ANNUAL PROGRESS REPORT -- NR:101-194 -- 1 NOVEMBER 1957 TO 1 NOVEMBER 1958

• Document Type: SPECIALCOLLECTION
• Collection: General CIA Records
• Document Number (FOIA) /ESDN (CREST): 00151834
• Release Decision: RIPPUB
• Original Classification: U
• Document Page Count: 10
• Document Creation Date: January 21, 2025
• Document Release Date: September 8, 1976
• Publication Date: November 1, 1958

4111,-
TITLE OF. PROJECT: Addiction Liabilities of Synthetic Substitutes
- for Codeine.
Objectives: To find a synthetic analgesic and antitussive
drug which would be as safe from the point of view of toxicity
and addiction liability as is codeine.
ABSTRACT (OR SUMMARY) OF RESULTS:
a. Since start of project:
This portion of the summary covers the period from
1 July 1951 to 1 November 1958. The project was originally
undertaken because no synthetic analgesic drug was available
which was as safe and which had as low addictiveness as codeine.
Adequate substitutes for the potent analgesics of the morphine
type were available, tut 75 per cent of the civilian and military
consumption of. narcotic drugs was in terms of codeine. Since
this consumption amounted to 16 to 20 tons yearly, it meant that
the United States had to continue to stockpile opium since
access to the opium producing areas might be lost in event of war.
Therefore synthetic substitutes for codeine were badly needed.
The role of the NIMH Addiction Research Center in this investiga-
tion, which WAS initiated at the request of the Committee on Drug_
Addiction and Narcotics of the National Research Council, has
consisted of the determination of the addictive properties of new
potential codeine substitutes. The clinical evaluation of the
analgesic, nntitussive and antidiarrheal properties of such new
drugs must necessarily be made elsewhere.
pals
The drug must be regarded as having definite
addiction liability since it induces morphine-like subjective
effects, suppresses abstinence, and abstinence is seen on with-
drawal; but its addictiveness is definitely less than that of
codeine or of morphine. Work with this compound is still in
progress and investigations of the butyl-ester will also be
carried out.
7. Metabolism of Normorphine. Studies on the excre-
tion and metabolic fate of normorphine were undertaken because
this drug was found to have definitely less addictiveness than
either morphine or codeine, although it was a more potent
sedative than either of these drugs. All studies have been
conducted in man. An analytical method for normorphine has been
developed which is based on extraction of the normorphine from
aqueous solution at pH 8.5 into a mixture of amyl alcohol and
ethylene dichloride. Normorphine is returned to aqueous solution
by extracting with 0.05 normal hydrochloric acid, after which
the silico-molybdic acid reaction is applied. The method gives
reproducible results, and consistent recoveries of added
normorphine. To our surprise, it was found that 50% of normor-
phine recoverable from urine was present in the "free" or readily
extractable form. This contrasts with morphine in which only 10 to 15% is present in the free form. About 70% of the total
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'7"-""
a
dose of normorphine is recoverable in the urine within 48 hours.
Treatment of the urine with heat and strong acid liberates
additional normorphine (so-called bound normorphine). Bound
normorphine, however, does not appear to be a glucuoronide,
since incubation with glucuoronidase does not elevate amount
of normorphine which is extractable. /n contrast, glucuoroni-
dase readily liberates bound morphine. Both free and bound
normorphine have been identified by means of counter-current
distribution and paper chromatography.
Work so far suggests that normorphine may be
effective because less of the drug is bound than is the case
with morphine. In effect, more free normorphine would be
present, leading to a higher concentration of free normorphine
in brain than is.the case with morphine. In order to test this
hypothesis, animal work with refined techniques will be necessary.
. Similar studies are to be carried out on 1-3-
Hydroxy9T!orphinan.
PLANS FOR FUTURE
Immediate: During the coming year we intend to complete
further direct addiction studies on the important constipating
drug, R-I132. Preliminary work with the butyl-ester corres-
ponding to.R-1132 will also be carried out. Work on d-methadoner__
and d-3-Methoxy-N-phenethylmorphinan will be completed. We will
Paoe 10
also study the addictiveness of one compound in the benzmorphan
series, and one compound in the morphinan series. Both of the
latter two drugs have been reported to be nonaddictive in monkeys.
We will also continue working on the metabolism of the demethylate
congeners of morphine and morphinan.
Long Range: We intend to continue the search for substi-.
tutes for codeine until drugs are found which are, in the opinion
of the Committee on Drug Addiction and Narcotics, completely
satisfactory substitutes for codeine. .
REPORTS AND PUBLICATIONS (during the current report period).
1. Fraser, H. F., Isbell, H., Eisenman, A. J., and Van -
Horn, 0. D.: Studies of Normorphine in Man. J. Pharmacol. &
Exper. Therap., 122: (1) 22A (Jan.) 1958. (Abstract)
2. Fraser, H. F., and Isbell, H.: Human Pharmacology
and Addiction.LIabiLty of Certain Compounds Related to Morphine
or Codeine. I. Normorphine. II. Norcodeine. Nan. 19th Meet.,
Comm. on Drug Addiction & Narcotics, Nat'l. Res. Council, 29-30
March 1958,
3. Fraser, H. F., Wikler, A., Van Horn, 0. D., Eisenman,
A. J., and. Isbell, H..: Human Pharmacology and Addiction Liabilit:
of Normorphine. J. Pharmacol. & Exper. Therap., 122: 359-369
(Mar.) 1958.
4.. Fraser, H. F., Isbell, H., and Van Horn, G. D.:
Norcodeine in Man. Federation Proc., 11: (1) 367 (Mar.) 1958.
Harris Isbell, M.D.
Director /)-73
b. During the current reporting period:
During the current reporting period (1 November 1957
to 1 November 1958) the addictive potentialities of 6 drugs
were evaluated wholly or in part and the metabolic fate of
normorphine investigated. The results are presented below under
individual headings:
1. Norcodeine. Work with norcodeine was undertaken
because normorphine had been shown to possess considerably less
addictiveness than morphine. It was therefore thought of interest
to extend the work to norcodeine. In doses of 75 mg. norcodeine
induced subjective effects in former morphine addicts similar to
those caused by codeine.. It also caused mild respiratory .
depression and pupillary constriction. It suppressed abstinence
from morphine efftctively when substituted for morphine in
patients addicted to that drug. Patients who took the drug,
in doses increasing to 1,000-1,500 mg. daily over a.period of
60 days, developed marked sedation and other morphine-like side
effects. When the drug was withdrawn, definite but very mild
abstinence occurred.
Since this drug is effective orally and since
abstinence is milder after withdrawal than is abstinence from
codeine, it is regarded as a potentially promising substitute.
It, unfortunately, is not a synthetic drug.
ANNUAL PROGRESS REPORT
Report Prepared By: Harris /sbell, M.D. 1 _November 1953
For the period 1 November 1957 to 1 November 1958
NR: 101-114.9
CONTRACT:
, ANNUAL RATE:
CONTRACTOR:.
NAonr-17-5S
(ONR-1441:MJ0:set)
� U. S. Public Health Service
National Institute of Mental Health
. Bethesda 14., Md.
(Inquiries concerning finances and conti-act
should be sent to this address. Inquiries
about technical work should be sent to
address below).
Director
NIIIH Addiction Research Center
USPHS Hospital
Lexington, Kentucky
PRINCIPAL INVESTIGATOR: Harris Isbell, M.D.
Assistants: H. F. Fraser, M.D.
C. R. Logan �
G. D. Van Horn
0. A.
W. H. Wz: l ch
M. L. Glass
C. R. Brown
Russell Moss
Raymond Cox
Jewell Sloan
Pa,la 6
5. 1-3-Hydroxy-morphinan. No subjective effects
were seen after single doses ranging up to as much as 100 mg. of
this compound hypodermically or orally. When, however, patients
were given 25 mg. of the drug hypodermically three times daily
mild morphine-like effects did appear. 360 mg. of the drug
daily suppressed abstinence partially in patients who had been
receiving 240 mg. of morphine. This drug definitely will have
law addictiveness, and more complete exploration by formal 10-day
substitution and direct addiction is indicated.
6. l-(3-Dinheny1-3-carbonitril-proov1)-4-pheny1-4-
carbethoxypiDeridine (R-1132). This compound is a derivative of
meperidine, developed at the Eupharma Laboratories in Belgium,
and was part of a program designed to develop a drug with consti-
pative effects. but without central nervous system effects. The
drug has been shown to suppress abstinence in monkeys; a single
dose being effective for a period of as long as 30 days.
Since the drug is insoluble all studies were
carried out orally. No subjective or objective effects were
observed in nontoletant morphine addicts who received 20 mg. or
less of the compound orally. Doses of 50 to 90 mg. caused, in
the majority of the patients, pupillary constriction,. sedation,
nausea, vomiting, and subjective effects resembling those seen
after oral or hypodermic administration of morphine.
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The methods used for studying addiction liabilities
of new drugs have been described in detail in the project
description and-in previous reports and need not be repeated here.
During the period 1 July 1951 to I November 1958, 51
new drugs or mixtures of drugs were tested for addictive poten-
tialities. Detailed information concerning these substances can
be found in the annual reports submitted between 1954 and 1957.
Original object of the project has been partly solved since two
substances which were outstanding as possible substitutes for
codeine for suppression of cough were discovered. These sub-
stances were (1) d-3-Methoxy-N-methylmorphinan (dextromethorphan),
and (2) narcotine. Continuing clinical investigations indicate
that both drugs are as effective as codeine as antitussives.
Both drugs are on sale in the United States. .
Although satisfactory compounds for relief of cough
have been developed, some doubt still remains that drugs which
are as effective in relieving pain as codeine are available.
Some eight compounds with definite promise were uncovered in past
work. The drug, d-propoxyphene (Darvon, Lilly), has received the
most attention and appears to be the most promising.' This drug
was shown to have fewer addictive properties than codeine. It is
now being actively marketed by the Eli Lilly Company both as the
--
pure material and in combination with aspirin. Further detailed
studies on its analgesic effectiveness are underway.
Pac::
2. d-Methadone. This drug was reinvestigated at
the request of the Committee on Drug Addiction and Narcotics,
NRC. It induced-no subjective effects in doses of 200 mg.
parenterally or orally, but did suppress abstinence almost
completely when 650 mg, daily were substituted for morphine in
patients who had been receiving 240 mg. of that drug every 24
hours. On withdrawal of d-methadone, after substitution for
morphine for 10 days, extremely mild abstinence, was observed.
If d-methadone has any addictiveness it is of quite a low order.
Direct addiction experiments are now underway and will be com-
pleted within the next six months.
3. N 3-0xo-3-ohen 1 roml -normorohine. Twenty to
30 mg, or this drug induced subjective effects in former morphine
addicts which appeared to be equivalent to those caused by 30 mg.
of morphine. The drug was a very effective suppressor of
abstinence froM morphine. It is regarded as having.a high addict-
iveness and is being dropped from further consideration.
N-Phenethyl-morrthine. Fifteen mg. of N-phenethyl-
morphine subcutaneously induced objective and subjective effects _
in nontolerant former addicts equivalent to those caused by 30 ng.
of morphine. 140 mg. of the compound every 24 hours effectively
suppressed abstinence in patients addicted to morphine. The drug
is regarded as having high addictiveness and is being dropped
from further consideration.
page
180 mg. of R-1132 daily suppressed abstinence
nearly completely when substituted for morphine for 24 hours in
patients who had_been receiving 240 mg, of morphine daily.
R-1132 also suppressed _abstinence effectively over
a 10-day period when 180 mg. were substituted for 240 mg. of
morphine in 5 patients. When R-'1132 was discontinued, definite
but mild abstinence was observed.
In direct addiction experiments the dosage of
R-1132 was elevated quite slowly to. 135 to 285 mg. daily in
5 'subjects. With such a dosage schedule the subjective effects
were mild and consisted primarily of sedation. The patients were
quite constipated. Nalline precipitated mild but definite
abstinence in these patients. When the drug was discontinued
after 60 days, definite but mild abstinence was seen in L of the
5 subjects.
.This is a very interesting and possibly important
drug which might have definite military usefulness. It is
possibly the most effective and safest constipating agent known,
and therefore might be of value in. the symptomatic treatment of
diarrhea, especially in tropical areas. It has been reported
to actually be a life-saving agent in treating cases of infantile
diarrhea in the Belgian Congo.