N,"@4D V@.. --G:ARE Public Health Service partment of@ HEALTH, EDUCATIO NATI 0 N AL IN STITUT ES OF HEALTH 28 January 19552 ADOICTlOt4 RESEARCH CENTER "AnONALINTITU'rgS - U. S. PU GLIC HSAI.TW Sg§tV.C. NCIIIT,%L go%2000 of MCHTAL HEALTH S'Ince wrttt.ng -,2Io you last December 6th we have comolefed a number of experiments @hich are des--ribed below. f L au otenine. No further/-wor-k has bcen carried out with this substance due to the effec,-'s of 2 doses ranging up to 2 mg. orally. Le t ter rec.-. ived. frori Dr va6- @s of the i\'a f i,,-na I I @is t 1 fute of %,',en fd I Hea I t h Ica tes that no s ign I f ican t ef fect s othe r f han a trans len f u'r'Op in b lood pr2es sure occurred a f t er a s much as I fr.@.;-tint-ravenously to normal volunteers. The lnstifute appears to bz-'fur.)iig l.ts afterficn to other substances found in the cohoba beans and I wi2f'l await with interest any infor.na- tion from this s@ourc,@,. The Institutes havz kindly a-gree-@' to supply ne with cohobd'snuff so thaf we can ascertain- whether there is anyfh!nC2-;; ln,-@h-.s.bean -th@f i-nduces :vfficient mznfal change f o be of I nt-cres t Ch o L'@.!)-25 @,",Ie have'now complefzd i2L2r orl a z.l,) e a s a n An t I d2 o t e ' .4 seven expe-rimenf:. I he f i S t t -wo @@,l t h e s e we r e re!-3.o rt c,-jl on September 15, 1954. -T'he remainina exoertinent,. are described in order and are numbzred 3 to 2 7. In general the effects of chlorpror,iazine hdvz not been as'good as would have L-cen an+lci- pafe,l fro,-n @@.e two original experiments. Although@fin g.-.neral, th,:re is d fr.--nd indicat-ing reduction of the LSD-,- ects the only conslst,7nfly si-ni@rican4- c.',.-nge ',a: becn 'in pupil;ar,@ size. Ex-.ieriment 3. t n f h I s e xne r ir-.e n t t he a n t 1-4o f a I e2 f f cc f s o f I 0,C ,n ch I o.rproma7-i7ne Given- r@n'tru@es before 60 incg. o.f LS!) were stud'Ied in 'i patieifs, lncludl'.ij 6 w@i tes I necrt-.,. e puroo,se of f@e e 2x c),:: r 1 ine r. vi a s t o s t u dy t @ e d o s e , a n g.@ ,) v z r %v'fl !I c 6 n tidotdi effe,--fs c ou I d b e @., x o,, c t ed The dosc oT' ch torpro.-naz !,-.e w la S e I evated 2,3 rrc. above t hat g iv2en In Experinent and the dose of LSD Nvas @levafed /1-0 M'cg. Cbserv3flon4 inci'udzd @nee erks pupillary size, systolic blood pressure, aid question,-iaire. 'nil these measures vizre obtai7ned hourly for two hours prior to I administration and for cl@ht hours after aclministration of LSD. -Declassifieci by 1%1,7475@ date I"b icrpromazine was c, iven or a II j 3 minutes before the LSD. Controls in'cluded adr-linistrariofi oT" a double placebo; placebo plus LSD; and chlorpronazine plus i placebo.2 h,ieasurer,-enfs of -e pfol,-fed knee jerks, pupillary size and blood pressure wer in the usual way and the a-rea undcr fhz'cur-ves d,7.6'zrrr-ined wit'n a planimzter. The nun-L-er.of posifive'answerifs on 1'.Sz question- naire was coun'Led over the observa-fion period,@anj the ciinica! grade assigned on the basis of the ques2t'lonnairz plus f.@e attenddntts notes. The results foe the placebo and LSD, and for chlorprcrrazine plus LS,:) were correctzd far placebo effecils and the dl-flerence be@--vee-n the conditions analyzed by t,@@-c 'If"- 2 tes f . The results. arc shown in the. table. Altho uch -a I I . f he results-are in the dir.ecl,-ior of chiorpromszine reducing the @LSD-effecfs, the only sign7f.Icant changes were seen in pupilia-,-,,,' size and in the !grade of '@he reaction. Exoeriment--4. This expertrrienf was carried out in t@.e same .Ya v usin.c 6 vh-f-te and t'nec2ro oa.tenf (a diffzrenf group from that used in Experiment 3). Results are shown in the fable. It is noted that fh-is..was the ncst successful expzriment., si_rnificar!l antidotal eff"@e@cts being observed on knee2 jerks, pup-iffary size, number of questions, 'and nea,,el,/ s!Gni-fica-n@ rcsulfs bzing obtained on blo,)d pressure and clini.cal Gira.de or resporse. Experim.enf 5 Th is was essenf i.3 I ly: 3 rcpei' 2i t ion of cx,.ner imen 4. us irt,= an ent ire ly" n evt rrovo o f I 0-- n egro --a I,- 1 en f s e o n s 1 gn i f 1 c a n f e f fec -ria s o n p u,@D !-'I I a el s I z z 4,;, a r I y s i f i c a n 2 'fecfs on cli.,iical Grzde were observed. Exoerimen@ 6. This experiment was desi'orcd to fest f.ie effects o f c h I o rp r o.-id z I n c i n r z v c r s i n g f h c e f f e c t s o f L $D. T h -@ I'l e(,,ro pal'ie,-,fs recei-i@:e, LSD one an' one-half hours prior to rece 1 t/ n chlorpromazine. 1-he r-zs u 1 fs are shown in the fable. T h e o n y sIE;_nifi2:canf. effect was or pupillary size. E @., o e r 1 r,-, c.- n f7 T h i s ? x r -- r c z d x t' y i swas E x p e r i ri z -. f6 e x c z o f h d f 5 m. c--, c-h I o r r on, a2-z i n e wa s v e n i n @' I-,! nius cu I a r I y one and one-ha I f ,ours aT er,,3 largz 7,ndiv Trj'ua I 1 zz-- ,JOS a 0 jc' LSD t de s. i g r 3 d '2 , I 2 gned to ob@airi a r--spon.se in at patizr..'is). e r e s a s 1 n f 1 @@- i c s c n -,-3 u p i r@ r i aid in flie cliiicif credz of fh7z reaction. date Disc-iss ton. 'As sfated above th4v or iglnaI prcmis i ng exper ir.-ten f s .t on ef fects of ch lorpromaz inz 'in b I c c king the effects of 'LSD, have not been born'e ouf'@oo veil by 2add.Ifional experiments. Although f-Se exparinents shovi an ovzrall trend f'o reduction in the LSD-reaction, if is doubl'ful that further work with c.@forprcmazir. is indicated. P-irt of the difficulf,,t is probably due to the fact tkat the re2vponse to both LSD and chlorpromazine is highly incltvidu,!f The best ex pe r tne n t wo v I d be' one I n wh i ch t h e dos e o f bo t h d rv Gs -.va s Individualized. CA 101. Another lot of thi.- material was obfained and the effects 2 compared -alth those of the original lot. The secon d lot proved to be jus@ as potenf as tr@e firs@-in inducing typical mar;hvana- I 1 k e s ub cct I v e c f f ec t s , p I v s a ma r k ed d e g r e e o f pos f u ra I @ypo f on s o r,. f n d o2 s e s o f I - I o 2 rr, g o r a y n e x c r Tme n t s us i n g 6 subjects, the effects of srrcking tobacco P cn-which the drug had been dried were studied and compared wtfh thost sccn in the same subjects 2affer oral administratton of thv compound. In general it is cerfai.,i that '.-he drug is effzcfive when snoked in this way. Larger amounts are requircLI and the r e s u I f s a r e mo r e, e r'r a t I c For exarpti: in 2 patients def in2 ite subjecftye and t@@rdiovas--ular effects viere s.,,.zn a-fier s-noking only I rrg. of the druc.. In sor.@i o'@ 'I-fie other pd@ler'tS,, only r-,.ild effects were o!)szr-vcd a-f@ter srioking as 2 r,-,,.-ch as If, cf clruc. Afferipts to improve cons-!.sfence of t h c effects by norz carzful f disfrit;vflor, in dryina th-e drug on 'twe @ob,3cco are under@vay. Combined aciin!ntstraf !on oil LSD an'. d CA-101. These zx,!o,?r I.-nen;-s are @@urrently in progress. .@llatienls.are receivi'no orally AC -,icg. o f LSD p I us L/"'-@ mg . o f CA.- I C I . Controls lncl-vde, a- 2 placebo; L56' alone; a..-id C^'-101 a[one. O.esulfs so far Indicate ti ) Evel ';..r- nc. in the ma@ority CA-101 will induce det'inife mild subjecffve effects 2 i of subjects; C/O-) Cie-half mc. of induces definite cardio- vascular effects (but nof.!@@ealf- wzakness or fainfing) in alt the subjects; (3) LSD-d-ocs-.nof bloc< the car2diovascular ef-Fc.,-@c --f 4 1 %"A - I 0 1 d o f b ' o c,c f h e sub iecf Ive o-.' L'o Z) I i e L ro u Li jec'live effects of 1/2 me. -A- I 0 1 a r e s o, m @ 1-d @-h-a @ no 2 a c c e ua 0 n o f c e T'f e c il s o f f h e LSD a r c - olw-ser,,ted -when f.@e mixture is These ex I 1-1 ,o; r I -..ie n f s vi. i I I-i en f uci i' ly bz exf2erdc@--4 @o inci@.,Iz co:rbina@ ic.,-,s -of a iarger -dose of- @'-A-101 wi th LSD. S i r, c,-'e r ey y olo-r s@. H'a 8 s be I I Dirzcfor of Research Hl:rn eclassified by --_1,87470-, date E X P E R I iv-tc- NT3 s c F I 0 EFFE%..i C) fo@G CH L R P R C'v',A Z I N E GIVEN 3 0 ivi I NU@. ES BEFORE 6C NCG. LSD-25 -PLACEBO 2 P"V, I C-:"4 i F I'@'; N@SE AS U.R E @.LSD. 4. LSD CE %.,' DIFFER'N-E DIFFEREJ%@ 2 r Knee jerk 1.47 1.44 4- 0.03 ry lz C. 22. 4- 2.50 0.01. Pupilla e 2,72 Blood'Pressure III 0 00725 0. 35 N.S. QuesFions 32 2C 12 Gracia 0.5 0.6 0.05 Figures are means on 7 pat. I en f.s 26 iv,@ I t e- and I ne' gro. DeclassiT@ied by @l a7475 date 3 T E X P i@,,E NT 4 75 1,,13. Cf- CH L C.P, P R OiA Z I N E GIVEN 30 t.,,11-4UTES BEFCRE 60 MCG OF LSD-25: PL CEBO S I C-N IF !CA \CE l@-!EASU,RE 4- LSD2 4- LSD DIFFERENCE tlt ff CF DIFFERENCE Knee Jerk 0.95 -0.0 1'.03 4 68 < 0.01 Pupillary size 4.78 .2.80 1-.9 3. 0.01 Blood ressure 3.07,@@ 12.88 1.29 2. .10> 0.05 1.@ivesf ion 4.0 95 5.25 <01.k--) I Grade 1 2.2 1.0 1. 2.362 < > 0. "IS ---------- Figures are ,,ieans of 7 patients., 6 white and I negro, Figures for knee jerks, pupillary size, and blo d pressure represen@ area under fimz-acfion curves (S hou 2 rs). v c s f i o n s s h oit n umb e r 0 f Po s ive a n s,,@te r s 1 n 8 h o u r s . I n i c a I 9 r a dz s o n 1 -4 b a s i 3 . tr I)eclassifieci bY -,l 87475-'-, 0 date 1977 -tl7l EXPE.R Iti@eNT 5 7 5 IVa3 - (T CH L CR P R Llv'A Z' I NE GIVEN 3C hiiNUTES BEFORE 60 IVCG. LT LS:----, CEBL) t@l-EA S UR E 4- LSD LS D FFERR-NCE Knee'Jerk zoo 2.02 2 .02 Plipi I lary Size 2.96 2.06 Blood Pressure 1.35 2 Ques,lions 7 6 5 20 N.S. C I i nca de 1.3 0.8 2 I o 5 - - - - - - - - - - - - - - - @igures are means of@-observali, ions on 12 ne@ro pafienf-z, fj,,ures-in knee jerk,., Pupillary size and bi" areas under curvz. ood przssure -resenf 3 ions., el%do""!)er Of POs if ive ansviers in 8 hour period a-@ drug. i.-tica I %-7rades on 1-4 bas is -E)eclassified by 167475-- e -17 dat E X P E R I tt'ENT 6 EFF'ECTS OF 7 5 ti'G CH L U P.01 U;A Z I (.,.A L L Y GIVEN 1-.1/2 HOURS AFTER 60 TV,.CG LSD-25. --P LA-C E B2 0 c P t.-i S I Gtl I F I CA iNC E t,@EA S UR E 4. LSD 4. LSD Di FE.0,E@,ICE t it OF DIFFEPENC-C- Knee Jerk. 3.28 2.55 0.73 1.49 2 Nos* Pupillary 'Ilze 3.59 2.07 1.42 4.38 O. C) I 1.32 0.49 1.@7 N.S. Blood Pressure i.sil!5 Questions 672 "70 3. N.S. Grade I ..'I 1.0 0.1 N.S. F ig'ures are means of observaf ions on 12 negro pat 1 c n f s ovcr 6-1/2 hour period after C2PI@,,I-given. F'igures represent area under fi@-ne-action curve (knee jerk, blood pressure, pupi I lary s ize). c z -o n s s ii o -,-, n u r.-.b c r o f po c i @ I v@- a s r s u r 1 n.9 6 hours. (;Iinicai grade on basi s- of i-4. Declassifi6d bY -187475 A ttB 127 ;date 7 EXPER I&,!ENT 7 EFFECTS OF 2 5 i@ivg. C) F CH-L -O-Z P R avpa Z I NE I -,VI - GIVEN; 1-1/2 H.@S. AFTER VARIABLE DOSE OF LSD,25. Gi'41 F2 i C-@ Col. P LikcE BO 6 i@l DIFFERENCE DIFFER@R.NICE 0 DIFF. t@1,EASURE 4.. LSD. 4. LSD Knee Jerk 1 .@66 1.90 -0.24 N.S. 2 2.62 0. O.Co. ;PPO!Ilary Size 2..57 1.35 1.22 Blood Pressure i.23 o.90 0.33 -Nos Guestions 74 63 2 05 Cl-inic,al Grade 1.9 1.4 O.S. Firjures dre average of observations on 12 'r,-.-.gro patients over 6-1/2 hotir s period after administration of CP.%'i Dose of L"-@-8D varied bei',Necn 60 and iso mcg. t)eclassified by -187475---.-. ?ate