tn tti CL 5 tD (-S 6zv) Cie qp Page 2 WORK ACCD.4P L I SHED TO DAT MEN_ WI@-I The re c-ru I trne n t a n d began in July,. 2 I Us$ The training of p@e'r-sonnel was completed in [.,a t c@septem,ber and an additional resear.ch ward was opene .d In October 1951. The work 2on the-human pharmacology and toxicity of.3-methoxy-n-.. methy[morphinan, as well as the work on the defection of euphoria, was completed durinc the s "mer. Work on the relief,of.abstinence and substitutioa of this comoownd for morphine was complet2ed In December 1951'. The results to date.can be sumf6arized as follows: Doses of less than 30 MS. di-metboxy-a-methy[morphinaa produced no untoward toxic effects in foriner morphine addicts. Doses of 2 20 to 30 mg., effher hypo4dermically or orally, Induced euphoria similar to and eqt@-al ln,intensify to fhaf seen after the adminis- tration of 30 m morphine. Other morphine-like effects such as aauso_lay vomit2ing, mios-is and resoi-ratory depression'. were obseryed with the larger"doses. The compound was found to Induce Its effects more quickly when administered orall@y as compared with hypodermic -administration. It relizved abstinence from morphi.n-z 2 and cou Id be s ubs f I tv f ed f or r-iorch tne I n add I c4*-cd pe rs ons r Substituilloa was comqlete as contrasted With codetne,",whi-.h will not supp-ort...ohys icall-dependence.on no'rohine completely. Fo 1. t o @.v- lng- withdrawal of 3-.-nethoxy-n-riefi%yinorphinan after substitution for morphine, a typical morohine@-like abstinence syndrome appeared. For further details o2T' these studies see +he reports'fo the Drug Addiction Committee, National Research Council, whic,@ are attached. S7475-- by 3 d ADD I CT I Ctt FHET IC ANALGESIC' s TH [CH MIGHT'SERVE AS SUBSTITUTE$ FOR CODE IM BACKGRCUND INFCPJO.ATION In late June of 1951 $300000 was made available by the Depart.-nent of Defense for determ2tnin.9 the addiction ltablitty of dl-3-nethoxy.n.,.Iethylmorphinan (met.@oxy-dromoran) In the hope 'fhit this drug mig@'t- rtp'resent. an adequ'ate synt.,teftc subsfitwfe for code.ine* This grant was made:following fl@4a submission of a Project .4,escrip-tion entitled "The Determination of the Addiction Liability@of synthetlc-Analgesics of the Codeine Type." "The projject wa"3 supported for the following reasons: Dvc to;fhe curre'nfly disturbed International situation It was'possible tha2t the United SfLateS mighf be cut off from all Its usual@'sources@ of opium.. Synthetic analgesics are available which are entirely adequate for the replacement of morphine. However none of the available synthetic analcesics ara as safe for general use as is codeiii,@,. &!or.:! the.-. per ceii@ of the Armed Forcest rzquirements2. for narcotics i3:@or codel-,ie rather' th-an for morphine'L Finding a syn,hetic s bsfifu+e for u codel,t@ is, fhzreforc, of considerable importance and i.- was hoped that mathylafion of 3-hydroxy-n.,-nethylnorphi@ian a synthetic dr2u.-i of'morphi-ie-li!ee structure., would produce such a compound. Ttie f a c I 1 1 t I zs o f t h c Ari'd I c -t io n Res ea rc4@ t e r we re not sufficient to carry out the work unless additional funds coul4- be obtained. z4- 7 Declassif'ied by date PA41ilqpll tiol 4o I ppe ul U014Dnpaj 4uzlolj@nt q4tm Snip mmu P pizIA 4461wC uO!4!tod ul sdnois -ID440,-10 ladoid 'IA442 +O uOI.4n4l4sc4AS -zulzPOD se sr,,.or#Douul But .zq SP Pzr-IPI:@-zJ zq 0.4- 41 -IC$ A14uzl,->'.J$ns PD-DAP2,J 4 Ot: t Ph% ZA 1 4 PA, I J aP 2 q 4o A 4 1 1 1 q p q A w 2 I U01.4zlPPP'z@4 4n uOl4PI 4.4 a Aq ui)1.4zzJIP jzdoid 344 ul PDJZ41P $PA% uvl oujojp lo A41AI 4DP z44 4L'44 St 021-1,32 uPiowo-21p a44 ul sSn-IP lPuOI41PPP DS344 f3ul4PS149DAUI JO$ UCSPZ la zql epzlpn4s 209 ll!m E j3qwftN uOI4120d ut lA44'zw uPq4 10440 $4u2ln4l4tqns 441^ UPJOWOJP 2 10 SZA14PAIJZP lPuOI41PPt' 4P44 padoq $1 41 "J24PI '*A41ilqpll I UOF4:'IPPP mol ATZA z,Apq illm Alqpqo.Ad pup padolZAap, Alitau p Aq pzbpnf spj (Dlu4D24 $SOP ul 4u2lf>P ZAltt'n4l4uP 4uzllzzx,z UP aq o4 ples SI j2owotl AJ04P40JOJ4xaP@z44 zsnpdzq P21PA4$ Sulaq ZJP ueulqdjowIA44zw-V -Axoq4atL--E lo sjztuos a q.L 2 Z I J.ZS 2,UOPP44ztu' D44 Ul tz4PJDIfA 2wOs 441'h Pup uPA.,owojp-Axo44auj 10 tJzwOcl AJO4v4OJOA31 Put AjO4P40JOJ4x3P 2144 441'A 00 SuloS ^ou 2 szull aSD44 BUOIP IJOA *upulqdjowIA44zu-$-tl-4xO44au'-E-IP St UP44 Bill-aulapoo ajow' Sulaq jo atlwojd zAP6 qDI4^ SAJP P..Sulpulj $o ado4 244 ul S2pOAO 41al tPA 41 *Snip IA2,u 2144 04 S401PPP zul4diow/40 uOl4zlPPO 0512 J 2)U.-J 01 4DzJlP 441m SIPZP 421qiA ainpanoid IP4uzwljadxa lpalblj'o JAO 10 DA14 4JPd 4Ao palljPD 4.OU ZAP4 4ZJOj3J2044 '621 varn IPJ2kUaS jol aulapod to alet SP Oulaq se-pzpjo6aj aq 40uu]?D UOSPZJ '$144 iol pup Ilaulqdtow JO 4P44 0 4u3l*Alnba A41103001qpll U014:@]'PPV spq tipulqdjowIA44 P44 SnOtA qo SI 41 zaminder- o f t h a v a ilable under- hz current gr!ant from the DeACt;t -n f e must be. Spe I2 n screening, It Is hoped that an additional grant c4n be obtained for continuat,ton of the. work'during the fiscal year 1953. if a promising drug 2 Is revealed,by thC.3Creening.test, intensive work'with it will begin as soon as Possible during fiscal year' 19S3. if so such drug is founds screening should continue, 2 EXPERIMENTAL PROCEDURES Drugs being screened will-be subjected to-the following types of I n ves t I ga t I on: A. Huma n - P ha rme co I o a and Toxicity. This involves thz 2 Mr adw. I n S t ra t I On of Progressively Increasing doses of the drug under study to hu;-nan voltinfeers chiefly former 2 morphine addicts Observations on resplrafo;ry minute volume, pup-,i,flary size blood Pressure and pulse rate, etc.', are-.,'made following i't5e administration of the drugs'. S. Admtn2istration to Human Volunteers of Sinple Doses of the Drups Bein Scree 19 ned for the Defection of Eu;Dhorla. This expert.-nenf Is conducted in exactly the same way as the studies on 2 human pharma'colog,/,,.excec' t ffhbf detailed obse.-v.,aiL91otis on ihe phystolo _cical,eff'ects 'o f the d ruc are ,io made., 2 beca-us e t a k Ing -ble effects Of Ob3ervat ions ten,-4s to ne-gate the p I eas' ' ura T %yo -2-ne t hods- are used for gau ging the OT the d r,u gs "euphortal? induced by the drugs.. These are, 1) unobtrusive clinical observations for the appzarancz of behavior rzsembling tha2,l seen- after the administration of morphine, and 2) the admi-nisfratton of Projective psychological tests. 187475 be4classifis d4 @E- date age C* T-he t"n I tfea t I @S-1 iz,,q.te Doses of the 1) r v Under Study to en-f-s Showtnci Signs-of Moderate to hiarked Abstinence from Opiates* Any drug-whtch.. on the basis of the screening test, appears to be promising as a potential substttufe for codeine will be subjected to additional s-tudiesee@ 1) substitution of the drug for morphine in strongly addicted persons$ followed by abrupfwithdraw2al of the new drug, 2) direct addtcti-on of fbrmer morphine addict volunteers, under.two conditions (a) 'very hig@h-dose levels,, such as would be expected In'tinaturat' addiction under conditions of abuse, (b) conditions of low-dosage, such as would be expected during long c2ori'tinued clinical administration of the drug. D. Evaluation of Data. The drug we are seeking@ .should have the follow.ing charadterisficsoo, 1) It should be a weak analgesic, as Judged by,@ntma.1 experimentation; 2) The ra2tto"of toxicity to therapeutic effect should be favorable in both animals and man; 3)@ It should be a good antitussive agent; 4),should relizve abstinence from morphine only partial-ty; 5) s,@ould not substi@u-#@c for morp.%Ine complefeiy; 6) should Induce only a mild grade of physical depeadehce la a@,i f-,.-s f dos.30e* n I nf orna t I on submitte:d to t @-i eDrug Addiction Coir,,nitl2ee by the pharmaceutical companies and universities wtil be - sufficient to evaluate the actions of fhe drug7 i-n an-imals. Studies on add on,4 la tt,-,,teld I:nformation on the toxicology;,. p ha col;ogy and euphoric potency of the drug to man and on Its ability to produce znd support physical dependence. From these data a satisfactory evaluation of fhe addiction liability of the com2pound can be made. E. Location of the Project_. The experiments described above will be carried out In the Addiction Research Center U. S. Public Health Serv.lce Hospital, Lexingtonj Kentucky. Thts'hospitat Is devoted entirely to the treatment and study of drug addiction and Is the only place ln'the world whe2re a study such as those described above can be satisfactorily carried out. "The lnstitutiot) provided the two necessary facilities for-this type of work.& 1) a-targe pool- of pattent@ volunteers, 2) strict environmental :Control which prevznfs @the Introduction of drugs other than those under study Int2o the situation. F. Exoerlmental Personnel. The work will be carried out under the direction of Harris Isbell, M.D.p Director of the Addiction Research Center. This tnyesfigator has had -o-t- I cd r @rg- a dd I'c almost eight years experience In nerc 2 tion and b astisted by- two other experienced &lied Ica IOfficers, Dr., H. F. Fraser an,4 Dr. Abraham Wiklerl both of'whom have had extensive experl'znce In research In addiction and h-ave many pu-bitcatlosys In this field. 8 15' 4-F-E 6--i add It -th the 41@ a t @Ttr*o n n c I t h e part-t.ime -services of. a heffilst and a PsycholociSt W I I I he -.1 A ci O.' rvaflable. Sub-p2rofe$31onal personnel I n-c I ude 5 Psychiatric Aides a Medical Technician, Biological Aide, Ser-urity Aide- .a@n,d Clerk-Stenographer. -A special- ward for condttcfing these studies lias already been set up and Is 2 In operatio'M'a G. Estimate of Cost. Personnel 'S Psychiatric Aides GS-5 I Clerk-Sfenogr'apher GS-4 ----------- I.Security Aide CPC-5 2 ---------- @-I Medical Techniciam t Biological Aide GS'- .6 - - - - - - - - - - 20 ke se 'rve- f or n I h td I f f e re n t i a I and ..overtime pay, w I + h i n'-g:r a de rat2ses, efa 3. Miscellaneous @e'xpense3 It should be noted that personnet cost for the fiscal, ym r 1953 will be higher due to the recent salary Increase 0 er fed vernment 2 iployees. Ifem for miscet'laneous expenses Gran @e of drugsj, chemicals, glassware' 1.1cluje,s money'for the purc.%aj d h foqra ic. papee 2 p .r@p@, I,c- an. p o 7 Harrit Isbell, NA.D. D I rc- i-arr- a-a Resc1arch Hi:rn Attachments 2 4 January 1952 Ir, y 37475- 4 FES l;j7i