkalolss lcsc their uterotonis effect.

Now great the isflvenco of saturating the doutle bord iu ring D can be, ray be illvstrated by reans of the follovizs exarple. Ergotrainc is a powerful aytorie, ehoracterizsd by a voy strcsg ená protrastod constrictory action; but n cases vhere cxcessiva utorine tonus is liablo to hirder the somsal prozress of parturition, it is able to brivg about relsxatico o2 the uzerus or to restore tro nozzol tono. As e rocult of the hyéregenatico of the natural alkaloics of the polypaptide type, thore is nov a ecnsicorable prospect that e paber ofirportant ciscasos, such as hypertonsion, perinhsral. vasoular disordzrs, epd avgina peotoris, vhich vere formsrly outside tho field of indieations of the crget alkaloids, nay te trcated suacessfully vith the dilydro Corivatives. So fer the only alkaloids vhich have ntteined therapeutic importance are those éerived fron D-dihydrolyserçic 35/eeia.

It bas been -noted that barbitviates aêninistered to patients under the influsuce. of ISp-25 abolish tho psyshie effcsts of Whe latter érug. It ks vell-knova that the tarbituratos cot initially cr subaortical structures.. Eo cite- of. actica of Len-25 is pot hadza. It is beliovéd.: 13/that the crug nots prizariiy en tho cortex' to. proñuce a doprcssion, and-ihere is ahundant evidonod to. tuscost this, that is, inercased'cccp. rerlczes, dilatioi o the puils, salivatfos, cupboria, and izeresseù aecessibility. Ore nighe think o2 tho ofzects ef LsD-25 as baiug évo to e reloaso or- tho lowor canters fros tortieal. control.. It voald hold, then, that auy dvg vhioh cspressos tho subsortical dosters wauld, by blockiug the subcortical relezce cffcctively, nallity the paychis cction of LsD-25. Chis vould te furtker evidense for and surzort of tho presqat. belicp that LSp-25 iu the ezounts veeá. asts prirsraly oo tho cortex, that. tho. nourolbgisal cyptczs foilcviag acninistratiou are dirootly attributable to this cortieel effcat, nud that the psychie phenozeue vitnasced under its influonco are tho result of soheprtical discharges no loager fall under full ccntrol of the cortex. -

20

[PAGE 27]
Kayer-Grosa and cthers 51/ joivted out that the ticarndoss cativity of Lon-i5 sa zests that the iucesiaasive ay prers nlght te cavsed ly ca anti-enryatic seissitva cn tio cercbeal. celivlar muelenien. Shace glueose ás vorally re, zréed as tre roát Leportant ted perhapa the only subatireo rcgutred ty thé erve celis, is saereà logtal to enalyze the iurluecze of tho drvg es haaa cardoiydaite mtabolioa. Tentyfou perons vere g1ven 0.04 to 0.07 milligzazs 02 Esp-25. 0a tha folloving day, veder tia, seso conáitions, control experirants vere mnêo on 19 persoas, 15 or vhcz vere idantical with thcse who had alzeady reccived 150-25.

Avalyses of bleod saroles indicated that the bexece roncphospkate values and the earbonyátate velues inzreased in those svojeets vho hid .. been civea LoD-és. A plsvsisle expismatios, whinh tecars at onco epparest, vas that the carhohyórate motebolies vas inrcrroged in the presenze or LSp-25 and sould pot pass toyond ths hexose nonophosphato otoge. If ihe thecry is aécpted that L8d-25 biosks the dooorpositio? of the hexost popophospbate, end furthexzore ir this blocking astien is held respousibio for the psyshid spotoss, thon the direst iutake "of cerbohyérates, vaioh ean to vtilized vavkout detour via the haxose monophorphs.e stage, shcuió iafluazce the oliuleal pisturo of the iutozication. Althovd ths authors, Kayer-Gross et al., could noz arrive at evsh defiuite couclvsions tecauss of ths lack of sufzicisrt éate, sit vas, neverthaless, eviéest that tho spapteratoleey (cqtisal iliusions, alienation o peréspticn. lask of cozcestraticn pover, cuphoria, etc.) was nodified erd yartly discppeated aiter the Aatravesous náninistration of a 33-percezt gluzosa solution.

.Since previous. researeh had showo that ISD-25. irterfored vith the carbohydrate retebolisn and there resulted -an inorcased coneentration of hexoss Lonophosphite, Mayer-Gross aa/ etterpted to soive the tinopayahologieal srptoks aod thc biointeusity rolaticnshio chenical chancas Sinee schszophenio patients are koovo to havo a Results shoved that, alihough the psyeholcslsal effecvs vere minimal, there yaa. an inerosse in tlooi hexcte vonopbesphate. Tais averaze increase ves l.h6 rilligsas per l0o niiliters or slcod. Vador control conditions there was a rees fall of l.l7 nilligress psr 10o nillilitors of blood.

Asong a grorp of sohizoid patielts yodergoins trvatzent vith LSo 85, tvo vere dlabeties vho Rad to te trassierred to the medicel servieo delore the traatzont vas coslete. eo/Coriously, their insulin xeguiroments vere lovered tezporarily after, vaking the Lsp-25. Although the roaping and validity or this obsorvazion aro as yet vszartain, it seeas evlcert that LSD-25 does interfere vith the carbohydrate mstavoliou.

t 2

[PAGE 28]
In vlev of Ue sarzed statlertty tateen the poyohologicsl spptens of Me5 and reocalive, e perallel sorues of caperk ents on the influence of moseeline oa te hleel ch-sistry ws cnrrted oat on 9 rornal céulto. Turec-tenths or a fiert ef mrscalisy hycozhlorice vas acsiisteied intre oseulerly. Asalvecs wre rase for chvsott, hekote renophorphate, allali raserve, Destis ccid, pyzuvie neld, iuorganis phosphate, total acid celuble phospeate, lizotd phcerkate, adenosins triphetphate. No sicoiricant varistione eoula Lo detected iu auy of. ihcse cnalyses. reehanisn ef vesealine is epparontly different freu that or LSb-25.

d-l-Vothylaphattre hvârozhloriee (rotheörine) in coses of h0 to 6o millgezo enà l3o-ã5 ta éoses of 4o to (o gaz vere given by intravenous isjectica vo petitats surfering iren various Eantol cisorders and their clinizal ani Lioshenical eifests studied. Sl/Aftor an iuitial phase or reloxatico toth drves produccd an cggravarion er the clanical pisturo; vhile dcprsssive pationts tecare poco retarded and depresced, or nore agltated, schizcphrenic patiests shoved sigis o: increased vithdrawel and tessiós and an coceatuaiion of catstonis asé cetaloptis fcatures. Abzeetion frecusntly oscurred, ccpeoially iu psychoscurotic pationts.

Repid mood cvirgs were soratines observed eiter the injecticn of ISD-25. Nothedrine did pot vroduce this effeot, but it rore veadily pro- 1 voked hellucivctions in schisophrezia patiants.

The bioshenicel studies inçiaated that the effects ef toth drass on the plzsza sárevalite level vere similar. Thrce pheses could by distipgoisked aftar tho ivtecticzs: an initial rize of the acreralin. level, a.drop teloy the storting level, and finally a secondary rise. Individuel ceses reinly dirrered in thé speed vith vhish thaso phases followsd cach. other. Somotizes, atd espesially,efter the. injectica of LSp-25, the aärersline level évareased tozore the initialrise could be obseryod.. When, however,. LSD-25 vas given by.routh,. he initialineroase ef tha adrenalize coarestration wan clecrly evideut

A noñorate inerense of the blood svgar ccncontration sosetimss folloted the iciesticn or nasthedrine, but the offcots of LSp-25 on the blood sugar concentratiou -ere harály sigaifisant.

Because LsD-25 iutexicatien is rarked by danersonalizatiov and vegetctive' syaptcas. it propably arfests ths piá-rraiy eud the innerbrain. The intorication,se ecsordsree vith Sroll's concept, ds- likely a di- or zosenceptslosis. It is still vacertais, hovever, hor extonsive the efrest of LsD-25 is; hou many, i2 aoy, peripheral-or central netabolie precesses are raleased: and hov ray iutenediary tosde corpoveds ray bo cevolopod in the aatval relcase of cxternally visible symptoas. 5h/

[PAGE 29]
Aecoeu to told api lsít n5/, he Isp effezt in tho viee czoe of Ats eyrntertolery reczotes tit ef dclrina treraao, althovgh ta de(pte in vach toie ponouzced in the latter.

Toxie Iffeets of ISD-65

Accordinz to a Polash source, ch/ research in the Uaán inöleeted tht the hran ergasit ean assontlote es mch as o.15 pevtnt of erçot iu flour. In anirci czverients the use cr ergot rerultod in cangrene; the cers, hooves, teeth, 'and hair vere arfested. or all animals, cattle vere affcotedfihe worst.

It is a krova fast that the lydrolytte prosusts of tho crçotanines consiso of the Lntatolically isportont sursrasccs like pumsonia,. sucoinie Lozd, sad tho euao aszds ard vhat lysergis aoid-lske substasecs ray clso ts picpared mvon phyoiologizai zitcbolis substanass. 39/ Fion thdso fects the azalogy can te órava thst tro hozsn orzanisa raght bo ablo to rors tezins sisilsr 2n ratvze to L52-f5, vhásh ihen Dight teeae active in peptids censinations. Theso in turo piçat then be transromed by the diteosed organicn taro biologiaally aetive toxies. Thare are some indieations that soeh lesg-suspeated tot higherto vodected seçondaiy toxins nighe ts iäentisal with lsd-25 or svtstanses closely reletad to it. Veriftcatica of such an bypotheais is coatiogeus vpes tho Gevelopreut of precice rothoãs for the.detectios of these tozins.

In order to givo soze insicatios of the nimuto qvantitites of ISD-25 vhich are reçuzres to ariluezse the huan rird, Tablo 4 is presented.

Ninom Aation Valves of Cershsal Acents in Haian Dasaoy

23

[PAGE 30]
Hatofi, hé/ 1a teportinz his tarsonal ezyoriences during Lsn-25 intozicatioa Cia snteequent istentetion by pncalire, pointed cat Uat Uhe phgeiological etrees or toth drugs is shdar, In teir payehetogie effeet thay differ; lsp-2) producas an hebepharenie-type reaction and metcaline, a catatonic-lkke states

Fishor and othors 32/ mado e eomparativo stuày of the effeets of ISD-25 and coscaline frce the stanágoints of poychopatholozy and physiopatholesr. They confirzed previovs obcorvations of Hormna and Stoll that LsD-25 preduens sehisophrenia-like dictureancns, bearing particularly on,afrect, percopticn, and thought. The coxparative toxicolcgy of Lsp-25 auid zescaline, tosted in fcur subzects, shoved that azim dses of 130  o LsD-25 and 0.5  of mascelino offected the aeze psychic phonorera. Hovever, cortain qualitative dirferonces listed ia Taole V vere also noted.

TABLE V

Comparetive Effects of ISD-25 and lescalire

Pavchic Phencrenn Produced

Effect of LSD-25.

Miyporic acid test slightly disturbednore disturtad Cinnanic acid test positiyes pesitive\*

«Also posivive in cases of schizcyhrenia

Tho psychophysiologichl and pbysiopatholcgieal differences botueen LSD-25 eud kescalino could possibly be due to the smzller ancunts of LSD-25 admivistered. LSD-25 dces, hovever, appear 100 tizs sore toxic

[PAGE 31]
than nosea) tne, vhen tested coupar.tively, usin; the lervae ef Xencote. levia Peaan. Ia harms, Lsu-2p is 2oco times rore rotrat Shaa rasredi: Retabolie rubstonces, ir actunily prosent daring cchinopiaronia, mauzt te eloser nkin to meucaline thay to L2D-25. Tus, LsD-25 irits a special consiéeratien as a perehotic, not rastricted rerely to tho psyehopetholozical phencazra observed in Lsp-25 Entozicatioa, dut beyend this in cougectiea with a whole serios of nov questicns and probleus in the entire cesoral field of psyehopbysical ccrrelations and in the special field ef schisoghrenia. If tha current vorking hypothesis is eccepted, morely, that tho relecse o qcute schizophrenic "crive" stenôs in e tize relatioa vith enáogerous retabolic disturbancss and presuanbly vith the ceereticn of toxic ratabolic substances - then the possibility of ths existence of such substances rust bo investigated, using both physicchenieal and biological methoás.

Anderson ct al 113/ adninistered fro 60 to 600 gaa of LSD-25 orelly to 4 porzal volusteers and 19 psyehictris patients. One rale patient vith psyehogenie arnesia vas given 6o0 garn LSD-25 vhich cavcpć a very labile state vith the nood fiuctuating betreen agressive euphoris and egitated depressicn, transient auditory hallccinations, bsdy imge disturbanco aná tine discréer. It vas concluded that over a certain minimal dose there is no clcar reletionship tetveen the clinical picture and the axount of LSD-25 takon.

Blickenstorfer 39/ suonrized the follcving obsarvatious of Buscaino loh/ and cthers in conuection vith LSD-25 intcxication: (1) schizophrenies possuss greater resistones to the crus and have taken up to S0o gara; (2) related belier in the texic eticloy or sehisophrenia and inclusios of LSD-25 vith -other so-called schizophrenic substeness such as atrepine, búlbceaphine, and meséaline; (3) records the conclusica that -LSD-25 ictoxicstion is an.espesislly suitasle psychosis nodel of schisophrenis as it produces, in ccntrest to rescaline, hecephrenic phenozena;-(k) the tao.fundarental disturbarces thich. cohtrol the paychotie syndrozo dre nffaet and intontional sphere: (5) ISD-25. nds beon tested as ran aid to psychotkeraw: (6) because of ths tolerance to Lso,25, it might be one of Easy tharapsusie egents in shoek theripy: (7) LSp-25 and histanine my possibly te antagonistic asents; (8) epileptic persons could clcarly differentiste LSD-25 hallucinaticns fren ccmon haliucinations; (9) reported the results of Rorschach ená other tosts or patients unãor the inflvorce of LSU-25; (20) spidors, undor the effccvs or uiuste traces of LSD-25, vepve nsts of zost unusual strvcture.

Fron studies carried out ou aniicals, seientists have deterzined that LSD-25 is an extremely safs and relativély ncntoxie subotance. Ths lethal iutravonous, dose vas é5 milligrans per kilograu aid' the lethal

5

[PAGE 32]
sukeutaneous dore ws a35 anlligraers per kilegren in lshorata., animnls. By catrapolatin: Uheee dtea to haens, a procecure cpen to qusetion, the lstil. dos. in 50 petcont of the nases is calealatud to Lo 4,550,03) Ea. As ueosparisón, ietueen 70 and 31o carz are recarded as effcetive, althrug it las been reoorted thas éco gema have leen civen to a sehisoçhrenie. Uaing 50 caza as a ninimr efrective dose, this is only l/90,Co o2 the hethal doce. Uagoctionsdly, this is àn waazing sproad tetveen tho cifective and the lethal dose.

The first vorkers to curry cut restarch vare siuck by the analogy betvean the iutoxicatiss prodveed by Lsd-25 and mazcalive celiriua, although the cetivd ácces o2 these tuo products áre quite diflerent; LSD-25 is 2000 tros rore cfcctive than she mescaline on a veight basis. 2i/ An analogous relatiouship has tsen fovod vhen comparing the toxicity ef the tvo suostunses is colá-bicoded anirzls. Thc lcthal dosc of rascalino iu tadpoles is l0o to lcco tines greater than that or LSD-25.

In additios, rescaline prosuces irportant changes in hepatic function dezonstrabie by tho usual laboratory tests, vhereas, LSn-25 produces a mach slighter chapge vhich is made evidant only by an ultresepsitive test.

Psychophysiolcgical Effycts of LSD-25

As far as syatozic effects are ccncerned, both noral and psychopathic subjeats respend in alzost the ssne manuor to LsD-25 and ray,. therefore, te consicored as one group. Eovever, this is not the case vith the Eeutal cffects; therofore, nomal and psychopathic patients have to be considered separately in this respeet.

Uo to the presont, LSD-25 has usually been acainistered orally, gencrally in the nornins en an empty storach. It is tctive in coses as small as 10 Cora. (ceu saa voulé cequpy no sore coace than tra point or a pin) A dose cr ho. to ico garra is active in nozt cases. Doses as high as éoo gams have been velr-toleratei. by psyehopathie patients. In ceneral, peychopathic patients shov greater resistance to the systenic and mntal eifects than do norral subjeets.

The first effects of an ective cose of LSD-25 generally appoar vithin one-half hour vith a raxim dolay in tho onset ef three hours. Naximn eifecsiveness is reached on an averace after 2 hours, and the effects porsist fren 3 to 6 hours. Dalayed errects zay be cbsorved for 1 or nore Gays but rarely for more than-l veck.

The symptons produced by LSD-25 have beon considered by K,A. Stoll as expresnions of aeute exogonic psyehosis, analogcus to those proãuced.

- 26 -

[PAGE 33]
by aleohol. opia, cocaive, hshich, mercnline, and dho myietaalues. These latter substaces ae, hotever, osly aetive in the higer dozee

There is no uniãorn reaetion to LSp-25. To main types of reactions ray, hovever, be dłstingisihed:- (1) Hanie, expansive ressticn vith poyekcaotor exeltezent, cuphoria and less frequently égpression; (2) A sel:izcshrenie reaction vith slozing o2 rentaì processes, inhibitious; cuticn, ecversonalizatiou and hallucinations.

Tho ujority of dubjects presont e mixture of these extrene types. Tho nasic resenze to tho action of lsD-25 is balieved to bo due to its offoct ou tho sphere o intoution, cud the schizophronic reaction to the nction on the sphere o arrect.

In goneral, LSb-?5 teuda to reizforce pre-oxisting tendoncies, producing a carisature of the subjeat; the cyelothyeic pationt orten bacozzs cuphoric while sho sehizoid besozes a true sohizephrero. Tus, LSD-25 reveals latont tescsneies, and its efrect my bo consicered, to a ccrtain deree, as a personalicy test. Fast expericnce kas showe thct LSD-25 prcluses such an ovorvielmiug erosicual and intellsstural uohoaval in the indiviçeal that ary cacri-ents vith this substance rvss be very rigidly ccutrolled. Ouce in e Sviss mantal hospital, e preetical 'joker spcoked a fev framulós of LSD-25 ioto a staff nurre's cofiee. Tae 1 frentic cirl, apparently driveu to believe that sho had bacczs schizophrenic, leaped to her death fron the hospital rocitop. 18/

DeShon, 17/ Rinkel, 47/ Pesker, h0/end othors have éescribod in sumary articles the rantal chenges exserimensally procuced by LsD-?5 which vas eéministered. 17 tires to 15 noral adult volunteero. The érus
vas aministered orally in doses racging froa 20.to 90 cara(in. zost
casos, oneca per kilparéa of bodv veicht) in adovt one-half of a
. glass of water at 0S30. hours op the day of the experiront, the sudject
havina cdtoa no íood siuçe tee previoos evenivg. The rzin obesrvaticcs throvghcut the. cerirent werson the clinical psychistrio pisture.
eRoutire peurological and ciroulatory systen cxarinasieno vore nou done, ;but signa oocurrieg in these areas vere poted if ohserved..

. Results of these investigatiors are presented in the six followisg categories:

SURJnorIvE SnpTOs - Taese syaptors were procent in all cubjeets. They vore usvally tho first to aypear, lastuno frca 15. ciuates arter adainistration of the IsD-25 vatil bodtize. Tho most ccron suujeotive syspicn vas a deerense in eppotite. Freçuent corplaints vere heaciraas, igiddinoss, faiutness, and tremlousncss ant shakiag. À stass of pcor

27

[PAGE 34]
coordiratten, viich could not lz cecerteleod obketivelż, vaa fiequent. Rezt fn luciéavce uue sabjcetive teeltara of vorcas and ratigse; chillhrecs tud coólcess or the vole or part er tlo vody; fallness, lueo, cad "Sury raoliugs" in the absasan; nécaonces of the vhole or part of tke body; headache; varzthz ligruess; drovsiness; pausea; and stiffncsc.

CHNGES I TLTC AD SPEECH - These stezs vere Tound in all of the experitants. The most frocuent type of disturhanee was difficulty ia tho pover of expresoion aud coneontratiou. Hext thare occurred rotaréatiqs, press of idins, hositascy and indacision, blocking, ond imsairant or ébstraet thinking. less frecverely observed vero poverty o thorght, lecssness and disconraetion, end aistractibility. Thoso chassrs in thirking cnd caceh cpreared vithin 45 ytnutes efter aùniuistraticn o2 the LSn-25 aadlzsted into the leteaftornoou.

CHANCES E EOTION, !COD, AD ATFECT - Tse alteratioUs, .vhich vere presont in all of the cxperizonts, eppeared froa 15 micutes after the adninistration of the LSD-25 ustil evasing. Clear cut bluntivg of affect and suspicioosnass were the rost ccson syrptcns in this eatogory. Tensica tnd tiprebousioa, as vell as colings or usreality vith disturbasces in body irsses, vere noted in the injovity of cbservatioss. Ruphoria vith a shsllov elation and silliness vere orten seon as-vere depressios, conbized vith depoudoney, inccdision, insccurity, passivity, 1 and fcclings of being "lost." Rostility asé reseuizsnt vere observed in pon instarces and, on rare oocasicns, abivslence and intonsilied feclings of reality end Creater understanding vore noted.

DISFURBANES CF PRCPTIOi - Thase disturbances vere eccTon; thoso of visual peraeption predozinated. Iudividuals vould seo rippling, or movepants of objcets, or the cpjeats vould vary in sizo and, shapa. Colerdistuztanees were comon, such as ceeing yellos, oranre, or pink colors vhero there vere nono. Disturbanaes or. Castavory and avditory perceptiou vere lecs Rregvont, tho hatter diaturbanses vere rainly in distinguishing the origin of a soupd - distant or near. Tire seuse vas disțorbed iv il of tho cxçorizonts end was characterizod by the fecling of tire boing either aceeloreted or rotarded. Tne phaacmsva appsared fros k0 nisutes to about 7 hours ciser the iogestion of the LSD-25.

DISTURES  SAVICR - Thse renistatiens vere sesn in 15 exgovimoato frcn £5 nisures arter tho cézinistration of ISD-25 vetil evening. Uscereevivity, vith lack of spontanoity and Suitistiva, waa most cozonly observed. Overactivity or iuapprcpriate bahavior vas rarely roted. Often bohavior was acsoointed vith psyohouotor sadifestations such as cnilivg, gisglins, and lavghing vhich seoned rore

23

[PAGE 35]
eppreprlate thoa irarptopriate. Agatcosivenoss, drematimatien, playfeluess, perplexlty, rnl necavivtsa o:turred caly o:easiouslly.

NOREID IEAS AUD SRSOXY EJFRETES - ThOse eXpOriCnCCE Ançluzed idecs er leicrcpea esd iévas ¿f iuflucnce. Faa vlsval hallucinaticas wera all forrsd inies, baut in oss suoject thase vero preceded by erude flastas er licht. Tree visual illusiors, viizh eryeared iu .many exearizerts, vere ef cozplcz visual ioterpretation vhich, houever, the suhjcet cid pot talirve; fer exple, secing a tharmostat oa tho vall as a erueifix, althouch really koyinn hat the caperieuce vas an illusioo. qhe one tuotas:e er avditory halluniseticas vas of tolls. Tvo instaneas of qustatory hallesanatioas vere of mtallic avá otrer "funy" tastes. Ore instesce ef haptic hallucinatisus vas a rather vivia experience in a tubject of his trousers boing vet Iroz vrine. The morbić idezs and cepsory avteriesee: apntared rost irequontly fra 1 kour and 30 ninutes after the acninistretion or LSp-25 at 0330 hours" in the roraisg to early afteraocn.

The cpurso of recstion to Isp-25 vas presented in thrce phasos vithin the first 12 to 16 hcurs, and a fourth ohase eppeared as an after-cficct. "Phase I, the prodrcrni phase, ropresented the psriod letueon the adainistraticu of tlo érvg and the lsicht of tho roaction. Te çfsocts were usvally subjective syzstos end covearcd frcn 20 nimutes to l hokr aud 30 niputes ettor ths Ls-25 had been aézinisrered. Phase Il rapresouted the height of the reastion or tho Eross cyoptcratis departure fros norzal. It lay wvithis a tizs span of 1 hour to over 5 hours arter the 'drug had been ingested. Phase IIl vas the pericd fren the haight of the reostion aotil evening. Tais phase vao dharasterizcé predanirately by :a reduzed eetivity, poverty of thought, flst affest, indirferonce, and a shallov feclisg toãe cerparable to a sirple schizophronio reaotics type. None of the 15 facividuals ého wąre subjesteü. to. IsD-25: had returned to normal vhep last soen by, the,auchors fata l50oheurs to 1900 hous on the day. of. the ęapopinnt. The cffests in-phass. II vere.not:neçassaralya contiuuation os thece ia phase iI. lose of ths phsss vas cleariy der rerccted, and their tizs lnits for a:given experizeot cculá be doterined only roughly end is retrospect.

Phase IV inaludsd the efter-offeets yhich lested fral ono to soveral days. It ves not seeu in all subjeots nor elosely observed in any of thes. Althouch all subjcets reoorted that they felt norzal.ths folloving mornivs, a fev vore rotçd to le more arbdued in behevior and speech, noze isdvsveicus, and perhaps nore insrospessiye for several. days folloving the experuunt. A striking observatios thooghout the day or the cxporizant vas tho appoarasee of signs coi spptczs in Aves. Lharo sytqtous vere o2 losg dvzation, cuch es áuliffcrereo and blustlog o? affect,

29

[PAGE 36]
there vere at lecat vave-llke alterations is thasy intinsity. The oubjeetive syapttar vere for tae most pert trauslensi although Cuey vere seattered phreughout the day of the erperixont, Uhere vas a tendoney for thar: to clussor at the begineieg and to a lesser enteat at tho end of péase II. In gouoral, there vás maah rore urizority or tho elinical poyehiatnio pisturo in phaso II then in phese It. la il experisbets, phase JI vas déeiseuly sahizoid, end in one experizant eacn, mnic-like and schizo-effcctive.

Katz l/ published his porsonal and subjectivo reactions efter taking LSD-25. Furtaor, dy ceseribirg his visual hallusimations at the tize or their ocourrezee, an artist vas chle to skotah and thon reproduco in vivia colors thoso bicarre fastisies er the buan nind vhich sean to be soxowheo ccmnooplaso to the sehisophrsnis. He stated that for hours he ishabited. a nichtzare vorld in vhich he cmporissoed the torzonts of holl and the ecstooies of hoaven. Since there are no vords in tho Baglish laaguage to copvey the sensztions, visicns, illusions, hallucinations, colors, pattorns and dirersicns vhioh his disordercd nind rovealed, he stated that he vill never be anle to deseribe aäequately vhat happaned during his excursicn into madnoss.

Ae voluntesred to teccre a temporary radran in the interests of meüical research on rental illnesses. This is ore phase of rescarch vhory sose of the Cainea pigs have to be hurans; aninals catrct daseribe their sensations. The montal conditioa produced by this drug closely roscztles acute schizophronia, the zost pravalent and rost sericus forn of nautal discase in Canada. It is reported that cne-halr of tho patiouts in sental hospitals suifer fros soze forn of this-torrible montal torture.

Iu 1952 Stoil 33/ susaitted 11 nornal edults to the Rorschich test, these -being uucer-tko isfluecce.or s0 garn or Lsn-25 and repeated it at a leter date vithout the LSD-25. A Rorschach syodrone vas procuced by the disinhibition of the thougnt procossess.vitbts dscrense of precinion and vealth of convent. Iu spito of the snall muster of ceses frch which to juógo, the changes do not soen to be accidontal sinco the relovant factors becote chssged in a correspondin sense ani leaa to a-logiuai conelusion. The clisical picture or IsD-25 intcxicsiion, ccrrosponáing to tho LSD-25 influonesi Rorsehach syoérore, is regarded as vnspeciiia and as an instance of the exogenous readtior type. Poth sypical payshoorganic traits occur as co others sugsostive cf sohicophrenia. Upon ropetiticu 02 the tast without ISD-25, siniiar acé ofton icantioal sesults wore orcsined. The test subjeote, hovever, oftes nenticned, upou repeating a response, trat vithout the LSD-25 this response woulà uot have cecurred to thes.

30

[PAGE 37]
Rit. etrorccris paitiy", a pev p.. hohzefe. pal prozesar. Slean cad nouns 11/ otseryi stgpiriceat chesps in trvar 1ea cawoeu The icsolts mdieaed inereed sutoncote lability ln ll heotihy centrer as voll ns in 12 patjents vith predozinout depressloa, but usnodiried funetsonirg in th: 7 schizughonics tcoted,

Therayautic Use of 10n-25

By artifically creaticg e conditica liko schisophronia, as in tho cace of Kate, l8/ irvostizators hope to find the enavers to a mrber cr hithorto bareling qustiozs. the psychtatrist veste to knov: Mhar does he sce? Ehat ,does he think? Hov éoes le think? Kow caa he bast le approachad by'a therepist? Anevers to suah questions are not easy to obtain fron tho chreais psychotic who las little or no iosight and is usually unecunieative. ire bzoshentst secks informatlou vhioh ray finally lead to a cure for sohizophrenie. lhat tozie substanéo is. presont in the poyehotie vhich is. abseut fron the body of tha noraal person? If this suzstance can te iasrtificd, then is is cozecivablc that a chczical ageus caa te crcated to coucteraet it. Thia could theoretioally lsad to the core of half of the rental patients.

Since it vas previously chova that LSD-25 vsually producod a eupboria in reutal paticats, a study vas rade E0/ on the affeet, cogaition, and exprassion of 5 "noral" patients and 15 depressed patienis. The "sorcal" pationts recoived a single orol dose or 20 gaza, asá tis depressed patients raceived batveen 20 and lco cim by nouth daily for a ronth. Fhysiolcgieal rezsticzs ivaluded rise in blosà prossure .and pulse rats, myóriosis, end isooordinatios; but in a fev esscs there vas a profound fall in blcod pressure and pulse rate. VUapleasant side eifects vere nausua, parcstheszes, and tensios. Neatal chanaas includpd cumhoria or éysphoria, cnd hallusinaticzs of cil uoéalitios. Icsas were trassmitted iato visual hallueisatioss of exvra-ordinary plastieity., lost patiants reactsd vith cuxzety to thsod distortloss in reality cud becarz cozatrieted. Irecuantly,tta dector-yatieut relationahip was faproved vish zreedea or erfoot but pos ecztest. Occasionally, the latezt content or the hallusinations was elisited by free associstioa. Or the 15 dspressed patiosis, 3 recováred to thets pre-psyehotio levol, h zecovered fron their dapressioa and vere soasidszed Anproved, 4 cerived no bensfis, and the treatzout of h was disscztinved prematurely.

Vithin the lizits of. this saaole, ISp-E5dces pot eppear te have:8 signiricant therapsutie advassase cver othisr drugs Sn cases or denression, alihovch it asnears to te valusble as an aöjuvant in a Juiser cf casss. It presents coze disaávanteges. Tho aaorexia it produses ay ceccntvate

31

[PAGE 38]
1 velght loga. teere is rocs tenderey for incata to mopea afté proloaged docage, aliicoph thus ray be refevable to lctuced food Lutcie. Insomnin is often eggrevated,

The porsibilities o yersonalsty cxploatioss through direet communieatics envicicned y Stoll. ze rot realized. Laile Lsb-5, was not of valuo it prautins irco verbal excksnçe, it is of potential use An perscnality eplorution ty the aalysis of the helluosmations vhich it produces; zor cxzple: ore patient reported a colorzul modieval pagent ead vado a sketeh of it. Ater tho crfcets of Ls-25 had vors sãf, tha sketeh wzo prerented to the patiost vho at iirst could nake notnins of it. On free ashosintion, the patiant brought up the idsn thit the wedieval figures vere reolly psychietrists, with vhea tho patient had been assoaiated. Oze rimre vas ¿rova vth an open coor íor a couth aud e tinãow for the ore sood eye. This psyehiatrist taled too rach and saw only halr of tho pationts' difszsulties. Another figue drewn slantviss or lozniag vas.acosidered a árenkerd. A third vas picturad as a knisht with a visor éravn cotl cpen end elosod. Assosiatioss to this draving svgrostéd that the psvehiatrist vas two-fcsed. A fourth arorcled figure vas in renlity a iozale, sucsesting that he was cffeninate. The rodioval sottinz vith its rich pezztry aná hapless figures suzzested the srbivalence and dissppointzant about psycho-tharepy. Tauu, neither the patisnt nor tha psyohintrist ves loft ia doubt es to the . patient's regative feelings vhich- kad previcusly gone uureccgnized. 1

By coptrast, projcetive tostins during LSD-25 intoxicztion vas lcss revcnlinz than that cone durins the rorzal vaking state. All patients showed rarked coestrieticn iu the Forn-Intorpretation tast. It vas ipforred thut ths patient etterpted to. compeneate tho orfocts of LO)-25 by an. incrensed effort at adjustmest.

These data eppear in keepizs vich Conerau's coscryation 12/ that po Gofinits cenelusicns can ba draim as to tho dlasnostic and thorapeutic value of LSD-25;

Bencdetti. 56/ adzinistored 2 sinzle 50 gana doses of cral LsD-25 vithin a span o2 2 nosrs to a pationt vith an alsoholie ballspofmoais. At the begiouins o2 the third hour an. ceute rsilisisatoris Psyshoass vas obsorved vhieh lested for four kours. Daring this psyohosis tvo teparate, but sioultanoously oecurrzag groups of peyehopathologienl phenozena vare obscrved. , The first isoludeã these cptisal snd spabial hallusizataozs, and the cecondvas-strongly atgcessive of tha-classical-aleohol kallusinosis, differiog culy in tho propoocerancs or cptical disturbausss.

Lsh-25 aids psyehiatey in ths followin5 manner: 39/lll/ it-is highly suitcd for the experinestal produstion of intoxicatiou dus to its

[PAGE 39]
simple tethod of epąlicatioo und lecause it proluçes  persrnal antagonian In the patient curiág latroductiea; (2) it posserses didnetive vale in self-exgerhsuts of the pigsiciae: (3) in peyetotherepy it faciltiates the coutzot appreach sith the patient; (4) as e therepeutio chock apent, it zppears, to give results sisilar to othar rothods. Interostingly, Uhe LSa-25 intcxicatien, aster an initial. mauia-liko suage, can ba shided as depressive catatcaic, Nebephrenie, or paranoid. Sueh shaézs or colerings depend, in cll. probability, lore upon perscnal dispcsition than upon direet astien of LSn-25, vhich, like rany other poiseus, can apparently cnly proeucs the unspecific syndroza of en acute exczaneus renstion tpe.. It is hardly suitable in the frareverk df sorml peyoholezy as a porsouality toss, in spite or tho many individval difrerences oceurring during intoxieation. LAke all intoxicarts it diseloses pathological tendescics. These, while not so importapt in evezyéay life, parnit cosjecture of the nanner. in vhich a person ray tecoe psychotic.

A chemical analysis of norzal cerebrospinal fluid has diselcsod the presonce of ll szinc aciês: conspicuous by its absence is the aniao acia tryptophane. Tryptcphans is. hozever, one of the constitutents of LSD-25. Iu practically all vosae, resulting in an exogenous reaetien type one cen expect ths follcving: (e) pathological decorposition of protein; (b) that the substances of prctein deccrposition ray enter tho cerohrospinal fluid; (o) that thuse substançes are protably closely related to the amino acid tryptophano vhich is a constiiutent of LSD-25. Tnis sinilarity tatveen trjptophace and IsD-25 ruy only be accidantal. However, it zay serve as an indicator that LsD-25may also cceur is human notabolisu. kether the hody retatolisn is capable of fomning suck a chemical substance usder certain circunstances canpot te theoretically decided.

Busch and others h3/ edsinistered LSD-25 to 29 patients vith verious type of rental discurtances.Trey expressed the belicf,thnt the érus inducos-e costrollable toxis state vithin the rervous syston vhith xe-activetes anxcioty and ferr vith appereutly just cpough cuphoris to Fermit reçall ef ths provokisg oxpertences. It doss this vithout the sluagishness of spsech dirfioulsins so frequensly encountered viih turytal. On the basis of this prelizinary irvestigatien, LSD-25 ray offer a eaus for nore readily gaining aocess to the chronidally witharava pavicuts. Further, it mey serve as a nev tool for shortening peyohotherapy.

The offects. os LsD-25 and rescaline vere studied in schizophreric patients by Hcch and cuhers L8/ It vas foind that psyéholegicnl ehances vere produced in these patients aud that their rental syuptomatolow vas

[PAGE 40]
carkedly ecaravated. The observatioas tade vith the chove-ceationed druge on norl iudividuls vere eapored vith thoss or cchisephreaie prtiente. lesenlino-and L5p-25 are drugs that dicergaaice the peyehie iate pration of a percou. This dicerzanisatiqs is rveh rore cpparent in sehisophenies than in tercals. The reasticus óf 59 sehizcçhranie paticats vho cere given synthetic rscaline sulrate vere classiried under the follaving headings: (1) physiolecical syrptors in tto autonenie, rotor, avd sensory epheres: (2) dizturtanees o pereeptuzl aetivity, (3) tzntal coutent, (h) encticnal elterations Anxiety inereare was the nost frequent erotionsl chonçe in schizcphronie patients unêer the inrluance cf tle drog lany papierts displeyeù hostility, and paranoid nanisestaticns vere very frequent.

Frederking 50/ employed both LSD-25. and mesealine in psychotharapy. In the ccurse cf carly cxperironts, he noticed that-tho state of intoxication, so prcduces, was meaningful and significant, its content beiug sinilar in charaeter to those of dreers. Esch poriod of intcxication trought-out particular characteristies of the person on thon the experirent vas condzcted. It ssezed to be an attenpt to present ani solre his Lxportent problors. Ths author obzerved that his patients. in thair -respective states of intoxicatics, as in thsir dreans, Cenerally prolucsà those coatouts that vere at the tize ripe for expression and fcr transforcation in tho direstion of a cure. In one particular case, a naò áccused ef isurder claimad that he had no recolieeticu of the deed. Vader the intoxication of 0.5 gran of mascaline and 75 game of LSD-25, the accused adnitted that he haá not conitted tho erirs but that "another one of hin" had done it. It vas concluded that although the accused had actually coaitted the surdor, it was dore vhile in a state of surcon-'sciousness, 2 fact considored earlier dy the author (Frederkits).

The rany phenorana svch as colored pictures and experienccs of bodily transfc olic in character, or reprosent childhood, SC

The inaications for e treaimsat or this zind must be strictly dorined, and particular cireurspection is indicatod vith vary ankicus patieuts suspected of schisophrenia. The physician must have subzitted to an intoxication lizselr to te able to realize its possible eifects. Ths effect of rescaline is stronger'and more overuhelning. lovever, LSD-25 is usually zore effeetive in bringing out remazibrances.

Delay, and others 11S/ recently showed that LSD-25 produced 2 Byndrores, in addition to other disturbances. The first vas the acute exocenous toxic symérene o Stoll; the second was described as the hypertrophy synêrcre of the exterior persoaality.

[PAGE 41]
Abrazen et nl. lt3/ have nccestly.crlisised sme of tha eaeiter reporto cs the cocets os le: dazes er Imne) co noecnal sobteta. found that foe a gives croup et Snliviécals suiteble evalcatico of respouzes to thia érog cculá not te rade vithsus the, tse of a xero dose ctatrol group. Tartkey, at tho tire vhen their dota wero corpiled Chere veie no investicasious In the literataro vatad justify tha couslusioss shat the syptecs ero sicaifiecstly related to lsd-s5 antaxieaticns. Cu the bacis or teats perrorend on 26 nopusyehocic, intallicant adults vho wire given Pren cne to three doses of LaD-25 (nero, 25-75 gana, and leo-2s cenin), end to vaon a questlonnaine investigating chauges in tha yhysiolosteal cnd perzeptual pharemona vas given ao hourly iutervals, the follovirz cooslusions vere érawo by tho authors.

l. Symptons sost sigoificastly related to the ingesticn of 50 Cams of the drvg ere (in order of dsercasias sigaificance): unateadiuens, drena-lite feelins, paresthesias, inuer treuolins, pressure in cars, difficulty in fccusing vision, veaksess, lightnees of liios, liys drava raek es ir sniling, éizsipess, drowaivess, sensitivity of skin, and peculiar feeling of lmuts. less sigaificaat, but protably relaced are: inoreased salivutico, inareased eppetite, eveating, cold, and fatigue.

2. Stptons nost sigsifieantly related to the ingestion of lco gas of the creg are (iu srdor or deerensing sigairisauce): thirga rovits asout subjects, unstendinens, paresthesias, weakmess, drean-like feelis, Mllness, nevsea, dissinsss, sensitivity cr skio, poculisr fcaliog er lirms, inner trembling, sweating, Ligatsess of lirts, blurred cyesicht, difisulty in Poousing visics, and objaets ssening too rar avay. Ths less sisnifioant tut prosably related syoptons aro: freling of choking, puubsoss of lips, csffisulty in breathizs, cola, pressure in cars, and altoration ofchepes and. colors.:

3. Teere ny be differences dn subjcotire sevevity and quallty of the ryzotos vhzoa are.cpoted yzéer doth tze 50- and 2oo ca cozes of the dtag. hovvor, several. syrptoes are. corzen to bovh she 5o- ead 100 -gaaa doses, but a Ceater deçree of rcsponse vas notad unéen sh hich dose. The sycptons sozson to both aro: foeling of illness, hoavitess of limbs, vausea, fuouy tast io mouth, objeots socmins too fer avey, sud anxicty.

4. For the tvo drug doses, there is a sigaificart correiatica of .83 betwcon ths relstive position of nyrptons, aeeoraing to fregvenzy : of positive response. :

2.7

[PAGE 42]
b. 52 esza muaásy e avtors, eu of h, custe bes, uder zero dee 2 ia ron 3; vaier 2-75 tt it is epproztátely 10; aud under N J-225 A it 1s cbeat D. S5e differerees croaa Uhe thrce crcuns tre all ct:tistictlly reliable at botter tlon the .Ol level of sicirlcauce.

6. The peok effect cndor zoro'dosoge occurs 1a tho firat. 1/2 hour, ond tht of the lov dos: occvrs 1 1/2 eud 2 1/2 toars arter tle drug. The peek toa the hizh dose cecurs 2 1/2 hoas aiter tho érug, and the effatt is louzer lascies than, for cithir cf the other cosages. These stotczants vore tased on grevy results aná individcal variability is not considsred borp.

7. The pècr of syntoas a subicet revorts uaéer a low dose correlaics .ço vith she turtor he rcports ucier tha high doce. Although the tverase meucer of syetcrs iseroases, he raineains his relative positicu vithin ths grorp. Theze is also n relatiovship as higà es .65 and .Go botveen subjects relativo position unéer zero aad vnder -low asd high cosos of LSD-25, respeetively. Tbis incicates a fcirly hich cegree of pradictability o the puzber o respoases cu tho basis of tho purbar o responses undor the plssobo.

8. The reliability of respcaces to.the qcesticnzaire has baen fouad high, Teat-rotest correlation as high as .77 vas cbtained-in cozpariug the tctal nuzbar of syztozs roported at tuò separate testings uodor 1 the saze dosage.

9. The puzicer cf svaotórs reported end the cubject's boêy voisht have been showa either to te usrelated or uot related in the cxpaeted direction.

[PAGE 43]
1ght a5 . ap 11va. duri: 1 Lelieved to heave teen jafzetei iy bread 1: typtal. Fhe hadnaeisatzoxs, tha cenes ater1a, pmd temporary r mtal teol sl raaztioss to crsot Cà

ISp-25 tms renorted vy leyl 5h/ to relax the nind ead to produze an inoreased eres to talk. Advastege of this fect can bo utilized both for therapeutic vscs and for creratiozal uses. Valuatle disolosure nay bo dotaised fren persoas ueder Lsd-i5 iutoxisaticn since the eblliiy to thisk is tot rarzealy ipaired. The process of disslplined, logicál abstrast thirkis, retained in alzost all cases of intoxicatios, coulá hovever, only te acecslished with cossidsrable affort.

It vas revorted by a Ruraarian scientist that to the bast of his kovlego (1gk azd carlier) razeo-analysis vos not enplcyed in excaination i thst coustry.lared-hyonosis ves sozetizes used for troatzant but never for exninatiou.al/

Prior to lorià lar J the police were not kuom to esloy aktedron to elieit conicssions fron prinosqra,. Fovever, judging by the zesvlis of tacatuonts or tosay, this covrce belioved that this drug was baing used, although ho hzs no dircot evidirze.

In talkins vith a Tonsarian police offioer cnd handveiting coperts who hod been employed durire tho early stogas of the cfiair-linürenty, tho sovrco coneluied that ihe Cardisal vas drussed. lis conñoaston vas induced by ths alicrzate uso of aktedron end ssopolrains, tho ferass specding uo shrsiclocical rcaosions cnd rho latter siowing then dow. The source rezorts havisg toard of this mothod being used. It vas estimatod that ie thzs proscdure vore carried os for four days, all o2

[PAGE 44]
ie Cardinl's intibltions vould Le cerpletely annihilated. Forther, : wevld lce no csncarn fer roral codes, ianily, or cthies.

2 Yon 20 March M53, Pr, Iare Zador, a nephaw ty varringe of Dr. leil, e Kaagriaa Hinister in knshington, was arrested for the iupropar use : the Civg evipen. Mhis y to a cluo to the origin or eharges that . Voil vas the mau vho arministered the Jrugs to Caráiual Nindzenty. ther Weil vas fstoken for his raphew or it could have beon that til vas at one tizs associated with Zaacr in truth sorun rescareliye Lated lruo

The systenatic use of drugs for the productioa of artificial tyehoses is vot nev, but rather datos froa tho early work of Kraopolin 1 l893, accordins to Nayer-Croos. h2 kxçarineats have been perforzed i which mescaline, hsshish, bulbocapaise, cccaine and sinilar chanical ibstanses prcduced eyeitatios of the central rervous systan and sher rosults which charceterized then as strategic Loaieal agents.

Mescaline is fourd in vide use es an intoxicant to prodvce ccstatic states for special religicus otcasioss among Red Inlian trires in loxico J and in lorth kzariea near the lexisan Border. The reseal buttcas chaved bv tha Irdisus vere icentifisd as parts o? a cactus plant. Early roports discloso that the érug vus renticsed in ths. cosoriytion or this part or Haxico by Sahagun early in ths l6th century and that the "prophotio" qeality of peyotl, ths nstive camne of ths prepared cactus, vas probably kouu to Astse rodicine before the ccsquest by Cortez.

The nctive ingredieut in peyotl vas stuäied in l8çß, and the forzula elucicated in l918. Kascaline is 3, 4, 5 - tripsthoxyphenylethylanine. It has the folloving strueture:

It chould be realized that ths outward bahavior of the subject acutely intoxisated with resealise is relatively norral. He nay he abscrbed in his exariences and vill talk cbout freely tut rapiorslly. Only if tha intoxicatios has beccze extrere may he lose control,of hiuself aud sink ixto a slecp-like stupor or dclirivn. ljashish, in coutrast,

[PAGE 45]
adüitfoa, it has teen suerected that inadeqrite detoxicalien of sirllar tubstaceo in ths ltver ray lead to thair ceevalatioa in ila bleed, causing rcatal. disorder. lence, the study el layatte functicu is Lpotaat in the etlologs of psyehiatrie diçeases.

In n reccnt publication luxley 55/ pointed cut the chose siilarity of tho chesical ccerositioa of zascstiae end adrenalin. Bubsequant , vork 1ncicsted thit LSp-25 had a structurel bioshonical.reletiouship to thesé ecmpousds. Tron cnep the diseovery that aérenoshrere, vhich is a product, ef ths éecespositica of aörenaline, ean. prcdnee rany of tho syrptons obsorved ib Tascaline sotoxicatics. Bot cárauoehren protably oecvrs speatenecusly in the huran bosy. In ctker vords, cach ons of us ray te capahle of manuiectorinz a chesical, mizute cesas of which are knovn to cause prosound changos in conscicusuess. Certaiy of theso chayzes ara cinílar to those vhich cccur in. sehiscphzonia; a plague o the Tvcotieth Cectury. Is tho mental disozdar due. to a. chezital disorder? And is the chenital. discrder due, in turn, to poychological distresses effecting the cdrenals?

7 The action of rossáline is to iuhibtt the productiou of ensyzes vhich
regulate the supply of clucose to the brain vhich is in consteat need of svgar. Vhen the norzal ratioa of surar is-reduced, the ability cr fuculty to résorter and think straixht is little afscsted; visual dapreèsions are prcatly inteosified; the vill suffers a profound change
for ths vorcej and, interest.ia spece is-dizuinished and-intercst-in tire fulls elzost.to zczo.

Tó' rost people, mesoalive is élnost- ccrslctely inuocucus. Unlike clgohel, .it does not drive the taker iato vainhibited actien. . Undsr tho «ufluence of réscalice, a run aísés his oan basiross aud suilers no : compsptutory haorover.. Of the lorg-range concecuonces of taking rosealiuo regularly veiy lietle is kaowa. Although superior to cocaina, cpiu, aleohol srá tobacco, it is not the idsul drua. Unfortuaately, thore is a miuopityvho fisd in tho érug caly koll or purgatory.

At dirferent tires, Hosh snd othors k9/ acninistored soüiun amytel, ;-pervitin, and resoaline to ecsh of l6 patiosts sufsoring fron tho pseudonourotie fonm of schizophrenia (Gzoup I), 24 yatievts svfforing frca ao overt, forn of schizophrenia vith slight to kocerato doterioretioa (Group IT), and 9 cehizophrenie patients warh:ssvete. ceroriorasion (Groio lI). In the first group, scaion erytal shoved a norcalinatiou ol 75 ycicent of the patients. vith pervisin,. 56 parcent o2. tho patieuts norialised, éhereas uudor resczline no norzalizatioa took plece. Instead, in every pzticnt under zescaline an intonsification of see aspecps of the existing cliuieal picture vas achieved. In Group Ii, 62.5 pörcent

[PAGE 46]
ef the ttut. choed nopulimatita viuh ecytel, 2.2 Jreent nonmlizattca vith ierci.le, end en iutensifieatiea vith moscaline In N.o pereent. In Group ml, norenlizatioa vith agrtal vas kh rercent, and vith pervitin 22.2 pereent. Again maneeline intensiried sous aspeets of the cljnical. victures in qll patients.

Peunes .10/ adzinistered sodiwa eytal, pétvitin hydroehlorids aud rescaline sulrste to 55 schisopirenies. In adltion, 25 of those patlonts recoived laD-25. She pisrmcological actios of codius arytel vas classifiad as a noralizer of clinical sptomatelog/; moccaline snd ISp-25 as intensiziors; end, porvitin tended Lo produce as unstable state vith edual represcntztion of both norzzlization and intensiricatice.

Solns loS/ tested the msnoothylanide of lysergic acid (Le) on both normal and Entally sick pationts. Small doses aisinistored subevtanecusly t normal people produced indisferencc, paralysis of tte mind vith intersive.éepersonalication, and insomia. Adninistored to schisophronies with paranoid-hsllucinatorie states, it proluced a state sinilar to a reversible chanieal lobotoy. LAl nay therefore te regarccd as a nev type of sedative vhich is cirferent fren the barbiturats and rorphine type crugs, and also fron the sympathicolytic and paraspmpathicolytic drugs.

[PAGE 47]
Nethodo for Inereasin: Production of Parot

Keasures vhieh have boen er could be emplsyed by naticns to inerease thoir swpplies ef valuable ergot drugs as vell as LSd-25' are Jisted as follous iu accencins order of difficulty of accoplishrent fros the stendpoins o seientific eapubility:

Tae Jotrodaction of Vore Eccicient Tochnisuns.  Lils couid te carrieu out us a zow coro and with a minii of scionsilic efrort in countries vhore labor is cheap and in vhich there is a great ceal or contralised control of farning. Such a progran night effeset a sutstantial inerease in ergot prccuction. Appropimtely 50 percent of she ergot on grain crops is lost during the harvesting und threshins because the selerotia boing very lcosely attached to thé host plant are easily jarred loose. They fall to the ground and are ovarlooked. Hovever, onee the erzot is harvested, edequate stcrage faoilities should be rade available imediately to prevent cetoricraticn of alkaloid content. Ergot datericrates steasily unless and until it is properly treates and stored. Eceptiounlly slov collection and iproper storage are sone reasons the so-called "Hussian ergot" never neesured es hish in alkaloid content as did tho ergots frels. other countries.

The Seloction of Hichly Suscestible Host Crons and Straina ci 0 is tho ero2 rost to OTGO on and is therefore cood commerei Crop is inportant, ut the actual infection is govoraed by Suscoptibiltiy may be 2 tereà dy the introiuction of late or early blocm áng rye vuéer C Certain ins of crçot projuce rore er one alkaloid andther. It is also koun ergots are hie Je and are nutable variaticn nctually ccsurred is several years ago then a scientist reported that he had disccvered ergot vhich contained absolutely no alkaloids.

In comparative brcocins tests Deufel. l19/ found that it vas more advantogeóus to grov ergos on tstraploid rye than on diplcid Pothisen rye; it not only forzed larger solerotie - cue probably to batter nutrisioral conciticos - but vas ncre readily insocted than the ciploid rye. The alkaloiá content in percentage is somswhat higher in tha largor Erains than in the smalier gvaiss. ihe test area per square zoter yielded under like conditions 3 tizes the anount of alkaloids.

2

AFT5ESXB

Cloe1 AveD-Nt: 02 toe

1:2

[PAGE 48]
Ervelernnt ce viald Irorel-tien Ceébudaecs. - The actual recntias ef ineculioi are cotin: tat icisluia. se techaieve cousists e. collertin: coeidia spers free ierected plarts snd auplyirs these arores to the hoss ilever. A. Stoll or Ssitcerland hes eeveieped a rachias which peatures thd notes of the iye sutloresceece piant, and 0e rathod is used in otter ccuutries. Actuei inounlzticns recuires a preat deal. o2 riilled lacor an efricinet incculatica requties -individual atieuticn. Ruch lcss efriciont techniçves pight inelulo sprayivg the plants vith selerotia just tefore tho flswering period or élcolins thz earth vith cpores juat arter tho last frost. lecpite the techaiçus of inoculation ysed, the resuits vill depend larcely en veather conditicas.

The. Hore Effietent Vtiliratlca of Alroloiaal Content of Ercot in tho Kopefaa e or s.  hno ciriszent potevzo er hca yaalcs o ilcn a given auouit of raw crgot reçuires the ultimte is pharroscutioal skill. Shis has teen doze by Sasdoa Ltd., and othors. - Jhvertheless, resaarsh in this arca ofiera a dorinite challenge to scicntists.

Biosynthosis. - Ccparatively speakin5, rosearch in the biosynthosis of eraot has terely coratehrd ths surface. Clevicers purnue has bcen growm on etifieial nçia, end althouch thsre are consietizg reports on the quality anù cczreial value or this product, several covovrips are actively studying this vrozedure. If azd uhzs cezplste biosyatlesis is accorolished on a practical scale, kowletgeable scurees fael that Sandoz vill probably te respozsible for it. Oze inóieetion ef suscoss iu this verture woulà te the tarzed evrtailreut of their rav ergot procurezent. The varvial svothesis of scmz of ihs ergot allaloido and the total syathesis of ona alkaloid - ergoscvire - hzs alroady been accoplishad.

Ono or all of thsse steps could be umndertsken py any vation, cepending upou the long-reogé drrand for ergot dreas and uon tho lovel of séientifio affort, persozral, and facilities àllotted to this objsctiva. S7/

Switzerland-has manifcsted irterest in certain phasos of U.S. vork which pertains to ths biosyatkosis of ergot alkaloids. 30/

Caltivaticn of Srgot in the Soviet Blos

Haturally cecurring ergot is cessidored of comvoial valve in Dolgaria, Creehoslovkia, Eastern Cerzay, Hmgazy, Poland and Rania. The erçot of castero europcan origis hes a lozer alialoić contozt than nost vestern curcpean varietios.

[PAGE 49]
Bolr rja. - Specinl uress have been set esiéo for trowing ergot in Igarie. / Whothor the phomatcavical iaduotry of thr.t ceuntzy is pable o procossing raw ergot is, as yot, uekucin. In the past igaria ras been one ef ehe test ccaregs or supply of ergot containing elkaloid ergotauine. 37

Czechcslovckta. - Suecessful cultivation of ergot hes been reported a Csechoslovckie. Tha rothods ured are thore which reportedly vere velcped cná publishie ly tho Swios. Ths ergos eultivatica procran , cerried cuż.bf the Divisicn or Plant Cultivation of tho Ministry of riculture.k/ Czsch faizers are being encouraged to cultivate this ep.l6s/ The goverrzsnt is also reported to be peying a cood price for : 657

Eastern Coranv, -- Ergot is now cultivated in the Plant Resoarch stitute or tko Acadeny of seieace, Caterslcton. The Plart Researeh :stitute undsrtock the cultivaticn of ercot es a result o a failure : l951 to obtain frcz the East Gorran and niddlo Gorzan rye fielos tough ergot o sufficient potesey to zeet the pharzzccpcsial standard : East Gorcany. 7/

Large-scale ficld excerinents inyolving incculation procedures re carried out in 1952 and 1953;f71/ and the constancy of alklcid atent of verious indigenous streis as well as Hongarian, Portugese, à Firnish strains vas recently eporteò after an exteasive end vellqurented survey by the Plant Resoarch Institute.f6S

Brrot extract, valned at 5o.2 theúcand Ls (Cernaa Dxt Narks), was -duccd durirg tho first nalr of l953, at VEB Arzeinittuzverk, Dresden. nty kilctrers of Secsle cornutun extract (ergot) vere to bo celivered the Russian adziulstration iu East Cerrnny in 1953.73 Fgotazino 1 ergotoxine are currontly listed ns availaole in the lt Arztokalender . Ergot proücots are not curreutly listed azons the Siate reserves pharnaccutical supplics.f7k/

There is also 2 leboratory vhich is exelusively devoted to research ergot alkeloids at Araseinittelverk, Dresdea (AlD), loccted in the cer Kadaus avd Ccmany, Gartenstrass 19/21 in Drescen-Radebeul. addition,jcrk on ergot is carried out in tho Biological Institute at plant.75/ This vork ray be courected vith artificial culture aods forgrowing ergot. Ono report indicates that an unsuecessful copt hasteeu Eace at this factory to grow ergot iu subserged culture. fungus grev but it containod vone of the ergot alkaloids.l/ 5 22 1

CULLtaLU-A Caly

h

S-E-G-R-F-T CA-Internal-Use-Only

[PAGE 50]
Hunarz. -- Preat is croro 1a livogary pnd Is kaoza to hrive beea expouted barote lorid Var 1. Raagury was at one tie tegarded as ons of the lest courses or topply of crgot contasuieg crcotsaine. 2/

Resenreh vas raportedly umdertaken in 1953 to develop aptifictal eulture of crzot. A Husparida resrareh installation, losateà nenr tha city o2, Pudhpest, ras conúveted cxperirosts en ficld apzvying vlth the epores nud ecnidla cr enzot, vsiug 90-lco kilozrazs, 1gò-a2o ibs.) per hectazo (2.47l acrts).

Poland. Le In Poland, the people ere Leing encouragcd by radio to collcet crcos and soud is to the previssinl crgot tuying cffiacr because "considsrablo quausitios of rav, uoprosessed crgot are nenced in a certain chenteal process". €9/ Host of the kzowa rescarch on ercot is carried oue vider the Deosrtront of Agriavlture. lhe Justitute of Phytopathology or the Agrisultural Sihool, Fosean, is doing resocrch op this problcn. Tao sstirisial sultivation of crgot has reportedly begun in both the fiold ccd in the losoratory. "Ia the laboraiory, by cultivatisg ergot in srticial nutrients, it has proved possible to obtain fuzgus iormations simtler to selerotia". Laboratory produced ergot reportedly coutsins the three.aotive substerces: crgotoxino, histazine, end tyzazize vhich are formed in ergot usder natural. conditions. 70/ 1

Ruzsia. - Ergot was collested for export at least vp to mid-leh9, and depeucins npon the elizate, lcoo to 3coo kilogtens of crgot were collected anzually. 68/

Sovist lrioz: -- Fcscarch on ergot eultivation and colleotion is contered o the Hinisty of Asriaultore. Sore or tho vork has taken place at the Institute of Plast Protection, Leningrad Asaccry of Agricultural Ssienses, Iesssctad. Emperizents conduetod in 1939 audicated thet the korayleg cr rye vith E solcson containing crrot conidia vas a suiteble rsthod for ecmeroial purposes.lo Lay since bsen reported that there vers seill furthor probiens to bo rolved. Thase included the eultivation of artirisial msdia, the phauscological tostizs of celerotia of other fungi, and ths davelopmmot of new straius of ergot vhich could ba grora os plavts other thas rye.

Iu recent yesrs no Russian (aown ergot has appeared in foreiçu markots. Ergot has coeorred tazurally in the rye fislas ol Eusska for many years, and it probatly has rot díndaished. Jhis say bs the renuls of its lov aliloid soutent vhieh makes it cozareially unattraotive. é2/ Thoro is opeculation anoss ergot spoeialists that Russian prgot is mid with the Spavish and Poztrgere qualily predust cnd sold us vhe latter. Tha nixtures bave at tiuas appeared quire obvious.

4.5

[PAGE 51]
Culcivetten ef Ercot fn Cther Couitrios

In lestera Eurege, ergot is celtivated thvcash artirictal Iuoculation of rye iu ccmereicl quameities prinoípally in Suitzerland, Auctria, cad Vest Cerzsny. Ertot in Éarope, ¿amsrahly, is proásced over an area er som 250o to koco eeres vith an évere yiold e? 1o kilopars per sere during normal ycars, the chier predvcer teiug Gitserlaud vith some 2000 acres. Ergot is elso cultivated to a lesser extont in Japan end India. Indie also collcets large cnouats of natural ergot. Hatural ergot also cceurs naturally in fairly large gentities in ths province of Kenitoss, Canada, and in the Uaited States, princirally iu Hienesota. However, it is collcoted ccmereizlly ouly vhen the prico ef tho Europcan msterial teccmos so expeuszve that the cost of labor is not a finaucial deterrent. 4/

Soze attompts at artificinl cultivation have been made in the United States, but those hnave not teca eccnozically suscecsful tocause of the foreign cczpetition. The bost avzilcble infortios indisitcs thet the enual procuctico in Svitserland is cbout 50 tons; Avstria end Cerreny preduee less then 10 toas cach;.Japan producas aporoximtely 5 tons. 76/ Portugal and Spsin are noted for proáucing quantities of higher quality erzot, vhich oceurs naturally in those areas vhere cereals are Grown in ths Icerian Peninsule. 85/

India. - In l952, the goverpnent of laáras, Iudia, sanctioned a plan for the cultivation er ergot on e ko ecre plot in the Kilgiri Hilis of Hacres vith e prosustion target of 25o0 lbs., per year. Aeeording to tho dircetor of Agriculture of the govermont c Kacras, experironts have shown that ergot of high alkaloiá coatent can be produced in that area. Sors specirens are szid to contain doublc the alkaloid content of the test iiported varieties. 25/

It is reported that prior to J953, 75 tons of vild ergot vere. ±.: shipped to Saudoz yearly for several years.: Noue vere shipped iu 1953. 86/

Jepan.  Japen grovs ergot as c eczoreial produet end there has been Ecze basic resoarch in the field of artificisl fornestation. M. Ato and covorkers or the Takede Rescarch Laboratory, Jepaa, have published reports on the alialoid produstivity of the ergot fungus. 82

Ssitzerland. -- Daring World Var II, the Sandos fia in Switsevland,. unable to cutain supplios of ergot because or the exigorcios of var, started to Grov their ovn. Sitzerland vas and still is the maio vorld producer of finiched ergot preparaticns: Currontly, Serdos purohases rav crcot on coutract fron several countries iucluäing the Uaitéd States.

[PAGE 52]
One sourre visited faudoe ía Jue» l05). and rportad that thet cetrae hac a nee preeesa fe: mtiag artiftetal er zot. Serdos his been ahle to isolate this zvpos :rd geor ys an taeks, diadler to yenialllta. 1o/ Althoegh thto pre:qss is possjole, ao coat hentioa has reaa reeoivid to date. Fls proitss ray rot to cepletaiy satisfactory cince Easdos otill ohtaias crgos izea tletr eva rye faeles. 2/ The ahove precaas moy rorely to lerça-szale prodvcvioa of tho spore iucculant usad to infcct rye.

The possibility of, tark culture is supported by the fact that sone Swits cisot rields vere vot harvested aad that Tedlan vild crgot vas not importcd in l953. Frevious ahipcents or ergot ixom India amointed to 75 tons per emus for several years. 85/

Oaly Sazdos of Csitrerlast is covsidered ty nost cources to he expert at the Siosial technicue of inosulazios. Thsy are sorevhas sçeretive ahcut this process, esd as a rasult, it is vary difficuls to learn their ¿actee o sucsess. It is tolicved that rye is inoou» lated vith a culture of spores suspesded in a fivid radiua. A vire brush izprcgaatad vath the catorisl is drava ty hand aeross tho hand of tho rye, iucsulstizg the vhole head. There are tvo main ressons for the artirlalal culsivavion of ergot. Firot, Sandos hopes to attain a higher yield, a szeeäier svpoly, aud scza coztrol over the costs juvolved. Socons, they are tryiag to costrol ths alkaloids in the ergot by the preparation ef certain strains'of fvsgus.

In Switzerlasd as in osher countries vhore ergot is produced by ertificial iroculation, achisss have beea develoçeá for the collectiou of ergot. 70/

United Stntes,  Rsecst attempts háve besn rado dn the Usited States by several rescarch crovps to preduse eract elasloids by feruentatioh rsthocs. The mothods vere cimilar to those usod for the preparatioa e antibiotics. Teoczetically, at lesst, since ergot disease cf rye is cansed by a fosgus vhioh ean to maintaizod ia eeltore, this prcress is reasidls. Eo dote, tho vork hos tces saily concerrad vith the. developnost or suitabls srovth nedia. Strain seisstion or Claviceps has also been started.

47

[PAGE 53]
Although fiold lnoeulet:. ; has been svccessfully accorplished tor gny year, oa an eerirental tazis ror loratory vc2, isceulatiea ea a profitatle ccrzzreial ceale ls not been aecoplished in the United Stales. 37/

The United States hes 55 aeres for ercot production (1252)r'h5 are in Michigu and l0 in linnesota.

Prade iu Treot and Ercot Alkaloias

The latoct duotations of February l95h indicate that ergot cen te sutainod on prozpt shápmost fron Fortuzal at 16 shillings (2.24) por lb. Many sources have stated that cuali anounts of ergot are processed iuto the basic alkaloiás in varices countries, but the largest prośucer is Sandoz Ltd., Basel, Syitsorland. Kest international trade is, therefora, sonducted vith this company. Cns U.S. cozpany is knoim to have. purchased l00 grars of ergct altaloiás frou Sandoz in 195l. 10/

Various sources roported nrcerous purchoses of ergot and its Zerivatives by the Satallites throughout the vorld, indicating a zotable intorest or tho Scviet Rloc in these substances. Specific chipzent have included:

l. lungary purchased 35 tons of ergot from Belgiua thrcugh Centralzpex. 77/

2. A notorious East-West trader contracted to purchise 250 grams drgotin (Cop concentraticn) Sren Laboratories Espanoles Zalta S.., Kadric. 78/ This shiphent vent to en Austrian receiver vho purchased ea edditional lot or 250 grars of ergotin, zalting a total of 500 grans. 7/

3. Fortuguese agents also canvassed Spain, purohzsins large enounts f ergot at a very high price for shipzent hehind the "Iron Curtain" Carough Fortugeso ports. 77/

4. Sonetime durins 1951, the Soviets purchased a large quautity of w ergot, derivative fron Sandoz, Ensel, Suitzerland. This vas srchably the largast order Sanãos ever received. The érus involved ves ither LsD-25 or d-lysergic asid, probably the forzer (acecrding to tource). Thd quantity supplied vas allegedly sufsicient for cpproxiaately 50,000,000 normal dcses. So/ This auount fer exceeds cstimated rld production, hovever, and the amount shipped if any, vas probably uch less.

. 5. In 1952, the Yugoslav Covernzent purehzsed 700 grans"of ergottine fron Intersanitzs SA, er Iegano, Suitzerlzad. This purehasc vas for a nilitary office in Belgrade. S1/ 25/

h8

[PAGE 54]
Posslb1liy of eh1in Tsot

It is unltely ih.t isv ergot, voald to stockpiled es such locuso or its extron tndzney to deteriorate. Thore are no ideal Tacilities sor storing it over a peried of yéars. Even the pedryiag and sybzequent vacuua storaçe of' ergot is cptsive and not alsya cfrcative. It is, therefore, assurad that ir any steskpiling vere uzdertalen, the totel alkalolás of. the ergst vcuid ts first converted into lysergic acid or that one partisular elkaloté weulà be isolnted. In either case the prodvet voulć,than he relatively stable aud coulà de nore csvily storcò. 67/

[PAGE 55]
All-Union Insticute of Pont Protoction, Acadary of Aericultural Scienees immai i. i, Lemn, Lomia wia. - ino rcllomink persons nave coon associated wiun tne Ali-union Anstitute of Plant Protoction. Their publications relating to orgot are cited.

BILAI, V. A. and PICOPLICHKA, H. H. Poisonous Fungi on Kernels of Careels, l5k6.

BOLOTNIKO7, S. M. and NOVOSICKAYA, S. A. "Contributien to the Quantitative botorrination of the Alkaloids of Secale cornutun," Pharnacy, Noscow, vol 6, no 4, 19k5, p 28.

GRE3ENNIKO7 Winter Rye in Siberia, Novosiborsk, 19L9, p 53.

LYNOVSKY, I. P. "Ergot and Ergotisa (Fafania),", Prebleis of Nutritio2, vol 3, no 5, 193h, p 2.

MiSALa3, N. A. Nethods of Cultivetine Srrot for ledicinal. Purroses, State Publisning nouse or Kedical Literature, Roscos, leul, p 38.

MARICIASEVa, V. A. "Prornosis of the Anticipative Davelopnent of Ergot," All-Union-Institute.of Plant-Frotection; Leningrad, 2935,p.205. E. ….

"Hethod of Prognosis of the Developaent of Claviceps Purpuree Tul.," Proceodings of the Soientific Hoseares lerks of the Ail-Unicn Institute of Plant Protection, Laningrad, 2A 1935, 1935, p 535.

"The Principal Pests and Diseases of Crop Plants," Lonin . Academy of Agricultural Sciences, Leningrad, 1936, p ik6.

MUSHNIKOVa, K. S. "Orain Ergcts and Measures of Conbatting Them," 2934; p 24.

USSR

APPEiIDIZ C

Installations nl Persons Asseciatad With de temven on

I. Sovict Bloc

[PAGE 56]
OkOLOv, F. and AKITy, I. "Deereaze in the Toxic Properties or Ergot in the Precss of Proad Eakine," Translation of tho Sanitary y:ioco Instituso, Ginzt, Aoscex, 1929, p 117.

OSHEV, A. ani SHOHEPETKOV, A. "Renoval of Ergot fro Rye Sced," Scleotion and Soed Growinz, vol 19, no 12, 1952, p 71.

PIDOPLIC:Ki, H. M. and sILAI, V. I. "Poisonous Fungi on Kerncls of Corals," Ukraine Acadoay of Sciences, vol 19, no 12, 1352, jP72.

PROKOFEV, H. V. and SHAPIRO, S. D. Prodection of Liquid Extracts of Ercot (Erzotira) in Amdcles for Iniscvion, Hedical incastry of the US5R, 2547, p 33.

RIKSKAYA, M. and A?TOV, I. "Data on Ergot Fat Constants and on the Stability of its Toxic Proçerties in Relation to the Perioi .of Preservation," Translation of the Sanitary Syaiene Institute, Ginza, Sosccw, 1929, p 129.

SNORODINTSEVA, S. D. "Kental Disorders as Remote Sequels of Ergotisn," Translation of the Ural Scientific Psychiatric Institute, vol 2, 1935, p 122. 1

TAT'LANIN, A. R. "Production of Vitamin D," Food Indistry, Noscow, . 1943, p 62.

VLADIIRSEII, S. V. "Geographical Distribution of Ergot of Rye in USSR and Zonos Mhere Its Harnful Effects Have a Serious Significance," Soviet 2otany, no 5, 1939, p 77.

ZABOLOTYA, Ye. S, "Alkalcićs of Ergot". Tr, VILAR, Nio X, Medgis, (All-Union Inst. of Rssearch of Medicinal and Aromatic Plants) Moscow, 1950

Czechoslovakia

1. Charles University, Prague. -- The following persons have been associated wica Charles university.

SKARNITZEL, Dr. (fau) - Is a Professor of Pharmacology. He lectures frequently cn ergot and acts as advisor to the ergot cultivation program.

\*S-F-C\~R-E-T CiA-Internal-UseOnly

51

[PAGE 57]
ZDElEK, Dr. 'lyslivccek - hs Chief of the Psychiitric Clinic in 1952. This elinic; in 1952,.wis vorkinz on Yaricus drugs, such as pentotinl, evipin, insnlin, ind ergotin. (Pentothalsodiunivas used to incerrorute political prisonors at tais clinic yith sone success, according to one unconfirmed report.) 50/

2. Ministry of Arioulture, Nivision of Plant Cultivation. - The Division of rlant Cultivation monitors t.e ergot cultivation program.

NOVAK, Dr. (fnu) - Is kowm to have worked for the NMinistry and .on location in the ergot fields.

3. Ministry of Azriculture. Pestarch Institute for the Cultivatien of Plants. -- Docent r. ucolf RosOEOkA snas directiy connecteu witn the ergot program. Currently residing in Zbraslav. 89/

h. Medicinal Herbs Niational Entersrise, in Zbraslav and Vitavous. This enterpriss purcnssos, nanaios, and processes medicinal neros. It also organizes their cultivation.and collectien 9/

5.. Pharmaceutical and Diocheical Resoarch Institute, 17 Kourimska, Prague 12, -- or. J. v. RY.jak or this institute nis recuested reprints of tuo U. S. articles en ergot and ergot preparations. 91/

6.. Other persens -whe have heen connected vith research on ergot. Their publications are listed.

BERNASEK, J. and VOTAT, Z. "Study of the Effect of Certain Ergot Substances", Journal of Czechoslovakian Tedicine vol 88, p 593 1949.

BLAZEK, Z. and FUCHERA, N. "Current Status of Artificial Ergot Projicticn", Journal of Czechoslovikian edicine, vol 85, p 1281, 1940.

i NEUMAlN, J. "Effect of a New Alkaloid of tze Ergot Grcup on the Heart", Journal of Czechoslovakian Nedicine, vol 88, p 500, 1949. 2

POLAK, E. "On the Relation of Ergotaaine and the Action of Electrolytes", Sull, Internat. cl, Sc. Hth. Acad. Se., Prague vol 27, p 440, 1925.

SZABO, S. "Ergobasine in labor", Hedical Mossenser, vol 63, p 2L, 1941.

OIA Interna) U4o-Only

[PAGE 58]
1. Plont. ences Gatorslesan ins folloining persons have Soen aasociatsd vita institute.

NOTHES, Prof. Dr. E. and SILiLR, H. - Reportod 7/ that this Instituto decided to cultivite ergot as a result of a failuro tò ebtain sufficicnt hirh quality ergot fron the East Genan and Misilo Serman rye lields to ncet the pharaacopeial 'standard of East Germany.

HUELE, Pro. Dr. - Is hoad of an ergot projoct currently in progress. This project, undoterained in scope, is scheduled for complotion y 1956. 3/eppe

1 2. Arznei-itteluerk Dresden (AwD). -- Corplete laboratory engaged in rescarch cn the erros aixaloios is locuted at the former adaus and Co., Gartenstrasse 19/21 in Jresden-Radejeul/75/775/. 日

3. Biclosical Institute of Areneiaittelverk, (avo) Sresden -- This Institute is also engagod in reseircn on ergot.

1 SIEBECk, Dr. Walter - Is head of ergot reserrch at this Institute. Hungary

1. Aoriculture Research Station, Hernan Otto 15, Budapost. -- This station covers approximaveiy lo to z0 zcres. mhe ceaical section covers approximately 4 acres. Work here includes rosearch on medicinal plants.

BEKESY, Dr. Nikolaus - Invostigated the alkaloidal content of various European and American ergot samples. He has also vorked on artificial cultivaticn and special apparatus for inoculatioa.

RUDOLF, Prof. De Giovannini - Is director of the Rescarch Stations. . Experiments on medical plants in early l9h9 included work on ergot, and intensive rasearêh was wndertaken to grow ergot on artificial media. 7/

2. University of Szered,  In l9L9 this University had 3 departments engaged in rosearen on ergot.. They were the Departnent of Phirmacognosy, Department of Fharnacology, and the Departmont of Bactoriology.

Ce

Bost Gomner

6=B=C=R=3-T GLA-Internel-Use-Only

53

[PAGE 59]
1. Plant Pesearch of the deudeey of Sciences, い:15

NOTSs, Pro!. . L. and SILER, H. - Reported 7/ that/this Institute decided to cultivito crrot as a rasulyof a failure tö cbtain sufciciont hiza ouality errot Cren tge Sast Geñzan and Midsle Jersan rye fields to mcet tie pharsacopeial staneard of East Geraany.

progresä This project, undeternined ip scepe, is schedaled for comption  1955. 93/S/

2. Arznoizittefaark Dresden (Auo). -- pomplete laboratory engiced
in rescarcn cn the srrds aiksioias is locatod at the foraer "adaus and
Co., Gartenstrasse 19/2hin esden-Pacebéul 75/95/. é

3. Biolegical Instithte of Arenginittolvork, (Ayo) Dresden -- This Institute is also engagec ilraseur on ezov.

SIEBEOk, Dr. Wlter.- Is hegd of ergot resoarch at this Instituto. Hungary

l. Asriculture Resossch Stat Hernan Otto 15, Budapost. - This station covers a Sey l to zacresr ahe eaical seetion covers approxizately h acres.ork here incledes research on nedicinel plants.

BakeSY, Dr. Mkólaus -Investisated ahe alkalsidal content of various Aaropaan and American ertot spples. Eo has also xorked on artiicial cultivatien and special apparatus for incculacion. 85/

RUDOLF AProf. De Giovannini - Is director S the Rescarch Stations. Jperiments on sedical plants in early Tgi9 includad work on ergot, and intensive research was wndertaien to grex ergot on artificial modia. 97/

2. University of Szered,  In 19L9 this Universie had 3 departe mops ongagoa in researcs on errot. They vere the Docarurant of Pharmacognesy, Departzent of Fhsrmacology, and the Departgoni of Bacteriolozy.

Haot Gerruny

53

[PAGE 60]
IAtiOvICs, nr. Gyorry 0 Antibiotic specinlist, Dpurtrent of Bacteriolory, us invulved in aspects of alkaloid investigations án 1919.

JA.iCso, Dr. iklos - Under tãe Dopartnent of Pharrcacology, Has involved in aspects of ergot alkaloid investigations.

Poland

l. Deoartmodt of Arriculture, Instituto of Phvtopatholov of tho Apricultare :cnooi in roen at this inscicito. na ais uritton a papor ontitlod "Ergot, tho. Eneny and Friond of Xan" shich insicates a kcen avareness ef the therapcutic and unccnventional uses to vhich ergot may be put. 70/

2. Hinistry of Hoalth. The Institate o Vedicinsls, Varsas.  This Instituto coorcinatus ans plans aii scientizic recearca on nedicines in Poland and is cne of the probabls installations whish would ençare in ergot rescarcn. 92/

II. Other Countries

Austria

l. Univorsity of Orss. - The folloaing persons have been connected with this Instituce.

HECHT, .Dr. Nartin (lccation is not certain) - Has a specific interest in crgot and is the son of Dr. Halter Hecht. He is currently engaged in roseurch on inoculation nethods.. He clains to have obtained 2ho kilograns of ergot per acre with these inoculatien methods. tie enployes. a zotor drivon injection maohine with a capacity of one to two acres per hour. 96/ 7

HECHT, Im. Walter- Is vell-trained in botanicais and has had a specific interest in ergot for several years.

l. Takeds Researeh Laboratory. -- M. A3E has published reports on ren on ergot rmngus ena tae production of alkaloics in ergot fungus in culture odiu, 82/

2. Experimental Farn for the Cultivation of Hodicinal Plents, : a-ken, inis farn is attacnoa to tne Laticnal hyrionic Vary. 63/

51

[PAGE 61]
KAláTt, Er. T. - las lad a contisving Suterest in tlo dovelcpznt of crgot aud its alkuloids.

3. Hakemntr-Teki Co., Ie., Toyo, - This Coupany mcintains. experinzutal crcoe raria.

Tojo, Katsco - is ranaging director of this ccrpany cnd is elso interested in ergot prosuction. He has visiteà ths U.S. to obitçin iufoization on tho subject. 83/

NKvRA, Taisuke- has visited the Unitcd States for inforzation oa this su-jact.

4. Other Jasanase toisntints -- The folloving persons have published articles cn ergot.

AASLOTO, T. Yakogaky Zasshi A. J. Phar. Soc. Janan, vol 66, 1916, p 22.

OGATA, A. J. Fhara. Soc. Javen, vol 52, 1932, p 25.

OGIU, X. OZNOTO, T., SDANOTO, K. Fol, Phar. Jaen, vol 44, 1 1948-49, p 75.

OTAI, F. J. Phar. Soe. Japan, vol 52, 1932, p 25.

SUGDOTO, S. Fol. Pha. Janen, vo1 32, no 11o, 19:l.

TAOTO, T. J. Phaa. Soe. Japan, vo1 64, 194, p 225.

Svitzerland

1. Sendoa Pharossutical Ltd. Besel,  The folloving persons are connected vith roscarch op crgot.

STOLL, Dr. Arther - Is Prosidant of tho Saudon Pharraceutioal Ltã. Re is a vorid authority on the industrial preparation ond use of the crgot draçs. Ozo reforence points out that ho vsed ergot in the trestmsnt of asimals siffering fron tho ofiocta of chozioal warfare agents. However, vhen ths threat of thas type of tarfare ceased curivg tho Horld Kar II, he stosped his irvestigatious. 80/

NosNual, Dr. A. - Has the first irvestigator to use-ISp-25 on hizcolf for tho purpose of tostins the psyekogenie cirects of the substance. In eddition, he vas one cf the carly investigators

ài

[PAGE 62]
who accozplisland the preparatien of Lsa-25 ty coavertias lysergie actd into tke diethyl taide derivutive.

Went Gorrmny

1. Kali-Chanle, A0, 20 Soknce tei Eonover. -- Dr. Ing. 0. REMAUX of this firn has staved that zora on tao isolation of tho crgot alkaloiós is in progress.

2. Institute of Phanceutien) Chanistry, Hains Coiversity. Prof. Ir. RO alkaloids in saprophytic culture at a meoting of the Gerran Pharraceutical Society is October 1953. 9/

FrecCC

1. University of Strasbourg. -- Madeze Chauduc VI/LARD reported the forzntion or crgot alizoids in vitro, obtaining up to 0.7 parcent alkaloids in an cight veek old culture. l02/

56

[PAGE 63]
APTEUDIX D

Clotsary of Scientifie Tarmo

nluation of en.czotión'laden eporicnce duviug its jon vith aa uaderatsnäing papeho-therapist.

ubstance secreted by verves vhich sets in notion the ading to museular coatractions.

1 undition zarked by coldcess and cyanosis of ihe hands

and 1-

,.Ly of esotiosal experience.

PlaT--AV

aine or beuzedrize.

himmO-

, a large Croup of organic basic substances fousd in plants.
ally bitter in taste aad physiologically active.

MBALOID-They

ltaneous existence of costradictory anã coutrasting ,are and hete) toward the sare person,

eo

edrine.

AU'TETAMn

, loss of appotite for food.

. -A psychozeurosis characterised by apprehansicn anć eomspanied by a veriety' o othsr syrptons such as

.excitability and cepression.

musculer coordization.

teid fron tho soLATAcEa; used as an anti-spesmodis gas poisouivs; 1s aiso calles dl-hyoszyauine.

AROPIN an!

ion of teing dozinated by subjective, self-centered sought o teravier..

liTIS." tiv

SYSTEl--Tho furetiosal divisicn of the nervous system as the Elauds, heart ond snooth maseles with thoir wrvetion.

,alkaloid dezived from Corycalis bulbosa.. It has an Nect on tho reflex and notor cozivities of striated i recognized es e psychogenic agent..

57

[PAGE 64]
C/FFifi--An allnlold extreeted frea tea and coffee; uced as a cardiae, recpiratory, renal and paychic stimulant.

CATAlrol--A conditicn chureeterinel ty a vay rizicity of the muscles und in vhich the pstisut tenás to reazin in any positios tht ho is placed.

CATANOIi--A for of sehizoplrenia characterised by negstivistic reaetions, phases of stuper or exciiuzoot, and izpulsive or stercotyped behavior..1

CMTRAI, KRyCJS SYSTZA--To brain end the spinal cord, including their nervous and ená organs. Also called cerebrospinal-or voluntary pervous systea.

CEREERAL CORTEX--Cortex of the brain coposed minly of gray and céperitious substance.

CEREROSPINAL ERVOUS SYSTEI--Sycoayzous vith Central Hervous System.

CHORL HYDRATE--Used as an anodyus, hypnotic, and antispaszodic in ivsomnia, rania, deliriun trexens, hysteria, tetanus and labor.

CoCAIE--An alkaloid frcs the leaves of Erythroxsies eeca; páralyzes the ends ef the sensory norves; stisulates the central pervous system; mainly used as a local anaesthetic.

CHOREO-ATEIOTIC--Reforring to both chorea an& athetosis, chores is a nervous affection narked by ruscular tvitching. Atketocis is a conditios rarked ty slov ropeated, involuntary, muscular distortion .of parts of a liro or alrcot the entire bocy.

COMPULSIO--An irresistible impulse to perfora soze act ccatrary to cne's bettor. judgezent.

CYCLOTYM/.--Te recurrent altorations fro manic to depressioa states as seen in certais paychoses.

DMPERSONALIZAiIOn--Loss e the sense of personal identity, or the personal owership of tho perts of cne's body.

DEPnESSIOl--An ezotiozal state characterized by dajection, uppleasant ruciuations or forebolings.

DIEnCLFHALOSIS--Diseese of the posterior divisioa of the prosehcephalon or forebrzin.

58

[PAGE 65]
DIEaTRE (hdtothter1d)--n-(2-ehtoro ethyl) ditenzylaatue hydrochlor!ee used for tgaertcasjon. Occasionally cauces mntal conlusio) mnd poatural typotencion.

DIURESIS--Incrcased cccretion of urinò.

DIS/RTintA--Stacxering ttuttering or other irpzrfect utterances duo to disorder in the nervous systen.

MDNC--Pertainirg to pr prevaleat in-e particular dictrict of regicu. Said of a dissase vhieh czevrs rore or less corstautly in any lozality ard is pot sporzdis or epidcaic.

EPILEpnTC--Partaisiog to, or affccted vith, epilepsy, a discase charasterizcd by fits or ettasks of loss of consciousness, vith a successicn ef tonic or clozis cosvulsicas.

ErIOLoCY--The sus of kaovledge regarding the csusation of any disease.

EUPNORIA--Nell-beiog; absence of pain or distress.

EOGEiC--Dovelop or originatisg outside the body.

HAILUCINOSIS--A psychosis zarked by hallucisations.

MAPTIC EALIUCNUPION--A tactile hallucinstios or hallueination of touch.

HASHIST--Fenale flover tops of Cacpabis sativa, a variety o2 cowzon hevp. Capnabis is antispsszodie aud rarcotie. In largo doses is .produces rsntal exaitation, iztoxicevion. and a sessation of double conscicusness. Also kuoan a: MnDiUAliA.

MEsmmC--Pertoining to hebephresia, a clinical fora or dsmsntin preccox, (sshizephrenia) vorked by rapid dstoriorsticn, halluoiua absurd dolucions, ssnssless Jaughtor, and silly ranserisns.

HEmHOM--The bronice has been recozmnded as an eutononic nervous system blockins agent. The caipound is also used in the form of'its icdide.

HYDERGnE--Aydrogeeated ergot alkaloids, apecifically dihydroergocornine ethaccsulfonate, dihydrcorgoeristine Eethanesulfonato and disyóroergcorvptine methasosulfosate (ușed in peripheral vascular disocse and hypertensiov).

[PAGE 66]
JPROEITIC--Meesive xobility.

MAs 07 RLriCR--An idca which causes the possvssor to sepposs that Whe vords and aetions of othors rafer to hizsalf er to pcojeet the causes of his ot iraginary dirficulties upon sczeone elso.

IsOleRS--A set of substances vhich have the same mmiber of atozs, but differ in ths ordor in vàich the atoas are errauged ia the nolecule.

LCRYSTICN--The secretion and discharge of tears.

MlIC--Pertziniag to or erfected with rania, a phase of montal. disorder characterized by as expensive ezotional stete, elation, hyporirritability, overtalkativeness or flight of iceas.

HESCALrE--Froz rzscal buttons, the flovering heads of Anhaloaiu or Lophophcra caotus. A poisonous alcloid, it procvces aa intoxicatiou wish delusions of color and Lusic.

MESmCEPRALOSIS--Discsse of the nid-brain, the srallest of the six divisions of the brain.

HETAPOLTS--Te sur of ell the physicni and chezical processes by which living orgasized substarce is produced and mintzined, and also the transforuaticn by vhich energy is raãe cvailable for the uses of the organisu.

MinSrREE--Trade nsza for d-Dosoxyephedrine Hydrochloride; also celled Pervitin. A coutral nerveus systes stizulant.

MOCTRITIO--Tre Pessage er urise.

HOPRIASIS--Dilation of the pupil.

NEGATTVISi--An ezotional disorder characterized by stubborness, refusal, and rebollios cgainst axthority. Also au aéjustmsnt rechanisn ly whieh the irdivicual unccnsciously fails to recoguize the existence of á problen or obstacle, or of the unpleasent fects that confront hin.

NEUIROPHILIA--Increzse in the number of poutrophil leucceytes in the dlood.

HICOrllJC ACID--Also kaoxn es Mizcin, enti-pellegra vitesin. lins been used to, produee vasodilatiou.

[PAGE 67]
ONc)c--Haotenirg tre process of child-bdtth. A rediciue which nccelerates delivery.

PAenDUC--Widely epidenie.

PANuOIh--A chrcaic, slovly progressive psychotic disorder mrked by the presence of syotematized delusioas vhich ere built up Lu a logical for. 1

PANpTESIa-Morbid or perverted sensatica; an abnorral teusation.

FARURTTION--Thz act or prozess of giving birth to a child.

AssIVITY--A state cavked by delusicnal feelivgs of being influenced by others or by outsião forces or inflveaces.

PArEOOGICAL--Fertaining to that branch of nedinine vhioh treats the essential natrre of disease, expscially of the structural and functional charcos cavsed by discase.

Tll--A derivative of aphetanine icenticel vith rethedrine; used to'stinulate the celtral rervous syaten. 1

--The flovering tops of the Nexican cactus, Ashaloniua; used by the natives to prodvee e state of intoxicatiol uxed by ieelings cestasy. Costains tte drus zoscaline. 135/

PATgOlCGY--Tne seiesce of boaily functioss in disease, or as modizied by disease.

Ria--Tne passage of, abuormally large aounts or noral urise: Tà ACTiOg--Tenãisg to.iucrease blooà Pressure.

L--2-Fenzyl-2-inidazcline. Used es a vasodilator in periphoral vascular diceaso.

ONSURCSIS--A form of schizophrenia.

mOmnc--Origivatins cu the basis of psychological faotors; atera :tlso applied to ISp-25, hashish, bulbcsapuise, zoscaline, and other drugs which cause rental rifccts.

MOToR--Pertaiuing to uotor effcots of cerebral or psydhic retivity.

61

[PAGE 68]
P5tczo2ls--A profound mutal aisorder, uscally iavolvin the total percorality; the indivicunl'a rrntal tunetions are co prozouadly diotupted that he is inenpacitated froa participating in everyday astivities.

ep.NEJaosIS--A disturbanee 1n bodily funetion, thinkint, fecling, and essduet due to exoticeal tensicns which have dovelopod es a result ; deprivnticas, frustratioss, end conflicts; a fonetional. tzozicnal disoyder.

FanOLoY--The patholos/ of reutal disordors; the branch of medicine vhich cesls with the causes and cature of rantal discase.

:CH TEST--A test for intelligetce. vhich also reasuzes the crotional eiszcnts of the personality.

1 :zd--Resemblius schizcçhrenia; a term epplied to the seclusive, usial and iutrcspective type of.persouality.

;DRik--A psyehotie ccudition, usually occurring during or shortly t edolescesee and charactorised by disoricataticn, loss o2 s vith reality, disorganized patterns of thinking and feelins, s ní et.

"stnlz elkaloid fros the root of certain of the Solanaccze plants. pisopous nerve depressant, rydristic asd wpnosie.

roprietory naze for the conosodiua salt of isouylothylrzeia. Used es a sedative tefors ceceral enostzocia.

1 ttgouad in which the colecule contains the sazs puaber ators as another, but in which the spatial the atons is different.

aving a dostructive effoct cu syrpatbetio fibors; also 'ta transmissicn of nervo irpulse in Rutcnonic conglia.

mary sensation acecpanying an cotual percoption; "ig of a sensation in cne place due to stimulation "er place; also the conditica in vhich a stimulus of recived ar sonsatieu of a diffcrent seuse, as when i a censation of color.

rapidity of respiration; a respiratory usyrosis ,thallow dreatding.

62

[PAGE 69]
Toxli--A peicouous substance of zicrobie,vegetable or muiaal orisla.

VASocopornTCzIC:--Mie coastriction of blood vessela leadiag to derersed blood flov to u part.

VASONorOR--lervous control over the coutraetioa or dilation of bloed vessels.

VECETATIVT--Vegetative syoten, the syapathetic nervous systen. Alco reans to fuuctiou 'involuntarily or unconsciously.

63

[PAGE 70]
. FIGURES 1-10

Laboratory Experirents Shoving the Effects c2 LSD-25

[PAGE 71]
Figure l, Lifo Cvela of Ervot, Sauree of Laserrle Acid

Ergot.is tho nutural sourco of special alkaloids, yielding lysorgic acid as a hydrolyais procict. The grain-like crgot is the end result of a special fuges infceiion (Claziceps purpurea), affootinz uuch ereps as rye. Tho spores are brought tó tho young ovaries of· tho rye by wind, insects and most recently and effectively, ty large-scale spraying of laboratery cultures.

a. Head of rye vith proninent hardened, dark-red fungus bodics: crgot.

b. Sprouting ergot with soveral stalked globular heads. at

c. Flask-theped cavities inbeddod in the surface of a single hcad.

d. Single cavity with nunerous tubs-like sexual sacs .or asci.

e. Filifor ascospores in closed and cpen saes.

f. Singlo ascospore, capable of infecting rye flowers, 1mng forming a nyceliun therein.

g. lyceliua, spreading in the grain tissue, forming toedlike, escxual spores (conidia) for further infections.

[PAGE 72]
The handwritins, undor Uho irfluencoof ISD-25, bocamo shaly: tho much enlerged lettors sprerd out, ofton separated, and fro quently becnmo unirtelligible.

人

a. Normal writirg.test. (Tost Persen 33.)

b. 1SD-25 writing test, L hours after é0 gaana 1 ISD-25 edzinittratios. (Test Perscn 23.)

c. Normal writing test. (Test Percon 21.)

d. LSD-25 writing tost, 3 hours after. £0 gaana LSD-25 eeministration. (Tost Pcrson 21.)

Figure 2. Srfoct of 1oo-2q on Toadaritier. Sh/

[PAGE 73]
By Laszlo Hatefi

The interferenco of Is5-2g vith his, ability to draw was strikingly illustrated ir'solf exparisonts by the author. JSD-25 preiucèd different yayeho-patholcgical roacticns of tho hobophrenic tyre. The drawings show a tendercy to expansioas and soz relationship to picturos produced ty psychotic pationts.

At 9:25, 50 camn of ISD-25 woro taken orally.

At 9:35, test person was coapletely nermal. Drawing A.

At l0:15, an additienal 50 gaa of LsD-25 wero takon orally.

At lodO, test person felt less certain, sew objoct rightly but eculd not draw it correctly, interrupted drawing ropoatedly. Drawings 3 and C.

At lld5, test person failed in successive attompts, the contcurs of the zodol appeared noraal, but rct thoso of the drawines. Drawings D, E, end F.

Picue 3. ret of tmaa en hraine Cests. bo

[PAGE 74]
Ficure h. Erfest of 1Sp-25 on the Hon Electro-Encuaiceal. 01/

By Gastaut et al.

The clectro-enzephalozreph records brain veves, or electric potentials crigizatiuz in the brain, by ronns of clectrcdes placed upou ths sealp cnd uearby surfases, as indicated epecifically inthe Ereçhs and belox. ISd-25 causes a slight inerease in the alphe-rhyth end the occurrence of the bets-rhythu in thc central regioas.

Ta-entericr tesporal; T-siczle tezporal; Tr-posterior teaporel; Pp-zolsr frcutel; Fo-per froztl; C-ceztzal; P-partetal O-cesipital: F=-ccisn frezzal; C=-=die eestrel; Pp-zedies parietal...

The 7 graphs in A above represont lesds fron the right half of the scull-henisphere and tho contral line.

Tho 7 grapha in B abovs represent thoso rroa the loft half and thc centrel line.

The tracinzs to the left of the vertical separation-recorded before Lsp-25 injection--are charactarized by an alpha-vhytha from the parietal, terporal and ossipital regicns of l0 cycles per second vithout a central beta-rhvtha.

The tracings to the right--rocorded 3 hours after injaetion of Isp-25--shoy the aloha-rhythn froa the sare regions.irith 13 cveles por second. and a beta-rhrihs in the central regions iith 21 cyelos por second.

[PAGE 75]
leI  Aplati  tr an pu de I5  ebe, ltatépose ¿dite, r (er apean e LSD .

traef le peges lo lazi) (metll6

trn 1) gut,

B

FiMiatiemeat prepryif do trarpr  petitsn dLD. ttes dues rensin diquérs dun lgur Latahte our un lapins Jr 1 0.

.C

Fig. 2  Répeass do tearé préalsbiemrat aplati pa l LsD 2 & diliérestes biqatacer du tiroimtvpt.

[PAGE 76]
Figuro 5. Eecuct or IsD-25 oa the Eloctre-Corticocrerh lio

ly J. bolay et al.

The clectre-ccrticograph, as a record, results fros thie use of clectroles in dircct contact vith the ceretral cortex. The nost charectoristic result, so different frea the électroencephalogram, is the flattening of the tracing by LSD-25, signifying the susponsion of the spontaneous rhythmic astivity of the brain. This contrasts with tho persistence of rosponses to the internittent light stimulation of the stroboscope.

A. Tracing of cortical layer vaves. At left: nornal;
at right: flattoning after injection of LO gama/kg LSD-25.

Tracing of cortical layer waves of the avake, resting rabbit. ravolt. n is al reetine

Traoing of cortical layer waves of the awakc, resting .rabbit after injectien of 15 ga=ia LSD-25.

Tracing of corticel layer waves of the àxake, resting rabbit aftor injection of 25 ganza LSD-25.

Tracing of cortical layer waves of the awake, resting rabbit, after injection of 35 ganza LSD-25.

Tracing of cortical layer.waves ef. tho axake, resting rabbit 18 minutes after this injection.. Tracing of corticel layer waves of the awake, resting rabbit 2 hours after this injection.

B. Progrossive flattsring of wave tracings by Faall doses of LSD-25 in rabbit (2.5 kg.)

C. Responses of wave tracings, previously flattenqd. by LSD-25, to diflerent speeds of.the stroboscope.

[PAGE 77]
Fizure 6. Tho Rorschrch Teat fer thn Cffeat of lsn-35 ob the tind. 55

Tho voll-knoun psychological test, aiso referred to as tho ink-blot test, soacvres cortain treits and Cencral personnlity trende, based upon ths subjeet's interpretation of. ink blots of varying design and color. Theso tests nust be cnalysed by expericnced diarnosticians, uho nay.gain an'insight in the psycholegical structure of individesls end thus discover hidden emotional tchsions, repressions end attitudes. It is logical therefore, to use this test also on individcals wnder tho influenco of LSD-25, since this psychogenic substance affects the emotions and porsonality in general.

This test was actually carried out by W. A. Stoll on 1l adult subjects without apparent mental abnormality, under the influonco of LSD-25, aftor receiving 30 gaasa orally. liot less than 3 months later the test was repsated without. LSD-25. Conpariscn of the results with and without LSD-25 indicated a general loosening of mental prccesses, disinhibition of affectivity and flueney of thought processes. The Rorschach syndrone under tho influence of LSD-25 corresponds to tho clinical picture of an intoxication that is regerded-as wnspecific and as an instanco of the exogenous reaction typo. Besidss typicel psychoorganic traits others cccur suggestive of schizophrenia.

This is, thorefore, one further test that may be carried out on humans to exanine the efzect of psychogenic agents. Ink blots Iron the Rorschach tasts are illustrated to indicate to the reader the greater variety of nental inpressions suggested by these indefinite forns. No matter what the patient's interprotations--vhsther he sees a bat, a gorille, waiters boving to each other,, a girl riding on a horso or perhaps a nan's face in the shadoxs--he unknoxingly exposes his intimate fantasy or life and general personality trends.

[PAGE 78]
Ficure 7. pcfect of Isn-25 tn the Bood Adranaling hevel ana e

Dy D. W. Liddoll tnd .Toil-Malherbo

The peychelogical effects of drugs and their applications in psychiatry are of great interest, although little is knom thus far of, their nechanism ef cction. The authors therefore undortook to study the changes or blood adrenaline lovels and to corrclate then with mental changes. Adrenaline was detormined on carples ef plasma taken froa 3 patients ater oral adrinistration of L0 gama ISD-25, and tho results were plotted on the eccompanying chart.

These bicchenical studies shoved that one can distinguish 3 phases in psychotic pationts .after oral or intravónous adninistraticn of LSD-25:

l. An initial rise of the .adrenalins leval..

2. Its drop below the starting leval.

3. A secondary rise.

The rising adrenalins concontration, soemingly esseciated with tension and anxicty, often with shivering and an appeerance of Ecose flesh; the falling adrenaline concentration appavently connectod with relaxation and euphoria.

[PAGE 79]
Figure B. Vantal aud Nuseuler Disorder ResnlUng fros Tare mr o2

By Y. do Giacomo

Tho adninistration of 300 to 500 gama LSD-25 to psychotic paticnts lod to rosults not unlike those observed after administratien of bulbocapnins-cxperisental catatonia.

A. Faco fixed and inexpressive.

B.. Loaning posture of heed and trunk.

C. Greatly prolcnged muscular-inacticn; head, arms, end logs raisod above the bed level..

[PAGE 80]
Pirure 9. Effocta of 1.9 nnd tcn-29 ca the Hovenont. or tho

By. E. Rothlin nnd A. Corlctti

Tho waltzing couse represents a special strain, having a congenital and hereditury tendeney to earry cut characteristic internittent circuiar turn or vaitzing movenents, illustretod bolow in a slow movinz picturo record.

These rovementt are possioly caused by a disturbance of coordinating functiens in the brain sten. There is now evidence that psychozenic substances such as ergot allaloids and thoir derivatives variously afsect this behavior and thus prosent a uew mothcd for their study.

After edainistrstien of ethyl- end diethylanido (LE and LSD-25) derivatives or lysergic acie, (the hydrolysis product of the ergct alzalcids,) only partial turns are carried out with shert turns to the left and right.

a. Slow moving picture record of a waltzing mouse.

b. Course of moveropts of a waltzing nouse bofere (left), and after (right), the isjection of 2 ag. per ke. lysergie acid ethylamice (and ISD-25).. Tizs exposure in tho dark, tho animal havinr. been rencorcd luainous.

[PAGE 82]
Firuro 10. Tho Effogt ef LOD-25 en a Ssidor's Wuaving AS11UY: 2/

By P.nitt

While man shous narked constitutional and tuzporal flucteations in Soth subjtctive and objective tests, the spidor,:ith a rathor highly organized nervous systen, shous orly slight Mluctuations. Its wrge for web construction nay bo used as a sensitive qualitative and even quantitative reagent for drug influence, provided the tosts are mado during the wara season of the yoar.

With LSD-25 tão spider produces a perfect web, since the distractions are evidsntly culled; thus he can concentrato en its construation and an inproved exactituds of the angles. (In contrast with mescaline thoro is an increasing irrcgularity in the construction of the web and à decreased accwrecy of tho angle struoture.) Xothedrine or pervetin overstimulates and thus prevents coordination and completion of the web.

a. Nornal web; presenting spiral threads, coiled around spokes, shich radiate fros the hub or the spicer's resting place.

b. ISD-25 web; perfected by the improved utilization of stiruli, the Ereater exactitude of the engles, the check on distractions.

e. Nethedrine eb; incompleted and spoiled by overstimulated, restless andt restricted weaving.