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Increased ctivation of Indirectssociations under Psilocybin

Semantic

Manfred Spitzer Markus Thim m Leo Hermle Petra Holzmann Karl-Artur KovarHans Heirnann Euphrosyne Gouzoulis-M ayfrank Ud o Kischka andFrank Schneider

K e y W o r d s : E x p e r i m e n t a l p s y c h o s i s , h a l l u c i n o g e n s , p s i l o c y b i n , p s y c h o l i n g u i s t i c s , s e m a n t i cp r i m i n g , w o r d a s s o c i a t i o n sBIOL PSYCHIATRY 1996 ;39: 1055 - -105 7

n troduc t ionThe spread of activation in semantic networks can be measuredusing semantic and indirect semantic pr iming effects in lexicaldecision tasks (Spitzer et al 1993a and b) . For example, inthought-disordered schizophrenic patients , activation spreadsfaster and far ther than in non-thought-disordered patients andnorm al subjects , which results in an increased direct and indirectsemantic pr im ing effect (see below). This has been interpreted asthe result of a decreased signal- to-noise ratio in cortical neuralnetworks that process semantic information. Such a decreasedsignal- to-noise ratio has been related to a decreased dopa miner-gic modulat ion (Servan-Schreiber et al 1990; Cohen and Servan-Schreiber 1992, 1993), which we recently were able to confirmdirectly in a s tudy on the effects of L-dopa on semantic andindirect semantic pr iming (Kischka et al 1995).

As dop mine was found to have a focusing effect on theactivity in semantic networks, i .e ., it increases the s ignal- to-noi seratio and reduces the spread of activation (measured as reducedindirect semantic pr iming) , we set out to investigate the effect of

From the Sektion Experimentelle Psychopathologie, Psychiatrische Universit[i-tsklinik, Heidelberg, Germany (MS, MT); Christophsbad, Fachkrankenhaus ftirPsychiatrie und Neurologie, G6ppingen, Germany (LH); PharmazeutiscbesInstitut der Universit~it T(ibingen, Germany (PH, K-AK); Psychiatrische Uni-versit~itsklinik, Tiibingen, Germany (HH, FS); Psychiatrische Klinik derRWTH, Aachen, Germany (EG-M); and Neurologische Universit~itsklinik,Magdeburg, Germany (UK).Address reprint requests to Manfred Spitzer, M.D., Ph.D., Sektion ExperimentellePsychopathologie, Psychiatrische Universit~itsklinik, Voss-Str. 2, 69 115 Hei-delberg, Germany.Received June 5, 1995; revised July 27, 1995.

the hallucin ogenic agent psilocybin on this task. Since psilocybinis known to act on the serotonin (5-HT) system and has effects of

broaden ing conscious experiences, we hypothesized that itmight exert a defocusing effect on semantic networks ( i.e . ,decrease the s ignal - to-noise ratio), which should lead to anincreased indirect semantic pr iming effect.

To test this hypothesis directly, we conducted a double-blind,placebo-controlled study on the effects of psilocybi n on semanticand indirect semantic pr im ing as part of a larger project that wasdesigned to assess the behavioral effects and pharmacokineticproperties of this halluci nogenic agent ( the results will bereported elsewhere; cf . Holzmann 1995).

Method sThe same lexical decision paradigm as in previous s tudies wasused (see Spitzer et al 1993a and b for details). The subject hadto decide whether a given str ing of characters is a word or not. Toinvestigate how far activation spreads, word pairs of differentsemantic d is tance - -c lose ly re la ted words ( b lack-white ) , ind i-rectly related words (such as lemo n-swe et ) , and nonrelatedwords (such as c loud -cheese ) - -a re presen ted in qu ick (200msec) succession, and the effect of the relation between thewords on the reaction time of the lexica l decision of the latter ismeasured. I t is well established that a word (e.g. , black ) isrecognized faster if it is preceded by a m eaning fully related word(e.g. , white ) . This effect is called semantic pr iming (cL Spitzeret al 1994). I f the relation between the words is ind irect, there isno such gain in the speed of the response, i .e ., sweet is not

1996 Society of Biological Psychiatry 0006-3223/96/ 15.00SSDI 0006-3223(95)00418-1

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1056 BIOL PSYCHIATRY Br ie f Rep ort s1996;39:1055 1057

Table I . Mean Reac t ion T imes (RT, in Mi l l i seconds) and (Di rect ) Semant ic as Wel l a s Ind i rect Semant ic Pr iming Ef fec t s (SP andISP, in Mill iseconds and as Percentage Scores) per Semantic Condit ion and Intervention (Placebo vs. Psi locybin)

Time after ingestion of agent (min)Semantic condition 0 50 150 220RT placebo, related 598 595 611 600RT placebo, indirectly related 608 608 620 621RT placebo, nonrelated 670 742 704 644RT psilocybin, related 646 735 674 634RT psilocybin, indirectly 671 743 704 645relatedRT psilocybin, nonrelated 693 852 748 673Priming effects

SP (msec) placebo 26 72 35 41SP (msec) psilocybin 47 117 74 40ISP (msec) placebo 15 59 26 21ISP (msec) psilocybin 23 110 44 29SP (%) placebo 4.5 10.5 5.2 6.2SP (%) psilocybin 6.4 13.1 10.0 5.8ISP (%) placebo 2.6 7.9 4.1 3.2ISP (%) psilocybin 2.9 11.8 5.6 3.8

recognized fas te r when preceded by lemon in normal subjec ts(absent indirect semantic priming effect) . As mentioned above,in thought-diso rdered schizophrenic patients , such an indirectsemantic priming effect was found.

Permission to use psi locybin within an experimental set t ingwas obtained from the local inst i tut ional review board as well asf rom the German equ iva len t o f the Food and Drug Admin is t ra -t ion (Bundesgesundheitsamt, Bundesopiumstel le , Berl in) . Eightnormal male subjects (mean age: 39.4 years, 7 f ight-handed, 1left-handed, al l physicians who had given writ ten informedconsent before the beginning of the study) received ei ther acapsu le con ta in ing 0 .2 mg/kg body weigh t o f ps i locyb in o rplacebo, in random order, on 2 days at least 1 week apart atapprox imate ly the same t ime of day (11 :00 A M). To avo idrepeti t ion effects , two versions of the lexical decision paradigmwere used and al ternatively performed by the subjects beforedrug intake and 50, 150, and 220 min after drug intake.

ResultsMean reaction t imes, as well as (direct) semantic and indirectsemantic priming effects per semantic condit ion and intervention(placebo vs. psi locybin) are presented in Table 1. The error rateswere genera l ly low (0-2%) , and showed no re la t ion to semant iccondit ion or drug. In part icular , there was no increase in theamoun t of errors under placebo in ei ther semantic condit ion.

Hal luc inogens a re known to s low down reac t ion t imes , whichwe also observed in every semantic condit ion. To assess thespecif ic effects of the hallucinogenic agent on semantic pro-cesses, priming effects were calculated not only as differencescores but also as percentage scores ( i .e ., as percent of speed gaindue to the semantic relat ion of the words) . This measure is moreconse rvativ e since it takes into account gene ral reaction t ime andcompensa tes fo r the e f fec t o f genera l s lowness , an i s sue we have

discussed in detai l in our paper on indirect semantic priming inschizophrenia (cf . Spitzer et al 1993b).

A two-way ana lys i s o f va r iance (ANOVA) measur ing theeffect of intervention (placebo vs. psi locybin) and t ime (beforedrug intake vs. 50 min after drug intake) on the indirect primingeffect (percentage score) produced a tendency only for t ime [F(1,7) = 5.09; p = .059], but nei ther a main effect for interventionnor a s ignif icant interact ion. With respect to indirect semanticpr iming , however , the more sens i t ive measure o f sp read ingsemantic act ivation, we specif ical ly tested the priming effects forsignif icance and found a nonsignif icant increase of indirectsemantic priming under placebo, whereas this increase wassignif icant under psi locybin [ t(7) = 2.82; p = .026]. Table 1further indicates a nonsignif icant increase in semantic priming(difference and percentage scores) af ter the intake of ei therplacebo or psi locybin, with a numerical ly larger effect underpsi locybin.

To demons t ra te the e f fec t o f ps i locyb in on ind i rec t semant icpr iming , the d i f fe rence o f the p r iming e f fec t s be tween thepsilocybin and the placebo runs was plotted, using the moreconser vative percentage scores (Figure 1).

iscussionThe f inding that psi locybin increases indirect semantic primingin normal subjects adds to our general understanding of theef fec t s o f ha l luc inogen ic agen ts on cogni t ive func t ions . Fromanecdotal records and very few controlled studies these agentsare believe d to have subjective effects that sometimes arereferred to as broaden ing conscio usness and enhanc ing cre-at ivi ty (references in Pletscher and Lad ewig 1994). Alth oughmost object ive measures have fai led to support these claims, ourdata suggest that the agent in fact leads to an increased avail-abil i ty of remote associat ions and thereby may bring cognit ive

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F i g u r e 1 . M e a n p l a s m a l e v e l s o f p s i l o c i n , t h em a i n m e t a b o l i t e o f p s i l o c y b i n , w h i c h i sf o r m e d r a p i d l y a f te r d ru g i n t a k e d a t a fr o mH o l z m a n n 1 9 9 5 ) , a n d h a l l u c i n o g e n - i n d u c e di n c r e a s e i n i n d i r e c t s e m a n t i c p r i m i n g .

c o n t e n t s t o m i n d t h a t u n d e r n o r m a l c i r c u m s t a n c e s r e m a i n n o n -a c t i v a t e d ; h o w e v e r , t h e g e n e r a l l y d e c r e a s e d p s y c h o l o g i c a l p e r -f o r m a n c e u n d e r h a l l u c i n o g e n i c a g e n ts s u g g e s t s t h a t t h e i n c r e a s e di n d i r e c t p r i m i n g e f f e c t i s d u e t o a d e c r e a s e d c a p a c i t y t o u s ec o n t e x t u a l i n f o r m a t i o n f o r t h e f o c u s i n g o f s e m a n t i c p r o c e s s i n g .H e n c e , s u b j e c t i v e l y e x p e r ie n c e d i n c r e a s e s i n c r e a t i v i t y a s w e l l a st h e b r o a d e n i n g o f c o n s c i o u s n e s s h a v e b e e n f o u n d t o p a r a l l e ld e c r e a s e s i n o b j e c t i v e p e r f o r m a n c e m e a s u r e s .

F r o m a m e t h o d o l o g i c a l p e r s p e c t i v e , o u r d a t a i n d i c a t e t h a ti n d i r e c t s e m a n t i c p r i m i n g i s a h i g h l y s e n s i t i v e m e a s u r e t h a ta p p e a r s t o r e s p o n d n o t o n l y t o p h a r m a c o l o g i c i n t e r v e n t i o n , b u ta lso to the psycho log ica l e f fec ts o f the se t t ing o f the s tudy . Thef o l l o w i n g p o s t h o c s u g g e s t i o n m a y a c c o u n t f o r t h e f i n d i n g o fc o n s i s t e n t t h o u g h n o n s i g n i f i c a n t ) i n c r e a s e s o f p r i m i n g e ff e c t su n d e r p l a c e b o . I t i s n o t e w o r t h y t h a t b e f o r e t e s t i n g , s u b j e c t sa p p e a r e d a n x i o u s , t i g h t , a n d t e n s e , a s t a t e k n o w n t o p r o d u c es t e r e o ty p e d v e r b a l a s s o c i a t i o n s a n d d e c r e a s e d p r i m i n g e f f e c t sc f . S p i t z e r 1 9 95 ). W h e n a b o u t 3 0 - 4 0 m i n a f t e r d r u g i n t a k e t h e

s u b j e c t b e c a m e a w a r e o f e i t h e r b e i n g o n p l a c e b o o r b e i n g o np s i l o c y b i n , t h e y t e n d e d t o b e c o m e m o r e r e l a x e d a n d u n w i n d i n g ,which i s a s ta te known to fac i l i ta te access to a wider scope o fa s s o c i a t i v e m a t e r i a l . T h i s i s a t e s t a b l e h y p o t h e s i s a n d w ec u r r e n t l y p l a n t o u s e i n d i r e c t s e m a n t i c p r i m i n g t o i n v e s t i g a t es e v e r a l n o n p h a r m a c o l o g i c a l l y i n d u c e d s t a t es o f a n x i e t y a n dgenera l a rousa l .

I n c o n c l u s i o n , w e h a v e d e m o n s t r a t e d t h e e f f e c t o f a h a l l u c i -n o g e n i c a g e n t , k n o w n t o a f fe c t t h e 5 - H T s y s t e m , o n t h e s p r e a d o fa c t i v a t i o n d u r i n g l e x i c a l a c ce s s . T h i s m a y s e r v e a s a n e x a m p l e o fh o w s u b j e c t i v e p s y c h o p a t h o l o g y , o b j e c t i v e p s y c h o l o g i c a l m e a -s u r e m e n t s , a n d u n d e r l y i n g b r a i n p h y s i o l o g y v i z ., n e u r o m o d u l a -t i o n ) c a n b e l i n k e d w i t h i n a s i n g l e c o n c e p t u a l f r a m e w o r k .

This work was supported by a grant from the Deutsche Forschungsge-meinschaft DFG Sp 364/I-2) to the first author.

R e f e r e n c e sC o h e n J D , S e r v a n - S c h r e i b e r D 1 9 9 2 ) : C o n t e x t , c o r t e x a n dd o p a m i n e : A c o n n e c t i o n i s t a p p ro a c h t o b e h a v i o r a n d b i o l o g yi n s c h i z o p h r e n i a . P s y c h o l R e v 1 2 : 4 5 - 7 7 .C o h e n J D , S e r v a n - S c h r e i b e r D 1 9 9 3 ) : A t h e o r y o f d o p a m i n ef u n c t i o n a n d i t s r o l e i n c o g n i t i v e d e f i c i t s i n s c h i z o p h r e n i a .S c h i z o p h r B u l l 1 9 : 8 5 - 1 0 4 .H o l z m a n n P P 1 9 9 5) : B e s t i m m u n g v o n P s il o c y b i n - M e t a b o l it e ni m H u m a n p l a s m a u n d - u ri n A n a l y s i s o f p s i l o c y b in m e t a bo -l i t e s i n h u m a n p l a s m a a n d u r i n e ) . P h D t h e s i s , T t i b i n g e n ,G e r m a n y .K i s c h k a U , K a m m e r T , W e i s b r o d M , M a i e r S , T h i m m M , S p i t z e rM 1 9 9 5) : D o p a m i n e r g i c m o d u l a t i o n o f s e m a n t ic n e t w o r ka c t i v a t i o n i n s u b m i s s i o n ) .P l e t s c h e r A , L a d e w i g D e d s ) 1 9 9 4 ) : 50 Years o f LSD. CurrentS ta tus and Per sp ect i ves o f Hal luc inogens . N e w Y o r k , L o n -d o n : P a r t h e n o n .

S e r v a n - S c h r e i b e r D , P r i n t z H , C o h e n J D 1 9 9 0 ) : A n e t w o r km o d e l o f c a t e c h o l a m i n e e f f e ct s : G a i n , s i g n a l - t o - n o i s e ra t i o ,a n d b e h a v i o r . S c i e n c e 2 4 9 : 8 9 2 - 8 9 5 .

S p i t z e r M 1 9 9 5 ) : A n e u r o c o m p u t a t i o n a l a p p r o a c h t o d e l u s i o n s .C o m p P s y c h i a t r y 3 6 : 8 3 - 1 0 5 .

S p i t z e r M , B r a u n U , M a i e r S , H e r m l e L , M a h e r B A 1 9 9 3 a ) :I n d i r e c t s e m a n t i c p r i m i n g i n s c h i z o p h r e n i c p a t i e n t s . S c h i z o p hR e s 1 1 : 7 1 - 8 0 .S p i t z e r M , B r a u n U , H e r m l e L , M a i e r S 1 9 9 3 b ) : A s s o c i a t i v e

s e m a n t i c n e t w o r k d y s f u n c t i o n i n t h o u g h t -d i s o r d e r e d s c h i z o -p h r e n i c p a t i e n t s : D i r e c t e v i d e n c e f r o m i n d i r e c t s e m a n t i cp r i m i n g . B i o l P s y c h i a t r y 3 4 : 8 6 4 - 8 7 7 .

S p i t z e r M , W e i s k e r I , M a i e r S , H e m a l e L , M a h e r B A 1 9 9 4 ) :S e m a n t i c a n d p h o n o l o g i c a l p r i m i n g i n s c h i z o p h r e n i a . J A bn o r m P s y c h o l o g y 1 0 3 : 4 8 5 - 4 9 4 .