Leor Roseman

Significance Lysergic acid diethylamide (LSD), the prototypical “psychedelic,” may be unique among psychoactive substances. In the decades that followed its discovery, the magnitude of its effect on science, the arts, and society was unprecedented. LSD produces profound, sometimes life-changing experiences in microgram doses, making it a particularly powerful scientific tool. Here we sought to examine its effects on brain activity, using cutting-edge and complementary neuroimaging techniques in the first modern neuroimaging study of LSD. Results revealed marked changes in brain blood flow, electrical activity, and network communication patterns that correlated strongly with the drug’s hallucinatory and other consciousness-altering properties. These results have implications for the neurobiology of consciousness and for potential applications of LSD in psychological research.

Introduction: It is a basic principle of the ‘psychedelic’ treatment model that the quality of the acute experience mediates long-term improvements in mental health. In the present paper we sought to test this using data from a clinical trial assessing psilocybin for treatment-resistant depression (TRD). In line with previous reports, we hypothesized that the occurrence and magnitude of Oceanic Boundlessness (OBN) (sharing features with mystical-type experience) and Dread of Ego Dissolution (DED) (similar to anxiety) would predict long-term positive outcomes, whereas sensory perceptual effects would not. Material and Methods: Twenty patients with treatment resistant depression underwent treatment with psilocybin (two separate sessions: 10mg and 25mg psilocybin). The Altered States of Consciousness (ASC) questionnaire was used to assess the quality of experiences in the 25mg psilocybin session. From the ASC, the dimensions OBN and DED were used to measure the mystical-type and challenging experiences, respectively. The Self-Reported Quick Inventory of Depressive Symptoms (QIDS-SR) at 5 weeks served as the endpoint clinical outcome measure, as in later time points some of the subjects had gone on to receive new treatments, thus confounding inferences. In a repeated measure ANOVA, Time was the within-subject factor (independent variable), with QIDS-SR as the within-subject dependent variable in baseline, 1-day, 1-week, 5-weeks. OBN and DED were independent variables. OBN-by-time and DED-by-time interactions were the primary outcomes of interest. Results: For the interaction of OBN and DED with Time (QIDS-SR as dependent variable), the main effect and the effects at each time point compared to baseline were all significant (p = 0.002 and p = 0.003, respectively, for main effects), confirming our main hypothesis. Furthermore, Pearson’s correlation of OBN with QIDS-SR (5 weeks) was specific compared to perceptual dimensions of the ASC (p < 0.05). Discussion: This report further bolsters the view that the quality of the acute psychedelic experience is a key mediator of long-term changes in mental health. More specifically, future therapeutic work with psychedelics may consider investigating ways which enhance mystical-type experience and reduce anxiety, given the growing evidence that this serves the efficacy of the treatment model.

Psychedelic drugs are making waves as modern trials support their therapeutic potential and various media continue to pique public interest. In this opinion piece, we draw attention to a long-recognised component of the psychedelic treatment model, namely ‘set’ and ‘setting’ – subsumed here under the umbrella term ‘context’. We highlight: (a) the pharmacological mechanisms of classic psychedelics (5-HT2A receptor agonism and associated plasticity) that we believe render their effects exceptionally sensitive to context, (b) a study design for testing assumptions regarding positive interactions between psychedelics and context, and (c) new findings from our group regarding contextual determinants of the quality of a psychedelic experience and how acute experience predicts subsequent long-term mental health outcomes. We hope that this article can: (a) inform on good practice in psychedelic research, (b) provide a roadmap for optimising treatment models, and (c) help tackle unhelpful stigma still surrounding these compounds, while developing an evidence base for long-held assumptions about the critical importance of context in relation to psychedelic use that can help minimise harms and maximise potential benefits.

<h2>Summary</h2> Lysergic acid diethylamide (LSD) is a non-selective serotonin-receptor agonist that was first synthesized in 1938 and identified as (potently) psychoactive in 1943. Psychedelics have been used by indigenous cultures for millennia [1]; however, because of LSD's unique potency and the timing of its discovery (coinciding with a period of major discovery in psychopharmacology), it is generally regarded as the quintessential contemporary psychedelic [2]. LSD has profound modulatory effects on consciousness and was used extensively in psychological research and psychiatric practice in the 1950s and 1960s [3]. In spite of this, however, there have been no modern human imaging studies of its acute effects on the brain. Here we studied the effects of LSD on intrinsic functional connectivity within the human brain using fMRI. High-level association cortices (partially overlapping with the default-mode, salience, and frontoparietal attention networks) and the thalamus showed increased global connectivity under the drug. The cortical areas showing increased global connectivity overlapped significantly with a map of serotonin 2A (5-HT_2A) receptor densities (the key site of action of psychedelic drugs [4]). LSD also increased global integration by inflating the level of communication between normally distinct brain networks. The increase in global connectivity observed under LSD correlated with subjective reports of "ego dissolution." The present results provide the first evidence that LSD selectively expands global connectivity in the brain, compromising the brain's modular and "rich-club" organization and, simultaneously, the perceptual boundaries between the self and the environment.

Psilocybin with psychological support is showing promise as a treatment model in psychiatry but its therapeutic mechanisms are poorly understood. Here, cerebral blood flow (CBF) and blood oxygen-level dependent (BOLD) resting-state functional connectivity (RSFC) were measured with functional magnetic resonance imaging (fMRI) before and after treatment with psilocybin (serotonin agonist) for treatment-resistant depression (TRD). Quality pre and post treatment fMRI data were collected from 16 of 19 patients. Decreased depressive symptoms were observed in all 19 patients at 1-week post-treatment and 47% met criteria for response at 5 weeks. Whole-brain analyses revealed post-treatment decreases in CBF in the temporal cortex, including the amygdala. Decreased amygdala CBF correlated with reduced depressive symptoms. Focusing on a priori selected circuitry for RSFC analyses, increased RSFC was observed within the default-mode network (DMN) post-treatment. Increased ventromedial prefrontal cortex-bilateral inferior lateral parietal cortex RSFC was predictive of treatment response at 5-weeks, as was decreased parahippocampal-prefrontal cortex RSFC. These data fill an important knowledge gap regarding the post-treatment brain effects of psilocybin, and are the first in depressed patients. The post-treatment brain changes are different to previously observed acute effects of psilocybin and other 'psychedelics' yet were related to clinical outcomes. A 'reset' therapeutic mechanism is proposed.

Responses to psychedelics are notoriously difficult to predict, yet significant work is currently underway to assess their therapeutic potential and the level of interest in psychedelics among the general public appears to be increasing. We aimed to collect prospective data in order to improve our ability to predict acute- and longer-term responses to psychedelics. Individuals who planned to take a psychedelic through their own initiative participated in an online survey (www.psychedelicsurvey.com). Traits and variables relating to set, setting and the acute psychedelic experience were measured at five different time points before and after the experience. Principle component and regression methods were used to analyse the data. Sample sizes for the five time points included N= 654, N= 535, N= 379, N= 315, and N= 212 respectively. Psychological well-being was increased two weeks after a psychedelic experience and remained at this level after four weeks. This increase was larger for individuals who scored higher for a ‘mystical-type experience’, and smaller for those who scored higher for ‘challenging experience’. Having ‘clear intentions’ for the experience was conducive to mystical-type experiences. Having a positive ‘set’, as well as having the experience with intentions related to ‘recreation’, were both found to decrease the likelihood of having a challenging experience. The trait ‘absorption’ and higher drug doses promoted both mystical-type and challenging experiences. When comparing different types of variables, traits variables seemed to explain most variance in the change in well-being after a psychedelic experience. These results confirm the importance of extra-pharmacological factors in determining responses to a psychedelic. We view this study as an early step towards the development of empirical guidelines that can evolve and improve iteratively with the ultimate purpose of guiding crucial clinical decisions about whether, when, where and how to dose with a psychedelic, thus helping to reduce risks while maximising potential benefits in an evidence-based manner.

Perturbing a system and observing the consequences is a classic scientific strategy for understanding a phenomenon. Psychedelic drugs perturb consciousness in a marked and novel way and thus are powerful tools for studying its mechanisms. In the present analysis, we measured changes in resting-state functional connectivity (RSFC) between a standard template of different independent components analysis (ICA)-derived resting state networks (RSNs) under the influence of two different psychoactive drugs, the stimulant/psychedelic hybrid, MDMA, and the classic psychedelic, psilocybin. Both were given in placebo-controlled designs and produced marked subjective effects, although reports of more profound changes in consciousness were given after psilocybin. Between-network RSFC was generally increased under psilocybin, implying that networks become less differentiated from each other in the psychedelic state. Decreased RSFC between visual and sensorimotor RSNs was also observed. MDMA had a notably less marked effect on between-network RSFC, implying that the extensive changes observed under psilocybin may be exclusive to classic psychedelic drugs and related to their especially profound effects on consciousness. The novel analytical approach applied here may be applied to other altered states of consciousness to improve our characterization of different conscious states and ultimately advance our understanding of the brain mechanisms underlying them.

In recent years, the scientific study of meditation and psychedelic drugs has seen remarkable developments. The increased focus on meditation in cognitive neuroscience has led to a cross-cultural classification of standard meditation styles validated by functional and structural neuroanatomical data. Meanwhile, the renaissance of psychedelic research has shed light on the neurophysiology of altered states of consciousness induced by classical hallucinogens, such as psilocybin and LSD, whose effects are mainly mediated by agonism of serotonin receptors. Few attempts have been made at bridging these two domains of inquiry, despite intriguing evidence of overlap between the phenomenology and neurophysiology of meditation practice and psychedelic states. In particular, many contemplative traditions explicitly aim at dissolving the sense of self by eliciting altered states of consciousness through meditation, while classical psychedelics are known to produce significant disruptions of self-consciousness, a phenomenon known as drug-induced ego dissolution. In this article, we discuss available evidence regarding convergences and differences between phenomenological and neurophysiological data on meditation practice and psychedelic drug-induced states, with a particular emphasis on alterations of self-experience. While both meditation and psychedelics may disrupt self-consciousness and underlying neural processes, we emphasize that neither meditation nor psychedelic states can be conceived as simple, uniform categories. Moreover, we suggest that there are important phenomenological differences even between conscious states described as experiences of self-loss. As a result, we propose that self-consciousness may be best construed as a multidimensional construct, and that "self-loss", far from being an unequivocal phenomenon, can take several forms. Indeed, various aspects of self-consciousness, including narrative aspects linked to autobiographical memory, self-related thoughts and mental time travel, and embodied aspects rooted in multisensory processes, may be differently affected by psychedelics and meditation practices. Finally, we consider long-term outcomes of experiences of self-loss induced by meditation and psychedelics on individual traits and prosocial behavior. We call for caution regarding the problematic conflation of temporary states of self-loss with "selflessness" as a behavioral or social trait, although there is preliminary evidence that correlations between short-term experiences of self-loss and long-term trait alterations may exist.

Psychedelic therapy is gaining recognition and the nature of the psychedelic experience itself has been found to mediate subsequent long-term psychological changes. Much emphasis has been placed on the occurrence of mystical-type experiences in determining long-term responses to psychedelics yet here we demonstrate the importance of another component, namely: emotional breakthrough.Three hundred and seventy-nine participants completed online surveys before and after a planned psychedelic experience. Items pertaining to emotional breakthrough were completed one day after the psychedelic experience, as were items comprising the already validated Mystical Experience Questionnaire and the Challenging Experience Questionnaire. Emotional breakthrough, Mystical Experience Questionnaire and Challenging Experience Questionnaire scores were used to predict changes in well-being (Warwick-Edinburgh Mental Wellbeing Scale) in a subsample of 75 participants with low well-being baseline scores (⩽45).Factor analyses revealed six emotional breakthrough items with high internal consistency (Cronbach's alpha=0.932) and supported our prior hypothesis that emotional breakthrough is a distinct component of the psychedelic experience. Emotional breakthrough scores behaved dose-dependently, and were higher if the psychedelic was taken with therapeutic planning and intent. Emotional breakthrough, Mystical Experience Questionnaire and Challenging Experience Questionnaire scores combined, significantly predicted subsequent changes in well-being (r=0.45, p=0.0005, n=75), with each scale contributing significant predictive value. Emotional breakthrough and Mystical Experience Questionnaire scores predicted increases in well-being and Challenging Experience Questionnaire scores predicted less increases.Here we validate a six-item 'Emotional Breakthrough Inventory'. Emotional breakthrough is an important and distinct component of the acute psychedelic experience that appears to be a key mediator of subsequent longer-term psychological changes. Implications for psychedelic therapy are discussed.

Psilocybin therapy shows antidepressant potential, but its therapeutic actions are not well understood. We assessed the subacute impact of psilocybin on brain function in two clinical trials of depression. The first was an open-label trial of orally administered psilocybin (10 mg and 25 mg, 7 d apart) in patients with treatment-resistant depression. Functional magnetic resonance imaging (fMRI) was recorded at baseline and 1 d after the 25-mg dose. Beck's depression inventory was the primary outcome measure ( MR/J00460X/1 ). The second trial was a double-blind phase II randomized controlled trial comparing psilocybin therapy with escitalopram. Patients with major depressive disorder received either 2 × 25 mg oral psilocybin, 3 weeks apart, plus 6 weeks of daily placebo ('psilocybin arm') or 2 × 1 mg oral psilocybin, 3 weeks apart, plus 6 weeks of daily escitalopram (10-20 mg) ('escitalopram arm'). fMRI was recorded at baseline and 3 weeks after the second psilocybin dose ( NCT03429075 ). In both trials, the antidepressant response to psilocybin was rapid, sustained and correlated with decreases in fMRI brain network modularity, implying that psilocybin's antidepressant action may depend on a global increase in brain network integration. Network cartography analyses indicated that 5-HT2A receptor-rich higher-order functional networks became more functionally interconnected and flexible after psilocybin treatment. The antidepressant response to escitalopram was milder and no changes in brain network organization were observed. Consistent efficacy-related brain changes, correlating with robust antidepressant effects across two studies, suggest an antidepressant mechanism for psilocybin therapy: global increases in brain network integration.

Objective To explore whether psilocybin with psychological support modulates personality parameters in patients suffering from treatment‐resistant depression (TRD). Method Twenty patients with moderate or severe, unipolar, TRD received oral psilocybin (10 and 25 mg, one week apart) in a supportive setting. Personality was assessed at baseline and at 3‐month follow‐up using the Revised NEO Personality Inventory ( NEO ‐ PI ‐R), the subjective psilocybin experience with Altered State of Consciousness ( ASC ) scale, and depressive symptoms with QIDS ‐ SR 16. Results Neuroticism scores significantly decreased while Extraversion increased following psilocybin therapy. These changes were in the direction of the normative NEO ‐ PI ‐R data and were both predicted, in an exploratory analysis, by the degree of insightfulness experienced during the psilocybin session. Openness scores also significantly increased following psilocybin, whereas Conscientiousness showed trend‐level increases, and Agreeableness did not change. Conclusion Our observation of changes in personality measures after psilocybin therapy was mostly consistent with reports of personality change in relation to conventional antidepressant treatment, although the pronounced increases in Extraversion and Openness might constitute an effect more specific to psychedelic therapy. This needs further exploration in future controlled studies, as do the brain mechanisms of postpsychedelic personality change.

Recent studies have started to elucidate the effects of lysergic acid diethylamide (LSD) on the human brain but the underlying dynamics are not yet fully understood. Here we used 'connectome-harmonic decomposition', a novel method to investigate the dynamical changes in brain states. We found that LSD alters the energy and the power of individual harmonic brain states in a frequency-selective manner. Remarkably, this leads to an expansion of the repertoire of active brain states, suggestive of a general re-organization of brain dynamics given the non-random increase in co-activation across frequencies. Interestingly, the frequency distribution of the active repertoire of brain states under LSD closely follows power-laws indicating a re-organization of the dynamics at the edge of criticality. Beyond the present findings, these methods open up for a better understanding of the complex brain dynamics in health and disease.

Abstract Studying transitions in and out of the altered state of consciousness caused by intravenous (IV) N,N-Dimethyltryptamine (DMT - a fast-acting tryptamine psychedelic) offers a safe and powerful means of advancing knowledge on the neurobiology of conscious states. Here we sought to investigate the effects of IV DMT on the power spectrum and signal diversity of human brain activity (6 female, 7 male) recorded via multivariate EEG, and plot relationships between subjective experience, brain activity and drug plasma concentrations across time. Compared with placebo, DMT markedly reduced oscillatory power in the alpha and beta bands and robustly increased spontaneous signal diversity. Time-referenced and neurophenomenological analyses revealed close relationships between changes in various aspects of subjective experience and changes in brain activity. Importantly, the emergence of oscillatory activity within the delta and theta frequency bands was found to correlate with the peak of the experience - particularly its eyes-closed visual component. These findings highlight marked changes in oscillatory activity and signal diversity with DMT that parallel broad and specific components of the subjective experience, thus advancing our understanding of the neurobiological underpinnings of immersive states of consciousness.

Growing evidence from the dynamical analysis of functional neuroimaging data suggests that brain function can be understood as the exploration of a repertoire of metastable connectivity patterns ('functional brain networks'), which potentially underlie different mental processes. The present study characterizes how the brain's dynamical exploration of resting-state networks is rapidly modulated by intravenous infusion of psilocybin, a tryptamine psychedelic found in "magic mushrooms". We employed a data-driven approach to characterize recurrent functional connectivity patterns by focusing on the leading eigenvector of BOLD phase coherence at single-TR resolution. Recurrent BOLD phase-locking patterns (PL states) were assessed and statistically compared pre- and post-infusion of psilocybin in terms of their probability of occurrence and transition profiles. Results were validated using a placebo session. Recurrent BOLD PL states revealed high spatial overlap with canonical resting-state networks. Notably, a PL state forming a frontoparietal subsystem was strongly destabilized after psilocybin injection, with a concomitant increase in the probability of occurrence of another PL state characterized by global BOLD phase coherence. These findings provide evidence of network-specific neuromodulation by psilocybin and represent one of the first attempts at bridging molecular pharmacodynamics and whole-brain network dynamics.

Recent studies have supported the safety and efficacy of psychedelic therapy for mood disorders and addiction. Music is considered an important component in the treatment model, but little empirical research has been done to examine the magnitude and nature of its therapeutic role.The present study assessed the influence of music on the acute experience and clinical outcomes of psychedelic therapy.Semi-structured interviews inquired about the different ways in which music influenced the experience of 19 patients undergoing psychedelic therapy with psilocybin for treatment-resistant depression. Interpretative phenomenological analysis was applied to the interview data to identify salient themes. In addition, ratings were given for each patient for the extent to which they expressed "liking," "resonance" (the music being experienced as "harmonious" with the emotional state of the listener), and "openness" (acceptance of the music-evoked experience).Analyses of the interviews revealed that the music had both "welcome" and "unwelcome" influences on patients' subjective experiences. Welcome influences included the evocation of personally meaningful and therapeutically useful emotion and mental imagery, a sense of guidance, openness, and the promotion of calm and a sense of safety. Conversely, unwelcome influences included the evocation of unpleasant emotion and imagery, a sense of being misguided and resistance. Correlation analyses showed that patients' experience of the music was associated with the occurrence of "mystical experiences" and "insightfulness." Crucially, the nature of the music experience was significantly predictive of reductions in depression 1 week after psilocybin, whereas general drug intensity was not.This study indicates that music plays a central therapeutic function in psychedelic therapy.

Near-death experiences (NDEs) are complex subjective experiences, which have been previously associated with the psychedelic experience and more specifically with the experience induced by the potent serotonergic, N,N-Dimethyltryptamine (DMT). Potential similarities between both subjective states have been noted previously, including the subjective feeling of transcending one's body and entering an alternative realm, perceiving and communicating with sentient 'entities' and themes related to death and dying. In this within-subjects placebo-controled study we aimed to test the similarities between the DMT state and NDEs, by administering DMT and placebo to 13 healthy participants, who then completed a validated and widely used measure of NDEs. Results revealed significant increases in phenomenological features associated with the NDE, following DMT administration compared to placebo. Also, we found significant relationships between the NDE scores and DMT-induced ego-dissolution and mystical-type experiences, as well as a significant association between NDE scores and baseline trait 'absorption' and delusional ideation measured at baseline. Furthermore, we found a significant overlap in nearly all of the NDE phenomenological features when comparing DMT-induced NDEs with a matched group of 'actual' NDE experiencers. These results reveal a striking similarity between these states that warrants further investigation.

Recent evidence indicates that psilocybin with psychological support may be effective for treating depression. Some studies have found that patients with depression show heightened amygdala responses to fearful faces and there is reliable evidence that treatment with SSRIs attenuates amygdala responses (Ma, 2015). We hypothesised that amygdala responses to emotional faces would be altered post-treatment with psilocybin. In this open-label study, 20 individuals diagnosed with moderate to severe, treatment-resistant depression, underwent two separate dosing sessions with psilocybin. Psychological support was provided before, during and after these sessions and 19 completed fMRI scans one week prior to the first session and one day after the second and last. Neutral, fearful and happy faces were presented in the scanner and analyses focused on the amygdala. Group results revealed rapid and enduring improvements in depressive symptoms post psilocybin. Increased responses to fearful and happy faces were observed in the right amygdala post-treatment, and right amygdala increases to fearful versus neutral faces were predictive of clinical improvements at 1-week. Psilocybin with psychological support was associated with increased amygdala responses to emotional stimuli, an opposite effect to previous findings with SSRIs. This suggests fundamental differences in these treatments' therapeutic actions, with SSRIs mitigating negative emotions and psilocybin allowing patients to confront and work through them. Based on the present results, we propose that psilocybin with psychological support is a treatment approach that potentially revives emotional responsiveness in depression, enabling patients to reconnect with their emotions. TRIAL REGISTRATION: ISRCTN, number ISRCTN14426797. This article is part of the Special Issue entitled 'Psychedelics: New Doors, Altered Perceptions'.

Investigating changes in brain function induced by mind-altering substances such as LSD is a powerful method for interrogating and understanding how mind interfaces with brain, by connecting novel psychological phenomena with their neurobiological correlates. LSD is known to increase measures of brain complexity, potentially reflecting a neurobiological correlate of the especially rich phenomenological content of psychedelic-induced experiences. Yet although the subjective stream of consciousness is a constant ebb and flow, no studies to date have investigated how LSD influences the dynamics of functional connectivity in the human brain. Focusing on the two fundamental network properties of integration and segregation, here we combined graph theory and dynamic functional connectivity from resting-state functional MRI to examine time-resolved effects of LSD on brain networks properties and subjective experiences. Our main finding is that the effects of LSD on brain function and subjective experience are non-uniform in time: LSD makes globally segregated sub-states of dynamic functional connectivity more complex, and weakens the relationship between functional and anatomical connectivity. On a regional level, LSD reduces functional connectivity of the anterior medial prefrontal cortex, specifically during states of high segregation. Time-specific effects were correlated with different aspects of subjective experiences; in particular, ego dissolution was predicted by increased small-world organisation during a state of high global integration. These results reveal a more nuanced, temporally-specific picture of altered brain connectivity and complexity under psychedelics than has previously been reported.

Background: Recent years have seen a resurgence of research on the potential of psychedelic substances to treat addictive and mood disorders. Historically and contemporarily, psychedelic studies have emphasized the importance of contextual elements ('set and setting') in modulating acute drug effects, and ultimately, influencing long-term outcomes. Nevertheless, current small-scale clinical and laboratory studies have tended to bypass a ubiquitous contextual feature of naturalistic psychedelic use: its social dimension. This study introduces and psychometrically validates an adapted Communitas Scale, assessing acute relational experiences of perceived togetherness and shared humanity, in order to investigate psychosocial mechanisms pertinent to psychedelic ceremonies and retreats. Methods: In this observational, web-based survey study, participants (N = 886) were measured across five successive time-points: 2 weeks before, hours before, and the day after a psychedelic ceremony; as well as the day after, and 4 weeks after leaving the ceremony location. Demographics, psychological traits and state variables were assessed pre-ceremony, in addition to changes in psychological wellbeing and social connectedness from before to after the retreat, as primary outcomes. Using correlational and multiple regression (path) analyses, predictive relationships between psychosocial 'set and setting' variables, communitas, and long-term outcomes were explored. Results: The adapted Communitas Scale demonstrated substantial internal consistency (Cronbach's alpha = 0.92) and construct validity in comparison with validated measures of intra-subjective (visual, mystical, challenging experiences questionnaires) and inter-subjective (perceived emotional synchrony, identity fusion) experiences. Furthermore, communitas during ceremony was significantly correlated with increases in psychological wellbeing (r = 0.22), social connectedness (r = 0.25), and other salient mental health outcomes. Path analyses revealed that the effect of ceremony-communitas on long-term outcomes was fully mediated by communitas experienced in reference to the retreat overall, and that the extent of personal sharing or 'self-disclosure' contributed to this process. A positive relationship between participants and facilitators, and the perceived impact of emotional support, facilitated the emergence of communitas. Conclusion: Highlighting the importance of intersubjective experience, rapport, and emotional support for long-term outcomes of psychedelic use, this first quantitative examination of psychosocial factors in guided psychedelic settings is a significant step toward evidence-based benefit-maximization guidelines for collective psychedelic use.

Background: Psilocybin has shown promise as a treatment for depression but its therapeutic mechanisms are not properly understood. In contrast to the presumed actions of antidepressants, we recently found increased amygdala responsiveness to fearful faces one day after open-label treatment with psilocybin (25 mg) in 19 patients with treatment-resistant depression, which correlated with treatment efficacy. Aims: Aiming to further unravel the therapeutic mechanisms of psilocybin, the present study extends this basic activation analysis. We hypothesised changed amygdala functional connectivity, more precisely decreased amygdala-ventromedial prefrontal cortex functional connectivity, during face processing after treatment with psilocybin. Methods: Psychophysiological interaction analyses were conducted on functional magnetic resonance imaging data from a classic face/emotion perception task, with the bilateral amygdala and ventromedial prefrontal cortex time-series as physiological regressors. Average parameter estimates (beta weights) of significant clusters were correlated with clinical outcomes at one week. Results: Results showed decreased ventromedial prefrontal cortex-right amygdala functional connectivity during face processing post- (versus pre-) treatment; this decrease was associated with levels of rumination at one week. This effect was driven by connectivity changes in response to fearful and neutral (but not happy) faces. Independent whole-brain analyses also revealed a post-treatment increase in functional connectivity between the amygdala and ventromedial prefrontal cortex to occipital-parietal cortices during face processing. Conclusion: These results are consistent with the idea that psilocybin therapy revives emotional responsiveness on a neural and psychological level, which may be a key treatment mechanism for psychedelic therapy. Future larger placebo-controlled studies are needed to examine the replicability of the current findings.

Abstract Can the use of psychedelic drugs induce lasting changes in metaphysical beliefs? While it is popularly believed that they can, this question has never been formally tested. Here we exploited a large sample derived from prospective online surveying to determine whether and how beliefs concerning the nature of reality, consciousness, and free-will, change after psychedelic use. Results revealed significant shifts away from ‘physicalist’ or ‘materialist’ views, and towards panpsychism and fatalism, post use. With the exception of fatalism, these changes endured for at least 6 months, and were positively correlated with the extent of past psychedelic-use and improved mental-health outcomes. Path modelling suggested that the belief-shifts were moderated by impressionability at baseline and mediated by perceived emotional synchrony with others during the psychedelic experience. The observed belief-shifts post-psychedelic-use were consolidated by data from an independent controlled clinical trial. Together, these findings imply that psychedelic-use may causally influence metaphysical beliefs—shifting them away from ‘hard materialism’. We discuss whether these apparent effects are contextually independent.

Psychedelic microdosing describes the ingestion of near-threshold perceptible doses of classic psychedelic substances. Anecdotal reports and observational studies suggest that microdosing may promote positive mood and well-being, but recent placebo-controlled studies failed to find compelling evidence for this. The present study collected web-based mental health and related data using a prospective (before, during and after) design. Individuals planning a weekly microdosing regimen completed surveys at strategic timepoints, spanning a core four-week test period. Eighty-one participants completed the primary study endpoint. Results revealed increased self-reported psychological well-being, emotional stability and reductions in state anxiety and depressive symptoms at the four-week primary endpoint, plus increases in psychological resilience, social connectedness, agreeableness, nature relatedness and aspects of psychological flexibility. However, positive expectancy scores at baseline predicted subsequent improvements in well-being, suggestive of a significant placebo response. This study highlights a role for positive expectancy in predicting positive outcomes following psychedelic microdosing and cautions against zealous inferences on its putative therapeutic value.

Psychedelics have attracted medical interest, but their effects on human brain function are incompletely understood. In a comprehensive, within-subjects, placebo-controlled design, we acquired multimodal neuroimaging [i.e., EEG-fMRI (electroencephalography-functional MRI)] data to assess the effects of intravenous (IV) N,N-Dimethyltryptamine (DMT) on brain function in 20 healthy volunteers. Simultaneous EEG-fMRI was acquired prior to, during, and after a bolus IV administration of 20 mg DMT, and, separately, placebo. At dosages consistent with the present study, DMT, a serotonin 2A receptor (5-HT2AR) agonist, induces a deeply immersive and radically altered state of consciousness. DMT is thus a useful research tool for probing the neural correlates of conscious experience. Here, fMRI results revealed robust increases in global functional connectivity (GFC), network disintegration and desegregation, and a compression of the principal cortical gradient under DMT. GFC × subjective intensity maps correlated with independent positron emission tomography (PET)-derived 5-HT2AR maps, and both overlapped with meta-analytical data implying human-specific psychological functions. Changes in major EEG-measured neurophysiological properties correlated with specific changes in various fMRI metrics, enriching our understanding of the neural basis of DMT's effects. The present findings advance on previous work by confirming a predominant action of DMT-and likely other 5-HT2AR agonist psychedelics-on the brain's transmodal association pole, i.e., the neurodevelopmentally and evolutionarily recent cortex that is associated with species-specific psychological advancements, and high expression of 5-HT2A receptors.

Introduction: As their name suggests, ‘psychedelic’ (mind-revealing) compounds are thought to catalyse processes of psychological insight; however, few satisfactory scales exist to sample this. This study sought to develop a new scale to measure psychological insight after a psychedelic experience: the Psychological Insight Scale (PIS). Methods: The PIS is a six- to seven-item questionnaire that enquires about psychological insight after a psychedelic experience (PIS-6) and accompanied behavioural changes (PIS item 7). In total, 886 participants took part in a study in which the PIS and other questionnaires were completed in a prospective fashion in relation to a planned psychedelic experience. For validation purposes, data from 279 participants were analysed from a non-specific ‘global psychedelic survey’ study. Results: Principal components analysis of PIS scores revealed a principal component explaining 73.57% of the variance, which displayed high internal consistency at multiple timepoints throughout the study (average Cronbach’s α = 0.94). Criterion validity was confirmed using the global psychedelic survey study, and convergent validity was confirmed via the Therapeutic-Realizations Scale. Furthermore, PIS scores significantly mediated the relationship between emotional breakthrough and long-term well-being. Conclusion: The PIS is complementary to current subjective measures used in psychedelic studies, most of which are completed in relation to the acute experience. Insight – as measured by the PIS – was found to be a key mediator of long-term psychological outcomes following a psychedelic experience. Future research may investigate how insight varies throughout a psychedelic process, its underlying neurobiology and how it impacts behaviour and mental health.

Psychedelics including lysergic acid diethylamide (LSD) and psilocybin temporarily alter subjective experience through their neurochemical effects. Serotonin 2a (5-HT2a) receptor agonism by these compounds is associated with more diverse (entropic) brain activity. We postulate that this increase in entropy may arise in part from a flattening of the brain's control energy landscape, which can be observed using network control theory to quantify the energy required to transition between recurrent brain states. Using brain states derived from existing functional magnetic resonance imaging (fMRI) datasets, we show that LSD and psilocybin reduce control energy required for brain state transitions compared to placebo. Furthermore, across individuals, reduction in control energy correlates with more frequent state transitions and increased entropy of brain state dynamics. Through network control analysis that incorporates the spatial distribution of 5-HT2a receptors (obtained from publicly available positron emission tomography (PET) data under non-drug conditions), we demonstrate an association between the 5-HT2a receptor and reduced control energy. Our findings provide evidence that 5-HT2a receptor agonist compounds allow for more facile state transitions and more temporally diverse brain activity. More broadly, we demonstrate that receptor-informed network control theory can model the impact of neuropharmacological manipulation on brain activity dynamics.

Lysergic acid diethylamide (LSD) and psilocybin are serotonergic psychedelic compounds with potential in the treatment of mental health disorders. Past neuroimaging investigations have revealed that both compounds can elicit significant changes to whole-brain functional organization and dynamics. A recent proposal linked past findings into a unified model and hypothesized reduced whole-brain hierarchical organization as a key mechanism underlying the psychedelic state, but this has yet to be directly tested. We applied a non-linear dimensionality reduction technique previously used to map hierarchical connectivity gradients to assess cortical organization in the LSD and psilocybin state from two previously published pharmacological resting-state fMRI datasets (N = 15 and 9, respectively). Results supported our primary hypothesis: The principal gradient of cortical connectivity, describing a hierarchy from unimodal to transmodal cortex, was significantly flattened under both drugs relative to their respective placebo conditions. Between-condition contrasts revealed that this was driven by a reduction of functional differentiation at both hierarchical extremes - default and frontoparietal networks at the upper end, and somatomotor at the lower. Gradient-based connectivity mapping indicated that this was underpinned by a disruption of modular unimodal connectivity and increased unimodal-transmodal crosstalk. Results involving the second and third gradient, which, respectively represent axes of sensory and executive differentiation, also showed significant alterations across both drugs. These findings provide support for a recent mechanistic model of the psychedelic state relevant to therapeutic applications of psychedelics. More fundamentally, we provide the first evidence that macroscale connectivity gradients are sensitive to an acute pharmacological manipulation, supporting a role for psychedelics as scientific tools to perturb cortical functional organization.

This theoretical article revives a classical bridging construct, canalization, to describe a new model of a general factor of psychopathology. To achieve this, we have distinguished between two types of plasticity, an early one that we call 'TEMP' for 'Temperature or Entropy Mediated Plasticity', and another, we call 'canalization', which is close to Hebbian plasticity. These two forms of plasticity can be most easily distinguished by their relationship to 'precision' or inverse variance; TEMP relates to increased model variance or decreased precision, whereas the opposite is true for canalization. TEMP also subsumes increased learning rate, (Ising) temperature and entropy. Dictionary definitions of 'plasticity' describe it as the property of being easily shaped or molded; TEMP is the better match for this. Importantly, we propose that 'pathological' phenotypes develop via mechanisms of canalization or increased model precision, as a defensive response to adversity and associated distress or dysphoria. Our model states that canalization entrenches in psychopathology, narrowing the phenotypic state-space as the agent develops expertise in their pathology. We suggest that TEMP - combined with gently guiding psychological support - can counter canalization. We address questions of whether and when canalization is adaptive versus maladaptive, furnish our model with references to basic and human neuroscience, and offer concrete experiments and measures to test its main hypotheses and implications. This article is part of the Special Issue on "National Institutes of Health Psilocybin Research Speaker Series".

Psychedelics are undergoing a major resurgence of scientific and clinical interest. While multiple theories and frameworks have been proposed, there is yet no universal agreement on the mechanisms underlying the complex effects of psychedelics on subjective experience and brain dynamics, nor their therapeutic benefits. Despite being prominent in psychedelic phenomenology and distinct from those elicited by other classes of hallucinogens, the effects of psychedelics on low-level sensory - particularly visual - dimensions of experience, and corresponding brain dynamics, have often been disregarded by contemporary research as 'epiphenomenal byproducts'. Here, we review available evidence from neuroimaging, pharmacology, questionnaires, and clinical studies; we propose extensions to existing models, provide testable hypotheses for the potential therapeutic roles of psychedelic-induced visual hallucinations, and simulations of visual phenomena relying on low-level cortical dynamics. In sum, we show that psychedelic-induced alterations in low-level sensory dimensions 1) are unlikely to be entirely causally reconducible to high-level alterations, but rather co-occur with them in a dialogical interplay, and 2) are likely to play a causally relevant role in determining high-level alterations and therapeutic outcomes. We conclude that reevaluating the currently underappreciated role of sensory dimensions in psychedelic states will be highly valuable for neuroscience and clinical practice, and that integrating low-level and domain-specific aspects of psychedelic effects into existing nonspecific models is a necessary step to further understand how these substances effect both acute and long-term change in the human brain.

A central question in neuroscience is how consciousness arises from the dynamic interplay of brain structure and function. Here we decompose functional MRI signals from pathological and pharmacologically-induced perturbations of consciousness into distributed patterns of structure-function dependence across scales: the harmonic modes of the human structural connectome. We show that structure-function coupling is a generalisable indicator of consciousness that is under bi-directional neuromodulatory control. We find increased structure-function coupling across scales during loss of consciousness, whether due to anaesthesia or brain injury, capable of discriminating between behaviourally indistinguishable sub-categories of brain-injured patients, tracking the presence of covert consciousness. The opposite harmonic signature characterises the altered state induced by LSD or ketamine, reflecting psychedelic-induced decoupling of brain function from structure and correlating with physiological and subjective scores. Overall, connectome harmonic decomposition reveals how neuromodulation and the network architecture of the human connectome jointly shape consciousness and distributed functional activation across scales.

Recent findings have shown that psychedelics reliably enhance brain entropy (understood as neural signal diversity), and this effect has been associated with both acute and long-term psychological outcomes, such as personality changes. These findings are particularly intriguing, given that a decrease of brain entropy is a robust indicator of loss of consciousness (e.g., from wakefulness to sleep). However, little is known about how context impacts the entropy-enhancing effect of psychedelics, which carries important implications for how it can be exploited in, for example, psychedelic psychotherapy. This article investigates how brain entropy is modulated by stimulus manipulation during a psychedelic experience by studying participants under the effects of lysergic acid diethylamide (LSD) or placebo, either with gross state changes (eyes closed vs open) or different stimuli (no stimulus vs music vs video). Results show that while brain entropy increases with LSD under all of the experimental conditions, it exhibits the largest changes when subjects have their eyes closed. Furthermore, brain entropy changes are consistently associated with subjective ratings of the psychedelic experience, but this relationship is disrupted when participants are viewing a video─potentially due to a "competition" between external stimuli and endogenous LSD-induced imagery. Taken together, our findings provide strong quantitative evidence of the role of context in modulating neural dynamics during a psychedelic experience, underlining the importance of performing psychedelic psychotherapy in a suitable environment.

Back to table of contents Previous article Next article Letters to the EditorFull AccessIs Poorly Assisted Psilocybin Treatment an Increasing Risk?Eduardo Ekman Schenberg, Ph.D., Franklin King IV, M.D., João Eusébio da Fonseca, Leor Roseman, Ph.D.Eduardo Ekman SchenbergSearch for more papers by this author, Ph.D., Franklin King IVSearch for more papers by this author, M.D., João Eusébio da FonsecaSearch for more papers by this author, Leor RosemanSearch for more papers by this author, Ph.D.Published Online:1 Jan 2024https://doi.org/10.1176/appi.ajp.20230664AboutSectionsPDF/EPUB ToolsAdd to favoritesDownload CitationsTrack Citations ShareShare onFacebookTwitterLinked InEmail To the Editor: In the July 2023 commentary, “Must Psilocybin Always ‘Assist Psychotherapy’?” (1) Goodwin et al. raised interesting questions about paradigms for the therapeutic use of psychedelics. These substances are already applied in diverse ways, from community and relational Indigenous practices (2) to uses deemed “recreational” but which also include self-treatment (3, 4). Thus, while psychedelics indeed need not always “assist psychotherapy,” interactive elements with the substance’s effects have been deemed essential for safety and efficacy across a variety of existing paradigms.However, the assertions that the intervention used in the phase 2 trial referred to by the authors (5) are “simply ensuring, as is intended, psychological and physical safety” and that it “is applied in a stereotyped way, whatever the drug dose,” as distinct from psychedelic-assisted (psycho) therapy (PAT), where “complex interaction with a therapist during the active drug experience clearly complicates interpretation,” merit further scrutiny. The minimum necessary procedures to prevent harms should be distinguished from PAT. Conversely, there are striking similarities in the guiding principles of the therapist training for this trial (6) with those of PAT models. While not all of these studies have released a manual, some, such as MAPS and Yale, have (7, 8). To the best of our knowledge, the manual for the COMPASS phase 2 trial has not been made publicly available, thereby limiting detailed comparisons. Compounding these issues are potential biases and conflicts of interest involved in developing a proprietary synthetic formulation of psilocybin, which not only raises ethical concerns regarding Indigenous rights (9), but could potentially influence efforts to more easily bring a drug to market by downplaying the role of therapy. Critically, we submit that this role includes optimizing both safety as well as efficacy in relational processes which cannot be treated independently of the drug effect itself (10).The occurrences of suicidal ideation and related behaviors in the largest clinical trial with a psychedelic to date (5) suggests that careful consideration of the PAT concept may result in safer approaches. It seems reasonable to speculate that higher rates of serious adverse events in the 25 and 10 mg psilocybin groups might have been mitigated with greater emphasis on relational elements during preparation and integration—rather than simply “psychological support.” In addition, cases of boundary violations and abuse (11), correctly highlighted as important issues in PAT (and unfortunately in medicine generally as well [12]), are not, however, justifications for no therapy.The term “psychedelic-assisted (psycho) therapy” does not intend to “capture the true mechanism of change,” but rather to delineate a holistic approach developed over decades, starting with LSD (13). It creates a therapeutic container to prevent unassisted or poorly assisted drug administration. We understand efforts to simplify processes for regulating systems for drug approval and consequent accessibility, but not at the costs of downplaying the complexity of intrapersonal, interpersonal, and contextual processes. Oversimplification is not clarity, and suggesting effectiveness comes only from drug administration may lead to unintended harms.Instituto Phaneros, São Paulo, Brazil (Schenberg); Massachusetts General Hospital and Harvard Medical School, Boston (King); Psychotherapist in private practice, Lisbon (Fonseca); Department of Psychology, University of Exeter, Exter, United Kingdom; Centre for Psychedelic Research, Imperial College London, London (Roseman).Send correspondence to Dr. Schenberg ([email protected]).Dr. Schenberg is Director of Instituto Phaneros, a Brazilian non-profit offering psychedelic-assisted therapy research training and is scientific advisor to investment fund Ocama Partners. Dr. King holds stock in COMPASS and Cybin, has consulted for Cybin in the previous 24 months, and sits on the scientific advisory board of Apex Labs for which he owns stock equity. Mr. Fonseca was one of the lead therapists of the COMPASS trial (COMP 001), done at the Champalimaud Foundation in Portugal between 2020 and 2022. He is a psychotherapist at the Liminal Minds Clinic, providing ketamine-assisted therapy. Dr. Roseman's current research into psychedelic peacebuilding is funded by Christian Angermayer, a significant investor of COMPASS through ATAI Life Sciences.References1. Goodwin GM, Malievskaia E, Fonzo GA, et al.: Must psilocybin always “assist psychotherapy”? Am J Psychiatry 2024; 181:20–25Abstract, Google Scholar2. Celidwen Y, Redvers N, Githaiga C, et al.: Ethical principles of traditional Indigenous medicine to guide western psychedelic research and practice. Lancet Reg Health Am 2022; 18:100410Medline, Google Scholar3. Johnson MW, Hendricks PS, Barrett FS, et al.: Classic psychedelics: an integrative review of epidemiology, therapeutics, mystical experience, and brain network function. Pharmacol Ther 2019; 197:83–102Crossref, Medline, Google Scholar4. Kopra EI, Ferris JA, Winstock AR, et al.: Investigation of self-treatment with lysergic acid diethylamide and psilocybin mushrooms: findings from the Global Drug Survey 2020. J Psychopharmacol 2023; 37:733–748Crossref, Medline, Google Scholar5. Goodwin GM, Aaronson ST, Alvarez O, et al.: Single-dose psilocybin for a treatment-resistant episode of major depression. N Engl J Med 2022; 387:1637–1648Crossref, Medline, Google Scholar6. Tai SJ, Nielson EM, Lennard-Jones M, et al.: Development and evaluation of a therapist training program for psilocybin therapy for treatment-resistant depression in clinical research. Front Psychiatry 2021; 12:586682Crossref, Medline, Google Scholar7. Mithoefer M, Mithoefer A, Jerome L, et al.: A Manual for MDMA-Assisted Psychotherapy in the Treatment of Posttraumatic Stress Disorder, Version 8.1. Santa Cruz, CA, Multidisciplinary Association for Psychedelic Studies (MAPS), 2017. https://maps.org/mdma/mdma-resources/treatment-manual-mdma-assisted-psychotherapy-for-ptsd/Google Scholar8. Guss J, Krause R, Sloshower J: Yale Manual for Psilocybin-Assisted Therapy of Depression, 1st ed. 2020. doi: 10.31234/osf.io/u6v9y. Accessed at Aug 21, 2023Crossref, Google Scholar9. Gerber K, Flores IG, Ruiz AC, et al.: Ethical concerns about psilocybin intellectual property. ACS Pharmacol Transl Sci 2021; 4:573–577Crossref, Medline, Google Scholar10. Modlin NL, Miller TM, Rucker JJ, et al.: Optimizing outcomes in psilocybin therapy: considerations in participant evaluation and preparation. J Affect Disord 2023; 326:18–25Crossref, Medline, Google Scholar11. McNamee S, Devenot N, Buisson M: Studying harms is key to improving Psychedelic-Assisted Therapy-participants call for changes to research landscape. JAMA Psychiatry 2023; 80:411–412Crossref, Medline, Google Scholar12. DuBois JM, Walsh HA, Chibnall JT, et al.: Sexual violation of patients by physicians: a mixed-methods, exploratory analysis of 101 cases. Sex Abuse 2019; 31:503–523Crossref, Medline, Google Scholar13. Schenberg EE: Psychedelic-Assisted Psychotherapy: a paradigm shift in psychiatric research and development. Front Pharmacol 2018; 9:733Crossref, Medline, Google Scholar FiguresReferencesCited byDetailsCited byPsychological Support for Psilocybin Treatment: Reply to Letters on Our CommentaryGuy M. Goodwin, F.Med.Sci., Ekaterina Malievskaia, M.D., Gregory A. Fonzo, Ph.D., Charles B. Nemeroff, M.D., Ph.D.1 January 2024 | American Journal of Psychiatry, Vol. 181, No. 1Improving Clinical Outcomes and Informing New InterventionsNed H. Kalin, M.D.1 January 2024 | American Journal of Psychiatry, Vol. 181, No. 1 Volume 181Issue 1 January 01, 2024Pages 75-76 Metrics KeywordsDepressive DisordersDrug/Psychotherapy CombinationEthicsMedication-Assisted TreatmentPharmacotherapyPsychotherapyResearch Design and MethodsPDF download History Received 22 August 2023 Accepted 8 November 2023 Published online 1 January 2024 Published in print 1 January 2024

The compound 3,4-methylenedioxymethamphetamine (MDMA) is a potent monoamine releaser that produces an acute euphoria in most individuals.In a double-blind, placebo-controlled, balanced-order study, MDMA was orally administered to 25 physically and mentally healthy individuals. Arterial spin labeling and seed-based resting state functional connectivity (RSFC) were used to produce spatial maps displaying changes in cerebral blood flow (CBF) and RSFC after MDMA administration. Participants underwent two arterial spin labeling and two blood oxygen level-dependent scans in a 90-minute scan session; MDMA and placebo study days were separated by 1 week.Marked increases in positive mood were produced by MDMA. Decreased CBF only was observed after MDMA, and this was localized to the right medial temporal lobe (MTL), thalamus, inferior visual cortex, and the somatosensory cortex. Decreased CBF in the right amygdala and hippocampus correlated with ratings of the intensity of global subjective effects of MDMA. The RSFC results complemented the CBF results, with decreases in RSFC between midline cortical regions, the medial prefrontal cortex, and MTL regions, and increases between the amygdala and hippocampus. There were trend-level correlations between these effects and ratings of intense and positive subjective effects.The MTLs appear to be specifically implicated in the mechanism of action of MDMA, but further work is required to elucidate how the drug's characteristic subjective effects arise from its modulation of spontaneous brain activity.

There is renewed interest in the therapeutic potential of psychedelic drugs such as lysergic acid diethylamide (LSD). LSD was used extensively in the 1950s and 1960s as an adjunct in psychotherapy, reportedly enhancing emotionality. Music is an effective tool to evoke and study emotion and is considered an important element in psychedelic-assisted psychotherapy; however, the hypothesis that psychedelics enhance the emotional response to music has yet to be investigated in a modern placebo-controlled study.The present study sought to test the hypothesis that music-evoked emotions are enhanced under LSD.Ten healthy volunteers listened to five different tracks of instrumental music during each of two study days, a placebo day followed by an LSD day, separated by 5-7 days. Subjective ratings were completed after each music track and included a visual analogue scale (VAS) and the nine-item Geneva Emotional Music Scale (GEMS-9).Results demonstrated that the emotional response to music is enhanced by LSD, especially the emotions "wonder", "transcendence", "power" and "tenderness".These findings reinforce the long-held assumption that psychedelics enhance music-evoked emotion, and provide tentative and indirect support for the notion that this effect can be harnessed in the context of psychedelic-assisted psychotherapy. Further research is required to test this link directly.

Psychedelic drugs such as lysergic acid diethylamide (LSD) were used extensively in psychiatry in the past and their therapeutic potential is beginning to be re-examined today. Psychedelic psychotherapy typically involves a patient lying with their eyes-closed during peak drug effects, while listening to music and being supervised by trained psychotherapists. In this context, music is considered to be a key element in the therapeutic model; working in synergy with the drug to evoke therapeutically meaningful thoughts, emotions and imagery. The underlying mechanisms involved in this process have, however, never been formally investigated. Here we studied the interaction between LSD and music-listening on eyes-closed imagery by means of a placebo-controlled, functional magnetic resonance imaging (fMRI) study. Twelve healthy volunteers received intravenously administered LSD (75 µg) and, on a separate occasion, placebo, before being scanned under eyes-closed resting conditions with and without music-listening. The parahippocampal cortex (PHC) has previously been linked with (1) music-evoked emotion, (2) the action of psychedelics, and (3) mental imagery. Imaging analyses therefore focused on changes in the connectivity profile of this particular structure. Results revealed increased PHC–visual cortex (VC) functional connectivity and PHC to VC information flow in the interaction between music and LSD. This latter result correlated positively with ratings of enhanced eyes-closed visual imagery, including imagery of an autobiographical nature. These findings suggest a plausible mechanism by which LSD works in combination with music listening to enhance certain subjective experiences that may be useful in a therapeutic context.

Contemporary investigations regard creativity as a dynamic form of cognition that involves movement between the dissociable stages of creative generation and creative evaluation. Our recently proposed Dynamic Framework of Thought (Christoff et al., 2016) offered a conceptualization of these stages in terms of an interplay between sources of constraint and variability on thought. This initial conceptualization, however, has yet to be fully explicated and given targeted discussion. Here, we refine this framework's account of creativity by highlighting the dynamic nature of creative thought, both within and between the stages of creative generation and evaluation. In particular, we emphasize that creative generation in particular is best regarded as a product of multiple, varying mental states, rather than being a singular mental state in and of itself. We also propose that the psychedelic state is a mental state with high potential for facilitating creative generation and update the Dynamic Framework of Thought to incorporate this state. This paper seeks to highlight the dynamic nature of the neurocognitive processes underlying creative thinking and to draw attention to the potential utility of psychedelic substances as experimental tools in the neuroscience of creativity.

Psychedelic drugs, such as psilocybin and LSD, represent unique tools for researchers investigating the neural origins of consciousness. Currently, the most compelling theories of how psychedelics exert their effects is by increasing the complexity of brain activity and moving the system towards a critical point between order and disorder, creating more dynamic and complex patterns of neural activity. While the concept of criticality is of central importance to this theory, few of the published studies on psychedelics investigate it directly, testing instead related measures such as algorithmic complexity or Shannon entropy. We propose using the fractal dimension of functional activity in the brain as a measure of complexity since findings from physics suggest that as a system organizes towards criticality, it tends to take on a fractal structure. We tested two different measures of fractal dimension, one spatial and one temporal, using fMRI data from volunteers under the influence of both LSD and psilocybin. The first was the fractal dimension of cortical functional connectivity networks and the second was the fractal dimension of BOLD time-series. In addition to the fractal measures, we used a well-established, non-fractal measure of signal complexity and show that they behave similarly. We were able to show that both psychedelic drugs significantly increased the fractal dimension of functional connectivity networks, and that LSD significantly increased the fractal dimension of BOLD signals, with psilocybin showing a non-significant trend in the same direction. With both LSD and psilocybin, we were able to localize changes in the fractal dimension of BOLD signals to brain areas assigned to the dorsal-attenion network. These results show that psychedelic drugs increase the fractal dimension of activity in the brain and we see this as an indicator that the changes in consciousness triggered by psychedelics are associated with evolution towards a critical zone.

A general feeling of disconnection has been associated with mental and emotional suffering. Improvements to a sense of connectedness to self, others and the wider world have been reported by participants in clinical trials of psychedelic therapy. Such accounts have led us to a definition of the psychological construct of 'connectedness' as 'a state of feeling connected to self, others and the wider world'. Existing tools for measuring connectedness have focused on particular aspects of connectedness, such as 'social connectedness' or 'nature connectedness', which we hypothesise to be different expressions of a common factor of connectedness. Here, we sought to develop a new scale to measure connectedness as a construct with these multiple domains. We hypothesised that (1) our scale would measure three separable subscale factors pertaining to a felt connection to 'self', 'others' and 'world' and (2) improvements in total and subscale WCS scores would correlate with improved mental health outcomes post psychedelic use.To validate and test the 'Watts Connectedness Scale' (WCS).Psychometric validation of the WCS was carried out using data from three independent studies. Firstly, we pooled data from two prospective observational online survey studies. The WCS was completed before and after a planned psychedelic experience. The total sample of completers from the online surveys was N = 1226. Exploratory and confirmatory factor analysis were performed, and construct and criterion validity were tested. A third dataset was derived from a double-blind randomised controlled trial (RCT) comparing psilocybin-assisted therapy (n = 27) with 6 weeks of daily escitalopram (n = 25) for major depressive disorder (MDD), where the WCS was completed at baseline and at a 6-week primary endpoint.As hypothesised, factor analysis of all WCS items revealed three main factors with good internal consistency. WCS showed good construct validity. Significant post-psychedelic increases were observed for total connectedness scores (η2 = 0.339, p < 0.0001), as well as on each of its subscales (p < 0.0001). Acute measures of 'mystical experience', 'emotional breakthrough', and 'communitas' correlated positively with post-psychedelic changes in connectedness (r = 0.42, r = 0.38, r = 0.42, respectively, p < 0.0001). In the RCT, psilocybin therapy was associated with greater increases in WCS scores compared with the escitalopram arm (ηp2 = 0.133, p = 0.009).The WCS is a new 3-dimensional index of felt connectedness that may sensitively measure therapeutically relevant psychological changes post-psychedelic use. We believe that the operational definition of connectedness captured by the WCS may have broad relevance in mental health research.

Psychedelics were used in the treatment of psychiatric conditions prior to their prohibition in the late 1960s. In the past three decades, there is a revived research interest in the therapeutic potential of psychedelic drugs with expected FDA approvals for treatment of various conditions. Given the exponential scientific growth of this field, we sought to characterize, analyze, and visualize trends in its top-cited articles. Bibliometric analyses are quantitative approaches to characterize a scientific field, including evaluation of the impact of academic literature. The bibliometric analysis and visualizations were conducted with R-tools for comprehensive science mapping. The top-cited 100 articles were cited between 82 and 668 times (median 125; mean 158). Fifty-four percent of the T100 articles were produced in the past decade (2010-2020). Network and author impact analysis highlighted key figures and primary collaboration networks within the top 100 publications. UK, USA, Switzerland, Spain, and Brazil lead the field. Results are discussed in terms of research growth, access, diversity, and the distribution of knowledge and experience in the field. These aggregated data and insights on the second wave of psychedelic research facilitate research evaluation, data-driven funding policies, and a practical map for researchers and clinicians entering the field.

To understand how pharmacological interventions can exert their powerful effects on brain function, we need to understand how they engage the brain's rich neurotransmitter landscape. Here, we bridge microscale molecular chemoarchitecture and pharmacologically induced macroscale functional reorganization, by relating the regional distribution of 19 neurotransmitter receptors and transporters obtained from positron emission tomography, and the regional changes in functional magnetic resonance imaging connectivity induced by 10 different mind-altering drugs: propofol, sevoflurane, ketamine, lysergic acid diethylamide (LSD), psilocybin, N,N-Dimethyltryptamine (DMT), ayahuasca, 3,4-methylenedioxymethamphetamine (MDMA), modafinil, and methylphenidate. Our results reveal a many-to-many mapping between psychoactive drugs' effects on brain function and multiple neurotransmitter systems. The effects of both anesthetics and psychedelics on brain function are organized along hierarchical gradients of brain structure and function. Last, we show that regional co-susceptibility to pharmacological interventions recapitulates co-susceptibility to disorder-induced structural alterations. Collectively, these results highlight rich statistical patterns relating molecular chemoarchitecture and drug-induced reorganization of the brain's functional architecture.

Psychedelic therapy has witnessed a resurgence in interest in the last decade from the scientific and medical communities with evidence now building for its safety and efficacy in treating a range of psychiatric disorders including addiction. In this review we will chart the research investigating the role of these interventions in individuals with addiction beginning with an overview of the current socioeconomic impact of addiction, treatment options, and outcomes. We will start by examining historical studies from the first psychedelic research era of the mid-late 1900s, followed by an overview of the available real-world evidence gathered from naturalistic, observational, and survey-based studies. We will then cover modern-day clinical trials of psychedelic therapies in addiction from first-in-human to phase II clinical trials. Finally, we will provide an overview of the different translational human neuropsychopharmacology techniques, including functional magnetic resonance imaging (fMRI) and positron emission tomography (PET), that can be applied to foster a mechanistic understanding of therapeutic mechanisms. A more granular understanding of the treatment effects of psychedelics will facilitate the optimisation of the psychedelic therapy drug development landscape, and ultimately improve patient outcomes.

Psychedelic-assisted psychotherapy with psilocybin is an emerging therapy with great promise for depression, and modern psychedelic therapy (PT) methods incorporate music as a key element. Music is an effective emotional/hedonic stimulus that could also be useful in assessing changes in emotional responsiveness following PT.Brain responses to music were assessed before and after PT using functional Magnetic Resonance Imaging (fMRI) and ALFF (Amplitude of Low Frequency Fluctuations) analysis methods. Nineteen patients with treatment-resistant depression underwent two treatment sessions involving administration of psilocybin, with MRI data acquired one week prior and the day after completion of psilocybin dosing sessions.Comparison of music-listening and resting-state scans revealed significantly greater ALFF in bilateral superior temporal cortex for the post-treatment music scan, and in the right ventral occipital lobe for the post-treatment resting-state scan. ROI analyses of these clusters revealed a significant effect of treatment in the superior temporal lobe for the music scan only. Voxelwise comparison of treatment effects showed relative increases for the music scan in the bilateral superior temporal lobes and supramarginal gyrus, and relative decreases in the medial frontal lobes for the resting-state scan. ALFF in these music-related clusters was significantly correlated with intensity of subjective effects felt during the dosing sessions.Open-label trial. Relatively small sample size.These data suggest an effect of PT on the brain's response to music, implying an elevated responsiveness to music after psilocybin therapy that was related to subjective drug effects felt during dosing.

Psilocybin therapy for depression has started to show promise, yet the underlying causal mechanisms are not currently known. Here, we leveraged the differential outcome in responders and non-responders to psilocybin (10 and 25 mg, 7 days apart) therapy for depression-to gain new insights into regions and networks implicated in the restoration of healthy brain dynamics. We used large-scale brain modelling to fit the spatiotemporal brain dynamics at rest in both responders and non-responders before treatment. Dynamic sensitivity analysis of systematic perturbation of these models enabled us to identify specific brain regions implicated in a transition from a depressive brain state to a healthy one. Binarizing the sample into treatment responders (>50% reduction in depressive symptoms) versus non-responders enabled us to identify a subset of regions implicated in this change. Interestingly, these regions correlate with in vivo density maps of serotonin receptors 5-hydroxytryptamine 2a and 5-hydroxytryptamine 1a, which psilocin, the active metabolite of psilocybin, has an appreciable affinity for, and where it acts as a full-to-partial agonist. Serotonergic transmission has long been associated with depression, and our findings provide causal mechanistic evidence for the role of brain regions in the recovery from depression via psilocybin.

The question of how spatially organized activity in the visual cortex behaves during eyes-closed, lysergic acid diethylamide (LSD)-induced "psychedelic imagery" (e.g., visions of geometric patterns and more complex phenomena) has never been empirically addressed, although it has been proposed that under psychedelics, with eyes-closed, the brain may function "as if" there is visual input when there is none. In this work, resting-state functional connectivity (RSFC) data was analyzed from 10 healthy subjects under the influence of LSD and, separately, placebo. It was suspected that eyes-closed psychedelic imagery might involve transient local retinotopic activation, of the sort typically associated with visual stimulation. To test this, it was hypothesized that, under LSD, patches of the visual cortex with congruent retinotopic representations would show greater RSFC than incongruent patches. Using a retinotopic localizer performed during a nondrug baseline condition, nonadjacent patches of V1 and V3 that represent the vertical or the horizontal meridians of the visual field were identified. Subsequently, RSFC between V1 and V3 was measured with respect to these a priori identified patches. Consistent with our prior hypothesis, the difference between RSFC of patches with congruent retinotopic specificity (horizontal-horizontal and vertical-vertical) and those with incongruent specificity (horizontal-vertical and vertical-horizontal) increased significantly under LSD relative to placebo, suggesting that activity within the visual cortex becomes more dependent on its intrinsic retinotopic organization in the drug condition. This result may indicate that under LSD, with eyes-closed, the early visual system behaves as if it were seeing spatially localized visual inputs. Hum Brain Mapp 37:3031-3040, 2016. © 2016 Wiley Periodicals, Inc.

• Scores for psychological flexibility improved following a psychedelic experience. • Improvements in scores for psychological flexibility and depression correlated. • Emotionally cathartic and mystical experiences improved psychological flexibility. • Low baseline scores for psychological flexibility predicted greater improvements. • Estimated changes in psychological flexibility improved for those at drug retreats.

Recent findings have shown that psychedelics reliably enhance brain entropy (understood as neural signal diversity), and this effect has been associated with both acute and long-term psychological outcomes such as personality changes. These findings are particularly intriguing given that a decrease of brain entropy is a robust indicator of loss of consciousness (e.g. from wakefulness to sleep). However, little is known about how context impacts the entropy-enhancing effect of psychedelics, which carries important implications for how it can be exploited in, for example, psychedelic psychotherapy. This article investigates how brain entropy is modulated by stimulus manipulation during a psychedelic experience, by studying participants under the effects of LSD or placebo, either with gross state changes (eyes closed vs. open) or different stimulus (no stimulus vs. music vs. video). Results show that while brain entropy increases with LSD in all the experimental conditions, it exhibits largest changes when subjects have their eyes closed. Furthermore, brain entropy changes are consistently associated with subjective ratings of the psychedelic experience, but this relationship is disrupted when participants are viewing video — potentially due to a “competition” between external stimuli and endogenous LSD-induced imagery. Taken together, our findings provide strong quantitative evidence for the role of context in modulating neural dynamics during a psychedelic experience, underlining the importance of performing psychedelic psychotherapy in a suitable environment. Additionally, our findings put into question simplistic interpretations of brain entropy as a direct neural correlate of conscious level. Significance Statement The effects of psychedelic substances on conscious experience can be substantially affected by contextual factors, which play a critical role in the outcomes of psychedelic therapy. This study shows how context can modulate not only psychological, but also neurophysiological phenomena during a psychedelic experience. Our findings reveal distinctive effects of having eyes closed after taking LSD, including a more pronounced change on the neural dynamics, and a closer correspondence between brain activity and subjective ratings. Furthermore, our results suggest a competition between external stimuli and internal psychedelic-induced imagery, which supports the practice of carrying out psychedelic therapy with patients having their eyes closed.

Abstract Psychedelics like lysergic acid diethylamide (LSD) and psilocybin offer a powerful window into the function of the human brain and mind, by temporarily altering subjective experience through their neurochemical effects. A recent model postulates that serotonin 2a (5-HT2a) receptor agonism allows the brain to explore its dynamic landscape more readily, as reflected by more diverse (entropic) brain activity. We postulate that this increase in entropy may arise in part from a flattening of the brain’s control energy landscape, which can be observed using network control theory to quantify the energy required to transition between recurrent brain states measured using functional magnetic resonance imaging (fMRI) in individuals under LSD, psilocybin, and placebo conditions. We show that LSD and psilocybin reduce the amount of control energy required for brain state transitions, and, furthermore, that, across individuals, LSD’s reduction in control energy correlates with more frequent state transitions and increased entropy of brain state dynamics. Through network control analysis that incorporates the spatial distribution of 5-HT2a receptors from publicly available (non-drug) positron emission tomography (PET) maps, we demonstrate the specific role of this receptor in reducing control energy. Our findings provide evidence that 5-HT2a receptor agonist compounds allow for more facile state transitions and more temporally diverse brain activity. More broadly, by combining receptor-informed network control theory with pharmacological modulation, our work highlights the potential of this approach in studying the impacts of targeted neuropharmacological manipulation on brain activity dynamics. Significance Statement We present a multi-modal framework for quantifying the effects of two psychedelic drugs (LSD and psilocybin) on brain dynamics by combining functional magnetic resonance imaging (fMRI), diffusion MRI (dMRI), positron emission tomography (PET) and network control theory. Our findings provide evidence that psychedelics flatten the brain’s control energy landscape, allowing for more facile state transitions and more temporally diverse brain activity. We also demonstrate that the spatial distribution of serotonin 2a receptors - the main target of LSD and psilocybin - is optimized for generating these effects. This approach could be used to understand how drugs act on different receptors in the brain to influence brain activity dynamics.

Psychedelics are used in many group contexts. However, most phenomenological research on psychedelics is focused on personal experiences. This paper presents a phenomenological investigation centered on intersubjective and intercultural relational processes, exploring how an intercultural context affects both the group and individual process. Through 31 in-depth interviews, ceremonies in which Palestinians and Israelis drink ayahuasca together have been investigated. The overarching question guiding this inquiry was how psychedelics might contribute to processes of peacebuilding, and in particular how an intercultural context, embedded in a protracted conflict, would affect the group's psychedelic process in a relational sense. Analysis of the interviews was based on grounded theory. Three relational themes about multilocal participatory events which occurred during ayahuasca rituals have emerged from the interviews: 1) Unity-Based Connection - collective events in which a feeling of unity and 'oneness' is experienced, whereby participants related to each other based upon a sense of shared humanity, and other social identities seemed to dissolve (such as national and religious identities). 2) Recognition and Difference-Based Connection - events where a strong connection was made to the other culture. These events occurred through the expression of the other culture or religion through music or prayers, which resulted in feelings of awe and reverence 3) Conflict-related revelations - events where participants revisited personal or historical traumatic elements related to the conflict, usually through visions. These events were triggered by the presence of 'the Other,' and there was a political undertone in those personal visions. This inquiry has revealed that psychedelic ceremonies have the potential to contribute to peacebuilding. This can happen not just by 'dissolution of identities,' but also by providing a space in which shared spiritual experiences can emerge from intercultural and interfaith exchanges. Furthermore, in many cases, personal revelations were related to the larger political reality and the history of the conflict. Such processes can elucidate the relationship between personal psychological mental states and the larger sociopolitical context.

Major depressive disorder is often associated with maladaptive coping strategies, including rumination and thought suppression.To assess the comparative effect of the selective serotonin reuptake inhibitor escitalopram, and the serotonergic psychedelic psilocybin (COMP360), on rumination and thought suppression in major depressive disorder.Based on data derived from a randomised clinical trial (N = 59), we performed exploratory analyses on the impact of escitalopram versus psilocybin (i.e. condition) on rumination and thought suppression from 1 week before to 6 weeks after treatment inception (i.e. time), using mixed analysis of variance. Condition responder versus non-responder subgroup analyses were also done, using the standard definition of ≥50% symptom reduction.A time×condition interaction was found for rumination (F(1, 56) = 4.58, P = 0.037) and thought suppression (F(1,57) = 5.88, P = 0.019), with post hoc tests revealing significant decreases exclusively in the psilocybin condition. When analysing via response, a significant time×condition×response interaction for thought suppression (F(1,54) = 8.42, P = 0.005) and a significant time×response interaction for rumination (F(1,54) = 23.50, P < 0.001) were evident. Follow-up tests revealed that decreased thought suppression was exclusive to psilocybin responders, whereas rumination decreased in both responder groups. In the psilocybin arm, decreases in rumination and thought suppression correlated with ego dissolution and session-linked psychological insight.These data provide further evidence on the therapeutic mechanisms of psilocybin and escitalopram in the treatment of depression.

Psychedelics offer a profound window into the functioning of the human brain and mind through their robust acute effects on perception, subjective experience, and brain activity patterns. In recent work using a receptor-informed network control theory framework, we demonstrated that the serotonergic psychedelics lysergic acid diethylamide (LSD) and psilocybin flatten the brain's control energy landscape in a manner that covaries with more dynamic and entropic brain activity. Contrary to LSD and psilocybin, whose effects last for hours, the serotonergic psychedelic N,N-dimethyltryptamine (DMT) rapidly induces a profoundly immersive altered state of consciousness lasting less than 20 minutes, allowing for the entirety of the drug experience to be captured during a single resting-state fMRI scan. Using network control theory, which quantifies the amount of input necessary to drive transitions between functional brain states, we integrate brain structure and function to map the energy trajectories of 14 individuals undergoing fMRI during DMT and placebo. Consistent with previous work, we find that global control energy is reduced following injection with DMT compared to placebo. We additionally show longitudinal trajectories of global control energy correlate with longitudinal trajectories of EEG signal diversity (a measure of entropy) and subjective ratings of drug intensity. We interrogate these same relationships on a regional level and find that the spatial patterns of DMT's effects on these metrics are correlated with serotonin 2a receptor density (obtained from separately acquired PET data). Using receptor distribution and pharmacokinetic information, we were able to successfully recapitulate the effects of DMT on global control energy trajectories, demonstrating a proof-of-concept for the use of control models in predicting pharmacological intervention effects on brain dynamics.

Lysergic acid diethylamide (LSD) is a potent psychedelic drug, which has seen a revival in clinical and pharmacological research within recent years. Human neuroimaging studies have shown fundamental changes in brain-wide functional connectivity and an expansion of dynamical brain states, thus raising the question about a mechanistic explanation of the dynamics underlying these alterations. Here, we applied a novel perturbational approach based on a whole-brain computational model, which opens up the possibility to externally perturb different brain regions in silico and investigate differences in dynamical stability of different brain states, i.e. the dynamical response of a certain brain region to an external perturbation. After adjusting the whole-brain model parameters to reflect the dynamics of functional magnetic resonance imaging (fMRI) BOLD signals recorded under the influence of LSD or placebo, perturbations of different brain areas were simulated by either promoting or disrupting synchronization in the regarding brain region. After perturbation offset, we quantified the recovery characteristics of the brain area to its basal dynamical state with the Perturbational Integration Latency Index (PILI) and used this measure to distinguish between the two brain states. We found significant changes in dynamical complexity with consistently higher PILI values after LSD intake on a global level, which indicates a shift of the brain's global working point further away from a stable equilibrium as compared to normal conditions. On a local level, we found that the largest differences were measured within the limbic network, the visual network and the default mode network. Additionally, we found a higher variability of PILI values across different brain regions after LSD intake, indicating higher response diversity under LSD after an external perturbation. Our results provide important new insights into the brain-wide dynamical changes underlying the psychedelic state - here provoked by LSD intake - and underline possible future clinical applications of psychedelic drugs in particular psychiatric disorders.

Contemporary research on serotonergic psychedelic compounds has been rife with references to so-called 'mystical' subjective effects. Several psychometric assessments have been used to assess such effects, and clinical studies have found quantitative associations between 'mystical experiences' and positive mental health outcomes. The nascent study of psychedelic-induced mystical experiences, however, has only minimally intersected with relevant contemporary scholarship from disciplines within the social sciences and humanities, such as religious studies and anthropology. Viewed from the perspective of these disciplines-which feature rich historical and cultural literatures on mysticism, religion, and related topics-'mysticism' as used in psychedelic research is fraught with limitations and intrinsic biases that are seldom acknowledged. Most notably, existing operationalizations of mystical experiences in psychedelic science fail to historicize the concept and therefore fail to acknowledge its perennialist and specifically Christian bias. Here, we trace the historical genesis of the mystical in psychedelic research in order to illuminate such biases, and also offer suggestions toward more nuanced and culturally-sensitive operationalizations of this phenomenon. In addition, we argue for the value of, and outline, complementary 'non-mystical' approaches to understanding putative mystical-type phenomena that may help facilitate empirical investigation and create linkages to existing neuro-psychological constructs. It is our hope that the present paper helps build interdisciplinary bridges that motivate fruitful paths toward stronger theoretical and empirical approaches in the study of psychedelic-induced mystical experiences.

Recent work with noninvasive human brain imaging has started to investigate the effects of 3,4-methylenedioxymethamphetamine (MDMA) on large-scale patterns of brain activity. MDMA, a potent monoamine-releaser with particularly pronounced serotonin- releasing properties, has unique subjective effects that include: marked positive mood, pleasant/unusual bodily sensations and pro-social, empathic feelings. However, the neurobiological basis for these effects is not properly understood, and the present analysis sought to address this knowledge gap. To do this, we administered MDMA-HCl (100 mg p.o.) and, separately, placebo (ascorbic acid) in a randomized, double-blind, repeated-measures design with twenty-five healthy volunteers undergoing fMRI scanning. We then employed a measure of global resting-state functional brain connectivity and follow-up seed-to-voxel analysis to the fMRI data we acquired. Results revealed decreased right insula/salience network functional connectivity under MDMA. Furthermore, these decreases in right insula/salience network connectivity correlated with baseline trait anxiety and acute experiences of altered bodily sensations under MDMA. The present findings highlight insular disintegration (ie, compromised salience network membership) as a neurobiological signature of the MDMA experience, and relate this brain effect to trait anxiety and acutely altered bodily sensations–both of which are known to be associated with insular functioning.

Background: Chronic Pain is among the leading causes of disability worldwide with up to 60% of patients suffering from comorbid depression. Psychedelic-assisted therapy has recently been found effective in treating a host of mental health issues including depression and has historically been found to be useful in treating pain. Reports of self-medication for chronic pain using psychedelic drugs have been widely documented, with anecdotal evidence indicating widespread success in a range of pathologies. Aims: In preparation for an upcoming trial, to better understand how those with lived experience of chronic pain self-medicate with psychedelic drugs, and to establish, in detail, their therapeutic protocols and practices for success. Methods: As part of patient-involvement (PI) for an upcoming trial in this population, 11 individuals who reported self-medicating with psychedelic drugs took part in a 1-h semi-structured discussion, which was then transcribed and thematically analyzed. Results: Across a range of psychedelic substances and doses, reported pain scores improved substantially during and after psychedelic experiences. Two processes, Positive Reframing and Somatic Presence, were reliably identified as playing a role in improvements in mental wellbeing, relationship with pain, and physical (dis)comfort. Inclusion of other strategies such as mindfulness, breathwork, and movement were also widely reported. Due to the data's subjective nature, this paper is vulnerable to bias and makes no claims on causality or generalisability. Together, these results have been used to inform study design for a forthcoming trial. Conclusion: This pre-trial PI work gives us confidence to test psychedelic therapy for chronic pain in a forthcoming controlled trial. The results presented here will be instrumental in improving our ability to meet the needs of future study participants.

Abstract Psychedelic drugs show promise as safe and effective treatments for neuropsychiatric disorders, yet their mechanisms of action are not fully understood. A fundamental hypothesis is that psychedelics work by dose-dependently changing the functional hierarchy of brain dynamics, but it is unclear whether different psychedelics act similarly. Here, we investigated the changes in the brain’s functional hierarchy associated with two different psychedelics (LSD and psilocybin). Using a novel turbulence framework, we were able to determine the vorticity, that is, the local level of synchronization, that allowed us to extend the standard global time-based measure of metastability to become a local-based measure of both space and time. This framework produced detailed signatures of turbulence-based hierarchical change for each psychedelic drug, revealing consistent and discriminate effects on a higher level network, that is, the default mode network. Overall, our findings directly support a prior hypothesis that psychedelics modulate (i.e., “compress”) the functional hierarchy and provide a quantification of these changes for two different psychedelics. Implications for therapeutic applications of psychedelics are discussed.

Abstract The human brain is a complex system, whose activity exhibits flexible and continuous reorganisation across space and time. The decomposition of whole-brain recordings into harmonic modes has revealed a repertoire of gradient-like activity patterns associated with distinct brain functions. However, the way these activity patterns are expressed over time with their changes in various brain states remains unclear. In this study, we develop the Harmonic Decomposition of Spacetime (HADES) framework that characterises how different harmonic modes defined in space are expressed over time , and, as a proof-of-principle, demonstrate the sensitivity and robustness of this approach to specific changes induced by the serotonergic psychedelic N,N-Dimethyltryptamine (DMT) in healthy participants. HADES demonstrates significant decreases in contributions across most low-frequency harmonic modes in the DMT-induced brain state. When normalizing the contributions by condition (DMT and non-DMT), we detect a decrease specifically in the second functional harmonic, which represents the uni- to transmodal functional hierarchy of the brain, supporting the hypothesis that functional hierarchy is changed in psychedelics. Moreover, HADES’ dynamic spacetime measures of fractional occupancy, life time and latent space provide a precise description of the significant changes of the spacetime hierarchical organization of brain activity in the psychedelic state.

Music listening is a staple and valued component of psychedelic therapy, and previous work has shown that psychedelics can acutely enhance music-evoked emotion.The present study sought to examine subjective responses to music before and after psilocybin therapy for treatment-resistant depression, while functional magnetic resonance imaging (fMRI) data was acquired.Nineteen patients with treatment-resistant depression received a low oral dose (10 mg) of psilocybin, and a high dose (25 mg) 1 week later. fMRI was performed 1 week prior to the first dosing session and 1 day after the second. Two scans were conducted on each day: one with music and one without. Visual analogue scale ratings of music-evoked 'pleasure' plus ratings of other evoked emotions (21-item Geneva Emotional Music Scale) were completed after each scan. Given its role in musical reward, the nucleus accumbens (NAc) was chosen as region of interest for functional connectivity (FC) analyses. Effects of drug (vs placebo) and music (vs no music) on subjective and FC outcomes were assessed. Anhedonia symptoms were assessed pre- and post-treatment (Snaith-Hamilton Pleasure Scale).Results revealed a significant increase in music-evoked emotion following treatment with psilocybin that correlated with post-treatment reductions in anhedonia. A post-treatment reduction in NAc FC with areas resembling the default mode network was observed during music listening (vs no music).These results are consistent with current thinking on the role of psychedelics in enhancing music-evoked pleasure and provide some new insight into correlative brain mechanisms.

N,N-Dimethyltryptamine (DMT) is a serotonergic psychedelic, known to rapidly induce short-lasting alterations in conscious experience, characterized by a profound and immersive sense of physical transcendence alongside rich and vivid auditory distortions and visual imagery. Multimodal neuroimaging data paired with dynamic analysis techniques offer a valuable approach for identifying unique signatures of brain activity - and linked autonomic physiology - naturally unfolding during the altered state of consciousness induced by DMT. We leveraged simultaneous fMRI and EKG data acquired in 14 healthy volunteers prior to, during, and after intravenous administration of DMT, and, separately, placebo. EKG data was used to derive continuous heart rate; fMRI data was preprocessed to derive individual dynamic activity matrices, reflecting the similarity of brain activity in time, and community detection algorithms were applied on these matrices to identify brain activity substates. We identified a brain substate occurring immediately after DMT injection, characterized by increased superior temporal lobe activity, and hippocampal and medial parietal deactivations under DMT. Superior temporal lobe hyperactivity correlated with the intensity of the auditory distortions, while hippocampus and medial parietal cortex hypoactivity correlated with scores of meaningfulness of the experience. During this first post-injection substate, increased heart rate under DMT correlated negatively with the meaningfulness of the experience and positively with hippocampus/medial parietal deactivation. These results suggest a chain of influence linking sympathetic regulation to hippocampal and medial parietal deactivations under DMT, which combined may contribute to positive mental health outcomes related to self-referential processing following psychedelic administration.

Abstract The human brain is a complex system, whose activity exhibits flexible and continuous reorganisation across space and time. The decomposition of whole-brain recordings into harmonic modes has revealed a repertoire of gradient-like activity patterns associated with distinct brain functions. However, the way these activity patterns are expressed over time with their changes in various brain states remains unclear. Here, we investigate healthy participants taking the serotonergic psychedelic N, N-Dimethyltryptamine (DMT) with the Harmonic Decomposition of Spacetime (HADES) framework that can characterise how different harmonic modes defined in space are expressed over time. HADES demonstrates significant decreases in contributions across most low-frequency harmonic modes in the DMT-induced brain state. When normalizing the contributions by condition (DMT and non-DMT), we detect a decrease specifically in the second functional harmonic, which represents the uni- to transmodal functional hierarchy of the brain, supporting the leading hypothesis that functional hierarchy is changed in psychedelics. Moreover, HADES’ dynamic spacetime measures of fractional occupancy, life time and latent space provide a precise description of the significant changes of the spacetime hierarchical organization of brain activity in the psychedelic state.

Abstract A central question in neuroscience is how consciousness arises from the dynamic interplay of brain structure and function. Departing from the predominant location- centric view in neuroimaging, here we provide an alternative perspective on the neural signatures of human consciousness: one that is intrinsically centered on how the distributed network architecture of the human structural connectome shapes functional activation across scales. We decompose cortical dynamics of resting-state functional MRI into fundamental distributed patterns of structure- function association: the harmonic modes of the human structural connectome. We contrast wakefulness with a wide spectrum of states of consciousness, spanning chronic disorders of consciousness but also pharmacological perturbations of consciousness induced with the anaesthetic propofol and the psychoactive drugs ketamine and LSD. Decomposing this wide spectrum of states of consciousness in terms of “connectome harmonics” reveals a generalisable structure-function signature of loss of consciousness, whether due to anaesthesia or brain injury. A mirror-reverse of this harmonic signature characterises the altered state induced by LSD or ketamine, reflecting psychedelic-induced decoupling of brain function from structure. The topology and neuroanatomy of the human connectome are crucial for shaping the repertoire of connectome harmonics into a fine-tuned indicator of consciousness, correlating with physiological and subjective scores across datasets and capable of discriminating between behaviourally indistinguishable sub-categories of brain-injured patients, tracking the presence of covert consciousness. Overall, connectome harmonic decomposition identifies meaningful relationships between neurobiology, brain function, and conscious experience.

Lysergic acid diethylamide (LSD) is an atypical psychedelic compound that exerts its effects through pleiotropic actions, mainly involving 1A/2A serotoninergic (5-HT) receptor subtypes. However, the mechanisms by which LSD promotes a reorganization of the brain’s functional activity and connectivity are still partially unknown. Our study analyzed resting-state functional magnetic resonance imaging data acquired from 15 healthy volunteers undergoing LSD single-dose intake. A voxelwise analysis investigated the alterations of the brain’s intrinsic functional connectivity and local signal amplitude induced by LSD or by a placebo. Quantitative comparisons assessed the spatial overlap between these 2 indices of functional reorganization and the topography of receptor expression obtained from a publicly available collection of in vivo, whole-brain atlases. Finally, linear regression models explored the relationships between changes in resting-state functional magnetic resonance imaging and behavioral aspects of the psychedelic experience. LSD elicited modifications of the cortical functional architecture that spatially overlapped with the distribution of serotoninergic receptors. Local signal amplitude and functional connectivity increased in regions belonging to the default mode and attention networks associated with high expression of 5-HT2A receptors. These functional changes correlate with the occurrence of simple and complex visual hallucinations. At the same time, a decrease in local signal amplitude and intrinsic connectivity was observed in limbic areas, which are dense with 5-HT1A receptors. This study provides new insights into the neural processes underlying the brain network reconfiguration induced by LSD. It also identifies a topographical relationship between opposite effects on brain functioning and the spatial distribution of different 5-HT receptors.

Abstract Do psychedelics affect sexual functioning postacutely? Anecdotal and qualitative evidence suggests they do, but this has never been formally tested. While sexual functioning and satisfaction are generally regarded as an important aspect of human wellbeing, sexual dysfunction is a common symptom of mental health disorders. It is also a common side effect of selective serotonin reuptake inhibitors (SSRIs), a first line treatment for depression. The aim of the present paper was to investigate the post-acute effects of psychedelics on self-reported sexual functioning, combining data from two independent studies, one large and naturalistic and the other a smaller but controlled clinical trial. Naturalistic use of psychedelics was associated with improvements in several facets of sexual functioning and satisfaction, including improved pleasure and communication during sex, satisfaction with one’s partner and physical appearance. Convergent results were found in a controlled trial of psilocybin therapy versus an SSRI, escitalopram, for depression. In this trial, patients treated with psilocybin reported positive changes in sexual functioning after treatment, while patients treated with escitalopram did not. Despite focusing on different populations and settings, this is the first research study to quantitively investigate the effects of psychedelics on sexual functioning. Results imply a potential positive effect on post-acute sexual functioning and highlight the need for more research on this.

Abstract The mechanisms by which Psilocybin Therapy (PT) improves depression remain an important object of study, with scientists actively exploring acute psychological experiences and neurobiological processes as candidates. In a phase 2, double-blind, randomized, active comparator controlled trial involving patients with moderate-to-severe major depressive disorder, we investigated whether acute psychological experiences could meaningfully account for the unique efficacy of PT versus Escitalopram Treatment over a core 6-week trial period. An exploratory-factor-analysis-derived single-factor of depression was used as the outcome. Among a comprehensive set of acute experiences related to psilocybin, so-called “mystical experience” and “ego dissolution” were unique in mediating the effect of treatment condition on depressive response with high specificity. Higher reported levels of mystical experience, emotional breakthrough, and intense responses to music-listening were furthermore associated with greater antidepressant response. These results provide qualified support for the causal mechanistic role of acute psychological experiences in the treatment of depression via PT.

Abstract Affective symptoms such as anxiety, low mood, and loneliness are prevalent and highly debilitating symptoms among older adults (OA). Serotonergic psychedelics are novel experimental interventions for affective disorders, yet little is known regarding their effects in OA. Using a prospective cohort design, we identified 62 OA (age ≥ 60 years) and 62 matched younger adults (YA) who completed surveys two weeks before, and one day, two weeks, four weeks, and six months after a guided psychedelic group session in a retreat setting. Mixed linear regression analyses revealed significant well-being improvements in OA and YA, amplified in OA with a history of a psychiatric diagnosis. Compared to YA, acute subjective psychedelic effects were attenuated in OA and did not significantly predict well-being changes. However, a psychosocial measure of Communitas emerged as a predictor in OA, suggesting that the relational components in psychedelic group settings may hold particular value for OA.

Abstract LSD and psilocybin are serotonergic psychedelic compounds with potential in the treatment of mental health disorders. Past neuroimaging investigations have revealed that both compounds can elicit significant changes to whole-brain functional organization and dynamics. A recent proposal linked past findings into a unified model and hypothesized reduced whole-brain hierarchical organization as a key mechanism underlying the psychedelic state, but this has yet to be directly tested. We applied a non-linear dimensionality reduction technique previously used to map hierarchical connectivity gradients to pharmacological resting-state fMRI data to assess cortical organization in the LSD and psilocybin state. Results supported our primary hypothesis: The principal gradient of cortical connectivity, describing a hierarchy from unimodal to transmodal cortex, was significantly flattened under both drugs relative to their respective placebo conditions. Between-condition contrasts revealed that this was driven by a reduction of functional differentiation at both hierarchical extremes – default and frontoparietal networks at the upper end, and somatomotor at the lower. Gradient-based connectivity mapping confirmed that this was underpinned by increased unimodal-transmodal crosstalk. In addition, LSD-dependent principal gradient changes tracked changes in self-reported ego-dissolution. Results involving the second and third gradient, which respectively represent axes of sensory and executive differentiation, also showed significant alterations across both drugs. These findings provide support for a recent mechanistic model of the psychedelic state relevant to therapeutic applications of psychedelics. More fundamentally, we provide the first evidence that macroscale connectivity gradients are sensitive to a pharmacological manipulation, specifically highlighting an important relationship between cortical organization and serotonergic modulation.

Abstract Psychedelic-assisted psychotherapy with psilocybin is an emerging therapy with great promise for depression, and modern psychedelic therapy (PT) methods incorporate music as a key element. Music is an effective emotional/hedonic stimulus that could also be useful in assessing changes in emotional responsiveness following psychedelic therapy. Brain responses to music were assessed before and after PT using functional Magnetic Resonance Imaging (fMRI) and ALFF (Amplitude of Low Frequency Fluctuations) analysis methods. Nineteen patients with treatment-resistant depression underwent two treatment sessions involving administration of psilocybin, with MRI data acquired one week prior and the day after completion of the second of two psilocybin dosing sessions. Comparison of music-listening and resting-state scans revealed significantly greater ALFF in bilateral superior temporal cortex for the post-treatment music scan, and in the right ventral occipital lobe for the post-treatment resting-state scan. ROI analyses of these clusters revealed a significant effect of treatment in the superior temporal lobe for the music scan only. Somewhat consistently, voxelwise comparison of treatment effects showed relative increases for the music scan in the bilateral superior temporal lobes and supramarginal gyrus, and relative decreases in the medial frontal lobes for the resting-state scan. ALFF in these music-related clusters was significantly correlated with intensity of subjective effects felt during the dosing sessions. These data suggest a specific effect of PT on the brain’s response to a hedonic stimulus (music), implying an elevated responsiveness to music after psilocybin therapy that was related to subjective drug effects felt during dosing.

Abstract Psilocybin therapy for depression has started to show promise, yet the underlying causal mechanisms are not currently known. Here we leveraged the differential outcome in responders and non-responders to psilocybin (10mg and 25mg, 7 days apart) therapy for depression - to gain new insights into regions and networks implicated in the restoration of healthy brain dynamics. We used whole-brain modelling to fit the spatiotemporal brain dynamics at rest in both responders and non-responders before treatment. Dynamic sensitivity analysis of systematic perturbation of these models enabled us to identify specific brain regions implicated in a transition from a depressive brain state to a heathy one. Binarizing the sample into treatment responders (&gt; 50% reduction in depressive symptoms) versus non-responders enabled us to identify a subset of regions implicated in this change. Interestingly, these regions correlate with in vivo density maps of serotonin receptors 5-HT 2A and 5-HT 1A , which psilocin, the active metabolite of psilocybin, has an appreciable affinity for, and where it acts as a full-to-partial agonist. Serotonergic transmission has long been associated with depression and our findings provide causal mechanistic evidence for the role of brain regions in the recovery from depression via psilocybin.

Are psychedelics able to induce lasting changes in metaphysical beliefs? While it is popularly believed that they can, this has never been systematically tested. Here we exploited a large sample derived from prospective online surveying to determine whether and how beliefs concerning the nature of reality, consciousness, and free-will, change after psychedelic use. Results revealed significant shifts away from ‘physicalist’ or ‘materialist’ views, and towards panpsychism and fatalism, post use. These changes remained detectable at 6 months, and were associated with the extent of past use and improved mental-health outcomes. Path modelling suggested that the belief-shifts were moderated by impressionability at baseline and mediated by perceived emotional synchrony with others during the psychedelic experience. The observed belief-shifts post psychedelic use were confirmed by data from an independent controlled clinical trial. Together, these findings imply that psychedelic use has a causal influence on metaphysical beliefs – shifting them away from ‘hard materialism’.

The role of the thalamus in mediating the effects of lysergic acid diethylamide (LSD) was recently proposed in a model of communication and corroborated by imaging studies. However, a detailed analysis of LSD effects on nuclei-resolved thalamocortical connectivity is still missing. Here, in a group of healthy volunteers, we evaluated whether LSD intake alters the thalamocortical coupling in a nucleus-specific manner. Structural and resting-state functional Magnetic Resonance Imaging (MRI) data were acquired in a placebo-controlled study on subjects exposed to acute LSD administration. Structural MRI was used to parcel the thalamus into its constituent nuclei based on individual anatomy. Nucleus-specific changes of resting-state functional MRI (rs-fMRI) connectivity were mapped using a seed-based approach. LSD intake selectively increased the thalamocortical functional connectivity (FC) of the ventral complex, pulvinar, and non-specific nuclei. Functional coupling was increased between these nuclei and sensory cortices that include the somatosensory and auditory networks. The ventral and pulvinar nuclei also exhibited increased FC with parts of the associative cortex that are dense in serotonin type 2A receptors. These areas are hyperactive and hyper-connected upon LSD intake. At subcortical levels, LSD increased the functional coupling among the thalamus's ventral, pulvinar, and non-specific nuclei, but decreased the striatal-thalamic connectivity. These findings unravel some LSD effects on the modulation of subcortical-cortical circuits and associated behavioral outputs.

Integrating independent but converging lines of research on brain function and neurodevelopment across scales, this article proposes that serotonin 2A receptor (5-HT2AR) signalling is an evolutionary and developmental driver and potent modulator of the macroscale functional organization of the human cerebral cortex. A wealth of evidence indicates that the anatomical and functional organization of the cortex follows a unimodal-to-transmodal gradient. Situated at the apex of this processing hierarchy-where it plays a central role in the integrative processes underpinning complex, human-defining cognition-the transmodal cortex has disproportionately expanded across human development and evolution. Notably, the adult human transmodal cortex is especially rich in 5-HT2AR expression and recent evidence suggests that, during early brain development, 5-HT2AR signalling on neural progenitor cells stimulates their proliferation-a critical process for evolutionarily-relevant cortical expansion. Drawing on multimodal neuroimaging and cross-species investigations, we argue that, by contributing to the expansion of the human cortex and being prevalent at the apex of its hierarchy in the adult brain, 5-HT2AR signalling plays a major role in both human cortical expansion and functioning. Owing to its unique excitatory and downstream cellular effects, neuronal 5-HT2AR agonism promotes neuroplasticity, learning and cognitive and psychological flexibility in a context-(hyper)sensitive manner with therapeutic potential. Overall, we delineate a dual role of 5-HT2ARs in enabling both the expansion and modulation of the human transmodal cortex.

Abstract Music is a highly dynamic stimulus, and consists of distinct acoustic features, such as pitch, rhythm and timbre. Neuroimaging studies highlight a hierarchy of brain networks involved in music perception. Psychedelic drugs such as lysergic acid diethylamide (LSD) temporary disintegrate the normal hierarchy of brain functioning, and produce profound subjective effects, including enhanced music-evoked emotion. The primary objective of this study was to investigate the acute effects of LSD on music-evoked brain-activity under naturalistic music listening conditions. 16 healthy participants were enrolled in magnetic resonance imaging (fMRI) while listening to a 7-minute music piece under eyes-closed conditions on two separate visits (LSD (75 mcg) and placebo). Dynamic time courses for acoustic features were extracted from the music excerpts, and were entered into subject-level fMRI analyses as regressors of interest. Differences between conditions were assessed at group level subsequently, and were related to changes in music-evoked emotions via correlation analyses. Psycho-physiological interactions (PPIs) were carried out to further interrogate underlying music-specific changes in functional connectivity under LSD. Results showed pronounced cortical and subcortical changes in music-evoked brain activity under LSD. Most notable changes in brain activity and connectivity were associated with the component timbral complexity, representing the complexity of the music’s spectral distribution, and these occurred in brain networks previously identified for music-perception and music-evoked emotion, and showed an association with enhanced music-evoked feelings of wonder under LSD. The findings shed light on how the brain processes music under LSD, and provide a neurobiological basis for the usefulness of music in psychedelic therapy.

Impairments in social cognition and interactions are core psychopathologies in schizophrenia, often manifesting as an inability to appropriately relate to the intentions and feelings of others. Neuroimaging has helped to demarcate the dynamics of two distinct functional connectivity circuits underlying the social-affective processes related to mentalization (known as Theory of Mind, ToM) and somatic-affiliation (known as Embodied Simulation, ES). While evidence points to abnormal activation patterns within these networks among those suffering from schizophrenia, it is yet unclear however, if these patients exhibit this abnormal functional connectivity in the context of social-affective experiences. The current fMRI study, investigated functional connectivity dynamics within ToM and ES networks as subjects experienced evolving cinematic portrayals of fear. During scanning, schizophrenia patients and healthy controls passively watched a cinematic scene in which a mother and her son face various threatening events. Participants then provided a continuous and retrospective report of their fear intensity during a second viewing outside the scanner. Using network cohesion index (NCI) analysis, we examined modulations of ES-related and ToM-related functional connectivity dynamics and their relation to symptom severity and the continuous emotional ratings of the induced cinematic fear. Compared to patients, healthy controls showed higher ES-NCI and marginally lower ToM-NCI during emotional peaks. Cross-correlation analysis revealed an intriguing dynamic between NCI and the inter-group difference of reported fear. Schizophrenia patients rated their fear as lower relative to healthy controls, shortly after exhibiting lower ES connectivity. This increased difference in rating was also followed by higher ToM connectivity among schizophrenia patients. The clinical relevance of these findings is further highlighted by the following two results: (a) ToM-NCI was found to have a strong correlation with the severity of general symptoms during one of the two main emotional peaks (Spearman R = 0.77); and (b) k-mean clustering demonstrated that the networks' NCI dynamic during the social-affective context reliably differentiated between patients and controls. Together, these findings point to a possible neural marker for abnormal social-affective processing in schizophrenia, manifested as the disturbed balance between two functional networks involved in social-affective affiliation. This in turn suggests that exaggerated mentalization over somatic-affiliative processing, in response to another's' distress may underlie social-affective deficits in schizophrenia.

Abstract Psychedelic drugs, such as psilocybin and LSD, represent unique tools for researchers in-vestigating the neural origins of consciousness. Currently, the most compelling theories of how psychedelics exert their effects is by increasing the complexity of brain activity and moving the system towards a critical point between order and disorder, creating more dynamic and complex patterns of neural activity. While the concept of criticality is of central importance to this theory, few of the published studies on psychedelics investigate it directly, testing instead related measures such as algorithmic complexity or Shannon entropy. We propose using the fractal dimension of functional activity in the brain as a measure of complexity since findings from physics suggest that as a system organizes towards criticality, it tends to take on a fractal structure. We tested two different measures of fractal dimension, one spatial and one temporal, using fMRI data from volunteers under the influence of both LSD and psilocybin. The first was the fractal dimension of cortical functional connectivity networks and the second was the fractal dimension of BOLD time-series. We were able to show that both psychedelic drugs significantly increased the fractal dimension of functional connectivity networks, and that LSD significantly increased the fractal dimension of BOLD signals, with psilocybin showing a non-significant trend in the same direction. With both LSD and psilocybin, we were able to localize changes in the fractal dimension of BOLD signals to brain areas assigned to the dorsal-attentional network. These results show that psychedelic drugs increase the fractal character of activity in the brain and we see this as an indicator that the changes in consciousness triggered by psychedelics are associated with evolution towards a critical zone. Author Summary The unique state of consciousness produced by psychedelic drugs like LSD and psilocybin (the active component in magic mushrooms) are potentially useful tools for discovering how specific changes in the brain are related to differences in perception and thought patterns. Past research into the neuroscience of psychedelics has led to the proposal of a general theory of brain function and consciousness: the Entropic Brain Hypothesis proposes that consciousness emerges when the brain is sitting near a critical tipping point between order and chaos and that the mind-expanding elements of the psychedelic experience are caused by the brain moving closer to that critical transition point. Physicists have discovered that near this critical point, many different kinds of systems, from magnets to ecosystems, take on a distinct, fractal structure. Here, we used two measures of fractal-quality of brain activity, as seen in fMRI, to test whether the activity of the brain on psychedelics is more fractal than normal. We found evidence that this is the case and interpret that as supporting the theory that, psychedelic drugs are move the brain towards a more critical state.

The article The hidden therapist: evidence for a central role of music in psychedelic therapy, written by Mendel Kaelen, Bruna Giribaldi, Jordan Raine, Lisa Evans, Christopher Timmerman, Natalie Rodriguez, Leor Roseman, Amanda Feilding, David Nutt, Robin Carhart-Harris, was originally published electronically on the publisher's internet portal.

Abstract Brain activity can be understood as the exploration of a dynamical landscape of activity configurations over both space and time. This dynamical landscape may be defined in terms of spontaneous transitions within a repertoire of discrete metastable states of functional connectivity (FC), which underlie different mental processes. However, it remains unclear how the brain’s dynamical landscape might be changed in altered states of consciousness, such as the psychedelic state. The present study investigated changes in the brain’s dynamical repertoire in an fMRI dataset of healthy participants intravenously injected with the psychedelic compound psilocybin, which is found in “magic mushrooms”. We employed a data-driven approach to study brain dynamics in the psychedelic state, which focuses on the dominant FC pattern captured by the leading eigenvector of dynamic FC matrices, and enables the identification of recurrent FC patterns (“FC-states”), and their transition profiles over time. We found that a FC state closely corresponding to the fronto-parietal control system was strongly destabilized in the psychedelic state, while transitions toward a globally synchronized FC state were enhanced. These differences between brain state trajectories in normal waking consciousness and the psychedelic state suggest that the latter biases a global mode of functional integration at the expense of locally segregated activity in specific networks. These results provide a mechanistic perspective on subjective quality of the psychedelic experience, and further raise the possibility that mapping the brain’s dynamical landscape may help guide pharmacological interventions in neuropsychiatric disorders.

EDITORIAL article Front. Pharmacol., 22 July 2022Sec. Neuropharmacology https://doi.org/10.3389/fphar.2022.979764

Abstract Importance Psilocybin therapy shows antidepressant potential; our data link its antidepressant effects to decreased brain network modularity post-treatment. Objective To assess the sub-acute impact of psilocybin on brain activity in patients with depression. Design Pre vs post-treatment resting-state functional MRI (fMRI) was recorded in two trials: 1) Open-label treatment-resistant depression (TRD) trial with baseline vs 1 day post-treatment fMRI (April-2015 to April-2016); 2) Two-arm double-blind RCT in major depressive disorder (MDD), fMRI baseline vs 3 week after psilocybin-therapy or 6 weeks of daily escitalopram (January-2019 to March-2020). Setting Study visits occurred at the NIHR Imperial Clinical Research Facility. Participants Adult male and female patients with TRD or MDD. Intervention(s) (for clinical trials) or Exposure(s) (for observational studies) Study 1: Two oral doses of psilocybin (10mg and 25mg, fixed order, 7 days apart). fMRI was recorded at baseline and one day after the 25mg dose. Study 2: either: 2 x 25mg oral psilocybin, 3 weeks apart, plus 6 weeks of daily placebo (‘psilocybin-arm’), or 2 x 1mg oral psilocybin, 3 weeks apart, plus 6 weeks of daily escitalopram [10-20mg] (‘escitalopram-arm’). fMRI was recorded at baseline and 3 weeks after the 2nd psilocybin dose, which was the final day of the 6-week daily capsule ingestion. Main Outcome(s) and Measure(s) Beck Depression Inventory and fMRI network modularity. Results Study 1: In 16 adults (mean age [SD], 42.8 [10.1] years, 4 [25%] female), psilocybin therapy was associated with markedly decreased BDI scores at 1 week (mean difference, -21; 95% CI=[-27.3, -14.7], P &lt;.001) and 6 months (mean difference, -14.19; 95% CI=[-21.3, -7.1], P &lt;.001). Decreased network modularity at one day post-treatment correlated with treatment response at 6 months (Pearson, 0.64; P =.01). Study 2: In 43 adults (42.7 [10.5] years, 14 [33%] female), antidepressant effects favoured the psilocybin-arm at 2 (mean difference, -8.76; 95% CI=[-13.6, -3.9], P =.002) and 6 weeks (mean difference, -8.78; 95% CI=[-15.6, -2.0], P =.01). Specific to the psilocybin-arm, improvements at the 6-week primary endpoint correlated with decreased network modularity (Pearson, -0.42, P =.025). Conclusions and Relevance Consistent efficacy-related functional brain changes correlating with robust and reliable antidepressant effects across two studies suggest a candidate antidepressant mechanism for psilocybin therapy: decreased brain network modularity. Trial registration ClinicalTrials.gov identifier: NCT03429075

Smoking rates are particularly high during adolescence and young adulthood, when the brain is still undergoing significant developmental changes. Cross-sectional studies have revealed altered brain structure in smokers, such as thinner frontal cortical areas. Attention-deficit/hyperactivity disorder (ADHD) increases the risk of becoming nicotine-dependent, and has also been associated with abnormalities in frontal gray matter structure. The present study examines the relationships between smoking, cortical thickness and ADHD symptoms in a longitudinal design that compares adolescent and young adult smokers (n=44; 35 ADHD-affected) and non-smokers (n=45; 32 ADHD-affected) on frontal cortical thickness. Average frontal cortical thickness was estimated through structural magnetic resonance imaging (MRI) at two time points (mean ages 17.7 and 21.1 years), on average 3.4 years apart. Smokers had a 2.6% thinner frontal cortex than non-smokers and this difference was not explained by ADHD or other confounding factors. The rate of cortical thinning across the 3.4-year MRI measurement interval was similar in the total group of smokers compared to non-smokers. However, speeded thinning did occur in smokers who had started regular smoking more recently, in between the two measurements. These novel regular smokers did not differ significantly from the non-smokers at baseline. This suggests that the thinner frontal cortex was not a predisposing factor but rather a consequence of smoking. Although smokers had more ADHD symptoms overall, smoking did not influence the developmental course of ADHD symptoms.

The ritualistic use of ayahuasca can induce a feeling of unity and harmony among group members. However, such depoliticized feelings can come in the service of a destructive political status quo in which Palestinians are marginalized. Through 31 in-depth interviews of Israelis and Palestinians who drink ayahuasca together, and through participatory observations, such rituals were examined. In this setting marginalization was structurally rooted by the group’s inability to recognize Palestinian national identity or admit the ongoing Israeli injustice toward Palestinians. Although the groups avoided politics, they still find their way into these rituals. This happened through occasional ayahuasca-induced revelatory events, in which individuals were confronted with a pressing truth related to the oppressive relations between Jewish Israelis and Palestinians. Three case studies of such revelatory events are described in this paper. Affected by emotions of pain, anger, and guilt, these participants developed resistance toward the hegemonic Israeli ritual structure. This was followed by an urge to deliver an emancipatory message to the rest of the group, usually through a song. Moreover, affected subjects developed a long-lasting fidelity to the truth attained at these events. In time, this fidelity led to the expansion of ayahuasca practices to other Palestinians and the politicization of the practice. The article draws on Badiou’s theory in Being and Event (1988) to analyze the relations between the Israeli ritual structure, the Palestinian revelatory event, and the emancipatory fidelity that followed. Badiou’s theory elucidates the egalitarian revolutionary potential, which is part of the sociopsychopharmacology of psychedelics.

ABSTRACT Introduction: The question of how spatially-organized activity in the visual cortex behaves during eyes-closed, LSD-induced, visual psychedelic imagery has never been empirically addressed, although it has been proposed that under psychedelics the brain may function "as if" there is visual input when there is none (de Araujo, et al., 2012). We suspected that eyes-closed psychedelic imagery might involve transient local retinotopic activation, of the sort typically associated with visual stimulation. To test this, it was hypothesised that under LSD areas of the visual cortex with congruent retinotopic representations would show stronger RSFC compared to areas with incongruent retinotopic representations. Method: In this work, resting-state functional connectivity (RSFC) data was collected from 10 healthy subjects under the influence of LSD and, separately, placebo. Using a retinotopic localiser performed during a non-drug baseline condition, non-adjacent patches of V1 and V3 that represent the vertical or the horizontal meridians of the visual field were identified. Subsequently, RSFC between V1 and V3 was measured with respect to these a priori identified patches for both LSD and placebo. Results: Consistent with our prior hypothesis, the difference between RSFC of patches with congruent retinotopic specificity (horizontal-horizontal and vertical-vertical) and those with incongruent specificity (horizontal-vertical and vertical-horizontal) was significantly greater under LSD than placebo (p=0.0017, 1-tail, Cohen's d=1.6). Conclusion: The result suggest that activity within the visual cortex under LSD becomes more dependent on its intrinsic retinotopic organization. This result indicates that under LSD, in the eyes-closed resting-state condition, the early visual system behaves as if it were seeing spatially localized visual inputs. Reference de Araujo, D.B., Ribeiro, S., Cecchi, G.A., Carvalho, F.M., Sanchez, T.A., Pinto, J.P., De Martinis, B.S., Crippa, J.A., Hallak, J.E., Santos, A.C. (2012) Seeing with the eyes shut: Neural basis of enhanced imagery following ayahuasca ingestion. Human brain mapping, 33:2550-2560. Meeting abstract presented at VSS 2016

Abstract Psilocybin therapy is an emerging intervention for depression that may be at least as effective as standard first-line treatments i.e., Selective Serotonin Reuptake Inhibitors (SSRIs). Here we assess neural responses to emotional faces (fear, happy, and neutral) using Blood Oxygen-Level Dependent (BOLD) functional Magnetic Resonance Imaging (fMRI) in two groups with major depressive disorder: 1) a ‘psilocybin group’ that received two dosing sessions with 25mg plus six weeks of daily placebo, and 2) an ‘escitalopram group’ that received six weeks of the SSRI escitalopram, plus two dosing sessions with an inactive/placebo dose of 1mg psilocybin. Both groups had an equal amount of psychological support throughout. An emotional face fMRI paradigm was completed at baseline (pre-treatment) and at the six-week post-treatment primary endpoint (three weeks following psilocybin dosing sessions). An analysis examining the interaction between patient group (psilocybin vs. escitalopram) and time-point (pre-vs. post-treatment) showed a robust effect in a distributed network of cortical brain regions. Follow-up analyses showed that post-treatment BOLD responses to emotional faces of all types were significantly reduced in the escitalopram group, with no change, or even a slight increase, in the psilocybin group. Specific analyses of the amygdala showed a reduction of response to fear faces in the escitalopram group, but no effects for the psilocybin group. Despite large improvements in depressive symptoms in the psilocybin group, psilocybin-therapy had only a minor effect on brain responsiveness to emotional stimuli. We suggest that reduced emotional responsiveness may be a biomarker of SSRIs’ antidepressant action that is not shared by psilocybin-therapy.

Abstract Studying transitions in and out of the altered state of consciousness caused by intravenous (IV) N,N-Dimethyltryptamine (DMT – a fast-acting tryptamine psychedelic) offers a safe and powerful means of advancing knowledge on the neurobiology of conscious states. Here we sought to investigate the effects of IV DMT on the power spectrum and signal diversity of human brain activity (6 female, 7 male) recorded via multivariate EEG, and plot relationships between subjective experience, brain activity and drug plasma concentrations across time. Compared with placebo, DMT markedly reduced oscillatory power in the alpha and beta bands and robustly increased spontaneous signal diversity. Time-referenced analyses revealed close relationships between changes in various aspects of subjective experience and changes in brain activity. Importantly, the emergence of oscillatory activity within the delta and theta frequency bands was found to correlate with the peak of the experience, and particularly its eyes-closed visual component. These findings highlight marked changes in oscillatory activity and signal diversity with DMT that parallel broad and specific components of the relevant subjective experience and thus further our understanding of the neurobiological underpinnings of immersive states of consciousness.

The capacity to accumulate information over time is crucial to our functioning in an ever-changing world. Recently, in healthy subjects, we showed that brain uses a distributed and hierarchical network of brain areas to process information over time. Specifically, we revealed hierarchy of information processing over time from early sensory areas toward high order perceptual and cognitive areas. Here, we investigate this issue in first-episode schizophrenia patients. Previous studies posited that schizophrenia is the result of impairment of hierarchical temporal processing by the brain, claiming for impairment in use of context while being processing information. The hierarchical temporal deficit is a fundamental trait that may be a better target for the study of etiology and pathophysiology of the disease. We intended to map, in schizophrenia patients, the topographical organization of temporal scales using an ecologically relevant auditory stimulus - a real-life story. In addition, we assumed that studying healthy siblings, who are at high-risk for cognitive dysfunctions, will enable to determine functional neuromarkers of predisposition to disorder. The fMRI data were analyzed using inter-subject correlation approach. The time-courses within each brain area in schizophrenia patients were estimated against healthy controls and unaffected siblings of the patients. Among patients, we observed impaired hierarchy with processing intact in low level but disturbed in high level. The sibling group showed an intermediate effect. Better understanding of the underlying neural circuit involved in information processing in schizophrenia patients may assist in early identification of functional neuromarkers for the disease.

Abstract Psilocybin therapy for depression has started to show promise, yet the underlying causal mechanisms are not currently known. Here we leveraged the differential outcome in responders and non-responders to psilocybin (10mg and 25mg, 7 days apart) therapy for depression - to gain new insights into regions and networks implicated in the restoration of healthy brain dynamics. We used whole-brain modelling to fit the spatiotemporal brain dynamics at rest in both responders and non-responders before treatment. Dynamic sensitivity analysis of systematic perturbation of these models enabled us to identify specific brain regions implicated in a transition from a depressive brain state to a heathy one. Binarizing the sample into treatment responders (&gt;50% reduction in depressive symptoms) versus non-responders enabled us to identify a subset of regions implicated in this change. Interestingly, these regions correlate with in vivo density maps of serotonin receptors 5-HT 2A and 5-HT 1A , which psilocin, the active metabolite of psilocybin, has an appreciable affinity for, and where it acts as a full-to-partial agonist. Serotonergic transmission has long been associated with depression and our findings provide causal mechanistic evidence for the role of brain regions in the recovery from depression via psilocybin.

Background: Psilocybin is a serotonin type 2A (5-HT 2A ) receptor agonist and naturally occurring psychedelic. 5-HT 2A receptor density is known to be associated with body mass index (BMI), however, the impact of this on psilocybin therapy has not been explored. While body weight-adjusted dosing is widely used, this imposes a practical and financial strain on the scalability of psychedelic therapy. This gap between evidence and practice is caused by the absence of studies clarifying the relationship between BMI, the acute psychedelic experience and long-term psychological outcomes. Method: Data were pooled across three studies using a fixed 25 mg dose of psilocybin delivered in a therapeutic context to assess whether BMI predicts characteristics of the acute experience and changes in well-being 2 weeks later. Supplementing frequentist analysis with Bayes Factors has enabled for conclusions to be drawn regarding the null hypothesis. Results: Results support the null hypothesis that BMI does not predict overall intensity of the altered state, mystical experiences, perceptual changes or emotional breakthroughs during the acute experience. There was weak evidence for greater ‘dread of ego dissolution’ in participants with lower BMI, however, further analysis suggested BMI did not meaningfully add to the combination of the other covariates (age, sex and study). While mystical-type experiences and emotional breakthroughs were strong predictors of improvements in well-being, BMI was not. Conclusions: These findings have important implications for our understanding of pharmacological and extra-pharmacological contributors to psychedelic-assisted therapy and for the standardization of a fixed therapeutic dose in psychedelic-assisted therapy.

ABSTRACT Recent studies have started to elucidate the effects of lysergic acid diethylamide (LSD) on the human brain but the underlying dynamics are not yet fully understood. Here we used ‘connectome-harmonic decomposition’, a novel method to investigate the dynamical changes in brain states. We found that LSD alters the energy and the power of individual harmonic brain states in a frequency-selective manner. Remarkably, this leads to an expansion of the repertoire of active brain states, suggestive of a general re-organization of brain dynamics given the non-random increase in co-activation across frequencies. Interestingly, the frequency distribution of the active repertoire of brain states under LSD closely follows power-laws indicating a re-organization of the dynamics at the edge of criticality. Beyond the present findings, these methods open up for a better understanding of the complex brain dynamics in health and disease.

LSD is a potent serotonergic psychedelic compound. Findings indicate that psychotherapeutic applications of LSD and related psychedelic compounds have value in the treatment of mental health disorders. Deepening our understanding of LSD brain action may shed light on the mechanisms underlying the effectiveness of psychedelic therapy. A recent model hypothesized reduced whole-brain hierarchical organization as a key mechanism underlying the psychedelic state, but this has yet to be directly tested. Here, we applied an unsupervised manifold learning technique that is sensitive to cortical hierarchy to pharmacological resting-state fMRI data to assess cortical organization in the LSD state. Results directly supported our primary hypothesis: The Principal Gradient, describing a hierarchical transition from unimodal to transmodal cortex, was significantly contracted under LSD relative to placebo. Between-condition contrasts revealed that this was primarily driven by a reduction of functional differentiation at both hierarchical extremes - default and frontoparietal networks at the upper end, and somatomotor cortex at the lower. In addition, results pertaining to the visual-somatomotor Second Gradient revealed that LSD reduced the differentiation of visual from auditory/somatomotor and association regions. Significantly, gradient changes tracked state-specific changes in specific dimensions of self-reported LSD experience. These findings support a recent mechanistic model of the psychedelic state that has relevance to therapeutic applications of psychedelics. More fundamentally, these findings provide the first evidence that cortical hierarchical organization can be modulated in a state-dependent manner, highlighting an important relationship between the features of neural topography and ongoing conscious experience.

To estimate the efficiency of glucocorticoid signaling in multiple sclerosis in vivo, we measured mRNA expression of glucocorticoid receptor (GR), mineralocorticoid receptor (MR) and four genes regulated by GR and implicated in immune function, in whole blood. GR expression and MR expression were significantly lower in 52 patients than in 18 controls. In contrast, expression of GR regulated genes was increased (significantly for glucocorticoid induced leucine zipper, GILZ), especially in mildly impaired patients. Reduced GR expression appears to be compensated, either by hyperactive hypothalamo–pituitary–adrenal axis or by intracellular adaptations.

Increased copy number of chromosome enumeration probe (CEP) targeting centromere 17 is frequently encountered during HER2 in situ hybridization (ISH) in breast cancer. The aim of this study was to clarify the clinicopathologic significance of CEP17 copy number gain in a relatively large series of breast cancer patients. We analyzed 945 cases of invasive breast cancers whose HER2 fluorescence ISH reports were available from 2004 to 2011 at a single institution and evaluated the association of CEP17 copy number gain with clinicopathologic features of tumors and patient survival. We detected 186 (19.7%) cases of CEP17 copy number gain (CEP17 ≥ 3.0) among 945 invasive breast cancers. In survival analysis, CEP17 copy number gain was not associated with disease-free survival of the patients in the whole group. Nonetheless, it was found to be an independent adverse prognostic factor in the HER2-negative group but not in the HER2-positive group. In further subgroup analyses, CEP17 copy number gain was revealed as an independent poor prognostic factor in HER2-negative and hormone receptor-positive breast cancers, and it was associated with aggressive histologic variables including high T stage, high histologic grade, lymphovascular invasion, p53 overexpression, and high Ki-67 proliferative index. In conclusion, we found that elevated CEP17 count can serve as a prognostic marker in luminal/HER2-negative subtype of invasive breast cancer. We advocate the use of the dual-colored fluorescence ISH using CEP17 rather than the single-colored one because it gives additional valuable information on CEP17 copy number alterations.

Abstract To understand how pharmacological interventions can exert their powerful effects on brain function, we need to understand how they engage the brain’s rich neurotransmitter landscape. Here, we bridge microscale molecular chemoarchitecture and pharmacologically-induced macroscale functional reorganisation, by relating the regional distribution of 19 neurotransmitter receptors and transporters obtained from Positron Emission Tomography, and the regional changes in functional MRI connectivity induced by 10 different mind-altering drugs: propofol, sevoflurane, ketamine, LSD, psilocybin, DMT, ayahuasca, MDMA, modafinil, and methylphenidate. Our results reveal that psychoactive drugs exert their effects on brain function by engaging multiple neurotransmitter systems. The effects of both anaesthetics and psychedelics on brain function are organised along hierarchical gradients of brain structure and function. Finally, we show that regional co-susceptibility to pharmacological interventions recapitulates co-susceptibility to disorder-induced structural alterations. Collectively, these results highlight rich statistical patterns relating molecular chemoarchitecture and drug-induced reorganisation of the brain’s functional architecture.

Abstract Lysergic acid diethylamide (LSD) is a potent psychedelic drug, which has seen a revival in clinical and pharmacological research within recent years. Human neuroimaging studies have shown fundamental changes in brain-wide functional connectivity and an expansion of dynamical brain states, thus raising the question about a mechanistic explanation of the dynamics underlying these alterations. Here, we applied a novel perturbational approach based on a whole-brain computational model, which opens up the possibility to externally perturb different brain regions in silico and investigate differences in dynamical stability of different brain states, i.e. the dynamical response of a certain brain region to an external perturbation. After adjusting the whole-brain model parameters to reflect the dynamics of functional magnetic resonance imaging (fMRI) BOLD signals recorded under the influence of LSD or placebo, perturbations of different brain areas were simulated by either promoting or disrupting synchronization in the regarding brain region. After perturbation offset, we quantified the recovery characteristics of the brain area to its basal dynamical state with the Perturbational Integration Latency Index (PILI) and used this measure to distinguish between the two brain states. We found significant changes in dynamical complexity with consistently higher PILI values after LSD intake on a global level, which indicates a shift of the brain’s global working point further away from a stable equilibrium as compared to normal conditions. On a local level, we found that the largest differences were measured within the limbic network, the visual network and the default mode network. Additionally, we found a higher variability of PILI values across different brain regions after LSD intake, indicating higher response diversity under LSD after an external perturbation. Our results provide important new insights into the brain-wide dynamical changes underlying the psychedelic state - here provoked by LSD intake - and underline possible future clinical applications of psychedelic drugs in particular psychiatric disorders. Highlights Novel offline perturbational method applied on functional magnetic resonance imaging (fMRI) data under the effect of lysergic acid diethylamide (LSD) Shift of brain’s global working point to more complex dynamics after LSD intake Consistently longer recovery time after model perturbation under LSD influence Strongest effects in resting state networks relevant for psychedelic experience Higher response diversity across brain regions under LSD influence after an external in silico perturbation

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