This randomised, double-blind, placebo-controlled crossover study (n=17) investigated whether 5-HT2A receptor activation mediates psilocybin’s effects on emotional processing. It finds that psilocybin (15 mg/70 kg) shifted emotional biases towards positive cues and reduced recognition of negative facial expressions, effects that were fully blocked by the antagonist ketanserin.
Background
Serotonin (5-HT) 1A and 2A receptors have been associated with dysfunctional emotional processing biases in mood disorders. These receptors further predominantly mediate the subjective and behavioural effects of psilocybin and might be important for its recently suggested antidepressive effects. However, the effect of psilocybin on emotional processing biases and the specific contribution of 5-HT2A receptors across different emotional domains is unknown.
Methods
In a randomized, double-blind study, 17 healthy human subjects received on 4 separate days placebo, psilocybin (215 μg/kg), the preferential 5-HT2A antagonist ketanserin (50 mg), or psilocybin plus ketanserin. Mood states were assessed by self-report ratings, and behavioural and event-related potential measurements were used to quantify facial emotional recognition and goal-directed behaviour toward emotional cues.
Results
Psilocybin enhanced positive mood and attenuated recognition of negative facial expression. Furthermore, psilocybin increased goal-directed behaviour toward positive compared with negative cues, facilitated positive but inhibited negative sequential emotional effects, and valence-dependently attenuated the P300 component. Ketanserin alone had no effects but blocked the psilocybin-induced mood enhancement and decreased recognition of negative facial expression.
Conclusions
This study shows that psilocybin shifts the emotional bias across various psychological domains and that activation of 5-HT2A receptors is central in mood regulation and emotional face recognition in healthy subjects. These findings may not only have implications for the pathophysiology of dysfunctional emotional biases but may also provide a framework to delineate the mechanisms underlying psylocybin's putative antidepressant effects.
Papers cited by this study that are also in Blossom
Vollenweider, F. X., Vollenweider-Scherpenhuyzen, M. F. I., Bäbler, A. et al. · NeuroReport (1998)
Studerus, E., Kometer, M., Hasler, F. et al. · Journal of Psychopharmacology (2010)
Vollenweider, F. X., Kometer, M. · Nature Reviews Neuroscience (2010)
Kometer, M., Cahn, B. R., Andel, D. et al. · Biological Psychiatry (2011)
Central to the pathophysiology of mood disorders is a bias toward the processing of negative relative to positive emotional information across perceptual, attentional, and behavioural domains. Depressed individuals demonstrate lower accuracy in recognising happy facial expressions, slower responses to positive stimuli, and altered neural responses to emotional cues — patterns that both reflect and perpetuate the affective state. Serotonin is believed to play a key regulatory role in such emotional processing biases, and the 5-HT2A receptor subtype in particular has been associated with emotional excitability and perceptual sensitivity. Psilocybin, a partial 5-HT2A agonist, has demonstrated antidepressant effects in clinical trials, but whether these reflect a correction of negative emotional processing biases — similar to the mechanism proposed for SSRIs — and whether 5-HT2A receptors specifically mediate these effects, had not been experimentally established. This study aimed to address this question directly using a double-blind, placebo-controlled, 2×2 factorial design with pharmacological blockade of the 5-HT2A receptor.
Seventeen healthy right-handed volunteers (11 male, 6 female; mean age 26.0 years) participated in a four-session randomised double-blind placebo-controlled crossover study. Each session consisted of pre-treatment with either ketanserin (50 mg, a selective 5-HT2A antagonist estimated to block the relevant receptor population at this dose) or placebo, followed one hour later by psilocybin (215 µg/kg) or placebo. The four conditions were separated by at least two weeks. Outcomes assessed included acute subjective drug effects (5D-ASC questionnaire; PANAS positive and negative affect), facial emotional recognition accuracy (Reading the Mind in the Eyes Test, RMET), goal-directed emotional behaviour (emotional go/nogo task using emotionally valenced words), and electroencephalographic (EEG) measures including event-related potentials (P300) recorded during the go/nogo task.
Psilocybin significantly increased positive affect on the PANAS (F1,16 = 16.61, p < 0.001, ηp² = 0.509), an effect that was fully blocked by ketanserin pre-treatment, confirming 5-HT2A mediation of psilocybin's acute mood effects. Similarly, psilocybin significantly reduced error rates specifically for negative facial expressions in the RMET, whilst leaving recognition of positive expressions unchanged — a selective bias towards positive facial information — that was also blocked by ketanserin. In the emotional go/nogo task, psilocybin significantly increased reaction times and reduced P300 amplitudes specifically to negative and neutral stimuli relative to positive stimuli, indicating a response bias toward positive emotional content and reduced neural processing allocation to negative cues. In contrast to the 5-HT2A-mediated effects on mood and facial recognition, some goal-directed behavioural effects of psilocybin in the go/nogo task were not fully reversed by ketanserin, suggesting partial involvement of other receptor subtypes (such as 5-HT1A) in these effects.
The findings demonstrate that psilocybin biases emotional processing toward positive relative to negative information across three distinct psychological domains — mood state, facial recognition, and goal-directed behaviour — and that the mood and perceptual effects are mediated by the 5-HT2A receptor. This pattern is directly opposite to the negative emotional processing biases characteristic of depression, providing a plausible psychological mechanism for psilocybin's antidepressant effects that parallels — but likely differs mechanistically from — the emotional bias correction attributed to SSRIs after weeks of treatment. The strong acute positive mood effects of psilocybin, and the shift in perceptual and behavioural responding away from negative stimuli, are interpreted as consistent with a direct serotonergic correction of the affective information processing architecture that maintains depressive pathology. The partial contribution of non-5-HT2A receptor mechanisms to some behavioural effects — particularly the go/nogo context sequencing effects — is noted as warranting further pharmacological dissection. The healthy volunteer sample limits direct generalisation to clinical depression populations.
Psilocybin produces a selective and consistent bias toward positive emotional processing across mood, perceptual, and behavioural domains, with mood and facial recognition effects mediated by 5-HT2A receptors. These effects are the mirror image of the negative emotional biases observed in depressive disorders, providing empirical support for an emotional processing mechanism of psilocybin's antidepressant action and highlighting the 5-HT2A receptor as a key mediator of its emotionally relevant pharmacological effects.
entral components in the pathophysiology of mood disorders are biases toward the processing of negative compared with positive emotions across different psychological domains, including perception, attention, and behavior. For example, depressed subjects need more intensely happy facial expression to correctly label happinessand are slower in responding to positive but not to negative words in emotional go/nogo tasks. A crucial role for serotonin in the regulation of emotional biases is evidenced by genetic and pharmacologic studies, while the differential contribution of 5-HT subreceptors across psychological domains in humans is less well understood. However, accumulating evidence suggests that serotonin 1A (5-HT1A) and 2A (5-HT2A) receptors are particularly implicated in the pathophysiology of dysfunctional emotional biases, because 5-HT1A and 5-HT2A receptor densities are altered in depressive, bipolar, and anxiety disorders. In line with this view, 5-HT1A receptor agonists, such as buspirone or pindolol, have been particularly used as add-on treatment to enhance the antidepressant effect of selective serotonin reuptake inhibitors (SSRIs). Also, more recently, preferential 5-HT2A receptor agonists revealed anxiolytic and antidepressive effects in different animal models of mood disorders. In humans, activation of 5-HT2A receptors has been identified as the primary mechanism underlying the acute subjective effects of classical psychedelics, such as psilocybin, which, at low to medium doses, are predominantly characterized by heightened mood and visual disturbances. Furthermore, psilocybin induces neuronal activity and neuroplastic effects in prefrontallimbic circuits implicated in mood disorder. These findings suggest that psilocybin, whose bioactive metabolite psilocin activates 5-HT2A, 5-HT1A, and serotonin 2C (5-HT2C) receptors, may not only produce acute mood-enhanging effects but may also induce sustained antidepressant or anxiolytic effects. In support of this view, a gradual reduction of depressive symptoms and trait anxiety over 6 months was observed after a single dose of psilocybin in a recent placebo-controlled pilot study in terminal cancer patients. Taken together, these findings suggest that psilocybin might bias emotional processing away from negative information by activating 5-HT1A, 5-HT2A, or both receptors. Assessing this hypothesis might help to unravel the psychopharmacologic mechanism underlying the pathophysiology of dysfunctional emotional biases and the recently proposed antidepressant and anxiolytic potential of psilocybin. To this end, here we investigated for the first time the effect of psilocybin on emotional processing biases across psychological domains. We also disentangled the specific contribution of the 5-HT2A receptor by antagonizing it with ketanserin. First, we assessed behaviorally the ability to recognize the emotional state of another person from facial cues, which has been previously shown to be biased toward negative emotions in depressed and anxious subjectsand to be related to serotonergic tone. Second, response selection and inhibition to emotional cues were quantified by behavioral and event-related electroencephalogram measurements in an emotional go/nogo task. These are crucial components of goal-directed behavior in social environmentsand are regulated by the 5-HT system. Finally, we evaluated and quantified acute psilocybin-induced mood effects using clinical relevant rating scales.
Seventeen healthy, right-handed subjects (11 male subjects, 6 female subjects, mean age 26.0 Ϯ 4.36 years, 15 university students/graduates, 1 high school diploma, 1 apprenticeship) were recruited through advertisement from the University of Zürich. All subjects were healthy according to physical examination, including electrocardiography and detailed blood analysis. The Mini-International Neuropsychiatric Interview for DSM-IV, the Expert System for Diagnosing Mental Disorders, and the Hopkins Symptom Checklist 90-Revisedwere used to exclude subjects with present or antecedent psychiatric disorders or a history of major psychiatric disorders in first-degree relatives. The absence of drug dependence or present drug abuse was verified by urine drug screening and a self-report drug use questionnaire. Seven subjects reported having previous experiences with psilocybin or other hallucinogens (mean lifetime experiences 2.4 Ϯ 1.1 times) and three subjects with 3,4-methylenedioxymethamphetamine (MDMA) (mean lifetime experiences 3.3 Ϯ 2.5 times). Eight subjects reported to have rarley or sporadically used cannabis (Ͻ4 joints per month). Subjects were informed by a written and oral description about the procedures of the study, including that they would receive on each experimental day in a double-blind manner two substances, either placebo ϩ placebo, placebo ϩ psilocybin, ketanserin ϩ placebo, or ketanserin ϩ psilocybin. Furthermore, they were informed about the possible risk of psilocybin administration and the broad spectrum of its consciousness-altering effects that may range from alterations in sensory perception, mood, thought, and the experience of self. To minimize the influence of the individual's expectations, we emphasized that the psychological effect of psilocybin is known to vary largely between and within subjects. The study was approved by the ethics committee of the Canton of Zürich. The use of psilocybin in humans was authorized by the Swiss Federal Office of Public Health, Department of Pharmacology and Narcotics, Bern, Switzerland.
Using a double-blind, within-subject, placebo-controlled randomized design, subjects received on 4 experimental days, separated from each other by at least 2 weeks, placebo or ketanserin (50 mg) (pretreatment) followed after 1 hour by placebo or psyilocybin (215 g/kg) (treatment). These specific doses were chosen because they have previously been shown to effectively induce or block the associated changes in conscious states, respectively. The time delay between pretreatment and treatment was 1 hour to ensure maximal 5-HT2A receptor occupancy. Experiments started approximately 130 minutes after treatment and self-report ques-tionnaires were given 360 minutes posttreatment to retrospectively rate their subjective experience since drug intake.
The 5-Dimensions Altered States of Consciousness (5D-ASC) questionnaire, a self-rating scale with 94 visual analogue items, was used to quantify the subjective psychological effects of psilocybin. Eleven subscales were recently constructed. Of primary interest in regard to the current study was the blissful state subscale measuring experiences of pleasure, peace, and love and the anxiety subscale quantifying anxiety associated with derealization and depersonalization. The German version of the Positive and Negative Affect Schedule (PANAS) was used to assess the self-reported positive and negative affectand the German version of State-Trait Anxiety Inventory (STAI) was used to quantify state-anxiety.
The accuracy of inferring emotional states from the eye region was measured by a German adaptation of the Reading the Mind in the Eyes Test. Briefly, 36 black-and-white photographs of the eye region of persons expressing different subtle emotional states (e.g., ashamed) were presented on a computer screen together with four words describing the states of the persons. Participants were instructed to choose the word that described the state of the person most accurately. The total number of correct recognitions was computed for different valence categories (positive, negative, and neutral). Because the previously used valence categorizationwas based on a small sample of 12 undergraduate women who rated the picture in combination with the target word, pictures and target/distracter words were rerated seperately in a study comprising 40 subjects (Supplement 1).
In the emotional go/nogo task, emotionally valenced words (positive, negative, neutral) were presented in easy readable font (Universe) in the middle of the computer screen. We used emotional words as stimulus material because they have, in contrast to faces, a stronger impact on cognitive versus perceptual processesand therefore allow better differentiation of the performance in the emotional go/nogo from the facial recognition task. Participants were instructed by text appearing at the beginning of each block to press as rapidly as possible a response button when words of one valence category were presented (go cues) and withhold responses to words of another valence category (nogo cues). The following blocks were presented once in the first half and once in the second half of the experiment in a randomized order: 1) positive go, neutral nogo, 2) positive go, negative nogo, 3) neutral go, positive nogo, 4) neutral go, negative nogo, 5) negative go, positive nogo, and 6) negative go, neutral nogo. Each block contained a pseudoranomized presentation of 30 go trials and 10 nogo trials, resulting in a total of 360 go trials and 120 nogo trials. To enable a parametric assessment of sequential facilatory and inhibitory processes, the number of go cues preceding nogo cues in the trial order was counterbalanced in all blocks from zero to six according to previous studies. In each trial, words were presented for 280 msec followed by a fixation cross, which was used to reduce eye movements. The presentation time of the fixation cross was randomized from 1200 msec to 1400 msec to discourage anticipatory responses. Words were taken from the Berlin Affective Word List Reloadedand were matched for number of letters, syllables, phonemes, frequency of appearance, number of orthographic neighbors, and imageability. Furthermore, negative and positive words were matched for arousal but differed in valence ratings (Supplement 1).
Electroencephalogram recordings were made using BioSemi ActiveTwo electrode system with 64 scalp electrodes (BioSemi, Amsterdam, The Netherlands). Additional electrodes were attached on the outer canthus of each eye to record the horizontal electrooculogram and infraorbitally and supraorbitally to the left eye to record the vertical electrooculogram. Electrophysiologic signals were digitized at 512 Hz.
Electroencephalogram data were high-pass filtered at .5 Hz to attenuate channel drifts. Bad channels were interpolated using spherical splines, and eye movements and blinks were removed by applying the extended infomax independent component analysis algorithm. Electroencephalogram data were low-pass filtered at 30 Hz. All trials (correct and incorrect) were segmented separately for each valance go/nogo combination from Ϫ200 to ϩ1200 msec relative to stimulus presentation. To avoid remaining artifacts in further analysis, segments with activity exceeding Ϯ75 V in any channel, gradients of 50 V/second, and activity below .5 V for at least 100 msec were excluded from further analysis before averaging. Event-related potentials were rereferenced to the average reference before N2 and P300 amplitudes were quantified against baseline activity. Peak amplitudes were obtained from the four midline electrodes that revealed highest amplitudes across all drug conditions. The N2 was therefore defined as the most negative peak from 250 to 450 msec at electrode AFz, Fz, FCz, Cz, and the P300 was defined as the most positive peak from 450 to 700 msec at FCz, Cz, CPz, Pz (Figurein Supplement 1).
PANAS. Repeated-measures analysis of variance (ANOVA) with pretreatment, treatment, and subscale as within-subject factors revealed that psilocybin significantly increased PANAS scores [F(1,16) ϭ 16.608, p Ͻ .001, p 2 ϭ .509]. Importantly, the triple interaction between pretreatment ϫ treatment ϫ subscale [F (1,16) ϭ 21.160, p Ͻ .001, p 2 ϭ .569] showed that psilocybin significantly increased positive affect subscale after pretreatment with placebo (p Ͻ .00001) but not ketanserin (p ϭ 1) (Figure). In contrast, psilocybin did not increase negative affect, either after pretreatment with placebo (p ϭ 1) or after pretreatment with ketanserin (p ϭ 1). STAI-State. Repeated-measures ANOVA revealed a significant pretreatment ϫ treatment interaction [F (1,16) ϭ 14.708, p Ͻ .01, p 2 ϭ .480]. Bonferroni-corrected post hoc analyses of this interaction indicated that ketanserin increased STAI scores in placebotreated (p Ͻ .01) and psilocybin-treated (p Ͻ .000001) subjects. In contrast, psilocybin did not change STAI scores after pretreatment with placebo (p ϭ .515) (Figure). 5D-ASC. Psilocybin significantly increased 5D-ASC scores [F (1,16) ϭ 78.059, p Ͻ 1 Ϫ6 , p 2 ϭ .823] and pretreatment with ketanserin reduced this psilocybin-induced increase [F (1,16) ϭ 87.223, p Ͻ 1 Ϫ7 , p 2 ϭ .845]. Bonferroni-corrected post hoc analysis on the triple interaction between pretreatment ϫ treatment ϫ subscale [F (10,160) ϭ 9.549, p Ͻ 1 Ϫ11 , p 2 ϭ .374] indicated that psilocybin increased the blissful state subscale, as well as the experience of unity, insightfulness, complex imagery, elementary imagery, changed meaning of percepts (all ps Ͻ 1 Ϫ9 ), the disembodiment (p Ͻ 1 Ϫ8 ), audio-visual synesthesiae (p Ͻ .00001), impaired control and cognition (p Ͻ .001), spiritual experience (p Ͻ .01), but not anxiety (p ϭ 1), subscales after pretreatment with placebo. Psilocybin did not increase any of these 11 subscales after pretreatment with ketanserin (all ps ϭ 1) (Figure).
Error Rate. A repeated-measures ANOVA using pretreatment, treatment, and valence as within-subject factors revealed a main effect of valence [F (2,32) ϭ 16.857, p Ͻ .0001, p 2 ϭ .513]. Psilocybin modulated error rates depending on the valence of the facial expression [F (2,32) ϭ 5.460, p Ͻ .01, p 2 ϭ .254]. This interaction between treatment and valence was further modulated by pretreatment [F (2,34) ϭ 3.886, p Ͻ .05, p 2 ϭ .181] because psilocybin increased error rates for negative faces only after placebo (p Ͻ .05) but not ketanserin pretreatment (p ϭ 1) (Figure). Overall, this interaction indicated a relative enhanced performance for positive compared with negative items, particulary in the placebo ϩ psilocybin condition (p Ͻ .00001) and somewhat in the ketanserin ϩ psilocybin condition (p Ͻ .01) but not in the placebo ϩ placebo (p ϭ .44) and ketanserin ϩ placebo conditions (p ϭ 1). A second repeated-measures ANOVA on the valence of the chosen word using pretreatment and treatment as within-subject factors revealed that psilocybin biased to choose higher valenced words [F. Subsequent Bonferroni-corrected post hoc analyses showed that RTs to go-stimuli were decreased for the sixth repetition (maximal repetition) of positive (p Ͻ .01) and neutral (p Ͻ .01) but not negative go-stimuli (p ϭ .10) compared with zero repetition (minimal repetition). Interestingly, psilocybin modulated these sequential emotional effects, which is indicated by the significant triple interaction between treatment ϫ valence ϫ number of repetition [F (10,160) ϭ 2.500, p Ͻ .01, p 2 ϭ .135]. Specifically, the decrease in RTs between zero and six repeating positive trials reached Bonferroni-corrected significance after treatment with psilocybin (p Ͻ .001) but not placebo (p ϭ 1), while a significant increase of RTs between zero and six repeating negative trials were observed after psilocybin (p Ͻ .01) but not placebo treatment (p ϭ 1) (Figure). Bonferroni-corrected post hocs showed that psilocybin decreased the P300 amplitude only after pretreatment with placebo (p Ͻ .01) but not ketanserin pretreatment (p ϭ 1). Importantly, the psilocybin-induced decrease was dependent on the word valence [F (2,32) ϭ 3.94, p Ͻ .05, p 2 ϭ .198] because the decrease was most pronounced for neutral (p Ͻ 1 Ϫ13 , Ϫ.97 V) followed by negative (p Ͻ 1 Ϫ12 , Ϫ.85 V) and positive (p Ͻ 1 Ϫ10 , Ϫ.71 V) words. The significant triple interaction between pretreatment ϫ treatment ϫ valence [F (2,32) ϭ 4.164, p Ͻ .05, p 2 ϭ .207] revealed the complex nature of the drug effects on the emotional processing. Specifically, during placebo ϩ placebo condition, Bonferroni-corrected post hocs indicated higher P300 amplitudes for negative compared with neutral words (p Ͻ .001). In contrast in the placebo ϩ psilocybin condition, the positive stimuli evoked higher P300 amplitudes compared with neutral stimuli (p Ͻ .05). The strongest effects were seen in the ketanserin ϩ psilocybin condition because P300 amplitudes were much higher for positive (p Ͻ .00001) and negative stimuli (p Ͻ .00001) compared with neutral stimuli (Figure).
Our data show that psilocybin biases emotional processing toward positive relative to negative information, an effect that is consistent across different psychological domains. Specifically, psilocybin first enhanced positive mood states; second, decreased recognition of negative facial expression; and third, increased behavior toward positive relative to negative cues. In contrast to these generalized effects of the serotonergic agonist psilocybin, a more specific role for 5-HT2A receptors in elevating mood and attenuating the recognition of negative facial expression is indicated by the finding that the preferential 5-HT2A antagonist ketanserin blocked these psilocybin-induced effects.
Psilocybin predominantly enhanced positive mood states, as evidenced by the marked increase in the positive affect but not negative affect subscale scores of the PANAS questionnaire, as well as by the increase in blissful but not anxiety subscale scores of the 5D-ASC questionnaire. These strong effects of psilocybin on mood contrasts with the usually lacking acute mood effects of drugs that modulate the serotonergic tone such as acute tryptophan depletionor SSRI administration. This apparent disparity suggests that a specific activation of certain 5-HT subreceptors is necessary to acutely enhance mood. Indeed, the finding that the preferential 5-HT2A antagonist ketanserin blocked the moodenhancing effects of psilocybin suggests that 5-HT2A receptors are implicated in regulating positive mood states. Moreover, we argue that the additional stimulation of 5-HT1A or 5-HT2C receptors by psilocybin is rather unlikely to contribute to the mood effects of psilocybin, because ketanserin has nearly no affinity to 5-HT1A receptors and about fiftyfold higher affinity to 5-HT2A compared with 5-HT2C receptors (National Institute of Mental Health Psychoactive Drug Screening Program:). Furthermore, the serotonin 2B/5-HT2C agonist meta-chlorphenylpiperazin induces anxiety rather than positive mood states. Finally, it is unlikely that expectation of receiving psilocybin considerably contributed to the mood effects, because various drug combinations were administrated in a double-blind procedure and subjects were instructed that the psychological effects of psilocybin vary largely between and within subjects.
Serotonin 2A receptors appear also to be crucially involved in the recognition of negative facial expressions, because ketanserin blocked psilocybin-induced attenuation in recognizing negative emotional states from the eye region of human faces. This finding is in line with the central role of serotonin in emotional facial recognition as previously established by pharmacologicand genetic studiesbut extends this notion by showing that specific activation of 5-HT2A receptors likely biases facial recognition away from negative emotion. This mechanism might also contribute to the attenuated recognition of negative facial expression as previously observed after a single dose of MDMAand after chronic administration of SSRIs, because MDMA has a moderate affinity at 5-HT2A receptorsand chronic SSRI administration changes 5-HT2A receptor density.
In the emotional go/nogo task, psilocybin enhanced the response bias toward positive relative to neutral and negative emotional stimuli, which was evidenced at the behavioral level by the psilocybin-induced increase in reaction times to negative and neutral compared with positive stimuli. In addition, this response bias was modulated by the sequential context of the stimuli across all drug conditions, an effect that was augmented by psilocybin ad- ministration. That is, across all drug conditions, sequential repetition of positive and neutral stimuli facilitated processing, as indicated by decreased reaction times to positive and neutral stimuli. Interestingly, this sequential facilatory effect was lacking after negative stimuli, a finding that has not yet been reported in emotional go/nogo tasks but was previously observed in semanticand negative affective priming tasks. Given that this lacking facilitation has been interpreted as an inhibition of negative concepts within the attentional (66) or memory system (65) and that psilocybin prolonged reaction time for repeated negative stimuli but decreased it for repeated positive stimuli, psilocybin may also increase inhibition of negative relative to positive concepts in the attentional or memory system. Support for such a psilocybin-induced shift in the attentional system was revealed by the effect of psilocybin on event-related potentials. The event-related potentials analysis indicated that across all drug conditions, the word valence affected early and late response selection, inhibition, and attention processes as indexed by the decreased N2 and enhanced P3 component for emotional relative to neutral stimuli. Most importantly, while psilocybin and ketanserin did not modulate these valence-specific effects during the N2 time range, psilocybin strongly decreased the P300 component in all valence conditions and particularly for negative and neutral stimuli. Because this valence-dependent P300 decrease was equally present in both the go and nogo conditions, it is conceivable that this psilocybin-induced change in emotional processing is neither specific for response selection (go) nor specific for inhibition (nogo) but rather reflects a more general process underlying the P300. For instance, the P300 amplitude is strongly modulated by the amount of attentional resource allocation, and several behavioral studies previously showed that psilocybin attenuates attentional performance. This suggests, on the one hand, that the strong psilocybin-induced decrease of the P300 seen across all valence conditions might reflect an important electrophysiological index of the previously reported psilocybin-induced attentional deficits. On the other hand, the small valence-dependent decrease suggests that psilocybin may attenuate the allocation of attentional resources to neutral and negative stimuli more strongly than to positive stimuli, which results in a relative positive attentional bias. Contrary to the crucial contribution of 5-HT2A receptors in modulating mood states and emotional face recognition, the psilocybin-induced relative bias toward the processing of positive emotions in the go/nogo task were not blocked by pretreatment with ketanserin. Thus, the psilocybin-induced emotional bias might rather be due to a stimulation of 5-HT1A or 5-HT2C receptors than 5-HT2A receptors. However, the strong valence-independent reduction of the P300 seen after psilocybin administration was partially reversed by ketanserin, indicating an involvement of 5-HT2A receptors in the valence-independent attentional performance.
In the present study, psilocybin produced behavioral and electrophysiological effects that were opposite to the dysfunctional emotional processing bias seen in depressed subjects in emotional facial recognition, goal-directed behavior, and mood states. For example, in the emotional go/nogo task, psilocybin increased RTs and decreased P300 amplitudes, particulary for negative and neutral stimuli, while depressed subjects were delayed in responding to positive cues (2,3) and displayed increased P300 component for negative stimuli. Thus, it appears that psilocybin may have the potential to acutely shift dysfunctional emotional biases in depression. Such an acute shift might, in con-junction with the reported effect of psilocybin on neuroplastic factors, lead to sustained adaptations and may therefore account for the discussed antidepressive potential of psilocybin-like compounds. Hence, further studies using different and multiple doses of psilocybin are indicated to explore whether the effect of psilocybin on emotional biases are dose-dependent and whether psilocybin may shift the negative emotional biases seen in depression. Furthermore, here we identify 5-HT2A receptor activity as a potential crucial pharmacologic target in the treatment of negative mood states and negative emotional facial recognition bias. In line with this finding, negative mood is associated with pessimistic attitudes (74) and medication-free major depression patients with high pessimistic attitudes have increased 5-HT2A receptor binding in the prefrontal cortex compared with healthy control subjects. Furthermore, chronic administration of SSRIs not only shifts negative mood states and negative bias in facial recognition in depressed patientsbut also seems to normalize alterations in 5-HT2A receptor densities in depressed subjects. In summary, the present study indicates that the assessment of the effects of psilocybin provides a valuable framework to identify neuropsychopharmacologic mechanisms underlying dysfunctional emotional biases and the putative antidepressant effects of psilocybin and related compounds.
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