ipartment of HEALTH, EDUCATION. \4u WELFARE - Public Health seryi,.p N ATI 0 N A L I N ST ITU T E.@,--- 0 F H EA LTH 1* almy1mg. ACORUS THC ADDICRION RESEARCH CENTER MATTONALim-nruT%s *#'MZMTAL HIA2IRM 24 January. 1916,@,,) U. L PUlLtC HEALTM SCXVICS HOSPITAL got 2000 Lazt*sT*n. Kcxrucxy t am attaching for youe information copy of a request to the Office of Naval Research for renewal of our project here. In the event the CNR fe2els the project should be continued I will arrange to have.fhe business office of the Naf lone I -institutes of Ffealth send@this on at the proper time, later in the sprino. You will notice that the amount of m ney requesfecr i-s som,.zwhat Greater than in previous years, .This is necessar-2@- in order to 'to cover the provide funds ' increase in Civil Service pay Auhich went into effect in Mari:h 195@5. You have, no do(jbfy by'now received a copy of my letter to Dr. Pcgge of The '@N"M. a. t,,ierrill'Cornoany concerninc-, efforts to rever2se the LSD reacf.'ion with Frenqiyc.l. This experirrznf -!as und,-r-'aken for two reasons: -(-[) we had received persistent repor..s from other laboratories that large doses of Frenqu,,,[ would amel-io"rafe the LSD reaction, and (2) because the comoany claimed th2at in our original blocking experiment f@e degre'e of mental effect was not sufficient for the effects of Fr,-nquel to be evident. As you see from the data in the letter, this reversal experiment was a complete failure. @qe we re u n,3b[. f distinguish Frenque-I Injections from olacebo injecfions. 2 CU,4BlMT]ONS OF HYOSCINR.- AND'LSD Thespl exr)-Irlrrents were carried out In an attempt to cle.errrine whefh'er Hyoscine Y/ould arnelloralre or enhancz fh- LSD reaction. T%.,,o series of experiments were done. In the first serie,1,s 11 negro subjects received in randoriized order Hyoscinz olacebo plus LSD olac@-bc: Lfyoscine placebo plus LSD; 0.42 rna. o.F' Hyoscine plus LSD placebo; 0.42 mg. Hyoscine plus L@D.: 0.64 rl'"$ Hyoscine plus LSD; 0.65 mg.- Hyoscin,., plus LS,:). Both Hyoscine- and LSD were glv orally under "blindlt conditions. The dose of LSD was micrograms. tvicasuremenfs were.those described in prc us reports. Resulfs are shown in left side of fab-le. You will note ...and 0.84 mg. of Hyosctne Increased pvplllary that 0.64 mg dtiatation seen after LSD, reduced blood pressure response f@ncreased the humber.of positive answerst,and Increased the clinical.grade of reaction, but the last was not significant as compared with Hyoscine placebo and LSD. In the second series of experiments 12.subjec-s were used and-received in randomized order: Hyosclne placebo olus LSD placebo; Hyoscine placebo plus LSDO 1.3 ma. Hvos.cin,.- plus LSD placebo; and 1.3 mg. Hvoscine plus LtD. Results 2 were simila.r.buf more-marked with lower doses of Hyo-scine than in the first series. There was ma.rked Increase in, puptil-ary dilatation, marked decrease in blood pressure response, marked enhancement In the number of positive quest2ions., and atn increase In the clinical arade of reaction which, however, was not statisf.ically significant. In this last series of experiments th-e side -,-ff,-.cfs of Hyoscine were v,,-gry prominent and i'n'cluded sensafl'ons 2 o@ giddiness and dlzziness.,.marked blurri.nc of vision, marked dryness of m ufh, absence of Orspirafi;ns and slichf con- fusion. It was very e.Asy to see that fhe patients had both LSD and,Hyo,.tcine .,ffecfs. Impre 2 'ssion was that of a c.ombination of druo foxicities rat,Ker than of anv--specific enhanceminf of the LSD reaction. The Hyoscine.side effects orobably make --@ica I use of this combination impract 2 DL A&4PHETAMINE AND LSD These experiments were carried out because Hoch has stated f@ta.t ,ncfha.,Mohefa.-itne-ar@-.zliorafes the LSD reaci'ton and also use ot a beca iheoreilcai consir,eraf2lon advanced by Dr. @ilkler. Eleven subjects were used and rece.iv,.-d in randomized cyrdzr: di-amohetamine olacebo plus LSD placebo; d@-am'o@efamine ofacebo u S, . L SD d I -a mph e f am i ne p I u s L 5-D -p I a c e b@o n d I 2 ar,-,oh If a @m i ne p7 plusLSDO lo f,@ cir,,;- a i ve n o ra i I Y. The d7se o'T' a r.-, o-i e a z ,ta s 2(- ma . a n (-4 f h -. dose of LSD via s 6 'v rn 1,@- roc ri ms a r-, n i r.,:! 2 was given one hour prior to LSD to provide time for di-amphe@anine h C. on I y effects to develop. R c s u Ifs are shown in the table. si'gnificanf channe with the combination as compared %-iifh LSD 9 alone .-/as Increase In the blooe-4.pressure responso.0 EfT'ecfs with this dose of di-amphe@ariine a,lone-- irt@o-ur st..t-bj--cts, ho,-Ievzr, - - - ------- were mild and the worl- really needs repefition., either usino fer!C,e doses of di.-wamphe-famfne or somz more potent sympafho-- m ime t I c ei-.i I n'e', i uch a s de x t roamph e t a m I ne , I n do s.e s s uf f I c 2 i-c n f to induce a more definite reaction in our patients. RESERPINE AND LSD The experi'menfs orev'iously reported have been amplified usinc larger amounts of Reserpine. It was felt that fhis.work 2 is important because of reports by Br6die, Hlmwich., '4boley and others on the possible relationships between LSD, Serofonin, and release of Serc@onin by Reserpin'e. In these new experiments. 12 negro subjects received in random balanced orde@r: Reserpine placebo plus LSD placebo; Reserpine 5 m'. orally plus LSD placebo,& Reserpine placebo plus LSD; Reserpine 5 mg. orally plus LSD; Reserp.ine 7.5 mg. orally plus LSD; Reserpine 6 mg. orally plus LSD.- r,osage times are 'hd-wn In the table., 2 it is s evidenf.thas'.fScre -tas no block-ing of.fhe LSD effect on any of our measurements. The most' infer@'iting observation was that the patien-fs ' 2 seemed to be worse when they rei:elved-7.5 ma. of Rescroine oralli or 6 mg. intramuscula-r-ly 6lus LSD. The intensifical,ion of the reaction was most @,r,cminent In the 2 grouo fha-' recei-vcd PeseroTne intrar,..uscularly. In bath these 'rouos-, pal'ten-s develooed tremors and ankle c l,orus "Iizn i'a-I 1,/, n@zrvous ne ss , --on-Cus i-on, ar-przh-4ns ion, 26nd r,-.orz frequzn-f-@-and more v',Ivi,@ hallucina@ions were riapor-e,4,,. T'lese c.@an,,@es are not apperznf in the figures -a' Iz 'oecausz our m-ethoc!s of measurer,-.ent are n 2 f adequaf,-. in the f 0 0 o reveal them. in ratiig knee j@-.r'&-s, -nofhlna is atio@ve.-d for I-remors or for i--Ionus. In asslgniio clinical crades., 2 no allo%-,ance is made for 1-h-z intensity of symptoms. At the presznf time .ve are una-ble to de-erriinz @,he@her the incrzase represents a specific enhanc-c,-nc-nf of the LSD reaction by Pe&ei:2o?ne. O.- !.,Z, p ox f e e I thaf &'his observation @as greef.theoret ica I im-portance and ma%, -o s s 1 b I y h a ve'' s ome or.a c c-a u s c 2 o I a n to a e'ru-> to , s t,3 b I I s III f h(@, I e-@ e ro us et'feci' o;' -6,eseroiIne on the LqD reacl'iort firmly bv s@u--4yina the effect of R c s,-., r,-) i n c 2 combi6ed wifh.mini.-,ial doses of LSD, (2) to develoo ra@ina systems which will ai lo%y for the neurological c.@ange@s an; alferat' ions in intens ii-Y and. quali'ily of syr-lol'oms, ('@)7 IT' tIC cani fir-,ii-,i-esfablish that Rzseroiie makes the LSD reaction worse, and si'ujy the et'fccfs of Reserpi_nz on to LSF--;. ------------------------ F oT ,I I ilIE BU M, f I 2 of this n (Tbser ved with doses 0 Lqo effects h. a I.iving the drug intra- lty. @,"Ie have now been S subs@ance ora 2 ed the dose t(' 15 mg muscularl y and have gradually increas -ih I ch e ,t ions ave bein observed include s ns 0 1 t xc symptoms h 2 lrafion. Effects Ilband around the headi, nausea,, and persp two hours. of a l@hin ten minutes and last less than -are aipparenf w 2 s of co lor on the wa One of 4 patients reported szeinq s. @vle are still gradually Increasing the dose* OLIOLIQUI fh(! National Institute 2 asked by Doctor Kefy of ivle have been' Ith to study the effects Of this crude drug- of hiental Hea ration Is now goin!g on. Doses of O.,9 grarn Pre I imi nary Q:xplo of the ground seeds I:aooroxima'el2y 20 seeds) caused no I discernible effe;'Ct other than subject'ive reports of blurred vision In 2 of 4 patients., @!!e are continuing to Increase 4he d sec I repor' if any strikin-G. res.ul2@s are 0 .@raduall,/ and wil olb ty 1 ne d NEUDOSURGICKL PROJEC-1 Af THE TATICI\AL INS'TITL,'I-E N-SS OF NEI-IROL-OC-ICLLl. 2 r)lSr-AS@'S AN'r" 'LtiNrL' c: NIH* I have discussed thi's projec'§- .Yt-th Docfor If has been orooosed to study.the e'fects of druqs.on perceptual 2 T tract's, 'oafhwarys, and responses using neurosuirgical o6tients In whom @orfical exploration and extirpation is carried out for e-ollepsy. Bo$'h Dr* @ylikler ani myself believe tha-f th2is would be a very important projec' vihich would have areat theorzfic,ii sigr-rlficancz. It is certainly wor'hy of suoparl., bu-t.neither of us are in anv oosl'4-iorr to advise as to 2 !Y. -@t- rlcf can be zup6or,@-c f -.a n c a Sincerely your( rris' Isbell, Ni.D. 0 Director HI-.rn:lw Enclosures: 3 Tablzso C00Y o-r Pro Descr i,,of !on f.y. 1957. EFF.ECTS:'OF CUIBINATIC@IS OF IIYOSCINE tND LSD s e Placebo- Placebo- 0.42 mg. 0.42 mg. 0.64 mg. 0.85 mg. Placebo- Placebo- 1.3img. 1.3 mg. Plactbo LSD Hyoscine,Hyoscine Hyoscine Hyoscine Placebo LSD 2 Hyoscine Hyoscine 4 LSD LSD 4@ LSD LSD 0.61 2.59* 4 0.51 4. 2.73" 3.30" 2.46* 4 O;i, 8 3 3. 0,9* 4 1.4i"' 4 3626'@ rk @y 2 3.87" 4.36@' 4. 41@@ 0.54 t' 3645" 4 2. 00" 4 654t I i-o 4 3.51* 4 1.15 2 z c ol I c d 4- liO3 4 2.29 0.19 4 1.48 I 3 7 4 1 19*-,.', 0. 7 3 4 2.00 0. 5 1 4 0.43-,,@419. ,jsure c r of sifive 10 8 a ..29* Boi@ I 0 6 1 14" 10 6 5 4 2 swers ni^,,jl .54@" I i@ O2s I I 0 1 22" 0 142 6 0 0.4 1. 5" adc Experiments to left of double,,Ilne, means of-obtervations on 11 patitnts- @o right.,, means-of-12 patients. Significantly different from 8 placobo-placebo SI-gnlflcantly different from placebo-LSD a-fFECTS alBINING 20 mg. DL Atv',PHETAMi.- 60 mcgmo LSD Placebo- Amphetamine- Measure Placebo- Placebo Placebo LSD Amphetamine LSD Knee Jerk 4-1.21 4 2.88 1.13 4. 3.24 Pupillary. Size .4. 0.48 4 4.20 4. 1.00 4. 3.98 S'ystolic Blood 4 0.92 4 2.98 4 2.74 4.77i.,* P r c s s u- rz Number of P,03,1 t i ye 12 84 21 98* Answers Clinical Grade 2 0.14 1.4 O@. I-la 1.18 All figures are mea"ns on II'-subjects. Knee jerk, pupillary_size,,,'and systolic bload pressure 'expressed as area under time-acfion curve duri.ng first 8 hours after adminis- tration of LSD. Clinical.@grades on'basis of I - 4. S t a t I s f i ca I I y s i gn i i I can 4t f ro.4. -'- I ace.bo-p I ace bci. p Statistical-ly significant fro.-n placebo-LSD. EFFECR OF RF-SERPINP 014 ltITENcITY OF LSD PEACTION 4 6 7 asure Placebo I Peserpine4@ Placebo Reserpine Posgrptne Reserpine Placebo 2 LSD Placebo LSD5 5.0 mg 11011 7.5 Mg Iloll 6. 0 mg I. M. LSD LSD 4 LSD .-.c Jerk' @0.27 40.34 @0.5 .40.36 12.72 40.53 @2*95 4Oi4 @3'.47 @0433 @3.33 $0.27 a t y -0.11 4 0.4 -0.96 @0.39 @3.85 40.56 43.33 40444 43.92'@0.28 13.35 @0.33 S[Ollc oo.I essure .@0.91 40.4 40.76 @06 36 42.54 40.54 42007 LO.,59 4 IS AO.36 .11.81 40.49 2 rr, c, r 18 @8 33 @10 121 @20 110 @22 120 424 163 430 3 inical 0 0 2.r-'S -11-0.28 2037'40.27 2 .,2.17 @0,3 2.5 40.7 Figures r.epresent mean area $. standard errors under time-action c ui- ve a nd are -means of va I ues on 12 subjects.' -presents means of counts 4- standard errors of number of positive answers after LSD was given* B,ised on 'rating scale of 0-4. 9.5 mg, ot9-ally 10'and 2 hours prior to LSD. 75 riicg.. ora,lly. 2.5 mg,, oobil.y 22p 10 and 2 hours prior to LSD* .2,0 mg,.. tnfratnusc?larly 22s 10 and 2 hours prior to-LSD.