-, -r
                                            -ATION. AR\ID V
                               eAL'rH, EP,'J(,
                                      PUBLIC HEALTH SEZ?VICE
                                      Lexington,, Kenfticky
        lt4 REtLYiP4G. ADDRESS TMIS
     Nl&eti Addiction Research Center-                 2        14 July 1934
               Cur experiments on tolerance to    LSD-25  @ave  been   proceeding
               well althouch I contilnue to be    sorewhaf surprised by the
               re@su I ts wh i@h to me ar,,, @@ie r,).o-, t amaz lnci demons t rat i,-)n of
               druc tolerance I  have  ever  seen.  l.have  had  7  pitienfs  who
               have n2ow-beer, fae    'the d           ore than 42 days.  One of
                                  ing       rUC  Tor  m
               t h c s e p ae n t s' r e c e 1 v e s I m c GM . / k c,.. d a 1 1 y , 4 r e c e 1 v e'o rr. c c -i
               daily, and 2 receive 2 mccm-7kc,. @ally.- All 7 are quit,-, fo.-leranll--
               to bof h f he phys lo l2og i ca I a nr-l men t a I ef fecf s of the drug.
               V,e have atterr"p' fed to bre a k f.@ rou-h t h is to I e r6n@ci b,/ a dmi n is@er-
               ing double,  i- r i p I e a nd' quad r-'(jo I e dos es .We have not yet obser@,,ed
               f-ill resfoi--5tior, of .*he LSD-effecf wit2h any of th@,se. dos,--s @,i h 1 f-- h
               in the case  of one of  fhe patients receivin-0 2 mc,,,n./kc,.  daily,
               ar,novnfed f,@, 532  -ccmo@  fo@at  dose. 1--ncreasinc the dos,-.  seems  @o
               res'lore the physiolcic-ical   effects fo-a  areafer  degree  t'iian  the
               Mental eft'zcfs) w,@icz are--, pr-e-s-enf in only mild dq.-,-ree and  %,ihich
               do not  persist  for  more  flian  one  or two    hours.     Discortinuafion
               of the dru   for tv.,o  days  in  one  patient  was  followed  by  almost
               complete  restoration  of   the   initial   effect,   2Adninistra@ion   oT'
               200 ma.  oT'  @he  metabolic  blocker., SKF-525.9  did   not   overcomef he
               tolerance.
               '%Ve have also bev.,n affempftrg to study "antidotes' for LS@D-25.
               Vj'e ha-;e dcne cuife a ntim,-er of experirlonfs in 4,hich 0.2     cf
                                                      c.)-ior to L'D. This    druc
               pc         I'al -,;as giver,
               appears to  det'inifely  alter  !be  L.')D rescf,ion, i:n.'I-haf  anxiety,
               n e r.v o v s n e s s .9 a n d i n s o.-n n i a a r e rn a r k - d I y - r e d v c e2 dHo v e rh
               r,ri.c,! paid is that of partial drun'-,,,ness  induced by     ba.-bi-
               ura le
               @-,'e have conolefed two ex-eriments with Corynanfhine.  The
                                      L
               pa t i e n t s us ed we r e ex I r er,-,e I y szns i t i v e s ub i -Lc t s who 2ca ve t,-r ad
                                                              i          I    -
               3 to 4 reactions to a 4C,-mc-.In. dose of LSD-25.    T h e y r e o T v e @,i

                              in a. randorr-ized             order'15 m-c. Corynanfhine folio-,ved by placebo;
                              placebo -fol lo,,ved by 40 rrcgm. LSD- Corynanfhine; 15 ma.                                                  
followed
                              by 40 mcgm. LSD.  'there @ies no evidence of any dimin6fion in
      2                        either the menta               I or p!iysioloc-ica               I effects of the L,SD.                      
Other
                              experimenfs  are  to  be-  done,-  u@inc  less  sensitive  subjects.
                                                                                                                                               
f
                              As yet we have no.f2 h.ad an opportunity to fry Banfh-ne.
                              -While in Washinaton recently,  I had a very inferestina visit
                              with Dr. Edward-'@:varts who is working with LSD and Bu@onfenine.
                              As  you  know,  he  @as  been  able  to  demonstrate  very  definite
                              effects of'bofh drucs,in dogs and monkeys.2                                           As a res v I f of f h i s q
                              .neurophysiolocical studies have been undertaken.  Th-ese include-.
                              the  effects  of  LSD  on  peripheral  nerves.  In  the  frog,   LSD
                      -.-,apparently ral,ses f.@c threshold but does not change height of
                              .the  action  pof'enfial  oncp  the  threshold  is  crossed.   Other
                              neurophys io log i ce I work is concerned w i f h t he e f f ec ts o it LSD
                              on the entire optical fracf., from the optic nerve all the way
                              back to the optical cortex.  t'Npparenfly some. kind of results
                              are beina obr@ined  bu'i- as Yef they ar2le -not                                                             
Other
                              s te t emen f s i nc 1 u-,'.,z or,,- illi a             i n hui-nan s vbje-- f s             LSD   cause@l
                              mar1l.ed slo,,qiiii of sit-le reacfion time  bu'.- had                                        little zffec-
                                   'licker fus           i o n  f r"equency
                              on   T
                              Dr.   Choiclen, a           t-,,l e e'r   c T' t h e N           s t.-a f.T' a -id w,@ o      is using LSD
                              in   !he  fr,7,almeni  of  psyct%or i-c-@-oat ienfs,  sou,
                                                                                                                  gh t  me  out  vil- 1 1 e   I
                              wa s   in  Bef.@esda              f-.e  h a s  a,-)o a r e n t I y  ob s c ry C,4          C d  47,1(,
                                                                                                                  2                   Io i:,
                              of   folora-n(@',-.  to       LSD  in       these  osycholic  oafien',Is.     Dzcau                              
of
                                                                                                                               Li        s e
                              the  develop.,nent            of  to2terance               he  alfern       dfes   LSD  and  mescaline.
                                                                                    .9
                              Fl@ es-fafes   there   is  no  --ross   folerance  to  these   two  drucs.
                                  recently  obfa            lned       a       small       supply       of       an       in@eresfina 
substance
           2                   i n. the  cannabino!  series  wfiich  appears   to  be  exfre,,,iel,@  p,:)'i-en,.
                              I  have  now  given             11     subjccfs     doses     of     I     to      2.5      mc.      of  11 h  i 
s
                              druc.       Ti-le   f i rs f    2  pa i i zn @s                   iy  i  den  f  i  T'  i  ed  @.1le  ef  
-1"ec@iz
                              as   be i -Ig   I ike  f hos e  o f  n@ a r i i,4v in3  an(-,',  na f u-a                      a I I  pa @ i,--n
'-s
              C',0            since  the  first  2  have  expected  riari@luana-                               1- i '<e  ef fects .
                              Pe. 4@,,ien f s  beg in  f,--  r,!ool- f               s ub je-@ @ i ve  e f fec f s  w i f h i ,-t       2     
to
                              4  ,hours         Effzcf.;  a,--)p@-,,3r   to              most  oronine.)@  6. to  8                 ho-.,rs
                      r       afi',Ar  the'     d r u      s  a 6,,2r, i n 1 s @ e r e r',  a -i ci:  a r a  s f I I I  p r e s -@ r,          
o
                              hours   laf-@     r. ; ai d   i i  s orn z  ca         s  c v c,-,   I o n     r
                                                                                                                    L,, c s -- r i
                              S u b JI c c  2v e  e f f e c t s   i s  v e r-v      a           c x cep       f- h @@,l
                                                                                                                   @.   the  sL.-bjec-s  are
                              very  pos it      i v e  f h z y  r e s e,.-b I      f   o s e -o f  ni a r i h u a n a .     ',r h Cy  s a y    
e
                              effects  of         I  rnc; .  a r e  e a, u a       o  o n e  o         wo  c i ca r e f t e s  c f             
e e s
                                                                         , I
                              marihu@-,na        ex--ep t f h a f r n z-y a rpea. r s I oNy I                 a T, d p,-. r s 1.3     T'O      
a

                     very  long-period of ti-ne.   They are described as consisting
                     of a s ers atior) of men t a I re I ax a f ion accompan  ied,  howe,.,ver  ,  by
                     physic,31't  tension,  increased appreciation of musi-.,  joke-:,
                     and of her tt, I nc-s    The  chara  c@er  Is  f  lc  behay  lor  observed  in
                     mari@uana'   smo(@rs   (gi-glina,    silliness)    has    not    been    seen
                     but the expeririental      situation   has   not   been   conducive    to    the
                     appearance of such behavior.   No hallucinations, perceptual
                     distortion, etc..,  have been-reported.
                     With  larger  doses   (2   to   2.5   ng.)   the   syrripfoms2   became   quite
                     unp I ea s an I.- in 6 of the II subjecis 6 to  8  hours  a  f  ter  admi  n  I  s-
                     fration.  'The unpleas.an@ syrnoloms  included dizziness,                 fee.tiric
                     of   great   weakness,   marked   dr@-;@sinessl    nausea    and    vorniting
                     Weak n es s has pers is fed for 48 to 72 hou2rs a f f er  admi  n  is  f  ra  f  ion
                     of-the   drug.   One   patient   fainted   on   coing    to    the    bathroom
                     the morning a'ffer having received a 2-m'. dose.
                     Neurolocical   examination   in   these   patients    so    far    has    been
                     negafiv@ with     'I he  dIoses  usea'.  However,   galf   cout-J   not    be
                     test2ed in  some  'Patieits  wh,o  becan,-@  so  -.,.,eat,,  they  relkuszd  to
                     get  6u@'  of   bed.   There   is   a.   very   definite   tend@-ncv'for   t@e
                     pulse  rate   to   becomi   raoi(-i and a tendency for the blood
                     pressure to fall.        The resul@s- su,:@g-es@ @lla@ sor.-,c2- cardlovasct.;Iar
                     disturbance, possibi,,l posfurci-I  hypol-en.-.ion, may  '
                                                                   .1                occii1r. I  hope
                     to                        in   @h-e           -@z  T'v fl v r e .Because   of   @'nz
                     app,-..3rance of tll-tise foxi- re-acfi-,)ns,    I  .5m not  olannina      to
                     increase the dose beyond 2.5 mg.,  in            the    irtimediate    fu@ure.
                     It  is  no feworthy   that   the   atien.ts    s'@iow    'lie    characteristic
                                                       p
                     marihuan2a  facies    3 whic.,i   consist   chiefly   of   marlp-led    conjunctival
                     reddening     and      pseudopfosis
                     I'  hopc,,  soon  to  have  some  information  on   Bufol'en'@.ne,   but   ha@-z
                     not carried    o v t a'n y e x :D e r i,.-n e n t s a s y e t
                                  6                     ')Incerely yours,,
                                                       Ha rr i s I s b e IIfv'iD
                                                       Direcfo.r of    Research
                        r n
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