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

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

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 contro

Characterization and prediction of acute and sustained response to psychedelic psilocybin in a mindfulness group retreat

Meditation and psychedelics have played key roles in humankind’s search for self-transcendence and personal change. However, neither their possible synergistic effects, nor related state and trait predictors have been experimentally studied. To elucidate these issues, we administered double-blind the model psychedelic drug psilocybin (315 μg/kg PO) or placebo to meditators (n = 39) during a 5-day mindfulness group retreat. Psilocybin increased meditation depth and incidence of positively experienced self-dissolution along the perception-hallucination continuum, without concomitant anxiety. Openness, optimism, and emotional reappraisal were predictors of the acute response. Compared with placebo, psilocybin enhanced post-intervention mindfulness and produced larger positive changes in psychosocial functioning at a 4-month follow-up, which were corroborated by external ratings, and associated with magnitude of acute self-dissolution experience. Meditation seems to enhance psilocybin’s positive effects while counteracting possible dysphoric responses. These findings highlight the interactions between non-pharmacological and pharmacological factors, and the role of emotion/attention regulation in shaping the experiential quality of psychedelic states, as well as the experience of selflessness as a modulator of behavior and attitudes. A better comprehension of mechanisms underlying most beneficial psychedelic experiences may guide therapeutic interventions across numerous mental conditions in the form of psychedelic-assisted applications

Rostral Anterior Cingulate Thickness Predicts the Emotional Psilocybin Experience

Psilocybin is the psychoactive compound of mushrooms in the psilocybe species. Psilocybin directly affects a number of serotonin receptors, with highest affinity for the serotonin 2A receptor (5HT-2Ar). Generally, the effects of psilocybin, and its active metabolite psilocin, are well established and include a range of cognitive, emotional, and perceptual perturbations. Despite the generality of these effects, there is a high degree of inter-individual variability in subjective psilocybin experiences that are not well understood. Others have shown brain morphology metrics derived from magnetic resonance imaging (MRI) can predict individual drug response. Due to high expression of serotonin 2A receptors (5HT-2Ar) in the cingulate cortex, and its prior associations with psilocybin, we investigate if cortical thickness of this structure predicts the psilocybin experience in healthy adults. We hypothesized that greater cingulate thickness would predict higher subjective ratings in sub-scales of the Five-Dimensional Altered State of Consciousness (5D-ASC) with high emotionality in healthy participants (n = 55) who received oral psilocybin (either low dose: 0.160 mg/kg or high dose: 0.215 mg/kg). After controlling for sex, age, and using false discovery rate (FDR) correction, we found the rostral anterior cingulate predicted all four emotional sub-scales, whereas the caudal and posterior cingulate did not. How classic psychedelic compounds induce such large inter-individual variability in subjective states has been a long-standing question in serotonergic research. These results extend the traditional set and setting hypothesis of the psychedelic experience to include brain structure metrics

Effective Connectivity of Functionally Anticorrelated Networks Under Lysergic Acid Diethylamide

Background: Classic psychedelic-induced ego dissolution involves a shift in the sense of self and a blurring of the boundary between the self and the world. A similar phenomenon is identified in psychopathology and is associated with the balance of anticorrelated activity between the default mode network, which directs attention inward, and the salience network, which recruits the dorsal attention network to direct attention outward. Methods: To test whether changes in anticorrelated networks underlie the peak effects of lysergic acid diethylamide (LSD), we applied dynamic causal modeling to infer effective connectivity of resting-state functional magnetic resonance imaging scans from a study of 25 healthy adults who were administered 100 μg of LSD or placebo. Results: We found that inhibitory effective connectivity from the salience network to the default mode network became excitatory, and inhibitory effective connectivity from the default mode network to the dorsal attention network decreased under the peak effect of LSD. Conclusions: The effective connectivity changes we identified may reflect diminution of the functional anticorrelation between resting-state networks that may be a key neural mechanism of LSD and underlie ego dissolution. Our findings suggest that changes to the sense of self and subject-object boundaries across different states of consciousness may depend upon the organized balance of effective connectivity of resting-state networks

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 dat

Towards mapping neuro-behavioral heterogeneity of psychedelic neurobiology in humans

Precision psychiatry aims to identify markers of inter-individual variability that allow predicting the right treatment for each patient. However, bridging the gap between molecular-level manipulations and neural systems-level functional alterations remains an unsolved problem in psychiatry. After decades of low success rates in pharmaceutical R&D for psychiatric drugs, multiple studies now point to the potential of psychedelics as a promising fast-acting and long-lasting treatment for some psychiatric symptoms. Yet, given the highly psychoactive nature of these substances, a precision medicine approach is essential to map the neural signals related to clinical efficacy in order to identify patients who can maximally benefit from this treatment. Recent studies have shown that bridging the gap between pharmacology, systems-level neural response in humans and individual experience is possible for psychedelic substances, therefore paving the way for a precision neuropsychiatric therapeutic development. Specifically, it has been shown that the integration of brain-wide PET or transcriptomic data, i.e. receptor distribution for the serotonin 2A receptor, with computational neuroimaging methods can simulate the effect of psychedelics on the human brain. These novel 'computational psychiatry' approaches allow for modeling inter-individual differences in neural as well as subjective effects of psychedelic substances. Collectively, this review provides a deep dive into psychedelic pharmaco-neuroimaging studies with a core focus on how recent computational psychiatry advances in biophysically based circuit modeling can be leveraged to predict individual responses. Finally, we emphasize the importance of human pharmacological neuroimaging for the continued precision therapeutic development of psychedelics. Keywords: computational modeling; fMRI; neuroimaging; precision psychiatry; psychedelics; serotonin

Changes in global and thalamic brain connectivity in LSD-induced altered states of consciousness are attributable to the 5-HT2A receptor

Background:Lysergic acid diethylamide (LSD) has agonist activity at various serotonin (5-HT) and dopamine receptors. Despite the therapeutic and scientific interest in LSD, specific receptor contributions to its neurobiological effects remain unknown. Methods: We therefore conducted a double-blind, randomized, counterbalanced, cross-over study (ClinicalTrials.gov, NCT02451072) during which 24 healthy human participants received either (i) placebo+placebo, (ii) placebo+LSD (100 µg po), or (iii) Ketanserin, a selective 5-HT receptor antagonist,+LSD. We quantified resting-state functional connectivity via a data-driven global brain connectivity method and compared it to cortical gene expression maps. Findings: LSD reduced associative, but concurrently increased sensory-somatomotor brain-wide and thalamic connectivity. Ketanserin fully blocked the subjective and neural LSD effects. Whole-brain spatial patterns of LSD effects matched 5-HT receptor cortical gene expression in humans. Conclusion: Together, these results strongly implicate the 5-HT receptor in LSD's neuropharmacology. This study therefore pinpoints the critical role of 5-HT in LSD's mechanism, which informs its neurobiology and guides rational development of psychedelic-based therapeutics. Funding: Swiss National Science Foundation (SNSF, P2ZHP1_161626, KHP), the Swiss Neuromatrix Foundation (2015 - 0103, FXV), the Usona Institute (2015 - 2056, FXV), the NIH (R01MH112746, JDM; DP5OD012109, AA; R01MH108590, AA), the NIAA ( P50AA012870-16, AA & JHK), the NARSAD Independent Investigator Grant (AA), the Yale CTSA grant (UL1TR000142 Pilot Award, AA), and the Slovenian Research Agency (ARRS J7-6829 & ARRS J7-8275, GR)