Doc 0000151827

The page features a dark background with a stylized graphic of a vault door on the left. White text overlays the right side of the page, stating that the document was obtained from "The Black Vault," an online database of declassified government documents, specifically from the MKULTRA/Mind Control Collection. The text indicates that over 20,000 pages have been declassified by the CIA and are available for download. A yellow hyperlink directs the viewer to "http://mkultra.theblackvault.com" for access. There are no photographs, handwritten annotations, official stamps, forms, diagrams, tables, redactions, or visual evidence of experimental procedures visible on this page. THE ADDIC!ION LIABILITY OF SY!lTHETIC SUBSTITUTES FOR CODEI!JE (Projact Description) Raquest to the Office of Naval Research for Renewal of Contract 1tR 101·149 NAonr-11-57 (Ol-m:44l:HJG: set) · 1. Background lntormation. Since July 1951 a proJect desl~ned ~o develop a synthetic drug which would be as safe as codeine with respect to toxicity, antitussive activity, and addiction 11ab111ty has been carried on wi thln the rtatlonal Institute ot J.tental Health Addiction u. s. Research Center, Public Health Service Hospital, Lexington, Kentucky. This pr.oject has been financed !n largs part by funds . trom the. Office ot Navnl Research, and this description consti- or tutes request t.o r rene~l the proJect tor the period 1 July 19.58 to 30· June 19$9. A syntllet!c substitute tor codeine is badly needed s!nce opium, or morphine derived from opium, constitute the only or sources codeine. Unless a synthetic substitute for codeine . . is round the United States must continue to ~tocl~ile opium in order to provide adequate supplies of codeine tor both the c1vl11an and military population ln the event o! war. Fac1llt.b~ o! the N!NU Addiction Research Center ara not su.f'!ic!ent to C3rry out this worlt, in addlt!on to routine drug testing requi:-ed --· Pag_e 2 for the evaluation ot all new analgesles, unless additional tunds are the Department of Defense. supplie~through 2. Worlt Aceomp 11 shed to Date. Previous work has been summarized 1n the annual progress . v sent to Captain F. H. Quimby and Captain T. K.·Roebush, ~epo~t Head of the Physiology Branch, Office ot Naval Research •. . Tvm drugs have been developed are promising substi- ~!ch tutes for codeine tor relief of cough. These drugs area i) daxtro-methorphan, and 2) narcotine. Neither drug possesses any s!gn!ttcant addiction 11ahi11ty and both have relatively low toxicity. Continuing reports to the Committee on Drug Addiction and National Research Council, and e11n!ea! reports Nareo~!es, appearing ln the literature Indicate that these drugs are ettect!ve cough suppressants. The antitussive phase ot the problem has, ln a sense been solved. the~etore, AJthough the ant1tuss1ve problem ls no longer as pressing there are still no compounds available tvhich are known to be as ettect!ve and as sate as codeine tor the relief of mild grades or pain. over 46 new drugs or mixtures ot drugs have been screened tor this purpose. The outstanding substancas so far developed are -dl- and -d-alpha-4·d1methylam1no-1 ,2-d!phenyl-3- methyl-4-prop!onoxybutane, or -dl· The page displays a typed document with handwritten annotations. A circle in the top right corner contains the handwritten number "133". There are also two small horizontal dashes originating from the right edge of the page. To the right of the page's bottom corner, a handwritten phrase "B-5" is partially visible. The document itself appears to be a research proposal or progress report, with a section titled "Background Information" and contract details provided. No photographs, official stamps, forms, diagrams, or evidence of experimental procedures are visible. compounds available tvhich are known to be as ettect!ve and as sate as codeine tor the relief of mild grades or pain. over 46 new drugs or mixtures ot drugs have been screened tor this purpose. The outstanding substancas so far developed are -dl- and -d-alpha-4·d1methylam1no-1 ,2-d!phenyl-3- methyl-4-prop!onoxybutane, or -dl· and -d-propoxyphene. The add1et1vcness of these compounds !s so low that the Committee on Drug Addiction and Narcot1c:s has ruled that they need not be p--52 Page J ·subJected to the controls imposed by the Harrison Act. Prelim inary clinical data indicated that they were nearly as effective . .... as codeine !or the relief of paln. Complete data on toxicity and clinical use are still not available and more recent reports 1 indicate that their analgesic potentialities may not be as great as was originally claimed. During the past 18 months important leads been r~ve developed concerning the demethylated derivatives ot morphine and morphinan. Normorphlne has been shown to be an active agent ( tor inducing sedation in man. It suppresses abstinence !rom morphine completely, but, unlike morphine, abstinence !allowing withdrawal after direct addiction is quite mild. These studies are now being extended to include norcodeine, -1-J-hydroxy- morphinan (!·nordromoran) Evidence and!-3-metho~y-morphinan. - ot some activity in d-isomers ln the methadone series has also . been obtained. we·hope to develop and complete studies on these within the next 18 months. co~ounds 3. Need for Continuation or the ProJect. or The chief need for continuation ~~e project !s related to conflicting reports concerning the analgesic potency or - or -dl- and d-propoxyphene. Original clinical trials tor relief chronic pain were promising. More rec3nt trials against post partum pain and chronic pain due to cancer have not been .,.......-.. ·favorable. There is also insuttic!ent information concerning the toxicity ot propoxyphene. lt ts, uncertain therefore~ that·a satisfactory substitute for code1ne·tor relief ot pa1n has been round. · For this reason, 1t ls· essential to continue the search tor other synthetic substitutes. In addition, t~e - larger the number ot compounds testad the greater would be the or chance finding a completely adequate substitu.te for codeine. 4• Work Proposed. During the period from l July 19$8 to 30 June 19$9 we propose to test the clinical pharmacology and addictive proper or ties narcodeine, !-3-methoxy-morphlnan, _2-methadone, methadone, and to .~-p!perldyl ~3-methoxy-N-phenethylmarph!nan, undertal~ preliminary examination of some compounds ln the mepcr!d1ne·series. In addition, studies or other The page contains typed text, with the header "Page 2" and a document number "B-52" handwritten in the bottom right corner. There are two dark circular ink marks near the top center of the page, appearing as bullet points or possibly hole punches. A faint line is visible to the right of the header. A small checkmark is present in the right margin near the top. There are no images of people, locations, equipment, or subjects, nor are there any diagrams, schematics, tables, or forms visible. The text itself is the primary visual content, and there are no visible redactions or evidence of experimental procedures. for codeine. 4• Work Proposed. During the period from l July 19$8 to 30 June 19$9 we propose to test the clinical pharmacology and addictive proper or ties narcodeine, !-3-methoxy-morphlnan, _2-methadone, methadone, and to .~-p!perldyl ~3-methoxy-N-phenethylmarph!nan, undertal~ preliminary examination of some compounds ln the mepcr!d1ne·series. In addition, studies or other substances ,· regarded as potential codeine substitutes by the Committee on . Drug Addiction and Narcotics will be carried out, as. advice concerning possible compounds tor testing is received. 5. Methods. Methods used are the standard addlet!on-liability testing methods ot the Addiction Research Canter. The methods are NI~m accepted as standard hy the Committee on Drug Addiction and • Narcotics and have been described in previous proJect descrip- tions, "nlch should be consulted for details. 1)-5" ·I -· Page S 6. Evaluation of Data. Evaluation of data obtained 1n the_ add!ction-11ab1l!ty program has also been discussed in previous proJect descriptions. 7. Location or Project. The work will be carried out· in the Research Nl~tti Addicti~n Center, PHS Hospital, Lexington, Kentucky. This institution provides the two :f'acillties tor the typ·e of work to necessa~y or be undertalten2 l) a pool patients who 'Will volunteer :f'or with drugs, and 2) strict environmental control ~xperiments or prevents the introduction drugs other than those under ~leh study in an experimental situation. 8. Exoerimental Personnel. Work will be carried out under the direction ot Harris· Isbell, M.D., Director, NIMH Addiction Research Center. This 14 investigator has had years o:f' experience in research on narcotic drug adcii~tion and has published many papers .in the field. He will be ass_isted by two other experienced physicians, Dr. H. F. Fraser and Or. Abraham \iil<.ler, both of whom have had extensive experience in research on drug addiction, with many publications. The part-time services of a biochemist, neuro pharmacologist, and research psychologist are also available. or A special ward for the conduct these studies is currently in operaticn. -- Po.se 6 9. Est lll'_a tc d Cost.. . The estir~ted costs are shown on the attached sheet. It - will be noted that the ~ount ot money requested !s higher than in past years. The increase !s due to increased costs ln the personnel·servlces account; to within-grade promotions for persons who have been with the project s!nee its inception in 1951; need to provlde money tor Civil Service retirement (whiCh - was formerly not paid from operating funds}; and to The page is a typed document with a handwritten annotation "B-5" in the bottom right corner. The document also features a circled black dot near the top center, which may be a scanning artifact. A faint horizontal line appears near the bottom left corner, possibly from the original document's binding. The text itself appears to be a continuation of a report, discussing pharmacological research related to pain relief. There are no photographs, stamps, forms, diagrams, or evidence of experimental procedures visible on this page. than in past years. The increase !s due to increased costs ln the personnel·servlces account; to within-grade promotions for persons who have been with the project s!nee its inception in 1951; need to provlde money tor Civil Service retirement (whiCh - was formerly not paid from operating funds}; and to provide tor ,C!vll Service pay raise antlclpated during the current t!scal year {1958). l! the Civil Serv1ce pay raise does not eventuate, this 1tem could ~e eliminated from the budget. On the other hand, tr the raise is greater than that provided tor ln the budget(6%) the figure will need to be increased accordingly. v· Harrls Isbell, M.D. Director Attachment 27 January 19.58 ....... ~ The document is a typed page with numbered sections 4 and 5 discussing proposed work and methods. There is a handwritten annotation "B-5" in the bottom right corner and a black circular mark at the top center of the page. There are no photographs, stamps, forms, diagrams, tables, or redactions visible. The paper appears to be aged and slightly yellowed. The document is a typed page that contains text only. The page is numbered "Page 5" in the upper right corner. There are no images, stamps, or handwritten annotations visible. The text is divided into numbered sections, with "6. Evaluation of Data," "7. Location of Project," and "8. Experimental Personnel" being the headings. There is a handwritten note "B-4" in the lower right corner of the page. No visual evidence of experimental procedures, equipment, or facilities is present. This document is a typed report featuring text and no images or diagrams. The page is numbered "Page 6" in the upper right corner. It contains predominantly black text, with a few handwritten annotations including a "B-" in the lower right corner. The "Estimated Cost" section is marked with a handwritten line and circled "6%" indicating a potential point of interest or calculation. There are no photographs, stamps, forms, tables, or redactions visible on this page.