Doc 0000151834

ANNUAl. PROGRESS REPORT !,November 1958 Report Prepared By: Harris Isbell, H.D. 1 t-lovember 1957 to 1 November 19.58 For the period· NR: 101-149 l:A.onr-17-58 · CONTRACT: -(ONR•44l:MJO:set) .. ANNUAL RATE: ~' . · .. .. U. S. Public Health Service CONTRACTOR: National ~nstitute of l·Iental Health Be t.hesda 14. f·~d. (Inquiries concerning finances and contract. should be sent to this address. Inquiries about te~~nical work should be sent to address below). Director NIHH Addiction Research Center USPHS Hospital · Lexington, !{cntucky PRINCIPAL INVESTIGATOR: Harris Isbell~ J.t.D. Assistants: H. F. Fraser, M.D. C. R. Logan · G. D. Ven Horn O. A. K?.lly t.'. H. \·t:: 1 ell 1:1. L.. Glass C. R. Drovln Russell t-'!oss na::;-mond. Cox Jc\v"3ll Sloan g-?7 • TITLE OF PROJECT: Addiction L1ab111t1es of Synthetic Substitutes tor Codeine. ObJeeti'les: To find a synthetic analgesic and antitussive drug which would be as sate from the point of v!ew of toxicity and addiction liability as is codeine. ABSTRACI' (OR SUMl"ARY) 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 analgesic drug available s~thetic w~s which was as sate and which had as low addictiveness as codeine. Adequate substitutes for the potent analgesics of the morphine 75 type were available, 1ut per cent or the civilian and military consumption ot. 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 Addiction Research in this investiga NI~m Cen~er tion, which was initiated at the request of the on Co~~ittee 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, nnt!tussive, and antidiarrheal properties of such ncv drugs must necessarily boa made elsewhere. j}-d - 3 Pag~ The methods used for studying addiction liabilities ot 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 1_951 to l November 1958, .51 new drugs or mixtures of drugs were tested for addictive poten tialities. The image is a dark, digitally rendered scene depicting a secure vault door on the left side, with a blue glow emanating from it. The text on the right side of the image is white, with a stylized heading "THE BLACK VAULT" in a glowing, script-like font. Below this, a block of text explains that the document was obtained from The Black Vault, an online database of declassified government documents, specifically the MKULTRA/Mind Control Collection. The text also provides a URL: "http://mkultra.theblackvault.com". There are no photographs, handwritten annotations, official stamps, forms, diagrams, tables, redactions, or visual evidence of experimental procedures visible on this page. The document is a declassified CIA report titled "ANNUAL PROGRESS REPORT." Visual elements include handwritten annotations like "143" within a circle on the top right, and "B-84" in the bottom right corner. The page appears to be a typed report with fields for "Report Prepared By," "For the period," "CONTRACT," "ANNUAL RATE," and "CONTRACTOR." The "CONTRACTOR" section lists an address and details about inquiries. Below this, "PRINCIPAL INVESTIGATOR" and "Assistants" are listed with names. There are no photographs, diagrams, or visual evidence of experimental procedures. methods used for studying addiction liabilities ot 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 1_951 to l 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 t\to substances which were outstanding as possible substitutes for '· codeine· for suppression of cough t.,.ere discovered. These sub - stances were (1) d-3-Methoxy-N-methylmorphinan (dextromethorphan), and (2) narcotine. Con~inu!ng 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, sor.1e doubt still remains that drugs 'Which \ are as effective ln relieving pain as codeine are available. Some .eight compounc:is with definite promise were uncovered in past. work. The drug, ,!!..Propoxyphene (Darvon, Lilly}, has rece!vedthe most attention and appears to be the most This drug promi~ing.· . . . was shown to have fewer addictive properties than codeine. lt is now being actively marketed by the Eli Lilly Company both as thc_-_: pure material and in combination with aspirin. Further detail~d studies on its analgesic effectiveness are underway. _,...._ •'0 ""' -., ...... ·f~,.., h.· b. During the current reporting period: During the current reporting perlocl (1 November 1957 to 1 November 1958) the addictive potentialities of 6 drugs were evaluated whol.ly or in part and t}le metabolfc tate of' normorph!ne investigated. The results are presente~ below under individual headings: 1. Noreode1ne. work with norcodeine was undertaken because normorph!ne had been shown to possess considerably less addictiveness than morphine. It wa~ therefore thought of interest to extend the work to norcodelne. In doses of 75.mg. norcodeine induced subjective effects in forll!-er morphine addicts similar to those caused by codeine •. It also caused mild respiratory depression and pupillary constriction. It suppressed abstinence from morphine ~ffectively \·Jhen substituted for morphine in patients addicted to that drug. Patients who took the drug~ in doses increasing to 1,000•1,500 mg. dally over a.period of 60 days, developed marked sedation and other morphine-lU~e side effects. When the· drug was withdrawn, definite but very m!ld . abstinence occurred. Since this drug ls effective orally and since abstinence addicted to that drug. Patients who took the drug~ in doses increasing to 1,000•1,500 mg. dally over a.period of 60 days, developed marked sedation and other morphine-lU~e side effects. When the· drug was withdrawn, definite but very m!ld . abstinence occurred. Since this drug ls effective orally and since abstinence is milder after withdrawal than fs abstinence from codeine, it ls regarded as a potentially promising substitute. It, is not a synthetic drug. untor~unately, ( !3 -cf -- .... 2. !!•f4ethadone. This drug was re!nvestlgated at the request of the on Drug Addiction and Narcotics, Co~~ittee 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 after substitution for ~f ~-methadone, morphine for 10 days, extremely mild was observed. abstlnenc~ If -d-methadone has any add! cti vene~s 1 t. 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-oxo-3-phenyl-Erouyl)-normorph!ne. Twenty to or· 30 mg. this drug induced subjective effects in former morphine . addicts which appeared to be equivalent to those caused by .30 mg. ot morphine. drug was a very suppressor of ~he effec~lve abstinence from It 1s regarded as having. a high addlct- ~orphlne. 1veness and ls being dropped from further consideration. 4. N-Phenethvl-morphine. Fifteen mg. of N-phenethyl- . morphine subcutaneously induced obJective and subjective effects in nontolerant former addicts equivalent to those caused by 30 Mg. of morphine. 140 mg. of the compound every 24 hours errectively suppressed abstinence in patients addicted to morphine. The drug l$ as having high addict!veness and ls being dropped regar~ed from further consideration. .I ~-·· 5. 1-3-Hydroxy•morphinan. No subjective effects seen after single doses ranging up to as much as 100 mg. of ~re this compound hypodermically or orally. When, however, patients 25 were given mg. of the drug three times daily hypoder~ically mild morphine-like effects did appear. 360 mg. of the drug dally suppressed partially.in patients who had been ap~tinence 240 receiving mg. o! morphine. This drug definitely will have low add!ctiveness, and more complete exploration by formal 10-day . substitution and direct addiction is indicated. 6. 1-(.3-D!phenyl-3-carbon!tril-prop;vl)-4-Ehenyl-h carbethoxyp!Peridlne (R-1132). This compound is a derivative of meperidine. This page contains a typewritten document with handwritten annotations. There are no photographs, stamps, forms, diagrams, tables, or visual evidence of experimental procedures. The only handwritten elements are a circled number "143" at the top left, and "B-8" at the bottom right. There are no redacted or obscured sections on the page. 360 mg. of the drug dally suppressed partially.in patients who had been ap~tinence 240 receiving mg. o! morphine. This drug definitely will have low add!ctiveness, and more complete exploration by formal 10-day . substitution and direct addiction is indicated. 6. 1-(.3-D!phenyl-3-carbon!tril-prop;vl)-4-Ehenyl-h carbethoxyp!Peridlne (R-1132). This compound is a derivative of meperidine. developed at the Eupharma Laboratories in·Belg!um, and was part of a program designed to develop a drug with consti pat1ve 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 1n nontolerant morphine addicts who received 20 mg. or or 50 less the compound orally. Doses or 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. - Page i 180 mg. of R-1132 "dally suppressed abstinence 24 nearly completely ~en substituted for morphine for hours in mg. patients who had-been receiving 240 of morphine daily. R•ll32 also suppressed ~bstinence effectively over a lO•day period when 180 mg. were substituted for 240 mg. of morphine in S 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 s·subJects. With such a dosage schedule the subjective effects were mild and consisted primarily of sedation. The patients we·re quite constipated. Nall~ne precipitated mild but definite abstinence in these patients. When the drug ~s discontinued 4 after 60 days. definite but mlld abstinence was seen in of the 5 subJects. ·This ls a very interesting and possibly important drug which might have definite military usefulness. It is possibly the most effective and safest constipating agent knovm, 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 1n treating cases of infantile diarrhea 1n the Belgian Congo. _, • The drug must be regarded as having definite addiction liability since it induces morphine-like subjective ... .. ettects, suppresses abstinence, and abstinence is seen on with• dra\-tal; but its addict!veness is defi_nitely less than that or codeine or of morphine. Work with The document is a typed page containing text about drugs and their effects. There are no images, photographs, stamps, forms, diagrams, tables, or redactions. The only handwritten annotation is "B-8" in the bottom right corner of the page. The page appears to be a section of a report or research paper, focusing on the addictive properties and effectiveness of certain drugs as antitussives and analgesics. infantile diarrhea 1n the Belgian Congo. _, • The drug must be regarded as having definite addiction liability since it induces morphine-like subjective ... .. ettects, suppresses abstinence, and abstinence is seen on with• dra\-tal; but its addict!veness is defi_nitely less than that or codeine or of morphine. Work with this compound is still in progress and investigations of the butyl-ester will also be carr led out. 1. of NormorEhine. Studies on the excre ~~etabolism tion and fate of were undertaken because ~etabolic normorp~lne this drug was found to have definitely les-s 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 is based on extraction of the normorph!ne from whi~ 8.S aqueous solution at pH into a mixture of amyl alcohol and ethylene dichloride. Normorphine is returned to aqueous solution by extracting with 0.0$ normal hydrochloric acid, after which the sllico•molybdic acid reaction is applied. The method gives reproducible result·s, and consistent recoveries of added normorphlne. To our surprise, it was found that 50% or normor ph!ne recoverable from urine \vas 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 1)-77 ·• -· . dose of normorph!ne is recoverable 1n the urine within 48 hours. Treatment of the urine with heat and strong acid liberates additional normorphine (so-called bound normo~phine)·. Bound normorphlne, however, does not appear to be a glucuoron!de, since incubation with glucuoronidase does not elevate amount of normorph!ne which is extractable. In .contrast, glucuoronl 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 or the drug is bound than is the case with morphine. In effect, more tree normorphlne would be present, .leading to a higher concentration of tree normorphine in brain than is.the case with morphine. ln order to test this hypothesis, animal work with refined techniques will be nec~ssary. Similar studies are to be carried out on -1-3- Hydro~rph1nal'1. PLANS FOR FUTURE Immediate: During the coming year we intend to complete turther direct addiction studies on the important constipating drug, R-1132. Preliminary work with the butyl-ester c~rres­ ponding to.R-1132 will The page is a typed document with "Page 4" in the upper right corner. There are no photographs, diagrams, tables, or forms visible. The text discusses the addictive potential and effects of drugs like norcodeine, referencing a reporting period from November 1957 to November 1958. Handwritten marginalia, "B-8", is present in the lower right corner. There is a single black ink dot near the top center of the page. hypothesis, animal work with refined techniques will be nec~ssary. Similar studies are to be carried out on -1-3- Hydro~rph1nal'1. PLANS FOR FUTURE Immediate: During the coming year we intend to complete turther direct addiction studies on the important constipating drug, R-1132. Preliminary work with the butyl-ester c~rres­ ponding to.R-1132 will also be carried out. Work on ~-methadone~~­ and ,S.-3-f-1ethoxy-N-phenethylmorphinan will be completed. \·le \vill Page 10 also study the addictiveness of one compound in the benzmorphan series, and one compound ln the morph!nan series. Both of the latter two drugs have been reported to be nonaddictive in monkeys. We will also continue \-Torking on the metabolism of the demethylatz, congeners of morphine and morphinan. . Long Range: We intend to. continue the search for substi- tutes !or codeine until drugs are found which are, in the opinlcn of the Committee on J.?rug Addiction and Uarcot·ics, completely satisfactory substitutes for codeine •. REPORTS AND PUBLICATIONS (during the current report period}. 1. Fraser, H. F., Isbell. 11. Eisen.T.an, A. J., and Van 1 Horn, G. D.: Studies of Normorphine in Man. J. Pharmacal. & Exper. Therap., ~: (1) 22A (J~n.) 1958. (Abstract) 2. Fraser, H. F., and Isbell, H.: Human Pharmacology and Addiction .L tabil.~ty of Certain Compounds Related to Morphine or Codeine •.I . Normorph!ne. II. Norcodeine. Nin. 19th f-1eet., Oomm. on Drug Addiction & Narcotics, Nat'l· Res. Council, 29-30 Harch 1958. 3. Fraser, ·H. F., Wikler, A.J Van Horn, Q. D., Eisenman, A. J., and· Isbell, H.s Human Pharmacology and Addiction Liabllit.: of Noi.'"morphine. J. Pharmacol. & E.xper. Th~rap., ~: 3·59-.369 1958. __ O~ar.) 4. Fraser, H. F., Isbell, H., and Van Horn, G. D.: ll: Norcode!ne in Han. Federation Proc., (1) 367 (Har.) 19.58. Harris Isbell, M.D. Director This page is primarily text-based, containing a typed report that appears to be a scientific or medical summary. There are no photographs, diagrams, or tables present. The only handwritten annotation is a small "B-8" in the lower right corner, possibly a page or document identifier. There is also a faint underline beneath "d-Methadone" and "N-(3-Oxo-3-phenyl-propyl)-normorphine" and "N-Phenethyl-morphine", suggesting they might be keywords or names of particular interest. No official stamps or redactions are visible. The page contains typed text detailing drug experiments, with two numbered entries: "5. 1-3-Hydroxy-morphinan" and "6. 1-(3-Diphenyl-3-carbonitril-propyl)-4-phenyl- carbethoxypiperidine (R-1132)". Handwritten marginalia in the bottom right corner reads "B-7". There are no images, official stamps, forms, diagrams, schematics, organizational charts, tables, or structured data. There are no visible redactions or obscured content. The page contains typed text detailing research experiments, likely clinical trials, involving a drug labeled "R-1132" and its effects on patients undergoing morphine withdrawal. There is a handwritten annotation at the bottom right corner reading "B-78". No photographs, diagrams, forms, or official stamps are visible on this page. The document page contains text printed in a standard font, with a page number "8" at the top right. There are no photographs, diagrams, forms, or structured data visible. There is a handwritten annotation "B-77" in the bottom right corner. No official stamps or redactions are present. The page is a typescript document with standard margins and line spacing. There are very few visual elements besides the text itself. At the top right, there is a handwritten annotation "Page 9". Near the bottom right corner, there is another handwritten annotation "B-76", followed by a line. There are no images, stamps, forms, diagrams, or tables on the page. There is no obscured content or redactions. The document appears to be a straightforward textual report. This document page contains typed text, primarily a list of scientific publications. There are no images of people, locations, equipment, or subjects. The page is annotated with handwritten marginalia on the right side, including a signature that appears to be "Harris Isbell, M.D. Director" and a number or code "13-75". No official stamps, forms, diagrams, tables, structured data, or visual evidence of experimental procedures are visible.