Doc 0000151874

The image displays a graphic overlay on what appears to be a dark background. On the left side, there is a stylized, metallic vault door with various intricate mechanisms and a glowing blue light emanating from it. To the right of the vault, text describes that the document was obtained from "The Black Vault," an online database of declassified government documents, specifically mentioning the MKULTRA/Mind Control Collection. The text indicates that the collection houses over 20,000 declassified CIA pages and provides a URL for free download. There are no photographs, handwritten annotations, stamps, forms, diagrams, tables, redactions, or other visual elements related to experimental procedures. MAY 1 1959 PDDICTIVENESS OF BENZIMIDAZOLE DERIVATIVES T~ Preliminary Report Hunger, et al (1) and Gross and Turian (2) have found that some basically substituted benztmldazole deriv~tlves have analgesic activity. Since these compounds constitute a completely ne\-r chc:n!eal class o1' ana1ges·1cs$ two compounds were referred to the Addiction Center,.USPHS Resear~~ Hospital, Lexington, Kentucky, tor determination of their addictive potentialities ln man. This report presents the accomplished prior to 1 1959. It is pre ~rk ~~y 1 liminary ln nature a.nd does not. contain sufficient Information to any final statement of the add1ct1veness of the ~rrant compounds as compared with morphine and codeine. lt 1s presented at this time tor purposes of information only. The speclflc compounds referred study r~r ~re l•(Beta-diethylam!noethyl)-2-(benzyl-4-chloro)-5-nitro benzimidazole NIH-7$86. ARC 1-G-1) and l•(Beta (Ba~93901 d1ethylam1noethyl)•2~(p•ethoxybenzyl}·5-nitrobenzim1dazole met.ha."'le sulfonate (Ba-20684, NIH-7607, ARC 1-G-2). In. this report~ the drugs will be !dent11'1ed by their NIH code nt:mbers. As a these compounds possess a morphine-like class~ 4}. spectrum of pharmacological activity (2.3 They arc 1 /J-17J Pase 2 .. ·, · .... : ': .. · · analgesic in mice end rats, cause the Straub reaction in mice, sedation and miosis ln dogs, and pupillary exeitem~nt in dilatation cats, and respiratory depression in rabbits and other animals. NIH-7586 ~; analgesic ln mice (2 3,4) by both subcu• 1 taneous and ornl [ED•SO:l.S mg/kg (3)]. In addicted ro~tes monkeys, lt twice as potent as morphine in suppressing ~s abstinence from morphine (5). Soma clinical prel~!nary <4>. experimentation has be~n done i11 SWitzerland In man, NIH-7586 is reported to have a good analgesic effect 1n doses ot 1S mg subcutaneously or 25-50 mg orally. Respir atory depression reported after intravenous adm!nts ~s tration, no "excessive" respiratory depression after subcutaneous administration, and no respiratory depression alter oral administration (4). Ho~ver, Dr. N. B. Eddy received 1n.tonnat1on that the compound to be marketed \\'aS tor oral administration only because of respiratory depression after parenteral administration. NIH-7607 !s an extremely potent compound ln animals. The ED-50 (subcutaneously) tor analgesia in mlce ~s 0.0012 mg/kg (3). NIH-7607 1s about 1700 times as potent as !n thls spec!ea. NIH-7607 was 1500 times as ~~rphine potent (0.002 mg NIH-7607:3 mg morPhine) subcutaneously 1n abstinence ln the nddlcted monkey. No allev!~tlng information on trials in is available. ~~n i • /---.._ \ Page .3 Methods Druss. Because ot reports of respiratory depression after parenteral administration, the oral route ot The document is a typewritten report, dated May 1, 1959. There is a handwritten annotation in the upper right corner, a circled "154" and a handwritten number "B-143" in the lower right corner. The rest of the page consists of standard text explaining the addictiveness of two benzimidazole derivatives, with no visual elements such as photographs, diagrams, stamps, or forms. The text appears to be the entirety of the content on this page. spec!ea. NIH-7607 was 1500 times as ~~rphine potent (0.002 mg NIH-7607:3 mg morPhine) subcutaneously 1n abstinence ln the nddlcted monkey. No allev!~tlng information on trials in is available. ~~n i • /---.._ \ Page .3 Methods Druss. Because ot reports of respiratory depression after parenteral administration, the oral route ot adm1n1s• tra-tion was used exclusively. NIH-7586 was available in - compressed tablets each containing 25 mg. NIH-7607 ~s given !n solution 1n d1st1lled water 1n.concentrat1ons of O•Ol and 0.1 mg per ml. Drugs were administered with patients 1n the tasting state. Idont!ty ot tha drugs was unknown to the patients but was known to tha observers ("single-blind"). Effects of s!nole doses. These tests were conducted !n non-tolerant former morphine addicts volunteered ~o tor the experiments. Drugs at 7:30 ~re ~dm!nlstered a.~ Observations were made at hourly intervals 11:30 un~11 a.~ or and at intervals hours until 9:30 p.m. t~ thereat~er At each observatt·on the patient completed a simple question naire cons1etlng of the following ttl feel the . que~tlons: ~~d!c!ne"; "The feel!ng!.!s l!kes morphine. marihuana; barbiturates, benzedr!nej heroin"; "I dontt feel anything"; "I am relaxed"; "I have a drive"; u1 am nauseated"; "I am sleepy"; and "I ~"'uld lUte more". At each observation or time, the diameter the pupils determined under ~s cond1t!ons ot constant light and accommodation by comparing the size of the pupils v1th those ot blackened in c1~cles 1-mm steps on a card (Experienced observern agree as to . il-/<;; ' . or size pupil within 1 mm using this simple method). The aides also made general observations and notes on the behavior ot the patients. In1tlal doses used 2S mg ~re or or NIH-7586 and 0.01 mg NIH-7607. The doses were gradually increased from trial to tr!al until de£!n1te subJective and obJective effects were ol:Sta1ned,a1'ter ~h1ch a su£t1cient number ot l)atients were given the dose found. to be effective ln tt,e preliminary trials to permit a or rough quantitative evaluation potency ln inducing subJective effects as compared v1th mQrphlne or codeine. In the case of NIH•7S86, subJective and obJective morphine-like effects began to appea_r 'When 100 mg wre or g1ven so 13 patients received thia amount the drug. 1 ln the case ·ot NIH-7607, morph1ne•11ka ettects began to or appear when doses 0.15 mg were administered at an t~ interval ot two and one-halt or atter a single dose hours~ of 0.25 mg. . The questionnaires mg wre or g1ven so 13 patients received thia amount the drug. 1 ln the case ·ot NIH-7607, morph1ne•11ka ettects began to or appear when doses 0.15 mg were administered at an t~ interval ot two and one-halt or atter a single dose hours~ of 0.25 mg. . The questionnaires completed by the patients ~re scored as negat..ive (clenlt\1 ot any subJective ettect). poslt!ve for.op1ates (effects reported ~o be like those ot morphine or heroin}, positive tor other drugs (reported or to be similar to those barblt.Ul'a.tes, mar lhuana,;~or or questionable (some subjective effect benze~rine), or reported no det1n1ta being similar bu~ 1dentit1c~t1on to any drug was made) • 5 Page Dttrerence in the size of the pupils after the drugs was calculated by subtracting the diameter atter the drugs from the diameter prior to the drugs. The area the ~~der timu actiun for pupillary constriction kas then curv~ calculated by the method of \"'inter and Flataker (6) • .S ubst!tutJon o,r NIH-7586 and 7601 f'or ?4 hours. ,. Five patients addicted to and on 60 mg ~1o ~re stablliz~d iQ ot morphine sulfate four dally wara ttm~s ava1labl~ for these tests. The patients received their last dose or at 4:00 p.m. In the succeeding twenty-four ~orphlne hours the NIH-7$86 and 7607 orally in pat!ents~recelved doses and at intervals wh1Ch were thought, on the basis ot preliminary experimant3, to ~e approxi~tcly cq~ivalcnt to 10 to 40 p~r cent or the patients' accustomed dose of morphine. Since thase patients have received ~~uld thre~ doses ot 60 reg of morphine (total of JSO mg) !n the period (the fourth dose ot 60 mg would tall at 24~hour or the 24t.A'l !lour)~ !tle do;;es cU-ugs under test \iere thought. to be equl•.ralant to 18 t.o 72 mg of morphine sul!ate • . . In case of NlH-7$86, the doses selected 2S and th~ ~re So mg at 10:00 p.m., 6:00 a.m~and 10:00 a.m. ot the test period. In the case ot the doses chosen NlH-760~ ~re 0.0$ and 0.1 ng at 10:00 2:00a.m., 6tOO a.m., p.m.~ 10:00 a.m. and 12&00 M of the test par1od. Observations to: the of abstinence hourly trom the 1nte~s1ty ~ra r IJ-/3 \ • 14th (6:00 a.m.) to the 24th (4:00 p.m.) hour after giving the last dose o! morphine and the intensity ot abstinence calculated 1n uhourly-polnts" by the method ot Himmelsbach (7). The area under the This page contains typewritten text from a declassified CIA document, likely a report or memo. There are no photographs, diagrams, tables, or forms visible. The only handwritten annotation is the alphanumeric code "B-142" in the bottom right corner, potentially a document or page identifier. There are no official stamps or redactions on the page. This document page displays typed text divided into sections titled "Methods" and "Effects of single doses." There are no photographs, diagrams, tables, or official stamps visible. The page does contain some handwritten annotations in the lower right corner, appearing as "• B-141." There is no obscured content or visual evidence of experimental procedures, equipment, or facilities. test par1od. Observations to: the of abstinence hourly trom the 1nte~s1ty ~ra r IJ-/3 \ • 14th (6:00 a.m.) to the 24th (4:00 p.m.) hour after giving the last dose o! morphine and the intensity ot abstinence calculated 1n uhourly-polnts" by the method ot Himmelsbach (7). The area under the action curve was calculated t!~ by the systam of Winter and Flataker thus converting the data to e single figure, termed "po!nt-hoursA. The data were with data obtained in another co~ared experiment in which 9 patients received 18 mg (10 per cant ot their accustomed dose} 36 mg (20 per cent), ·and 90 mg 1 (50 per cent) o£ morphine sulfate subcutaneously 1n similar or tests. Regression lines, estimate of the potency NIH-7$86 and lUH-7607 given orally as compared with the 95 potency ot morphine given subcutaneously, and per cent confidence limits, vere calculated according to the methods described by Bliss (8). Results SubJect 1ve r.;rect,s. The results are presented !n Table 1 and are compared with the results obtained with 20 and 30 mg o! morphine sultate orally and with 60 and 90 mg of codeine sulfnte orally ln another experlment. Five ot 13 pnt1ents who received 100 mg of NIH-7586 reported t.'l.a t the ef'f'ects wre s !Ini 1ar to those of an op!ateJ 7 of 14 patients received 20 ·and 30 mg ~nereas ~o or morphine orally reported positively tor opiates. ln 5 casa of codeine, and 6 ot 14 patients reported ~~e --- positively tor opiates; thus, as Judged by this system, NIH-7.586 appears to be roughly one-third to one-fifth as potent a$ in inducing subjective ettects and is mor~h!ne or roughly equal to codeine in this respect. Six 7 patients received 0.2$ mg of NIH-7607 reported poslt1vely tor ~o opiates. Therefore, NIH-7607 appears to be more than 80-120 times as effective as morphine orally as an "euphoriant". After these doses ot both NIH-7586 and 7607, or behavior the patients resembled that seen after morphine with alternating periods or ana sorr~olenc~ ~ketulness Ina", ( ''coast "nodding11 sera tching, 1r.creased loquacious ) 1 ness, etc. being observed. fuplllary Mean figures for pupillary ~nstrictlon. constriction as the area under the tine action expresse~ z. curves are ln Table The results, w1th respect sho~ to rough relative potencies of NIH-7586 and NIH-7607, agree with those described under "subJective etrcctsn. Suppression. of Abstinence. Both. Nlli•7S86 uncl NIH-7607 partially suppressed abstinence fuplllary Mean figures for pupillary ~nstrictlon. constriction as the area under the tine action expresse~ z. curves are ln Table The results, w1th respect sho~ to rough relative potencies of NIH-7586 and NIH-7607, agree with those described under "subJective etrcctsn. Suppression. of Abstinence. Both. Nlli•7S86 uncl NIH-7607 partially suppressed abstinence from morphine .. ln the doses usad. The results are shown in Figure 1. As indicated ln the figure, 1 mg ot morphine subcutaneously was equivalent to 2.62 (l.00-6.59) mg ot·NIH-7586 orally, and 1 mg of NIH-7607 orally \las equivalent to $9.3 or (15.55•136.5) mg morphine subcutaneously. The curves fJ~/J7 Page 8 met the requirements for slgniflcance of slope and parallelism. The figures in parentheses are the 95-per · cent confidence limits. Discussion Both NIH-7586 and NIH-7607 induce morphine-like subJective effects and suppress symptoms of abstlne~ce from ~orphine. Both drugs, therefore, have addictive properties. The data, however, are insufficient to permit any statement about the degree or addictiveness·as compared v!th morphine or code inc at thl!:i time. Further \vorlt. on the relative euphoriant potencie~ and cautious exploration of the effects of the two drugs when given hypodermically seems indicated. &ddition, since these compounds are L~ / the prototypes of new chemical series or analgesics, 3 or a direct addiction experiment with one them seems !ndlcnted. Qunntitatively,NIH-7607 is the most potent suppressor of abs~inence ~o~. lt ls. however, probably not as potent in man as !n th~.monkey. Summary 1. A prel~lnary examination of the addictive pct~tlaiit!es of l-(Beta•d!ethy!aninoetbyl)-2•(benzyl• 4-c..'lloro) -5-ni tro benz im! dazo le ( N.IH-7.S86) and 1-(Beta diethylam1noethyl)·2-{p-ethoxybenzyl)-5•nitrobenz1mldazole methane sulfate (NlH-7607) hes been ll".ade. /3-!J/ ·I 2. Both NIH-7586 and NIH-7607 cause p~p!llary and subJective e!tccts non ~onstr1ct1on ~~rph1ne-l1ke L~ tolerant torr.:e·r morphine addicts. NIH-7$86 ls 1/Sth to 1/.Jrd as potent as inorphlne 1n inducing subJect 1va errect..s, \-lhereas lllH-7607 !s· 80 to 120 times as potent as morphine. 3· · Both Nlli-7$86 and NlH-7607 will· suppress symptoms , o1' abstin.ence from morphine. _.. ?age 10 REFERENCES - J., 1. l!l.lriCER, A. J. KEHRI.E, ROSSI, A., and HOFFf. .i AN,. K. 1 1 Synthese bas!ch subst1turlrter, analgetisch wir.ksauer Experientia lJ: 400, 1957. tenzi~icazol•Derivate. 2. GROSS, F. and TUIUl.IAn, n.: Ben%!micazole c!ar!vatives with marl;ad analgesic action. Experientla J...l: 4G1-403 (Oct.) 1957 •. 3• £tDY, N. D.: Personal communication. 4• CIBA PHARHA.CElJTICAJ. PRCl:IUCTS, lijC.: Crier.tation Data. Ba 19390. A patent analgetic. U·Hmeographed Report) S. DENEAU, ·G. A. i-1c:CARTHY, D~ A., ancl This page is a typed document with a page number "Page 4" at the top right. There is a handwritten annotation on the bottom right corner reading "B-140". The text describes a research study involving drug administration and patient responses, mentioning specific drug codes like "NIH-7586" and "NIH-7607", and subjective effects like "morphine-like effects". The document has a single watermark or stamp-like mark at the bottom right corner. There are no photographs, diagrams, or forms present. lJ: 400, 1957. tenzi~icazol•Derivate. 2. GROSS, F. and TUIUl.IAn, n.: Ben%!micazole c!ar!vatives with marl;ad analgesic action. Experientla J...l: 4G1-403 (Oct.) 1957 •. 3• £tDY, N. D.: Personal communication. 4• CIBA PHARHA.CElJTICAJ. PRCl:IUCTS, lijC.: Crier.tation Data. Ba 19390. A patent analgetic. U·Hmeographed Report) S. DENEAU, ·G. A. i-1c:CARTHY, D~ A., ancl SEEVERS, M. li.: 1 Physical dapendenee liability studies in the monkey. 11 P• 11, Min. ot 20th Meet. on Addend~ Co~~ittee Drug Addiction and Narcotics, Aead. ot Set., r~tl. . Natl. Research Council, Dlv. Ned. Sci. {Jan.) 1959. 6. WINTZR, an4 L.: Studies on Heptazone ~A. PLATJU~, ( 6-io;Qrpho 11no-4,· · 4-D !phenyl•3 •He ptanone iiydroehlor ide} in CoiU-parison wl~l ot.her Analgesic Agents. J. ?ilarmacol. und Exper. Therap. 2sa 305•317 (March) 19SO. !3-!Jy Page 11 7. HII·~!ELSE.I\CH, c~ K.: Studies of cert.a in Addiction Characteristics of (a) Dlhydrcmorphine ("Paramorphan"), (b) DihyG.rodasoxymorphin~-o ("Dcso.morphine"), (c) Dihydrodcsoxycodeinc-D {~Desocodelne"), an~ (d) :.~ethyldihydror..orph!none ("l·~etoponT1). J. Plurr.llilcol. and Exper. Ther~p. fl.: 2.:,9·249 (Oct.) 1939. 8. BLlSS, C. 1.: The S~tlstlcs of Bioassay. New Yo~l~ Acac~mic Prass Inc. 1S52 • • Table 1 SubJective Effeets.of NIH-7.586 (Ba-19.390, I•G-1) and NIH-7607 (Ba-20684 I-G-2) Given O~a11y 1 I Nwnber of Patients RespondinG I Dose No. Positiv( Positive Drug of for for Other Question- l~lg. Ss. Opiates Drun_s able Necativr - lUH-7506 100 13 5 1 3 4 - r~IH-7607 0.25 7 6 1 0 0 f'tOrph!ne *~" ~ 1~ 7 1 [ll 3 3 l"terphlne .30 14 7 2 "3 2 * Codeine 60 14 5 1 [l] 4. ~ Codeine ~ 90 14 6 1 2 -- * Placebo 14 1 [11 1 12 For method of- see scoring~ tex~. Figures in brackets represent patients \iho also reported positively for opiates. * Data from another experiment. /J-;)~ • ...... ....• 13 P::lge Table 2 Pupillary Cor.striction ~\fter NIH-75e6 (Ba-19390, l-G-1) and NIH-7607 (Ba~2o604, 1-G-2) r ~~· Drug Dose Hean Area Under Curv( (m~) ::,s. ( Lm lio ur s ± S. E ~ ) NIH-7$86 100 13 8.14 ;t 0.81 NIH-7607 0.25 7 10.9 ± 1 • .35 . * ~1orphine Sulfate * 20 14 11.4 ± 2.5 ·, l•1orph1ne Sulfate 30 14 17.1 ± 3.2 Codeine Sulfate * 60· 14 9.0 ± 1.7 Codeine Sulfate * 90 14 14.4 ± 2.4 -- Placebo 14 0)+ ± 1.63 Data another experiment. ~ rro~ l • ,',I ~ ~­ l ~ = (j) ~ 0::: :_) \ 0 0 This page is a typed document, likely an excerpt from a scientific report. There are no photographs, diagrams, or tables. The only visual elements beyond the text are a handwritten annotation in the bottom right corner that reads "B-139" and a circular dot in the header that may be a smudge or a remnant of a stamping process. The document discusses drug experiments, specifically the effects of morphine sulfate on pupil size and abstinence in patients. The page contains typed text describing experimental procedures and results, with the title "Page 6" at the top right. A handwritten annotation "13-138" appears in the bottom right corner. There are no images, stamps, forms, diagrams, or tables. The text itself is the primary visual element, detailing scientific measurements and comparisons related to drug experiments. The overall appearance suggests a research document or report. ·, l•1orph1ne Sulfate 30 14 17.1 ± 3.2 Codeine Sulfate * 60· 14 9.0 ± 1.7 Codeine Sulfate * 90 14 14.4 ± 2.4 -- Placebo 14 0)+ ± 1.63 Data another experiment. ~ rro~ l • ,',I ~ ~­ l ~ = (j) ~ 0::: :_) \ 0 0 ' I 13 0 )- - ~ \ 'NIH-7607 I- z 9 \NIH-7586 ·.....: - 120 ~ 0 0], ® - (L . ·~ 6' wI 110 -~ 0 z J)l"': 'Do w 100 z +7;,\ - I- 90 (j) m G) .\ <! Y=215.18-72.91 logX 80 lL 0 >- 70 I- e --- (j) z I I mg. NIH-7607= 59.3 (15.6-136.5)mg. MORPHINE ( w 60 llmg. MORPHINE= 2,'62 (I.00-~.~9}mg.~IH-7856 I- 1 I I z 0 1 1 0.25 0.6 18 36 75 150 ' LOG. DOSE (mg.TOTAL) IN SUBSTITUTION PERIOD The page contains typed text with some handwritten marginalia. A handwritten annotation "D-137" appears in the bottom right corner of the page. There are also two black dots near the top of the page, one slightly to the left of center and another just above the "Page 7" text. Two very faint, thin horizontal lines are present near the right edge of the page towards the bottom. The text discusses experimental results related to opiates and drug potencies. There are no photographs, stamps, forms, diagrams, or specific visual evidence of experimental procedures or equipment beyond what is described in the text. This page contains typewritten text and a handwritten annotation. The text is organized into titled sections: "Discussion" and "Summary 1." The "Summary" section lists chemical names and corresponding NIH codes. In the bottom right corner, there is a handwritten annotation in dark ink that appears to be "B-136". There are no photographs, stamps, forms, diagrams, tables, or redactions visible on this page. The page contains typed text and a handwritten annotation. The typed text references "NIH-7586" and "NIH-7607" and discusses their effects related to morphine. There are no photographs, official stamps, forms, diagrams, tables, or redactions visible. A handwritten annotation, "B-135," is present in the bottom right corner of the page. The document appears to be page 9 of a larger report. The image displays a page from a declassified document, labeled "Page 10" at the top right. The primary content is a list of references, formatted in a numbered list with author names, titles, publication details, and dates. There are no photographs, diagrams, tables, forms, or official stamps visible. The document does contain a handwritten annotation in blue ink at the bottom right, "B-134." There are also two handwritten dots or smudges near the top center of the page, and a small dash-like mark to the right of "Page 10." No content appears to be redacted. This document page resembles a bibliography or list of references, with numbered entries for "HIMMELSBACH, C. K." and "BLISS, C. I." The text is typed, and the page is identified as "Page 11". There are no photographs, diagrams, forms, stamps, or redactions apparent on this page. The only visual additions are some handwritten characters in the bottom right corner, reading "B-133". This document page contains a single table titled "Table 1: Subjective Effects of NIH-7586 and NIH-7607 Given Orally." The table presents data categorized by drug, dose, number of subjects, and the number of patients responding positively for opiates, other drugs, questionably, and negatively. There are no photographs, diagrams, or organizational charts. handwritten annotions include a page number "12" in the top right corner, with "B-132" written in the bottom right. There are no official stamps visible. This document page contains a table titled "Table 2" which presents data on "Pupillary Constriction After NIH-7526 and NIH-7607". The table has columns for "Drug", "Dose (mg)", "No. of Ss.", and "Mean Area Under Curve (Im Hours ± S.E.)". Below the table, a footnote indicates that the asterisk (*) denotes "Data from another experiment." There are also handwritten annotations on the page, including "Page 13" at the top right and "D-131" near the bottom right. The page appears to be a scan of a typewritten document with a slightly yellowed background, and some minor ink marks and smudges are present. This is a black and white scientific graph with handwritten annotations. The graph plots the "Intensity of Abstinence - 'Point Hours'" on the y-axis against "Log. Dose (mg. Total) in Substitution Period" on the x-axis. Three lines are depicted, representing different conditions or subjects: "NIH-7607" with circle markers, "MORPHINE" with filled circles, and "NIH-7586" with outlined circles. There are handwritten equations associated with two of these lines. Additionally, there are handwritten labels in the upper right corner, including a likely page number or identifier "B-130". No photographs, stamps, forms, or redacted information are visible.