Robin L Carhart-Harris

Imperial College London | Imperial · Division of Experimental Medicine

Psychedelic drugs such as psilocybin and ketamine are returning to clinical research and intervention across several disorders including the treatment of depression. This chapter focusses on psychedelics that specifically target the 5-HT2A receptor such as psilocybin and DMT. These produce plasma-concentration related psychological effects such as...

N,N-Dimethyltryptamine (DMT) is a serotonergic psychedelic that induces a rapid and transient altered state of consciousness when inhaled or injected via bolus administration. Its marked and novel subjective effects make DMT a powerful tool for the neuroscientific study of consciousness and preliminary results show its potential role in treating me...

Background: Resurgent psychedelic research has largely supported the safety and efficacy of psychedelic therapy for the treatment of various psychiatric disorders. As psychedelic use and therapy increases in prevalence, so does the importance of understanding associated risks. Cases of prolonged negative psychological responses to psychedelic thera...

Serotonergic psychedelics induce altered states of consciousness and have shown potential in treating a variety of neuropsychiatric disorders, including depression and addiction. Yet their modes of action are currently not fully understood. Here, we provide three systematic reviews and meta-analyses of three hierarchical levels relevant to the effe...

Abstract Recent controversies have arisen regarding claims of uncritical positive regard and hype surrounding psychedelic drugs and their therapeutic potential. Criticisms have included that study designs and reporting styles bias positive over negative outcomes. The present study was motivated by a desire to address this alleged bias by intentiona...

Integrating independent but converging lines of research on brain function and neurodevelopment across scales, this article proposes that serotonin 2A receptor (5-HT2AR) signaling is an evolutionary and developmental driver and potent modulator of the macroscale functional organization of the human cerebral cortex. A wealth of evidence indicates th...

Quantifying the complexity of neural activity has provided fundamental insights into cognition, consciousness, and clinical conditions. However, the most widely used approach to estimate the complexity of neural dynamics, Lempel-Ziv complexity (LZ), has fundamental limitations that substantially restrict its domain of applicability. In this article...

Quantifying the complexity of neural activity has provided fundamental insights into cognition, consciousness, and clinical conditions. However, the most widely used approach to estimate the complexity of neural dynamics, Lempel-Ziv complexity (LZ), has fundamental limitations that substantially restrict its domain of applicability. In this article...

Psilocybin and lysergic acid diethylamide (LSD) experiences can range from very positive to highly challenging (e.g., fear, grief, and paranoia). These challenging experiences contribute to hesitancy toward psychedelic-assisted psychotherapy among health care providers and patients. Co-use of 3,4-Methylenedioxy methamphetamine (MDMA) with psilocybi...

A central goal of neuroscience is to understand how the brain orchestrates information from multiple input streams into a unified conscious experience. Here, we address two fundamental questions: how is the human information-processing architecture functionally organised, and how does its organisation support consciousness? We combine network scien...

A central goal of neuroscience is to understand how the brain orchestrates information from multiple input streams into a unified conscious experience. Here, we address two fundamental questions: how is the human information-processing architecture functionally organised, and how does its organisation support consciousness? We combine network scien...

Background: Lysergic acid diethylamide (LSD) is an atypical psychedelic compound exerting 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. Methods:...

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...

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)...

Background: Psilocybin Therapy (PT) is being increasingly studied as a psychiatric intervention. Personality relates to mental health and can be used to probe the nature of PT's therapeutic action. Methods: In a phase 2, double-blind, randomized, active comparator controlled trial involving patients with moderate-to-severe major depressive disor...

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...

Background: Psilocybin therapy is receiving attention as a mental health intervention with transdiagnostic potential. In line with psychotherapeutic research, qualitative research has highlighted the role of reductions in experiential avoidance (and increases in connectedness) within psilocybin therapy. However, no quantitative research has examine...

Background In a recent clinical trial examining the comparative efficacy of psilocybin therapy (PT) versus escitalopram treatment (ET) for major depressive disorder, 14 of 16 major efficacy outcome measures yielded results that favored PT, but the Quick Inventory of Depressive Symptomatology, Self-Report, 16 items (QIDS-SR 16 ) did not. Aims The p...

Following decades of prohibition, psychedelic drugs are returning to mainstream psychiatry and neuroscience. When paired with psychotherapy and administered in a supportive context, so-called psychedelic therapy shows promise in treating depression, anxiety, substance misuse, and end-of-life distress. Large therapeutic effect sizes and positive saf...

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...

Background: 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. Methods:...

Quantifying the complexity of neural activity has provided fundamental insights into cognition, consciousness, and clinical conditions. However, the most widely used approach to estimate the complexity of neural dynamics, Lempel-Ziv complexity (LZ), has fundamental limitations that substantially restrict its domain of applicability. In this article...

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)...

Recent findings suggesting the potential transdiagnostic efficacy of psychedelic-assisted therapy have fostered the need to deepen our understanding of psychedelic brain action. Functional neuroimaging investigations have found that psychedelics reduce the functional segregation of large-scale brain networks. However, beyond this general trend, fin...

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 s...

Background: Past research reports a positive relationship between experience with classic serotonergic psychedelics and nature relatedness (NR). However, these studies typically do not distinguish between different psychedelic compounds, which have a unique psychopharmacology and may be used in specific contexts and with different intentions. Like...

Abstract Background: Past research reports a positive relationship between experience with classic serotonergic psychedelics and nature relatedness (NR). However, these studies typically do not distinguish between different psychedelic compounds, which have a unique psychopharmacology and may be used in specific contexts and with different intent...

Scientific theories on the functioning and dysfunction of the human brain require an understanding of its development—before and after birth and through maturation to adulthood—and its evolution. Here we bring together several accounts of human brain evolution by focusing on the central role of oxygen and brain metabolism. We argue that evolutionar...

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...

Background The non-selective serotonin 2A (5-HT 2A ) receptor agonist lysergic acid diethylamide (LSD) holds promise as a treatment for some psychiatric disorders. Psychedelic drugs such as LSD have been suggested to have therapeutic actions through their effects on learning. The behavioural effects of LSD in humans, however, remain incompletely un...

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...

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...

Schizophrenia and states induced by certain psychotomimetic drugs may share some physiological and phenomenological properties, but they differ in fundamental ways: one is a crippling chronic mental disease, while the others are temporary, pharmacologically-induced states presently being explored as treatments for mental illnesses. Building towards...

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 18...

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...

Emergence is a profound subject that straddles many scientific disciplines, including the formation of galaxies and how consciousness arises from the collective activity of neurons. Despite the broad interest that exists on this concept, the study of emergence has suffered from a lack of formalisms that could be used to guide discussions and advanc...

Rationale Classic psychedelics are currently being studied as novel treatments for a range of psychiatric disorders. However, research on how psychedelics interact with other psychoactive substances remains scarce. Objectives The current study aimed to explore the subjective effects of psychedelics when used alongside cannabis. Methods Participan...

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...

Schizophrenia and states induced by certain psychotomimetic drugs may share some physiological and phenomenological properties, but they differ in fundamental ways: one is a crippling chronic mental disease, while the others are temporary, pharmacologically-induced states presently being explored as treatments for mental illnesses. Building towards...

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...

The present study examines prospective changes in personality traits relevant to social functioning as well as perceived social connectedness in relation to the naturalistic use of psychedelic compounds in an online volunteer sample. The study also examined the degree to which demographic characteristics, social setting, baseline personality, and a...

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, c...

A central question in neuroscience concerns the relationship between consciousness and its physical substrate. Here, we argue that a richer characterization of consciousness can be obtained by viewing it as constituted of distinct information-theoretic elements. In other words, we propose a shift from quantification of consciousness—viewed as integ...

Emergence is a profound subject that straddles many scientific disciplines, including the formation of galaxies and how consciousness arises from the collective activity of neurons. Despite the broad interest that exists on this concept, the study of emergence has suffered from a lack of formalisms that could be used to guide discussions and advanc...

Background: Anorexia nervosa (AN) is a serious and life-threatening psychiatric condition. With a paucity of approved treatments, there is a desperate need for novel treatment avenues to be explored. Here, we present (1) an overview of the ways through which Public Patient Involvement (PPI) has informed a trial of psilocybin-assisted therapy for AN...

Complex systems, from the human brain to the global economy, are made of multiple elements that interact in such ways that the behaviour of the `whole' often seems to be more than what is readily explainable in terms of the `sum of the parts.' Our ability to understand and control these systems remains limited, one reason being that we still don't...

In the last 15 years, psychedelic substances, such as LSD and psilocybin, have regained legitimacy in clinical research. In the general population as well as across various psychiatric populations, mental well-being has been found to significantly improve after a psychedelic experience. Mental well-being has large socioeconomic relevance, but it is...

Healthful behaviours 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—is cons...

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. The RElaxed Beliefs Under Psychedelics (REBUS) model postulates that 5-HT2a receptor agonism allows the brain to explore its dynam...

Favourable regulatory assessments, liberal policy changes, new research centres and substantial commercial investment signal that psychedelic therapy is making a major comeback. Positive findings from modern trials are catalysing developments, but it is questionable whether current confirmatory trials are sufficient for advancing our understanding...

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 redu...

Microdosing is the practice of regularly using low doses of psychedelic drugs. Anecdotal reports suggest that microdosing enhances well-being and cognition; however, such accounts are potentially biased by the placebo effect. This study used a ‘self-blinding’ citizen science initiative, where participants were given online instructions on how to in...

Microdosing is the practice of regularly using low doses of psychedelic drugs. Anecdotal reports suggest that microdosing enhances well-being and cognition; however, such accounts are potentially biased by the placebo effect. This study used a ‘self-blinding’ citizen science initiative, where participants were given online instructions on how to in...

Objective To conduct a systematic review of modern‐era (post‐millennium) clinical studies assessing the therapeutic effects of serotonergic psychedelics drugs for mental health conditions. Although the main focus was on efficacy and safety, study characteristics, duration of antidepressants effects across studies, and the role of the subjective dr...

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 neurobiolo...

A central question in neuroscience concerns the relationship between consciousness and its physical substrate. Here, we argue that a richer characterisation of consciousness can be obtained by viewing it not as a monolithic construct, but rather as constituted of distinct information-theoretic elements. In other words, we propose a shift from quant...

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...

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...

Serotonergic psychedelics have been suggested to mirror certain aspects of psychosis, and, more generally, elicit a state of consciousness underpinned by increased entropy of on-going neural activity. We investigated the hypothesis that language produced under the effects of lysergic acid diethylamide (LSD) should exhibit increased entropy and redu...

Most biological brains, as well as artificial neural networks, are capable of performing multiple tasks [1]. The mechanisms through which simultaneous tasks are performed by the same set of units are not yet entirely clear. Such systems can be modular or mixed selective through some variables such as sensory stimulus [2,3]. Based on simple tasks st...

The broad concept of emergence is instrumental in various of the most challenging open scientific questions—yet, few quantitative theories of what constitutes emergent phenomena have been proposed. This article introduces a formal theory of causal emergence in multivariate systems, which studies the relationship between the dynamics of parts of a s...

The non-selective serotonin 2A (5-HT 2A ) receptor agonist lysergic acid diethylamide (LSD) holds promise as a treatment for some psychiatric disorders. Psychedelic drugs such as LSD have been suggested to have therapeutic actions through their effects on learning. The behavioural effects of LSD in humans, however, remain largely unexplored. Here w...

Therapeutic psychedelic administration and contact with nature have been associated with the same psychological mechanisms: decreased rumination and negative affect, enhanced psychological connectedness and mindfulness-related capacities, and heightened states of awe and transcendent experiences, all processes linked to improvements in mental healt...

A central goal of neuroscience is to understand how the brain orchestrates information from multiple input streams into a unified conscious experience. Here, we address two fundamental questions: how is the human information-processing architecture functionally organised, and how does its organisation support consciousness? We combine network scien...

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, gathering large-scale naturalistic data from psychedelic users prospectively, i.e. before and after use of a psychedelic...

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...