Robin Carhart-Harris

• Professor at University of California, San Francisco

This handbook is currently in development, with individual articles publishing online in advance of print publication. At this time, we cannot add information about unpublished articles in this handbook, however the table of contents will continue to grow as additional articles pass through the review process and are added to the site. Please note...

Purpose of the study Psilocybin is a rapidly-emerging treatment for depression, yet its impact on sleep is not well understood. We sought to explore the literature on sleep and psilocybin use, and explore the topic using our own primary data. Findings Whilst clinical trials demonstrate large depressive symptom improvements, the impact of psilocybi...

This article presents a neuroscientific interpretation of Carl Jung's theory of archetypes, and their experience in altered states of consciousness. We begin by rehearsing the Free Energy Principle and Predictive Processing as foundational frameworks which subserve and inform the thesis that follows. The following sections examine three aspects of...

Introduction. Being diagnosed with a life-threatening illness (LTI) is often accompanied by feelings of fear, uncertainty, and loneliness that can severely impact mental health. Relatively few interventions are available to address the existential concerns of individuals facing LTI, while treatment of the underlying physical ailment typically remai...

Psychedelics have robust effects on acute brain function and long-term behavior but whether they also cause enduring functional and anatomical brain changes is unknown. In a placebo-controlled, within-subjects, electroencephalography, and magnetic resonance imaging study in 28 healthy, entirely psychedelic-naive participants, anatomical and functio...

Background Access to psychedelic drugs is liberalizing, yet responses are highly unpredictable. It is therefore imperative that we improve our ability to predict the nature of the acute psychedelic experience to improve safety and optimize potential therapeutic outcomes. This study sought to validate the ‘Imperial Psychedelic Predictor Scale’ (IPPS...

Background Psilocybin therapy (PT) produces rapid and persistent antidepressant effects in major depressive disorder (MDD). However, the long-term effects of PT have never been compared with gold-standard treatments for MDD such as pharmacotherapy or psychotherapy alone or in combination. Methods This is a 6-month follow-up study of a phase 2, doub...

Introduction: Meditation practice and psychedelic use have attracted increasing attention in the public sphere and scientific research. Both methods induce non-ordinary states of consciousness that may have significant therapeutic benefits. Thus, there is growing scientific interest in potential synergies between psychedelic use and meditation prac...

Disorders of consciousness (DoC), including the unresponsive wakefulness syndrome (UWS) and the minimally conscious state (MCS), have limited treatment options. Recent research suggests that psychedelic drugs, known for their complexity-enhancing properties, could be promising treatments for DoC. This study uses whole-brain computational models to...

Psychedelic experiences open a colorful view into drug-induced changes in conscious awareness. Small-sample studies on psychedelic drug action have gained traction in recent years. Yet, today’s means for measuring changes in subjective experience are mostly limited to legacy questionnaires of pre-assumed relevance, which could be complemented by bo...

Recent clinical trials have found that the serotonergic psychedelic psilocybin effectively alleviates anxiodepressive symptoms in patients with life-threatening illnesses when given in a supportive environment. These outcomes prompted Canada to establish legal pathways for therapeutic access to psilocybin, coupled with psychological support. Despit...

A single dose of psilocybin, a psychedelic that acutely causes distortions of space–time perception and ego dissolution, produces rapid and persistent therapeutic effects in human clinical trials1–4. In animal models, psilocybin induces neuroplasticity in cortex and hippocampus5–8. It remains unclear how human brain network changes relate to subjec...

This quality improvement study investigates the association of interruptions during psychedelic therapy with ratings of intensity of experience.

Developmental stuttering (DS) is a neurodevelopmental speech-motor disorder characterized by symptoms such as blocks, repetitions, and prolongations. Persistent DS often has a significant negative impact on quality of life, and interventions for it have limited efficacy. Herein, we briefly review existing research on the neurophysiological underpin...

This study aimed to investigate differences in long-term psychological effects, acute subjective effects, and side effects associated with psychedelic use in adolescents (aged 16–24), compared with adults (aged 25+). Data from two observational online survey cohorts was pooled, involving adolescents (average age 20.4 ± 2.2, N = 435) and adults (ave...

Background Chronic pain is a leading cause of disability worldwide. Fibromyalgia is a particularly debilitating form of widespread chronic pain. Fibromyalgia remains poorly understood, and treatment options are limited or moderately effective at best. Here, we present a protocol for a mechanistic study investigating the effects of psychedelic-assis...

Psychedelics are serotonergic drugs that profoundly alter consciousness, yet their neural mechanisms are not fully understood. A popular theory, RElaxed Beliefs Under pSychedelics (REBUS), posits that psychedelics flatten the hierarchy of information flow in the brain. Here, we investigate hierarchy based on the imbalance between sending and receiv...

Background Reference to an intrinsic healing mechanism or an ‘inner healer’ is commonplace amongst psychedelic drug-using cultures. The ‘inner healer’ refers to the belief that psychedelic compounds, plants or concoctions have an intrinsically regenerative action on the mind and brain, analogous to intrinsic healing mechanisms within the physical b...

Background There is growing evidence for the therapeutic effects of the psychedelic drug psilocybin for major depression. However, due to the lack of safety data on combining psilocybin with selective serotonin reuptake inhibitors (SSRIs) and serotonin-norepinephrine reuptake inhibitors (SNRIs) and concerns that there may be a negative interaction...

This study demonstrates that changes in mindfulness predict subsequent changes in well-being in a data set including individuals who recently engaged in psychedelic use.

Altered states of consciousness (ASCs), induced e.g. by psychedelics, show great potential to treat widespread mental health disorders like depression and PTSD. However, access to such treatments is restricted by legal, medical, and financial barriers. Here, we explore the potential of circular breathwork to serve as an accessible, non-pharmacologi...

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...

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...

Access to psychedelic drugs is liberalizing, yet responses are highly unpredictable. It is therefore imperative that we improve our ability to predict the nature of the acute psychedelic experience to improve safety and optimize potential therapeutic outcomes. This study sought to validate the ‘Imperial Psychedelic Predictor Scale’ (IPPS), a short,...

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 e...

Aim Psychedelics have recently gained attention as potential therapeutic agents for various psychiatric disorders. Previous research has highlighted that a diminished sense of self, commonly termed “ego‐dissolution” is a pivotal feature of the psychedelic‐induced state. While the Ego‐Dissolution Inventory (EDI) is a widely acknowledged instrument f...

The transition towards the brain state induced by psychedelic drugs is frequently neglected in favor of a static description of their acute effects. We used a time-dependent whole-brain model to reproduce large-scale brain dynamics measured with fMRI from 15 volunteers under 20 mg of bolus intravenous N,N-Dimethyltryptamine (DMT), a short-lasting p...

Background There is growing evidence for the therapeutic effects of psychedelics. However, it is still uncertain how these drugs interact with serotonergic antidepressants (serotonin reuptake inhibitors (SRIs)). Objective This study explores the interaction between psychedelics and SRIs in terms of therapeutic effects. The objective is to compare...

Background To investigate the association between pre-trial expectancy, suggestibility, and response to treatment in a trial of escitalopram and investigational drug, COMP360, psilocybin, in the treatment of major depressive disorder (ClinicalTrials.gov registration: NCT03429075). Methods We used data ( n = 55) from our recent double-blind, parall...

5-MeO-DMT is a tryptamine being developed as a potential antidepressant that may display a distinct therapeutic mechanism due to its unique pharmacology and subjective effects compared to typical psychedelics. In this article, we parallel the relatively distinct phenomenology and behavioral effects of the acute and post-acute effects of 5-MeO-DMT t...

Application of complexity measures to neurophysiological time series has seen increased use in recent years to identify neural correlates of global states of consciousness. Lempel-Ziv complexity is currently the de-facto complexity measure used in these investigations. However, by simply counting the number of patterns, this measure theoretically t...

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 in...

UNSTRUCTURED This study demonstrates that changes in mindfulness predict subsequent changes in well-being in a data set including individuals who recently engaged in psychedelic use.

A growing body of work shows that autonomic signals provide a privileged evidence stream to capture various aspects of subjective and neural states. This work investigates the potential for autonomic markers to track the effects of psychedelics - potent psychoactive drugs with important scientific and clinical value. For this purpose, we introduce...

N,N‐dimethyltryptamine (DMT) is a psychedelic compound that is being studied as a therapeutic option in various psychiatric disorders. Due to its short half‐life, continuous infusion of DMT has been proposed to extend the psychedelic experience and potential therapeutic effects. The primary aim of this work was to design an infusion protocol for DM...

1 Summary The relationship between the acute effects of psychedelics and their persisting neurobiological and psychological effects is poorly understood. Here, we tracked brain changes with longitudinal precision functional mapping in healthy adults before, during, and for up to 3 weeks after oral psilocybin and methylphenidate (17 MRI visits per...

Rationale Therapeutic administration of psychedelics has shown significant potential in historical accounts and recent clinical trials in the treatment of depression and other mood disorders. A recent randomized double-blind phase-IIb study demonstrated the safety and efficacy of COMP360, COMPASS Pathways’ proprietary synthetic formulation of psilo...

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...

In medical trials, ‘blinding’ ensures the equal distribution of expectancy effects between treatment arms in theory; however, blinding often fails in practice. We use computational modelling to show how weak blinding, combined with positive treatment expectancy, can lead to an uneven distribution of expectancy effects. We call this ‘activated expec...

We conducted a meta-analysis using individual participant data from three, two-dose psilocybin trials for depression (N=102) with the aim of assessing the risk of symptom worsening. Clinically significant symptom worsening occurred for a minority of participants in the psilocybin and escitalopram conditions (∼10%) and for a majority of participants...

Recent research has demonstrated the potential of psychedelic therapy for mental health care. However, the psychological experience underlying its therapeutic effects remains poorly understood. This paper proposes a framework that suggests psychedelics act as destabilizers, both psychologically and neurophysiologically. Drawing on the ‘entropic bra...

Mystical experiences and ego dissolution are essential to understanding the lasting psychological effects of psychedelics or even natural religious experience. The main objective of the article is to present evidence of construct validity in the adaptation to Brazilian Portuguese of the Hood Mysticism Scale (HMS) and the Ego-Dissolution Inventory (...

N,N-dimethyltryptamine (DMT) is a psychedelic substance and is being used as a research tool in investigations of the neurobiology behind the human consciousness using different brain imaging techniques. The effects of psychedelics have commonly been studied using EEG and have been shown to produce suppression of alpha power and increase in signal...

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...

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...

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...

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...

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...

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:...

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...

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...

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...

Background: Therapeutic administration of psychedelic drugs has shown significant potential in historical accounts and in recent clinical trials in the treatment of depression and other mood disorders. A recent randomized double-blind phase-IIb study demonstrated the safety and efficacy of COMP360, COMPASS Pathways’ proprietary synthetic formulatio...

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...

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...

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...

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...

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...

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...

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...

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...

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...

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...

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...

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...

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...

This document details an authors' response to a critique of their work entitled: Skepticism About Recent Evidence that Psilocybin Opens Depressed Minds.

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...

Background: 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. Methods: Qualitative analysis of all N, N-DMT experiences posted to the r/DMT Red...

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...

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...

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...

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...

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...

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...

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...

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...

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...

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...

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...

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...

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...

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...

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...