Robin Carhart-Harris's research while affiliated with University of California and other places

Publications (60)

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In this paper, we set an agenda for a psychedelic science of spirituality and religion based on attachment theory. Attachment theory proposes that people develop internal working models (IWMs) of interactions with others from their relational experiences with caregivers. Such IWMs then function as high-level priors or predictive models, enabling pe...
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Background: Music listening is a staple and valued component of psychedelic therapy, and previous work has shown that psychedelics can acutely enhance music-evoked emotion. Aims: The present study sought to examine subjective responses to music before and after psilocybin therapy for treatment-resistant depression, while functional magnetic reso...
Preprint
OBJECTIVE: Psychedelics have over recent years been subject to a fast-paced growth in scientific research, clinical applications, commercial investment, and substance use trends by the general public. Yet, concerningly little is known about the frequency of adverse side effects of psychedelic use, despite a breadth of anecdotal reports and largely...
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Background: Psilocybin is being studied for use in treatment-resistant depression. Methods: In this phase 2 double-blind trial, we randomly assigned adults with treatment-resistant depression to receive a single dose of a proprietary, synthetic formulation of psilocybin at a dose of 25 mg, 10 mg, or 1 mg (control), along with psychological suppo...
Article
Background: A trial of psilocybin (COMP360) versus escitalopram for major depressive disorder (MDD) was reported as negative, as there was no significant difference in the primary outcome, mean change in the 16-item Quick Inventory of Depressive Symptomatology-Self-Report (QIDS SR-16). However, analyses using three other depression scales (17-item...
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Psychedelic drugs, including lysergic acid diethylamide (LSD) and other agonists of the serotonin 2A receptor (5HT2A-R), induce drastic changes in subjective experience, and provide a unique opportunity to study the neurobiological basis of consciousness. One of the most notable neurophysiological signatures of psychedelics, increased entropy in sp...
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Microdosing is the practice of regularly using very low doses of psychedelic drugs. Anecdotal reports suggest that it may enhance well-being, creativity and cognition. Here, we use data from a self-blinding microdose trial, a large (n=240) placebo-controlled citizen science trial of microdosing to investigate whether tolerance develops during micro...
Preprint
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...
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N,N‐dimethyltryptamine (DMT) is a psychedelic compound that is believed to have potential as a therapeutic option in several psychiatric disorders. The number of clinical investigations with DMT is increasing. However, very little is known about the pharmacokinetic properties of DMT as well as any relationship between its exposure and effects. This...
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Background Major depressive disorder is often associated with maladaptive coping strategies, including rumination and thought suppression. Aims 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...
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A topic of growing interest in computational neuroscience is the discovery of fundamental principles underlying global dynamics and the self-organization of the brain. In particular, the notion that the brain operates near criticality has gained considerable support, and recent work has shown that the dynamics of different brain states may be model...
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Rationale 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’ a...
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Background Over the last two decades, a number of studies have highlighted the potential of psychedelic therapy. However, questions remain to what extend these results translate to naturalistic samples, and how contextual factors and the acute psychedelic experience relate to improvements in affective symptoms following psychedelic experiences outs...
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There is growing evidence for the safety and efficacy of psychedelic therapy in mental health care. What is less understood however, is how psychedelics act to yield therapeutic results. In this paper we propose that psychedelics act as destabilisers — both in a psychological and a neurophysiological sense. Our proposed framework builds on the ‘ent...
Preprint
The purpose of the RElaxed Beliefs-Questionnaire (REB-Q) is to measure changes in an individual’s certainty in their personally-identified core beliefs (a) within experimental conditions and (b) over time. Administration of the measure involves two components: (a) At baseline, participants identify core beliefs that they hold about themselves and/o...
Preprint
Background: The Relaxed Beliefs Under pSychedelics (REBUS) model proposes that serotonergic psychedelics decrease the precision weighting of neurobiologically-encoded beliefs, and offers a unified account of the acute and therapeutic action of psychedelics. Although REBUS has received some neuroscientific support, little research has examined its p...
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Objectives: To perform a Bayesian reanalysis of a recent trial of psilocybin (COMP360) versus escitalopram for Major Depressive Disorder (MDD) in order to provide a more informative interpretation of the indeterminate outcome of a previous frequentist analysis.Design: Reanalysis of a two-arm double-blind placebo controlled trial.Participants: Fifty...
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Scientific theories on the functioning and dysfunction of the human brain require a good understanding of both its development — before and after birth, and through maturation to adulthood — and its evolution from the ancestral primate brain. Adopting a complex-systems approach, here we propose that the apparent uniqueness of humans’ cognitive capa...
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Understanding the phenomenology and content of the inhaled N, N, dimethyltryptamine (N, N-DMT) experience is critical to facilitate and support ongoing research and therapeutic models targeting mental health conditions and central nervous system pathology. A qualitative analysis was conducted of all N, N-DMT experiences posted to the r/DMT Reddit c...
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In medical research, the gold standard experimental design is the blinded randomized controlled trial. Despite the central role of blinding, it is rare for trials to assess blinding integrity and to incorporate this information into the interpretation of results. Here we use computational modelling to show that the combination of weak blinding and...
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This document details an authors' response to a critique of their work entitled: Skepticism About Recent Evidence that Psilocybin Opens Depressed Minds.
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Clinical research into serotonergic psychedelics is expanding rapidly, showing promising efficacy across myriad disorders. Resting-state functional magnetic resonance imaging (rs-fMRI) is a commonly used strategy to identify psychedelic-induced changes in neural pathways in clinical and healthy populations. Here we, a large group of psychedelic ima...
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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...
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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 unifie...
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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...
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Background: Across psychotherapeutic frameworks, the strength of the therapeutic alliance has been found to correlate with treatment outcomes; however, its role has never been formally assessed in a trial of psychedelic-assisted therapy. We aimed to investigate the relationships between therapeutic alliance and rapport, the quality of the acute psy...
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Significance What changes in the brain when we lose consciousness? One possibility is that the loss of consciousness corresponds to a transition of the brain’s electric activity away from edge-of-chaos criticality, or the knife’s edge in between stability and chaos. Recent mathematical developments have produced tools for testing this hypothesis, w...
Article
A highly sensitive LC-MS/MS method for the quantification of N,N-dimethyltryptamine (DMT) and its metabolites indole-3-acetic acid and DMT N-oxide in human plasma has been developed and validated. Chromatography was performed using a diphenyl column with gradient elution (0.1% formic acid in methanol/water). The mass spectrometer was operated in mu...
Preprint
In this paper, we set an agenda for a psychedelic science of spirituality and religion, based on a synthesis of attachment theory with the Relaxed Beliefs Under pSychedelics (REBUS) model. Attachment theory proposes that people develop internal working models (IWMs) of interactions with others from their relational experiences with caregivers. Such...
Preprint
Full-text available
In this paper, we set an agenda for a psychedelic science of spirituality and religion, based on a synthesis of attachment theory with the Relaxed Beliefs Under pSychedelics (REBUS) model. Attachment theory proposes that people develop internal working models (IWMs) of interactions with others from their relational experiences with caregivers. Such...
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Full-text available
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-medi...
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Within the context of scientific research, patient and public involvement (PPI) is defined as research performed “with” or “by” patients and members of the public, rather than “to,” “about”, or “for” them. When carried out systematically and thoughtfully, PPI has the potential to strengthen the quality and impact of research by fostering accountabi...
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The human prefrontal cortex is a structurally and functionally heterogenous brain region, including multiple subregions that have been linked to different large-scale brain networks. It contributes to a broad range of mental phenomena, from goal-directed thought and executive functions to mind-wandering and psychedelic experience. Here we review wh...
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Background The resurgence of research and public interest in the positive psychological effects of psychedelics, together with advancements in digital data collection techniques, have brought forth a new type of research design, which involves prospectively gathering large-scale naturalistic data from psychedelic users; that is, before and after th...
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Addressing global mental health is a major 21st-century challenge. Current treatments have recognized limitations; in this context, new ones that are prophylactic and effective across diagnostic boundaries would represent a major advance. The view that there exists a core of transdiagnostic overlap between psychiatric disorders has re-emerged in re...
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Many people who have had a near-death experience (NDE) describe, as part of it, a disturbed sense of having a “distinct self”. However, no empirical studies have been conducted to explore the frequency or intensity of these effects. We surveyed 100 NDE experiencers (Near-Death-Experience Content [NDE-C] scale total score ≥27/80). Eighty participant...
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The objective of the current study was to investigate the associations between lifetime classic psychedelic use and cardiometabolic diseases. Using data from the National Survey on Drug Use and Health (2005–2014), the present study examined the associations between lifetime classic psychedelic use and two types of cardiometabolic disease: heart dis...
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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...
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Mounting evidence suggests that during conscious states, the electrodynamics of the cortex are poised near a critical point or phase transition, and that this near-critical behavior supports the vast flow of information through cortical networks during conscious states. Here, for the first time, we empirically identify the specific critical point n...
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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 tria...
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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. Throu...
Article
Background Psilocybin may have antidepressant properties, but direct comparisons between psilocybin and established treatments for depression are lacking. Methods In a phase 2, double-blind, randomized, controlled trial involving patients with long-standing, moderate-to-severe major depressive disorder, we compared psilocybin with escitalopram, a...
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Background: With support from the Radcliffe Institute for Advanced Study at Harvard University, we convened researchers representing palliative care, psychosocial oncology, spiritual care, oncology, and psychedelic-assisted therapies. We aimed to define priorities and envision an agenda for future research on psychedelic-assisted therapies in patie...
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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....
Preprint
Healthful behaviors such as maintaining a balanced diet, being physically active, and refraining from smoking have major impacts on the risk of developing cancer, diabetes, cardiovascular diseases, and other serious conditions. The burden of the so-called “lifestyle diseases” - in personal suffering, premature mortality, and public health costs - i...
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Using data from the National Survey on Drug Use and Health (2005–2014), weighted to be representative of the US adult population, the present study investigated the association between lifetime classic psychedelic use and hypertension in the past year among adults in the United States. The results showed that respondents who reported having used a...
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Background: N,N-dimethyltryptamine is a short-acting psychedelic tryptamine found naturally in many plants and animals. Few studies to date have addressed the neural and psychological effects of N,N-dimethyltryptamine alone, either administered intravenously or inhaled in freebase form, and none have been conducted in natural settings. Aims: Our...
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This study was designed to identify trends in the top-cited classic psychedelic publications. The top 50 publications on classic psychedelics with the greatest total of number of citations and annual citation rate were identified and pooled. Unique articles (n = 77) were dichotomized by median year of publication (2010); the differential distributi...
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This paper introduces a new construct, the ‘pivotal mental state’, which is defined as a hyper-plastic state aiding rapid and deep learning that can mediate psychological transformation. We believe this new construct bears relevance to a broad range of psychological and psychiatric phenomena. We argue that pivotal mental states serve an important e...
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The neural circuit linking the basal ganglia, the cerebellum and the cortex through the thalamus plays an essential role in motor and cognitive functions. However, how such functions are realized by multiple loop circuits with neurons of multiple types is still unknown. In order to investigate the dynamic nature of the whole-brain network, we built...
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Purpose of review: Psychedelics are reawakening interest from psychiatry, cognitive neuroscience and the general public with impressive outcomes in small-scale clinical trials, intriguing human brain imaging work and high-impact journalism. Recent findings: This brief opinion piece offers a perspective on how psychedelics work in the brain that...
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Background: Evidence suggests that classical psychedelics can promote enduring changes in personality, attitudes and optimism, as well as improvements in mental health outcomes. Aim: To investigate the effects of a composite intervention, involving psilocybin, on pessimism biases in patients with treatment-resistant depression (TRD). Methods: Patie...
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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.
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The entropic brain hypothesis proposes that within upper and lower limits, after which consciousness may be lost, the entropy of spontaneous brain activity indexes the informational richness of conscious states. Here the hypothesis is revisited four years on from its original publication. It is shown that the principle that the entropy of brain act...
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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 p...
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Rationale: Depressed patients robustly exhibit affective biases in emotional processing which are altered by SSRIs and predict clinical outcome. Objectives: The objective of this study is to investigate whether psilocybin, recently shown to rapidly improve mood in treatment-resistant depression (TRD), alters patients' emotional processing biases...
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Plant-based psychedelics such as psilocybin have an ancient history of medicinal use. After the first English-language report on LSD in 1950, psychedelics enjoyed a short-lived relationship with psychology and psychiatry. Used most notably as aides to psychotherapy for the treatment of mood disorders and alcohol dependence, drugs such as LSD showed...

Citations

... For example, increased functional connectivity lowers the resting entropy in the parietal cingulate cortex and amygdala (Rowe and Fitness, 2018). Reduced Nucleus accumbens default mode network connectivity improves contentment (Shukuroglou et al., 2022), supporting the relationship between information erasure and resting synaptic flexibility. ...
... Lastly, a multi-centric trial investigating efficacy of 25 mg, 10 mg, and 1 mg of psilocybin in patients with treatment-resistant depression reported significant symptom reduction for the 25 mg treatment condition 3 weeks after baseline. 9 However, no placebo-controlled trial has been published to date, therefore limiting our understanding of the contribution of different pharmacological and nonpharmacological aspects of psychedelic-assisted therapy. Furthermore, all cited clinical trials used dosage regimens that are considered low (≤10 mg) or included a high dose (>20 mg), while omitting the moderate dose range. ...
... Here we analyze the data collected in a randomized controlled trial (see Carhart-Harris et al., 2021, Nayak et al., 2022 with the aim of assessing the superiority of a new therapy with psilocybin (P) versus that with escitalopram (E), in treating major depressive disorder. The dataset contains the scores obtained by n = 57 patients on a questionnaire, before and after a 6-week period of therapy. ...
... It builds on a paradigm initially proposed by Deco and colleagues to investigate the brain regions more prone to drive transition between awake and asleep states [12]. The same paradigm was recently extended to the clinical context for treatment-resistant depression, to find the brain regions that work in promoting a transition to a target healthy state in responders but not non-responders to treatment with the psychoactive compound psilocybin [13]. The approach revealed a map of brain regions that significantly overlaps with the density map of specific serotonin receptors (5HT 2A and 5HT 1A ) to which psilocybin is known to bind preferentially [14], corroborating the hypothesis that the therapeutic effects of psilocybin are linked to a modulation of the serotonergic system. ...
... In addition to ceremonial and recreational use, DMT has recently gained increased interest as a potential therapeutic agent for the treatment of mental disorders and drug dependence [6][7][8][9][10]. Currently, different and mostly intravenous DMT dosage regimens are under investigation in several clinical studies [11]. Acute high doses of DMT may produce a delirium in users, for which reasons intravenous perfusions may be preferred to gradually move individuals into states of altered consciousness [10]. ...
... The majority of studies examining rs-fMRI in healthy controls have focused on the acute effects of psilocybin in healthy populations, with a smaller number also exploring the acute effects of LSD and ayahuasca (23). To date 17 rs-fMRI studies have been reported (19,(24)(25)(26)(27)(28)(29)(30)(31)(32)(33)(34)(35)(36)(37)(38)(39). Study characteristics and the various functional connectivity analytic techniques used are summarized in ref 23 (23). ...
... The centrality of increased connectedness surrounding psychedelic experiences provides a compelling match with a core component of attachment theory, namely people's proclivity to develop strong interpersonal bonds (attachments). Arguably, increased connectedness in conjunction with psychedelic-assisted therapy can be experienced in relation to a wider and less well-specified set of targets (e.g., the universe, all of humanity, nature, see Watts et al., 2022) than those typically considered within attachment theory. It should be noted, however, that a sense of connectedness is a prerequisite to what may, and in other cases may not, develop into full-fledged attachment relationships. ...
... One possibility to assess whether IWMs are revised during or following psychedelic sessions, which would support our framing of IWMs as priors, is to observe attachment behaviors before, during, and after a psychedelic experience (e.g., emotional avoidance, engaging the therapist; Talia et al., 2017). Zeifman et al. (2022) have demonstrated preliminary evidence that psychedelics foster acute relaxation and post-acute revision of confidence in beliefs (about themselves and others) which are relevant to mental health and facilitate positive therapeutic outcomes. ...
... This is a fascinating hypothesis, with intriguing evidence in its favour [43], however, in light of flickering emergence, we are forced to ask: does the sense of self "flicker?" The sense of self can clearly be experienced as more or less intensely real (and, in some cases appears to vanish entirely) [44,45], although it generally seems stable during normal consciousness. If there is a link between temporal mutual information and the sense of self (an observable phenomena), then we are forced to wrangle with the question of temporal locality. ...
... 28,30,36,37,47 Moreover, networks of synchronized brain activity involve subcortical and cortical areas 156,157 that change during the psychedelic state. 35,41,158,159 Such changes in cortical network activity can, of course, also be analyzed with fNIRS neuroimaging. 87,160,161 The principal disadvantage that only cortical areas can be measured with fNIRS is put into perspective by the fact that the cortex is also always influenced by psychedelics and brain activity also changes there. ...