2.5 January 1960 Dr. Rudolf Bircher- Sando-- Phar:.mccuticals Sar.doz, Inc. novt->r,, Nea Jersey Dcar ILr. Bircher: t@,le ha-ve il.'In-ally conpleted our study o,,i tolerance to psilocybin 2 and LSL"-25 and cross-tolerance@.bcti-?ecn ti'iesc drugs in five subjects, supplc,-,,-,nting the earlier'study o.,'L' Dr. Isbell on .".'ive sublec",,s, '"he tables enclosed represent t@,,e cor,-.b.-'Lner-I data on all ten subjects* ,As @rou will note in Tabl-2'-' 3,, C-icra is no cloubt th,,,-t o*jr subjec4.,.s dcvelotled tolerance to LSD-25 (1-5 and after t.@iey tolerant to this drugs t.-toy exhatbited c4-ost- tole,--a-,ice -to rsLIoc@ybin (1'P'O wit'.i r2esdect to all r.eas@ares except possibly t:ie tc.-i-jerature-clevating effect of tlic-l la-'O,.ter druo. .%@-@n tie otie,- hand, tle evidenc@;; for develor,,--cn,&" of tolerance to @silocybin Is not so coi,-plate (altlioughly strongly s,.:r 2astive), and o several r,.-,c,,,sures (tei-,.-)era""ure, jo n 1. blo6d pressure and knee jerk), tic sublects re=-ained reactive .1 to LSD-25, aftizr c.ironi%-. atimin2istration of psilocybin for seven days. One possible reason for t.ie failure to demonstrate tolerance to psiloc,,rbin and cross-'6o.'Lerancc to LSD-2.-@ o.-i all -casures. is suo-estcd by t'.Iic data in T,,-ble I which lnd!cate thatp at least wit.-& resncct tb *.:-icir 2 on pupillary -%Ize and responses to qtt-cstio.-iraire, tlie doscs of LSD-25 and silocy-bin it,,e used tiere not cauloot4. @-,nt -- i.e.9 LSD-21@ r,4cg/,kc) proxj.,,iced grcatcr c.,.-fects than psilocybin 2 --/'"-g), a:-.cVorl period of c@irciiic adr-l.Li,.istration of ,Isilocybin i-.as too s.iort. Since the c-"-Iertion of tolaran,-e and cros-,t--tolcrance In regard to psilocysin -And Z'.SZ)-2' Is of considerable ticoretical sio.-Oif ,ac arc :>i- doing aziotlier study, wit.@i 2 la-ger @ioses of p@siloci,4.)In k'possibly u,:7 to 250 ;i:axirz."L laou.-) and lo,-iner of c!irciiic iiitoxicztion (1; days). 2 4 To do this In t:,;ie few riont.is I stilal rer,-.aining before my prospcct!vc sabbal;.cal y,-ar'ab@-oad.. t,,,e t-jill hav.-i to us-- ten new subjccts and I.-.eci-in t-l-ie s",,,tLciy wit,iln $'-,vjo at t."x,-. Also .6 %. ,It %;C .7 uN-- !-.,avc,. tha"L' i.,i to iii .h-"ve lea@'t of tl,"ic sunply of p.-biloc:ibin you so .'@@,-*nclily a f.,,w rontiis af-lo., ,.zra t-.,ou.'&d L:',,,; u:,an:; c;zrplet.lon of tl.it>, exper.1.1rent. 2 c;,rj(;rL74-@n" until we liave Ur,f c r Jt" i,.ra *@, El, 1I a,- 6 the cor-,plete psilocy',--in on @la.-id, sinca ae mu-,2t do so..m- prelir.--irarv of rctia:t-,,ie w , s I& L- 44 oursc-l,,.,,e.s to L, Ic,,nc; and ,k.erefore., '-de dzclsion or not A2, o iLi d,-- rLa.',.m tlie natt studv deze-,ids on t4lie possibility of your being able '6o send US @:0 E@OZ"S of PZT 4 a 6 %. C, C 4-1 w i 4@@2. r.Q .1 I C x -a ci v.-.. C !.I%- 3 I realize tizt tlile,, Os an eytraordlz,,ar,,,7 a,-.d that @mu 4 m@-Y 4-,Ot '.-iava til.at -,u'c.-i nsil--cytir. o.-4 h-and. be very c.-ateful if v u will let r@c 1,--w aa soon as possiblr,- uftat tlic prosoacts are, Wlt'.,i many Al'or ycur as3istance,, past rrd present., and 2 r-..,mrdc* Sincercly, ,i%ctino Dircct.-,r AW: biis Enclosures Table I Differences in Response to Coatrol Doses of LSD and Psilocybin D I FF.' R El,C L@:1 l@.1 RESPCNSR@- Te,.nperature 0.31 0.43 Pulse Rate +27-55 t 13-52 2 Blood Pressure +34.75 t 16-23 Punlhllary Size + 4..54 i Knee Jerk + 8.Lt,7 t 22-40 Responses on Questioanalre +39-25 1 12-30 Clinical C;rade + 0.35 i 0.25 Figures reprzsent mean differences t standard 2errors of the difi0erences betmeen means. of responses to tvro control doses of LSD-2;'@ (1-5 mcg/kg) and mean3 of responses to tv.,o control doses of Psilocybin (.150 mcg/kg). Notes* P < .02 p 0 1 Indicates LSD-25 stronger in effect than Ps1ilocybin indicates Psilocybin strong--r In effect than Lc-D-e'_5 Table 2 -25 1.5 mcg/kg of LSD Differences in Responses to Placebos of Psilocybin on first and secono controls* and i5o mcg/itg, D tl Uri r-i ir Plac2eb6 LSD-25 PsilocNibin Temperature + 0.98 -,0.63 +'-0.42--i o.64 1.24 i 0.5 Pulse Rate -11-53 i 13.30 selp-.62 18-40 .19.60 9.30 Blood Pressure - i.lo i 15-70 - 1.35 i 12-70 -25-40 11-60 Funillary Size - 0.29 :t .21.65 + O..5P- t 1-18 + o.io o.33 Knee Jerk W12-56 t 11.90 @14-83 t 21-75 4-17.BS i 18-70 Responses on Questionnaire + 0.90 i 1.31 + 0.60 t 6.10 + 4.90 9.65 Clinical Grad4 + 0.10 t 0.10 0-30 ± 0-20 + O.Po-t: o.41 Figures2 represent the mean differences t standard errors of the diffe@ences between measureme.-its on the first and second controls In 10 subjects' exce-ot th t for temperature None of the difference- a Change after psilocybiq were significant. Indicates that the average measurement was Increased on the second control, Indicates that it was decreased. 1 p .05 Table 3 Differences between Control Respon3e to LSD-25 and Psilocybin and Response after Chronic Administration of either Drug. After Psiloc, 2After LSD Chronically__ ybin Ciironicall)r LSD Psilocybin t Psilocybin LSD f-leasure cc) 'Direct" Tolernncel vcro--.--." Tolerance ,%erature 1.-93 0.79 1) - 1.85 t 0.61"* 1) - 1.87 t 0.1@7*"""* - o.5o -i o.59 2) - o.62 ± o.67 2) - o.63 I 0-it7 Pulse Rate t i6.6o -22,20 t 11.90a -47*70 -17-05 2 -33-05 Blood Pressure -79-60 1 -30-75 t 7.33 -33-55 1 10-15 .23-70@± 15-30 Pupillary Size -11-75 i 1. 6,,74"ti@ 5.77i 1.5r34p'@l@ 3-17 t 1.20* - 4.72 ± Knee Jerlt 23-55"-"@' .67-8t@ 16.97*."M -52.69 t 10-03*""' -41-79 . 19.5,a -71.16 Rcsponses on b Questionnaire -63.00 -21485 i 5.52 -16-95 i 7.69 .-57-10 19.20 Clinical Grad 0.3 1.235t 0,17 0.95 1 e - i.65 i 0.23-S 1.40 Oo32&@ 4" at 1. Indicates.differences obtained, using first contr6l values, 2, Indicates differences obtaineo. using second control values Figures represent the mean differe2nces ±standard errors between the average of the two controls (with the exception of I and 2 which were significantly-different) and the values found .@tien patient was tested with LSD.25 or psilocybin after receiving either drug clironically P .05 P >*05# < *10 P .02 1 b, t -. 2.20 P .01 (at t c 2.260 P o5)