ry, ti 4* 16. 2 Z iz (70 W f" 2 ri 31 0 406 at C 2 Al W In 0 W C a et a ox A x lot 'O (V) 0 0 0 C-4 OD a 2 a in L. U iq W -n Z ;i 00 F U W (A 40 a 2 ta de 4* OL 9 IU C C 0 0 U W to 2 40 9: U L. S. 1. xu Ott 1= 40 40 de F- 2 C W tn fn n Ct tO 16 m C4 :1 AD. 2 if) fo C'h CL ow ik Y-V 7( I to' 2 10 0 4- tj 2 10 v C 30 a to 0 W 16 V 4. $* W #ICI 3Z in , C W C-. = 0 W 09 U v 2 -IV .13 16 a Ch C) 2 0 to 0 tv 40 le le 4U C.." i;c 2 t the disturbed, International situation It it pass-lble that the United States might be cut off' from *11 its usu#l sources of opium. The single source 2 of codeine Is from opium or by synthesis from morphin4 derived from opium. At the time the projects were begun, there was no synthetic compound -!genera I se as was -codeine and avallabig which w4s &2SI safe for' u *Itholugh synthetic analgesics were available which would be, entirely adequatt@for the replacement of morphine# no synthetic was available which was as safe as codeine. W4reover, crore 2 -narcotics than 60 .0-er cent"@'*f the Armed forcgst require-meats for were for codeine rather than for morphine. The importance of the project Is therefore,obvIovs,,but unfortunat,ely the facilitie2s of the Addiction 2gsearch Center,--,acre not sufficient to carry out the work unless add.ttlonal. f-ind;s@ could be- obtained and,, of course, the work cannot be continued after July 1. IQS3 unless addtfldnai funds are made available* 11. %CRK ACCC?.P, t ISHD TO DATE Part of the work accompltshed I-* 6,a c- was- emb*,ct I @-d I, n .the- _Snnlja I prc!gg s:'-r-4e;)c r ts#,nt, 0 Dr. 2 H. ".@.u-!.nby P; of the ?hysl'ol'o.gy ?,ranch.. Offite of Nava I PCs earc!-,@ In faruary 1953* It may be briefly summartzed &s@ follows: Declas-sifi d ki, IS7.ti S74757 I FE-B to,- The ra c e,-n I c 3-methil--ether of N-methy[morphinan' possessed too high addiction liability for It to be,regarded as a safe substlfutt f r code I ne'. 2. 2All of the addiction liability of rocemic 3-methyl ,Cihier of N-methylmorphinon was found to be due---te.1th-c l.everetatery -Isomer* 3* The-dextrorotatery 3.qntthyl ethar of Nmcf-hyl-norph. tjtq_l Is devoid of addiction liability* Stec* this compound had been r7e--iort-ed to hsve powerful antitusstve effects to animals extensive clinical 2 testing in humans Is being carried out 4itsewhere. ?retlmlnary reports of rtswits were madc-*t tht meeting of the Drug Addiction Cc,=itteej, National Rtsearch Coune'll, in January 1.1953. Unfortunately, the reports of thg.-citnical-efficacy of the drus w-gre-conflictin-, #ad the mieff-er Is not as yet set-tiedo 41 This drug was found to possess fec high addiction liability 2 to be rec.-arded as -I li@fe $,-n#hctlc 3- avers 'It.is rather Ineffective whtn $;Ivcn orall.y and.-Products s i r A s i-de -c f@f ---Ftt'r@.her- lnvcz 2 ri rn a n t;n cf c It c f c@.a-tl of th 13 cc.mpound Is Aot **rr in t td S. dl, 6, and -t-2-2-diphenylamino-ethyl valerates. Work with-these 3 conpoun@ds has almost been completed. In dosas E)eclasslfied bj of@ 75 mg,j, all cc -we* mar lnt-I Ike tffects to former morphine: addicts-*, They are *Is* ret-st'lvely Inieffectivt In suppressing @bstlngncg from m-*rphlne. The low poteacy and low-addictlan liabilities of these compounds suggest that pre. limi'aary clinical trials of antitussive effect and side reac'tions are warranted* This compound has pro-.)ertl4s similar to those of the vsterates and, 2 therefore deserves a preliminary clinical trial. 3w III* KED FCR CCNTINI.ATICN Of THE PROJECT Alfhough qhe work to date has uncovered f'ive drugs which may have 2 posstbil.Ities as sy.nthetic substitutes for codeine, we believe the-project thould:be continued. The ,nost promlstnri of.the dru.gs studied -ti; the d-3-n-.ethyl ethtr of N-?ne t hy I m2.arphican. jhit drug Is completely devoid of addiction liability and has low toxicity. Unfortunately the reports concern-log Its clinical efficacy art conflict-Ing and of the moments If 13 not certa-to that It will serve as an adeq vate substitute for 2cocleint. The other four drucs have not be e a t."t ed. c I. I n I Ca. I I t Is,. be 1, I t V,-Od - tN i t' t htv 4r* @,norc @tcxlc., side rg,a.ctlons may 'De ;.ircdt-,Cedi for this reascrrl we Cann")+ certain that an adequate synthetic substitute for, codeine rs y-et on hand@o E)eclassified by -1 87475-@ date propost I n's addition& I drugs for t. period of one- yt4t, The drugs to es fed includes movidhinanj 2)' 1 and e. 3-hydroxy-2-n-dlmethy'lmorphinaft- 31 1 aitd SL 3-@ropy2l ethers of 3.hydroxymcf;3hinani 4) other agents as may be suggested after C003VItOttoft with fh;e Drug Addiction Committee of the National Restarbh "-'Ouncti. vo METHMS TO St. USED Those methods are the same as thate described In previous .projqct descriptions and in- the st-mi-annual report to the Cffice of Naval Research. They Includes 11 Deter mination of t4u-n,&n Phar.-teciolzr,-,v and T,--xicfty. This Involves adntnistratlon of progressi-vel2y Increasing doses a-f the dru!; under study to hum4n voluhteirs, chiefly former morphine addicts. t--bservat-ions on respiratory minute voluir4e Ile pupillary stri., blood pressure, pulat rate etc. are made folfowtn.; adininisfration of the d 2r U!G- 2. Ad:ninistratina r)f sill:le !@cs-es for the Defectinn of -ordticied in exactly the S cn2 wa y 4 Ifhose on human pharmacolory excc-:,f,dctailed-. f F. r- V @6 h 2 s. f o-c t ---i, i: r uare not .M'*dc,s because fli ct a k i n c,- of ahystolcsic.41 obsc-rvatlOn3 t Ctld S to ne-ate the picasurable cffects of the druc@s. New metheds -k used In gauging the 'euphoria' pr0oduced by the aruc.. ar Ceclaszified by 4--rl 8747r, date .Page 6 0 These are-, I 1--una us i7v'e c I in tc&i observat ton- r- the appear. -ert bch*vtor resembling that seen after administration once of ov of morphine, aimd: 2) oidmin2istratlon of projective and other tests. In both of fhe ab*vc types of tca.tlng,, drugs ore given to a randomized b&lance arder'and by code-. The order of administration Is unknown'to both the subjects end the observers. Both poiltive end negative control drugs (morphtnt..,-ccdglns, and pieceba) are used* 3. Administration of i)osts of the Dru@,,- to Patients ShowInr" Sic-,is of @Abstinence Fro.-n i@!.arihtne., This, type a.f ex,.crlmcnt2 Is c-&rried out by 0".t4intng patients who have been- taking larige- ar,-@ounts of opiates d4lly. Aft'tr stabil lZ3f IOA an the least.aenount of -mor,,)hlng whiciv would just ;;rcven.t the &P;:Iearan2cc of signs of abstinence morphitte it. abruptly wlth- drawn for ;>eriod'of 30 hours. At fhls time a slnt,-Ie larce dose of the drut,-, under study Is administered and observatt--as for intensity of abstinence 'are- can I nuttj* n c 2 -the t. a r-- e the ad:ninistraf ion of."@rph'.1ne end of cct!ctne @to -C. I W -a CZ lock. tar, for druos which h*,ie I i i I'c. or no effects on alstinencc from r-mrphineo 9 Declassified by ;Jat!3 m@or;h Inc. This 4 Suporession of technfe-reprosents the more- se.-tir t t tve@4r4f I acme-at of the oug d" igned ab@ove. Patients lth-stra'ag domendence, an morphine are selected. After2-& suitable stabilization 'pert6dg__the morphine Is abru.:)tl* discontinued and the administration of the test drug is begun before signs of abstinence *;)Pear* If 4b*ttaen'ce ls@.Supprested compt4ttqiy.of partially, adin2in-istra. tic* of the new drug Is continued for a period of 10 to-14 davs,, iffer which It Is., &bruptly withdrawn and observations for signs of absttnencar are@ made so Dlrt-et Addiction. Tta Itcch,ixtc tfivotv2cs the -administration of sufflctently@-'Iarse arrounts of the drug under test to former mor.phtne add.Ict volunteers vho h-ave been ,abstinent for a per@tad *v' at least three monflis before the experin-ent'is,be un. Suitable observations for-the detcctic2it of toterante are c4rried out during th4c period of odmintstra- tjon.- After 30 days,or more of chronic Intoxication,, the test drugs are abruptly wi-thdrawn. VI EVALLIATIZ@N i.-OF '&'dATA seek-Ing thoutd,@ave f@.e fo I I w 1 -'The drug -Wit-' 4 f-C . -s t'i -Cs I'I tS',So.u I dp r' bt -be -,a we4k',6na-ige:s '3'c -char,scf er i C04 y ,as jud ed by animal expertirentation- 21 the rat to- of to-I IC Ity to therapeutic effects should.be-favarable In ani.,.ials and In manj 3) It should'have a n t I t ti-ss-- 1 v-e.: e'f -f e c i s tn. animal oharmacol- agic4l exieriments- 4) it should be a C-oad antitussive agent Declassifi5ea date @YFEB 1977 5 I thoutd@ 'rel love or suppress ebstineAct from only partla I lys.- and prcfers-bly not st@ Al I; d, I It should ln-ivcg only 4k Mi-id@ cr4lde of phys Ica I d peade 4 ace undar. conditions of high dosage, Information submitted by: Ph4or2MaCtUt ICA I f IRMS I nd universities concerning drug's whlck sh ould bc tested will be tvatuate the act2i" *as of t@he drug in a ft@-tma l@s Studies an Its addiction liability will yield information on the pharmazolo ,c; Y. toxicology And. euphoric 2 Potency of the drug and on Its ability to produce and supp*rt physical de.2end4tnce on morphine. Fr@6m these data a satisfactory evaluation of the addtcfion ltability'o.f thc@compouad can be md2de. The deter-@itnation of a.-ititL-s,,sive effrtt mus--t be done el3cwhere.. Vil. LOCA@Ti-:)N Cf THE --Q(-IJECT The exptri.-nents described above 2 wtll be,carried out fit the Natlenal Institute of@tei:ntal Health, Addiction Research Centers, ilubilc,,.H,c<h S4rvice Hospital, Lexington, Kentucky. This hospital Is dzvofcd2 enfirtiv to the *f drus tddiction and, at the curri"af- ffne,,. Is fSe rnlv .0face a'c + .1 rr th e - vg,-i I c4- r -2- "I,e, s c-, s' r-. out. The-Instltvtlcn provic!es ,,Se two -tzccs@sary f,3cilitlcs for t h i s type O'f work*. 11 a po-o I o P-i'f I c n t t iiho will volu,-t2tcer for of the ty-,)e t.1-es'cr'@s"'bed above; 2) strict envlr-.nriental contrt.,I, peclassiijeci by 7 date of drugs ofker t htn@ those undtr study into the exatrimenta s I t'ud t Jan. Vitt* EXPER IhiENTAL @FERS:WT t*rk will be carried out under the direction Harris fsbglf*l M'.0,9 Director Of'..the Addiction Research-center. This inve2stigator has had nine years of exotriencg In research in narcotic dru addicti oft and has Published many Papers in this-f'tcld.. He will be *Ssisted,by two other txpcrtenced Physt,cf,anso Dr. H. F. prasgr and Dr, Abraham Vikitro'beth of when. have had ext"cnslve 4t*pertence In research In ad4ictlofts and have many publications in thl s fl4t Id.. In addition to the medic-II personnel, the P@4rt-time o-crylce.-s cf a blochtmlst 2 and--a- Profcsstcnal psychat ,cc- Is iwill be made available. A Special word for conducting these studies has already been sgf UP and Is in oper4tton of the time this project 4*scrip. flon is being written (-April 30, i?.53) 8 @ecia:3sified b-1&7470--. c 4 @EB 1977 dats' I EST 1.@.@TED C@7-ST Personnels 5 Piychiatric Aidas GS-5 I ilhys Ica I Scienct Aide GS-4 I Securify Aide C?c.S Sycboloi;lst cs-s 2 Biological Aide -GS-4 Reserve for Nl!gh t C- I f f crett f- I a I -Re V I t b I n-C-rade raises Vert 1. etc' Pays s @4ts el2l I lantous Ex@eASCS'@- To ta item 3 -it$ eel lancous. Expenses' Includes m-oney f or fhe purchaz'ia of drugs, Che.-ftIC413 glas!;Wdrcs e..iectrotn2ccp4dl. -ocraph lc atid ph tographic papers needtesp syr-I nces., c 2Tsearch- Directoro Declassified by -187475@ 7 d 4 EFQ l@Z-7