ANNUAL PROGRESS REPORT - NATIONAL INSTITUTE OF MENTAL HEALTH (1 NOVEMBER 1958 TO 1 MAY 1960)

• Document Type: SPECIALCOLLECTION
• Collection: General CIA Records
• Document Number (FOIA) /ESDN (CREST): 00151778
• Release Decision: RIPPUB
• Original Classification: U
• Document Page Count: 10
• Document Creation Date: January 21, 2025
• Document Release Date: September 8, 1976
• Publication Date: May 1, 1960

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TITLE OF PROJECT: Addiction Liabilities of Synthetic Substitutes for
Codeine.
Objectives: To find a synthetic analgesic and antitussive drug which
would be as safe as codeine with regard to toxicity and addiction liability.
ABSTRACT (OR ..C31\a/lARY) OF RESULTS:
a. Since start of project: S66. annual reports for 1952 through 1958.
b. During- the current reportinToeriod:
Continued from the period covered by Annual Progress Report
for 1 November 1957-1 November 1958, were the following investigations:
1. d-Methadone. The results of studies on this drug indicate that
although it possesses low abuse liability, it can produce toxic effects on
chronic administration in high doses. At non-toxic dose levels it may be
useful as a substitute for codeine as an antidiarrheal agent. Its analgesic
potency appears to be very low, while its antitussive activity has not been
investigated adequately.
2. 1-(3-Dirthenv1-3-carbonitril-2r0tyl)-4 phenv1-4 carbethoxy-
Diperidine (R-1132, Diphenoxvlate). Further studies revealed that while
subcutaneous doses of 10-50 mg* did not produce significant effects in
postaddicts, intravenous doses in this range did produce definite morphine-
like changes in behavior. These observations, as well as the results of
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Two other new compounds proved to have considerably less abuse-
liability than morphine:
1. D-3-Methoxy-N--ohenethylmorphinan (NM-7296A). This
compound was investigated for theoretical reasons. In singld doses on
oral administration, up to 1,000 mg did not produce euphoria consistently,
�
though 3 of 4 subjects repprted morphine-like effects while receiving 500 mg
four times daily. It appears to be about 1/25th as potent as morphine in
suppressing mprphine-abstinence phenomena, and in "direct addiction"
studies at daily dose levels equivalent to-48 mg of morphine, no abstinence
phenomena were observed. However, there is no evidence at present that
this compound will be useful clinically.
2. N-(1-Methyl-2-pineridinoethyl)-prooloanilide . Ed l (N1II-7602.
Phenampromid). In single doses subcutaneously, this compound produces
definite morphine-like effects, and at daily dose levels of 1135 mg (in three
evaii y divided doses per day), it suppresses morphine-abstinence
phenomena partially. However, at such levels, disturbing side-effects
occurred which were compared by the subjects to those of d-lysergic acid
diethylamide (LSD-25), cocaine or marihuana. For this reason, and
also because it does possess definite abuse liability, it is not likely that
this compound will prove to be an adequ'ate substitute for codeine.
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Currently under investigation are three other new compounds differing
basically in chemical structure from both the opiate derivatives and
synthetic analgesic t studied heretofore. 1-(p-Chlor-phenethyl)-2-methyl-
6, 7-dimethoxy-1, 2,3, 4-tetrahydro-isoquinoline Ed (NE-7872A) has been
found in preliminary clinical trials elsewhere to exert analgesic effects in
man comparable to those of codeine, and in monkeys it does not suppress
morphine-abstinence phenomena. 2-(Beta-hydroxyphene.thylP--r no)-pyridine
.Eel (PhenTramidol) and N-Isopropyl-2-methyl-2-propyl-1, 3-propanediol
dicarbamate (Carisoprodol) are currently marketed as "muscle relaxants"
(ascribed to internuncia.I blocking activity) and are said to relieve certain
types of pain. At present the data obtained in addictive studies on post-
addicts are insufficient to warrant rtatements about their abuse liabilities.
In addition, studies of a basic methodological nature were made during
the period of the present report to improve standards of comparison of
abuse liability of new compounds primarily intended for oral administration
with that of morphine. The results indicate that with respect to suppression
of morphine abstinence phenomena, 1 mg of morphire subcutaneously is
equivalent to 2.86 mg of morphine orally, 14. 7 mg of codeine orally, and.
35 mg of d-propoxyphene orally.
ANNUAL PROGRESS REPORT �
Report Prepared By: Abraham Wilder, M. 15. 1 May 1960
For the Period: 1 November 1958 to 1 May 1960
NR: 101:149
CONTRACT:
ANNUAL RATE:
CONTI7tACTOR:
�
Nionr -14-60 �
-
�U. S. Public Health Service
National Institate of Mental Health
Bethesda 14, Maryland
(Inquiries concerning finances and contract
should be sent to this address. Inquiries about
technical work should be sent to address below).
Director,
NIMH Addiction Research Center
USPHS Hospital
Lexington, Kentucky
PRINCLPAL INVESTIGATOR: Harris Isbell, M. 3D.
Assistants: H. F. Fraser, M. D.
Abraham Wikler, M. D.
C. R. Logan
G. D. Van Horn
0. A. Kelly
W. H. Welch
M. L. Glass
C. R. Brown
R. Moss
R. Cox
J. Sloan
;,)/
.0*".e.,.z
� c,
PLANS FOR FUTURE
Inamediate: Studies on the addiction liabilities of NM-7672A,
phenyraTridol and carisoprodol will be completed. In addition, similar
studies will be made on a butyl ester of R-1132, the methyl analogue of
phenazocine (theicounterpart of codeine in this series), and on I-3-Hydroxy.
N-propargyl-morphinan hydrobromide (NIE-604.5), an analgesic which is.
a mornhine-antagor.dst, and hence probably Of low addiction liability.
Long Range: The search will be continued for synthetic compounds
with therapeutic properties similar to those of codeine which, in the
opinion of the Committee on Drug Addiction and Narcotics, are completely
satisfactory substitute S for codeine.
REPORTS AND PUBLICATIONS (during the current report period).
1. Fraser, H. F. and Isbell, H.: Addiction Liabilities of (a) dl -2' -
Hydroxy-5, 9-dimethy1-2(2-phenethyl) -6, 7-benzmorphan HBr (NIH-7519),
and. (b) 1-3-Hydroxy-N-phenacylmor-ohinan methane sulfonate (NM-7525).
Addendum 3, Min. 20th Meet. Comm. on Drug Addiction and Narcotics,
Natl. Res. Council, Washington, I). C. Natl. Acad. Sc!. (Ian.) 1959.
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6: Fraser, H. F. and Isbell, H.: Human Pharmacology and
Addiction Liabilities of Phenazocine (cil -2'-Hydroxy-5,9-dimethyl-2-(2-
phenethyl)-6,7-benzmorphan F23r, NIH-7519) and Levophenacylmorpha..n
(1-3-Hydroxy-N-ithena.cylmorphinan methane sulfonate, NIH-7525). Bull.
on Narcotics, 12: (2) in pi�ess.
7. Fraser, H. F., Van Horn, G. D., Martin, W. a and Isbell, H.:
New Methods for Evaluating Addictio-n Liability of Morphine-Like Drugs.
I. Attitude 6f Opiate Addicts Towards Drugs. II. Short-Term Direct
Addiction Procedure.
Non-quotable Section, Min. 21st Meet., Comm. on
Drug Addiction and Narcotics, Natl. lies. Council, Washington, D. C.
Natl. Acad. Sci. (Tan.) 1960.
Abraham Wilder, M. D.
Acting Director
(Vice Harris Isbell, M. D.)
Page 0
2. Fraser, H. F. Isbell, H. and Van Horn, G. D,: Human Pharma-
cology and Addiction Liability of Norcodeine. J. Pharmacol. & Ex-per.
Therap. (in press).
3. Fraser, H. F. and Isbell, H.: PharMacology and Addiction
Liability of di- %rid d-propoxyphene. Bull. on Narcotics, 12:(1) in press.
4. Fraser, H. F. and Isbell,'7H. : Human Pharmacology and Addic-
tiveness of Ethyl 1-(3-Cyario-3, 3-phenylpropy1)-4-pheny1-4-piperidine
carboxylate hydrochloride (R-1132, Diphenoxylate). Bull. on Narcotics
(in press). -
5. Fraser, H. F,, Isbell, H. and Wolbach, A. B.: Addictiveness of
New Synthetic Analgesi.cs. I. Benzimidazole Derivatives: (a) 1-(Beta-
diethylaMinoethyl)-2-(benzy1-4-chloro)-5-nit.r.obenziraidazole (NIH-7586,
ARC I-G-1), (b) 1-(Beta-diethylamir.Jethy1) -2-(p-ethoxybenzyl) -5-nitro-
benzimida.zole methane sulfonate (NIE-7607, ARC I-G-2). IL -)-3-Hydroxy-
N-(3, 3-dimethylaLly1)-morphinan hydrobromide (NM-7446, ARC I-B-19),
LEL N-(1-Methy1-2-piperidinoethyl)-propicanilide hydrochloride (Phenana-
proraid, NM-7002, ARC I-I-1 and, N-E2-(EMethy13-phenethylamino)-propyri
-proploanilide sulfate (Diampromid, NIH-7603, ARC I- X-1). Addendum,
21st Meet., C9mm. on Drug Addiction and Narcotics, Natl. Res. Council,
Washington, D. C. Natl. Acad. Sci. (Ian.) 1960.
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2. di-2' -Eydroxy-5,9 dirriethy1-2 (2-phenethyl) -8,7 benzmorpha.n
EBr (NM-7519, Phenazocine). Euphoria, equivalent to 20-30 mg of
morphine (subcutaneously) is produced by 3-4 mg of this dri.35 by the same
route. With respect to suppression of morphine-abstinence phenomena,
1 mg of this compound is equivalent to 8.1 mg of morphine (in striking
contrast to results obtainied by others in the monkey, which indicated that
It was only one-sixth as potent as morphine in this regard), though the
intensity of the abstinence syndrome in "direct addiction" studies was
somewhat less than that of morphine.
3. Ethyl 4--oheny1-1 �3(phenylamino)-Dropy3.11-4-biberidine carboxy-
late ethane sulionate (ME-7590). In doses of 15-20 mg this drug produces
euphoria equivalent to 20-30 mg of morphine, and is about twice as potent
as morphine in supprep.sing morphine-abstinence phenomena.
4. 1-(Beta-die.thylaminoethyl)-2-(benzyl-4-chloro)-5-nitrobenzirni-
dazole (NrrI-7588). In oral doses of 100 mg this drug produces euphoria
and 2.62 mg are equivalent to 1 mg of morphine in suppressing morphine-
abstinence phenomena.
"direct addiction" studies confirm the opinion previously expressed, that
this compound does possess addictive properties, but the order of its
abuse liability is somewhat less than that of codeine. It is anticipated
that R-1132 will be marketed in the near future as an antidiarrheal agent.
3. Metabolism of Norrnorohine. Further studies were made to
determine the nature of the conjugated form of urinary normorphine.
Results thus far indicate ;hat this form is not a glucuronide nor an
ethereal sulfate.
Studies on postaddicts were completed on nine new compounds.
I.
Of these, seven were found to possess abuse liability comparable to that
of morphine, and therefore to be unsuitable as substitutes for codeine.
1. (-) 3-H17drox714V-phenacvlmorDhinan methane sulionate (NIH-7525,
Levonhenacylmorphan). The euphorogenic and. morphine abstinence-
suppressing potency of this compound is about ten times that of morphine,
though the intensity of the abstinence syndrome in "direct addiction" studies
was somewhat less.
5. l-(B eta -di ethylaminoethyl) -2 -(n-etho xyb enzyl) -5 -nitrobenzimi:-
dazole methane sulfonate (ZITS-7607). On oral administration this
compound is 80-120 times as potent as morphine in euphorogenic potency,
and about 60 times as effective as morphine in suppressing morphine-
abstinence phenomena,. After "direct addiction" to this drug, the intensity
of the abstinence syndrome is comparable to that of morphine.
6. l-3-Hydroxy-N (3,3-dimethylally1)-m.ornhinan FEBr (1\TM-7446).
The potency of this drug, with respect both to its euphorogenic and
morphine abstinence-suppressing activity, is comparable to that of morphine.
7. N-(2-E(Methyl)-phenethylarnino0-prooyl)-Drobioanilide (NIH-7603,
Diamoromid). Though its duration of action is much Shorter (two to three
hours), this compound produces euphoria in doses of 75 mg subcutaneously
equivalent to that of 20 mg of morphine, and at daily dose levels of 625 or
750 mg (in four divided doses per day), it substitutes adequately for morphine
In suppressing morphine-abstinence phenomena, for the relatively short
period of its action.