0 STLOIES CN THE D,IETHYLNi'ilD-E OF LYSERGIC AC ID Ill. EFFECT OF PHENCXYBENZA'VINE CN LSD-REACTION IN tvIAN. By Harr is isbe I I 2 VioD* Co R.-Logan and E. J. t,,Iiner F ron Al he U.- Deparf,-nenf of Health and fare Education., Pub I I c -'lea I th Ser7vice Naf-ional lnsfitu@-e of t,4en f a I Hea I f h Addiction oesearch Cehfer Lexington r%en uclil- y STLO I ES GN THE DIETLiYLAt-ilDE OF LYSERGIC ACID. I I I EFFECT Or' PHENOXYBE@2AtvilNE CN LSD-REACTION I N MAN. A number Of the signs and symptoms observed after administration of LSD -- pupillary dilatation elevation of blood pressure, gooseflesh2, anxiety, sense of gastrointestinal oppression-, etc. -- suggest hyperactivity of the sympathetic (adrenergic) nervous system. Rothitn and coworkers (1) have postulated that LSD has central vegeta ive (.autonomic) effects. Chlotpromazine partially ameliorates the' LSD-reaction (2'3 4) and since chlorpro.,razine is a peripheral 2(.5) and possibly a central (6) adrenergic blocker, one hyp.ofheslzc that chlorpromazine ameliorates the LSD reaction by virtue oT' central adrenergic blocking effe--ts. Recently Elder et at. (7i and Gogerty et al. (8) have presented some interesfina f'lndinas in expert-,-nfa2l Pretreatment with chlororom@zine 'reduces LSD-induced @yozrthern,ia 1 nrabbifs and "I'e'l 1 n' c -,,si a i 1 a" in cafs. IT' LSD is 'give.-i to rabbits wl,lhin two hour:; af'@er reszrpine., hyperthermia is accentuated. At this particular timd, release oi norepinephrine (9) and scrotonin (10) from brain is occurring. If LSD is given fen hour3 @affer reserpine (when norepinephrine and serof on in have-been deple.fe,d) LSD effects are affenuated. &lost important., phenoxybenzamine (dibenzyline), an adrenergic blocker with no known central effects, affenuated fffeline"mania" induced by LSD. Since very large doses of LSD are required to 2induce definite behavioral changes in animals and since the relation- ship of. any behavioral change induced in ani@nals to psychotic symptoms In humans is always doubtful, It seemed important to study the effect of phenoxybenzanine on the LSD psychosis in man. The purpose of the present'report is to present data showing that pretreatment with phenoxybenza.-ni2ne did not alfer significantly the mental symptoms produced by LSD in human subjects, despite d-efinite evidence of peripheral adrenergic blockade. GENERAL NtE'rrqGDS Subjects. All were formernorphine addicts serving sentences for violation of nar;rfi,-. laws v4.ho volunteered fcr 8 th.e exoerirenfs. All were physically healthy adult N'egro mates who preserted n'o evidende of p-sychosis on 'psych@tatric exalilination. Drtigs. -LSD fartrate and LSD placebo were administered oral ly In solution to patients in the fasting state. Phenoxy- benzamine and phenoxybenzamine placebo viere given in capsules. L-EP!ne.phrl'ne HCL and epinephrine placebo were administered subcutaneously. Soccific details o2n dosage are. given under the particul.ar experimentsw Experiments were "double-blind" neither the patients nor the observers knew what drugs had,been given. In evaluating the effect of phenoxybenzamine on the LSD reaction the following cornbinations of drugs were administered at intervals of seven days in ran2,,Icri b,31arcr@,J ar;'.cr: LSD placebo plus ohenoxybenzanine placebo, LSD plus phenoxybenza,-,,ine placzbo, LSD plus phzioxybenzar.-.ine, and LSD placebo olus phenoxybenzariine. tACt,@Od3 of t,leasurerienf. intensity of the LSD reaction w2as assessed by methods previously described (11). The following observations were.obfained -at hourly intervals twice before and elg.%f times'after administraficn of LSD, or LSD placebo: pupillary size 3 threshold for kneejerk sys"olic blood ,-)ressure n vinb e rof positive answers on- a riodification of fhe ciuzsfionnalre devised -by Abrar-,scr. ef at. 12 a nd the i:t inical gradz, L-ased on a-s@ort ne,-ifal s@afus (11). Areas unl-4,er f irre- 0 "inter and2 action curves vierz calculak'ed by the e f od f Flafaker (13) and resu-Its express.ed as ml.-.. hours (,ouplis), mm. hours (blood pressure), and degree-hours (kneelcrk). in addition resting pulse rates resting systolic blood pressures and pulse rates and sysfolic-p'ressure after standing for one minute were determined and time-action areas calculated. These latter measurements could not always be cbfaine2d (experlmznf 4) due to pos tura I hy of ens ion w i th resu I f an t fa i nt i ng on s f a nd i ng. p Effectsl.of epinephrine were assessed by measuring pulse rate and systolic and diastolic blood pressure at the fofidwina inferva'ls: 10 minutes before, and i.-nmediately before s2ubcutaneous injection of epinephrtne oi, eoinephrine placebo; 5 10 is 00 30.,'40.,'.and 60 minufes after injection of epinephrine'or placebo. Tirne-action areas were also calculated for fliese rleasurements. Exper_imenf 1. Effect of I mc cf Phe.-iox,,,benza,-ilnc Rea.cfion In-duced by 0.5-i.0 mccm./kg. of LSD* PSenoxybenza,-.iine or phenoxybenzaminc placebo was adminisfzred orally in capsules at 6 a.M*, and LSD or LSD placebo orally in at 8 a.r.7. thus-allowing three to four hgurs for adrener-I 2 c blockade to develop prior, to expected pe@k of LSD effects. Four -afien@s received cca-.ibinations of I .0 of phenoxybenzainine or ne p ace"Oo w i f @l V,.:-) -IInc!gr.,; kg. Qf LSD.or LSD -ilaccb@@. Since the nLrl-'--er of sub cc s was s.-na a s i n!-- ze r c s u3 were. slrii far to the !grovp fha 'r received I .0 mcg'm./kg'. ct LSD$ the resulfs will not be oresenfej in detail. Six patienfs received combination$ of 1.0 mg./kg. of phenoxyt"lcnz-amine or p.henoxvbenzariine pldcebo wifh 1.0 incG.,n./kG. of LSD or LSD placebo. Resul-ts' are pr esenfed in fable. 1. Bof 11 the number of answers and the clinical 2 gra,4e were less after the combina'f ion of LSD plus phenoxybenzar,-iine as compared with LSD alone. The differences however were not s.fafistically significant. Phenox.ybenzanine@ did reduce pupillary dilatation significantly after LSD, L-vt ha2d no effect cn the LSD-induced rise in restine,, systolic blood pressu re o.r on the decreased threshold for the kneelerk. tvlii,osis, posturat@ hypofension and postural fachycardia indicafed f.@af scrie degree of peripheral adrenzrgic bt'cckede hdd occurred after phe.n@oxybenz2amine alone. LSD was an effective antidote for the postural hypol'ension after this dose of phenoxybenzar@iine. -of Experiment 2. Blockin-g of Epinephrine by 1.0 mg./kg. Phenoxybenzamine. Since'no definite attenuation of the LSD reaction was ob2served 1 n t he pr-ev lous excycr lrien tit seer.-ed wise to determine whether fhe.dose of phenoxybc.,iz-@,:r.@.ne. used would significantly alfer the response @o epinephrine. Four pa f 1 en f s we re "C ha I I 0.4 To @'4.6 mg./70 kg. of 2 ,.pinephrine subcvfaneously before and three hours at'fer ingest@ion of 1.0 m ./kg. of phenox,,,benza.-n'ine. Results viere confroiled b,,, placebo injections before and after pfenoxybenzaminz. 1,,icasvre- ments'were those described above under general mefho,,46s. Results are shown in table 2. As 4xpected no blocking of' the: increas@e in oulse rate,. induced by epinephrine was observed after p'henoxybenzamine Rise in systolic blood pressure after epinephrine was reduced by ph enoxybenzamine 2 but the reduction was not significant statistically in this snia II croup. The decrease in diastollc pressure after epinephrine was enhanced after phenoxybenz'amine. These.results indicated that some degree of adrenergic blockade was present. Ex2erirrent 3. Blocking of Epinephrine by 2.5 mg. 2 /kg. of PhenoxXbenzamine4 Eight paf'ienfs received O.S. 1.0 and 1.0 MG./kg. (total of 2.5 mg./kg.) of phenoxybenzamine at 1&16 13 and 3 hours prior to challence with 0.6 mg./70 kg. of epinephrine. A second test with epinephrine was carried ouf.five hours after 2 -the last dose of phenoxybenzamine. The resul,ts are shown in .table 3. A definite diminution in the rise in systolic 'Ive hours after the pressure after epinephrine was observed T last dose of phenoxybenzaminz--as well as a marked enhancerienf of the decline in diastolic blood pressure at2'@zr both test doses of epinephrine. In addition all pa4tienfs were unable to.-stand quie'illy for niore than a minute vilthoj,f becoming dizzy or Since these fin ings were conoafible with a ain'TltnG. d considerable degree of adrenergic blockade this dosage of 0 dibenzyline was used in experimeil' 4. 4 Effect of 2.5 ma.zkq. of Phenoxybenzanine Experiment (Divided Doses) on f he LSD-Reacf ion. Ten oatienfs received 0.5 1.0 and 1.0 mg./kg. of phenoxybenzamine (.or phznoxybenza- -.mine placebo) 24 11 and 0- hours prior to 1.0 mcgm./kg. of LSD. Res2ults are shown In table 4. Althou!gh the effects of phenoxybenzamine were so pronounced that 5 of the patients fainted on standing for less than one-minute,, there was no reduction in the number of symptoms reported or'in flic intensity (clinical grade) of the reaction after phenoxybenza.-@-iine combined with LSD. A si-nificant redu2ct@ion in pupillary dianeter was noted but the ot$Lier tndicafors of LSD effect, including the rise in systolic blood pressure, were unaffected. LSD tended to antagonize the effect of phenoxybenzamine on the pulse rate when standing. DISCUSSICN No definite evidence of aftenuation of the LSD-indvced 6mental symptoms by phenoxybznzamine was observed in the experiments described above. If hardly seems likely that this could be due to Inadequate dosa-z o-l' phenoxybenzarrine, since@ signs of a considerable decrez of adrenergic blockade were present after phenoxybenzanine t@niosis, partial attenuation of epinephrine-induced rise in sysfolic,blood pressure accentuation Of epinephr-ine-induced drop in di'.sfolic p a ressure and marked Postural hYPofension 'and.fachycardia Even though the 4drenerGic blockade may not have been complete 2 the doses ,of LSD used were small so some.evidence of attenuation of the mental symptoms should have been defected. Fal-lu-re of ->henoxybenzariine to bicck the mental changes caused by LSD might indicate2 that fhe LSD reacfion is not n-edia.ted adrenergically. or thaf phen'oxybenzainine lacks central adrener,gic blocking actions. Since role of epinephrine and/or norepinephrine a's cenfral synapfic transmitters is still speculative these alternatives cann2ot be assesse@ at fi@e present time. Failure to confirm amellc>ration of the LSD" reaction observed in alir4-,als af-L ler phenoxybenzamine emphasizes fhal care Is necessary in extrapolafing behavioral changes in animals to men f a I symofrms in nan. 2 3 Lt @Ay 1.0 Ms./Ng. of P-he.-ioxybe -2.5' mg-,/k'C. of nzariine or p h e n ox,.,, - benza.:r,ine in ;Ihre' e doses) did not aftenuafe s3ionificanill,/ mental chanoes induced b' y 0.5 to I.-O mcgm./kg. of LSD-25. R E F EF\JC ES E.., Cerietti A. Konzeff H. Schalch, R.s and Taeschier '@'s egetafive LS'D-efT'ekfe. Exoerientia Zentrale v 12: (4) 154$ 1956. 2 2.. Hoch$ Experir.-.ental Psychiatry. Arn. Psychiaf. 787-790 (Apr.) 1955. 3. Schwarz S. E., Bickford 2. G* qo,-ne H. p. Reversibility of Induced Psychoses with Chlorpromazine. Proc t Staff @.ieef.. L%iayo Clln. 30: 407-417 (Sept. 2) 1955. 2 40 Isbell H. and Logan C. R.: Studies on. +he Diefhylamide of LyserG!c Acid. 11. Effects of Chlorpror@-.azine Azacyclonol and Reserpine on flic lnfensif%,, of the LSD-.Rcac'f !on. A..,vi.A. A.-ch. Neurol. & Psychiafo 772: 350-358 (Apr.) 1957. S. Fournel Ducrot R Ko I s k@, So Courvo;sier and Koetschef, P.: Prrprietes ohermecodynamicues du chlorhydralle de cloro-3-(di.-nethylamino-3-.orooyl)-10-phenofhlazine (4.560 R.Polo A mrch. Infernaf.2 de Pt'iermacod,,*n. ei' de'fherap. 92: 19:) 6. Bon va I I e f e I I anJ ';ebe; Tonus syr,,pafhi--,ue et acfivife eleci'rique corficale'o EEG Clir.. 19-I"4 1 95-7 2 31 'I r,, Top f J. H.1 Di[ i'c, survey CoGer a ri, of D-I,Yser-ic A-t, Diethylanlide ILSD) An' aj 'r S .F e@:,.e ra on P roc. Id: '@93-294 (i@viar. I'@-@"57. 8. Cog-zrfy, 1-i.., Elder... and Harita, A.: f I cation of Acfl.ons of LSO-25 by @eserdinz. Federation Proc. 16: 300 (i'via r .19 57. .9. Brodie B. B Olin, S.., Kuntzman, R. G. and S.hore, P. A.2: Possible In.errelaftonship between Reizase of Brain Norepinephrine an,@-11 Se-roo':)nir. by Pescrpine. Science 125: 111-03- 1294 (Jun. 0-'O) 1957. Pletscherl A... St'lore, P. A. and Brodie.,, Be B*: Scrotonin as a ',.'-ediator of Reserpine Action In Bra-in. J. Pharmacol. and Exper. J'herep. 116: 94-9; (Jane) 1956. II* [.S be I I P H. , Be I I e v I I I c , R. E. , F ra s e r., H - F"WI' I k Ie r., and '@ogan, C. t,.: Studies on Lysergic Acid Dizthyia-,Iide LSD-25 I. Effects in Fjr4-,ler '.'crphine Au'dicf:s and Ozyclop.,@ienf of Tolerance Duri.ne C,)ronic intoxication. A.i@i.A. Arch. @icurol. and Psychiat. 76: 46Q@-4'179 tNo-i.) KauT@man R . 12. Ab r a,-.is on H. A., jarvik, E,.3 2 A A iii . : I Cri C i,4 Kornefsky, Levine, and li'7agner, Lyi@erg Dicfhyla,-ni-de (LSD-25): 1. P@ysiological ard Perce::;Iludl Resprnses. J. Psycf;2ol. 40:'53 1955. .13. '.'-in fer, C. A.$ and Flataker.,L 'S 4'udies on io h e ny 1 -3 - h eo f a n .)n e h y J rc hc r i G'c i ,i 6 r,.> hI 1 n r,- 4 @-omoarlso.,i %,iifh Anal-esil'-- AGe;ifs. j. "1'herao. 93- 3()5-317 (i,,ia r .1950. ,cxper. TABLE I /Kg. of Phenoxybenzamine on the l@eacf liii Effect of I..o ivig. I n(luced by I .0 PAcgiii./Kt.]* of LSD TR TiViE@IT LSD Placebo LSD Plus Plus L 51) LSD Placebo 2p II e n ox y b e n z a m I n e Phenoxybenzarijine p I 0 s p I u s N,,IEASORE Placebo Placebo P li e n ox v b,.g n z a.T. i ri e Plienoxybenza.nine 31.6 2 16.6 57 14.9 80. 3 14 . I 30 9.9 vise-Rafe, 115 @'t 19.3 45.7 58.3 392 102 4. 82. I I I fanding ..-istol Ic Pressure 'ecumbent 29.4 11.1 4. 78 4. 5.0 4 100 4. 18.5 4. 52 15.2 .:'',is fol ic Pressure f'an4 I ng 2 4. 23.6 10.2 65 17.8 4. 68.9 32.8 53 18.3 @OJ j) IIlary Size 4. 3.7 0.8 12.9 0.7 4. 8.1 1.8 2 1.2 4.2 ;Ilar Reflex 2.8 Oi9 4. 5.9 4 2.0 4. 3.9 1 *9 0.44 0.6 of Answers 0.33 1.8 49 23 1964 6.6 0 4.' 0 @cal Grade 0 0 2.2 0.5 I 6 0.6 0 4. e F I gures are means 4 s fabdard errors 2 of obs erva t ions on 6 patients. i@n case of pulse raf and patellar reflex they represent time-action calculations I ood, p'res s ure pupillary ;Tlamcfer and are expressed as beaf-4o2urs lpul-se rate), mm. hours (blood pressure),, efc., Number of :,nswers rtpresenfs.number of positive responses on questionnaire after LSD (or,LSD pl@cebo) which 1,@'te nof scored positively before the dro7go Clinical grade assigned by riethod-of;lsbell ef al. L) r) c@D LLJ C,- 2 V) t4 ,el_ 4L,) 2 co 40 LU L- Li v C.: 2 LL. > w NO LO fl- C co co LO w zo -C 44 gw E go 2 x x 0 Lli co > 2 C4 co Lt@ LU z 2 CD >- ui ui 2 r_ ti w > w to =0 2 E 'IO U- 4- LAJ -0 2 do co w w 0. cn 2 E 44- U- ui 2 r= E co 40 6 (.0,; -7D 13 TABLE 3. Effect of 2.5 tlo./K@q. (Thr c Divided Doses) of plienoxyben' e zain i n 2 on Response to 0.6 &19. Epinel.)hrine /70 Kg* BEFORE PIlEt4OXYBEI\I-AlVilt\'E @P Pl-iEt,!t@,XYBEt@ZAtv',It,!E AFTI- Le, jRE Placebo El@)inephrine Epinephrind Elifnephrin,-, s c Ra t t 273 57 545 122 780 144 684 99 s f c I I cBlood ressure 129,JL .12 7 459 126 299 129 90 1 162 iesf@,l Ic Blood ressure 84 2 74 552 91 1 0,',-,2 148 -1286 442 -e of phen,@.-xybe (1) Tested two I)uurs after last do-s nzarnine'. (2) Tested five h-uurs offer last dose of 1:)Iienoxybenzaminei Figures are means @fandard errors of obs'rveft6nt on .8 'Subjects. SUP21W 3io sainst A 's4:)zfqns (I uO SUOI 4(?AJZ$qO 10 SJO.Iia 2 P-JPPuu4s f AWL 2 0 ZPQJO IE':"@, 0 t 0 LC*O t GO'l LC*O T S901 f 0 2 sizmsuv Jo Jo 6.0 f i-O Si t LV 31 f cc 8000 t zoo 2 (-,III 6-0 t 9'1 t St*8 t 7111 f S909 t Lol t O's .191104f I 2 Aioll I d I SIC t Vol L$O t S6 t Sol ZOVI t Col t Sloe t 2 6-69 t P*SZ O*L6 t 8 0 F. I -t 17*gc t .6401 t 6,SL t E-6 4u2,qwno3 ainssa Poo 2 '@N4 s SV -t- LSI t 8*6c 0#91 t z* ci" t I t s,ai C-9c t Bul PUP.! 2 1001 t@0"8v t O*El t V*LL t L*81 t 9s t s t 8*07, t 3 u jui o z u D QW-YO u 21 q d 3 u I tu e z u 3 cl X2 xo u 21 tl d o q 2-:) p I oqz:)Pl d d SV,-. 2 @,Snid (]SI zulwezuaqAxouz4d aulwezuaqaxouztld Snid oqadeld OSI 2 snld (]SI snid oqa3eld asi l@J31AIIV3 41 .(3si so B@i/- BI/I 0- I A(I 1)3:)npu uO 1 4 00-@d, bil UO \4 L% u w p u z cl A x5 o u ,A q d j o S 3 SO p a 1) A I 3 J ti B )1/ So?, JO 403JI3 31OVI