Doc 0000151840

THE ADDICTlOii LIABlLlTY OF SYN1'HET1C SUBSTITUTES FOR OODEli~ (Project Dcscr1pt1cn) to the Cfflee of Rasearch tor of Req~est r~val Renc~l Contract Nn 101-149 · (NAonr-17-~6). 1. !nforr:-.at!cn. Bt1-c1~oround Since 1951 the r-:atlo.a"'lal Institute ot f.~ental Health u. s. Add1ct.!on Researc.~ Center, PU:blic ·Health Service Hospital, Lexington, Y.y., has been carrying o.n a proj~et ·designed to dcvalop a synt!1etic: subst! t.ute tor code ina which would ba as safe as codeine and effact1ve with respect to tox1e1ty, a~ antitussive activity. const!pat1va act1v1ty, and addiction llab!l!t.y. Tha p·roJect has .bc~n financed ln large part by funds orr or from t.h12 lee !-laval RGsearch, and t.his descr !pt. ion eonsti or tutes a !or the project !or the period re~~est rene~~l 1 July 19S9 to' 30 June 196o. The ln!t!atod synthetic substitutes proj~ct ~~s bacau~e for codeine were badly nee~ad since op1~~ or ~rph1ne derived from opiu.--a constitute the only sourcas ot codeine. Code1ne is the mo~t widely used narcotic drug in bot.h c1v111nn and miltto.ry rucd!cal practice. Th~ United States consur.~s 16 to 20 tons of this drug. yaar ly so that, u.."lless actaquate synth2t lc subst! t.ut~s f! i /] -//. - 'r-- -· !n order to provlce adequate supplies tor both the civilian nnd military population tn the event of war~ The rae111t1es ot the Nl~~ Addiction Research Center are not autflcient to carry out tllls wrlt 1n add! tlon to tha evalua t.1on Qf potent new analgesics submitted by Lhc Co~~lttee on Drug Addictlon and Narcotics, r~tlonal Research Council, unless additional funds or are suppl1e4 Department Defense. throu~~ ~~e 2. Work to Accornol!sh~d t~te. Previous work hGs been su.a~r1zed in annual progress reports roruardecl t.o capt.. F. H. Quimby and capt. T. 1-t. Rucbush, Head, Physiology Dranch,·ottlcc of Naval than Resear~~. Mo~~ Sl drugs ha.va been screcncd·as potential substitutes tor eoda!n!;. Two very promising substitutes tor suppression ot cough, de7.tro and narcotine, have been discovered and both ara on methorp~~ the market. Nalther drug ls addictive and both are etrect!ve . and sate cough suppressants. llarcot.lne, un.rortunat.aly, ls not a synthetic drug but a by-product of oplu..~ processing. l!otJever, · continuing reports to the Committee on Drug Addiction and r:arcot 1c:.i* iffiC, and clln1cal reports 1.n the mecUea 1 11 t.era tur~ lnd!cato that both drugs are e!fectlva couoh suppreasant~. The anti tus$1Ve phase ot t.'1e problem is therefore, ln a sensa, no longer so· urgent •. /J-/IC e· The image displays a digitally rendered graphic on a black background, featuring a large, ornate vault door on the left side. The vault door is depicted in shades of gray and silver, with various gears, dials, and a prominent central locking mechanism. A bright blue, abstract light emanates from the right side of the vault door, casting a glow. To the right of the vault door, white text overlays the dark background, introducing "THE BLACK VAULT" in a stylized font and providing information about the document's origin and contents, including a URL. There are no photographs of people, handwritten annotations, official stamps, forms, diagrams, tables, redacted content, or visual evidence of experimental procedures. The document contains a typed title, "THE ADDICTION LIABILITY OF SYNTHETIC SUBSTITUTES FOR CODEINE (Project Description)", followed by a contract number. There is a handwritten annotation in pencil circling the number "150" in the upper right quadrant of the page. The text is organized into numbered sections, with "1. Background Information." being the only visible section heading. Handwritten in the bottom right corner is "B-H." and some illegible markings. There are no photographs, diagrams, or tables visible. · continuing reports to the Committee on Drug Addiction and r:arcot 1c:.i* iffiC, and clln1cal reports 1.n the mecUea 1 11 t.era tur~ lnd!cato that both drugs are e!fectlva couoh suppreasant~. The anti tus$1Ve phase ot t.'1e problem is therefore, ln a sensa, no longer so· urgent •. /J-/IC e· ~-· There are ho\."CVer no compounds available \1hich arc lmo\:ln to b3 as err~ct1vc and as sate us ~odoine for tha relief of - mild grades of pain. The outstanding substances ~o far uncovered ln the progrnm are ,:!!.- ana .S-Alpha-4•dimethylamino-1,2-d1pllenyl- # (..2.!.- 3-mathyl-4.-propionoxy!>utana or !!~rop_oxyphcne, "Darvon"). or Addl~tivcness these drugs 1s so low that tha Cor.mltt~c on Drug Addiction and I~rcQtlcs han rul~d that they need not be subJected to the controls Imposed ~y t.ha harrison Narcotic Act. Pre1!~1nary cl!nlcal data 1nd1catad that these druo~ ~~re nearly as errect1ve as codeine ln relieving pain. Unfortunately rnore recent 1ntormat.1on is not. nearly so tavorable, and we are now uncert31n·as to ~ether propo~yph~ne will be an adequate substitute for cadcine tor pain relief. Sufficient cl!nlcal data a~e st.lll·not av3.11able to assess toxicity or the compounds ln clinical ordlna~y p~actlcc. ? During t.he past year 3-~1ethyl-N-desn-.cU1ylr..orph·tna - (norcodelnc) and. d-methadone were sho\\'%1 to be less adcHcttve than codeine. Clinical trtnl of both substan~s has been recommended. 1-(3-D1pheny1-.3-carbonitr11-pro?Yl)•4-phenyl-4- ·· earb~thoxyp1pZ3r"1dine (n-1132}, '"ihic!'l hos been s..'"lotln t.o be extranely effective as a con~t1pative ag~nt and ~~lch may be capable replacing cod2lne or morphine for this purpose, o~ ~s stud!ed during tho year. Tilts c~mpound, though addictive ls IJ-/tff I -- less so than· codeine. TWo promising patent analg2sicsJ .3-Hydroxy-l;-phenet.hyl benzmorphnn (HlH-7519) and .3-Hydroxy-N- 1 . phenacylr.orphlnan (Ulit-7$2.$) were partly tnvcst!gated. Although 1 both drugs are many tit~s as potent as·roorph!nc, ab~t1nence ~s quite ~ild after withdrawal tollo~lng direct addiction experiments. A study of the 3•m&thy1 analogues of these drug.s waul d be oi interest. eonslc~rable 3• Need ror Cont!nua.tlon of the ProJect.. or At present, tha chlet J~st1£1cat1on tor ccntlnuatlon ~~e proJect !s the urgont need tor a s~stltute for relief of =ild grades or pain. As pointed out above~ propoxyphane no lonse~ seems to be as promising as ~s originally hop(;d. At. the mor.1r:nt. no completely sntis!actory substitute ror codeine fer pain relief has been· found. Fot-th1s rea!lon it ls cast;ential t.c continue the sear~~. OUrlng the period from 1 July 19$9 to 1 July 1960 we propo~ I ,/ to test the to be as promising as ~s originally hop(;d. At. the mor.1r:nt. no completely sntis!actory substitute ror codeine fer pain relief has been· found. Fot-th1s rea!lon it ls cast;ential t.c continue the sear~~. OUrlng the period from 1 July 19$9 to 1 July 1960 we propo~ I ,/ to test the clinical pharmacology and addict.lve propert.!a s of l 3-fi~ethoX"I.;-N-phen~thyl-bcnmorphan (the :na tllyl analogue ot NIH-7519) and of ;-r.~ethoxy•fJ-phenaeyl:r~rph1~n (the methyl 1 analo!J1!C ot !JlH-7S2.$). ric also will und.ertaka studies of !·3-Hydroxy-N•gamma ~~·dlmst.hylallylmorphir~n, n weak IJ".Orpltin.e ant.agcni st t.ha t. pos~csses anal ga#lc p1"opcart1 as • and fJ-/{f ot the butyl ester analogue or R•ll32. also hope to \~ .tn1t1ate studies on a nev group ot synthetic analgesics -- the b~nzimJdazoles. I~ add1t1on, studies of other substnnecv regarded a$ potential codeln~ subs~itutcs by the Oomm!ttce on Drug Add1ct1on and vll1 be carried out, as adVised Narcotic~ by that body. s. r~cthods. The cathods used are ~e stan~rd add!cticn l!ablllty testing methods of the Nl!~iH Addiction R~searc:h 03nter. Thc:;e tests arc acc~tea as lecal standards by U1~ Co~~itte~ on Drug · Addlct.ion and Narcotics ond have been descri.b~cl in previous cascript!ons, Which be consulted ror details. proJ~et s~ould 6. Evaluation of Data. EValuation of data has been covered !n previous project descr ipt.lons. 1. Location the Project. o~ WOrk will ba carried out 1n the Addiction Research Nl~~ Center, PHS Hospital Lexington. Ky. This institution prov!d2s 1 or the two !ac!l1t1es for the type to be n~cgssary ~rk undartaltcn: ( 1} pool of patient~ who will volunteer tor experincnts with druos, and (2) strict onv!ro~~ntal control, tth.lch preyents introduction of drugs oth:zr than those under stuay into the experimental situation. --·' Work Yill be out the direction of car~ied ~~dar itarr 1 s Director, HU·':I! Addiction Research Center. !~bell, M;D~, or Th!s !nvost.igator has hac! fifteen 1n rcsc3rch y~ar-s expsri~n.. ce . . on drttg cddiction and hlls nn ejttens ive bi hl iograp::y in narco~J.c th«: field. lfe will be assisted 'by .tlvo ot.hcr c~p<:riencad physicians. Dr. H. F. Fraser and Dr • .Abrahn:n W!Idcr, both c'C \/hom have had cxtcn.s!V\: research 1~ th.ls t~1;>e o!' ,. . ~ rk, and ~~ny · pub11cati~ns. The part.-t..tme services or a bioch~itti st, neurc> pharmacologlst- and rcsearc:..'l ps:;~olot]ist aTe also ava11a.blc. A t;pccial 1t.iard tor ~e ~ndt.tct. of these studies has bean mad~ .... ,.. available· by the hosp1 tal and !s currcnt.J.y This page is a typed document with a handwritten annotation in the bottom right corner, "B-110". There are no photographs, signatures, official stamps, forms, diagrams, tables, or visual evidence of experimental procedures. The page consists entirely of text detailing research on cough suppressants. There are no visible redactions or obscured content. research 1~ th.ls t~1;>e o!' ,. . ~ rk, and ~~ny · pub11cati~ns. The part.-t..tme services or a bioch~itti st, neurc> pharmacologlst- and rcsearc:..'l ps:;~olot]ist aTe also ava11a.blc. A t;pccial 1t.iard tor ~e ~ndt.tct. of these studies has bean mad~ .... ,.. available· by the hosp1 tal and !s currcnt.J.y In . ~perat.1on. 9. Cost. Est!r.~ted The cstL"'lat.ed eosts ar~ sho\..m on t-,_e attached sheet. The cmount. ct. money rccr..1csted is identical to t.llat )."equcstod tor t.he last yetu• (fiscal 19.$9) and amounts to The person~l services budget· r~rlccts some changes thnt have been r.m.de among th9 personnel ~rklng on thG proJect. !sball, i'1.D. liZlrr!~ Diructor 31 1959 J:.~n.u<~l·y P /~/ -... (/ iJ • . • I . e / 1. Personal Services 4 Aidzs (OS-6, Ps~~hiatr!c ·=~~· 1 Psychologist (OS-$) 1 .Anir.nl Caretaker (GS-3) 1 Clerk-Stenographer (GS-4) .. Prcr.lltml Pay .(n1cht. differential. holiday etc. pay~ . •· Civil Sarv1ce Retirement Total Personal Services 2. · Tr4V31 3· g1scallan;:ous (supplies., err.tipnent.. et.c.) TOTAL '...! • The document is a typed page with handwritten annotations. A date stamp "B-109" appears in the bottom right corner. The text discusses the effectiveness and addictiveness of various pain relief compounds, including propoxyphene and methadone. There are no photographs, forms, diagrams, or tables. The content is text-based information. The document is a typed page with some handwritten annotations. The typed text discusses promising analgesic drugs and the need for their continuation. There is a handwritten annotation in the top right corner reading "Page 4" and another in the bottom right corner that appears to be a document number "13-108". There are no images, photographs, forms, diagrams, tables, or official stamps visible. The overall appearance suggests a research or project report. The page displays typed text with a page number "Page 5" in the upper right corner. There are no photographs, diagrams, forms, or tables. A handwritten annotation "B-107" is present in the lower right corner of the page, with a short horizontal line beneath it. There is no visible evidence of experimental procedures, equipment, facilities, or any official stamps. The content consists solely of written text outlining research methods, data evaluation, and project location. The page contains typed text, a number "8." followed by "Experimental Personnel." and number "9." followed by "Estimated Cost." There is also a handwritten annotation in the top right corner reading "Page é" and another in the bottom right reading "P-106". There are several redacted or obscured sections of text within section 9, including a monetary amount. Below the main text, there is a handwritten "Attachment" with a date "31 January 1959", and a typed name and title, "Harris Isbell, H.D. Director", suggesting this is a cover page or attestation. This declassified MKUltra document appears to be a financial or budgetary breakdown. It contains a typed list of expenses categorized under "Personal Services," "Travel," and "Miscellaneous." Under "Personal Services," there are sub-items like "Psychiatric Aides," "Psychologist," "Animal Caretaker," and "Clerk-Stenographer," with numerical quantities indicated. There are also entries for "Premium Pay" and "Civil Service Retirement." The document includes a handwritten annotation "B-105" in the bottom right corner. Several vertical, shaded bars are present on the right side of the page, likely representing redacted monetary values associated with each line item.