rqycfiophirni@keololia 2, 14-i-150 (1061) From the'.National Institute of Ilental Hc,,tltli Addiction Researcli Center, U. S. Public Healtli Service Hospital, Lexin-ton, lienttxckv 2 Cross Toler-,ince Betiveen LSD ,iild Psiloevl)ill Br IL%nnis ISI;t.LL, A. B. WoLnAcir, A. IVIT@LEII tincl r,. J. IIINER 2 ;,@Beecii-ed Dece?itber 10, 1960) Recentlvit hasbeenslio-,i-n (HoF.NL-t-,- et al., 195Sa; DF-L--@.y et al., 19@')S; ISBF,LL, 1650) that O-Phospliorvi-4-li-v-ciro-x-r-'-\'-climethvl trvptamine (hereafter'referrecl to as psiloe-,.bin)"ZL coiilpouiicl isolated (HoF3tA--,- et al., 1958b) from certain species of niuz@hrooiiis that are used ceremoniauv 2 by.Nlexican Indians (IV-A@so,-@ and W-.isgo-N-, has psveliotoinimeti c properties similar to those of the dietli-rlamide of lvscr2-ic acicl (LSD----15). The close resemblan2ce of the patterns of sviuptoms induced by LSD and psilocybin suz@rested tlltt these dx-Lics produce meiittl aberrations by some common action or bv affectinc7 different mechanisms sharinc, a cornmon final patli-wav. Since the effects of LSD diminish rapidlv when the druc, is civen daflv (IsnF.LL et al., 1956), it ivis felt that if t-l@e LSD and psilocybin s-,-ndroines have a common mechanism. this h@-po- 2 thesis could be f@@her'tested bv deterniiiiinc, if"cross tolerance" between the two drucs e@dsted. In oi@her words, if the deo,,ree of the reaction induced bv a oi7en close of silocvbin -%vas si,-Tlificantlv 2 less in t person 0 p C. tolerant to LSD, cross tolerance would be said to e-,cist; and, convei--elv,. the reaction to t ci-ren dose of LSD should be reduced in a person tolerant 2 to psilocybin. In the latter case it is implied that '-direct-" tolerance to psilocybin can be developed. )Iethods Experiniciits. Two e-,cperinients were perfornied tt clii-t:ereiit times. Ex-Pe '=ent II N%-,,ts carried out to determine if aclniii-dstration of a ltrfrer close of psilocvbin civen over a lotip-,cr period of time than in Experi- ment I would create a greater degree2 of toler-,ince',,tnd cross tolertnce. A "cross-over" design usincr each patient as his oN%-n control ,vas employed in both e.@cperiments Lnd is.suniiiiarized in Table 1. Both experiruents consisted of seven 2periods: (1) first co-iilrol, in which meastiremeiits,@%-crc obtained after the test doses of pzilocvbintnd LSD, (2) first c7tronic adni@iii-stratioiz, in @viiiell patients received either psilocybin or LSD once diiilv in doses iiiere-,isiii,- to the test level over a periocl of 6--l-" divs, (3) first test of tolera?ice a?id cross tolCra7?ce, in which pitionts Nvere "chall6eii-ed" with the driia thev had been takin, 13 37.@ .rtiblo 1. Summary ol experimental desig)is lor Experiments I an(i 11 No. of I)riigti altd 2 Ilayd Iteiiiarks tilbjo@.to y ]'ji3 Ir@0; 1211, ],.41) 1.5 To obtaiii basal datil 1. l@irat control . . . . . . . .'I 7-8 1,81)3 I.r); 'PI3. I'd 150. if 8-0 LSI) 1.5, 111. 2 1-ti 210 Ilki 210, Pi, I,SD Ortier of tests ratidoniized. At least 5 diiyti between 2. Firbt eltroikic adiiiiiiistratioii1 6-7 I.SD iiici-eatiiiig ii) 1.5 Ilki iiicreiksiilg 1,0 150 To tlevelol) tolerance it 12 1,Sj) itiorcauilig W 1.5 l'u iiierttitsiiig to 210 2 3. Vii-et test of tollratice ati(i ei,ous-toleritneo . . . . . . .1 2 I'SI) 1.5, P,, Irt) I'll 1r)O. 1,81) I.r) ..test of t(litti-titico aitti cross 11 I-) 1,81) I.G. lii 210 I'ti 210, lll@1) 1.!-) tolt..I-Lillt;o 4. IVitli(irtwail lieriod . . . . .1, 7@-.10 ]'I 2 ]It To lose toloritileo Nt)iio Ntiiio 5. Secol)(I coilti-ol . . . . . . .17-8 I'l. 118 lf)O. 1,281) 1.5 1 18@1) l.r@. ],I, 11, lr,( To I-ci4i(!Itto coiktrot tilito, 11 8-9 l@l, l@s 210, 1.81) I.r@ 1.8 D1.5, III, 1-8 .-Io To test'loss of tolerititee 6. Secoiitl cliroiiie adiiiii)istratioti16-7 Pii itkereneiiig to 1r)o LSI) ittercituitig to 1.5 "Cros3-over" to develop 11 12 I'm2 to 210 LSI) iiiereatsiiig to 1.5 tolorltiico 7. Secoiid test of toleraitee atid .. . . . . . .1 2 I'd if)o, 1,81) 1.5 1,81) 1.5. l@'s I.-)() To-it2 of t-tilerance aiid cross it 2 I"i 210. ],St) 1.5 1,81) 1.5, ]':i 211) ttil(@i-ittico Sill)j(!C(.4 "X" 1,S,I) fil.4t. ],'II) z@; iii(!Illylitiilitlu of lynel-gic lkt:i4l; ]'I z@z illit(!(@llo; 1'.4 @- ])Nil4biyl)ili. 'J'lio ot-titir II( it) i-itefilm-l-io(i lti iii(lit-iktt@(i I)y itic oi-iter ill -,vliiell Cli(ty ikilll(-.Ir ill Clio bt!Ctiolk of tlit-. titititt It)r tliiti. litti-it)(1. 'Ieigiii-t-ti liflt!r tile HYIIII)Ol-i fill. tist@(Ifilgii itiolit-itt.@ til(@ tio4ti ilk 149 (test of -'4clirect tolerance") tnd on the subsequent day %iith the dru(r C2) they bad liot been takino, (test of "cros.3" tolerance), (4) a -teithdrawal or 44 washoiti" period, in -%,hicli the patients received placebos (Exppriiueiit 1) or no dnia (Experiment II) in order to lose tolerance, (5) a seco,pid @,co@ttrol period, in which the test doses of LSD and psilocvbiii were J. 'repeatNI, in order to replicate the cotitrol dita obtained iii the first control perip2cl'and to dieterinine if toleraiiec. ha(l been coiiil)letelv lost, (6) second chroitic adnii7ii-stratio?t, iii -,vhicli the patients received (laiiv doses of tha alternate drug that they lit-t(l iiot taken in the first period of chronic administration (-",cross-or-er"), and (-j) finauv, the second challenge, with test doses of LSD ancl psilocvbiii as in period 3. Dru,-,s aud Doses. LSD'aiicl p2silocvbiiil were given in 3G cc of cherry syrup at 8 a.m. with the patients fastin-. The s-,-rup, which was used to Ile 0 mask the bitter taste of the psiloc.vbin, ser-ve(I as the placebo. In t2he first and second control periods the patients received in randomized MCO.Ilkg of LSD, placebo, and 1.50 me 'ka, (Experiment I) or order 1.5 _g,, 0 2 0 before chronic acliidi,.istration @10 meg'ka- of psilocybin (E-xperinient II) of the drucs -,vas beoiin, Dettiled observiitions@ -%vere made on these test days. T2hese. control experiments -svere colicluctecl at intervals of tit least five davs in order that anv, tolerance conferred bv the fir,-@t cinio, ivoulcl be lost. Durina, the first and second periods of chronic administration the 2 patients in Experiment I received 0.25 inecr:kg of LSD or 25 mecy,"kc, of psilocybin on the first day. These (loses -.vere inereasef.1 0.25 (LSD) or -15 mcgil,-g (p,,:ilocybiii) daily iiiitil the patients were r2eceiving 1.5 mcgi,'kc, of LSD or 150 ilica;l@c, of psilocvl)iii on the sixth clav. These doges Nvere maintained until the tests of tolerance ,Lncl cross'tolerance were performed. In Experiment II the pitients recein-ccl 0.15 of LSD or 21 mcr,".-Ic, of psiloc)-bin oti tlic. first (iLv of chronic acliiiinistra. tion, inereasiiic, bl@, .15 mccli'kc, of LSD or 21 me,-I'kc, of psiloc-,-bin dailv 2 @ @ 0 VI. t! e n until ilie p,-Ltieiits were receivin(i 1.5 nicoili- of LSD or 210 iiic-;I@cr of z@ @i @ cl 0 2 psflocvbin oli the teiitli (lav. These (los4.-s were maintaiiied tliroucrii the twelf@li dav. The order in'ivhicli the pz7ttieiits received the di-,lcs in the first and second periods of cliroti2ic i(Iiiiiiii.,:tr-.ition -,vas r-,iiidomizecl iri both Experiiiients I and II. Dtirin