Doc 0000151778

.) · PROGRESS REPORT A~"NUAL Heport Prepared By: Abraham Wittler, 1vi. D. · · 1 May 1960 For the Period: ... 1 Nover.a.ber 1958 to 1 !·A:ay 1960 NR: 101:149 ., . CONTRACT: NAonr-14-60 ANNUAL RATE: --~~ ~ CONTRACTOR: -U. S. Public Health Service National L"'lstitute of Mental Health B.ethesda. 14, rA:aryland (Inquiries concerning finances and contract should be sent to this address. Inquiries about technical work: should be sent to address below). Director, :NI!v.il:I Addiction Research Center USPHS Hospital Lexington, Kentucky · PP..INCIPAL INVESTIGATOR: Harris Isbell, 11.D. Assistants: H. F. Fraser, M.D. Abraha1n M. D. ~Nitder r C. R. Logan G. D. Van Horn 0. A. Kelly W. H. \Velch 1... 1 :. L. Glass C. R. Brown R. Moss R. Cox J. Sloan . = - ~ ,. ' .) .. :Pace 2 TITLE OF PROJECT: Addiction Liabilities of Synthetic Substitutes for ... Codeine. Objectives: Tq find a synthetic analgesic and antitussive drug which would be as safe as codeine with regard to to4icity and addiction liability. ABSTRACT (OR SU111~Y) OF RESULTS: -··· . a. Since start of oroiect: Se~ annual reports for 1952 through 1958. •/ b. Durinq the current reoortina: oeriod: Continued from ' the period covered by Annual Progress Repor' t / . for 1 November 1957-1 N?vember 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 as a substitute for codeine as an antidiarrheal agent. Its analgesic use~ potency appears to be very low, while its antitussive activity bas not been investigated adequately. 2. 1-(3-Diphenyl-3-carbonitril-prooyl) -4 phenvl-4 carbethoxy niperidine (R-1132, Dipheno:z,.=ylate). Further studies revealed that while subcutaneous doses of 10-50 mq 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 ·.1 ndirect addiction11 studies confirm the opinion preyiously expressed, that this compound does possess addictiye properties, but the order oi its abuse liability is somewhat less than that of codeine. It is anticipated qe that R-1132 will marketed in the near future as an a.'P'ltidiarrheal agent. 3. of Normornhine. Further studies were made to ~.:!etabolism determine the nature of the conjugated form of urinary normorphine . . Results thus far in_dica.te Plat this form The image displays text overlaid on a background that includes a graphic of a bank vault door and a glowing blue abstract design. The text indicates that the document was obtained from "The Black Vault," an online database of declassified government documents, specifically from the MKULTRA/Mind Control Collection. It also provides a URL for the collection. There are no photographs of people, locations, equipment, or subjects, nor are there any handwritten annotations, signatures, official stamps, forms, diagrams, tables, or redactions visible on this page. The image is purely informational, using a thematic graphic to present the context of the document's source. The document is a typed report titled "ANNUAL PROGRESS REPORT." It features handwritten annotations, including a circled number "179" in the top-right corner and a handwritten entry "13-321" in the bottom-right corner. The report is formatted with clear headings for "Report Prepared By," "For the Period," "NR," "CONTRACT," "ANNUAL RATE," "CONTRACTOR," and "PRINCIPAL INVESTIGATOR." A list of "Assistants" is also provided. There are no apparent photographs, diagrams, or visual evidence of experimental procedures. somewhat less than that of codeine. It is anticipated qe that R-1132 will marketed in the near future as an a.'P'ltidiarrheal agent. 3. of Normornhine. Further studies were made to ~.:!etabolism determine the nature of the conjugated form of urinary normorphine . . Results thus far in_dica.te Plat this form is not a glucuronide nor ~'1 ethereal sulfate. Studies on p,:,staddicts were completed on nine new compounds. / 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-Hydrox-<r:..N-phenac-vlmor-ohina.."'l methane sulfonate fNIH-7525, Levoohenacylmorphan). 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. ' - Page 4 2. 91.-2'-Hydroxy-5, 9 dimethyl-2 (2-ohenethyl)-6, 7 benzmorphan HBr (NIH-7-519, Phenazoch1e). Euphoria, equivalent to 20-30 mg of morphine (subcutaneously) is produced by 3-4 mg of this drqg by t.~e same route. \Vith respect to suppression of morphine-abstinence phenomena, 1 mg of tlris compound is ~quivalel)t to 8. 1 mg of morphine (in striking eo contrast to results· obtain by others_ in the monkey, which indicated that . : . / . . it was only one-sixth as patent as m9rphine 1n this regard), though the intensity of the- abstinence syndrome in 11direct addiction studies was If somewhat less than t.i.at of morphine. 3. Ethyl 4-nhenyl-1 [3{phenylamino)-propyU-4-niceridine carboxy- late ethane sulfonate In doses of 15-20 mg this drug produces {~'TII-7590}. euphoria equivalent to 20-30 mg of morphine, and is about twice as potent as morphine in suppressing morphine-abstinence phenomena. • 6 • ...... 4. 1-(Beta-diethylaw..inoethvl) -2-{benzyl-4-chloro) -5-nitrobenzimi dazole (NT.ti-7586). In oral doses of 100 mq this drug produces euphoria and 2. 62 mg are equivalent to 1 mg of morphine in suppressing morphine- abstinence phenomena. ' 5. 1-(Beta-diethvlaminoethyl}-2-(n-ethoxybenzyl}-5-nitrobenzimi.:. dazole methane sulfon~te (NIH-7607). On oral administration this compound is 80-1.20 times as potent as morphine in euphorogenic potency, I and about 60 times as effective as morphine in suppressing morphine- abstinence phendmena.. .After "direct addiction" to this drug, the intensity ., ~ of the abstinence syndron;ie is comparable to that' of morphine. 6. 1-3-Hydroxv-N (.3, 3-dimeth•rl8llyl):..mornhinan HBr (!\TIH-7446). The potency of this drug, with respect both to its euphorogenic and / ~ morphine abstinence-suppressinq activity, is comparable to that of morphine. 7. N-(2-[(lvTethyl)-phenethylaminoJ-prooyl) -nronioanilide {1-.TIH-7603, Diamnromid}. Though'1t.s duration the intensity ., ~ of the abstinence syndron;ie is comparable to that' of morphine. 6. 1-3-Hydroxv-N (.3, 3-dimeth•rl8llyl):..mornhinan HBr (!\TIH-7446). The potency of this drug, with respect both to its euphorogenic and / ~ morphine abstinence-suppressinq activity, is comparable to that of morphine. 7. N-(2-[(lvTethyl)-phenethylaminoJ-prooyl) -nronioanilide {1-.TIH-7603, Diamnromid}. Though'1t.s duration of action is much shorter (two to three hours), this compound produces euphoria in doses of 75 mg subcutaneously and equivalent to that of 20 mg of morphine, ~t 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. fl--317 i .) .-~~- - Paqe6 Two other new compounds proved to have considerably less abuse- liability tha.11 morphine: 1. D-3-:rvrethoxy-N-nhenethylmorphinan (NIH-7296A}. This compound was investigated for theoretical reasons. In single doses on ,· .. oral administration, up to 1, 000 m_g did not produce euphoria consistently, . / though 3 of 4 subjects repQrted morphine-like effects while receiving 500 mg / four times daily. It appears to be about l/25th as potent a~ morphine in suppressing mprphine-abstinence phenomena, and in 11direct addiction" studies at daily dose levels equivalent to-48 n1g of morphine, no abstinence phenomena were observed. However, there is no evidence at pre-sent L1.at this compound will be useful clinically. 2. N-(1-Methyl-2-niperidinoethyl)-pronioanilide . Hcl (NTH-7602. ~ Phenamnromid). In single doses subcutaneously, this comr;ound produces definite morphine-like effects, and at daily dose levels of 1135 mg (in thr~e equally divided doses per day), it suppresses morphine-abstinence phenomena partially. However, at such ievels, disturbing side-effects occurred which were compared by the subjects to those of Q.-lysergic acid diethylamide (LSD-25), cocaine or marihuar...a. For this reason, and also because it does possess definite abuse liability, it is not that li~ely this compound will prove to be an adequ-ate substitute for codeine. JJ-:J/6 _/- _-)A . Pag-a 7 Currently under investigation are three other new compounds differing basically in chemical structure :from both the opiate derivatives a.lJ.d synthetic analgesics studied heretofore. 1-(p-Chlor-phenethyl)-2-methyl- 6, 7 -dimethoxy-1, 2, 3, 4-tetrahydro-isoquinollne Hcl (:NIH-7672A) has been found in clinical trials elsewhere to exert analgesic effects in prelimi...~ ry - . m~"l comparable to those p{ codeine, and in monkeys it does not suppress ., morphine -abstinence phenomena. 2- (Beta-~ydrox-JPhenethylam.ino)-pyridi:1e . Hcl (Phenyramidol) a..~d N-Isopropyl-2-meL~yl-2-propyl-1, 3-propanediol dicarbamate {Carisoprodol} are currently marketed as 1'm.uscle reia..~'lts" (ascribed to The page is text-heavy, featuring typed content that appears to be a research report. There are no images or diagrams. The only notable visual element is a handwritten annotation in the bottom right corner that reads "B-320". There are also two dark circular marks near the top center of the page, possibly ink blots or remnants of a binding mechanism. No stamps, forms, tables, or evidence of experimental procedures are visible. The document is a single page of text with a page number "Page 3" at the top right. There are handwritten annotations at the bottom right corner: "B-319". The text discusses "direct addiction" studies and the metabolism of normorphine. There are no images, photographs, forms, diagrams, tables, or stamps visible on this page. The document appears to be an excerpt from a report or study. been found in clinical trials elsewhere to exert analgesic effects in prelimi...~ ry - . m~"l comparable to those p{ codeine, and in monkeys it does not suppress ., morphine -abstinence phenomena. 2- (Beta-~ydrox-JPhenethylam.ino)-pyridi:1e . Hcl (Phenyramidol) a..~d N-Isopropyl-2-meL~yl-2-propyl-1, 3-propanediol dicarbamate {Carisoprodol} are currently marketed as 1'm.uscle reia..~'lts" (ascribed to internuncial bloctdng activity) a."'!d are said to relieve certain types of pain. At the data obtained in addictive studies on post- pres~nt 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 L"'ltended for oral admL"'listration with that of morphine. '_rhe results indicate t.1w.t with respect to suppression of morphine abstinence phenomena, 1 mg of morphine subcutaneously is equivalent to 2. 86 mq of morphine orally, 14. 7 mg of codeine orally, and 35 mg of d-propoxyphene orally. - f ·I o-,...;:, - .;;1,-=-- ::i '·J PLANS FOR FUTURE Iio.mediate: Studies on the addiction liabilities of NIE-7672A, phenyramidol carisoprodol will be completed. In addition, similar ~"ld. studies will be made on a butyl ester of R-1132, the methyl analogue of phenazocine (t.he···counterpart of codeine in this series), and onl-3-Hydroxy- ,,. ~,.. N-propa.rgyl-morpllinan h,ydrobromide (!-,Tm:-6045), an analgesic which is. a morphine-antagonist, and hence probably ~f low addiction liability. / Long Range: The search will be continued for synthetic compounds - / with therapeutic properties similar to those of codeine which, in L~e opinion of the Committee on Drug Addiction and Narcotics, are completely satisfactory for codeine. sub~J.tutes REPORTS AND (during the current Mport period}. PUBLICATIO~TS l. Fraser, H. F. and Isbell, H.: Addiction Liabilities of (a) dl-2'- Hydro:-..'Y-5, 9-dimethyl-2(2-phenethyl)-6, 7-benzmorphan HBr (1'-.i"'H-7519), and (b) l-3-Hydroxy-N-phenacylmorphlnan methane sulfonate (Nlli-7525}. Addendum 3, r.fin. 20th 1v1eet., Comm. on Drug Addiction and Narcotics, Na.tl. Res. Council, \vashington, D. C. Natl. Acad. Sci. (Jan.) 1959. 2. Fraser, H. F., IGbell, H. and Van Horn, G. D. : Human Pharma- cology and Addiction Liability of Norcodeine. J. Pharmacal. & Exper. The rap. (in press).· 3. Fraser, H. F. and Isbell, H. : Pharmacology and Addiction Liability of dl- and .Bull. on Narcotics, 12: (1) in press. d-propo~JPhene. J:· - . 4. Fraser, H. F. and Isbell/'H.: Human Pharmacology and Addie- tiveness of Ethyll-(3-Cy-aJio-3, 3-phenylpropyl)-4-phenyl-4-piperidine / carboxylate hydrochloride (R-1132, Diphenoxy"late). Bull. on Narcotics (in press). - 5. Fraser, H. and Isbell, H. : Pharmacology and Addiction Liability of dl- and .Bull. on Narcotics, 12: (1) in press. d-propo~JPhene. J:· - . 4. Fraser, H. F. and Isbell/'H.: Human Pharmacology and Addie- tiveness of Ethyll-(3-Cy-aJio-3, 3-phenylpropyl)-4-phenyl-4-piperidine / carboxylate hydrochloride (R-1132, Diphenoxy"late). Bull. on Narcotics (in press). - 5. Fraser, H. F. , Isbell, H. and Wolbach, A. B. : Addictiveness oi New Syntheti~ Analgesics ..I . Benzimidazole Derivatives: (a) l-(Beta (I'-ITH-7586, diethylaminoet...lJ.yl)-2-(benzyl-4-chloro)-5~nitrobenzimidazole ARC)-G-1}, (b) 1-(Beta-diethylamir.. .Jethyl) -2-(p-ethoxybenzyl) -5-nitro benzimidazole methane sulfonate (NIH-7607, ARC I-G-2). II. . 1-)-3-Eydro:h')" N-(3, 3-dimethylallyl)-morphinan hydrobromide (Nm:-7446, ARC I-B-19), m.. N-(l-Methyl-2-pipe:t:idinoet...1.yl)-propioanilide hydrochloride (Phenam promid, :t-.1IH-7602, ARC I-I-1 and, N-[2-{[Methyll-phenethylamino)-propyl] -propioa..""li.lide sulfate (Diampromid, NIH-7603, ARC I-J- 1). Addendum, 21st 111Ieet. , C9mm. on Drug Addiction and Narcotics, NaU. Res. Council, Washi.11.gton, D. C. Nati. Acad. Sci. (Jan.) 1960. P-3;3 ·I • < ) 6. Fraser, H. F. and.Isbell, H.: Human Pharmacology and . Addiction Liabilities of Phenazocine (Ql. -2' -Hydroxy-5, 9-dimethyl-2-(2- phenethyl)-8, 7-benzmorphan HBr, :NIE:-7519) and Levophenacylmorpha.!'l (1-3-Hydroxy-N~phenacylmorphinan methane sulfonate, NIH-7525). Bull. on Narcotics, 12: (2) in press. - J 7. Fraser, H. F. , Van Horn, G~ D., ~artin, W. R. and Isbell, H.: ~· New 1t!ethods for Evaluating Addiction Liability of wiorphine-Like Drugs. / of I. Attitude Opiate Addicts Towards Drugs. II. Short-Term Direct Addiction Procedure. Non-quotable Section, 1A1n. 21st !·. {. eet. , Comm. on Drug Addiction and Narcotics, Natl. Res. Council, Washington,. D. C. NaU. Acad. Sci. (Jan.) 1960. ~~ Abraham WiLder, 1.1. D. Acting Director {Vice Harris Isbell, M.D.) P-3;:z The page contains typed text detailing chemical compounds and their effects, numbered 2, 3, and 4, with associated NIH identification numbers. Handwritten marginalia in the bottom right corner reads "B-318". There is a horizontal line suggesting a separation of content at the top and a smaller horizontal line to the right of "Page 4". No photographs, stamps, forms, diagrams, tables, or experimental procedures are visible. The document appears to be a research or laboratory report. This page is a typed document with a header indicating "Page 5". There are no photographs, diagrams, forms, or tables. The text appears as dense paragraphs detailing various chemical compounds and their effects, likely related to drug research. There is a handwritten annotation at the bottom right corner: "B-317". A small, faint red markup is present in the top right margin. There are no official stamps or redactions visible. The document's content appears to be focused on the potency and effects of different substances, with numbered points suggesting a list of compounds. The document page is a typewritten report, numbered "Page 6" at the top right, detailing results of experiments with two compounds. Handwritten marginalia appears at the bottom right as "B-316". There is also a handwritten mark near the top middle, possibly an intentional dot or smudge within the page's paper texture. The page is predominantly text-based, with no images of people, locations, equipment, or facilities visible. No official stamps or forms are present, nor are there any diagrams, schematics, organizational charts, tables, or structured data. No redactions are visible on the page. The page is primarily text-based, with no photographs, forms, diagrams, or structured data. There are no official stamps visible. However, there is handwritten marginalia in the bottom right corner, consisting of alphanumeric characters "B-315". The text discusses new compounds and their potential as analgesics and muscle relaxants, mentioning their comparison to morphine and codeine, and investigating their abuse liability. There is no visual evidence of experimental procedures, equipment, or facilities. The document page, identified as "Page 8", contains typed text detailing "PLANS FOR FUTURE" and "REPORTS AND PUBLICATIONS". It includes details about drug addiction liabilities of specific compounds and published research. In the bottom right corner, there is handwritten annotation "B-314". There are no photographs, signatures, official stamps, or diagrams visible on this page, nor any visual evidence of experimental procedures or facilities. The image displays a single page of an official document, likely a scientific paper or report, based on the numbered entries and citations. The page appears to be a typescript with some handwritten annotations. There is no photographic content, diagrams, or formal stamps. The only discernible handwritten element is a symbol or code "B-313" in the lower right corner of the page. The text itself is a list of references, appearing to be academic citations for research related to pharmacology and drug addiction. There are no visible redactions or evidence of experimental procedures. The document is a typed page with numbered entries, likely a bibliography or list of references. There are two small, dark circles near the top, possibly from a hole punch. Handwritten annotations include the page number "Page 10" in the upper right corner, a signature above "Abraham Wikler, M. D. Acting Director (Vice Harris Isbell, M. D.)", and a lower right corner marking "B-3/2". There are no images, stamps, forms, diagrams, tables, or redactions visible on the page.