'LIX AkiNttUAL P. @Z, SS 7-'Z?OqT By and. c c,,i s 3 r cti C8t--- r. t to su-7z-arl.%e t!lo work or Nli'llf Addiction Rcsearch C@-.nter ror a, year In a -.-,Iiort tatlon*' and this Is becominq steadtly mra difflc4lt at our -act t&viti.-, nc2rzaze 1:,. s I., zc-. arad s-cope. TI),p pro grp-ia ,iow elkn!compasse3 v@o r:-t It! clinical of cllnlca@l studies on p 3 yclio 30.,--l t I c sclinical- cological I nvQ st I @@-2 t2 Lo,-i 3b I 0 C"-4 2 f r o.-,i clinical enLacrino@tc;c!' y to (!rL,(,i ei neurop.)-.ar:r.acolaoic,--l a.-ra P-nd r,,s:@,ch slk,.zzdio-. In 2tinl!7al--. In --.ac!z ,il o@r w.)rii ba,3 c ese. areas a e, the year# so obviously I can do no mor,-- thar. tr,-ic@L v, s@@@--,-tchlly on fc--w of' the tticii I 8 bave bacn dlrectly I.-iv,..)Ived i7,nd Krhic!,*@t I will @,N,! .@f -3 ell c s lcs v t l@ for t t! r -r. I r. I n tlv--ness of As you,know r-re Frandr has alound that cubstitutica of 2 new a.-v,-Iseslcz for rorp!ilnc In addIcIt.,.,d patlcnts for a puriod 4 't.'Our3 Is a 5enslt Iva. 2nd u s 4-4-f ul tast of t4l,,&c a b I 1 1 y a tlrug to sv,;noress 2 for' 21,, holrs ','-.as scvzral a-uVanta@,,,js,,, 0-*ily nlr,,LnaL t s of new an;-,1.3-zsics, the toxlclty or 6,hic.1-i Is frzquc;titly- 2 are rzriulreti. Vary I*IttlL- tol%-@-.runct: a,-.,j ucpcnaz:,-Lce are lust because of tliu uhort partod,of. d-o rat t@io uico4A-feirtable c@ u e jt t.@ie touf. pariodg eo 1LIL,1-6r-A exnerlz--4nt!i cen '-,te r@.T.Zated Wee;ilyo reflec-@led r;@,latl'vcl@.- w;@.- I I tlz,@, rest@.It-s witi t-,e cIL,.s,-Ic !-:)-day. sub3tltutlcn r@,@Ct!jC3d, Tl#-ka@ d.,jes r-ott. rfc@ourse rericc+%. t.,@c i#-&tzr,,slty 0-f of 2 oi-i% f f,@r ;?!,o r i i n e tl t'i@z test 4etzr su-ba -2-e c -n us of our 1;-t s*urlyirt- Alissociation tti 2 1: 1 z c a!s C-- ri Wt !IC or o -3 r%@', L V-@' fs of at L6- y I g t, ,,i so rtias COllacted hour!ypI r. t Pr *care% obtain.Zd-l dLllrrr4.q-' sub-.titutlon of IGO, 10 0 p,-&.r c;ant of' Lhe@:P--it I en,-*-s# a@ccu3tor,.e@,d iL40so of' .mrp-Iiina In a 24 hour period, The proce%-Alure used tra sas followst r-atient3 were stabfllz,--d on C-3 mg. of rour ti mes dallyt at 4 P,m* on d:3y prior to the test# t,%e last re!;ular d-o-se 'of' ror-phtne@ u@a-.;@ CIVCN; at@ 10 P*r.0 of t-lie uat,-. r.& i!nli 10 a.m* or the patli:nt recalved 4 subcutan,,Oua dosi., or an 10.1 (actually 2 in c@oses of .Iedlcat 60s, 12t 6 r a placp-,%-@o)* Usual obto@rvatlu.-i-s f,;r late.,Isi"6y of ub3tlr,,cnce ucre .-iaeiz fron, to tc3t day to t!ie 24th tour of a bat IAIC.1 Ca) 2 point SCOras caltulated accordir,:; to Vic ikr,@a tip-der the curvea ut,,13 caic-,,Ie,cd by t,c nd Flita lr @t U3 C@nv4r'.In all ti',.c data or. a patlciit for a pnrticular @day n 2 to one fl-ureo c-alled point-hours." mllected dzata O.-% 39 putliznts r-.fter sub;sf- it,,,." Ion of plac.-b,-.7y on arter aubztitutlon ol,'L' the reoularf s,-2bstitutl@.,n o.1,14' ;.I P-er ci;4flt of t'-Ie-- acctl!stor,.@@d dosa of Mc are F -u r.@,, 1, point lndlc;n,.I.c e r r o r.-. tha m-4:an for that partictlar PL-I'nt. t -,Lt I- curve. 4- 7, it is our'. C-d@e. t$.Zt this curve can bc def In!-* d so w; i I 1 "ler patl@t-,lt3 at t' e points air--,ad adding 04. y studied, @by ntudy-@* -other cdscs ng 2 and e.-eterminin- Ilimits of variations for different Groups or tl,.at, Ua can maka reasonably accurate estimations of the 4ose@' of' new anal-asics Uhicil vmuld be: 2 %F equivalent to a standard a.-iount of 3uppressi. abatinci,,ca*- Via wi -I 1.,ave t a study t,',Ic suppresslva potency Of two or v.-re, ui:s@i z-,i now znal,-,c 2 S Oct SIC:S a.-4d co.-@Dar dozo- 'lie nQw drug with that of L41--to effect curvc3 so-obtal@ncd wi t,'l t. stano-ar%.! r.-.o rp.1-4 lti,31 c-,;-r vG Slrcz we c:-an use a pa4i-@-,t only orce a wee*, t and for a 11--.ritcd nu.,-.Be,- ol' trla"sj, t'-Is Is obvlo,..sly .6 going to be a I Q.-I -r4nGa proj;-,ci.. @io not a-4 ^:)"Ct ta u,,-e a I Lo us,* n ty ..czre t ca 1 14-4c t, will Y, A 2 We also hope tO dcv--Ilc;) a q"-rtitatlvc sy3te.1 for of 461 n and t.!'.z rcsults #*.,i I Ib%-. 1f;ct,6-d lio pra.,-It c I t c r., 1,-, t t 3 t o-.r the FlnaLLy., studylr,,j the efficacy or a. '.'iort e. L.-,: ct addlctlon' ocadure In e-at,.zrirlnin- 7 o f a z lne -,ce extier dlrcc* withdrawal,, Patlc,,t3 wlll 2 recelvo tl,.c ncw cri. ror a pcrlod of I Cays wit4@'t L,,,.a- dose -beino Llc*4atci rapldly as- tolerarce pur.-ilts al!,Id observations for lntensity,-@ abstinenco carrlad@@*ut for IO'd-,yr after' abrupt dlscontin dicat@ion. Ca@lculat uatlen or t' Ions ro a.,..a t InQ;ice wi&ll be ct-is-iverted to area this case) and co-@ipared with tha- I i a r4 ay of Ibler rorsliln-- or 2 cadclras Currcttly tev@-..n dmozl tnclu%,4-lng era b c I P;. gsl.'.udied by thls mt'.Iiodo At the tl--;e this rzport uis written utu-%4,iee o,". 2@ll us 31rC.2 .-cli s t!-ia t ri@@ f Ir@al, cvaluatlon or Aziy cf is possi@--le. !Llou@everp st@m,- of tlic- riasults are of con3l.--lc.-rable t.nt-irest so W the follo ii^ ry renorts of IV Lty. -co ounu co arm ire 3% an tRe S r t'WICO 3 2r-o"@ 1,5 t Hill bout IS art nr. a drug n SIC. in the tinznc4 M,3 Wr rabs as potent 2 V6 bab in su;Qrcs nd is pro ir!:Sic CtiVia e thls 2-3 ir-.3 id"nf- t icts r r ty CC ierant f 0 2 h"*- -rz lo LY f o r :7;,O to ),.O is I Ing wzra ,.,r 0 In Ulf the first Inc Of 70-, 2 til ho 2 tests f Ux tlv_ Al r c@o ri,-.4 t + U '75 urs VAS 6 I @ , . i na IC WI 'a QJY Of rpht,-Ia L,n.,@tIirea tl-.a UV r a .7f a acc**e@ litt.% I r4,i@l C@VaL-y, throe: hours waa' 7 t ft;z av-:zraZc: score 1-11 tli I 2 I-Itli-7!;W cvzry t.',.ree 1-.ours u-a:s "point-. wi,, i c. corre I.-S t o a point on t.!-.a c,.,rve seen after substitution o.-b" 5a per cc&-.t or the accu2sto of !Morp,.'.e I no Is -,a 13ec,-.use of t-lit r-rall n-u.7-@.P,*er cO subjec, 2 h-.Ve 6,.at -dz the statlstlcal comarative. p-otc4-iclz3 on ti%c-se c@,arvene T@%le wlll be t-ih,4: n =re data hava accumulated. P,.z @pou 2 see In 2 w4! ltft@,ve drat@.,.n t.'%e cur%,c 4.or tltaro-u-h t',Iiia two po'41.--.tz obtainc-icr wit,,% I"", zind m@,s e-v@ary ',&ours az,..d 2 art-.r ng. evary al,-. -on 13 L.'i-at 14-i t,@it flr:'.t t-st (12 ev-ry six s- ur s) It was eV Itiert rr-,=, 14'W.,ia-pection of t',Iie data th--it was 11-I"UPP re s s r., for onllt t4iraQ I.Iourzo or,* 1.*,t tl,.c of t.1ic aLl"@t-@tst 'Llan a or s@.,i.--rt 2 or C too I ow. ".Y -@-z!r- Cy Vi I c!i, I s ti C uv s t i,) 2 C i ch r s@ I r, - z C- C@ 0 a r c 1---a3t as C.,, --,n t a!i ia- It la, n.--L nea*-017 a-a ji't a I t! 3 in t'@,.i! r laulforna co--4@ou -nu lm'o consldera lnterast btc@auzz, it l@3@ aD ro t 1,-a@:: 3 A's Potent as la tests In ml C@o It is onlv one-fir L'% 'a apotant aS =r SUPP re--sin in 'Cy. It Possible tlia t-a ty to zupp.-CSS ,ach2ieved t..Ls 7nontolarant for-_er, of,- Z- C.- of ilk 'rlv -7521:i subi 1-4 ac Z,.- ecf t i a 2 c, ra P- t patients were to o Of' daily paticnt totzl dooe 49 dose ev4-ry ti I;-*- a pzi o ta I'.. to LIZ of c:,-t r p perio;l of su e.7 a@ in su pre-sainc,, abst In;-..nce In i-.a n rrertly iL-i" -ru@ay In dater.,Inc 2 urth.ar tests arc cu to@ .-Ore cx,tctlyt swppressive potercy one a.%ort dirzct add,lctlon tc3t has b,4c., nontolarant forxer r@orphina addict received 2 In dos@.-a Lncrzazina, cutineou3ty over the coursa of' I 00 ea 1'2 t@.trk,-. d:,-o rpL,, I n e- I 1 @6- a!wbavior-i I end ta bj c cI v-,T 2t I> -.1 a t.ory rate, na,ts@zap a n v%)-@l-t reeplr . . T.-e o t(@at i-,nd t"'axic effects VI t-','i do0 2 70 2 0 IWD d-@ ISO-LYSERGIC ACID 50 0. 0 B. VARIATIONS IN AMIDE GROUP.@ DANI-57 D-LYSERGIC ACID DIMETHYLAMIDE 10 10 23 L\ -32: d LYSERGIC ACID MONOETHYLAMIDE. 20 2 5 1 2 10 LPD-824 d- LYSFRGIC, ACID PYRROLIDIDE 10 5 LSM-775 d- LYSER61C ACID MORPHOLID'E 9 2 C. SUBSTITUT2IONS IN RING SYSTEM mLD-41 d-l-METHYL LYSERGIC ACID DIE@THYLAMIDE 3 33 370 ALD-52@ d-i.ACETYL LYSERGIC ACID D117THYLAMIDF- I 100 210 RGIC ACID DIETHYLAMIDE >86 2 103 BOL-146 d-2- BROM- LYSE I'@( BL- 6 1d- I- METHYL-2-BROM-LYSERGIC ACID < DIETHYLAMIDE >175 533 D. SUBSTITUTIONS IN RINGS AND VARIATIONS IN AMIDE 2-?4 d-l-METHYL-LYSERGIC ACID MONOETHYL- LA, 835 AMIDE 25 4 A;' d-f-ACETYL-L@SERGIC ACID MONOETHYL- AMIDE,..'I@ 7 2 39 < 130 '11"D-75 d-l-METHYL-LYSERGICACIDPYRROLIDIDE > 20 SEIE TE)(T @OR@@METHOD. OFESTIMATION@O TAKEN FROM DATA OF CERLETTI AND EPFNER 1 77@77: Tab'le c Al -ro I c ard si@co"_,,arbital. Lli LLJ 0 LlJ K ci Z, v U) (f) Lij 0 zz,z z Z 10 Z to 0 C5 Z Z-) 0 L-L V'V 0 C:): L-L A A V Lli Lli 2 uj n Lo Lo a) to LO N 0 to LO LO CO ui ol ol O' +1 0 0 0 00 0 0 +1 +1 +1 ro +10 0 +I +1 +1 +1 +1 2 v to fll- LO C) c> ci 0 o C) + + + + + + + + Lii U) +1 U) 0- 2 v to f,-- Lo CD 0 (\J n U) CD U') to C\j ,:D Uj to: toi c@ lei -t\i c@ C5- C\i 2 z L) @z 0 0 C> 0 0 z - 0 CD CPO 0 t7t 0 0 I-- 2 t@% CP2 0 N z 0 CJ V 0 cit -1 0 c-i @qr -i Z w--zz w_-ZZ W z Z 2 o o 0 Nojo o 0 0 0 I < ou l@o L) -i < W ui -1 cn cn a. 0 > cn tn > cn cn z a. LLI C\j icL CL LLJ HOURS AFTER DRUG DRUG 0 41/2 5 1/2 1 11/2 2 21/2 3- @31/2 .4 51/2 6 61/2 7 71/2 ONAL 0 2 6 7 .8 8 8 5 2 6 6 7 6 5 5 2 200 M, 9 ECONAL, 2 1 0 5 7. 6 7 8 0 3 4 4 4 5 4 100 mg 4 -3 PLACEBO 0 2 6 6 7 4 2 0 1 5 4 5 4 1 @VA- 21 2 hig 8 9 9 8 7 ro5 0 1 1 2 2 2 -1 '7, 8 9 9 2 5 2. 8:, 9 6 4 4 2 2 0 mg Fl G U R E S SHOW@NUMBER OF SUBJECTS'. OF 9 A'S LE E'P AT-@ THAT- PARTICULAR INTERVAL tik CY- HOURS AFTER -DRUG DRUG ll,/2 2 2 1/@ .3, 3 I/?- 4 41/22- 5 1 6 - -6 I/?- 7 71/2 0 1/2 I 5 SECONAL 0 '2. 6 7 8 8 8 5 2 6 6 7 6 5 5 2 200 Mg SECONAL 5 7 6 7.. 0 3 4 4 5 4 2 1,., 0 2 ioo Mg PLACEBO O' 2 6' 6 7 4 2 0 1 5 4 5 4 4 3 1 VA-21' .2 mg, 4 8 9 9 8 7 6 0 1 1 2 2 2 1 1 1 VA-21 2 8 9 7 B. 9 9 2 5 6 4 4 4 2 0 M3g FIGURES SHOW NUMBER'OF SUBJECTS OF: 9 ASLEE P AT.,TH'A.T,:PARTIGULAR@ INTERVAL ilk4 HOURS OF SLEEP ERIOD AFTER AFTER DIFFERENCE SIGNIPICANCE PLACEBO VA- 21 S.E CAM-12:OOM 1.1 2.8' @1.7±0.26