differential tolerance to biological and subjective effects of four closely spaced doses of...

8/13/2019 Differential Tolerance to Biological and Subjective Effects of Four Closely Spaced Doses of N,N-Dimethyltryptamine in Humans

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D i f f e r e n t i a l T o l e r a n c e t o B i o l o g i c a l a n d S u b j e c t i v eE f f e c ts o f F o u r C l o s e l y S p a c e d D o s e s o fN N - D i m e t h y lt r y p ta m i n e in H u m a n sRic k J. Strassman Clifford R. Qu alls and Laura M . Berg

T ol erance t o t he behav i ora l e f f ec ts o f the shor t -ac t i ng , endo genous ha l l uc i nogen , N ,N-d i me t hy l t r yp t ami ne (D MT ) i s s een i ncons i s t en t ly i n an i mal s, an d has no t been pro duc ed i nhumans . T he na t ure and t i me course o f r e sponses t o r epe ti t ive , c l ose l y spaced a dmi n i s t ra t i onso f an ha l l uc i nogen i c dose o f DM T were charac t eri zed . T h i r t een exper i enced ha l l uc i nogenusers r ece i ved i n t ravenous 0 .3 mg/ kg D M T f umara t e , or sa l ine p l acebo , f ou r t i mes , a t 30 mi nintervals , on 2 separa te days , in a random ized, double-bl ind, des ign. Tolera nce to psyche -de l i c sub j ec t i ve e ff ec ts d i d no t occur accord i ng t o e i ther c l i n ica l i n te rv i ew or Hal l uc i nogenR at i ng Sca l e s cores . A drenoco r t i co t rop i c horm one (A CT H) , pro l ac t in , cor ti so l, a nd hea r t ra teresponses decreased w i t h repea t ed DM T admi n i s tra t i on , a l t hough b l o od pres sure d i d not .T hese da t a demons t ra t e t he un i que proper t i e s o f D M T re l a t ive t o o t her ha l luc i nogens andunderscore t he d i f fe ren t i a l r egu l a t ion o f t he mul t i p le processes med i a t i ng t he e f fec t s o f DMT .K e y W o r d s N,N-d i me t hy l t ryp t ami ne , ha l l uc i nogens , t o l e r ance , s e ro t on i n r ecep t o r s , s ch i zo-phren i a , d rug abuseBIOL PSYCHIATRY 199 6;39 :784 --795

I n t r o d u c t i o nH a l l u c i n o g e n s p r o d u c e a u n i q u e s y n d r o m e o f p s y c h o l o g -i ca l e f f ec t s i n humans . P e rcep t ua l , cogn i t i ve , and a f f ec t i veprocesses a r e o f t en p rofound l y a l t e r ed , w i t h t he ma i n t e -nance o f a r e l a ti ve l y c l ea r s ensor i um (F reed man 1968) .T h e n e u r o p h a r m a c o l o g y o f c l a s s ic h a l l u c in o g e n s l y s e r-g i c ac i d d i e t hy l ami de (L S D) , mesca l i ne , and ps i l ocyb i n ,

F r o m t h e D e p a r tm e n t s o f P s y c h ia t r y R J S , L M B ) a n d M e d i c i n e C R Q ) , S c h o o l o fMe d i c i n e , a n d t h e D e p a r t m e n t o f Ma t h e m a t i c s a n d B i o s t a t i s t i c s C R Q ) ,U n i v e r s i ty o f N e w M e x i c o , A l b u q u e r q u e , N M .

A d d re ss r e p r i n t r e q u e s t s t o R i c k J . S t r a ssm a n , M. D . , 1 7 8 3 R o c k l a n d A v e n u e ,V i c t o ri a , B C V 8 5 1 X 1 , C a n a d a .R e c e i v e d Se p t e m b e r 1 9 , 1 9 9 4 ; r e v i se d Fe b ru a ry 2 2 , 1 9 9 5 .

emphas i zes s e ro t on i n (5 -HT ) mechan i sms (Gl ennon e t a l1985).

T o l e r ance t o ha l l uc i nogens ' behav i ora l e f f ec t s , bywhi ch r educed r e sponses occur w i t h r epea t ed admi n i s t r a -t i on , i s s een i n humans ( I sbe l l e t a l 1956) and l oweran i ma l s (F reedm an e t a l 1958). C ross - t o l e r ance , by whi chdrugs o f d i spa ra t e s t r uc t u r e , bu t p r esumed s i mi l a r mech-an i sm of ac t i on , p roduce t o l e r ance t o each o t he r , a l sooccur s (Ba l es t r i e r i and F on t ana r i 1959 ; Appe l and F reed-man 1968) . T o l e r an ce t o t he e f f ec t s o f t he na t u r a l l yoccur r i ng , shor t - ac t i ng t r yp t ami ne ha l l uc i nogen , N ,N-d i me t hy l t ryp t am i ne (DM T ) i s d i f f i cu l t t o e l ic i t in an i ma l s(Kov ac i c and Dom i no 1976) , and was no t seen i n oneprev i ous human r epor t (G i l l i n e t a l 1976) . I n add i t i on ,

1 9 9 6 R . J . S t r a ssm a n e t a l . 0 0 0 6 -3 2 2 3 / 9 6S S D I 0 0 0 6 - 3 2 2 3 9 5 ) 0 0 2 0 0 - Z


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D M T T o l e r a n c e i n H u m a n s B IO L P SY C HIA T RY 7 8 51996;39:784 795

L S D - t o l e r a n t i n d i v i d u a l s s h o w e d u n d i m i n i s h e d r e s p o n s e sto D M T (R o sen b erg e t a l 1 9 6 4 ) .

W h e t h e r t o l e r a n c e t o D M T i n h u m a n s c a n b e d e m o n -s t r a t ed i s im p o r t an t fo r a t l ea s t tw o r easo n s . A l th o u g hto l e r an ce t o l o n g e r - ac t i n g h a l l u c in o g en s o ccu r s r ead i ly ,t h e t i m e c o u r s e o f t h i s t o l e r a n c e m a k e s c a r e f u l s t u d y o fth i s p ro cess u n w ie ld y . I f t o l e r an ce t o a sh o r t e r - ac t i n g d ru gs u c h a s D M T c o u l d b e d e m o n s t r a t e d , i t m i g h t b e p o s s i b l et o s t u d y t o l e r a n c e d e v e l o p m e n t t o s u b j e c t i v e a n d b i o l o g -i ca l e f f ec t s o f t h e r ep ea t ed ad m in i s t r a t i o n o f an h a l l u c in o -g en w i th in a d ay .

T h e i n a b i l i t y o f L S D t o p r o d u c e c r o s s - t o l e r a n c e t oD M T c h a l l e n g e s t h e a s s u m p t i o n t h a t a l l c l a s s i c h a l l u ci -n o g e n s p r o d u c e t h e i r e f f e c ts b y s i m i l a r m e c h a n i s m s , a n de m p h a s i z e s t he i m p o r t a n c e o f d et a i le d p s y c h o p h a r m a c o -l o g i c a l c h a r a c t e ri z a t i on o f i n d i v id u a l m e m b e r s o f t h is d r u gc l a s s . I f t o l e r a n c e t o D M T w e r e i m p o s s i b l e t o d e m o n -s t r a t e , t h e ag en t w o u ld n o l o n g e r w o u ld b e co n s id e red aty p i ca l h a l l u c in o g en .

e t h o d sSubjectsE x p e r i e n c e d h a l l u c i n o g e n u s e r s w e r e r e c r u i t e d a s d e -sc r ib ed p rev io u s ly (S t r a s sm an an d Q u a i l s 1 9 9 4 ) . W i t -n e s s e d w r i t t e n i n f o r m e d c o n s e n t w a s o b t a i n e d . A l l v o l u n -t ee r s w ere f r ee o f cu r r en t ax i s I d i so rd e r s , d e t e rm in ed b ya sem is t ru c tu red p sy ch ia t r i c i n t e rv i ew (S t ru c tu red C l in i ca lI n t e r v i e w f o r D i a g n o s t i c a n d S t a ti s ti c a l M a n u a l o f M e n t a lD i s o r d e r s , 3 r d e d . , r e v i s e d ( D S M - I I I R ) [ S C I D - R - O P ][S p i t ze r e t a l 1 9 8 7 ] ) , an d w ere m ed ica l l y h ea l t h y , d e t e r -m i n e d b y p h y s i c a l e x a m i n a t i o n a n d l a b o r a t o r y s c r e e n i n gt e s t s . N o n e w a s t a k i n g a n y m e d i c a t i o n s r e g u l a r l y . A g e sr a n g e d f r o m 2 2 t o 45 y e a r s ( m e a n 3 5 . 5 y e a r s ) . T h e r e w e r en i n e m e n a n d f o u r w o m e n . W o m e n w e r e s t u d i e d d u r i n gth e ea r ly fo l l i cu l a r p h ase o f t h e i r m en s t ru a l cy c l e .

S tu d i e s t o o k p l ace i n t h e i n p a t i en t u n i t o f t h e U n iv e r s i t yo f N e w M e x i c o H o s p i t a l ' s G e n e r a l C l i n i c a l R e s e a r c hC e n t e r ( G C R C ) . A l l s u b j e c t s r e c e i v e d n o n b l in d t e s t d o s e so f i n tr a v e n o u s ( I V ) 0 .0 5 a n d 0 . 4 m g / k g D M T f u m a r a t e o ns e p a r a t e d a y s , a s d e s c r i b e d p r e v i o u s l y ( S t r a s s m a n e t a l1 9 9 4 ) . I n t r a v e n o u s ( I V ) D M T f u m a r a t e w a s a d m i n i s t e r e do v e r 3 0 s t h r o u g h a n i n d w e l l i n g f o r e a r m v e n o u s c a t h e t e r ,an d th e IV l i n e w as f l u sh ed w i th s t e r i l e s a l i n e fo r anad d i t i o n a l 1 5 s . C a rd io v ascu l a r r e sp o n ses w ere a s ses sedf r e q u e n t l y , a n d t h e H a l l u c i n o g e n R a t i n g S c a l e ( H R S[S t r a s sm an e t a l 1 9 9 4 ] ) w as ad m in i s t e r ed a f t e r d ru g e f f ec t sh ad r e so lv ed . T h ree su b j ec t s w ere d ro p p ed in t h i s p h ase :o n e b e c a u s e o f a v a s o v a g a l r e a c t i o n t o 0 . 4 m g / k g D M T ,o n e b e c a u s e o f a h y p e r t e n s i v e r e s p o n s e t o 0 . 4 m g / k gD M T , a n d o n e b e c a u s e o f a d y s p h o r i c r e s p o n s e t o 0 . 0 5m g / k g D M T .

ilot StudiesI n o r d e r t o d e t e r m i n e d o s e a n d i n t e r v a l p a r a m e t e r s f o r t h et o l e r a n c e s t u d y , w e p e r f o r m e d p i l o t w o r k w i t h t h r e ev o lu n t ee r s . P rev io u s l i t e r a tu re r ep o r t ed t h a t fo u r (d a i l y )d o ses o f l o n g -ac t i n g h a l l u c in o g en s e l i c i t t o l e r an ce ( I sb e l le t a l 1 9 5 6 ) . T h e o n l y p u b l i s h e d h u m a n D M T t o l e r a n c ep r o t o c o l d e m o n s t r a t e d n o t o l e r a n c e d e v e l o p m e n t w i t htw ice d a i l y se s s io n s , s ep a ra t ed b y 5 h o u r s , f o r 5 co n sec -u t iv e d ay s (G i l l i n e t a l 1 97 6 ). H o w ev er , f i e ld r ep o r t ss u g g e s t a r e f r a c t o r y p e r i o d o f o n l y 1 5 - 3 0 r a in ( S t a ff o r d1 9 92 ) . S i n c e p l a s m a D M T l e v e l s a r e n e a rl y u n d e t e c t a b l e3 0 m i n a f te r I V a d m i n i st r a t io n o f p s y c h e d e l i c d o s e s o f0 . 2 o r 0 . 4 m g /k g (S t r a s sm an e t a l 1 9 9 4 ) , w e b e l i ev ed a3 0 - 6 0 m i n i n t e r v a l w a s a n a p p r o p r i a t e t a r g e t .

I n o r d e r t o a s s e s s t o l e r a bi l i ty o f r e p e a t e d d o s i n g o f I VD M T , a n d t o m a k e c e r t a i n n o s e n s i t i z a t i o n t o r e p e a t e dD M T d o s e s o c c u r r e d ( G i l l i n e t a l 1 9 7 3 ) , w e g a v e am in im a l d o se , 0 . 0 5 m g /k g , ev e ry h o u r , f o u r t im es . T h ein t e rv a l w as t h en sh o r t en ed to 3 0 m in 1 w e ek l a t e r . T h i sp ro cess w as r ep ea t ed w i th 0 . 1 , 0 . 2 , 0 . 3 , an d 0 . 4 m g /k gD M T . O n e v o l u n t e e r f o u n d 3 h o u r l y i n je c t i o n s o f 0 .4m g / k g I V D M T t o o t a xi n g , r e f u s in g t h e f o u r t h d o s e. T h u s ,0 . 3 m g /k g g iv en a t 3 0 m in i n t e rv a l s , f o u r t im es , w asc h o s e n a s o u r t o l e r a n c e r e g i m e n .

Tolerance StudyS u b j e c t s w e r e a d m i t t e d t o t h e G C R C i n t h e m o r n i n g ,h a v i n g b e e n f a s t i n g s i n c e m i d n i g h t . O n e a n g i o c a t h - s t y l ec a t h e t e r w a s p l a c e d i n a n a n t e c u b i t a l v e i n f o r b l o o dd raw in g an d k ep t o p en w i th a s t e r i l e s a l i n e d r ip . A n o th e rca th e t e r w as p l aced i n t h e o th e r a rm fo r i n fu s io n s . T h i sa n n a l s o h a d a n a u t o m a t i c b l o o d p r e s s u r e c u f f a p p l i e d toi t . A Y e l lo w -S p r in g s In s t ru m en t s (Y e l lo w S p r in g s , O H )Y S I - 4 0 0 r e u s a b l e f l e x i b l e t h e r m i s t o r p r o b e c o n f i g u r e d t o aV i t a - L o g P M S - 8 p h y s i o l o g i c a l m o n i t o r ( C S P , I n c . , P a l oA l to , C A ) w as i n se r t ed i n to t h e r ec tu m fo r co n t in u o u st e m p e r a t u r e r e c o r d i n g. A c c u r a c y w a s 0 . 0 3 C .

B l o o d s a m p l e s f o r A C T H , p r o l a c t i n , a n d c o r t i s o l w e r ed r a w n a t - 3 0 a n d - 1 m i n , a n d s a m p l e s f o r D M T w e r ed r a w n a t - 1 m i n . B l o o d p r e s s u r e a n d h e a r t r a t e m e a s u r e -m en t s , an d b lo o d sam p les , w ere o b t a in ed a t + 2 , 5 , 1 0 , 1 5 ,a n d 2 8 m i n . B l o o d w a s c o l l e c t e d f o r a s s a y o f A C T H ,p ro l ac t i n , an d D M T fo r a l l t h e t im e p o in t s . C o r t i so l w asd r a w n o n l y a t 2 8 m i n a f t e r e a c h i n f u s i o n ( 2 m i n b e f o r esu b seq u en t i n fu s io n s ) , t o a s ses s t h e d eg ree o f p re in j ec -t i on ( b a s e l i n e ) c o r t i s o l n e g a t i v e f e e d b a c k o n A C T Hresp o n se .

A l l s u b j e c t s w o r e b l a c k e y e s h a d e s t o r e d u c e a m b i e n tl i g h t , an d t o p ro v id e a m o re i n t ro sp ec t iv e ex p e r i en ce . W eh a v e f o u n d t h a t m a n y s u b j e c t s w i l l o v e r l o o k s u b t l e e f f e c t si f th e i r e y e s a r e o p e n a n d t h e y a r e l o o k i n g a b o u t t h e r o o m .A n a b b r e v i a t e d v e r s i o n o f t h e H R S , c o n t a i ni n g o n l y


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786 BIOL PSYCHIATRY R.J. Stras sma n et al1996;39:784 795

q u e s t i o n s t h a t s h o w e d s i g n i f i c a n t e f f e c t s o f D M T v s .p l a c e b o f r o m o u r i n i t i a l d o s e - r e s p o n s e s t u d y ( S t r a s s m a ne t a l 1 9 9 4 ) , w as g iv en a f t e r th e 1 5 m in b lo o d d raw . I f t im er e m a i n e d b e f o r e t h e n e x t i n f u si o n , d i s c u s s io n f o c u s s e d o nd esc r ip t i v e , r a th e r t h an p sy ch o th e rap eu t i c , t o p i c s . H o w -e v e r , t he r i g o r o u s n e s s o f t he r e p e a t e d D M T s e s s i o ns o f t e nr e q u i r e d p s y c h o l o g i c a l s u p p o r t a n d g u i d a n c e a s t h e m o r n -in g p ro g res sed .

T h e n e x t i n fu s i o n b e g a n a t a p p r o x i m a t e l y + 2 9 m i n1 5 s . T h u s , + 3 0 fo r t h e f i r s t s e s s io n w as eq u iv a l en t t o 0f o r th e s u b s e q u e n t s e s s io n . T h e a b o v e p r o c e s s w a s r e -p ea t ed fo r t h e seco n d , t h i rd , an d fo u r th se s s io n s , w i th t h ef in a l t im e p o in t fo r d a t a co l l ec t i o n b e in g + 3 0 , r a th e r t h an+ 2 8 , o f t h e fo u r th se s s io n .

A l th o u g h th e s tu d y w as d o u b le -b l i n d i n d es ig n , i t w asa p p a r e n t q u ic k l y w h e t h e r D M T o r s a l i ne w a s a d m i n i s t e re das t h e f i r s t i n j ec t i o n o f t h e f i r s t s t u d y d ay . O n c e t h i s w ases t ab l i sh ed , v o lu n t ee r s k n ew th a t th e d ay ' s o th e r i n j ec t i o n sw o u l d a l s o b e e i t h e r D M T o r s a l i n e . T h e y a l s o c o u l dassu m e w h a t t h e seco n d s tu d y d ay w o u ld en t a i l ( i . e . ,r e p e a t e d a d m i n i s tr a t i o n o f t h e o t h e r s t u d y d r u g ) ; h o w e v e r ,t h e y d i d n o t k n o w w h a t t o e x p e c t r e g a r d i n g t o l e r a n c ed e v e l o p m e n t .ssays

P l a s m a l e v e l s o f D M T , e x p r e s s e d a s t h e fr e e b a s e , w e r em e a s u r e d b y g a s c h r o m a t o g r a p h y - m a s s s p e c t r o m e t r y(W alk e r e t a l 1 9 7 9 ). L im i t o f d e t ec t ab i l i t y w as 1 n g /m L .P l a s m a A C T H w a s a s s a y e d b y i m m u n o r a d i o m e t ri c a s s a y( N i c h o l s D i a g n o s t i c L a b o r a t o r i e s , S a n J u a n C a p i s t r a n o ,C A ) ; l o w e r l i m i t o f d e t e c ta b i l i ty w a s 0 . 2 p m o l / L . L i m i t s o fd e t e c t a b il i t y f o r c o r t is o l a n d p r o l a c t in r a d i o i m m u n o a s s a y s( D i a g n o s t i c P r o d u c t s , L o s A n g e l e s , C A ) w e r e 6 n m o l / La n d 1 D xg /L r e s p e c t i v e l y. D M T a s s a y s w e r e p e r f o r m e d i nt r i p l i ca t e , an d a l l o th e r s w ere p e r fo rm ed in d u p l i ca t e .StatisticsA l l a n a l y s e s w e r e p e r f o r m e d u s i n g S t a t is t ic a l A n a l y s i sS y s t e m f o r t he p e r s o n a l c o m p u t e r ( P C - S A S ) , v e r s i o n 6 . 04( C a r y , N C ) . V a l u e s a r e g i v e n a s m e a n s ( S E M ) . p V a l u e s< 0 . 0 5 a r e co n s id e red s ig n i fi can t .

O u r p r i m a r y s t a t i s t i c a l a n a l y s i s w a s a r e p e a t e d - m e a -s u r e s a n a l y si s o f v a r ia n c e ( A N O V A ) , w i t h r e p e a t e d f a c t o rsession ( fo u r o ccu r r in g i n o n e m o rn in g ) , an d a g ro u p in gf a c t o r dose ( p l a c e b o o r D M T ) . D e p e n d e n t v a r i a b l e s w e r es e v e r a l d e r i v e d v a l u e s f o r b l o o d c o n c e n t r a ti o n s o f p r o l a c -t i n , A C T H , a n d D M T ; h e a r t r a t e ( H R ) a n d m e a n a r t e r i a lp r e s s u r e ( M A P ) ; a n d r e c t a l t e m p e r a t u r e . T h e d e r i v e dv a r i a b l e s w e r e b a s e l i n e , A M a x , a n d A a r e a u n d e r t he c u r v e( A U C ) .

B a s e l i n e v a l u e s fo r t he f i rs t s e ss i o n w e r e m e a n s o f - 3 0a n d - 1 m i n v a l u e s f o r a ll b u t th e t e m p e r a t u r e d a t a,

a l t h o u g h t h e m e a n v a lu e s f o r - 5 t o - 1 m i n p o i n t s w a su s e d f o r t e m p e r a t u r e . F o r s u b s e q u e n t s e s s i o n s ( 2 - 4 ) ,

b a s e l i n e v a l u e s f o r M A P , H R , a n d b l o o d l e v e l s w e r et h o s e o b t a i n e d a t + 2 8 m i n , 2 m i n b e f o r e t h e n e x t i n f us i o n .F o r t e m p e r a t u r e , t h e b a s e l i n e s f o r s e s s i o n s 2 - 4 w e r e t h em e a n s f o r t he i m m e d i a t e l y p r e c e d i n g 5 m i n ( + 2 6 t o + 3 0 ) .A M a x w a s t h e m a x i m u m r e s p o n s e a b o v e b a s e li n e f o r e a chs e s s i o n . A A U C w a s t h e a r e a u n d e r t h e r e s p o n s e c u r v ea b o v e b a s e l i n e f o r e a c h s e s s i o n , c a l c u l a t e d b y t h e t r a p e -zo id a l ru l e .

F o r t h e H R S , m e a n s c o r e s f o r p r e v i o u s l y d e s c ri b e dc l in i ca l c lu s t e r s w ere ca l cu l a t ed (S t r a s sm an e t a l 19 9 4 ) .

T h e s e w e r e s o m e s t h e s i a ( v i s c e r a l / i n t e r o c e p t i v e , s o m a t i csen sa t i o n s ) , co g n i t i o n ( t h o u g h t p ro cesses an d co n ten t ) ,a f f ec t , p e rcep t io n , v o l i t i o n ( ab i l i t y t o i n t e r ac t w i l l fu l l yw i t h o n e ' s m e n t a l a n d p h y s i c a l s e l f , a n d o n e ' s e n v i r o n -m e n t ) , a n d i n t e n s i t y ( a g lo b a l a s s e s s m e n t o f r o b u s t n e ss o fe f f e c t ) . H R S s c o r e s a l s o w e r e a n a l y z e d b y r e p e a t e dm e a s u r e s A N O V A , w i t h r e p e a t e d f a c t o r s e s s i o n , a n dg ro u p in g f ac to r d o se .

T h e d o s e f a c t o r c o u l d h a v e b e e n t r e a t e d a s a r e p e a t e dfac to r . H o w ev er , o u r an a ly s i s i n d i ca t ed t h a t ad ju s t i n g fo rs e s s i o n f ir s t i n d uc e d i n d e p e n d e n c e b e t w e e n d o s e s .

W e d e f in e d t o l e r a n c e u s i n g e i t h e r o f t w o m e t h o d s .F i rs t , w h e n t h e A N O V A d e m o n s t r a t e d s i g n i f ic a n t D M T o rp l a c e b o e f f e c t s , w e p e r f o r m e d p o s t h o c c o m p a r i s o n s u s i n gp a i r e d t t e s t s . W e c o m p a r e d r e s p o n s e s f o r t h e f i r s t D M T(D ) v s . p l aceb o (P ) i n fu s io n s (P 1 D 1 ) an d fo r fo u r th D M Tv s . p l a c e b o r e s p o n s e s PnD4). I f P 1 D 1 d e m o n s t r a t e d as ig n i f i can t d i f f e r en ce , b u t P4D4 d i d n o t, t o l e r a n c e m a y b es a i d t o h a v e o c c u r r e d, s i n c e d r u g a n d p l a c e b o r e s p o n s e s n olo n g e r d i f f e r ed b y t h e l a s t s e s s io n .

S e c o n d , w e a l s o c o m p a r e d c h a n g e s i n r e s p o n s e s f r o msess io n 1 t o 4 fo r d ru g (D A D 1 ) an d p l ac eb o (P 4 P 1) . A n o th e rin d i ca t i o n o f t o l e r an ce i s i f r e sp o n se s d ec re ased s ig n i f -i can t ly b y se s s io n fo r e i t h e r d ru g o r p l aceb o . T h i s i s a l e s sro b u s t i n d i ca t i o n , h o w ev er , i f D4P4 w e r e s t i l l s ign i f ican t lyd i f f e r e nt ( i .e ., r e s p o n s e s t o D M T d e c r e a s e d o v e r t i m e b u tn e v e r r e a c h e d p l a c e b o v a l u e s ) .

e su l t sT h e m o s t i m p o r t a n t f i n d i n g s o f t h i s s t u d y w e r e t h a tt o l e r a n c e t o t h e s u b j e c t i v e e f f e c t s o f f o u r c l o s e l y s p a c e di n j e c ti o n s o f I V D M T f u m a r a t e , a s s e s s e d b y c l i n ic a li n t e r v i e w , a n d q u a n t i f i e d b y H a l l u c i n o g e n R a t i n g S c a l e( H R S ) s u b s c o r e s , d i d n o t o c c u r ; A C T H a n d p r o l a c t i nb l o o d l e v e l a n d h e a r t r a t e r e s p o n s e s s h o w e d t o l e r a n c e , b u tm e a n a r t e r ia l B P r e s p o n s e s d i d n o t; a n d p e a k D M T l e v e l sd i f f e r ed s ig n i f i can t ly ac ro ss s e s s io n s ; h o w ev er , l ev e l sw e r e v e r y l o w b e f o r e , a n d d i d n o t d i f f e r a m o n g , s e s s i o n s .


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T i m e r a i nFigure 1. Mean D MT free base levels in 13 volunteers after fourdoses of 0 .3 mg/kg intravenous DM T fumarate, administered at30 rain intervals. The number after DM T corresponds to thesession (e.g ., DM T 2 refers to the second DMT injection).T ime 0 values fo r sessions 2 -4 are +28 m in values fo rsessions 1-3, respectively.D M T B l o o d L e v e l sT h e r e w a s n o m e a s u r a b l e D M T b e f o r e a n y f i r s t s e s s i o n( D M T o r p l a c e b o d a y s ) , n o r a t 2 m i n a f t e r a n y f i r s tp l ace b o ses s io n . T h u s , o u r a s say e l i c i ted n o f a l se -p o s i -t i v e r ead in g s .

D M T A m a x v a lu e s d i ff e r e d a c r o ss s e s s i on s ( F = 4 . 76 ;p = 0 . 0 0 7 ) , r an g in g f ro m 4 4 . 5 (5 .7 ) n g /m L ( ses s io n 2 ) t o6 2 . 5 (6 . 6 ) n g /m L ( ses s io n 4 ) . I n ad d i t i o n , A A U C v a lu esd i f f e r ed s ig n i f i can t ly b y se s s io n (F = 4 . 4 0 ; p = 0 . 0 1 ) .R e s i d u a l D M T l e v e l s b e f o r e s e s s i o n s 2 - 4 , h o w e v e r , d i dn o t d i f f e r f ro m each o th e r (F = 0 . 5 8 ; p = 0 . 5 7 ). F ig u re 1p resen t s t h ese d a t a g rap h ica l l y .

S u b j e c t i v e E f f e c t sC L IN ICA L IN T ER V IEW S . 0 . 3 m g /k g I V D M T p r o d u ce d

a t y p i c a l s p e c t r u m o f p s y c h e d e l i c e f f e c ts . E f f e c t s d e v e l -o p e d b e f o r e t h e s a l in e f l u s h w a s c o m p l e t e d , p e a k e d a t 1 - 2m i n , a n d w e r e w e l l r e s o l v e d b y 2 8 m i n . R e s i d u a l i n t o x i -c a t i o n a t + 1 5 m i n w a s n o t s u f f i c i e n t t o p r e v e n t a n ys u b j e c t f r o m c o m p l e t i n g t h e H R S , a l t h o u g h m a n y v o l u n -t ee r s f e l t t i r ed an d a l t e r ed b e fo re t h e t h i rd an d fo u r thd o s e s o f D M T .

D M T e f f e c t s in c l u d e d t h e n e a r ly i n s t a n t a n e o us o n s e t o fa p h y s i ca l / so m at i c ru sh , b eg in n in g in t h e h ead , w h ich

q u ick ly led t o a d i s so c i a t ed s ta t e . V o lu n tee r s b rac ed fo rt h e e f f e c t s o f 0 .4 m g / k g D M T , w h i c h a l l h a d r e c e i v e db e f o r e , a l th o u g h o n l y t w o h a d r e c e i v e d 0 . 3 m g / k g i n p il o tw o r k . S u b s e q u e n t s e s s i o n s w e r e e x p e r i e n c e d w i t h l e s santicipatory a n x i e t y , a l t h o u g h e m o t i o n a l r e s p o n s e s t oc o n s e c u t i v e D M T s e s s i o n s w e r e s i m i l a r .A n a b s t r a c t , g e o m e t r i c , r a p i d l y m o v i n g , i n t e n s e l y c o l -o r e d , k a l e i d o s c o p i c d i s p l a y o f v i s u a l e f f e c t s f o l l o w e d t h e

r u s h , a n d w o u l d o f t e n l e a d to t h e p e r c e i v in g o f m o r erep resen t a t i o n a l im ag es , su ch a s p eo p le , c r ea tu res , an dc o m p l e x s c e n e s . A u d i t o r y e f f e c t s w e r e l e s s c o m m o n a n dw ere r e l a t i v e ly i n d is t i n c t so u n d s r a th e r t h an sp o k en w o rd s .T r a n s i e n t a n x i e t y a c c o m p a n i e d t h e o n s e t o f e f f e c t s , a n dch an g ed to e l a t i o n an d eu p h o r i a i n m o s t su b j ec t s . T h e f ea ro f l o s in g co n t ro l l e s sen ed th ro u g h o u t t h e m o rn in g , w h ichi s r e f l ec t ed i n t h e v o l i t i o n sco re o n t h e H R S , b e lo w .C o g n i t i o n w a s r e l a t i v e l y u n im p a i r e d , a l t h o u g h m o s t s p o k eo f a h e i g h t e n i ng o f e v a l u a t i v e p r o c e s s e s , o r f a s t e r a n d

c l ea re r t h in k in g .O n t h e s a l i n e p l a c e b o t r e a t m e n t d a y , a l l v o l u n t e e r s

ex p e r i e n ced a ru sh o f v a ry in g i n t en s i t y a s t h e f i r s td o s e w a s a d m i n i s t e r e d. O n c e i t b e c a m e c l e a r th a t n o D M Tw a s t o b e a d m i n i s t e r e d t h a t m o r n i n g , s u b j e c t s ' r e -s p o n s e s t o p l a c e b o w e r e n e g l i g i b l e f o r t he r e m a i n i n g t h r e eses s io n s .

H A L LU C IN O G E N R A T I N G S C A L E . M e a n H R S c l u s t e rs c o r e s a l l s h o w e d a r o b u s t e f f e c t o f 0 .3 m g / k g D M Tre la t i v e t o p l aceb o , co n s i s t en t w i th o u r p rev io u s d a t ad e m o n s t r a t i n g p s y c h e d e l i c e f f e c t s a t d o s a g e s o f 0 . 2m g /k g an d h ig h e r (S t r a s sm an e t a l 1 9 9 4 ) . D esp i t e i so l a t edses s io n e f f ec t s , i n sp ec t io n o f t h e m ean s (T ab le 1 , F ig . 1 )r e v e a l s l i t t l e i f a n y r e d u c t i o n o f D M T e f f e c t s a c r o s ss e s s i o n s . T h e H R S c l u s t e r d e m o n s t r a t i n g t h e g r e a t e s td e c r e a s e a c r o s s D M T s e s s i o n s w a s voli t ion a l th o u g h ad i r e c t c o m p a r i s o n o f D 4 D l r e v e a l e d o n l y a t r e n d ( p - -0 . 0 6 ) t o w ard s ig n i f i can ce . T h ese q u es t i o n s w ere r e l a t ed t oth e fo l l o w in g e f f ec t s : ch an g e in e f fo r t t o b rea th e ; ab i l -i t y t o f o l l o w s e q u e n c e o f e v e n t s ; a b i l i ty to ' l e t g o ' ;

ab i l i t y t o fo cu s a t t en t i o n ; f ee l i n g i n co n t ro l ; an da b i l i ty t o m o v e a r o u n d i f a s k e d t o . E v e r y volition

q u e s t i on d e m o n s t r a t e d t h e s a m e p a t t e r n o f d e c r e a s in gr e s p o n s e s c o r e s a c r o s s D M T s e s s i o n s .

Somaesthesia o r i n t e ro cep t iv e /v i sce ra l / so m at i c e f f ec t s ,sh o w ed a s l i g h t d ec rease ac ro ss s e s s io n s fo r b o th d ru g an dp laceb o co n d i t i o n s , a l t h o u g h s ig n i f i can t r ed u c t io n s w eren o t s een i n i n d iv id u a l co m p ar i so n s (n e i t h e r D 4 D 1 n o rPAP1 .O f i n t e r e s t w a s t h e e f f e c t o f p l a c e b o o n affect sco res .A l th o u g h a s ig n i f i can t P 4 P 1 r ed u c t io n i s s een ac ro ssp l ace b o ses s io n s , t h e e f f ec t p r im a r i l y i s d u e t o ch an g es i ns c o r e s b e t w e e n Px an d P2, su g g es t i n g a r ed u c t io n i nan x ie ty , o r s en se o f r e l i e f , a s i t b ecam e c l ea r t h a t t h e d ay


5/12

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D M T T o l e r a n c e i n H u m a n s B IO L P SY C HIA T RY 7 8 91996;39:784 795

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S e s s i o n n u m b e rFigure 2. Mea n HRS score s in 13 volunteers after four injectionsof 0 .3 mg/kg intravenous DMT fumarate or four injections ofsaline placebo, administered at 30 min intervals.w o u ld i n v o lv e o n ly r ep ea t ed p l aceb o in j ec t i o n s . F ig u re 2an d T ab le 1 d i sp l ay t h ese d a t a .

D M T o r p l a c e b o . C o r t i s o l b l o o d l e v e l s t a k e n a t 2 8 m i na f t e r each i n j ec t i o n ( i . e . , baseline a n d n o t m a x i m u mr e s p o n s e v a l u e s b e f o r e e a c h D M T i n j e c t i o n ) f o l l o w e dd i f f e re n t p a tt e r n s f o r D M T a n d p l a c e b o , a n d s h o w e d d o s ea n d s e s s i o n e f f e c ts , w h e t h e r o r n o t t h e 2 8 m i n s a m p l e f r o mt h e f o u r t h s e s s i o n w a s i n c l u d e d i n t h e A N O V A . L e v e l sro se s ig n i f i can t ly i n t h e D M T co n d i t i o n , an d th en r e tu rn edto i n i t i a l b ase l i n e v a lu es a f t e r t h e fo u r th i n j ec t i o n . In t h ep l aceb o co n d i t i o n , t h ey f e l l g r ad u a l ly an d s ig n i f i can t lya f t e r ev e ry se s s io n .

P R O L AC T IN , T ab le 1 an d F ig u re 5 d e m o n s t r a t e t h eg r a d u a l d e c r e a s e o f v a l u e s f o r p l a c e b o a c r o s s s e s s i o n( P 4 P I ) , a n d v a l u e s a f t e r D M T s e s s i o n s w e r e u n c h a n g e d(D 4D 1 ). T h u s , a l t h o u g h in i t i a l b ase l i n e v a lu es w ere s im i l a r(P ID I ) , b y se s s io n fo u r , t h ey d i f f e r ed s ig n i f i can t ly (P4 D 4 ).A s f o r A C T H , b a s e l i n e a d j us t m e n t s ( i .e ., c a l c u la t i o n o f Av a lu es ) a r e r e l ev an t fo r p ro l ac t i n r e sp o n se s .

A M a x a n d A A U C p r o l a c t i n v a lu e s f o r D M T f e l l s ig n i f-i can t ly o v e r s e s s io n (D 4 D 1 ) , su g g es t i n g so m e d eg ree o ft o l e ra n c e , a l t h o u g h p l a c e b o r e s p o n s e s w e r e s i m i l a r a c r o s s

Neuroendocrine Ef fec tsA C T H . T h e se d a t a a r e d i sp l ay ed in T ab le 1 an d g rap h -

i ca l l y i n F ig u re 3 . B ase l i n e v a lu es sh o w ed s ig n i f i can t d o sean d ses s io n e f f ec t s . F o r s e s s io n 1 , b ase l i n e v a lu es d id n o td i f f e r (P ID 1 ) , b u t d id so b y se s s io n 4 PnD4). B a s e l i n ev a l u e s f o r t h e D M T t r e a t m e n t r e m a i n e d s t a b l e o v e r s e s -s io n (D 4 D 1) , y e t t h o se fo r p l a ceb o f e l l s i g n i f i can t ly (P4 P l) -S in ce t h e re w ere s ig n i f i can t b ase l i n e e f f ec t s , b u t n oap p aren t ce i l i n g e f f ec t s , t h e ad ju s tm en t fo r b ase l i n e d i f -f e r en ces h e re i s j u s t i f i ed .

A M a x a n d 2 ~A U C A C T H d e m o n s t r a t e d s i g n i f i c a nt d o s ean d ses s io n e f f ec t s . P l aceb o r e sp o n ses w ere n o t s i g n i f i -can t ly d i f f e r en t ac ro s s s e s s io n s (P A P 1) . F o r A m ax an dA A U C , D M T - i n d u c e d r e s p o n s e s w e r e i n i t i a l l y s i g n i f i -c a n t l y g r e a t e r t h a n p l a c e b o ( D i P l ) , a n d d e c r e a s e d a c r o s sses s io n (D 4 D 1 ) . A M ax v a lu es r em a in ed s ig n i f i can t lyg r e a t e r t h a n p l a c e b o b y s e s s i o n 4 PAD4), b u t w e r e n o ts i g n i fi c a n t ly d i f f e r e n t f o r A A U C . T h u s , t o l e r a n c e a p p e a r sm o r e r o b u s t us i n g A A U C f o r A C T H .

O f n o t e i s th e a p p a r e n t c o n d i ti o n e d r e s p o n s e o f A C T Haf t e r t h e f ir s t p l aceb o d o se , s im i l a r t o th a t s een i n r e sp o n set o p l a c e b o i n o u r i ni ti a l d o s e - r e s p o n s e s t u d y ( S t r a s s m a n e ta l 1 9 9 4 ) . A l th o u g h D 4 a n d P I w e r e n o t c o m p a r e d d i r e c tl yh e re , r e sp o n se p a t t e rn s see n i n F ig u re 3 su g g es t t h a t b y t h ef o u r th d o s e o f D M T , t h e d e v e l o p m e n t o f t o le r a n c e h a dr e d u c e d A C T H r e s p o n s e s n e a r l y t o t he l e v e l o f t h eco n d i t i o n ed r e sp o n se t o i n i t i a l p l aceb o ad m in i s t r a t i o n .

CORTISOL. As can be seen in F igu re 4 , co r t i so l base -l i n e v a lu es d id n o t d i f f e r b e fo re t h e f i r s t d o se o f e i t h e r

CP lac l --Plac2 -~-Plac3 -D-Plac42 ~ D M T 1 D M T 2 ~ D M T 3 D M T 4

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o 1 I I P I I0 5 10 15 20 25 30

Time rainFigure 3. Mean A CTH plas ma values in 13 volunteers after fourinjections of 0 .3 mg/kg intravenous DMT fumarate or fourinjections of saline placebo, administered at 30 min intervals.Plac, saline placebo; number after Plac or DMT corresponds tothe sessions. Time 0 values for sessions 2-4 are +2 8 minvalues for sessions 1-3, respectively.


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790 BIOL PSYCHIATRY R.J. St ras sm an et al1996;39:784 795

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Time rainFigure 4. Mean cortisol plasma values in 13 volunteers after fourinjections of 0.3 mg/kg intravenous DMT fumarate or fourinjections of saline placebo, administered at 30 min intervals.

session (P4P1). However, values by the fourth session stilldiffered by treatment P4D4).

a r d i o v a s c u l a r E f f e c t sHEART RATE. Figure 6 and Table 1 demonstrat e that

baseline HR values were significantly different for DMTand placebo conditions. Before the first session, there wasno effect of dose; however, as the sessions progressed,there was a gradual increase of baseline values for DMTand a decrease for placebo.

In a repeated measures ANOVA, Amax HR demon-strated significant dose and session effects. Placebo re-sponse values were unchanged across session (P4PI).DMT response values decreased significantly across ses-sion (D4D1), and did not differ from placebo values by thefourth session (D4P4). It is, however, apparent in Figure 6that D 1is the only curve that differs, and this could be dueto anxiety when the subjects realize that they are receivingDMT for the first time, and experience some fear withrespect to the intensity of drug effect. This anxiety-producing factor would be gone in subsequent sessions,and the reduction in HR after that may have little to dowith tolerance.

There were no significant drug or session effects onAAUC HR.

MEAN ARTERIAL PRESSURE. Figure 7 and Table 1demonstrate no dose or session effects on baseline MAP.AMax and AAUC MAP responses differed by dose but notby session. The responses were essentially parallel acrosssessions, with DMT responses being consistently higherthan those of placebo. Responses for the fourth DMTsession did not differ significantly from the first (DAD1),suggesting no tolerance to MAP responses.

TEMPERATURE. Interpretation of these data is con-founded by the slow time course for this response to DMT.Our previous study demonstrated that temperature did notbegin to rise until 15 min after administration of either 0.2or 0.4 mg/kg DMT, and had not begun falling by 60 minpostinjection (Strassman et al 1994). Thus, the current dataare more likely due to cumulative effects of repeated DMTadministration (Fig. 8, Table 1). It is clear that baselineand physiolog ically mandated ceiling effects (e.g., sweat-ing) must be taken into consideration.

12

10

,-,1n 8I1

6

O P l a c 1 - P l a c 2 b P l a c 3 - o -P l a c4e D M T 1 + D M T 2 ~ D M T 3 -= -D M T 4

4 I I I I t I0 5 10 15 20 25 30

Time minFigure 5. Mean prolactin plasma values in 13 volunteers afterfour injections of 0.3 mg/kg intravenous DMT fumarate or fourinjections of saline placebo, administered at 30 min intervals.Refer to Figure 3 for an explanation of the legend. Time 0values for sessions 2-4 are +28 min values for sessions 1-3,respectively.


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100

90

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~ P la c l --Plac2 -~-Plac3 ~3 Pla4O 'D M T 1 + D M T 2 ~ - D M T 3 - =- D M T4

s t 1 I [ t [ 10 5 1 0 1 5 2 0 2 5 30

T ime rainFigure 6. Mea n heart rate (beats per minute [BPM ]) values in 13volunteers after four injections of 0 .3 mg/kg intravenous DMTfumarate or four injections of saline placebo, administered at 30min intervals. Refer to Figure 3 fo r an explanation of the legend.T ime 0 values fo r sessions 2 -4 are +28 m in values fo rsessions 1-3, respectively.

B ase l i n e v a lu es ro se fo r d ru g t r ea tm en t (D 4 D 1 ) an dr e m a i n e d s t a b l e f o r p l a c e b o ( P 4P 1) . T h e A m a x a n d A A U Cv a lu es , t h e re fo re , w ere sm a l l e r t h an b ase l i n e v a lu ec h a n g e s a n d t h e A N O V A r e s u l ts a r e o f q u e s ti o n a b l e v a l u e .I n a d d i t i o n , b e c a u s e o f m i s s i n g v a l u e s , a n o n r e p e a t e dm e a s u r e s A N O V A w a s u s e d , a n d re s u l ts o f th e s e a n a l y s e sa re n o t s t r i c t l y co m p arab l e t o t h o se o f t h e o th e r v a r i ab l e s .

i s c u s s i o nF o u r c l o s e l y s p a c e d h a l l u c in o g e n i c d o s e s o f N , N - d i m e t h -y l t r y p t a m i n e ( D M T ) f u m a r a t e d i d n o t p r o d u c e t o l e ra n c e t op s y c h o l o g i c a l e f f e c t s o f t h is s h o r t - a c t i n g c o m p o u n d . N e u -r o e n d o c r i n e e f f e c t s a n d h e a r t r a t e r e s p o n s e s d i m i n i s h e d t ov a ry in g d eg rees w i th r ep ea t ed d o s in g , su g g es t i n g t o l e r -a n c e d e v e l o p m e n t . B l o o d p r e s s u r e e f f e c t s w e r e u n -c h a n g e d , a n d t e m p e r a t u r e d a t a w e r e u n i n t e r p r e t a b l e b e -c a u s e o f t h e ir s l o w r e s p o n s e t i m e . W e i n t e r p r e t t h e se d a t aa s s u p p o r t i n g t h e u n i q u e p h a r m a c o l o g i c a l p r o p e r t i e s o fD M T r e la t i v e t o o t h e r c l a s s i c h a l l uc i n o g e n s , a n d t h ed i f f er e n t i al r e g u l a t i o n o f m e c h a n i s m s m e d i a t i n g s u b j e c -t i v e a n d b i o l o g ic a l r e s p o n s e s t o D M T .

Unique Properties of DMT Relative to OtherClassic CompoundsT o l e r a n c e h a s b e e n d e m o n s t r a t e d f o r n e u r o p h a r m a c o l o g -i c a l ( M c K e n n a e t a l 1 9 8 9) , e l e c t r o e n c e p h a l o g r a p h i c(W al l ach e t a l 1 9 7 2 ) , an d w h o le an im a l b eh av io ra l (F reed -m a n e t a l 1 9 5 8 ) a s s a y s o f h a ll u c i n o g e n e f f e c t s . H o w e v e r ,D M T e f f e c t s a r e n o t ty p i c a l in t h i s r e g a r d ( C o l e a n d P i e p e r1 9 73 ) , p r o b a b l y d u e t o D M T ' s u n i q u e p h a r m a c o d y n a m i cp ro p e r t i e s .

C u r r e n t r e s e a r c h i m p l i c a t e s t h e 5 - H T 2 r e c e p t o r f a m i l yi n m e d i a t i n g b e h a v i o r a l r e s p o n s e s t o h a l l u c i n o g e n s i nlo w er an im a l s (G len n o n e t a l 1 9 8 5 ; T i t e l e r e t a l 1 9 8 8 ) .D o w n r e g u l a t i o n o f th e 5 - H T 2 r e c e p t o r o c c u r s w i t h in 2 - 3d a y s a f t e r t r e a t m e n t w i t h p h e n e t h y l a m i n e h a l l u c i n o g e n s(L ey sen e t a l 1 9 8 9 ; M cK en n a e t a l 1 98 9 ) , in a t im e d o m ainc o m p a r a b l e t o h u m a n s t u d i e s d e m o n s t r a t i n g t o l e r a n c e t oh a l lu c in o g en s .

E v e n m o r e r a p i d c h a n g e s o c c u r w i t h s h o r t - t e r m e x p o -su re t o n o n h a l lu c in o g en ic ag o n i s t s , s im i l a r t o t h e t im ep a r a m e t e r s o f t h i s s t u d y ( T r u l s o n a n d K e l t c h 1 9 8 5 ; A n -d o rn 1 9 8 6 ) . H a l lu c in o g en s , v i a 5 -H T 2 s i t e s (C o n n an d

125

115

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-o-Ptac l ~-Pla c2 ~ 'Plac3 c-Plat4~ 'D M T 1 D M T 2 * D M T 3 - D M T 4

I J I I I I5 10 15 20 25 3O

Time, rainFigure 7. Mean arterial blood pressure (MAP, in mm Hg ) valuesin 13 volunteers after four injections of 0.3 mg/kg intravenousDM T fumarate o r four injections o f saline placebo, administeredat 30 rain intervals. Refer to Figure 3 for an explanation of thelegend. Tim e 0 values for sessions 2-4 are +28 m in values forsessions 1-3, respectively.


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37.7

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~ 3 - P l ac l - ~ P [ a c 2 - ~ ' P l a c 3 - ~ P l a c 4- e- DMT 1 + DMT 2 i - DMT 3 - - DMT 4

i t L l f f0 5 1 0 1 5 2 0 2 5 3 0

Time minFigure 8. Mean core (rectal) temperature values in 13 volunteersafter four injections o f 0 .3 m g/kg intravenous D MT fum arate orfour injections of saline placebo, administered at 30 min inter-vals. Refer to Figure 3 for an explanation o f the legend. Time " 0"values fo r sess ions 2 -4 are means o f +26-30 ra in values fo rsessions 1-3, respectively.

S an d e r s -B u s h 1 9 8 6) , li k ew i se i n c rease p h o sp h o in o s i t i d etu rn o v e r (S an d er s -B u sh e t a l 1 98 8 ) , w h ich , v i a r ecep to rp h o sp h o ry l a t i o n , d esen s i t i ze s t h e s i t e fo r ag o n i s t s . D esen -s i ti z a t io n o f 5 - H T 2 r e s p o n se s m e d i a t i n g P I h y d r o l y s i s i ss e e n i n 2 0 r a in , a n d d o w n r e g u l a t i o n o f r e c e p t o r n u m b e ro ccu r s w i th in 1 h o u r ( Iv in s an d M o l in o f f 1 9 9 1) . T h er a p i d i ty o f d e s e n s i ti z a t io n m a y r e l a te t o p h o s p h o r y l a t i o no f p ro t e in k in ase C (P K C ) , w h ich c an o ccu r w i th in 1 0 r a ino f p h o rb o l e s t e r ap p l i ca t i o n (S ib l ey e t a l 1 9 87 ) . B ecau seth i s r ap id d esen s i t i za t i o n can b e p rev en ted b y P K C in h ib -i t o r s (A g h a jan i an 1 9 9 4 ), i t w o u ld b e o f in t e r e s t t o d e t e r -m i n e t h e e f f e c t s o f D M T o n P K C f u n c ti o n .B eh av io ra l t o l e r an ce t o c lo se ly sp aced , r ep e t i t i v e i n j ec -t i o n s o f D M T i s s e e n i n c o n s i s t e n t l y i n l o w e r a n i m a l s ,includ ing cat (Gi l l in e t a l 1973) , ra t (Rech et a l 1975) ,m i c e ( C o o p e r e t a l 1 9 8 1 ) , a n d p r i m a t e s ( C o l e a n d P i e p e r1 97 3 ; S ch l e m m er an d D a v i s 1 9 8 6) . E v en in j ec t i o n s o fD M T e v e r y 2 h o u r s f o r 2 1 d a y s i n r a t f a i l e d t o p r o d u c ec o m p l e t e t o l e r a n c e ( K o v a c i c a n d D o m i n o 1 97 6) .

C r o s s - t o l e r a n c e f o r h a l l u c in o g e n s o c c u r s w h e n d i f f e re n td ru g s p ro d u ce t o l e r an ce t o each o th e r , an d su p p o r t s a

s i m i l a r m e c h a n i s m o f a c t i o n ( B a l e s t r i e r i a n d F o n t a n a r i1 9 5 9 ; A p p e l an d F reed m an 1 9 6 8 ) . D M T res i s t an ce i s n o t ,h o w e v e r , s e e n i n L S D - o r D O M - t o l e r a n t a n i m a l s ( R e c h e tal 1975).

I n h u m a n s , t o l e r a n c e d e v e l o p s a f t e r t h r e e o r f o u r d a i l ye x p o s u r e s t o p s y c h o a c t i v e d o s e s o f L S D ( I s b e ll e t a l1 9 5 6 ) , D O M (A n g r i s t e t a l 1 9 7 4 ) , p s i l o cy b in (H o l l i s t e r1 9 6 1 ) , an d m esca l in e (W o lb ach e t a l 1 9 6 2 ) . L S D sen s i -t i v i t y r e tu rn s t o n a iv e v a lu es j u s t a s q u i ck ly , ev en a f t e rh ig h -d o se t r ea tm en t fo r o v e r 2 m o n th s ( I sb e l l e t a l 1 9 5 6 ) .

C o n s i s t e n t w i t h a n i m a l d a t a , h u m a n D M T t o l e r a n c e i sd i f f i cu l t t o d em o n s t r a t e . A fu l l y h a l l u c in o g en ic d o se o fD M T t w i c e a d a y f o r 5 d a y s d i d n o t e v o k e t o l e r a n c e i nh u m an s (G i l l i n e t a l 1 9 7 6 ) , an d " f i e ld r ep o r t s " o f c lo se lys p a c e d , r e p e ti t i v e s m o k i n g o f D M T f r e e b a s e a r e c o n f l i c t-i n g r eg a rd in g t o l e r an ce d ev e lo p m en t (S t a f fo rd 1 9 9 2 ) .

H u m a n s t u d i e s h a v e s h o w n t h a t b o t h L S D a n d m e s c a -l i n e (B a les t r i e r i an d F o n tan a r i 1 9 5 9 ; W o lb ach e t a l 1 9 6 2 ) ,a s w e l l a n d L S D a n d p s i l o c y b i n ( A b r a m s o n e t a l 1 9 6 0 ;I sb e l l e t a l 1 9 6 1 ) , d em o n s t r a t e c ro s s - to l e r an ce t o eacho t h e r, s u p p o r t i n g a s i m i l a r m e c h a n i s m o f a c t io n . H o w e v e r ,h u m a n s h i g h l y t o l e r a nt t o L S D s h o w n o c r o s s - t o l e r a n c e t oa f u ll y h a l lu c i n o g e n ic d o s e o f D M T ( R o s e n b e r g e t a l1964).

W e b e l i e v e t h a t t h e s e c h r o n i c a d m i n i s t r a ti o n a n d c r o s s -t o l e r a n c e d a t a i n b o t h h u m a n s a n d o t h e r a n i m a l s s u p p o r tu n i q u e p h a r m a c o d y n a m i c , r a t h e r t h a n p h a r m a c o k i n e t i c ,p r o p e r t i e s o f D M T r e l a ti v e t o o t h e r c l a s s i c h a l l u c i n o g e n s,a s m ed ia t i n g i t s i n ab i l i t y t o e l i c i t t o l e r an ce . T h e r ecen td e s c r i p ti o n o f t h e e q u i p o t e n c y o f D M T t o t ha t o f 5 - H T i nd e c r e a s i n g r e s t in g p o t a s s i u m c o n d u c t a n c e ( A g h a j a n i a n1 9 9 4 ) , co m p ared t o l o w in t r i n s i c ac t i v i t y seen w i th o th e rh a l lu c in o g en s (G a r ra t t e t a l 1 9 9 3 ) m a y co n t r i b u t e t ou n d er s t an d in g th ese d i f f e r en ces .

i f ferent ial eve lopm ent of Tolerance to M TT o l e r a n c e d e v e l o p m e n t t o s o m e , b u t n o t a l l , o f t h e a c u t ee f f e c t s o f D M T s u g g e s t s th a t th e m e c h a n i s m s m e d i a t i n gth ese r e sp o n se a r e d i f f e r en t i a l l y r eg u la t ed .

D M T h a s n ea r ly eq u a l a f f i n i t i e s fo r t h e 5 -H T 1 A an d5 -H T z s i t e s (D e l ig an i s e t a l 1 9 9 1 ). C o m p lex fu n c t io n a li n t e r a c t i o n s b e t w e e n t h e s e t w o s u b t y p e s h a v e b e e n d e -sc r ib ed i n s in g l e - ce l l (A ran ed a an d A n d rad e 1 9 9 1 ) t ob e h a v i o r a l ( A r n t a n d H y t t e l 1 9 8 9) s y s t e m s . T h e e f f e c t o f5 - H T 1 A a g o n i s m o n 5 - H T z d esen s i t i za t i o n p ro cesse s a l som a y c o n t r i b u t e t o d i f f e r e n t i a l t o l e r a n c e d e v e l o p m e n t t oD M T . F o r e x a m p l e , t o l e r a n c e t o t h e 5 - H T ~ A a g o n i s t8 - O H - D P A T p r o d u c e d c r o s s - t o l e r a n c e t o L S D ( w i t hn ea r ly eq u a l 5 -H T IA an d 5 -H T 2 a f f in i t i e s [P i e r ce an dP e r o u t k a 1 9 89 ] ), a l t h o u g h L S D - t o l e r a n t a n i m a l s w e r e n o tt o l e r a n t t o D O I , a r e l a t i v e ly p u r e 5 - H T 2 c o m p o u n d ( K r e b san d G ey er 1 9 9 4 ) .


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T h e a f f i n i ty o f D M T f o r th e 5 - H T 2 c s u b t y p e i s n o tk n o w n . I f , h o w e v e r , i t w e r e s i g n i f i c a n t , t h e d i f f e r e n t i a la c u t e S h e l d o n a n d A g h a j a n i a n 1 9 9 1 ) a n d c o m p e n s a t o r yB e r e n d s e n a n d B r o c k k a m p 1 9 9 1 ) in t e r a c ti o n s o f th i s a n d

t h e 5 - H T 2 A s u b t y p e s w o u l d c o n t r i b u t e t o u n e q u a l t o l e r -a n c e p h e n o m e n a s e e n i n t h i s s t u d y .

D i r e c t D M T - i n d u c e d d e s e n s i t i z a ti o n o f 5 - H T s it e s m e -d i a t i n g i ts a c u t e e f f e c t s o n h e a r t r a t e r e s p o n s e s M c C a l l e ta l 1 9 8 7 ) m a y u n d e r l i e t h e t o l e r a n c e s e e n h e r e . D i f f e r e n t i a lr e s p o n s i v e n e s s o f c a r d i o v a s c u l a r e f f e c t s t o p e r i p h e r alc a t e c h o l a m i n e s B a g d y e t a l 1 9 8 9 ) r e l a t i v e t o d i r e c tb r a i n s t e m a c ti v a t i o n C l e m e n t a n d M c C a l l 1 9 9 0 ) m a yc o n t r i b u t e t o t h e d i s s o c i a t i o n o f b l o o d p r e s s u r e a n d h e a r tr a t e r e s p o n s e s .

I n a d d i t i o n t o d i r e c t i n g a f f e c t i n g 5 - H T s i t e s r e s p o n s i b l ef o r c o r t i s o l C a l o g e r o e t a l 1 9 9 0 ) a n d p r o l a c t i n r e s p o n s e sD i R e n z o e t a l 1 9 8 9 ) , D M T m a y e l i c i t n e u r o e n d o c r i n e

t o l e ra n c e b e c a u s e o f n e g a t i v e f e e d b a c k i n h ib i ti o n . H y -p o t h e s e s r e g a r d i n g p r o l a c t i n n e g a t i v e i n h i b i t o r f e e d b a c ka r e l i m i t e d b y t h e e a r ly s t a g e s o f c h a r a c t e r i z a t i o n o fc e n t r a l p r o l a c t i n r e c e p t o r s M u c c i l o i e t a l 1 9 91 ) .

H y p o t h a l a m i c - p i t u i t a r y - a d r e n a l H P A ) f a s t a n d i n te r -m e d i a t e f e e d b a c k c a n o c c u r d u r in g t h e t i m e d o m a i n o f th i ss t u d y W h i t n a l l 1 9 9 3 ) . R e p e t i t i v e , c l o s e l y s p a c e d i n j e c -t i o n s o f C R H t o h u m a n s , h o w e v e r , d i d n o t p r o d u c et o l e r a n c e t o A C T H o r c o r t is o l r e s p o n s e s , a l t h o u g h c o r t i s o ll e v e l s r e m a i n e d e l e v a t e d d u r i n g a c o n t i n u o u s C R H i n f u -s i o n S c h o p o h l e t a l 1 98 6 ). W e i n t er p r e t o u r H P A d a t a a ss u p p o r t i n g a d ir e c t e ff e c t o f D M T o n 5 - H T r e c e p t o rf u n c t i o n , b e c a u s e A C T H r e s p o n s e s f e l l i n t h e f a c e o fr e l a t i v e l y s t a b l e c o r t i s o l l e v e l s .I t s h o u l d b e e m p h a s i z e d t h a t a l t h o u g h D M T l e v e l sd i f f e r e d s i g n i f i c a n t l y a m o n g s e s s i o n s , t h e s e d i f f e r e n c e s

w e r e r e l a t i v e l y s m a l l . I t s e e m s u n l i k e l y t h a t t h e b i o l o g i c a la n d s u b j e c t i v e e f f e c t s n o t e d , e i t h e r t o l e r a n c e o r l a c kt h e r e o f , a r e t h e r e s u l t o f t h e s e d i f f e r e n c e s i n D M T l e v e l s .

H R S c l i n i c a l c l u s t e r s a r e m o r e s e n s i t i v e t o d o s e e f f e c t st h a n t h e b i o l o g i c a l v a r i a b l e s S t r a s s m a n e t a l 1 9 9 4 ) , a n d i ti s p o s si b l e t h a t t h e l a c k o f t o l e r a n c e t o t h e p s y c h o l o g i c a le f f e c ts o f D M T m a y b e d u e t o t h e s l ig h t l y h ig h e r l e v e l s o fD M T s e e n i n s u b s e q u e n t s e s s i o n s . S e p a r a t i n g s e s s i o n s b y6 0 o r 9 0 r a i n i n f u t u r e s t u d i e s m a y h e l p t o c l a r i f y t h i si s sue .

o n c l u s i o nT h e s e d a t a s u p p o r t th e u n i q u e n e s s o f D M T a m o n g c l a s s ich a l l u c i n o g e n s . W h e t h e r t h i s i s b a s e d u p o n p h a r m a c o d y -n a m i c o r p h a r m a c o k i n e t i c d i f f e r e n c e s r e m a i n s t o b e d e -t e r m i n e d . T o l e r a n c e t o s o m e , b u t n o t a l l, o f t h e e f f e c t s o fD M T s u g g e s t d i ff e r e nt i a l r e g u l a ti o n o f m e c h a n i s m s i n -v o l v e d i n t o l e r a n c e t o n e u r o e n d o c r i n e , c a r d i o v a s c u l a r , a n ds u b j e c t i v e e f f e c t s o f h a l l u c i n o g e n i c d r u g s . F u t u r e s t u d i e sa t t e m p t i n g t o d e v e l o p t o l e r a n c e t o D M T m a y u s e e i t h e r ac o n t i n u o u s i n f u s i o n o f D M T o r a g re a t e r n u m b e r o fi n j e c t i o n s .

This investigation was supported by N ational Institute on Drug Abusegrant R01-DA 08096; University of New Mexico General Clinical Re-search Center grant RR00997-15; and University of New MexicoDepartment of Psychiatry research funds. The authors thank David E.Nichols, Ph.D., for synthesis of the D MT fumarate used in this study ; thenursing staff of the GCR C, 5E, U niversity of New Mexico Hospital, fornursing support; and Joy McLeod, Alberta Bland, and Susan Lee forlaboratory assistance.

R e f e r e n c e sAbramson H A, Rolo A , Sk la ro fksy B , e t a l 1960) : P roduc t ionof cross- tolerance to psychosis-producing doses of ly-sergic acid diethylamide and psilocybin. J Psychol 4 9 : 1 5 1 -154.Agha janian GK 1994): LSD and phenethylamine hallucinogens:Com mo n sites of neuronal act ion. In Pletscher A ed) , 50Years of LSD: State of the Art and Perspectives of Halluci

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differential tolerance to biological and subjective effects of four closely spaced doses of...

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