Psychedelic drugs: neurobiology and potential for treatment of psychiatric disorders.

Renewed interest in the use of psychedelics in the treatment of psychiatric disorders warrants a better understanding of the neurobiological mechanisms underlying the effects of these substances. After a hiatus of about 50 years, state-of-the art studies have recently begun to close important knowledge gaps by elucidating the mechanisms of action of psychedelics with regard to their effects on receptor subsystems, systems-level brain activity and connectivity, and cognitive and emotional processing. In addition, functional studies have shown that changes in self-experience, emotional processing and social cognition may contribute to the potential therapeutic effects of psychedelics. These discoveries provide a scientific road map for the investigation and application of psychedelic substances in psychiatry.

Neural mechanisms of psychedelic visual imagery.

Visual alterations under classic psychedelics can include rich phenomenological accounts of eyes-closed imagery. Preclinical evidence suggests agonism of the 5-HT2A receptor may reduce synaptic gain to produce psychedelic-induced imagery. However, this has not been investigated in humans. To infer the directed connectivity changes to visual connectivity underlying psychedelic visual imagery in healthy adults, a double-blind, randomised, placebo-controlled, cross-over study was performed, and dynamic causal modelling was applied to the resting state eyes-closed functional MRI scans of 24 subjects after administration of 0.2 mg/kg of the serotonergic psychedelic drug, psilocybin (magic mushrooms), or placebo. The effective connectivity model included the early visual area, fusiform gyrus, intraparietal sulcus, and inferior frontal gyrus. We observed a pattern of increased self-inhibition of both early visual and higher visual-association regions under psilocybin that was consistent with preclinical findings. We also observed a pattern of reduced inhibition from visual-association regions to earlier visual areas that indicated top-down connectivity is enhanced during visual imagery. The results were analysed with behavioural measures taken immediately after the scans, suggesting psilocybin-induced decreased sensitivity to neural inputs is associated with the perception of eyes-closed visual imagery. The findings inform our basic and clinical understanding of visual perception. They reveal neural mechanisms that, by affecting balance, may increase the impact of top-down feedback connectivity on perception, which could contribute to the visual imagery seen with eyes-closed during psychedelic experiences.

A neurobiological perspective on social influence: Serotonin and social adaptation.

Humans are inherently social beings. Being suggestible to each other's expectations enables pro-social skills that are crucial for social learning and adaptation. Despite their high relevance for psychiatry, the neurobiological mechanisms underlying social adaptation are still not well understood. This review, therefore, provides a conceptual framework covering various distinct mechanisms underlying social adaptation and explores the neuropharmacology - in particular the role of the serotonin (5-HT) system - in modulating these mechanisms. This article reviews empirical results on social influence processing and reconciles them with recent findings from psychedelic research on social processing to elucidate neurobiological and neuropharmacological underpinnings of social adaptation. Various computational, neurobiological, and neurochemical processes are involved in distinct mechanisms underlying social adaptation such as the multisensory process of social information integration that is crucial for the forming of self-representation and representations of social norms. This is again associated with self- and other-perception during social interactions as well as value-based decision-making that guides our behavior in daily interactions. We highlight the critical role of 5-HT in these processes and suggest that 5-HT can facilitate social learning and may represent an important target for treating psychiatric disorders characterized by impairments in social functioning. This framework also has important implications for psychedelic-assisted therapy as well as for the development of novel treatment approaches and future research directions.

Psilocybin Induces Aberrant Prediction Error Processing of Tactile Mismatch Responses-A Simultaneous EEG-FMRI Study.

As source of sensory information, the body provides a sense of agency and self/non-self-discrimination. The integration of bodily states and sensory inputs with prior beliefs has been linked to the generation of bodily self-consciousness. The ability to detect surprising tactile stimuli is essential for the survival of an organism and for the formation of mental body representations. Despite the relevance for a variety of psychiatric disorders characterized by altered body and self-perception, the neurobiology of these processes is poorly understood. We therefore investigated the effect of psilocybin (Psi), known to induce alterations in self-experience, on tactile mismatch responses by combining pharmacological manipulations with simultaneous electroencephalography-functional magnetic resonance imaging (EEG-fMRI) recording. Psi reduced activity in response to tactile surprising stimuli in frontal regions, the visual cortex, and the cerebellum. Furthermore, Psi reduced tactile mismatch negativity EEG responses at frontal electrodes, associated with alterations of body- and self-experience. This study provides first evidence that Psi alters the integration of tactile sensory inputs through aberrant prediction error processing and highlights the importance of the 5-HT2A system in tactile deviancy processing as well as in the integration of bodily and self-related stimuli. These findings may have important implications for the treatment of psychiatric disorders characterized by aberrant bodily self-awareness.

Classic Psychedelic Drugs: Update on Biological Mechanisms.

Renewed interest in the effects of psychedelics in the treatment of psychiatric disorders warrants a better understanding of the neurobiological mechanisms underlying the effects of these substances. During the past two decades, state-of-the-art studies of animals and humans have yielded new important insights into the molecular, cellular, and systems-level actions of psychedelic drugs. These efforts have revealed that psychedelics affect primarily serotonergic receptor subtypes located in cortico-thalamic and cortico-cortical feedback circuits of information processing. Psychedelic drugs modulate excitatory-inhibitory balance in these circuits and can participate in neuroplasticity within brain structures critical for the integration of information relevant to sensation, cognition, emotions, and the narrative of self. Neuroimaging studies showed that characteristic dimensions of the psychedelic experience obtained through subjective questionnaires as well as alterations in self-referential processing and emotion regulation obtained through neuropsychological tasks are associated with distinct changes in brain activity and connectivity patterns at multiple-system levels. These recent results suggest that changes in self-experience, emotional processing, and social cognition may contribute to the potential therapeutic effects of psychedelics.

Effective connectivity changes in LSD-induced altered states of consciousness in humans.

Psychedelics exert unique effects on human consciousness. The thalamic filter model suggests that core effects of psychedelics may result from gating deficits, based on a disintegration of information processing within cortico-striato-thalamo-cortical (CSTC) feedback loops. To test this hypothesis, we characterized changes in directed (effective) connectivity between selected CTSC regions after acute administration of lysergic acid diethylamide (LSD), and after pretreatment with Ketanserin (a selective serotonin 2A receptor antagonist) plus LSD in a double-blind, randomized, placebo-controlled, cross-over study in 25 healthy participants. We used spectral dynamic causal modeling (DCM) for resting-state fMRI data. Fully connected DCM models were specified for each treatment condition to investigate the connectivity between the following areas: thalamus, ventral striatum, posterior cingulate cortex, and temporal cortex. Our results confirm major predictions proposed in the CSTC model and provide evidence that LSD alters effective connectivity within CSTC pathways that have been implicated in the gating of sensory and sensorimotor information to the cortex. In particular, LSD increased effective connectivity from the thalamus to the posterior cingulate cortex in a way that depended on serotonin 2A receptor activation, and decreased effective connectivity from the ventral striatum to the thalamus independently of serotonin 2A receptor activation. Together, these results advance our mechanistic understanding of the action of psychedelics in health and disease. This is important for the development of new pharmacological therapeutics and also increases our understanding of the mechanisms underlying the potential clinical efficacy of psychedelics.

Psilocybin exerts distinct effects on resting state networks associated with serotonin and dopamine in mice.

Hallucinogenic agents have been proposed as potent antidepressants; this includes the serotonin (5-HT) receptor 2A agonist psilocybin. In human subjects, psilocybin alters functional connectivity (FC) within the default-mode network (DMN), a constellation of inter-connected regions that displays altered FC in depressive disorders. In this study, we investigated the effects of psilocybin on FC across the entire brain with a view to investigate underlying mechanisms. Psilocybin effects were investigated in lightly-anaesthetized mice using resting-state fMRI. Dual-regression analysis identified reduced FC within the ventral striatum in psilocybin- relative to vehicle-treated mice. Refinement of the analysis using spatial references derived from both gene expression maps and viral tracer projection fields revealed two distinct effects of psilocybin: it increased FC between 5-HT-associated networks and cortical areas, including elements of the murine DMN, thalamus, and midbrain; it decreased FC within dopamine (DA)-associated striatal networks. These results suggest that interactions between 5-HT- and DA-regulated neural networks contribute to the neural and therefore psychological effects of psilocybin. Furthermore, they highlight how information on molecular expression patterns and structural connectivity can assist in the interpretation of pharmaco-fMRI findings.

P300-mediated modulations in self-other processing under psychedelic psilocybin are related to connectedness and changed meaning: A window into the self-other overlap.

The concept of self and self-referential processing has a growing explanatory value in psychiatry and neuroscience, referring to the cognitive organization and perceptual differentiation of self-stimuli in health and disease. Conditions in which selfhood loses its natural coherence offer a unique opportunity for elucidating the mechanisms underlying self-disturbances. We assessed the psychoactive effects of psilocybin (230 µg/kg p.o.), a preferential 5-HT1A/2A agonist known to induce shifts in self-perception. Our placebo-controlled, double-blind, within-subject crossover experiment (n = 17) implemented a verbal self-monitoring task involving vocalizations and participant identification of real-time auditory source- (self/other) and pitch-modulating feedback. Subjective experience and task performance were analyzed, with time-point-by-time-point assumption-free multivariate randomization statistics applied to the spatiotemporal dynamics of event-related potentials. Psilocybin-modulated self-experience, interacted with source to affect task accuracy, and altered the late phase of self-stimuli encoding by abolishing the distinctiveness of self- and other-related electric field configurations during the P300 timeframe. This last effect was driven by current source density changes within the supragenual anterior cingulate and right insular cortex. The extent of the P300 effect was associated with the intensity of psilocybin-induced feelings of unity and changed meaning of percepts. Modulations of late encoding and their underlying neural generators in self-referential processing networks via 5-HT signaling may be key for understanding self-disorders. This mechanism may reflect a neural instantiation of altered self-other and relational meaning processing in a stimulus-locked time domain. The study elucidates the neuropharmacological foundation of subjectivity, with implications for therapy, underscoring the concept of connectedness.

LSD acutely impairs working memory, executive functions, and cognitive flexibility, but not risk-based decision-making.

BACKGROUND: Psychiatric and neurodegenerative illnesses are characterized by cognitive impairments, in particular deficits in working memory, decision-making, and executive functions including cognitive flexibility. However, the neuropharmacology of these cognitive functions is poorly understood. The serotonin (5-HT) 2A receptor might be a promising candidate for the modulation of cognitive processes. However, pharmacological studies investigating the role of this receptor system in humans are rare. Recent evidence demonstrates that the effects of Lysergic acid diethylamide (LSD) are mediated via agonistic action at the 5-HT2A receptor. Yet, the effects of LSD on specific cognitive domains using standardized neuropsychological test have not been studied. METHODS: We examined the acute effects of LSD (100 µg) alone and in combination with the 5-HT2A antagonist ketanserin (40 mg) on cognition, employing a double-blind, randomized, placebo-controlled, within-subject design in 25 healthy participants. Executive functions, cognitive flexibility, spatial working memory, and risk-based decision-making were examined by the Intra/Extra-Dimensional shift task (IED), Spatial Working Memory task (SWM), and Cambridge Gambling Task (CGT) of the Cambridge Neuropsychological Test Automated Battery. RESULTS: Compared to placebo, LSD significantly impaired executive functions, cognitive flexibility, and working memory on the IED and SWM, but did not influence the quality of decision-making and risk taking on the CGT. Pretreatment with the 5-HT2A antagonist ketanserin normalized all LSD-induced cognitive deficits. CONCLUSIONS: The present findings highlight the role of the 5-HT2A receptor system in executive functions and working memory and suggest that specific 5-HT2A antagonists may be relevant for improving cognitive dysfunctions in psychiatric disorders.

Role of the 5-HT2A Receptor in Self- and Other-Initiated Social Interaction in Lysergic Acid Diethylamide-Induced States: A Pharmacological fMRI Study.

Distortions of self-experience are critical symptoms of psychiatric disorders and have detrimental effects on social interactions. In light of the immense need for improved and targeted interventions for social impairments, it is important to better understand the neurochemical substrates of social interaction abilities. We therefore investigated the pharmacological and neural correlates of self- and other-initiated social interaction. In a double-blind, randomized, counterbalanced, crossover study 24 healthy human participants (18 males and 6 females) received either (1) placebo + placebo, (2) placebo + lysergic acid diethylamide (LSD; 100 µg, p.o.), or (3) ketanserin (40 mg, p.o.) + LSD (100 µg, p.o.) on three different occasions. Participants took part in an interactive task using eye-tracking and functional magnetic resonance imaging completing trials of self- and other-initiated joint and non-joint attention. Results demonstrate first, that LSD reduced activity in brain areas important for self-processing, but also social cognition; second, that change in brain activity was linked to subjective experience; and third, that LSD decreased the efficiency of establishing joint attention. Furthermore, LSD-induced effects were blocked by the serotonin 2A receptor (5-HT2AR) antagonist ketanserin, indicating that effects of LSD are attributable to 5-HT2AR stimulation. The current results demonstrate that activity in areas of the "social brain" can be modulated via the 5-HT2AR thereby pointing toward this system as a potential target for the treatment of social impairments associated with psychiatric disorders.SIGNIFICANCE STATEMENT Distortions of self-representation and, potentially related to this, dysfunctional social cognition are central hallmarks of various psychiatric disorders and critically impact disease development, progression, treatment, as well as real-world functioning. However, these deficits are insufficiently targeted by current treatment approaches. The administration of lysergic acid diethylamide (LSD) in combination with functional magnetic resonance imaging and real-time eye-tracking offers the unique opportunity to study alterations in self-experience, their relation to social cognition, and the underlying neuropharmacology. Results demonstrate that LSD alters self-experience as well as basic social cognition processing in areas of the "social brain". Furthermore, these alterations are attributable to 5-HT2A receptor stimulation, thereby pinpointing toward this receptor system in the development of pharmacotherapies for sociocognitive deficits in psychiatric disorders.

Psilocybin-assisted mindfulness training modulates self-consciousness and brain default mode network connectivity with lasting effects.

Both psychedelics and meditation exert profound modulatory effects on consciousness, perception and cognition, but their combined, possibly synergistic effects on neurobiology are unknown. Accordingly, we conducted a randomized, double-blind, placebo-controlled study with 38 participants following a single administration of the psychedelic psilocybin (315 µg/kg p.o.) during a 5-day mindfulness retreat. Brain dynamics were quantified directly pre- and post-intervention by functional magnetic resonance imaging during the resting state and two meditation forms. The analysis of functional connectivity identified psilocybin-related and mental state-dependent alterations in self-referential processing regions of the default mode network (DMN). Notably, decoupling of medial prefrontal and posterior cingulate cortices, which is thought to mediate sense of self, was associated with the subjective ego dissolution effect during the psilocybin-assisted mindfulness session. The extent of ego dissolution and brain connectivity predicted positive changes in psycho-social functioning of participants 4 months later. Psilocybin, combined with meditation, facilitated neurodynamic modulations in self-referential networks, subserving the process of meditation by acting along the anterior-posterior DMN connection. The study highlights the link between altered self-experience and subsequent behavioral changes. Understanding how interventions facilitate transformative experiences may open novel therapeutic perspectives. Insights into the biology of discrete mental states foster our understanding of non-ordinary forms of human self-consciousness and their concomitant brain substrate.

Serotonin 2A Receptor Signaling Underlies LSD-induced Alteration of the Neural Response to Dynamic Changes in Music.

Classic psychedelic drugs (serotonin 2A, or 5HT2A, receptor agonists) have notable effects on music listening. In the current report, blood oxygen level-dependent (BOLD) signal was collected during music listening in 25 healthy adults after administration of placebo, lysergic acid diethylamide (LSD), and LSD pretreated with the 5HT2A antagonist ketanserin, to investigate the role of 5HT2A receptor signaling in the neural response to the time-varying tonal structure of music. Tonality-tracking analysis of BOLD data revealed that 5HT2A receptor signaling alters the neural response to music in brain regions supporting basic and higher-level musical and auditory processing, and areas involved in memory, emotion, and self-referential processing. This suggests a critical role of 5HT2A receptor signaling in supporting the neural tracking of dynamic tonal structure in music, as well as in supporting the associated increases in emotionality, connectedness, and meaningfulness in response to music that are commonly observed after the administration of LSD and other psychedelics. Together, these findings inform the neuropsychopharmacology of music perception and cognition, meaningful music listening experiences, and altered perception of music during psychedelic experiences.

Effects of serotonin 2A/1A receptor stimulation on social exclusion processing.

Social ties are crucial for physical and mental health. However, psychiatric patients frequently encounter social rejection. Moreover, an increased reactivity to social exclusion influences the development, progression, and treatment of various psychiatric disorders. Nevertheless, the neuromodulatory substrates of rejection experiences are largely unknown. The preferential serotonin (5-HT) 2A/1A receptor agonist, psilocybin (Psi), reduces the processing of negative stimuli, but whether 5-HT2A/1A receptor stimulation modulates the processing of negative social interactions remains unclear. Therefore, this double-blind, randomized, counterbalanced, cross-over study assessed the neural response to social exclusion after the acute administration of Psi (0.215 mg/kg) or placebo (Pla) in 21 healthy volunteers by using functional magnetic resonance imaging (fMRI) and resting-state magnetic resonance spectroscopy (MRS). Participants reported a reduced feeling of social exclusion after Psi vs. Pla administration, and the neural response to social exclusion was decreased in the dorsal anterior cingulate cortex (dACC) and the middle frontal gyrus, key regions for social pain processing. The reduced neural response in the dACC was significantly correlated with Psi-induced changes in self-processing and decreased aspartate (Asp) content. In conclusion, 5-HT2A/1A receptor stimulation with psilocybin seems to reduce social pain processing in association with changes in self-experience. These findings may be relevant to the normalization of negative social interaction processing in psychiatric disorders characterized by increased rejection sensitivity. The current results also emphasize the importance of 5-HT2A/1A receptor subtypes and the Asp system in the control of social functioning, and as prospective targets in the treatment of sociocognitive impairments in psychiatric illnesses.

Two dose investigation of the 5-HT-agonist psilocybin on relative and global cerebral blood flow.

Psilocybin, the active compound in psychedelic mushrooms, is an agonist of various serotonin receptors. Seminal psilocybin positron emission tomography (PET) research suggested regional increases in glucose metabolism in frontal cortex (hyperfrontality). However, a recent arterial spin labeling (ASL) study suggests psilocybin may lead to hypo-perfusion in various brain regions. In this placebo-controlled, double-blind study we used pseudo-continuous ASL (pCASL) to measure perfusion changes, with and without adjustment for global brain perfusion, after two doses of oral psilocybin (low dose: 0.160 mg/kg; high dose: 0.215 mg/kg) in two groups of healthy controls (n = 29 in both groups, total N = 58) during rest. We controlled for sex and age and used family-wise error corrected p values in all neuroimaging analyses. Both dose groups reported profound subjective drug effects as measured by the Altered States of Consciousness Rating Scale (5D-ASC) with the high dose inducing significantly larger effects in four out of the 11 scales. After adjusting for global brain perfusion, psilocybin increased relative perfusion in distinct right hemispheric frontal and temporal regions and bilaterally in the anterior insula and decreased perfusion in left hemispheric parietal and temporal cortices and left subcortical regions. Whereas, psilocybin significantly reduced absolute perfusion in frontal, temporal, parietal, and occipital lobes, and bilateral amygdalae, anterior cingulate, insula, striatal regions, and hippocampi. Our analyses demonstrate consistency with both the hyperfrontal hypothesis of psilocybin and the more recent study demonstrating decreased perfusion, depending on analysis method. Importantly, our data illustrate that relative changes in perfusion should be understood and interpreted in relation to absolute signal variations.

Effect of Psilocybin on Empathy and Moral Decision-Making.

Background: Impaired empathic abilities lead to severe negative social consequences and influence the development and treatment of several psychiatric disorders. Furthermore, empathy has been shown to play a crucial role in moral and prosocial behavior. Although the serotonin system has been implicated in modulating empathy and moral behavior, the relative contribution of the various serotonin receptor subtypes is still unknown. Methods: We investigated the acute effect of psilocybin (0.215 mg/kg p.o.) in healthy human subjects on different facets of empathy and hypothetical moral decision-making using the multifaceted empathy test (n=32) and the moral dilemma task (n=24). Results: Psilocybin significantly increased emotional, but not cognitive empathy compared with placebo, and the increase in implicit emotional empathy was significantly associated with psilocybin-induced changed meaning of percepts. In contrast, moral decision-making remained unaffected by psilocybin. Conclusions: These findings provide first evidence that psilocybin has distinct effects on social cognition by enhancing emotional empathy but not moral behavior. Furthermore, together with previous findings, psilocybin appears to promote emotional empathy presumably via activation of serotonin 2A/1A receptors, suggesting that targeting serotonin 2A/1A receptors has implications for potential treatment of dysfunctional social cognition.

The neurobiology of psychedelic drugs: implications for the treatment of mood disorders.

After a pause of nearly 40 years in research into the effects of psychedelic drugs, recent advances in our understanding of the neurobiology of psychedelics, such as lysergic acid diethylamide (LSD), psilocybin and ketamine have led to renewed interest in the clinical potential of psychedelics in the treatment of various psychiatric disorders. Recent behavioural and neuroimaging data show that psychedelics modulate neural circuits that have been implicated in mood and affective disorders, and can reduce the clinical symptoms of these disorders. These findings raise the possibility that research into psychedelics might identify novel therapeutic mechanisms and approaches that are based on glutamate-driven neuroplasticity.

Spatiotemporal brain dynamics of emotional face processing modulations induced by the serotonin 1A/2A receptor agonist psilocybin.

Emotional face processing is critically modulated by the serotonergic system. For instance, emotional face processing is impaired by acute psilocybin administration, a serotonin (5-HT) 1A and 2A receptor agonist. However, the spatiotemporal brain mechanisms underlying these modulations are poorly understood. Here, we investigated the spatiotemporal brain dynamics underlying psilocybin-induced modulations during emotional face processing. Electrical neuroimaging analyses were applied to visual evoked potentials in response to emotional faces, following psilocybin and placebo administration. Our results indicate a first time period of strength (i.e., Global Field Power) modulation over the 168-189 ms poststimulus interval, induced by psilocybin. A second time period of strength modulation was identified over the 211-242 ms poststimulus interval. Source estimations over these 2 time periods further revealed decreased activity in response to both neutral and fearful faces within limbic areas, including amygdala and parahippocampal gyrus, and the right temporal cortex over the 168-189 ms interval, and reduced activity in response to happy faces within limbic and right temporo-occipital brain areas over the 211-242 ms interval. Our results indicate a selective and temporally dissociable effect of psilocybin on the neuronal correlates of emotional face processing, consistent with a modulation of the top-down control.

Activation of serotonin 2A receptors underlies the psilocybin-induced effects on α oscillations, N170 visual-evoked potentials, and visual hallucinations.

Visual illusions and hallucinations are hallmarks of serotonergic hallucinogen-induced altered states of consciousness. Although the serotonergic hallucinogen psilocybin activates multiple serotonin (5-HT) receptors, recent evidence suggests that activation of 5-HT2A receptors may lead to the formation of visual hallucinations by increasing cortical excitability and altering visual-evoked cortical responses. To address this hypothesis, we assessed the effects of psilocybin (215 µg/kg vs placebo) on both α oscillations that regulate cortical excitability and early visual-evoked P1 and N170 potentials in healthy human subjects. To further disentangle the specific contributions of 5-HT2A receptors, subjects were additionally pretreated with the preferential 5-HT2A receptor antagonist ketanserin (50 mg vs placebo). We found that psilocybin strongly decreased prestimulus parieto-occipital α power values, thus precluding a subsequent stimulus-induced α power decrease. Furthermore, psilocybin strongly decreased N170 potentials associated with the appearance of visual perceptual alterations, including visual hallucinations. All of these effects were blocked by pretreatment with the 5-HT2A antagonist ketanserin, indicating that activation of 5-HT2A receptors by psilocybin profoundly modulates the neurophysiological and phenomenological indices of visual processing. Specifically, activation of 5-HT2A receptors may induce a processing mode in which stimulus-driven cortical excitation is overwhelmed by spontaneous neuronal excitation through the modulation of α oscillations. Furthermore, the observed reduction of N170 visual-evoked potentials may be a key mechanism underlying 5-HT2A receptor-mediated visual hallucinations. This change in N170 potentials may be important not only for psilocybin-induced states but also for understanding acute hallucinatory states seen in psychiatric disorders, such as schizophrenia and Parkinson's disease.

Modeling ketamine effects on synaptic plasticity during the mismatch negativity.

This paper presents a model-based investigation of mechanisms underlying the reduction of mismatch negativity (MMN) amplitudes under the NMDA-receptor antagonist ketamine. We applied dynamic causal modeling and Bayesian model selection to data from a recent ketamine study of the roving MMN paradigm, using a cross-over, double-blind, placebo-controlled design. Our modeling was guided by a predictive coding framework that unifies contemporary "adaptation" and "model adjustment" MMN theories. Comparing a series of dynamic causal models that allowed for different expressions of neuronal adaptation and synaptic plasticity, we obtained 3 major results: 1) We replicated previous results that both adaptation and short-term plasticity are necessary to explain MMN generation per se; 2) we found significant ketamine effects on synaptic plasticity, but not adaptation, and a selective ketamine effect on the forward connection from left primary auditory cortex to superior temporal gyrus; 3) this model-based estimate of ketamine effects on synaptic plasticity correlated significantly with ratings of ketamine-induced impairments in cognition and control. Our modeling approach thus suggests a concrete mechanism for ketamine effects on MMN that correlates with drug-induced psychopathology. More generally, this demonstrates the potential of modeling for inferring on synaptic physiology, and its pharmacological modulation, from electroencephalography data.

The influence of psilocybin on subconscious and conscious emotional learning.

Serotonergic psychedelics hold promise as a treatment modality for various psychiatric disorders and are currently applied in psychedelic-assisted psychotherapy. We investigated the learning effects of the serotonin receptor agonist psilocybin in a probabilistic cue-reward task with emotional cues in the form of neutral or fearful faces, presented either consciously or subconsciously. This study represents the first investigation into reinforcement learning with psilocybin. Across different dosages, psilocybin preserved learning effects and was statistically noninferior compared to placebo, while suggesting a higher exploratory behavior. Notably, the 20 mg group exhibited significantly better learning rates against the placebo group. Psilocybin induced inferior results with subconscious cues compared to placebo, and better results with conscious neutral cues in some conditions. These findings suggest that modulating serotonin signaling in the brain with psilocybin sufficiently preservers reinforcement learning.