(ESTIMATED PUB DATE) THE ADDICTION LIABILITY OF SYNTHETIC SUBSTITUTES FOR CODEINE (PROJECT DESCRIPTION) - REQUEST TO THE OFFICE OF NAVAL RESEARCH FOR THE RENEWAL OF CONTRACT NAONR-25-59, NR 101-149

• Document Type: SPECIALCOLLECTION
• Collection: General CIA Records
• Document Number (FOIA) /ESDN (CREST): 00151783
• Release Decision: RIPPUB
• Original Classification: U
• Document Page Count: 7
• Document Creation Date: January 21, 2025
• Document Release Date: September 8, 1976
• Publication Date: January 1, 1961

-
3. r-t.f.rt f'r Ctthuti the
Although a great deal of. progress 1.= been made and sub.stitatez rtre
'MO1,7 available for all par--.4..oses for which co-deim 13 used, !we til1 b.ve no
sinr.rie drars which is as ective and nonto;dc as code.ine. The arfo,gsics,
....
.�
rttr...--.71 ____..-1-,d -4,--t1.-",L-,,,....-t......._.,-1-1,-,r, are not ile,_-_,7,-1;:. ��"-s effective as Is c-odzine; cli..n.i...^,..z.0
.... ,....�... ,... ..... .... -.� 4m. . .--- LA ...� � 4. 41,4.4-.� sib ..., .......
. ,
�
inwrztigationoi 1-7.-1 is not".cornplete and further:none t.11:1t drag c...annot te
csiven by injection. lo zingle synthetic yst clitcove.md incorporn.- te3 all the
pro7nties of codeine. Vurther more data 13 ns,.e.,:led on the excretion, dizt:1-
.
bution, tolii and fate a these variot.r.; synthetic sl...-Lstittites.
44
ork :772-r�et...e.N"
-.. -La
Beteen I ,71:17 1.9;91 and I Zuly lzfn 7've propo2e, to test the clinical
,CCIOcrif rtd addictivcns
A 4 t.4.-o-Pi...-117.:ethylanaim-1-d r'� "3710 Uri
�
.sulZorie1,2-aimethy1.4-pherryl-3 pyrollidiml propionate ezter;
12 9 t". 7
Ir 47444.1437.7Pb.-4$ $ 4,4-14.7.7 4, ka tiss
1-2�.4'..eth-oxy-5�9-(11--rtg-thy-1-2 p nethy16, 7-benzznorphan; and
Acetoz7-3-=et.hyiamnir�...1-4; 4 -clipliterrgae. All of these corn:pounds have
been recon=ended or study by the Committee on Drag Addiction and
1k7atiora1 Pesemia Co=c11.
In ad-Ition the profieet on tie excretion of esoclatri,e and its n...etolites
will be corz:zicted asccn as a gas thromatograph Is obtained end placed in
opereen. rollowini this, dudes on the rastz.�,.,:tvAism. and fate a
ta4132, and pro-I:exc./VI:ens will be
tiatcd.
The methods used azv the Ettar-'f...,...4rd addiction liability testing' methods
of thr.: Addiction Fe--!-erizoil Center.
tosr.t.",are zccdCL-."^tk
ase
str..Inda,r-in by the, rom.;.---3' on .Dru..ej Arscucf4on and '0�-�
_...,rcotict� and save ben
described in previous project desori;:tions which should be conmated for
details.
The bic.,..ci".Tniwt.1 _methods used are also standard and Involve serArath.17...)
of the drugs ans.I their rn. sta`,...ilites by extraction with differential solvents e..�
various pil, zeparation from irbprities by rr chroziatography, ad
icd.'ritifir-tion by a variety of er.d reactions including gas chromatogrsphy,
ultraviolet speraphotometz7 and fluoresCS=Ce measurements.
G. r....,.,1111,von of ta
Evaluation of the data has been covered in prexious project d-acoritrtions.
Tar: L7v-rilLITY zuszTrr cc.1)=.
(Project Description)
Peciuest to the Cffice of rave/ Sesearth for the 1--",enec.,va1
Contract N.A.onr-25-59, IC?,'101-143
� ad irfo-4.r1At1on:
Zinc 12;51 the national 'Listitute Me.ntat Health Addiction Fesearch
Center has been carrying on a project With the object of disverinc; synthetic
El.lbstitute.s for' codeine which would be as tate as that drug with respect to
to:deity and addiction liability, and which would 10 be as eLtective
codeine az- an antitussive, anticliarrheai, and analgesic agent. The project
has been finarac-o-d partly by funds frn the C-Ifice of. Naval F:esearch. rrlds
descriV,Icra conditutes a reuet for ren ,e.val of the project for the period
.Tuly 11 to 30 :tine 1562.
Initially th.f:t project was undertaten becauc-e codeine was the mc-st widtsly
ur,ed narcotic drug in both civilian and military nledical practice. Cince
cc4e1re is dorived from opium, or made from morphine derived from opium,
this situatior_ made it necessary for the United :tees to stocl.,Ppile opium in
event of war. The facilities of the TIME Addiction Research Center were rr-t,
animals it induces a rather typical iipectrum of morphine-114e d:ects and
Its Prodgezic potency in animals is almost equal to that of codeine. In former
morphthe addicts only rnircir subjective and objective effects occurred-
following oral athrinistration of as much as A03 mg orally or 183
venausly. Thz.,- drag -ay..; otqy" 117th -as potc-nt as codeine intr' ?-,r:uscularly in
suoz:ressing aoctnence from 'morphine4 abrupt withitawal of
1-E--1 alter oral administration of doses running up to as much =1C Inv
daily for tt ctiths, o symptoms of abstinence wers reported. Cb7vioul..-17
is much less addictive than is codeine. D-aspite this, preliminary
worir irldlcates that the comr.7aund may be as effective as codeine in
relieving pain. if this is true, then I-K-I represents the greatest dc-grs-e of
dissociation between arr.r.ogesic poten^y and activeness yet achieved.
'Unfortunately I-K.4.:3 soluble only in highly acid solution and therefore is
very Irrita+-Ingon .170-1'.--tion.
.d."40%.1.0
B1ochezt-iw.1 studies on the :Tie of excretion, Incs.taboitarn, and fate of
codeine ware unde...t.t.k% the year. Codeine arid Its metaioolic products
were isoitcrl during administration and follovai discontimation of codeine
to 13rn6r 7morn'iln.e addicts, using paper crorsatography. The project in
rt complete inee final quantltation Is to be carried out, using a gas chronaio
qrah which h not yet been obtained. Arzc,-ng the objects of the project are to
cictGradne w.t7.irot:ortion of the codein4. Is 4.ze�mted as morphine and what
nor=,iine. This por�.'an of tho pr-3:i-act Is to be azt-r-ded to
of the pr :iIr.j ca.
gfubstituta.s.
7. L4-r tht= 7roiect
The or will be carrid out at the Nr..111 Addiction Resezaich..Centert
This Irmtitution rovides the two nessari
4,-Erz1b1, Lci'gton,-4
ir the tyryz of �Nrrr.1: to be underta-ten: 1) a pool of policrls who
w-I11 volunteer for ezz-orialeraz with th."�ugz, arid 2) strict envirom-entel control,
which ',�..revents irArouction of. dgs other thq-, those ur ty L.:to
erLeti nitatiori.
8.
Copieta bloche=1=1 facilities are also available.
The wortz will be carried out u.nder the direction. of IT.4.1rrlz
Director, 1T,U1' Addiction Pszear-,..h. Certer. Thi.a investigator has bad
15 years erverience in research on mrcotic drug dditio d has an
g ;�.1 phi? the 41
e2t.s a.... 'C. ,4134.14 � 40. .6.1.0��
Fie will be exsizte-ci by two other
phyrsicin, Drra. iL 7. Frazer and An. "0-Tt1er, both oZ
whota have done e4ensive .."1/4asea.mh in addiction 34-4 have rrity publiovVor_s.
The ;art-time services of a biocharlizt. ne.urop'r.arrna.colosizt� and research
psychologist areaizo available. A special ward for tho con.da..., et of theta
1..udies has been made avalla;:)le by the 1a.7.:pita1 and has been operating for
=ore than eight ynars..
7-4.1
0, Estimated Cost
The estirnaled coe-�3 are shrAm on the attached sheet. The amottut
=ray requested Is the same as that requested for its=1 year 1261.
rarriz Isbell, M. D.
Zirector
th
.Attachment
12-28-60
� 140.4 +0 ...I
sufficient to ct...v�ry out the wor4 in addition to evaluation oZ potent new
analacoics sus-znitted by the Cernmittee on r--rug Addiction and ..T.-".are�cti. cs of
the National i3esearch Council, =leas additiort_.11 'funds were supplied through
the 1,:er.artt of Wense.
e4.
'r'� A
01.4 C17.0rnnli"i"'`.1 to
or than ek, co=pcunds have been e=na..1'7.4r-.. in the nine years the pro,�-act
ha been ozxrat.L-4-r 4 Two 710r�"U:it Pi C� 2.4-ItituEsive drags (cextror_letizort,ilans -.4
crzld rarz.:,.tine) liere
...,
.� .....�-���3�*41
*".40""Ort-Artsrsi r.." ...ttrl 404^ A.nranox-Trilene
*"4
traryon, Lilly) were found to be less addictive than codeine and both are
ar..algesicscth.Iciiy, tut urfortur.ately they are less
let-12 4"-ii-fiv, than .40e4'il" to44.4.
ent rd r......ore toxic
(F4132) is a 1:ct,..,:nt diarrheal agent which is
_Suring the current year we have mtarnirrd nine new drugs. ri\,:o of. thes,..,,
p-'ido1 and ea:boort-4-1, -are reputed to bc..1 inte.zonunc.ali blociters that
am effective in relievinq path due to r.nuscaLlar
yr), irs 14.11". reN ft,
4AV
ac.irlictness, and therefora both have pcts-intiP-Ily reduc.:ed the
need for codeine r...3-1 an a=11,.;e:s1c.
rte rtf3w drug, 1-(p-Chicr-rilymetlay1)-2-rnr2thy14, 7-