8/13/2019 Human Psychopharmacology of N,N-Dimethyltryptamine

1/4

ELSEVIER Behavioural Brain Research 73 (1996) 121-124

B E H V I O U R LBRAINRESEARCH

H u m an p syc h op h ar m ac o logy o f N N - d ime t h y l tr yp t amin eR i c k J . S t r a s s m a n

Department of Psychiatry University of New Mexico Albuquerque NM87131-5326 USA

A b s t r a c t

We generated dose-response data for the endogenous and ultra-short-acting hallucinogen, N,N-dimethyltryptamine (DMT), ina cohort of experienced hallucinogen users, measuring multiple biological and psychological outcome measures. Subjectiveresponses were quantified with a new rating scale, the HRS, which provided better resolution of dose effects han did the biologicalvariables.A tolerance study then was performed, in which volunteers received four closely spaced hallucinogenicdoses of DMT. Subjectiveresponses demonstrated no tolerance, while biological measures were inconsistently reduced over the course of the sessions. Thus,DMT remains unique among classic hallucinogens in its inability to induce tolerance to its psychological effects.To assess the role of the 5-HT,A site in mediating DMT's effects, a pindolol pre-treatment study was performed. Pindololsignificantly increased psychological responses to DMT, suggesting a buffering effect of 5-HT1A agonism on 5-HT2-mediatedpsychedelic effects. These data are opposite to those described in lower animal models of hallucinogens' mechanisms of action.

1 I n t r o d u c t i o n

Human research with hallucinogenic drugs wasseverely curtailed by the passage of the ControlledSubstances Act of 1970 [21] . Nearly a generationelapsed before a renewal of clinical studies occurred inthe United States and Europe. These studies have begunto address gaps in basic understanding of effects andmechanisms of action created by this hiatus, duringwhich many of the standard methods of psychopharma-cology and psychotherapy research were developed.There are several reasons why the careful study ofhallucinogens has relevance to psychiatric research.(1) The clinical syndrome elicited by hallucinogensaffects all of the mental functions associated with humanconsciousness, including mood, perception, cognition,self-control and somatic awareness [5]. Generatingmechanistic hypotheses based upon systematic data col-lection will provide insights into many basic brain-mindrelationships.(2) Use and abuse of hallucinogens among youngadults is increasing [10,11], with an attendant rise inemergency room and psychiatric clinic utilization forassessment and treatment of adverse effects [7]. Thereis a need to understand how best to treat hallucinogen-elicited psychiatric disorders quickly, safely, and effec-

* Corresponding author.0166-4328/96/ 9.50 Elsevier Science B.V. All rights reservedSSSDI 0166-4328(96)00081-X

tively, in addition to providing accurate information toclinicians regarding effects and sequelae of hallucinogenuse and abuse.(3) The degree of overlap between endogenous psycho-ses and hallucinogenic drug inebriation has been debatedvigorously [8,12]. The appellations 'psychotogen' and'psychotomimetic' bespeak early efforts to relate the twosyndromes. Similarities appear to be greatest dur ingacute phases of schizophrenia [2]. Short-chain tryptam-ines remain attractive candidates for naturally occurring

psychotogens [3]. Current interest in mixed 5-HT2/DA2antagonists as anti-psychotic agents [14] also under-scores the importance of studying 5-HT2-active halluci-nogens as models for endogenous psychoses.(4) The ability of hallucinogens to enhance the psy-chotherapeutic process was an area of intense interestduring the first phase of hallucinogen research [17].Restrictions on human use of these drugs preventednecessary clarification regarding with whom, and howbest to utilize these drugs within a psychotherapeuticcontext. Recent advances in psychotherapy research [24]suggest models by which a more careful and systematicapproach to combining hallucinogen drug administra-tion with well-characterized forms of psychotherapymay proceed.We have been investigating effects and mechanismsof action of the short-chain tryptamine, ultra-short-acting endogenous hallucinogen, N,N-dimethyltrypta-

8/13/2019 Human Psychopharmacology of N,N-Dimethyltryptamine

2/4

122 Rick J. Strassman/Behavioural Brain Research 73 1996) 121 124m i n e ( D M T ) , i n a c o h o r t o f e x p e r ie n c e d h a ll u c in o g e nu s e rs s i nc e N o v e m b e r , 19 9 0 . T h r e e r e a s o n s p r o m p t e dc h o o s i n g D M T a s t h e c o m p o u n d w i t h w h i c h t o r e n e wclinical research with hal lucinogens. Firs t , i t is extremelyshor t - ac t ing [18] , and adver se ef f ec ts which migh t occu rin a busy c l in ica l r esearch un i t wou ld be eas ier tomanage . Second , i t i s a na tu ra l ly occur r ing ha l luc inogen[ 1 , w h o s e r o l e in n o r m a l a n d a b n o r m a l m e n t a l p r o c e s s e shas ye t to be exp l ica ted adequate ly . Th i rd , i t s r e la t iveo b s c u r i t y w o u l d n o t d r a w u n d u e a t t e n t i o n t o o u r w o r kin the ear ly de l ica te s tages o f r esuming th i s r esearch ,r e la t ive to the cer ta in f lu r ry o f in ter es t tha t a be t te rknown hal luc inogen , such as LSD, migh t .We chose to s tudy exper ienced ha l luc inogen user s fo rthe fo l lowing r easons : exper ienced user s would be lessl ike ly to pan ic dur ing the pow er fu l ha l luc inogen ic e f f ec t se x p e c t e d f r o m D M T ; t h e y w o u l d b e a b l e t o p r o v i d em ore de ta i led accoun ts o f D M T eff ec t s, par t i cu lar lyr e la t iv e t o o t h e r b e t t e r k n o w n c o m p o u n d s , s u c h a s L S Dand psi locybin, than naive subjects ; f inal ly , l iabi l i ty ford e v e l o p m e n t o f s u b s e q u e n t ' d r u g a b u s e ' w o u l d b e l e s sl ike ly to be sus ta ined in p rev ious o r cu r r en t user s .

2 Sum ma ry of experiments and resultsEach o f the th ree s tud ies to be descr ibed u ti li zedmale and f emale exper ienced ha l luc inogen user s who

were o therwise medica l ly and psych ia t r ica l ly hea l thy .Screen ing was r igorous , and inc luded a medica l h i s to ry ,phys ica l examinat ion , e lec t rocard iogram, u r ina lys i s ,comple te b lood coun t , 24- i tem chemis t ry panel , andthyro id funct ions . Sub jec t s were excluded who weretak ing any medica t ion r egu lar ly , o r who had a h i s to ryof h igh b lo od p ressure . Psyc h ia t r ic scr een ing inc luded asemi- s t ruc tu red psych ia t r ic in terv iew , the S t ruc tu redC l i ni c a l I n t e rv i e w f or D S M - I I I - R , O u t p a t i e n t [ 20 ] , a n da su rvey o f d rug use h is to ry . Those w i th cur r en t d ruga b u s e p r o b l e m s o r h i s t o r y o f p s y c h o s i s w e r e e x c lu d e d .I f vo lun teer s h ad a h i s to ry o f a major depress ive ep isode ,they were inc luded i f the depress ion had r eso lved a tleas t two year s befo re beg inn ing the s tudy , and theywere no t in s t r ess fu l l i f e c i r cumstances conducive to ar elapse. In add i t ion , i f vo lun teer s had no t ha d w hat theresearch team cons idered ' f u l l -b lown ' exper iences onhal luc inogen ic d rugs , they were no t en ro l led , as wew a n t e d t o e n s u r e t h a t v o l u n t e e r s c o u l d m a n a g e t h eh igh ly in tox ica ted s ta te o f a h igh-dose D M T sess ion .Stud ies a ll took p lace in the inpat ien t un i t o f theU n i v e r s i ty o f N e w M e x i c o H o s p i t a l C l i n ic a l R e s e a r c hCenter . Prospect ive vo lun teer s f i r s t r ece ived low(0 .05 mg/kg} and h igh (0 .4 mg /kg) scr een ing doses o fin t r aveno us ( i .v .) D M T fumara te , non-b l ind , to f ami l ia r -ize themselves w i th the r esearch se t t ing , p rov ide ano p p o r t u n i t y t o d r o p o u t b e f o r e e x t e ns i v e d a t a w e r eco l lec ted , and fo r id iosyncra t ic hyper tens ive r esponses

to the low dose to be no ted and exclude fu r therpar t ic ipa t ion .Ou r f i rs t dose - r esp onse s tudy u t i l i zed 0 .05 , 0 .1 , 0 .2a n d 0 .4 m g / k g i . v. D M T f u m a r a t e , a n d s a li n e p l a c e b o ,in a doub le-b l ind , r andom ized des ign, us ing 12 vo lun-teer s . These r esu l t s have been pub l i shed [22,23] . A newrat ing sca le fo r ha l luc inogen ef f ec t s , the Hal luc inogenRat ing Scale (HRS) , was developed , which c lus ter edresponses into s ix cl inical categor ies: Affect , Voli t ion,Somat ic Ef f ec t s ( 'Somaes thes ia ' ) , Percep t ion , Cogn i t ion ,and In tens i ty . Bio log ica l measures inc luded : hear t r a te( H R ) , m e a n a r te r ia l b l o o d p r e s s u r e (M A P ) , p u p i l d i a m e -t e r, c o r e t e m p e r a tu r e ; a n d a d r e n o c o r t i c o t r o p i n ( A C T H } ,/~-endorph in ( /~E), p ro lac t in (P RL ) , g row th horm one( G H ) , m e l a t o n i n , c o r t i s o l a n d D M T - f r e e b a s e b l o o dlevels . The 'p sychedel ic ' th r esho ld fo r DM T was a t0 .2 mg /kg , a t wh ich mo s t b io log ica l e f fec ts a l so dem on-strate d s ta t is t ical ly s ignificant dif ferences f rom sal inep l a c e b o . O n l y m e l a t o n i n s h o w e d n o s t i m u l a t i o n b yDMT, whi le GH levels , a l though s t imula ted , cou ld no tbe d i f f er en t ia ted by dose . Pup i l d iameter , HR, MAP,A C T H , / ~ E , D M T , a n d s u b j e c t i v e r e s p o n s e s a ll p e a k e dwi th in 2 min ; PRL and cor t i so l r esponses lagged by5 15 min , whi le t em pera tu re and g rowth horm one e leva-t ions d id no t beg in un t i l psycho log ica l e f f ec t s hadreso lved , by 15-20 min .

Psycho log ica l e ff ec ts began ne ar ly imme dia te ly dur ingthe DM T in fus ion , peak ed wi th in 2 min , and usual lywere comple te ly r eso lved wi th in 30 min . The h igherd o s e s o f D M T p r o d u c e d a r a p i d l y m o v i n g , m u l t i- d im e n -s ional, ka le idosc op ic d i sp lay o f in tense ly co lo red ab s t r ac tand representat ional images. Auditory ef fects were lesscom mo n, and were no t f r ank ha l luc ina t ions . T rans ien ta n x i e t y w a s c o m m o n , b u t u s u a l l y q u i c k l y b e c a m erep laced by euphor ia . D issoc ia t ion o f awarene ss fromthe phys ica l body was common, as were la te r f ee l ings o fa l te rna t ing hea t and co ld . The h igher dose ef f ec t s com-p le te ly r ep laced ongo ing menta l exper ience , and usual lyw a s d e s c r i b e d a s m o r e c o m p e l l i n g a n d c o n v i n c i n g t h a n' o r d i n a ry ' r e a li t y o r d r e a m s . L o w e r d o s e s ( 0 .1 a n d0 .05 mg /kg) p r imar i ly a f f ec ted phys ica l and af f ec tivefunct ions , w i th l i t t l e percep tua l d i s tu rbances . HRS datawere mo re cap ab le o f d i s t ingu ish ing be twee n dose leve ls( e.g ., be twe en 0 .1 a nd 0 .05 mg /kg) than were b io log ica lda ta . These da ta were in terp re ted in the l igh t o f5 -HT mecha n isms , especia l ly 5 -HT2 and 5 -HT1A s i teac t iva t ion .More exper imenta l s tud ies were then des igned , thef ir s t b e i n g a n a s s e s s m e n t o f D M T ' s a b i li t y t o i n d u c eto ler ance to i t s b io log ica l and psycho log ica l e f f ec t s .Prev ious a t tempts in humans had f a i led to e l ic i t to ler -ance [6 ] , whi le hero ic e f fo r t s in lower an imals wererequ i r ed to do so [13] .A fu l ly ha l luc inogen ic dose , 0 .3 mg /kg , o f i.v. D M Tfumara te , o r sa l ine p lacebo , was admin is te r ed a t ha l f -hour in terva ls , 4 t imes in a morn ing , to 13 exper ienced

8/13/2019 Human Psychopharmacology of N,N-Dimethyltryptamine

3/4

Ri ck J. Strassman/BehaviouraI Brain Research 73 199 6) 12 1-12 4 123h a l l u c i n o g e n - u s i n g v o l u n t e e r s . N e i t h e r c l i n i c a l i n t e r -v i e w s n o r H R S r e s u l t s d e m o n s t r a t e d d e v e l o p m e n t o fp s y c h o l o g i c a l t o l e r a n c e . H R d e c r e a s e d f r o m t h e f ir s t t os e c o n d s e s s io n , a n d d i d n o t c h a n g e t h e r e a f t e r , s u g g e s t i n g' r e d u c t i o n o f a n t i c i p a t o r y a n x i e t y , ' r a t h e r t h a n ' t o l e r -a n c e ; ' w h i le n o r e d u c t i o n i n M A P w a s s e en . A C T H a n dP R L r e s p o n s e s d i d d e c r e a s e o v e r t h e c o u r s e o f t h em o r n i n g , s u g g e s t i n g t o l e r a n c e d e v e l o p m e n t . T h i sd 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 w a s i n t e r p r e t e d a sb e i n g m e d i a t e d b y i n d e p e n d e n t l y r e g u l a t e d d e s e n s i t i z a -t i o n o f re l e v a n t 5 -H T r e c e p t o r m e c h a n i s m s . T h u s , D M Tr e m a i n s u n i q u e i n i t s i n a b i l i t y t o d e v e l o p t o l e r a n c e t oi t s psychologica l e f fec t s .

O u r l a s t s t u d y c o m p l e t e d a s s e s s e d t h e r o l e o f t h e5 -H T ~A s it e in m e d i a t i n g D M T e f fe c ts . T h i s w a s p e r -f o r m e d b e c a u s e D M T h a s n e a r l y e q u a l a f fi n it y f o r t h e5-HT~A and 5-HT2 s i t e s [4] , and the behaviora l e f fec t so f th e h a l l u c in o g e n 5 - m e t h o x y - D M T a r e b lo c k e d b yp i n d o l o l [ 1 9 ], a p o t e n t 5 - H T ~ a a n t a g o n i s t [ 1 6 ] .

T w e l v e v o l u n t e e r s r e c e i v e d a s u b - h a l l u c i n o g e n i c d o s e ,0 .1 m g / k g , i . v. D M T , o r s a l in e p la c e b o , i n c o m b i n a t i o nw i t h 3 0 m g o r a l r a c e m i c p i n d o l o l , o r p l a c e b o - p i n d o l o l ,i n a f o u r - c e l l d o u b l e - b l i n d , r a n d o m i z e d d e s i g n .V o l u n t e e r s f o u n d t h a t p i n d o l o l p r e - t r e a t m e n t e n h a n c e dD M T e f f ec t s b y t w o t o t h r e e t i m e s , w h i c h w a s s u b s t a n t i -a t e d b y s c o r e s o n t h e H R S , i n w h i c h f o u r t o s i x c l i n i c a lc l u s t e r s d e m o n s t r a t e d a s i g n i f i c a n t e n h a n c e m e n t b y p i n -d o l o l . P R L r e s p o n s e s w e r e r e d u c e d , w h i l e t h o s e o fA C T H w e r e u n a f f e c t e d . H R r e s p o n s e s w e r e b l u n t e d ,p r o b a b l y d u e t o p i n d o l o l ' s a n t i - s y m p a t h e t i c e f fe c ts ,w h i l e M A P e f f e c ts w e r e e n h a n c e d . T h e s e b e h a v i o r a ld a t a , o p p o s i t e t o t h o s e n o t e d i n t h e a n i m a l l i t e r a t u r e ,s u g g e s t a n i n h i b i t o r y e f f e c t o f 5 - H T~ A a g o n i s m i n t r y p -t a m i n e - i n d u c e d h a l l u c i n o g e n e s i s . P i n d o l o l b l o c k a d ea l l o w e d u n o p p o s e d 5 - H T 2 a g o n i s m , w h i c h w e b e l i e v ea l s o m e d i a t e d t h e e n h a n c e d M A P r e s p o n s e s t o D M T .T h e r e d u c e d P R L r e s p o n se s u p p o r t s a s t i m u l a t o r y r ol ef o r t h e 5 - H T I A s i t e i n h u m a n P R L s e c r e t i o n , w h i l e t h el a c k o f e f fe c t o n A C T H s u g g e s ts a m i n i m a l r o l e fo r t h i ss it e i n t h e D M T r e s p o ns e . T h e s e d a t a a l s o a r e i m p o r t a n tb e c a u s e t h e y d e m o n s t r a t e d i f f e r e n t ia l ( a n d a t t i m e s ,o p p o s i t e ) r e g u l a t i o n o f 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 d s 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 s i n h u m a n s .

3 C on c l us i ons and f ut ure d i rec t i onsD M T c a n b e s a f e ly a d m i n i s t e r e d t o e 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 i n f u l l y ' p s y c h e d e l i c ' d o s e s. B y s o d o i n g ,

e a r l i e r c l i n i c a l r e s e a r c h f i n d i n g s c a n b e e x t e n d e d t oi n c l u d e c o n t e m p o r a r y p s y c h o p h a r m a c o l o g i c a l m e t h o d -o l o g ie s , a n d b a s i c h y p o t h e s e s t e st e d . I n t h e c a s e o f D M T ,a b a t t e r y o f n e u r o e n d o c r i n e d a t a h a v e b e e n g e n e r a t e d ,a n d a n e w r a t i n g s c al e d e v e l o p e d . T h e l a c k o f t o l e r a n c et o D M T ' s p s y c h o l o g i c a l e ff e ct s h a s b e e n e s t a b l i sh e dm o r e r i g o r o u s l y , w h i c h s t r e n g t h e n s i t s r o l e a s a p u t a t i v e

e n d o g e n o u s ' p s y c h o t o g e n ' 1 -9 ]. O u r s t u d y o f t h e r o l e o ft h e 5 - H T I A si t e i n m e d i a t i n g D M T e f fe c t s i n h u m a n sh a s y i e l d e d r e s u l t s o p p o s i t e t o t h o s e e x p e c t e d f r o ma n i m a l d a t a .

C u r r e n t s t u d i es i n c lu d e a p r e - t r e a t m e n t p r o t o c o l u s i n gt h e o n l y c u r r e n t l y a v a il a b l e 5 - H T 2 a n t a g o n i s t , c y p r o h e p -t a d i n e , w h i c h w i l l e x p a n d p r e v i o u s h u m a n w o r k w i t ht h i s c o m b i n a t i o n [ 1 5 ] . I n a d d i t i o n , w e a r e b e g i n n i n g t od e v e l o p c o m p r e h e n s i v e d o s e - r e s p o n s e d a t a f o r t h el o n g e r - a c t i n g , a n d m o r e w i d e l y a b u s e d h a l l u c i n o g e n ,p s il o cy b i n ( 4 - p h o s p h o r y l o x y - N , N - D M T ) .

A c k n o w l e d g m e n tT h i s i n v e s t i g a t i o n w a s s u p p o r t e d b y t h e S c o t t i s h R i t eF o u n d a t i o n f o r S ch i z o p h r e n ia R e s e a rc h , N M J ; N a t i o n a l

I n s t i t u t e o n D r u g A b u s e g r a n t s R O 3 - D A 0 6 5 2 4 a n dR O 1 - D A 0 8 0 9 6 ; U n i v e r s it y o f N e w M e x i c o G e n e r a lC l i n i c a l R e s e a r c h C e n t e r g r a n t R R 0 0 9 9 7 ; t h e S c o t tR o g e r s F u n d o f t h e U n i v e r s i ty o f N e w M e x i c o ; a n dU n i v e r s i ty o f N e w M e x i c o D e p a r t m e n t o f P s y c h i a t r yr e s e a r c h f u n d s . T h e a u t h o r s w o u l d l i k e t o t h a n k D a v i dE . N i c h o l s , P h . D . , P u r d u e U n i v e r s i t y , f o r s y n t h e s i s o ft h e D M T f u m a r a t e u s e d in t h is s tu d y .

R e f e r e n c e s[ 1 Axelrod,J., The enzym aticN-methylationof serotonin and other

amines, J. Pharmacol. Exp. Ther., 138 (1962 ) 28-33.12] Bowers, M., Jr. and Freedm an,D.X., Psychedelic'experiences nacute psychoses,Arch. Gen. Psychiatry, 15 (1966) 240-248.1 3] Co rbett, L., Christian, S.T., M orin, R.D., Benington,F. and Smy-thies, J.R., HallucinogenicN-m ethylated ndolealkylamines n thecerebrospinal fluid of psychiatric and control populations, Br.J. Psychiatry, 132 (1978) 139-144.[4] Deliganis, A.V., Pierce, P.A. and Perou tka, S.J., Differential nter-actions of dimethyltryptamine DM T) with 5-HT la and 5-HT2receptors, Biochem. Pharmacol., 41 (1991) 1739-1744.[5] Freedman,D.X., On the use and abu se of LSD, Arch. Gen. Psychi-

atry, 18 (1968) 330-347.[6] Gillin, J .C., Kap lan, J., Stillman, R. and W yatt, R,J ., Thepsychedelic mo del o f schizophrenia: The case of N,N-dimethyl-tryptamine,Am. J. Psychiatry, 133 (197 6) 203-208.[7] Gold, M .S., Schuchard, K. and Gleaton, T., LSD use am ong UShigh school students (letter), J A M A , 271 (1994) 426-427.[8] Ho llister, L., Drug -induce d psychose s and schizophrenic reac-tions: A critical comparison, Ann. N.Y. Acad. Sc i . , 96 (1962)80-92.[9] Hollister, L.E ., Some general thoughts abo ut endogen ous psy-chotogens. In E. Usdin, D.A. H ambu rg and J.D. B archas (Eds.),Neuroregulators and Psychiatric D isorders, Oxford UniversityPress, New Yo rk, 1977, pp. 550-556.[10] Johnston, L.D., O 'Malley, P.M . and Bachman, J.G., NationalSurvey Results on Drug Use fro m Monitoring the Future Study ,1975-1992 , Vol. II. College Students and Young Adults, NationalInstitute on Drug Abuse, Rockville, MD, 1993.[11] Johnston, L.D., O 'Malley, P.M . and Bachman, J.G., Nat ionalSurvey R esults on Drugs Use fro m M onitoring the Future Study,

8/13/2019 Human Psychopharmacology of N,N-Dimethyltryptamine

4/4