This randomised, crossover, placebo-controlled study (n=17) investigated the role of 5-HT2A receptor in the hallucinogenic effects of psilocybin (8.75mg/70kg and 17.5mg/70kg). The authors found that 5-HT2A plays a central role in the psilocybin-induced modulation of visual processing.
Background
Recent findings suggest that the serotonergic system and particularly the 5-HT2A/1A receptors are implicated in visual processing and possibly the pathophysiology of visual disturbances including hallucinations in schizophrenia and Parkinson's disease.
Methods
To investigate the role of 5-HT2A/1A receptors in visual processing the effect of the hallucinogenic 5-HT2A/1A agonist psilocybin (125 and 250 μg/kg vs. placebo) on the spatiotemporal dynamics of modal object completion was assessed in normal volunteers (n = 17) using visual evoked potential recordings in conjunction with topographic-mapping and source analysis. These effects were then considered in relation to the subjective intensity of psilocybin-induced visual hallucinations quantified by psychometric measurement.
Results
Psilocybin dose-dependently decreased the N170 and, in contrast, slightly enhanced the P1 component selectively over occipital electrode sites. The decrease of the N170 was most apparent during the processing of incomplete object figures. Moreover, during the time period of the N170, the overall reduction of the activation in the right extrastriate and posterior parietal areas correlated positively with the intensity of visual hallucinations.
Conclusions
These results suggest a central role of the 5-HT2A/1A-receptors in the modulation of visual processing. Specifically, a reduced N170 component was identified as potentially reflecting a key process of 5-HT2A/1A receptor-mediated visual hallucinations and aberrant modal object completion potential.
Papers cited by this study that are also in Blossom
Geyer, M. A., Vollenweider, F. X. · Trends in Pharmacological Sciences (2008)
Vollenweider, F. X., Leenders, K. L., Maguire, P. et al. · Neuropsychopharmacology (1997)
González-Maeso, J., Sealfon, S. C. · Trends in Neuroscience (2009)
Gonza ´lez-Maeso, J., Weisstaub, N. V., Zhou, M. et al. · Neuron (2007)
Kometer and colleagues frame the study within converging evidence that serotonergic receptors, particularly 5-HT2A and 5-HT1A, are highly expressed in visual cortical areas and have been implicated in visual disturbances and hallucinations in conditions such as Parkinson's disease and schizophrenia. Previous work shows that the indoleamine psilocybin produces visual distortions and hallucinations that phenomenologically resemble some clinical visual disturbances and that these effects are primarily mediated via 5-HT2A receptors. Despite this, the neural mechanisms by which 5-HT2A/1A receptor activation alters visual perception and gives rise to hallucinations remain unclear. To address this gap, the investigators used high-density electroencephalographic (EEG) recordings together with topographic mapping and source estimation to measure how psilocybin affects the spatiotemporal dynamics of modal object completion in healthy volunteers. Specifically, they tested the effects of two psilocybin dose conditions (reported in the extracted text as 125 and 250 g/kg) versus placebo during a Kanizsa figure task that elicits modal completion, and related electrophysiological changes to self-reported visual hallucination intensity assessed with the 5D-ASC scale. The aim was to identify early electrophysiological markers and cortical sources linking 5-HT2A/1A receptor activity to altered object completion and visual hallucinations.
Seventeen healthy, right-handed volunteers (eight males, nine females; mean age 28.8 ± 3.5 years) were recruited and screened to exclude current or past psychiatric disorders, substance dependence, and certain personality risk factors. Twelve participants reported prior experience with psilocybin or other hallucinogens. The study received ethics approval and participants provided written informed consent. A within-subjects, randomized crossover design was used: each participant completed three experimental sessions separated by at least two weeks and received placebo (lactose) and two graded doses of psilocybin administered in identical gelatin capsules. The extracted text reports doses as "low-dose" and "high-dose" (LD, HD) with numeric values given as 125 and 250 g/kg; the units in the extraction are unclear. Testing for the Kanizsa experiment began 120 minutes after drug ingestion. During the task participants viewed Kanizsa figures (illusory triangle induced by three ‘‘pacmen’’ inducers) and matched non-Kanizsa control stimuli while maintaining central fixation. Stimuli were presented at 1 m viewing distance, subtended 3.7° visual angle, and were shown in four orientations to reduce habituation. Each session comprised 176 trials (88 Kanizsa, 88 non-Kanizsa) presented pseudorandomly with a 3-sec stimulus-onset asynchrony in two blocks; stimuli remained on screen for up to 300 msec after a button press or 2000 msec maximum. Participants made speeded button-press judgements indicating whether they perceived an illusory triangle; response finger was counterbalanced across subjects. Subjective effects were measured with the Altered States of Consciousness (5D-ASC) questionnaire, with particular focus on the Visionary Restructuralization (VR) factor for visual alterations and the Auditory Alterations (AA) factor. EEG was recorded with a BioSemi ActiveTwo system using 64 scalp electrodes, horizontal and vertical electrooculograms, bandpass filtered at 0.01–67.0 Hz and digitized at 256 Hz. Offline EEG preprocessing re-referenced signals to the average reference, bandpass filtered at 1–40 Hz, and segmented into epochs from −150 to +600 msec relative to stimulus onset. Trials with artifacts exceeding ±100 μV were rejected; mean numbers of accepted epochs per condition are reported (around 79–85). Analyses included waveform quantification of P1 and N170 components at selected electrode pairs, topographic analysis using spatial k-means clustering to identify dominant scalp maps across time, and source estimation with standardized low-resolution electromagnetic tomography (sLORETA) over time windows defined by topographic stability. Statistical analyses used repeated-measures ANOVAs (dose, hemiscalp, electrode, stimulus as within-subject factors) with Bonferroni-corrected post hoc tests. Correlations between psilocybin-induced source-density changes and VR/AA scores were computed voxel-wise and assessed with nonparametric permutation testing to correct for multiple comparisons.
Psychometric effects: Repeated-measures ANOVA on 5D-ASC scores showed a strong main effect of dose [F(2,32)=36.596, p<.00001, η²=.70], a main effect of factor [F(4,64)=12.924, p<.00001, η²=.45], and a dose × factor interaction [F(8,128)=7.09, p<.00001, η²=.31]. On the Visionary Restructuralization factor (VR), both low-dose and high-dose psilocybin produced significant increases versus placebo (post hoc p<.00001); VR did not differ significantly between low and high dose (p=.178). Auditory Alterations increased only for high dose versus placebo (post hoc p<.05). Behavioural performance: Reaction times increased dose-dependently under psilocybin [F(2,32)=18.841, p<.00001, η²=.54], and responses were faster for Kanizsa than non-Kanizsa stimuli [F(1,16)=36.037, p<.0001, η²=.69]. Error rates rose slightly with dose [F(2,32)=3.3291, p<.05, η²=.17] but remained very low across conditions (placebo 0.88%, LD 1.18%, HD 1.92%), indicating task performance was preserved. Electrophysiology overview: Both stimulus types elicited prominent visual evoked potentials, including P100 (P1) and N170 components. Topographic k-means clustering across the 600-msec poststimulus period identified nine predominant scalp topographies explaining 96.74% of the variance. Three early stable periods were common across conditions and defined the measurement windows: 0–86 msec, 90–144 msec (P1 window), and 148–223 msec (N170 window). P1 (90–144 msec): Waveform analysis revealed a main effect of electrode [F(4,64)=33.42, p<.00001, η²=.68] and an electrode × dose interaction [F(8,128)=3.43, p<.01, η²=.18]. Post hoc tests showed that P1 amplitude at occipital electrodes O1/O2 was significantly increased relative to placebo for both low-dose (p<.05) and high-dose (p<.0001) psilocybin, with no reliable effects at other electrode sites. Source estimation localized P1 activity to V2 and lateral occipital complex (LOC) bilaterally across conditions; in the high-dose condition the increase extended to right V1. P1 source increases did not correlate with reported visual or auditory hallucinations (all p>.17 for visual, p>.98 for auditory). N170 (148–223 msec): Psilocybin produced a dose-dependent decrease in N170 amplitude [F(2,32)=17.170, p<.00001, η²=.52], with post hoc contrasts showing significant differences between each dose condition. A dose × hemiscalp interaction [F(2,32)=5.30, p<.05, η²=.25] and inspection of waveforms indicated a stronger reduction over the right hemiscalp. Consistent with prior findings, N170 magnitude was greater for Kanizsa versus non-Kanizsa stimuli [F(1,16)=35.863, p<.0001, η²=.70], but the Kanizsa–non-Kanizsa difference diminished dose-dependently under psilocybin. Topographic analyses indicated that the effects were primarily strength modulations rather than changes in scalp map topography. sLORETA source estimates placed N170-related activity in LOC and V2 bilaterally, with stronger right-lateralized LOC/V2 activation for Kanizsa stimuli. Psilocybin reduced current source density within LOC, V2, and fusiform gyrus across both stimulus types. Importantly, reductions in source density over right-lateralized LOC, V2, and posterior parietal areas during the N170 timeframe correlated positively with the increased intensity of visual hallucinations (VR scores); no significant correlations were found with auditory-alteration scores (all p>.64 for auditory).
Kometer and colleagues highlight three principal findings. First, psilocybin produced differential modulation of early visual components: a dose-dependent decrease of the N170 (148–223 msec) alongside a modest increase of the earlier P1 (90–144 msec) over occipital sites. Second, the N170 reduction was more pronounced for Kanizsa figures than for non-Kanizsa controls, implying an effect on processes underlying modal object completion. Third, the magnitude of psilocybin-induced reductions in right-lateralized extrastriate (LOC, V2) and posterior parietal activation during the N170 window correlated with self-reported visual hallucination intensity. The authors interpret the findings to implicate 5-HT2A/1A receptor activity in object completion processes. Because the N170 enhancement for Kanizsa figures is thought to reflect boundary completion and region-based segmentation, the preferential attenuation of the N170 for Kanizsa stimuli suggests psilocybin disrupts mechanisms critical for interpolating object boundaries. By contrast, the slight P1 enhancement may relate to an increase in perceived brightness commonly reported after indoleamine hallucinogens; P1 is known to be sensitive to stimulus brightness and other low-level features, and the P1 source increases localized to V2/LOC and, at high dose, right V1. Kometer and colleagues propose that decreased stimulus-evoked activation in modality-specific cortical areas during the N170 time window may characterise hallucinations more generally. They suggest a model in which internally generated visual content (hallucinations) competes with external sensory processing for neuronal resources, resulting in reduced evoked responses to external stimuli. The observed correlation between reduced posterior parietal activation and hallucinatory severity is taken to indicate impaired allocation of attentional resources to external stimuli under psilocybin. The authors relate these mechanisms to clinical observations in Parkinson's disease and schizophrenia, noting parallels such as increased 5-HT2A receptor density in patients with visual hallucinations and prior reports of reduced extrastriate activation and diminished N170 in some patient groups. Finally, the discussion notes pharmacological caveats: psilocybin is a mixed 5-HT2A/1A agonist and has downstream effects that could involve dopaminergic systems. Nevertheless, existing evidence (5-HT2A knockout mice and blockade of effects by the 5-HT2A antagonist ketanserin) supports a primary role for 5-HT2A receptors in psilocybin's psychotomimetic visual effects. The authors acknowledge that 5-HT1A receptors are also widespread in visual cortex and may contribute, and they call for further studies to disentangle the specific receptor contributions and mechanisms underlying the spatiotemporal dynamics of object completion and hallucinations.
espite the fact that the visual and serotonergic systems are among the most explored research topics in neuroscience, there is sparse information about the role of serotonin (5-HT) in visual processing. However, the high expression of the 5-HT 1Aand 5-HT2A receptorsin the visual areas V1, V2, V3, and lateral suprasylvian cortex (LS) suggest a central role of the 5-HT 1A and 2A receptors in visual processing. Furthermore, 5-HT2A receptors have been implicated in the pathogenesis of visual hallucinations in Parkinson'sand schizophrenic patients. In support of this view, visual hallucinations in Parkinson's patients have been associated with increased density of 5-HT2A receptors in cortical visual pathwaysand effectively treated with the 5-HT2A receptor inverse agonist pimavanserin. Moreover, visual disturbances and hallucinations induced by the indoleamine hallucinogen psilocybin are mediated predominantly by the 5-HT2A receptorand resemble, in phenomenologicaland behavioral measurements, visual disturbances found in schizophrenia. Hence, there is an increasingly recognized role for the 5-HT2A receptors in the pathogenesis of visual hallucinations, but the brain mechanisms mediating between 5-HT2A receptor activation and visual hallucination are still unknown. To characterize further the role of the 5-HT2A/1A receptors in visual processing and to elucidate possible pathophysiological mechanisms of visual deficits and hallucinations, we assessed the effect of the mixed 5-HT2A/1A agonist psilocybin (125 g/ and 250 g/kg vs. placebo) in healthy volunteers. Electroencephalographic recordings were made while participants viewed Kanizsa and non-Kanizsa figures (Figure). Behavioral responses were recorded, and high-density electrical mapping with source analysis was used. This allowed for measurement of the spatiotemporal brain dynamics of visual modal object completion and its association with the appearance of visual hallucinations. Modal object completion refers to the illusory perception of object boundaries and their enclosing surface in the absence of any direct sensory information depicting these boundaries or surfaces. The brain's ability to interpolate the existence of object surface boundaries is essential for accurate object recognition in situations in which only ambiguous or incomplete retinal information of the object is available (i.e., due to partial occlusion or poor illumination). Modal completion has been of particular interest to vision scientists because it is critical for the accurate perception of objects and the delineation of multiple objects from themselves or their background. Imaging studies provide strong evidence that the intermediate lateral occipital complex (LOC) as well as the early visual area V2 are likely to play a major role in modal completion, but the involvement of the primary visual cortex is more contentious. Electrophysiologic studies have revealed that modal object completion of simple figures such as Kanizsa figures is predominantly indexed by the modulation of the N170 component, which appears to be driven primarily by the two critical processes underlying modal object completion, boundary completion, and region-based segmentation. In some previous studies, the presentation of Kanizsa figures, compared with control figures, have additionally been associated with an enhancement of the earlier P1and the subsequent closure negativity (N cl ) component. However, because the N cl component is more reliably induced by more complex fragmented images and reflects successful recognition of complex images, it is unlikely to be as relevant to the processing of the simple Kanizsa figures used in our experiment. The high density of 5-HT 1A (1,2) and 5-HT2Areceptors in LOC and V2, as well as the strong activation seen in these areas after psilocybin administration during resting state, suggest that psilocybin might influence modal object completion. Because these processes are so critical in defining one's perceptual experience, we aimed to characterize and understand the means through which 5-HT2A/1A receptor activity can alter this fundamental aspect of visual experience.
Healthy right-handed subjects (eight males, nine females, mean age 28.8 Ϯ 3.5 years) were recruited through advertisement from the University of Zürich. All subjects were healthy according to physical examination including electrocardiography, and detailed blood analysis. The DIA-X diagnostic expert systemand a clinical interview was used to exclude subjects with present or antecedent psychiatric disorders, regular alcohol or substance abuse, and a history of major psychiatric disorders in first-degree relatives. The screening procedure was supplemented by the Freiburg Personality Inventory FPIand Hopkins Symptom Checklist SCL-90-R (32) and a self-made substance consumption questionnaire. Because the personality trait factor "emotional lability" was identified to be a predictor for negative experiences during hallucinogen-induced altered states of consciousness, scores exceeding the mean value of normative FPI data by 2 SD were also used as exclusion criterion. Twelve participants reported having previous experience with psilocybin or other hallucinogens (mean lifetime experiences 5.5 Ϯ 4.7 times). None of the subjects consumed any psychoactive substance except alcohol, nicotine, cannabis, and caffeine more than once a year. After being informed by a written and oral description of the procedures of the study and the effects and possible risks of psilocybin administration, all volunteers gave written informed consent to participate in this study. The study was approved by the ethics committee of the University Hospital of Psychiatry, Zurich, and the use of psilocybin in humans was authorized by the Swiss Federal Office for Public Health.
Psilocybin was obtained through the Swiss Federal Office for Public Health. The psilocybin high-dose (HD, 250 g/kg), low-dose (LD, 125 g/kg), and lactose placebo (PL) were administered in gelatin capsules of identical number and appearance. On 3 experimental days, separated from each other by at least 2 weeks, the subjects came to the laboratory at 9 AM and confirmed that they had not eaten breakfast or taken caffeine that morning. In a crossover randomized design, all subjects received placebo and the two graded doses of psilocybin.
The Kanizsa experiment started 120 min postdrug ingestion. During the experiment, Kanizsa figures and control figures were presented at a distance of 1 m from the participants while they remained fixated on a central fixation-cross. All stimuli consisted of three "pacmen," each composed of a black circle with a sector of 60°r emoved. The removed sectors were either aligned such that the stimulus types induced the perception of an illusory triangle or they were rotated by 180°to no longer induce the illusory triangle percept ("Kanizsa" and "non-Kanizsa" conditions, respectively; see Figure). The stimuli subtended a visual angle of 3.7°and the support ratio, the ratio of the inducing length to the total length of one illusory contour of the triangle was 1:2. To reduce habituation, the stimuli were presented in four orientations of equal number, rotated 0°, 90°, 180°, and 270°. Eighty-eight Kanizsa figures and 88 non-Kanizsa figures were presented with a stimulus onset asynchrony of 3 sec in a pseudorandomized order in two blocks consisting of 44 Kanizsa figures and 44 non-Kanizsa figures each. Participants were required to respond as quickly as possible with a button press according to whether they saw an illusory triangle on each trial. The response finger was counterbalanced across the subjects to control for faster reaction times of index finger compared with middle finger of the dominant hand. Stimuli remained on the monitor for 300 msec after buttonpress or for a maximum of 2000 msec.
The Altered States of Consciousness (5D-ASC) rating scale (34) was used to asses the subjective effects of placebo and psilocybin with a primary focus on visual alterations and hallucinations. The 5D-ASC is a visual analogue scale consisting of 94 items that measure etiology independent alterations in consciousness, including changes in mood, perception, cognition, and experience of self and the environment. The five main factors are 1) Oceanic Boundlessness, measuring derealization and depersonalization accompanied by changes in affect ranging from heightened mood to euphoria and alterations in the sense of time; 2) Anxious Ego Dissolution, measuring ego disintegration associated with loss of self-control, thought disorder, arousal, and anxiety; 3) Visionary Restructuralization (VR) assessing visual illusions and (pseudo-)hallucinations, which includes the spectrum ranging from elementary to complex hallucinations; 4) Auditory Alterations (AA), comprising auditory illusions and (pseudo-)hallucinations; and 5) Reduction of Vigilance, assessing changes in vigilance and alertness. The results of the 5D-ASC data are given as percentage scores of maximum absolute scale values.
Electroencephalogram (EEG) recordings were made using Bio-Semi (Amsterdam, The Netherlands) ActiveTwo electrode system with 64 scalp electrodes. Additional electrodes were attached on the outer canthus of each eye to record the horizontal electrooculogram (EOG) and infraorbitally and supraorbitally to the left eye to record the vertical EOG. Electrophysiologic signals were bandpass filtered at .01 to 67.0 Hz and digitized at 256 Hz.
The EEG data were recalculated offline against average reference and bandpass filtered at 1 to 40 Hz. Correct response trials were segmented from Ϫ150 to ϩ600 msec relative to stimulus presentation. To avoid eye movement and other artifacts in further analysis, epochs exceeding Ϯ 100 V in any channel were excluded. The mean Ϯ SD number of accepted epochs per condition was 85.0 Ϯ 5.4 for Kanizsa placebo, 85.0 Ϯ 3.0 for non-Kanizsa placebo, 82.9 Ϯ 4.6 for Kanizsa LD, 83.2 Ϯ 3.7 for non-Kanizsa LD, 78.8 Ϯ 9.4 for Kanizsa HD, 79.4 Ϯ 9.8 for non-Kanizsa HD. These epochs were averaged time locked to Kanizsa and non-Kanizsa figure presentation time to compute the visual evoked potential (VEP). The 600msec poststimulus period of the VEP underwent three analyses to reveal the VEP waveforms, the scalp topography, and the source localization. This combination of analysis methods has been used increasingly during the recent years because it reduces experimenter bias associated with the selection of the appropriate time window for statistical analysis of the components. Waveform Analysis. To quantify waveform modulations, five symmetrical pairs of electrodes were selected over the maxima of the scalp topographies for the P1 and N170 components (PO7/PO8, PO3/PO4, O1/O2, P1/P2, P3/P4). The specific time windows used for calculation of the mean amplitude (vs. the baseline) were determined by the topographic analysis described next. The mean amplitudes of each of these time windows were then subjected to separate repeated-measures analysis of variance (ANOVA) with the within-subject factors dose (PL, LD, HD) electrode (PO7/PO8, PO3/ PO4, O1/O2, P1/P2, P3/P4), hemiscalp (left, right), and stimulus (Kanizsa, non-Kanizsa). Topographic Analysis. First, a spatial k-means cluster analysis identified the predominant topographies (also called template map) appearing in the normalized group-averaged event-related potentials (ERPs) as a function of time and experimental condition. This analysis was constrained by the temporal criterion that certain topographies must be observed for at least five consecutive data points (Ͼ20 msec at a 256-Hz sampling rate). The optimal number of topographies that explained the whole data set was determined by a modified cross-validation criterion. In a second step, we statistically verified that maps identified at the groupaveraged level also appeared on the individual subject level. Therefore, at each time point, the topography of the individual subjects' ERP was compared by means of strength-independent spatial correlation to all template maps and was labeled according to the one with which it best correlated. This revealed values of relative map presence (in milliseconds), which were then subjected to a repeated-measures ANOVA using stimulus condition, map and dose as within-subject factors. Source Localization. Standardized low-resolution electromagnetic tomography (sLORETA) was used to estimate the threedimensional intracerebral current density distributions underlying the ERPs within the timeframes defined by topographic analysis. sLORETA offers a solution of the inverse problem by assuming that the smoothest of all possible activity is the most plausible. The solution space of sLORETA (i.e., the lead field matrix) includes 6239 voxels and was computed with a three-shell spherical head model registered to the neuroanatomic atlas of Talairach and Tournoux (Brain Imaging Centre, Montreal Neurological Institute). Correlational analyses were performed to determine whether psilocybin-induced changes in the current source density within the timeframes defined by topographic analysis were related to visual or auditory hallucinations. First, the differences of the current source density between psilocybin conditions (LD and HD) and placebo were calculated separately. In a second step, these data were pooled and the Product-Moment correlations between these differences and the VR and AA scores, respectively, were calculated for each voxel. Significant correlations were identified using nonparametric permutation testing (39) that determined the critical probability threshold values for the observed r values with correction for multiple testing.
The subjective effects of psilocybin were assessed by the 5D-ASC rating scale. Repeated-measures ANOVA revealed a significant main effect of dose [F (2,32) ϭ 36.596, p Ͻ .00001, 2 ϭ .70], factor [F(4,64) ϭ 12.924, p Ͻ .00001, 2 ϭ .45], and dose ϫ factor interaction [F (8,128) ϭ 7.09, p Ͻ .00001, 2 ϭ .31]. Bonferroni-corrected post hoc analysis on the VR factor, which was of primary interest in regard to the current study, indicated a significant increase between placebo and low-dose psilocybin (p Ͻ .00001) as well as PL and HD psilocybin (p Ͻ .00001) but not LD and HD psilocybin (p ϭ .178). Bonferroni-corrected post hoc analysis on the AA factor revealed a significant increase between PL and HD psilocybin (p Ͻ .05) but not PL and LD psilocybin (p ϭ 1.0).
Reaction time was dose-dependently increased by psilocybin [F (2,32) ϭ 18.841, p Ͻ .00001, 2 ϭ .54] and was generally faster for Kanizsa compared with non-Kanizsa figures [F (1,16) ϭ 36.037, p Ͻ .0001, 2 ϭ .69; Table]. Although psilocybin administration did lead to a dose-dependent increase in error rates [F (2,32) ϭ 3.3291, p Ͻ .05, 2 ϭ .17], the error rates remained very low in all conditions (.88% for PL, 1.18% for LD, 1.92% for HD). We are therefore confident that participants were able to do the task under all drug conditions.
Under all three drug conditions both stimuli elicited prominent VEP, including the P100 and N170 component (Figure). The subsequent topographic analysis detected nine scalp topographies, which accounted for the 600-msec poststimulus periods across all conditions with a global explained variance of 96.74%. The first three periods of stable scalp topographies were identical across conditions lasting from 0 to 86, 90 to 144, and 148 to 223 msec (Figurein Supplement 1). These time periods were used to define the time window for quantifying the P1 and N170 VEP in a more objective mannerand for the subsequent source localization and correlation analysis (analysis referring to the P300 component can be found in Supplement 1).
During the time range of the P1 component (90-144 msec), a 3 ϫ 2 ϫ 5 ϫ 2 repeated-measures ANOVA (using dose, hemiscalp, electrode, and stimulus as within factors) revealed a main effect only for electrode [F (4,64) ϭ 33.42, p Ͻ .00001, 2 ϭ .68] and a significant interaction of electrode and dose [F (8,128) ϭ 3.43, p Ͻ .01, 2 ϭ .18]. Performing Bonferroni-corrected post hoc analysis of this interaction, the P1 amplitude was found to be significantly increased from PL only at the O1/O2 electrodes by LD (p Ͻ .05) and HD (p Ͻ .0001) psilocybin. No effect of psilocybin was observed at other electrodes, nor did any other interaction reach significance. This result indicates that the effect of psilocybin on the P1 component is locally restricted to occipital electrode sites and is independent of hemiscalp and stimulus condition (Figure). Furthermore, the main effect for dose [FTo elucidate further the topographic modulation of the P1 component, the spatial correlation procedure was used first to assess the number of timeframes a given topography from the groupaveraged data were present in a given condition across subjects (see Methods and Materials). These values were subjected to a repeated-measures ANOVA (using dose, stimulus, and map as within factors), which provided no evidence of topographic specificity to one stimulus or dose condition (all ps Ͼ .15). Source estimation from the 90-to 144-msec period yielded activity within LOC and V2 in both hemispheres across all conditions. The psilocybin-induced increase in the P1 component over O1/O2 electrode sites seen in the VEP waveform analysis was localized most strongly in V2 and extended to LOC and V1 in the right hemisphere in the HD condition. The psilocybin induced increase in the source density did neither correlate with visual (all ps Ͼ .17) or auditory hallucinations (all Ps Ͼ .98).
To quantify the modulation of the N170 component, area measurements over the 148-to 223-msec period were subjected to a 3 ϫ 2 ϫ 5 ϫ 2 repeated-measures ANOVA (using dose, hemiscalp, electrode, and stimulus as within factors). Psilocybin dose-dependently decreased the N170 amplitude [F (2,32) ϭ 17.170, p Ͻ .00001, 2 ϭ .52], and Bonferroni-corrected post hoc analysis revealed that the magnitude differences were significant between all dose conditions (Figure). The significant interaction between dose and hemiscalp [F (2,32) ϭ 5.30, p Ͻ .05, 2 ϭ .25] and the visual inspection of the VEP indicated a stronger psilocybin-induced decrease over the right compared with the left hemiscalp. In accordance with numerous previous studies, a significant main effect of the stimulus condition was observed [F (1,16) ϭ 35.863, p Ͻ .0001, 2 ϭ .70], with a greater magnitude in the Kanizsa compared with the non-Kanizsa condition. This magnitude difference between Kanizsa and non-Kanizsa conditions dose-dependently decreased as re- The topographic pattern analysis of the collective data indicated that the effects of strength modulation in the electrical field were not associated with topographic modulations. This was subsequently confirmed by subjecting individual subject data to repeated-measures ANOVA (all ps Ͼ .25). The source estimation revealed activity within LOC and V2 in both hemispheres in all conditions (Figure). Current source density was stronger within right-lateralized LOC and V2 in the Kanizsa compared with non-Kanizsa condition. Psilocybin dose-dependently decreased the differential activation of the two stimulus conditions and reduced the current source density within LOC, V2, and fusiform gyrus in both stimulus conditions. The psilocybin-induced current source-density reduction over right-lateralized LOC, V2, and posterior parietal areas correlated significantly with the increased intensity of visual hallucinations (Figure), whereas no correlation could be revealed with auditory hallucinations (all ps Ͼ .64).
This investigation revealed three main findings. First, the data indicate that the mixed 5-HT2A/1A-receptor agonist psilocybin distinctively modulates the two early visual processing components. Specifically, whereas we found a strong dose-dependent decrease of the N170 component (148-to 223-msec poststimulus), the earlier visual P1 component (90-to 144-msec poststimulus) was slightly increased over occipital electrode sites. Second, the reduction of the N170 component was stronger for the Kanizsa figure condition compared with the non-Kanizsa condition. Third, during this time range the decrease in activation over right-lateralized extrastriate and posterior parietal cortex correlated with the reported intensity of visual hallucinations. The timeframe of the N170 component has been regarded as a critical period for object completion on the basis of numerous findings of enhanced N170 amplitude and underlying LOC and V2 activation evoked by Kanizsa compared with control figures. The preferential reduction of the N170 amplitude in Kanizsa compared with non-Kanizsa condition by psilocybin indicates a central role of the 5-HT2A/1A receptors in object completion. Because two subprocesses of object completion, boundary completionand region-based segmentation, have been shown to underlay the enhanced N170 amplitude in the Kanizsa condition, it would be interesting to investigate further which of these two subprocesses is modulated by signal transmission at 5-HT2A/1A receptors. The finding that psilocybin slightly enhanced P1 amplitude may reflect a generalized effect of 5-HT2A/1A mediated increase in perceived brightness, which is often reported after indolamine hallucinogen administration. This is supported by previous studies using comparable Kanizsa figures showing the P1 component to be sensitive to stimulus brightnessas well as eccentricityand symmetry. Given that psilocybin strongly decreased the N170 amplitude in both the Kanizsa and the non-Kanizsa conditions, we suggest that it modulates additional processes beyond proper object completion. Disruption of these processes might play a role in visual hallucinations because their reported intensity was significantly correlated with the three-dimensional current source-density reduction over right-lateralized LOC, V2, and posterior parietal areas during the timeframe of the N170 component. This localization agrees with previous imaging studies reporting decreased extrastriate activation in response to external visual stimuli in patients with visual hallucinations compared with patients without hallucinations. Furthermore, we found decreased activation specifically during the time range of the N170 component. Decreased activation during this time range has been previously reported in studies investigating acousticand visual hallucinations. We therefore suggest that decreased stimulus-induced activation in modalityspecific cortical areas during the time range of the N1/N170 component may be a characteristic of acoustic as well as visual hallucinations. This relationship between the increased intensity of visual hallucinations and the decreased stimulus-evoked activation of extrastriate areas during the time range of the N170 component could reflect a competition for neuronal resources in the processing of internally (hallucination) and externally generated (sensory-driven) information. A comparable mechanism has previously been suggested to be relevant in the formation of acoustic hallucinations. Increased extrastriate activation, which could interfere with the processing of external stimuli, has been observed previously during visual hallucinations in the absence of external stimulation in various psychiatric disordersas well as after psilocybin administration. In line with this interpretation, we additionally found a correlation between reduced posterior parietal activation and hallucinatory severity. The posterior parietal cortex controls attention to visual stimuli by modulating visual cortex activityduring the time range of the N170 component. The reduced posterior parietal activation might therefore reflect a psilocybin-induced failure to allocate attention and thus neuronal resources to external stimuli. Importantly, we identified reduced extrastriate visual cortex activation during the time range of the N170 as a potential key component of 5-HT2A/1A agonist-induced visual hallucinations. Such a mechanism could also underlie the visual disturbances and hallucinations reported in Parkinson and schizophrenia patients, because increased 5-HT2A receptor densities have been found in these conditions and associated with visual hallucinations. In support of this notion, Parkinson's patients with visual hallucinations showed more pronounced impairments in visual object recognitionand more prominent reductions in extrastriate cortex activation to visual stimuli than patients without hallucinations. Moreover, a reduction of the N170 component has also been reported in schizophrenia patients and associated with visual hallucinations using Kanizsa figures. These observations are in line with our finding of a correlation between reduced extrastriate activation during the time range of the N170 component and the intensity of visual hallucinations. It is noteworthy, however, that two other previous studies using Kanizsa figures in schizophrenia reported either no reductionor a reduction only at a trend level. The apparent discrepancy between these results and our findings may result from the fact that only about 30% of schizophrenia patients typically report visual hallucinations (57) and many of the patients tested were medicated with atypical antipsychotics with 5-HT2A antagonistic activity. It might therefore be possible that a disrupted 5-HT2A receptor system may be relevant only to a subgroup of schizophrenia patients. We did not find a decrease of the P1 component after psilocybin administration, and the robust reduction of the P1 component reported in schizophreniawas not associated with psychotic symptoms; these findings suggest that the reduction of the P1 component in schizophrenia is not related to serotonergic alterations and may represent an endophenotype of the schizophrenia spectrum. Because psilocybin is a mixed 5-HT2A/1A agonist (60) resulting in downstream effects on the dopamine systems, the exact pharmacologic mechanisms of the observed psilocybin effects require further investigation. However, converging lines of evidence indicate that psilocybin's psychotomimetic effects are mediated through the 5-HT2A-receptor activation. For example, behavioral effects of psilocybin are lacking in 5-HT2A receptor knockout mice, and in humans, nearly all psychotomimetic effects including visual distortions and hallucinations can be blocked by the 5-HT2A antagonist ketanserinbut not by blocking downstream dopaminergic effects with haloperidol. These findings, in combination with evidence regarding the importance of the 5-HT2A receptors in the pathophysiology of visual hallucinations, indicate that the reported effects of psilocybin are likely to be mediated by 5-HT2A receptor activation. However, given that 5-HT 1A receptors additionally influence the psychotomimetic effects of indolamine hallucinogens (66) and 5-HT 1A receptors are widespread in the visual cortex, further studies are needed to exclude an additional contribution of 5-HT 1A receptor on the spatiotemporal dynamics of visual object completion and hallucinations.
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