DROMORAN PROJECT: ADDICTION LIABILITY OF SYNTHETIC ANALGESICS WHICH MIGHT SERVE AS SUBSTITUTES FOR CODEINE

• Document Type: SPECIALCOLLECTION
• Collection: General CIA Records
• Document Number (FOIA) /ESDN (CREST): 00153378
• Release Decision: RIPPUB
• Original Classification: U
• Document Page Count: 8
• Document Creation Date: January 21, 2025
• Document Release Date: January 15, 1983
• Publication Date: January 21, 1952

21- lanuary 1.952
DROMORAN PROJECT
ONR 441:F}-:op
NR 113-149
Ser. 31,540
Declassified by
Co
date 4 Frt.,
NNW
U.
WORK ACCOMPLISHED TO DAT
The recruitment and 414.41pIni,oz-rsonael began in July..
The training. of personnel was completed in [Ate -September and
an additional research ward was opened In October 1951. The
work on the..human pharmacology and toxicity of 3-methoxy-n-..
methYlmorphinan, as well as the work on the detection of euphoria,
was completed during the sOmer. Work on the relief of Abstinence
and substitution of this compownd for morphine was completed in
December 1951.
The results to-date can be summarized as follows: Doses
of less than 30 mg. dl-methoxy-n-methylmorphinan produced no
untoward toxic effects in former morphine addicts. Doses of
20 to 30 mg., ether hypodermically or orally, induced euphoria
similar to and equal in,intensify to that seen after the adminis-
tration of 30 m2. morphIne. Other morphine-like effects, such as
nausea, vomiting, miosis and respiratory depression, were observed
with the larger doses. The compound was found to induce its
effects more quickly when administered orally as compared with
hypodermic administration. It relieved abstinence from morphine
and could be substituted for morphine In addicted persons.
Substitution was complete as contrasted with codetne,'-which will
not _support..physicaldependejlce On- morphine completely. Fol.iow-
ing withdrawal of 3-methoxy-n-methylmorphinan after.substitutton
for morphine, a typical morphine-like abstinence syndrome appeared.
For further details of these studies see the reports to the
Drug Addiction Committee, National Research Council, wHich are
attached.
ef;ctazs;.1%ed by
GC.:41
ar
ADDICTICIN8kW ,AVTHETIC ANALGESICS
WilICH MIGHT "SERVE AS SUBSTITUTES FOR CCDEINE.
BACKGROUND INFORMATiON
In late June of 1951 $30,000 was made available by
the Department of Defense for determining the addiction
liability of d1.3-methoxy-n-methylmorphinan imethoxy-dromoranl
In the hope that this drug might represent, an adequate synthetic
substitute for codeine. This grant Was made following the
submission of a project description entitled "The Determination
of the Addiction Liability of Synthetic-Analgesics of the
Codeine Type."piThe project was supported for the following
reasons:
Dye to the currently disturbed international situation,
It was possible that the United States might be cut off from
all Its usual'sourcet of opium. Synthetic analgesics are
available which are entirely adequate for the replacement of
morphine. However, none of the available synthetic analgesics
are as safe for general use as is codeine. More than "0 per cent
of the Armed Forces' requirements for narcPtigs Is. for codeine
rather than for morphine. .Finding a synthetic'sUbstifute for
codeine is, therefore, of considerable importance And it was
hoped that methylafion of 3-hydroxy-n-methylmorphinan, a
synthetic druzi of.morphine-tike structure, would produce such a
_compound. The facilities of the Addiction Research Center were
not sufficient to carry out the work unless additional funds
could be obtained.
�
Deciassifled by 18747
date ----t-Fts--1377�,--
A-7
If is obvious thai n�methy1Torphinan has
addiction liability eqiatA to that of morphine, and for
this reason, cannot be regarded as being at safe as codeine for
. general use. We, therefore, have not carried at Part Five of
.�
our original experimental procedure which deals.with direct
former
addiction of/Morphine -addicts to the new drug. It was felt
that the time would be better spent In screening a number of
other compounds in the hope of fioding'a drug which gave promise
of being more codeine�like than is dl-3�methoxy�n�methylmorphinan.
Work along these lines Is now going on with the dextrorotatory
and levorotatory isomers of methoxy�dromoran and with some
',iterates in the-iTefhadone series. The isomers of 3�methoxy�
n�methylmorphinan are being studted because the dextrorotafory
isomer is said to be an excellent antitussive agent in dogs
(as judged by a newly 'developed technic) and probably will have
very low add1ct4on liability. Later, it is hoped that additional
derivatives of dromoran with substituents other than methyl In
position Number 3 will be studied. The reason for investigating
these additional drugs in the dromoran series is that the
activity of dromoran was altered in the proper direction by
mithylation, but the Addiction liability of the derivative was
not reduced sufficiently for it to be rearded as being- tnnocuoz)s
as codeine.- Substitution of ethyl, propyl or other groups in
position 3 might yield a num drug with sufficient reduction in
'addiction liability.
Declassified by
date
3 1977
41:
1
� 110
ce Il. ..eaminder-of thetimeavailaPle under the
�lialcooditt
-current geant from the DeAtctn4AA*rpoie muit be spent in
screening, it is hoped that an ,additional grant can be obtained
for continultIon of the work during the fiscal year 1953. If
a promising drug is revealed by the screening�test, intensive
work with if will begin as soon as possible during fiscal year
1953. if so such drug is found screening should continue.
EXPERIMENTAL PRCCEDURES
Drugs being screened will.be Subjected to the following
types of investigation:
A. Human.-PharmacolOpy and Toxicity. This involves the
administration of progressively increasing doses of the drug
under study to huMan volunteers, chiefly former morphine addicts
Observations on respiratory minUje volume, pupillary size,
blood pressure and pulse rate, etc..., arelnade following *Be
administration of the drugs.
B. Admi-nistration to Human Volunteers of Single Doses
-o.f the Drugs Being Screened for the Detection of Euphoria.
This esperiment is conducted in exactly the same way as the
studies on human pharmacology,., except Ifiibt detailed observations
on the physiological effects Of the drug are not made,,:beca'use
�taking of observations tends to negate the pleasurable effects
. of }he drugs. Two methods-are-used for gauging the "'euphoria"
induced by the drugs.
These are I) unobtrusive clinical
observations for the appearance of behavior resembling that seen
after the administration of morphine, and 2) the admiTlistration
of projective psychological tests.
�
�
187475,-
Declassified
date
C. The nlifeation-of=SInql; Doses of the Drug
Under Study to Showinp Signs of Moderate to Marked
Abstinence from Opiates. Any drUg-A,fhich, on the basis of
the screening test, appears to be promising as a potential .
-substitute for codeine will be subjected to additional
studies: 1) -substitution of the drug for morphine in strongly
'addicted persons, followed by abrupt withdrawal of the new
drug, 2) direct addiction of f6rmer morphine addict volunteers,
under two conditions, (a) Very high-dose levels, such as would
be expected in "natural addiction.under conditions of abuse,
(P) conditions of low-dosage, such as would be expected
during long continued clinical administration of the drug.
D. Evaluation:of Data. The drug we are seeking
-should have the following charaCterisfict: I) It should be
a weak analgesic, as judged by 'animal experimentation;
2) The ratio`of toxicity to therapeutic effect should be
favorable In both animals and man; 31 It should be a good
antitusstve agent; 4) should relieve abstinence from morphine
only partially; St should not substitute for morphine completely;
6) should Induce only a mild grade of physical dependence In
.dtrectaddiCtio:11--te4tpdcr-:-.conrlittoht.4 dosage.
1r:for:nation submitted to the Drug Addiction Committee
by the pharmaceutical companies and universities will be
sufficient to evaluate the actions of the drug in animals.
� DectaSTed by
__i B745�
a.
Studies on adds Ion4V41:441tertt:Ilield Information on the
toxicology-, pha acol6gy and euphoric potency of the drug
In man and on its ability to produce and support physical
dependence. From these data a satisfactory evaluation of .
fhe addiction liability of the compound 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 Service Hospital, Lexington, Kentucky.
This hospital is devoted entirely to the treatment and study
of drug addiction and is the only place In the world where
4 study such as those described above can be satisfactorily
S.
carried out. -The institution provided the two necessary
facilities for this type of work: II a Large pool of patient
volunteers, .2) strict environmenfal-'control which prevents
the introduction of drugs other than those under study into
the situation.
F. Experimental Personnel. The work will be carried
out under the direction of Harris Isbell, M.D., Director of
the Addiction Research Center. This investigator has had
almost eight years experience in narcotic drug addiction and
37,641-044;ioni4*,771Elt.1:-,fle_Td..-::HellIrbeattisted by*.
. . , .
two other experienced Medical Officers, Dr. H. F. Fraser and
Dr. Abraham Wikler, both of whom have had extensive experience
In research in addiction and have many pubItcatioffs in this field.
Dtclztssined by
date 4 FEE 1311
� 0-"3"Nre,lib
j
$1:1 � -
. .
in 'addit to'lh'e-xnedraiX-*.1:arSonneix the part-time
services of.e B cheffiist and a Psychologist will be nwie
available. Sub-professional personnel include �5 Psychiatric
Aides, a Medical Technician, Biological Aide, Security Aide-
-4'nd Clerk-Stenographer.
special ward for conducting these studies has already
been set up and is in operation".
C. Estimate Of Cost.
- U. Personnel
Nychiatric Aides GS-5
1 Clerk-Stenographer GS-4
I Security Aide CPC-5
Medical Technician GS-4_
'1 Biological Aide
2:- �
Reserve- .for night differential and - �
-Overtime pay, withinrgrade raises, etc
Miscellaneous expenses
OS SS 001.
0110m7y4r.sriAlit
-
It should be noted that personnel cost for the fiscal.
t F
yes r 1953 will be higher due to the recent salary increase
granted government employees. Item for miscellaneous expenses
Includes money-for the purchase of drugs, chemicals, .glassware,
..eleCtroenCiOhaldgraphWand:phofographitpaper,
1-11:rn
Attachments 2
4 January 1952
Harris Isbell, M.D.
Dtreci-or of Research
Declassified by �137475
pate
4 FEB 1977