-ARE u Pubfic Ka. Seriics A of, HEALTH, EDUCATION, -N S T I T U T2 E S N A T 1 O',14 r-"% L I 0 F H E A L 1* alftwoo..%Gottus 23 &4a y' 1 95 5 ACCICTI(ft RESEARCH CENTER t4,%Igo""IlITITUTn OP M2PgT4L HCALTH pUgLgC Mai.T* StStVICS HOS VITAL Box 2000 Lazi*STVm. KINTUCXY ted S I nce wr i t ing to you on 29 January 1955 we have-comple experiments on the blocking2 of LSD-reaction with R seroine. z a combination of LSD with C-9, and tolerance to LSD L>y prior admlntstration of,,.,LA'C-. So rle furf-her infor-,iaf ion is avai la,'.-le on C-9, and studi'es designe2d to shed licht on the characteristics of the mental effects induced by C-9 are underway. Trials for the blockade of LSD-reaction-wit,% 'Fren,quel' (4-piperdyl- diphenyl-carbino@) a.re in oroaress and will soon.@e complete. ExperTments are carr'ied on with cohob2a snuff, buf.to date no reaction has been obseived ifr the doses used. t-l@o re de f a i I T of the descriptions of the exoeriment'S together with tables are given belo,,ii. Reseroine (is I.-)D,B,focki;ig Agent'. 2 In this exoeriment 12 necro subjects received ttiz T'ollo-.vinc combinaticns-of drugs: (1) Reserpinz placeb6-LSD placebo- (2) Reserpine placebo-LSD; (3) LSD olacebo-Peserpine; (4) LSD- Reserpine. Reserpine tvas given orally in a dose of I 2 mg. ten , and ministration of the L hours I ma. two hours prior to ad placebo, or 60 mearl. of LSD. Placebos uszd for "eszrpine werz identical in appe@rance with table@s of the acfi,,,e drug. P-xp,--ri- ment was condu.cted in c,4otibio--.blind fashion. k-leasuremen'l s e.,e re fhose orevious lv de.-,cribed f rort thiz la@l-ora tOrV (eS@ lr-naf lOn rl'F knee jerk measurcr@ient of oupi I iary s 2ize, measurerrcn' o7 -,,Is;-,z I ic blood preslsure, adninist're-lion of questionnaire, hourly assess- ment of c,'In.1--al gr,!ide of reacf"on). -Data were anal,/Zcd -'-v same methods' exolained iri prevliou.-@ rc.-.or'rs, -o:r sz(-, n-o l@ c n be secn f, f h - le f,@af R,;?Serpine cal-t sign'f icani- cliange in any ov t s z rl,-., a's u r c., 2sc t h e r c f o r c conc:uded that in this dose, Resprrir,'c does nof :-.Ioc@K the LSD-reacf ion. I f rl lghl -ke c!c s T ra I e t o r c c)e ar' s @-.,o r k- usinc, larcer e@osc of pzriod of 2 a Rcserni.-ic aiti- a Ion-cr ing with administration prior to test' L SD 0-1@ in.crest, hot-,ev@.,r, --is the fact t.@a,' definite sid-- effects ;,ere obs5erved even %-jifh the small doses of Reserpine u,-tzd. LAE-32 A i r c f @r)-o c.-f c c f Since LAE-32 t sa .re la f I vz 1,,, 9 v.'?Tlch structurally closely rclaf,,d,.fo LSD-25 if wasirrlocotenf dru' elf that pr2ior actministraflon Of a dose 'pfor sites and fherei)y of -LAE mit-hf block the rece pre ve n f or modify the@ LSD-reacfion. Twelve negro patients were, therefore, Given In randomized order under double-blind-fechnique: (1) LAE place bo followed b@, LSD placebo; ( 2) LAE place@-,o followed by 60 LSD; (3) LAE I 500 mcgm. fo I lo%.led by LSD placebo; (4) t@AE, 500 mcgrh., follo wed In one hour by.LSD, 60 mcom. The LAI-:-32 used in thesc experiments was in the form of enter C_coaf ed pills rather than in the 2-corri of solution in ampules. Sug evidence of very mild LSD-like-effecfs was observed In fh'qesflve ese subjects with this dosage of LAE. The effects, however, were not significantly different statistically from those ob@ained with 2placebo (see faffel Also.$ there wa's no signtf-icanf difference between place@o-LSD and LAE-LSDT although a mild trend fowar-d reduction of the LSD reaction was observed which was not sufficiently !great to- warrant further exploration. Cross T31erane-c-P LAE-32 anf-I LS2D-25. This experimen'., was carried out at the sug esfion of Dr. Harold Abramson fn f'he hope that one nichf develop tolerance to LSD wifhou' incurring the unple-dsan@ side effects assoclafzd with developmen@ of @oference@ Iwith administration of LSD. Twel2ve ne!gro patients, therefor'e, rede.lved In r,andomized order by the dou-,Ie- blind technique: (1) LAE place@o for o@e wee@,- (2) LAE, 500 mcgm., for three days. follo@ye@ by 1000-incgm. LAE for'four days Patients were then tested with the standard dose (60 r2ncgrn-l IID-25. I f iya s not felf"hat it wa.s neccssari/ to do @he plac -.,'-)o-placeb-o and placebo-LAE cofflrol's at this time, since they were fairly well covered by th-e first expcrimenf.@ Methods of measurement of'f@e LSD-reacfion and analyzing the data were the same as prevlousl,/ reported. Durin,o the .@eek of ad.-..iin,'sfrafion of LAE-32 definite but mild LSD-li@e e@,r 4jecfs were reported by the patients, Vio- Save f.he 2 c- 1, T'ecis Of t,-iven by one of @t@c schedules we have used to de ve lop to lerance In the pasf. As can be seen by the was a'der,inife f Le tendenc'y for infenst@y of fhe-LSD-reacfton to he reduced fo I low'tng a iieeks ae-'2,-,ii n isf ra t !on. of LA--- i r, n i f i cB n I- re du,: f I" o n in knee -jerks, pup@iftery si,--e and systolic b-lood oresstire obsern,cd'ancl there were rearly significant reducf ions in the .number of answers to questionnai're and In the citnical grade of effect. I2t v.@ould appear that so.-ne de-ree of tolerance did develoo. To let-a nce, howe ve,, was f ar less f hen f ha f- I nduced @,y repeaf ed aclrlirisfraflon of LSD. This mef,'iod, therefore, does nof seen to .be a very pract ica I way of induclng to lerance fo LSD. Reproduc ib I II f yof t h,@-- LSD-25 Pesponse, In the course of the experiments described above three trials of the effect Of.60 Mc'gmo 6f LSD were carried out on the same .12 patients 'under nearly identical cond@itions. As@can-be seen from the table on reproducibility of the LS2D-response, the LSD-reactioi Is an,extrem,-.Iy consistent biological phenomenon. Reproducibility is, of coursz,--very Tmoorfant In testing the effects of various antidotal drvgs* Combination of LSO-25 with C-9. The purpose of this experiment was to study possible enhancement of blocking of2 the LSD-response by combining the drug with C-9. The same 12 patients- who were used in the LAE and Reserpine experiments received in randomized order accordi,ng to the double-LIind technique:- (1) C-9 placebo-LSD placebo; (2) C-9 pfaceL-o-LSD-250 (3) LSD place@o- 0.5 mg'. C-9; (4) LSD, 60 mcgm.2, -0.5 mg. C-9; (5) LSD, 60 mcgm., -1 me.. In addition to the usual LSD me.asurements (oupillary size, estimation of knee erks, measurenent of resting blood pressure, LSD questionnaire,;:Ojn'd assessment of clinical Grade), '&-he pulse rate and systolic blood "pressure of thelse patients were measur2ed at one- minute intervals for five tntnutesafter assuming the standing position. All measuremen 'fs v-.,zre made prior to administration of the drugs and once per hour fo'r-eight hovrs after administration of the .drugs. It was realized ffraf the obser,,,afton period was not st-,ffic@'enfl2,., long, but circumstanc@-,s'prevented -e-xf@.,nsion of the observation period for more than eight hours after administration of the drug. Results a,-;'e shown in the table. It should be noted that a .s-,ignifi-cant number of ans%-iers on the questionnaire occurred wl'th administration of C-9. Analys2is of the an swers shoyed, however, a very differen-f pattern from that seen affer LSD dose. High scores %-.rere ob'iatned on a group of symofoms resembling those seen after ac'nfrristrafian of Afropi-ne (dec reased salivafton, Jryness of mouth, drv tasfo., in mouth),. And o.-i svch questions -3s increase it, ",i, @ariiitiar L'--oa@Tern o' anorexia, I T .) u . T nervousness.. insom nia, plus visual perceptual distort ion was not observed.- 2 The card,o.vescular effc--fs oT' -C'-,? w,--re a-oparenf v z nw h f 0.5-ma. dose (see fable). lnso-Oar as the data oernif an'alys."S. C-9 did not block or accentuate the effects of LSD on the pupils. knee jerks or resting blood pressure. C-9 did L-lock in part the rise Irt blood pressure on standing after LSD alone. LSD, on the of her hand p6 rf ia I I y b I ocked he drop i n b lood press ur7. o n sf and 1 nc-, seen after 0.5 nic. C-9 alone. Y rmif to St ud f may be desira wh-zn condlf ions pe ively, using larger dose-,s combinaf iort- of LSD @ an 9 more intens 2 of LSD and prolonging .:..oeriod of observaf ion' fo-at least 16 hours. Before this ' c @3c -done, it wi I I be necessary f o@ de vz I o p "W ing between mental effects caused by C-9 a method of diffe'r'@nt 2 rading the and mental effects caused by LSD as wel-I ai a mz;hod 'of g @ef f,e csof both. ve r s c2,, ro-P the. LSD-React ion. "Fren Intravenously as a Re A few preliminary experiments of this kind have2'been carried @ou't Four patients received in randomized order: (11 60-75 mgm. fo I lowed in two hou 5 r@ic. Frenquel I v; (2) 60-75 mcg. LSD rs by 15-2 - * (3) LS followed in fwa hours by a Frznq-uel placebo Intravenously, D aczbo -ro I lowed in two hours by 25 mg. o@f Frenquel Intravenously. .p I 6 F'renquel alone induced no -neasureable drug effects. There were no ob vio us d I f f ere nce s I n the 1 nten s I t y a nd co ursz o f f h c. 2LSD-rea c @ io n-- in these pa.fients on the Frznquel trial as compared %vit-h the placel-o t'rial. V-/hile the number of patients is small, results do nof justify extensivz ex.laration of the antidotal effec.t of "Frenquet." p Admin,Tsfration of Frenquel@Orally.for One @7/eek as a Blocker Of L"@D-RzacTio Twelve negro subjects -re'ceived the following combinations of druc;s: ('I) Frenquet P-lacebo-LSD placebo; (2) Frznquet place,,-o- 2 60 mcgm. LSD; (3) Fren;quel''LSD place-o; (4) Frenquit@-LSD. Frenciucl (and Fren(luct olacebo) was administer'zd ora'il,/ in doses of 20 mg. three ti-nes da .ily for six days prior to'-adr@ilnistrafion of LS@') or LSD plac@-.bo. Proczdure vias carried@out in dou,-Ie-.'.)Iind fashion. The purpos-- of '-h@ experirrent %%,as not explained to the pa@tents. One weeks @ lme was a I lowed to elapse between adminisf r-ation of 2 eb'o to pzr-nit "washout" of. any Frenquel Frenquet .and Frenqvcl..plac t ha t migh f ha ve been 9 1 ve n pre v to us I Y. @.@,,efhods o@ "assessing The LSD-reac@ion were the same as those reportzd al@,ove. Although the experiment is 2 not yet comple',e and 'be code has not been broken, results so far strongly suggest thaf we will be @vnabl& fn Aistlnotilsh befween rrznquel and placebo. Another repcrl will be submitted as soon,as possiblz Nyhen he work Is c2omplefe. t.@,is"l.ianeo,us Informa.@ i.ory o C-9. (1) Stability. The alcoi%olic-solufion of original lo@ of has-;7e-@'n-ke5t for a lmc f a /ca- This mat2'zriai is aooarenlll,/ s when first received. trs ef f'ect I ve as (21 ik,,,,efhod of Administration. C-9 ap-pea,-s to be equally effl-ctivz n f-o-o-2@- @in in so-le@ drinks, or in g ven o dy alcoholic drinks* it is also effec'-Ivz when smoked (see le'-fer of 28 -houg.% s o' the drua are recuired January 1955)., all# larger amoj4lf T and the resul,s are more erra,fic. 131 Como-3 r- I so r, C@ard t,:@ vA scu I a r 'Ffects o f C-9 wif h I- h,:@, na and Par@ Intl of cardiovas of @.larthtia@@ xvl. he same k cu2lar ef-'t@'ecfs @ttachyc rdia at re.sf a-chvcardia and postural hype@ension on Srtanding@ occur afte dmrrilstration of art a [co ho I tc-extracf of mari'huana orally, affer smoking of marthu2ane eigaret-tes, and after 45-mg. of parahexyl orally, as after the administration of C-9. The-cardlovas7cular effects of C-9 are probably common to all active members of +he cannabinol group. (4) t@iental Effects of C-9. ET'for2f is now underway to obtain a better delineation of the effe-cts induced by C-9. The sul,-,Iccfive sensations Induced by the marihuana group have long been o@-scure. The descriptions in most of the writings on marihuana with respect to the 2 occurrance of vivid, depersonallzed, hallucinatory or catateptic sfates have seldom been observed when these drucs have been studied under controlled institutional conditions. 0-rdinarily the sub.ecftve effects induced 2 by marihuana in such circumstances appear to be rather mild, and so far descriptions given by -1 ns t I t ut iona I I zed paf 1 ent s he ve no f s hed a grea t dea I of I igh f o n the exact nature of the sensations -experienced. 2 Fo r t h I s re a so n , 12 patients were given a s@entence-comoiefion test, consisting of incomplete sentences chosen to yield infortration wi,',@ resoect 'o me n t a I s ta t us (af f mood, b I za r re 2thinking, efc), and somaf i c s im of ---i (dr yne s s of t he t-nou'f h , b I urr.1 nc of v i s ion , che nge s I n a ud I to r,/ acuity, etc). Va I !de f I no que sT io@'s a nd oz ne re I drug que s t lo ns are also incl2uded. IncoFnolefz,sentences which elicit-ed consistently positive responses we re selected from th I s or lo Ina I test and a new tru,,,-fa Ise test consistinq of over 3CO I ems constructed. This 2 true-false test is no%,i being admin-Lsferzei'to 30 nen. V..,'h - n t h e results are in, ifem analysis will be carried out and furthir wor'F-. conducted based on leads oll--Itainzd from f-he,. high 2 scorinc.1 items. (5) P re'[ 1 m I n a r y n i ca I --)e s c r 1 oF i o ri -of' t be C..;P- 9 e a c f to ti A description of the (-'-9 reacfion based on o.!)servations madz -in 3""i trials of.1 to 2.5 mg. 2of C-9 orally in 17 su.-jects has 1-cen prepared and is appended. If should !De born,-, In mi.-icl that, This description is przilmina'ry in nature and rray have to be modified as further 2 informaflcn is a-cu-iula@-d. FUt Lyre P 1,3 ns In addition fo stud'ics on the C-9 reacf ',on, fu@t,,re ola,-s r@i C! 2 n in& I ude. s't u -,' i -- sof @ll-tc of cn,,il-. Tnef lo.-is oT' S-:@,-o!'a L Si@ -'5 f he us- ot clzszr@iin,? as a a,, i c n C! @-,' r -.; a r. z e s n,-@ o f n e w s u b s t a n c e s f r o m 2t c U n i i.,,- r ii t v o f I I I 1 n 'I s a h e y e c 0 m c a v a a e Very s ine-cre I yo U!- s Ha r r s s e I 7 -Director of Research :rn Enclosures EtFtCTS OF I NW. R E S E R P 1 NIE I 0 HDUR S AND 2 FIOUR S Pp lop, To (5( W-C-M. LSD-25 DRW PLACEBO-PLACEBO PLACEB -LSD PLACEPO-P ERP lt\'E-LSD 2 0 ESERPINE PES p p nee Jerk 4' .0.62 4. 3.31 -L 1 .02 3.10 p 3 . p 2u llliry Size 4.0.3.5 4 3.02 0.31 35 p p p I oor? Prttsure 4 o.7@ 4 2.39 4 Cl.60 1.99 2 p p uesfi")hs 12, 93 14 101 p p linic,ii Grade 0 1.5 0 1.5 t@ 1. iDf '6nalytlng data same at In prior reports. lndi,rafes tlfgnifl'cant difference sfaflsficalIV from placebo'w. r,,t difftroocot be.fween Placebo-LSD and Reserpine-LSD are 'tlgntftcant. EFFECTS OF LAE-3 2 1500 kCGtA.) GIVEN CNE HOUR BEFORE 60 1 I"Gm OF LSD-25 DRTj6 t)R E PLACEBO-PLACEBO PLACEBO-LSD PIACEBO-LAE 2LAE-LSD p Kner Jerk 0.62 4 3.32 @'I.26 -t 2.46p' p Pup'lllary Size 4 0.35 4 3'02 2 4 0.67. 4. 2.91P illo(-@(I Pretsure O..7 5 t 2.40 P 4 0.56 4. 1.96P "4u' .-r of Questlc)ns m! 12 ioi p 32 78P 2 p Cl In I'ce Grade 0 I...5 0.3 1.2 P .@E @-,r Placebo qlvenlat 0700 a.m.; LSD give'n af 0800 aem.6 Figures are-Averages oi.i 12 s'ubjccfs'o o( in.dl6cates.difterence significant statistically from piacebo-placebo. E)Ifferences-6efween Placebo-placebo and placebo-LAE not signlfitanf. 'Diffetchcot befwzih placebo-LSD and LAE-LSD not sighiticah't. AE -nS EFFECTS AFTER A V/EEK OF PLACEBO AND A COTAPA R I S(XA Of -LSD FTER A'V/EEK OF L .32 DP, LJG MEASURE PLACEBO-LSB LAE2-LSD DIFFERENCE DIFFERE@'@@-E Knee Jerk 4. 3101 4 2,18 0.83 0 05 Pupillary Size 4 3.73 -V 2.46 1.27 O* 0 1 Systolic Blood Pressure 4 2,,30 4, 1.03 1.27 4-0.01 0 -ions Q u c s t 97 75 22 0.8 0.3 70.1 Clinical Grade 12 subjects. Method of analyzing data same as In previous roport3o Figures are average$ on STATISTICAL R@PRCDUCISILITY OF LSD-25 RESPONSE V,EASURE TRIAL I TRIAL 2 TRIAL Knee Jerk 3.32 3.01 3.31 2 4 0.47 4.- 0.38 0.52 Pupillary Size 3 . 0!2@ 3.73 3.02 4..0.20 4. 0427 10 Blood Pressure 2.40 22.30 2,39 4. 0936 4 0.18 40.38 Questions 101 97 93. 2 4 24 4 29 4. 19 Clinical Gi-ade I.s 1.1 1.5 4. 0.32 0.3 - 40011 2 Floures are means of values on 12 subjects standard error$, EFFECTS OF C(WB IN ING 60 NCGTA. LSD-25 WITH 0.5 MGM.? AND 1.0 MGM. C9@ U,EASURE I@RLG PI.ACEBC)-PLACEBO PLACEBO-LSD PLACEBO-0.5 C9 LSD"4.0.5 C9 L $D- 1,C 2 '2,88 2,96 P 3.32 p Knee Jerk 0.6!2 4 4 p Popillar@, S12e 2 4 0,,35 t 3 02 0.08 4. 2..70 c Resting Blood Pressure-' 0.75 2.40 P' -L 0.49 4 2.19 4,, 2.10 Questions 12 @ioi P 56 2P' 94P 37 p Clinical Grade 0 1.5 0. 3 102 1 2 90 112 p Standing Pulse R a t c 99 2 105P 116 109 g 107 I C)2 L Standing Blood -Pressure 119 7.@ P Figure significanf'ly d.iff4,rcnf from Placeb(?-,Plocebo. C Figure slgnificanti-Y diff(,rent -from.Placebo-C9, Figure slgnlflcartlg diff(.,rent from Placebo-LSD. Figures are means of results an 12 patie.nts. Placebo-Placebo and Placebo-LSD fl s ISO u 2 gure sed in LAE experiment. Data In top 5 measures ana ly2(:d as I n pre v lous report s . and 'standing" blood pressures obtained once per minute for 5 Data or. stancling" pulse rate. i(iinutes after standing. Valuc,s totalled for 5-minute period.and then totalled for each objerval !on* Final figure divided bv numbei- of minutgs (5)x number of observations (8) to attain averagq for-clay. h4cans of da I I y averages he n (,a I cu la ted'.'a s us ua I