'A FAR 7 PUBLIC HEALTH SERVICE Lex inaton, Kenftjc@-y IN PrJ--Yi,'4G. ADrF'--SS THE 15 September 19'j4 NI.I@4H, Addict ion Rese'6rch -enter Since my last letter of 14 July 1954 1 have co,,nplztee@ a con- s iderable arr-bunf more work wh ich is sumr.-,ar izzd be low. TOLERAN',-,"t TO LSD. These ex.perl.-nents, which were desc2ribe@l, in my letter of 14 -July, have been completed ar.-J the data have now been analyzed. tvly co.nclusiors were not alferec@ the statistical analy@is, .d,nd are as follows-. I.. Once foleranc@ to LSD @2,'as -been well developed,, it r equ 1 r c s T'ou r t o f 1 v,, t II-ne s h e aos c t o -.,vh i c h t @e oa 'r i c,,i s tcl,erant fo-restore llhe LSD-reac@ion to its oricinal ir..ensli,;, eye,,) t2hen @,@e duration of action is retafiv,:Iy short. 2. Toigrance to LSD is not overcorie b,/ admi,,iis4lzrlnr. 2 f 3 To I c r rce t o L'@@'D .1 s I Os f 1 n. re e days f 0 1 1 CN I n c e I s - con.t 16u,! f I o n I f f h .z .1 r t: 4 . v n c w a r d f c; x i c e fe c s vie r c o b s e r v e d e v @7 .i t 'I) o u f @. e p a consum,.;-d as much as I I rig. of @-')D L4Ljrirq c@)urse 20 If t e e x Pe r n c n I' o u c@i h r a .--Iz o f t t-, c r-e n c e w a s c! z-v c c' , S - r,@ w,3 c f 'T e r u f: . no -abst inence syr-.plorrs were 2 @rved on OR L@D., ANTi'DOTES F -inthine-have been 1. Corynanfhine. Pcsults with coryrc disappoiriting. In 10 pa-li@-,-tts no antidotal results were seen when 15 mg. corynanthine were a2dministered 30 minutes before 40 mcgrn,. of LSD. In a s'econd experiment, 15 mg. coryn-3nthine were administered 30 minutes before 2 hours after, and 4 hours a f L ter -'O mcgrm.-of L-)D, ustlng 9 slbjects. Controls included three placebo capsules with 4C mc@rm. LSD, and three p2lacebo capsules with a pla@cebo drink. The timinc; of the placebo capsule was the sa@r-e as 1'haf used when cory,-ianthine was adriirisfered with LSD. N'teasureI-ments inc-ludek'A puD!I.-I@&ry s..1.7-e,, kne-e- kerks, systolic blood pressure, 'L,2?D cuesfoonnaire, and esti.,ratio,-i of the clinical grade of meni ,at ef fecf-.. Pesults 3re sumriarized in the table. -1 hese resuf fs h.-ere by plcf f ing f he data on pupillary s-lz'e, knee jerk, anci blood pressvre, and measurino area u2ndsr t h e cu r-ie o ve r a 7-'I-Iou r pe r iod The ques t lonna ire was evaluated by counting the nu.,r@.ber of cosifive answers Cc.'-,ecks in ques I tons not marlr,.cc' pr tor to ar,',,-iin i s f ra f !.on cf LSD I'll i n ica i grddes were assig ncd as in prev i--us %,,or!< PI,3cebo efl'ect@s @N-ere e I imina ted by subtrac ion of f!)e prc-per cor, fro I Statistical an a ys is Y,;, a s' done by' the "i" tes t as appl i ec-J to d i t'ferences in pa'lred observations. A Glance at the table shovis fliere is no s i5 an 1 f !can 11 chanre i n any of 1'he rneasvrerren @s , in@ ica in!3 no significant enfidot'a- ct'fer-t Of corynanthine against LSI@. I shoul(-@@ I ike to learr, if you @,risft i-n-e to try lar-er doses of cor,/ranthine. 2 Sa n-.t.h i n eBan'thine alone had no effect on LSD re-3ci'tcn, neither did a combination of ba nfhlne plus corynanfhlnz. Exorr i- men'.-s. howevic'@-r. are still too fe-,w to permit stat.ls@ical analysis. .3. Chlorpro.-nazlne. In confrast ex-er2iments with chlorpro- mazine are at least prortising. Two sets of experime,-its ha\,c been completed. In one set, 'O ric. of chlorpromazine orally was followed in 30 minutes by 40 mcgrmo of LSD orally. In flie other set of experir-,ents, 75 mo. chlorpromazine orall,,, was followed by 40 mcgr.-n. 2LSD orally. Controls have. included (all tests being done in a randcmized order), placebo followed by placebo; placebo followed by LSD;,cl.-,Iorpromazine, followed by a placebo. The measvremen ts malie and Fo ethod of analysis are the sar,-,e as f h c s c described above. Inspe@i-lon ofthe,tables shows a signific2a,-il e i ne n s i t y o f reduction in menta I respo.-ise (nuriber oquesitcns and clinical crade) after 50 mg. chlorpromazinz as cor@ipared with the response after olacebo plus LSD. Dim inufion in blood pressure and pur@illary responses were alrrost sign,ficanli-, and very likely wouid be with a larger nvml-er of subjects. Af4-er 75 ng. chlorproriazline., signific@5nil rejucfio@ns in atl,responses, exceof oup.lilar,y, size, were observed. Failur-,-,-f@-, oblair, a s icr. if 1 c an @ r2dt.,c2t ion in pup i II a ry re s pon@- e -,,,,as due f ca,,, z r r45i,. f@ reaction in one of t.@c 7 patie-nfs. The trend, however, is fo%-iar-Ql reduc t ion of f he pu-> 1 1 la ry r es pons e . The anti dot a I e ff ec I,- s of chlorpromazi abouf eic,'-t', @@ours; af@er this f3ime L'!' ne persis reaci- ion r,-..ay reap--ear. effects were observed with- 50 mc,. of No s i g n i f i -c a chlorpromazine alone. After 75 mg., dqfinife drowsiness ensued' accoripanied by confus !on and afax la, vihich howevcr,'was not as is the case with barbiturates. 2 lf.seems to me that these observations need extension in the fol lowing ways'. 1. Confirmation in other laboratories. 2. Extension of my own series to alarger nuiiber of subjects. 3. Study 6f a wider rance of doses f i rs fus ing more chlorprcmazine and Ti'na I 2ty rnore 'LSD . 4 . Admi n i,s t r'a t !on of ch forpromaz i n,--. P.. -I" f. v-, r. L Sf, 5 . Admi n i s t ra f ion bf ch t-orprorraz lne oaren f-era I ly ra f her than orally..' It should be emphasized fhat-chlorpromazine 15 not a perfect a6@idote for LSD, at least in the dose con.'Uiiaiicns sfudieci. if does not com-pl"e'rely obliterate the response in all subjects. '!he effect is antidotal rather than competitive. With the la.-cjer doses of chlorproTtazine.,- drowsiness becomes a de2finite drawbac:k, e V e .1 L pa en I's @a ve r z c c i vz J LL'i Tnere is, hoviever, no ccnfusion or motor incoord inaf ion as is fl,-,c case. wi@,-,@ (Jo-ses of barbifur,3fes sufficienti2@, large to alleviai'L-.anxizfy caused by L S D CA-101. Results with this iiilerestino compound w6s partly s umr.)a r i zed i n my I e t t e r o f1 4 j u I y 1 954., a nd, s i nce f h a t f i,.-r-c it has been discussed wifli Vie h a s 7o n ow ma d c measurerrents of the blood pressure response on standing, before and a 'f e r adn, in is T flori of CA-101. Results show that this .compound Induces profound postural hypotension in doses of only 2 mg. Furthz?.r work with CA-101 has been deferred in order to concentrate on bufofenine. Hoyever, CA-101 appears'worfhy of further study. Cl2oser evaluation of mental effects utilizing a variety of definite psychological @ests in a-lar!ger number of lndividuats might be illuminafing. A more detailed study of the cardiovascular response is also indicated In the hope elucidafinc f-he mechanism. An antidote 2 'or drugs of this o'T 7 sort may also be needed. BUFOTENINE"@P'/ '.Vz now have carried out over one-hundred preliminary trials with- this s'ubsfance. This was dore in an effort to locate a dose-'ranre and to obfain s.-me idea of the2 'fects induced. Th@ dose has,b-een radually elevafed T'rcrn e 5 rncgrm. tot a f dose to 500 mcgrm. toda I dose. Wi f h doses of less than 2:')O mcgrm. neither subjective nor objective effects were observed. Between 250 to 5"WIO mcgrr.-,.,, we have had scaf@ere,@ reports of d'lzziness, cc-infusion ani siighf nervousness lestina for only an hour or two, As yet no consistent e-r-fzcfs on f,@e bloocl,przssure, knee jerk, puoil,ary s'tze, pulse ral.-c, ;!,tc., have bl--en observed. I intend fo 'F-eep2 zlevaflinc fh,7 dose folloy;in 9 r@iy return from Europe. As far as fhe worl- has cone, hcyicyer, results %Yifh fhts compounc! .3re not promisiric. Harris 1-@bell, Hl:rn 1 Z,/ E- F F E Cr 5 0 F 1 5 iv'G@4. CC R y 1,IAN,- TH I NE (CC- 1. GIVEN BEFORt' AND 2 H,(--iJRS AND FICYJRS AFTE.R LSD-25 Placeco "fl, of Significance LSD LSD Diff. 1 riff. 2 Of Diff. Knee Jerk 1.78 1.51 1 0.27 0.3 > 0.5 Oupi Is 3.08 2.84 O..24 0.57 0. 5 'Blood Pressure i 1.94 2.33 12 -0.44 0.94 0. 5 - ----------------- Questions 62.5 1 66.1 1 3.6' 0.49 --0.5 Grade 0 0 3 1.0 Values are means of"9 subject-s and are corrected Tor pla-c;r,',-o responses. 'V.. CHLORPRCT,,IAZ INS EFFE C)@'50 IVC, G I Vt- N 30 ',,j[NUTES BEFORE 40 tN/'iCGRPA. LSD ttiff of 2P I acebo cpm i 9.'l 1 f i --ance @ LSD L SD D i T- f D i f f of Di ff. Knee J e r k s 1.33 1.3 1 0.02 0.209 > 0.5 1.7 1 2 > 0. I Pupi I lar,,, Size i 4.00 2.93 1.07 Blood Pressure 2.09 0.77 1432 1.41 >0.1 Questions 77 44 33 3.72 0. 05 2 Grade 1.33 0.66 0.67 2.68- < 0. 05 @4- -Means per cent on 6 pa@ient,s.' Val-jUes corrected for placebo eff2cf. Under knee jerk, pupi'ls and-blood pre,ssure., figures represeni sciu,:-%re 8 inches under curve. Cu,zs@ions Number of positive answe rs on questionnaire. @,7rad e Cf. i n i ca 1, ' ade. r EFFECT OF 75 OF CHLORPRO@'AZINE GIVEN 30 NIIN. BEFORE 40 tV,.CGRNI. LSD P I a ce bo* c ptvl o f Significance 4. LSD LSD Diff. Diffe of Difference Knee Jerk 0.64 0.93 2 1.47 2.98 0. O'D Pupillary S@ i z e 3.50 4. 2.14 i.36 1.52 > 0.1 Blood Pressure 2.,31 1.06 1.25 2.14 > 0.05 Questions 91 35 56 2.3:' < 0 . 0:,) 2 Values are means on7pafl'z.nfs and are corrected for piscebo eT'fec'T. Under knee pupils,an'd b'iood pressure, figures represenl sqvare inches under curve. G2uestior-s Nurnbe'r of positive answers on questionnaire. Grade Clinical grade. chi 9 ....... ....... LO