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P h a r m a c o l o g i c a l a s p e c t s Brain mechanisms of hallucinogens and entactogens Franz X.Vollenweider,MD H allucinogens are a group of chemically hetero- geneous compounds,all with the ability to induce altered states of consciousness (ASC) characterized by profound alterations in mood,thought processes,perception,and experience of the self and environment other- wise rarely experienced except in dreams,contemplative and religious exaltation,and acute psychoses.The term hallucinogen seems to be somewhat inappropriate,since not all these drugs reliably produce visual and auditory hallucinations.1,2Therefore hallucinogens have been also This review focuses on recent brain imaging and behav- called psychotomimetic (psychosis-mimicking), psy- ioral studies of sensory gating functions, which assess cholytic (psyche-loosening),or psychedelic (mind-man- similarities between the effects of classic hallucinogens ifesting), reflecting the widely different attitudes and (eg, psilocybin), dissociative anesthetics (eg, ketamine), intentions with which these substances have been and entactogens (eg, 3,4-methylenedioxymethamphet- approached. As plant drugs,psychedelic hallucinogens have a long amine [MDMA]) in humans. Serotonergic hallucinogens and colorful history.Because of their ability to produce and psychotomimetic anesthetics produce overlapping a visionary and ecstatic state,they were often ascribed psychotic syndromes associated with a marked activa- magical or mystical properties.For centuries,they were tion of the prefrontal cortex (hyperfrontality) and other used restrictedly as sacraments in religious rites and peo- overlapping changes in temporoparietal, striatal, and ple in the Western world were hardly aware of their exis- thalamic regions, suggesting that both classes of drugs tence.Examples of the use of naturally occurring hallu- act upon a common final pathway. Together with the cinogens in various cultures include psilocybin derived observation that both hallucinogens and N-methyl-D- from the Aztec sacred magic mushroom teonanacatl, aspartate (NMDA) antagonists disrupt sensory gating in mescaline derived from the peyote cactus taken by rats by acting on 5-hydroxytryptamine (serotonin) 5-HT 2 Native Americans,or N,N-dimethyltryptamine (DMT), receptors located in cortico-striato-thalamic circuitry, the active ingredient of ayahuasca, a hallucinogenic these findings suggest that disruption of cortico-subcor- plant extract employed by Amazonian Indians.3 How- tical processing leading to sensory overload of the cortex ever,with the discovery of the hallucinogenic proper- is a communality of these psychoses. In contrast to hal- ties of the semisynthetic ergoline d-lysergic acid diethyl- lucinogens, the entactogen MDMA produces an emo- amide (LSD) by the Swiss chemist Albert Hofmann in tional state of positive mood, concomitant with an acti- 1943, hallucinogens and related compounds have vation of prefrontolimbic/paralimbic structures and a become the focus of modern scientific research.The deactivation of amygdala and thalamus. LSD-induced psychosis-like syndrome and the struc- Keywords: hallucinogen; psilocybin; entactogen; MDMA; NMDA antagonist; Address for correspondence: Psychiatric University Hospital Zurich, Clinical ketamine brain imaging; behavioral study Research Unit and Heffter Research Center Zurich, PO Box 68, CH-8029 Zurich, Switzerland Author affiliations: Psychiatric University Hospital Zurich, Clinical Research Unit (e-mail: [email protected]) and Heffter Research Center Zurich, Switzerland 265 P h a r m a c o l o g i c a l a s p e c t s Selected abbreviations and acronyms include phenylisopropylamines,such as 3,4-methylenedioxymethamphetamine (MDMA),3,4-methylenedioxy- AED anxious ego-dissolution ethylamphetamine (MDE),and related compounds. ASC altered states of consciousness This review summarizes recent experiments to elucidate CMRglu cerebral metabolic rate of glucose the neurobiological basis of the psychological effects of CSPT cortico-striato-pallido-thalamic psilocybin, ketamine, and MDMA, each representing CSTC cortico-striato-thalamo-cortical one of the three classes of psychedelics.Functional brain DA dopamine imaging with positron emission tomography (PET) was DMT N,N-dimethyltryptamine used to identify the brain regions or functional interac- DOI 2,5-dimethoxy-4-iodoamphetamine tions among the neurotransmitter systems involved in 18FDG 18F-fluorodeoxyglucose the action of these drugs.Furthermore,receptor mecha- 5-HT 5-hydroxytryptamine nisms of hallucinogenic and related drugs have been LSD d-lysergic acid diethylamide investigated by exploring the effects of specific receptor MDE 3,4-methylenedioxyethamphetamine antagonists on drug-induced psychological alterations MDMA 3,4-methylenedioxymethamphetamine and information-processing functions,such as sensori- NMDA N-methyl-D-aspartate motor gating as indexed by prepulse inhibition (PPI) of OB oceanic boundlessness the startle reflex. PCP phencyclidine The premise of the present review is that many of the PPI prepulse inhibition shared psychedelic effects of serotonergic hallucinogens VR visionary restructuralization and NMDA antagonists can be understood as an effect downstream of a common neurotransmitter system or tural similarity between LSD and serotonin (5-hydroxy- final pathway.First,both serotonergic hallucinogens and tryptamine [5-HT]) prompted the hypothesis that 5-HT NMDA antagonists produce sufficient overlapping psy- is involved in the pathophysiology of schizophrenia. chologial alterations despite different primary modes of Since then a number of newly discovered hallucinogens O or psychotomimetic agents,such as phencyclidine (PCP) N N CH3 and ketamine,have been used as models to study the H3CO NH3 neuronal basis of drug-induced ASC and its relation to N H3CO naturally occurring psychoses.4-6 N OCH3 Psychedelic hallucinogens can be classified by either H LSD Mescaline PCP chemical structure or their primary mode of action. Tinhdeo lamsoi-nceasl,lseudc h saesr postiolonceyrbgiinc anhda LlluScDin,aongde npsh eniynlceltuhdyle- OHH3C N CH3 NH2 amines,such as mescaline and 2,5-dimethoxy-4-iodoam- O NHCH3 HO phetamine (DOI) (Figure 1).Serotonergic hallucinogens N O H3CH N act primarily upon 5-HT1, 5-HT2, 5-HT6, and 5-HT7 PsilocinH (+)-MDMA Serotonin H receptors and partly upon the dopamine (DA) receptors D and D and the adrenergic α receptors.A second 1 2 2 Figure 1.Chemical structures of some important representatives of hallu- class of drugs with hallucinogenic properties often cinogens. Classic serotonergic hallucinogens include indolamines, referred to as psychedelic or dissociative anesthetics such as the semisynthetic lysergic acid diethylamide (LSD) and psilocybin/psilocin (the active principle of the sacred Aztec magic includes arylcyclohexylamines,whose most important rep- mushrooms), and phenylethylamines, such as mescaline (the resentatives are PCP and ketamine.These agents pri- active principle of peyote cactus). Indolamines and phenylethyl- marily act as antagonists of the N-methyl-D-aspartate amines share close structural features with the neurotransmitter serotonin (5-hydroxytryptamine [5-HT]). Dissociative or psyche- (NMDA) subtype of the glutamate receptor.Finally,a delic anesthetics include phencyclidine (PCP) and related drugs, third class of drugs,the so-called “entactogens,”produce such as ketamine. Entactogens, such as 3,4-methylene- psychedelic-like effects,but virtually no hallucinations. dioxymethamphetamine (MDMA), which produce psychedelic- like symptoms but virtually no hallucinations, are structurally They are closely related structurally to hallucinogenic closely related to both serotonergic hallucinogens (mescaline) and phenylethylamines and stimulant amphetamines and classic stimulants (amphetamines). 266 Brain mechanisms of hallucinogens and entactogens - Vollenweider Dialogues in Clinical Neuroscience - Vol 3 .No.4 .2001 action.Second,there is converging evidence from brain Psilocybin A 350 S-Ketamine imaging, behavioral, and electrophysiological studies MDMA 300 that both serotonergic hallucinogens and NMDA antagonists disrupt information processing within cortico- 250 striato-thalamic pathways implicated in the pathogene- bscore 200 sis of psychotic disorders. Since entactogens such as u 150 MDMA are expected to produce only mild psychedelic B s O symptoms,it will be of interest to know to what extent 100 MDMA-induced neurobiological alterations differ from 50 those seen in the states induced by hallucinogens and 0 NMDA antagonists. Positive Positive Changed sense Positive basic Mania-like experienced experienced of time mood experience derealization depersonalization Serotonergic hallucinogens and B 180 NMDA antagonists 160 140 Psychological effects e 120 or bsc 100 Among the key psychological functions that are altered u D s 80 by hallucinogens or NMDA antagonists are:(i) psychotic- E A like symptoms;(ii) changes in mood;and (iii) changes in 40 perception of time,self,and environment,including both 20 threatening or pleasant experiences of derealization and 0 depersonalization phenomena.These psychological func- Negative Thought Paranoia Loss of thought Loss of body experienced disorder control control tions share many aspects of prominent psychiatric symp- derealization toms of disorders such as schizophrenia or delusional dis- C 220 order,and can be assessed via standard psychiatric or 200 psychological rating scales.1 180 160 According to the work of Dittrich,7the common nucleus 140 of drug-induced ASC can be described by three dimen- e or 120 sions (factors) of the APZ questionnaire,which is an ASC ubsc 100 rating scale.2,8These dimensions are:(i) oceanic bound- VR s 80 lessness(OB),referring to dissolution of ego boundaries 60 associated with positive emotions ranging from height- 40 20 ns ened mood to sublime happiness and serenity or 0 grandiosity;(ii) anxious ego-dissolution (AED),including Elementary Scenery Synesthesias Changed meaning hallucinations hallucinations of perception thought disorder and loss of autonomy and self-control and illusions variously associated with arousal,anxiety,and paranoid ideations;and (iii) visionary restructuralization (VR) refer- Figure 2.Subscale scores of the altered states of consciousness (APZ) questionnaire for S-ketamine (n=68; 0.012 mg/kg/min IV), psilocybin ring to auditory and visional illusions,hallucinations,and (n=99; 0.26 mg/kg PO), and 3,4-methylenedioxymethamphet- altered meaning of perception.2,8As seen in Figure 2,both amine (MDMA) (n=74; 1.5-1.7 mg/kg PO) in healthy volunteers. psilocybin and ketamine produce either loss of ego With the exception of complex hallucinations after MDMA, S-ketamine-, psilocybin-, and MDMA-induced scores are all significant boundaries associated with positive emotions or negative compared with placebo. Values are means±SE, all P<0.05 or less. ego-disintegration associated with thought disorder and A.The oceanic boundlessness (OB) scale measures derealization loss of autonomy and self-control.9-12 and depersonalization associated with a positive basic mood ranging from heightened feelings to exaltation and alterations in the The ego-disintegration and the loss of self-control over sense of time. B.The anxious ego-dissolution (AED) scale mea- thought process and intentionality,and the uncertainty or sures ego-disintegration and loss of autonomy and self-control lack in differentiating between ego and nonego spheres associated with arousal and anxiety. C.The visionary restructuralization (VR) scale measures alterations in perception and meaning. observed in psilocybin- and ketamine-induced psychoses 267 P h a r m a c o l o g i c a l a s p e c t s are highly reminiscent of acute schizophrenic decom- inability of these patients to screen out,inhibit,filter,or pensation.13-17Also,the finding of heightened awareness gate extraneous stimuli and to attend selectively to associated with euphoria in psilocybin- and ketamine- salient features of the environment.Gating deficits may treated subjects is consistent with the view that the ear- cause these subjects to become overloaded with exces- liest affective changes in schizophrenic patients are often sive exteroceptive and interoceptive stimuli,which,in pleasurable or exhilarating.18-21 Furthermore, prospec- turn,could lead to a breakdown of cognitive integrity tive22 and comparative studies indicate that perceptual and difficulty in distinguishing self from nonself.44,45 disturbances including the heightened sensitivity,audi- In recent years,this theoretical construct has been suc- tory and visual illusions,and hallucinations reported by cessfully operationalized by measuring the behavioral ketamine- and psilocybin-treated subjects are promi- plasticity of acoustic startle responses,such as PPI and nent features of prodromal, early, and acute schizo- habituation.46 Symptomatic schizophrenia patients phrenic patients.21,23-25 Similar findings were reported in exhibit deficits in both PPI and habituation.Extensive comparable studies in healthy volunteers receiving psilo- lesion and drug studies in rodents have demonstrated cybin or the phenylethyamine hallucinogen mescaline.26,27 that sensorimotor gating functions, such as PPI, are Thus,the present evidence suggests that hallucinogen- subject to considerable forebrain modulation from induced ASC share many common phenomenological cortical, limbic, striatal, pallidal, and thalamic struc- features with the early acute stages of the schizophrenic tures, including cortico-striato-pallido-thalamic disorders and may provide useful models to elucidate (CSPT) circuitry.46,47Moreover,animal studies indicate the neuronal basis of productive symptoms of schizo- that hallucinogens,amphetamines including MDMA, phrenic pathophysiology.However,despite the number and NMDA antagonists disrupt sensorimotor gating of similarities between the psilocybin and ketamine in rats by interacting with different components of the models of psychoses,substantial differences have also CSPT loop. These findings are consistent with the become apparent in the limited human studies. “thalamic filter hypothesis of psychosis,”advanced by Specifically,it appears that both S-ketamine and racemic Carlsson and Carlsson.48This theory proposes that cor- ketamine produced more pronounced anxiety,thought ticostriatal pathways exert a modulatory influence on disturbances, and ego-disintegration than psilocybin. the thalamic gating of sensory information to the cere- Moreover,in contrast to psilocybin,both S-ketamine and bral cortex (Figure 3).49 Theoretically,an impairment racemic ketamine produced transient apathy,emotional of thalamic filtering should result in sensory overload withdrawal,and feelings of indifference,which resem- of the cortex, leading to a breakdown of integrative bled the negative symptoms of schizophrenia in many cortical functions,and subsequently to positive symp- ways.This finding is consistent with the view that keta- toms such as delusions,hallucinations,thought distur- mine and PCP induce thought disturbances and cognitive bances,persecution,and loss of a coherent ego expe- impairments in healthy subjects,which mimic those seen rience. In addition, various negative symptoms, such in schizophrenia,including deficits in working memory, as emotional and social withdrawal, could result attention,abstract reasoning,decision making,and plan- from—and be understood as—efforts to protect from ning.28-31Thus,it has frequently been argued that the state input overload. produced by NMDA antagonists may more closely On the basis of these findings and the thalamic filter mimic naturally occurring schizophrenias (Table I).10-12,28-41 model, ACSs induced by hallucinogens and NMDA antagonists in humans can be conceptualized as com- Cortico-striato-thalamic loops:a common pathway? plex disturbances that arise from more elementary deficits of sensory information processing in cortico- Theories regarding the neuronal basis of the sympto- striato-thalamo-cortical (CSTC) feedback loops.6,50The matology of schizophrenic psychoses have often sug- model proposes that NMDA antagonists may disrupt gested that deficits in early information processing may thalamic filter functions and produce sensory overload underlie the diversity of psychotic symptoms and cogni- of cortical areas,particularly of the prefrontal cortex, tive disturbances observed in the group of schizophre- by blocking NMDA receptors located on corticostriatal nias.42-44Such theories posit that a fundamental feature of pathways, while serotonergic hallucinogens may alter information processing dysfunction in psychosis is the thalamocortical transmission by stimulation of 5-HT 2 268 Brain mechanisms of hallucinogens and entactogens - Vollenweider Dialogues in Clinical Neuroscience - Vol 3 .No.4 .2001 Psilocybin Ketamine MDMA Schizophrenias Receptor level Primary locus of action 5-HT , 5-HT NMDA 5-HT transporter,* Unknown 2A 1A 5-HT , 5-HT , 2A 1A α,H 2 1 Downstream effects on GABA, D, 5-HT , D, D 1 2A 1 2 D, mGluR GABA, D, D, 2 1 2 mGluR Psychopathology Positive symptoms •Hallucinations/illusions ++ + - ++ •Delusions + + - ++ •Thought disorder + ++ + ++ Negative symptoms •Blunted affect 0 - + + - ++ - ++ •Withdrawal + + - ++ - ++ Depersonalization + - ++ ++ + ++ Derealization + ++ + ++ Neuropsychology •Attention disturbance + - ++ + + ++ •Distractibility + ++ - ++ •Working memory + ++ ? ++ •Associative deficits + + - ++ ? ++ •Planning/mental flexibility ++ ? ? ++ Cortical activity •Frontal (PET) ++ (acute) ++ (acute) (+) ++ (acute) -- (chronic)** -- (chronic) Table I.Comparison of effects of psilocybin (0.2-0.24 mg/kg PO), S-ketamine (0.01-0.02 mg/kg/min), and 3,4-methylenedioxymethamphetamine (MDMA) (1.5-1.7 mg/kg PO), and symptoms in schizophrenias (summarized from references 10-12, 28-31, and 33-41). 5-HT, 5 hydroxytryptamine; GABA, γ-aminobutyric acid; NMDA, N-methyl-D-aspartate; mGluR, metabotropic glutamate receptor; D1, D2, dopamine receptors; H1, histamine receptor; α, α adrenergic receptor. *MDMA has highest affinity for the 5-HT transporter (K=0.61 µM) and lesser for α (K=3.6 µM) 2 2 i 2 i and 5-HT receptors (K=5.1 µM) in rat brain. **Chronic administration of NMDA antagonists in rats decreases frontal cortical activity. 2 i receptors located in several components of the CSTC PET with the radiotracer 18F-fluorodeoxyglucose (18FDG) loop,including the prefrontal cortex,striatum,nucleus was used to assess drug-induced changes in the regional accumbens,and thalamus (for details,see reference 49). cerebral metabolic rate of glucose (CMRglu),as an index of cerebral activity.We found that a hallucinogenic dose Brain imaging studies of racemic ketamine increased neuronal activity in the prefrontal cortex (hyperfrontality) and associated limbic Until recently,many neural circuit models were based on regions,as well as in striatal and thalamic structures in animal studies,and implications for the effects of hallu- healthy volunteers,giving the first evidence that func- cinogenic drugs or disease models in humans were based tional alterations in CSTC loops may underlie the symp- on inferences from these studies.However,functional tomatology of drug-induced ASC.50This hyperfrontal- neuroimaging studies enable one to examine these ity finding was corroborated and extended in subsequent neural circuit models directly and test specific hypothe- studies in healthy volunteers in which the effects of hal- ses about the role of specific neural systems in the lucinogens and NMDA antagonists including psilocy- expression of ASC. bin,racemic ketamine,and S-ketamine were compared. 269 P h a r m a c o l o g i c a l a s p e c t s CSTC feedback loops Sensory association cortex First projected area Frontal Temporal cortex cortex Hippocampus Corpus mamillaria Glu Sensory input Glu Glu Ventral Ventral GABA striatum pallidum 5-HT DA DA VTA SNc Thalamus 5-HT 5-HT Raphe Figure 3.The limbic cortico-striato-thalamic-cortical (CSTC) feedback loops are involved in memory, learning, and self–nonself discrimination by linkage of cortically categorized exteroceptive perception with internal stimuli of the value system. The filter function of the thalamus, which is under the control of the CSTC feedback/reentry loops, is postulated to protect the cortex from exteroceptive sensory information overload, as well as from internal overarousal. The model predicts that sensory overload of the cortex and psychosis may result from thalamic gating deficits, which may be caused by ketamine by blockade of N-methyl-D-aspartate (NMDA)–mediated glutamatergic (Glu) corticostriatal and/or by increasing mesolim- bic dopaminergic (DA) neurotransmission. Excessive stimulation of serotonin 5-HT receptors (for example, by psilocybin) may lead to a similar 2 neurotransmitter imbalance in the CSTC loops, which again results in an opening of the thalamic filter, sensory overload of the cortex, and psychosis. VTA, ventral tegmental area; SNc, substantia nigra pars compacta; GABA, γ-aminobutyric acid; (cid:1), NMDA receptor. Modified from reference 49: Vollenweider FX, Greyer MA. A systems model of altered consciousness: integrating natural and drug-induced psychoses. Brain Res Bull. 2001;56:495- 507. Copyright © 2001, Elsevier Science. In particular,we found that,despite different primary Correlations between cerebral activity mechanisms of action,the two classes of drugs produced and psychological alterations strikingly similar brain activation patterns as indexed by normalized CMRglu.Both psilocybin and ketamine The correlation of changes in cerebral activation with markedly increased brain activity bilaterally in the fron- changes in self-assessment enables one to further cor- tomedial and frontolateral cortex,including the ante- roborate the role of specific neural substrates in these rior cingulate.Lesser increases were found in the tem- psychological functions.Correlational analysis between poromedial, superior, and inferior parietal cortices, normalized metabolic activity and psychological scores striatum,and thalamus.Decreases were found in the left of the APZ questionnaire revealed that the severity of caudate nucleus, bilaterally in the ventral striatum, OB correlated positively with CMRglu bilaterally in occipital lobe, and visual pathway.9-11 A correlational frontomedial superior,frontolateral,and left inferolateral analysis revealed that the metabolic hyperfrontality in prefrontal cortex,anterior cingulate,as well as bilaterally ketamine and psilocybin subjects was associated with a in inferior parietal and occipitomedial cortex.6There depersonalization/derealization syndrome,thought dis- were negative correlations between OB and CMRglu turbances, and mania-like symptoms.9-11 The hyper- bilaterally in the hippocampus and caudate nucleus,and frontality finding in ASC was further supported by evi- left amygdala and ventral striatum (Figure 4A). dence from brain imaging studies with ketamine and The OB dimension,which relates to the altered percep- psilocybin in healthy volunteers27,51and was also found in tion of time and space as well as the pleasurable expe- subjects treated with the classic phenylethylamine hal- rience of dissolution of ego-boundaries and which can lucinogen mescaline.52 culminate in transcendental or “mystical” states, sub- 270 Brain mechanisms of hallucinogens and entactogens - Vollenweider Dialogues in Clinical Neuroscience - Vol 3 .No.4 .2001 A. Oceanic F M G FMG boundlessness FSG FSG MG DLPC CAU IPL OCM OCM IPC FMG F CAU NAC HIPP DLPC AMY HIPP B. Anxious ego-dissolution AC PUT THAL THAL AC OF TMG OF C. Visionary restructuralization IPC GA&GS DLPC GA&GS GPE GL ParaHipp ITC GL GF Left hemisphere Right hemisphere Figure 4.Correlations between the three dimensions of the APZ questionnaire for altered states of consciousness (oceanic boundlessness [OB], anxious ego-dissolution [AED], and visionary restructuralization [VR]) and regional brain activity (cerebral metabolic rate of glucose [CMRglu]) in healthy volunteers under psilocybin (0.26 mg/kg PO) or S-ketamine (0.012 mg/kg/min IV) challenge (n=52, P<0.0001). A.The OB dimension. The activation of a prefrontal-parietal network in parallel with the deactivation of a striato-limbic-amygdala-centered network correlated with the OB dimesion measuring derealization and depersonalization associated with positive emotions ranging from enhanced mood to feelings of happiness and serenity, or grandiosity. B.The AED dimension. Thalamic hyperactivity in conjunction with decreased activity in orbitofrontal and ventral anterior cingulate cortex and left putamen correlated with the AED dimension measuring thought disorder and ego-disintegration, and loss of self-control variously associated with anxiety, panic, and paranoid ideations. C.The VR dimension. Activation of the dorsolateral prefrontal cortex (DLPC) and of components of the dorsal (inferioparietal cortex [IPC], angular gyrus [GA], supramarginal gyrus [GS]) and ventral stream (inferiotemporal cortex [ITC]) of higher order visual processing (ITC) in parallel with deactivation of strital and limbic regions correlated with VR comprising visual hallucinations, synesthesias and changed meaning of percepts. Positive correlations are indicated by circles and negative correlations by rectangles. FMG, frontomedial gyrus; FSG, frontosuperior gyrus; IPL, inferiorparietal lobe; OCM, occipitomedial cortex; CAU, caudate nucleus; NAC, nucleus accumbens; AMY, amygdala; HIPP, hippocampus; OF, orbitofrontal cortex; AC, anterior cingulate; PUT, putamen; TMG, temporomedial gyrus; THAL, thalamus; GL, lingual gyrus; GF, fusiform gyrus; GPE, globus pallidus; ParaHipp, parahippocampus. 271 P h a r m a c o l o g i c a l a s p e c t s stantially relates to functional alterations in an extended tions were found in left globus pallidus and parahip- frontolimbic-parieto-striatal network including the pocampus, and bilaterally in visual pathways (gyrus amygdala.Indeed,according to current views,in con- fusiformis and lingualis).Thus,it appears that visual hal- junction with parietal and limbic areas,the frontal cortex lucinations are associated with abnormal prefrontal acti- is critical for the construction and maintenance of a vation in conjunction with activation of sensory modal- coherent self.In its executive faculty,the frontal cortex, ity-specific cerebral structures involved in normal including the anterior cingulate, has an active role in perception,which is similar to the situation reported in structuring time,directing attention to relevant extero- patients with auditory hallucinations (Figure 4C).60 ceptive or interoceptive stimuli, and initiating and expressing appropriate behaviors.53-55The parietal cor- Hyperfrontality as an index of acute psychoses tex is important for determining the relationship of the self to extrapersonal space,based on visuospatial input The hyperfrontality finding and its association with pos- from the dorsal stream of visual information process- itive psychotic symptoms seen in drug-induced ASC is of ing.56Together with motor and somatosensory cortical particular interest because it appears to parallel similar areas, the frontolimbic-parietal network is sometimes findings in some studies in acutely ill schizophrenic and called “central neural authority”57 to express the idea nonschizophrenic psychotic patients.36,38,61,62Interestingly, that it constitutes a functional system crucially involved one of these studies reported that hyperperfusion in the in ego-structuring processes and the formation and rep- frontal,anterior cingulate,parietal,and temporal cor- resentation of a coherent self that is defined in time and tices,which correlates with positive symptoms includ- space. On the basis of these theoretical concepts, it ing formal thought disorder and grandiosity in drug- appears plausible that overstimulation of the central naive schizophrenic patients, was normalized after neural authority may lead to profound alterations of neuroleptic treatment, and that persisting negative self-experience and space/time perception,as reflected symptoms correlated with frontal,cingulate,basal,and by the increased OB scores in hallucinogen-induced thalamic hypoperfusion.38An activation of prefrontal ASC. Finally, the concomitant decrease in amygdala and cingulate cortex with transient exacerbation of pos- activity may account for the more pleasurable experi- itive psychotic symptoms was also reported in chronic ences associated with the OB dimension. schizophrenics during ketamine challenge.63These find- The severity of anxious ego-dissolution (AED) was pos- ings suggest that metabolic hyperfrontality (rather than itively correlated with CMRglu in the thalamus and left hypofrontality, as seen in chronic schizophrenia) is a temporomedial gyrus, and negatively correlated with pathophysiological manifestation of certain acute psy- CMRglu bilaterally in orbitofrontal cortex and adjacent chotic symptoms in drug-induced and naturally occur- anterior cingulate.Thus,it appears that AED and the ring psychoses.This view is further supported by the associated thought disorder depend mainly on thalamic finding that pretreatment with the atypical antipsychotic overactivity and orbitofrontal underactivity (Figure 4B). clozapine reduced S-ketamine-induced hyperfrontality This finding may indicate enhanced thalamic transmis- and thalamic activation associated with psychotic symp- sion and support the view that deficient thalamic gat- toms in normal volunteers.64 In the light of such evi- ing leads to sensory overload of the cortex and psy- dence,it would be expected that drugs that reduce or chosis.In fact,thalamic (and anterior cingulate-parietal) prevent excessive prefrontal activation might be useful overactivity was associated with disorganization in schiz- for treating positive and cognitive symptoms of schizo- ophrenic patients.58Malfunction of the orbitofrontal cor- phrenia. tex may account for the continuing intrusion of irrele- vant stimuli into the stream of mental activity and lead Convergence on neurotransmitter systems to the perseverations,thought blocking,and difficulty concentrating that are typically associated with AED.59 The hyperfrontality common to the psilocybin and ket- The severity of VR (including hallucinations) was posi- amine models of psychoses also supports the idea that tively correlated with CMRglu in the left dorsolateral psychedelic hallucinogens and psychotomimetic NMDA prefrontal and inferior temporal cortex, bilaterally in antagonists may mediate some of their effects through a temporo-parietal association cortex.Negative correla- common final pathway or neurotransmitter system, 272 Brain mechanisms of hallucinogens and entactogens - Vollenweider Dialogues in Clinical Neuroscience - Vol 3 .No.4 .2001 downstream of their primary locus of action.In particu- only about 36% of the variance of positive symptoms, lar,the similarity of the effects of psilocybin and keta- indicating that other neurotransmitter systems con- mine on ego functions,cognition,and perception under- tribute to the pathogenesis of ketamine- and psilocybin- score recent animal and human findings suggesting a induced symptomatology. In support of this view, we convergence in their behavioral effects,despite the dif- found that the D antagonist haloperidol has virtually no 2 ferences in their primary mechanisms of action. effect on psilocybin-induced cognitive impairments and Of particular relevance to sensory overload theories of reduced psychotic symptoms by only about 30% in drug-induced ASC are behavioral measures of sensori- psilocybin-treated subjects.12Similarly,recent results in motor gating functions, such as PPI of the startle healthy subjects demonstrate that ketamine psychosis response.65The cross-species study of homologue gating is not ameliorated by haloperidol pretreatment.41Com- functions such as PPI in animal and human models of parably,haloperidol had also virtually no effect on the psychosis offers a unique possibility for the exploration PPI-disruptive effect of the hallucinogenic 5-HT agonist 2 of neurobiological substrates relevant to schizophrenia. DOI and the NMDA antagonist PCP in animal models Symptomatic schizophrenics and never-medicated first- of psychosis.65,75 Given these findings, it appears that episode schizophrenia patients exhibit deficits in PPI, increased DA activity may play a minor role in both which have been suggested to be central to the psychotic psilocybin- and ketamine-induced ASC. symptomatology of the illness.42,66Indeed,the most strik- ing correlate of deficient PPI in schizophrenia is a mea- Role of serotonin sure of thought disorder derived from the Rorschach test.67Similarly,in rats,both serotonergic hallucinogens During the last decade, accumulating evidence from and NMDA antagonists produce deficits in PPI.68Exten- binding,electrophysiological,and behavioral studies in sive pharmacological studies in animals demonstrate animals suggested that indoleamine and phenylethyl- that PPI is modulated by multiple interacting neuro- amine hallucinogens may produce their psychological transmitters,including the dopaminergic,serotonergic, effects via the 5-HT receptors in the brain (for details, 2A cholinergic, GABAergic, and glutamatergic systems see references 76 and 77).However,although the pre- within CSPT pathways.46 ponderance of evidence suggested that hallucinogens are agonists at 5-HT receptors,this issue was clouded 2A Role of dopamine by studies that demonstrated LSD to be a partial ago- nist78or even an antagonist79at 5-HT receptors.More- 2A In keeping with the DA hyperactivity hypothesis of over, since LSD, 5-methoxy-DMT, DMT, and psilocin schizophrenia,we hypothesized that increased striatal have been shown to display high affinity for,and to act DA activity could also contribute to the S-ketamine- as agonists at,5-HT receptors,the role of 5-HT and 1A 1A and psilocybin-induced symptomatology in humans, 5-HT receptors in the generation of hallucinosis in 2A although S-ketamine and psilocybin have no affinity for man remains elusive. D receptors.69,70This hypothesis has been tested using The important question as to whether serotonergic hal- 2 PET and [11C]raclopride. Reduction in [11C]raclopride lucinogens are agonists or antagonists at 5-HT and 2A binding potential (BP) has been well established as an 5-HT receptors has recently been answered.Consis- 2C indirect measure of the change in synaptic DA concen- tent with animal studies,we have demonstrated that the tration in animal and human studies.71,72Indeed,both S- psychological effects of psilocybin in humans can be com- ketamine and psilocybin significantly reduced [11C]raclo- pletely blocked by the preferential 5-HT antagonist 2A pride BP in ventral striatum consistent with an increase ketanserin.12 In addition,preliminary data demonstrate in striatal DA concentration.73,74Moreover,these changes that the metabolic hyperfrontality and PPI disruptive in [11C]raclopride BP significantly correlated with deper- effects of psilocybin in humans can be reversed by sonalization, supporting the view that excessive DA ketanserin.80,81Since ketanserin has no affinity for 5-HT 1A transmission at D receptors contributes to the genera- receptors,this finding suggests that serotonergic hallu- 2 tion of positive psychotic symptoms in ketamine- and cinogens produce their central effects through a com- psilocybin-treated subjects.However,the DA-mediated mon action upon 5-HT receptors. The fact that 2 change in [11C]raclopride BP at D receptors explained ketanserin has about 100-fold greater antagonistic 2 273 P h a r m a c o l o g i c a l a s p e c t s potency at 5-HT than at 5-HT receptors indicates gens,85 appear to be ineffective when administered 2A 2C that the psychological effects of psilocybin are mediated directly into the DA-rich nucleus accumbens.92 by 5-HT rather than 5-HT receptor activation. 2A 2C This interpretation is corroborated by the finding that Role of glutamate the highly selective 5-HT receptor antagonist 2A M100,907,but not 5-HT antagonists,blocks the dis- Recent electrophysiological studies have produced new 2C ruption of PPI in rats produced by serotonergic hallu- evidence that both psychedelic hallucinogens and cinogens.82,83Moreover,the effects of serotonergic hallu- NMDA antagonists activate the serotonergic system and cinogens (LSD and DOI) on sensorimotor gating in rats enhance glutamatergic transmission via non-NMDA are mediated,at least in part,through 5-HT receptors receptors in the frontal cortex.93,94Whether this common 2A located within the ventral pallidum,83,84 a component of mechanism contributes to the higher-level cognitive,per- the CSPT loop.85 These findings suggest that both ceptual,and affective effects of serotonergic hallucinogen indolamine and phenylethylamine hallucinogens may and NMDA antagonists warrants further investigation.40 alter thalamic filter functions through 5-HT receptors Taken together, serotonergic hallucinogens and psy- 2A associated with pallidostriatal input to the thalamus.They chotomimetic NMDA antagonists produce schizophre- also support the view that antagonist actions at the 5- nia-like deficits in behavioral measures of sensory gating HT receptors may have an important contribution to such as PPI,and do so by actions localized to different 2A the unique clinical efficacy of atypical antipsychotics such parts of the CSPT circuitry.Despite their different pri- as clozapine in the treatment of the schizophrenias.86 mary mechanisms and sites of action,however,a com- Although psychotomimetic NMDA antagonists (eg,ket- mon denominator of the effects of these drug classes amine) act primarily through a noncompetitive NMDA is that they alter the dynamics of the integrated CSPT blockade of the NMDA subtype of the glutamate recep- circuitry such that normal information processing is tor,there is converging evidence implicating 5-HT mech- distorted by deficits in fundamental forms of sensori- anisms,particularly those involving 5-HT receptors,in motor gating. 2A the action of NMDA antagonists.For example,it has been shown that the psychological effects of ketamine Serotonergic amphetamines: MDMA are ameliorated by the mixed 5-HT /D and atypical 2 2 antipsychotic clozapine,but are virtually insensitive to Psychological effects typical antipsychotics that have preferential actions at D receptors,such as haloperidol.87 Moreover,prelimi- In contrast to serotonergic hallucinogens and NMDA 2 nary data from our laboratory show that clozapine antagonists,a typical recreational and nontoxic dose of reduces S-ketamine-induced metabolic hyperfrontality MDMA (1.5-7 mg/kg PO) produces an affective state and associated psychotic symptoms in healthy human of enhanced mood, profound well-being, happiness, volunteers.64,80These findings parallel observations in ani- increased extroversion and sociability,slight derealiza- mal studies demonstrating that the PPI-disruptive effects tion and depersonalization,little anxiety,and moderate of NMDA antagonists in rats are blocked by the atypical thought disturbances,but no hallucinations in normal antipsychotics (eg,clozapine or olanzapine),88,89 but are volunteers.95 Depersonalization phenomena are mild generally insensitive to typical antipsychotics (eg, and, in contrast to hallucinogens (eg, psilocybin), not haloperidol).90Moreover,the fact that the highly selective experienced as problematic or psychotic fusion, but 5-HT receptor antagonist M100,907 is also effective in experienced as a pleasurable state of loosened ego 2A blocking the PPI-disruptive effects of NMDA antago- boundaries as measured by the APZ questionnaire (Fig- nists in rats91strongly suggests that the psychotomimetic ure 2).Similar findings were reported with MDMA and effects of NMDA antagonists in humans involve 5-HT its congener MDE in healthy volunteers.96-100 2 receptor activation.Finally,studies in rats have indicated that the NMDA antagonists produce these gating deficits Brain imaging studies by actions within particular parts of the CSPT circuitry, including the frontal cortex and hippocampus.92Interest- To identify the functional neuroanatomy involved in ingly,NMDA antagonists,like serotonergic hallucino- the action of MDMA in humans,the effect of MDMA 274