Evidence for a common biological basis of the absorption trait hallucinogen effects and positive symptoms Epistasis between 5-HT2a and COMT polymorphisms.код для вставкиСкачать
American Journal of Medical Genetics Part B (Neuropsychiatric Genetics) 137B:29 –32 (2005) Brief Research Communication Evidence for a Common Biological Basis of the Absorption Trait, Hallucinogen Effects, and Positive Symptoms: Epistasis Between 5-HT2a and COMT Polymorphisms Ulrich Ott,1* Martin Reuter,1 Juergen Hennig,1 and Dieter Vaitl1,2 1 Center for Psychobiology and Behavioral Medicine, University of Giessen, Germany Department of Clinical and Physiological Psychology, University of Giessen, Germany 2 Absorption represents a disposition to experience altered states of consciousness characterized by intensively focused attention. It is correlated with hypnotic susceptibility and includes phenomena ranging from vivid perceptions and imaginations to mystical experiences. Based on the assumption that drug-induced and naturally occurring mystical experiences share common neural mechanisms, we hypothesized that Absorption is influenced by the T102C polymorphism affecting the 5-HT2a receptor, which is known to be an important target site of hallucinogens like LSD. Based on the pivotal role ascribed to the prefrontal executive control network for absorbed attention and positive symptoms in schizophrenia, it was further hypothesized that Absorption is associated with the VAL158MET polymorphism of the catechol-O-methyltransferase (COMT) gene affecting the dopaminergic neurotransmitter system. The Tellegen Absorption Scale was administered to 336 subjects (95 male, 241 female). Statistical analysis revealed that the group with the T/T genotype of the T102C polymorphism, implying a stronger binding potential of the 5-HT2a receptor, indeed had significantly higher Absorption scores (F ¼ 10.00, P ¼ 0.002), while no main effect was found for the COMT polymorphism. However, the interaction between T102C and COMT genotypes yielded significance (F ¼ 3.89; P ¼ 0.049), underlining the known functional interaction between the 5-HT and the dopaminergic system. These findings point to biological foundations of the personality trait of Absorption. ß 2005 Wiley-Liss, Inc. KEY WORDS: molecular genetics; absorption trait; T102C; serotonin; dopamine The personality trait of Absorption represents ‘‘an openness to absorbing and self-altering experiences’’ correlated with *Correspondence to: Ulrich Ott, Center for Psychobiology and Behavioral Medicine, University of Giessen, Otto-BehaghelStreet 10F, 35394 Giessen, Germany. E-mail: Ulrich.Ott@psychol.uni-giessen.de Received 6 December 2004; Accepted 21 April 2005 DOI 10.1002/ajmg.b.30197 ß 2005 Wiley-Liss, Inc. hypnotic susceptibility [Tellegen and Atkinson, 1974]. The items of the Tellegen Absorption Scale [Tellegen, 1982] describe strong emotional responses to the beauty of nature, music and poetry, synesthetic impressions, paranormal experiences, thinking in images, absorbed attending to movies or plays, vivid memories and daydreams, and a mystical widening of consciousness. A core feature of this wide variety of experiences is a special kind of focused attention wherein it appears that one phenomenal object occupies all representational resources: ‘‘objects of absorbed attention acquire an importance and intimacy that are normally reserved for the self and may, therefore, acquire a temporary self-like quality. These object identifications have mystical overtones. And, indeed, one would expect high-Absorption persons to have an affinity for mystical experience. . .’’ [Tellegen and Atkinson, 1974]. Recently, it has been proposed that LSD and nondruginduced mystical experiences share common neural mechanisms related to the serotonergic neurotransmitter system [Goodman, 2002]. There is converging evidence that the site of action of LSD is the 5-HT2a receptor [Aghajanian and Marek, 1999; Nichols, 2004]. Thus, inter-individual differences in the disposition to experience mystical states of consciousness could be based, at least in part, on the binding potential of serotonergic receptors. A similar hypothesis was formulated by Borg et al. , who found in a positron emission tomography (PET) study a significant association between the binding potential of 5-HT1A receptors and spiritual experiences, assessed with the scale ‘‘self-transcendence’’ of the temperament and character inventory [Cloninger et al., 1994]. The phenomena included in the Absorption scale show striking similarities to alterations of consciousness reported after LSD ingestion, namely fascination and absorption by perceptual or imaginational objects, synesthesia, and mystical states. Consequently, it was hypothesized that the proneness to Absorption was mediated partly by the serotonergic system. In order to test this hypothesis, an approach from molecular genetics was used to test for associations between the trait of Absorption and a candidate gene of the serotonergic system. The T102C polymorphism of the 5-HT2a gene was chosen due to its relevance for the pharmacological effects of LSD [Aghajanian and Marek, 1999; Nichols, 2004] and due to reported associations with schizophrenia [Williams et al., 1996; Abdolmaleky et al., 2004]. Positive symptoms in schizophrenic patients resemble hallucinations induced by psychostimulants and could be considered as extreme form of Absorption phenomena observed in healthy individuals. The 5-HT2A T102C marker located on chromosome 13 q14-q21 is a silent single nucleotide polymorphism (SNP) so that the C to T substitution does not alter the amino acid sequence and therefore the receptors encoded by the ‘‘C’’ and ‘‘T’’ allele are identical. 30 Ott et al. However, the 5-HT2a T102C polymorphism has been shown to be associated with numerous psychopathologies including schizophrenia [Polesskaya and Sokolov, 2002] indicating that this SNP is a marker polymorphism being in linkage with another still unidentified gene locus which is of functional relevance. The prevalence of the T- and C-allele in Caucasian populations is about 0.41 and 0.59, respectively [Bondy et al., 2000]. It was expected that the group with the T/T genotype of the T102C polymorphism would obtain higher Absorption scores, since a lower receptor binding in carriers of the C-allele of the 5-HT2a polymorphism has been revealed in a PET study [Turecki et al., 1999]. The close connection of Absorption with hypnotic susceptibility was the starting point for a second line of reasoning. Neuroscientific approaches to the hypnotic process emphasize the superior ability of highly hypnotizable subjects to regulate their attention [Crawford, 1994]. In a PET study, mental absorption during hypnosis was found to be correlated with increased activity in the anterior cingulate cortex (ACC) [Rainville et al., 2002]. The ACC is the key structure of the executive control network and a target area of the dopaminergic (DA) system [Raz and Shapiro, 2002]. Indeed, an association was found between hypnotic susceptibility and the catechol-O-methyltransferase (COMT) polymorphism [Lichtenberg et al., 2000]. COMT is an enzyme, which has a crucial role in the metabolism of catecholamines by inactivating them in the synaptic cleft. A SNP, a G!A transition in codon 158 of the COMT gene located at the q11 band of human chromosome 22, results in three to fourfold difference in COMT enzyme activity [Lachman et al., 1996] by coding for the synthesis of the amino acid methionine (MET) instead of valine (VAL). Heterozygotes (VAL/MET genotype) have intermediate levels of COMT activity [Lachman et al., 1996; Syvänen et al., 1997]. The prevalence of the MET and the VAL allele is about 50% in Caucasian populations. The Absorption scale was also administered in the study by Lichtenberg et al. . While Absorption was significantly correlated with hypnotic susceptibility, no relationship of Absorption with the COMT polymorphism was observed. However, there was a trend for individuals with the MET/MET genotype to obtain lower Absorption scores, which did not reach significance due to the high variance of the scores and the low sample size (N ¼ 109). Therefore, it was hypothesized that inter-individual differences in the capacity for absorbed attention were also influenced by genetic variations affecting the DA system. In order to test this hypothesis, the association between the trait of Absorption and the COMT polymorphism was investigated. A trend similar to that reported above [Lichtenberg et al., 2000] was expected. Interactions between the polymorphisms were tested because on the one hand 5-HT inhibits DA release via 5-HT2a postsynaptic receptors [e.g., Porras et al., 2002] and on the other hand hallucinations in schizophrenic patients which resemble effects of LSD and other hallucinogens can be reduced by typical antipsychotics which are DA-antagonists. Yet, a study on the influence of the DA-antagonist haloperidol on psychological effects of the hallucinogen psilocybin [Vollenweider et al., 1998] found that only some effects were reduced (derealization and depersonalization), while others were left unchanged (illusions, pseudo-hallucinations, synesthetic phenomena) or even enhanced (thought disorder, anxious ego-disintegration). Therefore, we had no directed hypothesis about the interaction between the 5-HT2a and the COMT polymorphism. The Tellegen Absorption Scale (TAS) was administered to 336 subjects (95 male, 241 female; age: M ¼ 24.7, SD ¼ 5.6 years), mostly students of the University of Giessen, Germany. In order to improve the psychometric properties of the TAS, the response format of the German version [Ritz and Dahme, 1995] has been changed from the original dichotomous format (‘‘True’’ or ‘‘False’’) to a five-point scale ranging from ‘‘does not apply’’ to ‘‘does fully apply’’ (coded as item scores from 0 to 4). DNA was extracted from buccal cells to avoid a selective exclusion of subjects with blood and injection phobia. Purification of genomic DNA was performed with a standard commercial extraction kit (High Pure PCR Template Preparation Kit; Roche Diagnostics, Mannheim, Germany). Genotyping of the 5-HT2a T102C and the COMT VAL158MET polymorphisms was performed by real time PCR using fluorescence melting curve detection analysis by means of the Light Cycler System (Roche Diagnostics). The primers and hybridization probes used (TIB MOLBIOL, Berlin, Germany) and the PCR protocols were as follows. 5-HT2a: forward primer: 50 -CTTATATGTGTGAGTCTGAGTGG-30 ; reverse primer: 50 -CCATGATGACGAGTATGTTT-30 ; anchor hybridization probe: 50 -LCRed640-CTTCTGATGCATTTAACTGGACAGTCG-phosphate-30 ; sensor hybridization probe: 50 -GACTTTAACTCCGGAGAAGCTAAC-fluorescein-30 . The PCR run comprised 55 cycles of denaturation (958C, 0 sec, ramp rate 208C/sec), annealing (608C, 10 sec, ramp rate 208C/ sec), and extension (728C, 10 sec, ramp rate 208C/sec) which followed an incubation period of 10 min to activate the FastStart Taq DNA Polymerase of the reaction mix (Light Cycler FastStart DNA Master Hybridization Probes, Roche Diagnostics). After amplification, a melting curve was generated by holding the reaction time at 408C for 2 min and then heating slowly to 958C with a ramp rate of 0.28C/sec. The fluorescence signal was plotted against temperature to yield the respective melting points (Tm) of the two alleles. Tm for the T allele was 56.808C and 63.408C for the C allele. COMT: forward primer: 50 -GGGCCTACTGTGGCTACTCA30 ; reverse primer: 50 -GGCCCTTTTTCCAGGTCTG-30 ; anchor hybridization probe: 50 -LCRed640-TGTGCATGCCTGACCCGTTGTCA-phosphate-30 ; sensor hybridization probe: 50 -ATTTCGCTGGCATGAAGGACAAG-fluorescein-30 . The PCR run comprised 55 cycles of denaturation (958C, 0 sec, ramp rate 208C/sec), annealing (578C, 10 sec, ramp rate 208C/sec), and extension (728C, 10 sec, ramp rate 208C/sec) which followed an incubation period of 10 min to activate the FastStart Taq DNA polymerase of the reaction mix. After amplification, the melting points were determined as described above. Tm for the VAL allele was 59.008C and 64.508C for the MET allele. The study was approved by the ethics committee of the German Association of Psychology and written informed consent was obtained from all participants. The Absorption scores of our sample were in good agreement with the normative data reported for the German version of the TAS [Ritz and Dahme, 1995], including the gender difference, that is, slightly lower scores for males (Table I). In contrast to the normative data, this difference did not reach significance in our sample. The genotype distributions for the T102C SNP of the 5-HT2a gene and the VAL158MET SNP of the COMT gene were in Hardy–Weinberg Equilibrium (see Table II). TABLE I. Means (SD) of the Absorption Scores* and Normative Data [Ritz and Dahme, 1995] Gender Sample (N ¼ 336) Normative data (N ¼ 252) Male Female Total 59.23 (22.17) (N ¼ 95) 63.69 (21.59) (N ¼ 241) 62.43 (21.82) 55.37 (19.91) (N ¼ 131) 66.29 (19.45) (N ¼ 121) 60.05 (19.98) *Note: The scores reported here are higher than those reported by Lichtenberg et al.  because of the polychotomous response format of the German version of the Absorption scale (see text). Absorption: Epistasis Between 5-HT2a and COMT 31 TABLE II. Frequencies of the two Determined Polymorphisms (T102C, COMT) and Absorption Scores (AS) of the Genotypes Genotypes T/T VAL/VAL Incidence (%) Mean AS (SD) VAL/MET Incidence (%) Mean AS (SD) MET/MET Incidence (%) Mean AS (SD) Total Incidence (%) Mean AS (SD) T/C 41 (12.2) 58.78 (23.64) 26 (7.7) 56.86 (15.39) 82 (24.4) 60.89 (22.68) 25 (7.4) 64.80 (24.91) 77 (22.9) 64.99 (22.50) 62 (18.5) 59.52 (20.13) 164 (48.8.) 60.22 (20.91) 19 (5.7) 68.20 (19.49) 41 (12.2) 60.39 (22.99) 30 (8.9) 61.85 (22.79) 90 (26.8) 60.38 (20.79) 59 (17.6) 68.00 (19.21) 159 (47.3) 59.37 (23.13) 118 (35.1) 57.85 (19.32) 336 (100.0) 60.46 (21.30) 90 Tellegen Absorption Scale [M±SEM] Total 15 (4.7) 76.33 (16.45) For the statistical analysis, based on theoretical considerations, subjects with one certain homozygous genotype were tested against the subjects with the two remaining genotypes grouped together. In the case of the T102C polymorphism, the T/T genotype, implying a higher binding capacity [Turecki et al., 1999], was tested against the T/C and C/C genotypes, that is, carriers without the C-allele were tested against carriers of the C-allele. In the case of the COMT polymorphism, the VAL/VAL genotype, implying an up to fourfold higher catabolic enzyme activity [Lachman et al., 1996], was tested against the VAL/MET and the MET/MET genotype because the VAL/VAL genotype is associated with a vulnerability to schizophrenia [Lachman et al., 1996] and the efficiency of the frontal executive control system. While some studies reported a less efficient executive control system associated with the VAL-allele in schizophrenic patients [e.g., Goldberg et al., 2003], also superior performance of executive attention was found to be associated with the VAL/VAL genotype in healthy subjects [Fossella et al., 2002]. Results of the two-way ANOVA 5-HT2a COMT showed a significant main-effect with respect to the 5-HT2a SNP (C-allele: F ¼ 10.00, P ¼ 0.002, Eta2 ¼ 0.029) and a significant interaction COMT 5-HT2a (MET C-allele: F ¼ 3.89, P ¼ 0.049, Eta2 ¼ 0.012). There was no main-effect with respect to the COMT SNP (F ¼ 0.073, P ¼ 0.395, Eta2 ¼ 0.002). In total, over 4% of the variance in Absorption was explained by these two genes. Carriers of the TT-genotype showed significantly higher TAS scores than subjects without a T-allele. Moreover, TAS scores were highest in subjects who are homozygous for the T-allele as well as for the VAL-allele of COMT (see Fig. 1). The present study demonstrated, for the first time, an association between the personality trait of Absorption and two 85 80 75 T102C 70 T/T C/C, C/T 65 60 55 50 45 40 MET/MET, VAL/MET C/C VAL/VAL COMT Fig. 1. Association of the trait of Absorption with genetic polymorphisms: Interaction between T102C and COMT genotypes. polymorphisms that affect the serotonergic and the dopaminergic neurotransmitter systems and account together for over 4% of the variance in Absorption as measured by Tellegen’s scale. Subjects homozygous for the T-allele, which is related to a higher binding affinity of the 5-HT2a receptor [Turecki et al., 1999], had significantly higher TAS scores. In addition, a significant interaction between the 5-HT2a and the COMT gene indicates that TAS scores were highest in subjects homozygous for the TT-genotype of 5-HT2a as well as for the VAL/ VAL genotype of COMT. Therefore, a high binding affinity of the 5-HT2a gene and a high catabolic enzyme activity of COMT are related to high Absorption. From a pharmacological point of view, the reported interaction between two SNPs of the 5-HT2a receptor gene and the COMT gene is highly plausible because the 5-HT system exerts an inhibitory effect on DA release via the 5-HT2a receptor [e.g., Porras et al., 2002]. The present results once more corroborate the assumption that personality traits within a normal range and psychopathological disorders have one common underlying dimension [Donnelly, 1998]: Phenomena of Absorption resemble— although in a very mild form—positive symptoms observed in schizophrenia and drug-induced hallucinations. Moreover, LSD exerts its effects via the 5-HT2a receptor [Aghajanian and Marek, 1999; Nichols, 2004], which showed a strong association with the trait of Absorption in our study. In the same line, the COMT gene is related to hypnotic susceptibility in healthy subjects [Lichtenberg et al., 2000] and to schizophrenia [Williams et al., 1996; Abdolmaleky et al., 2004]. While hypnotizability was found to be significantly correlated with Absorption, Lichtenberg et al.  failed to detect a significant association of the COMT gene with Absorption. However, the present study demonstrates that there is an association between COMT and Absorption, which is only revealed through an epistasis effect with 5-HT2a. It is well known that complex phenotypes of high heritability as personality traits are determined by many genes (Quantitative Trait Loci, QTL) and not only by single gene loci. Therefore, additional polymorphisms should be included in further studies, for instance the dopamine D4 receptor gene (DRD4) polymorphism, that was already found to be associated with the scale ‘‘self-transcendence’’ of Cloninger’s temperament and character inventory (TCI-ST) [Comings et al., 2000]. On account of the moderate sample size (N ¼ 336), the reported findings have to be interpreted cautiously and require replication. The reported interaction is mainly based on the small group of subjects carrying the VAL/VAL- as well as the TT-genotype. This combination of homozygous genotypes is seldom in the population resulting in a cell frequency of n ¼ 15 in our sample. In order to replicate our findings greater gene banks could focus selectively on these subjects to test for higher Absorption scores. 32 Ott et al. Nevertheless, several other studies provide additional evidence for a biological basis of Absorption and related personality traits. In a twin study, including 4300 North Americans, a broad-sense heritability (additive genetic variance þ dominance variance) of Absorption of 26% for males and 44% for females was found [Finkel and McGue, 1997]. The TCI-ST contains many items similar to those of the TAS. Initially, the TCI-ST was conceptualized as a character dimension thought to be mainly a result of culture and learning. It turned out, however, that it forms indeed a distinct genetic factor with an estimated heritability of 39% [Ando et al., 2002]. Association studies like the present one provide further pieces of the puzzle, that have to be fitted into models of brain functioning of altered states of consciousness in general [Dietrich, 2003] and of those induced by drugs or during acute psychosis [Vollenweider and Geyer, 2001]. The role of the executive attention network for states of absorption has already been mentioned in the introduction as well as the conflicting results regarding the influence of the VAL-allele on its efficiency. In order to elucidate the actual brain regions responsible for the personality differences, neuroimaging studies are needed that compare activation patterns of subjects with certain genotypes during corresponding tasks. Such a combination of molecular genetics with functional magnetic resonance imaging has already produced very promising results, indicating that brain activation of the ACC during an attention test is markedly influenced by polymorphisms affecting the dopamine neurotransmitter system (DRD4 and monoamine oxidase A, MAO-A) [Fan et al., 2003]. In the same way, distinct states of absorption— for example, induced by hypnotic audiovisual stimulation or concentrative meditation—could be compared in subjects with specific combinations of genotypes. The effects of specific polymorphisms on the local activation within neural networks seems to be much stronger than their effects on behavioral or questionnaire measures, so that differences can be detected with considerably smaller samples [Fan et al., 2003]. The present study indicates that there might be one underlying continuum for the trait of Absorption and positive symptoms in schizophrenia. Because complex syndromes like schizophrenia are likely caused by multiple genes, the study of endophenotypes like Absorption yield further insights into the genetic underpinnings of schizophrenia. REFERENCES Abdolmaleky HM, Faraone SV, Glatt SJ, Tsuang MT. 2004. Meta-analysis of association between the T102C polymorphism of the 5HT2a receptor gene and schizophrenia. Schizophr Res 67:53–62. Aghajanian GK, Marek GJ. 1999. Serotonin and hallucinogens. Neuropsychopharmacology 21:16S–23S. Ando J, Ono Y, Yoshimura K, Onoda N, Shinohara M, Kanba S, Asai M. 2002. The genetic structure of Cloninger’s seven-factor model of temperament and character in a Japanese sample. J Pers 70:583–609. Bondy B, Kuznik J, Baghai T, Schule C, Zwanzger P, Minov C, de Jonge S, Rupprecht R, Meyer H, Engel RR, Eisenmenger W, Ackenheil M. 2000. Lack of association of serotonin-2A receptor gene polymorphism (T102C) with suicidal ideation and suicide. Am J Med Genet 96:831–835. Borg J, Andrée B, Soderstrom H, Farde L. 2003. The serotonin system and spiritual experiences. Am J Psychiatry 160:1965–1969. Cloninger CR, Przybeck TR, Svrakic DM, Wetzel RD. 1994. The temperament and character inventory: A guide to its development and use. St Louis: Washington University Center for Psychobiology of Personality. Comings DE, Gonzales N, Saucier G, Johnson JP, MacMurray JP. 2000. The DRD4 gene and the spiritual transcendence scale of the character temperament index. Psychiatr Genet 10:185–189. Crawford HJ. 1994. Brain dynamics and hypnosis—attentional and disattentional processes. Int J Clin Exp Hypn 42:204–232. Dietrich A. 2003. Functional neuroanatomy of altered states of consciousness: The transient hypofrontality hypothesis. Conscious Cogn 12:231–256. Donnelly JP. 1998. A continuum model of personality disorder. Psychol Rep: 83:387–391. Fan J, Fossella J, Sommer T, Wu Y, Posner MI. 2003. Mapping the genetic variation of executive attention onto brain activity. Proc Natl Acad Sci USA 100:7406–7411. Finkel D, McGue M. 1997. Sex differences and nonadditivity in heritability of the Multidimensional Personality Questionnaire Scales. J Pers Soc Psychol 72(4):929–938. Fossella J, Sommer T, Fan J, Wu Y, Swanson JM, Pfaff DW, Posner MI. 2002. Assessing the molecular genetics of attention networks. BMC Neuroscience 3:14. Goldberg TE, Egan MF, Gscheidle T, Coppola R, Weickert T, Kolachana BS, Goldman D, Weinberger DR. 2003. Executive subprocesses in working memory: Relationship to catechol-O-methyltransferase Val158Met genotype and schizophrenia. Arch Gen Psychiatry 60:889–896. Goodman N. 2002. The serotonergic system and mysticism: Could LSD and the nondrug-induced mystical experience share common neural mechanisms? J Psychoactive Drugs 34:263–272. Lachman HM, Papolos DF, Saito T, Yu YM, Szumlanski CL, Weinshilboum RM. 1996. Human catechol-O-methyltransferase pharmacogenetics: Description of a functional polymorphism and its potential application to neuropsychiatric disorders. Pharmacogenetics 6:243–250. Lichtenberg P, Bachner-Melman R, Gritsenko I, Ebstein RP. 2000. Exploratory association study between catechol-O-methyltransferase (COMT) high/low enzyme activity polymorphism and hypnotizability. Am J Med Genet (Neuropsychiatr Genet) 96:771–774. Nichols DE. 2004. Hallucinogens. Pharmacol Ther 101:131–181. Polesskaya OO, Sokolov BP. 2002. Differential expression of the ‘‘C’’ and ‘‘T’’ alleles of the 5-HT2A receptor gene in the temporal cortex of normal individuals and schizophrenics. J Neurosci Res 67:812–822. Porras G, Di Matteo V, Fracasso C, Lucas G, De Deurwaerdere P, Caccia S, Esposito E, Spampinato U. 2002. 5-HT2A and 5-HT2C/2B receptor subtypes modulate dopamine release induced in vivo by amphetamine and morphine in both the rat nucleus accumbens and striatum. Neuropsychopharmacology 26:311–324. Rainville P, Hofbauer RK, Bushnell MC, Duncan FH, Price DD. 2002. Hypnosis modulates activity in brain structures involved in the regulation of consciousness. J Cogn Neurosci 14:887–901. Raz A, Shapiro T. 2002. Hypnosis and neuroscience: A cross talk between clinical and cognitive research. Arch Gen Psychiatry 59:85–90. Ritz T, Dahme B. 1995. Die Absorption-Skala: Konzeptuelle Aspekte, psychometrische Kennwerte und Dimensionalität einer deutschsprachigen Adaptation [The Absorption Scale: Conceptual aspects, psychometric properties, and dimensionality of a German adaptation]. Diagnostica 41:53–61. Syvänen AC, Tilgmann C, Rinne J, Ulmanen I. 1997. Genetic polymorphism of catechol-O-methyltransferase (COMT): Correlation of genotype with individual variation of S-COMT activity and comparison of the allele frequencies in the normal population and parkinsonian patients in Finland. Pharmacogenetics 7:65–71. Tellegen A. 1982. Brief manual for the multidimensional personality questionnaire. Unpublished manuscript. Minneapolis: University of Minnesota. Tellegen A, Atkinson G. 1974. Openness to absorbing and self-altering experiences (‘‘absorption’’), a trait related to hypnotic susceptibility. J Abnorm Psychol 83:268–277. Turecki G, Brière R, Dewar K, Antonetti T, Lesage AD, Séguin M, Chawky N, Vanier C, Alda M, Joober R, Benkelfat C, Rouleau GA. 1999. Prediction of level of serotonin 2A receptor binding by serotonin receptor 2A genetic variation in postmortem brain samples from subjects who did or did not commit suicide. Am J Psychiatry 156:1456–1458. Vollenweider FX, Geyer MA. 2001. A systems model of altered consciousness: Integrating natural and drug-induced psychosis. Brain Res Bull 56:495–507. Vollenweider FX, Vollenweider-Scherpenhuyzen MFI, Baebler A, Vogel H, Hell D. 1998. Psilocybin induces schizophrenia-like psychosis in humans via a serotonin-2 agonist action. NeuroReport 9:3897– 3902. Williams J, Spurlock G, McGuffin P, Mallet J, Nothen MM, Gill M, Aschauer H, Nylander PO, Macciardi F, Owen MJ. 1996. Association between schizophrenia and T102C polymorphism of the 5hydroxytryptamine type 2a-receptor gene. European Multicentre Association Study of Schizophrenia (EMASS) Group. Lancet 347: 1294–1296.