-l' 1-14 -@titilte of )[ental Hevitil kd(liction P,@e-@, Frotn tiic National Iii xiglmtoll, 1,@entuckv, U.S..,%. U.,ri. Ptiblic Healtil Hosi@t,,Il Le Cross Toler-.iiiee I)ctiveeti -Ilese-.iline ati(i LSD -2;) Witli % Coiiip-.ir2isnii of tilt,- aii(I LSD Iteii.tiotis Bv A. 11. Wf)[,IIACII. 3 r.., Tsu@.LL an,,l I-,. J. lit.N-F.R 2 IVitli 2 Fi,-um-s in the Text (Receit-ed Vocrt:iber S. 19t;]) .Mthou-11 some differences liavc'becti reportetl. the reactions producef I in r2dain bv the clietllvlainitle of l@ser,--ic acicl (LSD-'.3) ziiiill uiescalitic seem very similar. Both cl.Lu,,s cau.,e autonomic stiinulatioti mzinifeste(.1 by iiierea,-ed pupillarv size. incr2ease in pulse rite and bloo(I I)cessure, ,ind elevation of bodv temperature (Bk.LFSTItIE:Rl and Fo.-,-rt-NAPr: Bi:cH.A- IS13E:LL et (it., 19;-)C); STOCKI 2 Hocii el al. . --,-V.S; STOLL). Both create anxiety, difficulty in concentration ind tliinkin-, fu-lit of idetis, flue- t-Liations in mood, pereeptutil distortion in 2 aU sensorv modalities. tnte- and pseuclo-lialluciiiations usuallv of Nistial nature, and depeisonali. zation (A.BRAiiso--, et al.; BERI--\-c.ER; G(:TT:,i.@L,; tnd If.Ac- 2 LAY; HocH el al.; ISBELT- et al., 14)56; @)[AYEit-GROSS; RI-NXEL el al.- STOCKI--,-GS; 3TOLL). Sonic authors have referred to the iiient,,tl state induced bv either aaents as "experiinctital scliizoplireniii" (RI-NXEL et al.; STOCKI'-,C.S). The clinical resemblaiiee of tile syndromes caused by mescaline and L2SD-25 suo,,-est that tlie,.;c drugs, despite differences in chemical strue- ture, either share a common mechanism of action ortet on final common pathw-.tv. This hypothesis is strL-nc,,tliened bv reports of or oss tolerance 2 between the two clruas (B.A.LESTRI-ERT, 193-j, 1960; BALrSTRI@ERi ,iiid -TA FoN -.,-ARI). The purposes of this piiper 2 are: (1) to present t q,,ititititative compari- son of the effects of LSD-25 and mescaline in the same subjects.: aii(i (2) to show, in confiriiii-tion of BALF-STiurrRi (195-i un(I 19tio) B.@.Lr:.- sTniERt tn(I Fo@NT-A,-'@ARI. that direct tolerance develops to iiiesettline, and tlttt iqubjects tolerant tr) iiieset-tliiie tire cross tt)ler,-iiit to LSD iiii(I 2 L'ice vcrsa. .)Ietlio(Is Experi)yieitts. Two experinieiit.,3 -,vcre perfoi-ilied. Experiiiient I Nvzis a compari.,oti of tile effects aii@l % Lleteriiiitiittioii of the eqttiv-,tlcnt dosa(,(,@, of LSD, iiietic-,iliiie an(i pilocin in 10 -,til)ject- 4. The diit@8i oil I)sil,,)ciii N%@iii not be resented iii this paper but will be ivporfl,.tl Exl)cri. P ment IT wis t ;ttitiv of ert)@.,4 toleritic-c. IK!tNvoeti T,.31) ttitl tliu.,(@alitiv in 10 subjects. Experiiiietit I Expe-rime-ntal (Imign. A "aii2icle-blind" cross-over w;i.3 cni- ployed in this experiiiieiit (piticiit.,i (litt not lkno%v the tlru(,.14 tliea? were receiving, but observers (lid knonvn). Each sul)j2cet receive(], iii mizl-d order at weelilv intetvils, two (lo." of LSD in(I P14icebos were not included since E,-.pet-ietice (ISDILL Pt (II., that for?ncr niorl)liitic a4LI(licts (lo iiot rettet iziziri@ has shonvn c(ilv- to placebos. For comparison, placebo (latit frotti zitig-)tlier (ISIIELL et al.,@ 1959) are presented. -tvho roluiiteere(i for tltis cxi)ct-itiietit et- Siib-jecti. The subi6ets former opiite addicts %viio were serritig senteii(Ts for violttioti of U- itite(i States narcotic laxvs. Their aces varied between '-)5 to 3--i all were 2 physically liealtlin. iiiales, and iione presented anv evi(lence (,f the iiiajor ps choses. All liid p@iyehiitric (lia,-nose-3 of cliarieter or 1)(@rotiL%Iitv 2 y 0 disorders and all li,-td received LSD iii previotii cxlx-rinictit,4. General cotiditiotis. The subject- entered a wartl 2 tlcvote(i to clinical research the ni(,Iit before tlil, da-tv oii which test wis act- ministered aiid remziitieill until the followiiie, iiii)riiiii-. 01),ikrvt2tioiis were performed by specitilv trninett aides wit li Ion(, (,xl)erietice iti (letect- ina, behavioral changes clue to tiru(-S. Tiic p-,itietit., .vcrc totti notliin- 2 about the iiliture of the drti(ys tiiev,,vere to receive or the purl)o.@(-., of the e.xperiments. Drugs and do,5e-3. LSD tartrate and meseiline li2vdroclilori(le were administered ititrainusculi-trly in doses of O.-j5 ziti(I 1.5 moo,,,k- Mt [I. ZD -iline). Tlit, clriig coii ii- 2 (LSD), and 2.::.) ni,-,,ika, and 5.0 m- - (inese, cc, trations employed for LSD all(I iiieseiline were 'JO and I 1)1-)i 111211211 2 respectively, in distilled water. Prior to admiziistration cich Llt)sc wi.; diluted to % constant 5 nil volume ivitli sterile pyrogen-fi-ce pliv.,it)lo'Yie-,ii saline solution. The following cletailed ob.,ervations were iiitt(le at )iourly intervals @ifter 10 tuizitites rest iii be(l, tn%-ice befOL-0, iltlfl Cirlllt times aft2er tidniinistrzitioti of drif@ry.11: rectal i-,ite. systolic blood pro,-suL-c, pupillary"4ize, iiii(I tlir(-Itol(l for elicitzttik)ti of tli(, kneeierl,-. The metlio(l,@, used wort, those previotislv describe(I I)v Isi@'ELT, et aZ. (1956, 1961). In t(l(litiort tltc subjects (,@itfl tile help of'ztri ii(Ic.) 2 c6inplete(I a special (Itiestiotititive tt liouriv intervals froni -i.:;() iL.111 to 3.30 p.m. At these same times (,,etieral tiot(t-.4 oii belitivior N@-ei-Q "-rittt,ti 2 Clinical -ra(les of the inteii@,ity of the rettetiott wet-t- zt.,isigiieti to the System Of'IS13EX.L et (11. A?talysi-3 of cl4da. The c-litti-es iii roet..tl tenil)crattirL,, rztl pupillary size, blood pres,,;iir(, aTI(i thr"iiol(i for clicitatioii of ttie. 3 of the two pre-(Iru- jerk- were calculatcll I)v subtractitict the averace 2 observationsIfrom the vtlues obtaiiief.1 at the various hours after the drug. The areas under the time-action curves for each of the above, res were calculated bv the metlit)(I measurement2s composed of these fi,(,ni .'of Wi-"Eit and FLAT-kxER, thus convertinc, all the data on a particular drug, a particultr measurement, and, a plrticular day to one figure termed "degree-hours" (temperature), "rate hours it (pulse rate), 2etc. "Positive" answers on the questioiintire -.vere scored bv countiii- Lill positive responses that were not scoretl positively before the (Iruos were given. )Ieans.and standard errors of the means were calculated accord- 2 ing to standard statist@ical techniques (Ei),%vka.Ds). C@ilicultitions of ttie relative potency of LSD and mescaline were performecl on each of these paratacters, using a method (G-kDDnl) for four-poiiit assavs. 2In order to obtain time-action cu:n-es, clianaes in temperature, pulse rate, svstolic blood pressure, pupillary size, and tlire-.;Iiold for the kneeier.k- were tabulated and av-erzicc-d for each observation time after 2 0 the drugs. The number of positive responses on the questionnaire were also averaged at each observation time. In addition to pron-idino, datt on the time-action course, these tabtil@%tions identified the time at whic2h the greatest (peak) respolises occurred. Additional calctilitions of re- lative potency (GADDC,-.Nl) were made usino, these peak values. 0 In order to compare the patterns of su2bjective response the 5-i qiics. tions were classified into nine catecories'. 'nie questionnaires were then scored by counting the number of patients respondinc, po,%itivel-@, to a given question, after -,vliieh the scores for all the questions cons2titiititi- the particular cateoor-v were summed. Experimeiit II Expe-rime?ztal design. A "cro'z-s-over" desian i@sinc, each patient as his own control was emplo2ved in this e-%-periment aiid is summarized in table 1. The desic=,n was Similar to that used in testina cross-tolerance between LSD and psilocvbin (IsB= et al., 1961). Subjects. The same 10 subjects were employed who were used iii 2 F,xperiment I. Gemral c-anditions. Subjects were housed in the same special research Nvard mentioned in E-,:periment I. Temperature, respiratorv rate, aii(i bloo(I pressure -were measured three times dailv vfter the pitients lia2ct rested quietly in be(I durinc, days on which special measurements ,,rere The nine cate-orie4 tre slio%,,-n in Titble .5,,in(I are the same thif -,v4c-re tised in comp@tring LSD and psil2ocvbiti (ISBELL 1059). As previottslv expilincti, t lar7-e number of other c-,%to-oric-i could be devised aii(I iniinv (jut-itiotis cotild be clzt&,iific(i in various cateeories. The classification the0refore is completeIN arbitrirv. 4 Table 1. Su7it.,iiary of experinte?ttat Exlmri)iieitt 11 Drittr2.-i and period of CI.LIS @@ubjecti XI Stillj,.4-t.4 Y' 1. Ist control 7-21 TISD3 l.i, 3[ese. 5.0, To oi)tain ba&il (iiitii. -Ifesc.-I .5.0 LSD 1.5 Order of teit-s ran- domizer.l. 312iiiiiiitim of 3 davs I)et@%-c@en LSD and niesetiline 2 2. Ist chronic admini- 14 LSD 3[ese. To develop toler,-tzict- stration increasiii- iiicretisincr to 1..5 2 to 3.0 3. lat test of tolerance 2 LSD 1..5, Ifese. .5.0, Test of tolerance ind arid..cros3-tolemnee '.Nfese. 5.0 LSD 1.3 cross tolerance 2 4. lyithdrawal period 14 none none To lose tolerance 5. 2nd control 10-24 ')Iese. 5.0, LSD 1.5, To replicate control 2 LSD 1.3 Ilese. 3.0 data and test loss of tolerance lee 6. 9-nd chronic admini. 14 Ifese. LSD '4Cross-over" to devel- stration increasing inereasincr op tolerance to 5.0 to 1.5 7. 2nd test of tolerance 2 3lese. 5.0, LSD 1..5, Test of tolerance ttitl and crow-tolerance LSD 1.5 3tese. 5.0 cross-tolertnce Subjects "X" received LSD chronicallv 2 first. .'Subjects"Y"receivedmescaliiieclironicallr,first. 2LSD=cliethvlamide of lv3ergic acid; @lesc.=mesc-aline. The order of 2 dministration of ;he drug in each period is indicate@i bv the order in which tliev :ppear in the section of table for that period. Figures after svmbols for drug., ind:l. cate the dose 2in mcgilkg for LSD and for mescaline. not beina made. -4,11 measurements -were made by the same aides as in Experiment I. Drzigs and doses. LSD2 and mescaline were administered intramuseu- larly at 8 a.m. (durincr the control period ind on test davs) or at 6 a.m. (during the periods of chronic intoxication). :\o placebo; ivere emplovef.1 2 in this study because of the negliyible subjective response of our sub- jects- because placebos have no real value in assessina tolerance and cioss toler2ance, and beca'itse the addition of placebo trials would have PI'Olon,- d the experiment unnecessarily. In the fir-st and second control periods the patients iecei%-ed LSD 1.5 me2o,'I,-c,, Ltlcl iiiescaline 5.0 iii-'Icr ill randomized order before chronic adniinistrzitioti of the druc.,@-' was begun. Detailed observations were made on th2ee test dL-,-s. These control experiments ,vere conducted at intervals of at least five (I;tvs in order to prevent developnient of tolerance (Iiiriii- flic control Ix@rio2d. Durincy the first and second peliods of clivoiiic ii(Iiiiiiiistritiott. the ttionts received intraiiiiiscularly O.'3'0 of LSD or 1 in- kg of 6 p Cy I-- mescaline on the first diiv. These doses were increased by 0.31) me (LSD) or 1 mgjkg (mescaline) (laiiv until the pitients vere receiviii" .1-5 mcg,,kg of LSD or ;3.0 iiif, kr of mescaline on tlxe fifth day. These doses were maintained throu(rli the 14th (lay after bcc,,iiiiiirici ilironic 2 intoxication. On the 1;-)tlt day the pttionts .vere "challen,-,e(t" ,v-itli the dose of drug they had been receirin;, (test of "direct" toler@iiice). Oil the 16th dav they were @4 cliillenc,,,e(I with t2he test 4,lozie of.the ilteriiato drug (test oi "cross" tolerance). Oil both of these davs detailed measure- ments were made. 'nie Zatibnts thenmeeived no me(iic,,ttion for 14 davs in order to lose 2 tolerance'. FolloA-inc,y this withdrawal perio(l. '4second control" measurements were obtained after thepatictit.3: had received in 'randomized order mescaline .5.0 m-2@kg, and LSD 1.5 riie- ko,, ,,@ith at least five davs inter. vening between administration of eitlier drug. The patients then aaaiii received tile drugs chronicallv; those patients who had received LSD in the first period of c2hronic administration were given mescaline accordino, to the schedules described above and vice rersa. Thev %vere then " cliillenued" Ni-ith LSD and mescaline in the same manner as previously described. 2 Ob,servatio?i.?. On test davs all observations were performed in identical fashion to those described in E-%-perinient I. Analy-si3 of data. The areas under the time-actioii curves were obtained for each subject and each 2 test condition (includin- first and second controls and all 4;cliallenciiia" tests) in the manner described in Experiment I. In addition, mean peak- response values were obtained (as in Experiment I) for e-,icli paraiiieter except "c2linical o-,rade," since the latter consisted of oiilv a sin-le figure. The difference in the various area measurements after 1.5 meg,;kr, of LSD on the first and second controls were ev@iltiated bv a t-test for 2 paired observations (F@DWkRD.'3). Data on tile two sets of @ontrols after 5.0 MC,'/kg of mescaline were trctited ziinilarly. Increase in blood pressure was significantly oreater after LSD. There were no si-nificant differ- 2 0 ZD ences oil other parameterb (Table 2). In addition, tile differences I)et-.veen the two controls were craiiixt-l-d bv ct non-piraiiictric rank- order test for 2 paired observations ('WILCO-.',)-';). Since the siciiificances of ttie differ- ences by this latter statistical tccliiiique aareed well with those obtiiiie(I by the t-test oil the tinic-action (area) 2 ficures, onlv the latter are herein presented. In order to test for ecluiviilcncc of the doses of LSD and mescaline in Experiiiietit II. t]iL- .irerzi(,c peik vzilties ol)tiiiiect on tlio two controls with 1.5 iiioaik(, of LSD were eotiij)@irc-(l with the ,Lver,,I,,e values obtained Table'2. 1?.eproducibilily of reamisei to LSD and ?ttemalint in first axd iecol?,i con- frols (.V 10) 2 3[euure 0.516 -L 0.481) Temperature . . . : . . . . . . + 0.')82 0.3-i2 Pulse rate . . . . . . . . . . .. + 14.925 13.68 18-65 14.12 Blood pressure . . . . . . . . . + 33.35 14.031. -10.30 9.-Jl Pupillary change . . . . . . . . + 0.325 1.75 - 0.263 1.2j- 2 Kneejerk . . . . . . . . . 6."14 + 2.-j5 es to questionziaire . . . . + 10.35 9.68 4.60 8.56 Mgzrgrade . . . . . . . . . + 0.150@,- 0.-"Il 0.100 0.221 .Figures repre@'ent the mean differences the standard errors of the differenc". betyveen responses to LSD-25 (1.5 mcg,,,Ig) and niescaliiie (5.0 mgikg) in the first 2 and-second controls. + Indicates an ine'reased response on the second control. Indicates a dei@reased response in the second control. Indicates significance (P < 0.05). 2 on the two controls with 5.0 mg""I-g of mescaline (Table 3), 'usinc, the t-test for paired data. Similar calculations were made usino, the area measurements. 2 The differences in the response after chronic administration of both LSD and mescaline were evaluated bv comparing the responses after iirst and second chronic admini. 2 Table 3. Equitate7ice of dowqe of LSD strations of LSD and,'or mescalhie awd me3cali2te, Experintent 11 (-@ = 10 ,iith their respectiv-e first and 2 3lean Difference in second controls usin- the t-test 3tea3un respoase (-RLSD'lt3lesc) 0 for replicated dat2a (EDiN,--LRDs). Four dffferent comparisons ivere Temperature 0.0055 0.05 Pulse rate . . . + 2.80 1.85 made: (1) response to LSD after Blood pressure 4.15 1.441 chronic administration of LSD PupiRary chan"e -0.212 --O.li- 0 2 ("direct" tolerance to LSD), (2) Kneeierk . . . . +1.94 2.10 Responses to response to mescaline after chronic questionnaire 1.45 1.92 adn-dnistration of LSD (" cross Clinical grade . . -0.35 -O.:14 Figures respresent mean deferences tolerance to mescaline), (3) re. S;E. of differences bet,%veen mean peal- sponse to mescaline after chronic control responses to LSD-25 (1.5 mc,-,ikg,) administration of mescaline and mescaline (5.0 mollg). ("diiect" tolerance to mese-,t- 2 + Indicates LSD.25 stroncrer in effect line), and (4) response to LSD than mescaline. after chronic administration of - Indicates mescaline stroncer 'm 2 mescaline ("crosss" tolerance to effect than LSD-25. Indicates sic.,mificance (P < 0.02). LSD). The si,ins of the diffe- 2 rences were so arran-ed that a minus (-) sign indictted a decrease in the nieisurements tftcr chronic administration as compared iv-ith control, and a, plus sicn indicated 0 an increase. 7 Since mescaline has a lonaer duration of action than LSD the 0 2 differences (except for "clinical de") ,vere also evaluated, usiny grill values obtained at the peak of both LSD and mescaline reactions rather 2 than using the areas (intecrr-,ttcd time action curves) as described above. In addition, the differences were evaluated bv IViLcoxo--,-'s non-para. metric rank order test for paired observations. The2 si-nificance of the differences by these statistical techniques agreed well with those obtained by the t-test on the time-action (area) figures, so onlv the differences . obtained by the area methbd are shown in this paper. 2 Results Experij nent I. The objective and subjective chances induced by LSD 0 2 and mescaline .vere very similar. As can be seen in Table 4, both drucs Tabler4. Comparison ol the total co?irs'e o.1 the LSD and meicalint reactions Treatinent 2 measure Placebo' LSD-2.5 mescaune 2.53 Tempers- turet 2 + 2.7 '- 0.3 + 3.5 0.4 4.3 0.5 3.4 0.4 4.6 0.4 Pulse rate4 - +3-i.8 '-@14.5 +50.-" -10 .2 56.6 -,.7 38.4 9. 3 2 7 1. 1 1-j.'j Blood +15.6-'-13.5 '-45..5 12.5 6,5.2 10.1 45.4 1 3..5 + -, 6.6 12.4 pressurea 2 change-' + 0.2 1.4 S. 0 0.9 l-).g 1.6 10.4 1.6 - li.3 2.0 Kneejerk' - 20.-A 11.1 54.,) I 1.0 54.0 9.6 65 '5 15.1 --40.1 16.29 I>ositive answers,$ 0.1 0.3 37.1 4. '4 8 11.1 35.3 5.9 6-i.2 12.1 cLi2tical 2 0 1.85 0.2 gTa4e" 0 -.45 0.2 1.6.5 O.-'- 2.1 0.2 I Data from 9 other subjects in anotlier experiment (IssELL 2 1939). 2 Dose in mcgil-g. 3 Dose in. -mgikg. It ligum are means (O subjects on placebo; 10 on LSD and mescaline) '- stan- 2 dard erro rs of areas under time-action cur@ves ("deZ-Tee-hours," "be,,tt-houi@s," ete.)- The signs indicate increases (-4-) or decreases (-) in the measurement from pre- 2 drug controls. Means -- standard errors of number of quc--tions scored positively in the Iv before the druo,. 2 72/, hours alter the drug which %,rere not scored positive . 0 6 Means 4- statidard errorsof intetisitvoi mental reactionba-@ed ona scaleofo-4. caused increases over pre4-dnic, measurements in body temperiture, pulse rate, s3,stolic blood pressure, iiid pupillary size, and both decreased t-he threshold for elicitation of the lneeierk. The table also sho%vs that 8 Table 'a. Coniparimt of pattern olsubjectil-e responte on litestion?taire after )Ilejealiil'e 2 a-nd LSD.25 '-untber of rrspoti;" In cate-,@,r!r 2 @N-itmber of Total e Category questions* r"tw)ns" LSD niew;tiiii 2 possible placebo O.-. 5 1.5 2.5 :;.O General . . . . . . .2 . 7 70 0 18 30 19 "16 Difficultv in thinking 4 40 0 0 14 3 4 -Utemtio'n in mood 2. 3 30 0 14 13 6 9 Alterstion in touch . . . 4 40 0 13 -10 15 26 -Alte.rntion in hea2riiia 4 36 0 16 20 11 18 Visiial distortion . . . . 10 40 0 10 39 12 23 '.Eementarv" hauuci- neitions .. . . . . . . 5 45 0 8 L-10 8 21) "True" hallucinations. .1 40 2 0 2 8 1 5 Depersonalization . . . . 13 - 130 0 "IS 44 23 34 Refers to type of question, e.g., feebnz stranle " (general); "feet look old" (depersonaUzation); '4 am happy " (mood); " things look --mall " (-.-isual distortion); 14 is difficult to concentrate" (th2inking), etc. 2 Number of subjects times number of questions in cate,-,ory. 3 Based on responses of 10 different subjeicts in another experiment. 2 the changes in the various measures were far cteater than those that occurred in a different group of subjects after placebo. The magnitude of these changes was about the 2 same after O.-i 5 mea, I-o, of LSD and 2.5 mg, kg of mescaline, crafter 1.5 meryz kcr Table 2 6. Betaiice potencies of mescaline and -. c, of LSD and 5.0 mcr kg of 2 LSD calcitlated fro?n tnrious measure)ptents C, Relative 95%,co@'idetice mescaline. Both drugs induced 2 potencyl initts -v, alterations in 3le"u" anxiet mood 2 (crenerallv "euphoric"), diffi- Areas cultv in thinkin- and concen- 2 Temperature 0 2666-3, 31 tration, sensorv perceptual Blood pressure. 3084 22-i 5-4000 2392 2 17-, "2-,4 distortion particillarlv visual, P,PiL,2 . . . . Total answers 3355 248-i-5065 and both caused 2 true. and Peak values pseudo-hallucin,,ttions. The Temperature 32SO 3165-- 3401 subjective svmpto2ms reported ]Blood pressm-@- 3344 169S-- 'j5lS Pupils . . . . -Xi A 0 '-,1008- 4@)OI after mesetiline were 2 very Answers . . 49'j 3 2S3-11-10000 similitr to those described in CUnical grade 3460 2194- 5430 the 2 literature. Table 5 illu- Meg mescaline hel strates the similarity of the @@ It equal effect 2 3leg LSD-25 tarti-ate patterns of the subjective 2 Did not meet criterion for equiv-alellce response after LSD and 2 of. dosage. mescaline. LSD and mcscllin@- diff@red in tinie-actioil cotirc. In oeneral the 2 action of mescaline penist(?d Ion,-er than that of LSD .,Nitli peak effect 4-- 2 being reached later tndlor beiiio, lon,,er susttined I and 2). These curves show that pupillary dilltation after both iile.--,caline aii(i LSD lasts much longer than do the subjectiv-e effects. Tliev also qlxow that the peak subjective effects of meseilitic, as measured bv the 2 respon,:cs on the questionnaire, were less than those after' LSD. The -,ubjectiv6 effects of mescaline subsided more slowly than did those of LSD. L so 2 J 7 d 7 2 hrs afte,-olru; Fig. 1. Time comne of pupiltan- dilatation after LiDtnd me--callne isa k 2 /47 7 h rs atler al-u Fit. 2. Time coum of subjectire responn after LSD,,tnd Luesc-,Ulne 2 Calculations of relative potencv are summarized in Table 6. Sianifi- cant dose-effect slopes .vere not obtaiiiect for pul.,:e rate and threshold for th6 kneeierk for either area or peak data, so these measures are omitted from the table. Sigiiific-,int slopes -%vere obtaineill on all other measures and, vv-ith the exception of area incitsurenleiit for pupilltirv chan<,- which did not meet the criterion for equiv-alence of effects at the closes used, 2the regressioii for all these measures iiiet the re- quirements for equivalence of (losiiae and parallelisui. These calculations shoav that LSD tartrate is about 2400 to 4900 tiiiies as potent as iiiesea- line hydrochlorille, d6ependin- oil the measureiiielit clio,,eii. Oil a mole- cular basis, LSD is 4500 to 92-,5 tinies as potent as iiiescaliiie. It should 10 be noted that mescaline is more potent in dilatinc, pupils relative to its 0 potenck in inducing subjective responses than is LSD. 2 Experiment 11. Cross toleralice betzceen LSD a?id mescali?ie. Co@ilrol,3. The differences in responses to the same drua, in first Lnd second controls after LSD and mescaline are shown in Table-2. The oni.@, chance that was statistically significant (p<0.05) ,vas in inerea.,:e(i elevation of blood pressure after the second control doz@e of LSD. This could indicate simple variabiE2tV of response to LSD on this particular ptrameter.. The table shows that no significant de-ree of residual tolerance was present at the time the second controls were doiie. Fquivalence af dosage. The differences in the mean peak 2 responses to the tivo different active (Iruas (LSD and mescaline) are presented in Table,3. It will be noted that althoitcli Iotir of the six comparisons incli- cate'that LSD may have produced a somewhat stronger resp2onse than 'Mescaline, the only statisticattv ,:igiiffictint clifference betnveen the two drugs is in elevation of blood pressure. The magnittide of the difference is small and probablv reflects the rariabwtv of response on blood2 pressure. after LSD when administered on separate occasions to the same subjects (see abov-e). Since the majoritv of differences are poizi- -tive, there is some indication that. on the aver-Ace, the peal-, effects of 2 LSD may have been somenvhat stronger than those of mescaline. Simi- lar calculations usina, area measurenients instead of peak ialues oave identical results with one exception. Total pupillarv dilatation after 2 mescaline -was siomificantlv ctrea-ter than that after LSD. This difference from the results -,vith the peal- data reflects the more sustained iction of mescaline on the pupil. Tolerance and cross tolerance. The differenc2es in responses to LSD ancl mescaline after chronic administration of either druc, and their respective first and second controls are shown in Table T. In this table the first column of figures shows the difference in response to LSD Is 2 compared %ith the corresponding first or second co 'ntrol after chronic administration of LSD, and reflects "clixect" tolerance to LSD. The second column of figures shows the difference in response to mescaline 2 --" compared with the ,ippropriate control after chronic administration of LSD, and refIL-cts"cross"toleraiieetoinescaline. Siniiltrly,tliethiid column of fi,--ures presents measures of "'direct" tolerance to mescaline, 2 and the fourth column of fi!-@ures, "cross" tolerance to LSD. Inspection of Ttble -i slionvs that all the signs are negative, indicitin- an average decreise in response on all me-,isiires. In the case of " direct" 2 tolerance to LSD (first column of fi-iir"), the differeiices were stati.,:ti- cally significarit iii six of the seveit me-.istires. In the case of "direct" tolerance to mescaliiie (third column of fi,(,rures), statistically si-iiificitiit chano,e occurred in three measures, and in tile case of cross toler-.i tice ees of chan- occurred t,o LSD (fourth column of figures), si-iiificant degr e in four par-dmeters. The measures -%vb2ich reflected "direct" tolerance and "cross".tolerance most clearlv were pupillary diameter, responses on questionnaire, and the clinical -,rades. Table 7. Tolerance and crom tolerance 2 kfter LSD chronically (i4 days) -Uter melaline chronically (14 days) 3lessure test with LSD challens:ewititnies- test%-.,tthmeicaline chauenge with L@@1)2 caline "(!ro-s" 1q,te- "-lirk itkce "cross" r( ''direct" tolei ce t'l tr)ier. -lerance 2 to LSD raace to ittew-,vune to inewiliae to LiD Temperature 'O.2-i5 '-- (@139 - 0.303 0 -64- I' 14 0.39 O.-131 0.493 2 Pulse rate -16.90 --12.35 -48.10 13.03 3 - 33.00 16-15 24.20 1-.95 Blood @'46.25 14.103 --42.05 '-16.Wl -32.60-' 14.98 262.90 11-303 pressure Pupillarv- chan " - 12 .:'.'O 1.,"9 3 9.11 1.223 S.40 - I 'S 6.88 O.-, 6 3 ,,re 2 Kneeierk -40.25 16.251 - 53.S5 IS.-,92 S.-IS 1 1.', 1 - 19.58 13.5-6 Responses to 3.903 -69.30 '-15.633 -47.35 7.61 -56.40 O.-iO3 2 questionnaire - 40.85 Clinical grade - I.'-)O 0.202 - 1.40 0.323 - 1.45- 0.24 - 1.30 0.303 Figures represent the mean differences -.@- the :standard errots of the differences 2 between responses to first control doses of LSD.,-)3 (1.5 mcz,ikg) or mescaline (5.Omglkg) and identical "test" and "challenginiz" closes of these drtizs after a fir2st period of chronic intoxication i%-itit either cli-ii-: and, secotid control dozes of LSD-'-73 (1.5 mcg@kg) or mescaline (5.0 rna,lkg) and identical "test" and -'challeti!z- ingti do2ses of these drugs after a second period of chronic intoxication with t@e other drug. + Indicates increase in response after clironic into.-,ication. Indicates a decrease in response after chronic intoxic2ation. I Indicates significance (P < 0.05). 2 Indicates significance (P < 0.02). 3 Indicates si,-,nificince (P < 0.01). 2 Disetission @As e-.Kpected from the descriptions in the literature, the reactions induced by LSD and mescalhie proved remark-ablv similar, differin-, 2 chiefly in rate of onset and duration of action. Both druas caused similar chinaes in autonomic functions which were nearly identical in degree at doses inducina equivalent grades of mental aberration. The subjectire 2 symptoms reported after the two clni--s were verv similar in kind and incidence. It is, of course, possible tlitt the similaritv in the subjective response was partly caused by the methods of measurement and the experimental situation. All of our subjects had recei%@ecl LSD on other occasions and micht hive expected similar s ptoms from any drua 2 0 YM 0 given in this pirticular testinc@,, situation. In addition, the use of the questionnaire miy su(,v,.-est certaiii ;yinptoms. Ho%ve-ver there are coc7ent 12 reasons acr inst the similarity beinc, due to the e.,tperimental ,:ituatFion a or to suggestion. The patterns of effect after inaiiv other (Irus (am- phetamine, scopolamine, marihuana, etc.) in the -,4amc kiii(f of subjects and under the sime conditions differ markedly froiii the paitterii in(luct,(l by mescaline and LSD. In2 addition, the,.ziruilaritv between the LSD @iti(i mescaline reactions. is readilv apparent in the descrip!iotis in the literi,- ture, even though the subjects were tested under -%videl.v var-.,-iiicor c(iiicii- 2 tions with different mitliocls, and in subjects who received oiilv mescaline e or LSD. Thus it seems lik- Iv that the similarit-,- between t@e reactions caused bv LSD and me2scaline is a real phenomenoii and not all artifact due to i@e metho'ds of testing. T@e similarity of the effects of LSD and mescaline suggests that the two dimcs act bv common mechanisms or tlirou<-Ii some 2 final comnion pathw'av. This hypothesis is-' stron,-Iy reinforced bv the fiiidinf (in agreement,%-ith BALiEsT.Ri-ERi, 1-95-i) that definite cross tolerance develop- ed between both drugs on chro2nic administration. Direct tolertnce to mescaline and cross tolerance to LSD could not be demonstrated oil as manv measures in patients receivincr meschlitic chronieduv as could direct tolerance to LSD and cross tolerance to 2mescaline in patients receivina, LSD chronically. 'Efou-e-ver a Iiiuh degree of direct, and cross iable and least .tolerance. occurred in both instances on the most rel 2 variable of the measures (pupillarv chanze, responses on the question- naire, and clinical grade). Smee persons directlv tolerant to LSD are cross tolerant to psilo- eybin (ISBML, 1961) it seems likelv, althouch not proved bv direct e.xperiments, that persons directlv tolerant to psilocvbin would be cross tolerant to mescaline. LSD, me;caline, and psilocybin appear to con- stitute a 2definite group of druc, with identical or clo-,;@elv related bioloc, cal effects, just as morphine, methadone and meperid'uie constitute a bio- logicallv related crroup of analaesic drucys exhibitin- 2 0 0 .@, Iiic,,Il degrees of cross tolerance. Since psilocvbin is an indole and since LSD can be reacirded as an indol6, one might h3,potliesize that the similarities in b2iological effect ai@cl the development of tolerance and cross tolerance are related to similarities in chemical configuritioii. -liescaline is, however, not an indole, and altlioii