Psychedelic therapy has witnessed a resurgence in interest in the last decade from the scientific... more 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 imag...
Psilocybin therapy is an emerging intervention for depression that may be at least as effective a... more 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...
Background Psilocybin Therapy (PT) is being increasingly studied as a psychiatric intervention. P... more 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 disorder, we compared psilocybin with escitalopram, over a core 6-week trial period. Five-Factor model personality domains, Big Five Aspect Scale Openness aspects, Absorption, and Impulsivity were measured at Baseline, Week 6, and Month 6 follow-up. Results PT was associated with decreases in neuroticism (B = −0.63), introversion (B = −0.38), disagreeableness (B = −0.47), impulsivity (B = −0.40), and increases in absorption (B = 0.32), conscientiousness (B = 0.30), and openness (B = 0.23) at week 6, with neuroticism (B = −0.47) and disagreeableness (B = −0.41) remaining decreased at month 6. Escitalopram Treatment (ET) was associated with decrea...
Background: Recent controversies have arisen regarding claims of uncritical positive regard and h... more Background: 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.Aim: The present study was motivated by a desire to address this alleged bias by intentionally focusing exclusively on negative outcomes, defined as self-perceived ‘negative’ psychological responses lasting for at least 72 hours after psychedelic use. A strong justification for this selective focus was that it might improve our ability to capture otherwise missed cases of negative response, enabling us to validate their existence and better examine their nature, as well as possible causes, which could inspire risk-mitigation strategies. Methods: Via advertisements posted on social media, individuals were recruited who reported experiencing negative psychological responses to psychedelics (defined as classic psychedelics p...
Classic psychedelics are compounds that target the 5-hydroxytryptamine receptor type 2A (5-HT2AR)... more Classic psychedelics are compounds that target the 5-hydroxytryptamine receptor type 2A (5-HT2AR), inducing profound changes in consciousness. Although these compounds most closely resemble the natural neurotransmitter serotonin, their therapeutic and psychoactive action is still not well understood. Therefore, a quantitative atomistic description of their interaction in the 5-HT2AR receptor is required to shed light into their mode of action. In this work, we performed a computational characterization of the orthosteric binding pocket for classical and photoswitchable psychedelics by means of semi-flexible molecular docking, classical molecular dynamics and binding free energy computations to identify the interactions with the key protein residues. Two nearly degenerate binding poses were observed inside the orthosteric pocket. 5-HT (5-hydroxytryptamine) and LSD (lysergic acid diethylamide) show a preference for the canonical crystallized pose of the 5-HT2AR-LSD structure, in contr...
Psychedelic therapy (PT) is an emerging paradigm with great transdiagnostic potential for treatin... more Psychedelic therapy (PT) is an emerging paradigm with great transdiagnostic potential for treating a range of psychiatric disorders, including depression, addiction, eating disorders, post-traumatic stress disorder, and others. ‘Classic’ serotonergic psychedelics, such as psilocybin, lysergic acid diethylamide (LSD), N, N-Dimethyltryptamine (DMT) and 5-methoxy-N,N-dimethyltryptamine (5-MeO-DMT), form the main focus of this movement, but other substances including ketamine, 3,4-Methylenedioxymethamphetamine (MDMA) and ibogaine also hold promise. The development of these novel treatment modalities in the early 21st century has occurred concurrently with the wider use of advanced human neuroscientific research methods; principally neuroimaging. This has enabled assessment of drug and therapy brain effects with greater precision and quantification than any previous novel development in psychiatric pharmacology. We outline some of the major trends in existing data and suggest that the mo...
Background: Across psychotherapeutic frameworks, the strength of the therapeutic alliance has bee... more 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 psychedelic experience and treatment outcomes.Methods: This 2-arm double-blind randomized controlled trial compared escitalopram with psychedelic-assisted therapy for moderate-severe depressive disorder (N = 59). This analysis focused on the psilocybin condition (n = 30), who received two oral doses of 25 mg psilocybin, 3-weeks apart, with psychological preparation, in-session support, and integration therapy. A new psychedelic therapy model, called “Accept-Connect-Embody” (ACE), was developed in this trial. The primary outcome was depression severity 6 weeks post treatment (Quick Inventory of Depressive Symptomatology, QIDS-SR-16). Path anal...
Healthful behaviors such as maintaining a balanced diet, being physically active, and refraining ... more 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 - is considerable. Consequently, interventions designed to promote healthy behaviors are increasingly being studied, e.g. using psychobiological models of behavioral regulation and change. In this article, we explore the notion that psychedelic substances such as psilocybin could be used to assist in promoting positive lifestyle change conducive to good overall health. Psilocybin has a low toxicity, is non-addictive, and has been shown to predict favorable changes in patients with depression, anxiety, and other conditions marked by rigid behavioral patterns, including substance (mis)use. While it is still early days for modern psychedelic sci...
Supplemental material, MDMA_Prosocial_Effects_Supplementary_revision_submission for Acute effects... more Supplemental material, MDMA_Prosocial_Effects_Supplementary_revision_submission for Acute effects of MDMA on trust, cooperative behaviour and empathy: A double-blind, placebo-controlled experiment by Anna Borissova, Bart Ferguson, Matthew B Wall, Celia JA Morgan, Robin L Carhart-Harris, Mark Bolstridge, Michael AP Bloomfield, Tim M Williams, Amanda Feilding, Kevin Murphy, Robin J Tyacke, David Erritzoe, Lorna Stewart, Kim Wolff, David Nutt, H Valerie Curran and Will Lawn in Journal of Psychopharmacology
Poor behavioral inhibition is a common feature of neurological and psychiatric disorders. Success... more Poor behavioral inhibition is a common feature of neurological and psychiatric disorders. Successful inhibition of a prepotent response in ‘NoGo ’ paradigms requires the integrity of both the inferior frontal gyrus (IFG) and the serotonergic system. We investigated individual differences in serotonergic regulation of response inhibition. In 24 healthy adults, we used 18F-altanserin positron emission tomography to assess cerebral 5-HT2A receptors, which have been related to impulsivity. We then investigated the impact of two acute manipulations of brain serotonin levels on behavioral and neural correlates of inhibition using intravenous citalopram and acute tryptophan depletion during functional magnetic resonance imaging. We adapted the NoGo paradigm to isolate effects on inhibition per se as opposed to other aspects of the NoGo paradigm. Successful NoGo inhibition was associated with greater activation of the right IFG compared to control trials with alternative responses, indicati...
The present study examines prospective changes in personality traits relevant to social functioni... more 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 acute subjective factors (e.g., emotional breakthrough experiences) influenced trajectories of personality and perceived social connectedness. Participants recruited online completed self-report measures of personality and social connectedness at three timepoints (baseline, 2weeks post-experience, 4weeks post-experience). Linear mixed models were used to examine changes in outcomes and the moderation of these outcomes by covariates. The most substantive changes were reductions in the personality domains Neuroticism, and increases in Agreeableness and social connectedness. Notably, reductions in Neuroticism and increases in Agreeableness cov...
Importance Psilocybin therapy shows antidepressant potential; our data link its antidepressant ef... more 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 da...
Healthful behaviours such as maintaining a balanced diet, being physically active and refraining ... more 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 considerable. Consequently, interventions designed to promote healthy behaviours are increasingly being studied, e.g., using psychobiological models of behavioural regulation and change. In this article, we explore the notion that psychedelic substances such as psilocybin could be used to assist in promoting positive lifestyle change conducive to good overall health. Psilocybin has a low toxicity, is non-addictive and has been shown to predict favourable changes in patients with depression, anxiety and other conditions marked by rigid behavioural patterns, including substance (mis)use. While it is still early days for modern psychedelic scienc...
Studying transitions in and out of the altered state of consciousness caused by intravenous (IV) ... more 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 particular...
Psychedelic therapy has witnessed a resurgence in interest in the last decade from the scientific... more 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 imag...
Psilocybin therapy is an emerging intervention for depression that may be at least as effective a... more 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...
Background Psilocybin Therapy (PT) is being increasingly studied as a psychiatric intervention. P... more 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 disorder, we compared psilocybin with escitalopram, over a core 6-week trial period. Five-Factor model personality domains, Big Five Aspect Scale Openness aspects, Absorption, and Impulsivity were measured at Baseline, Week 6, and Month 6 follow-up. Results PT was associated with decreases in neuroticism (B = −0.63), introversion (B = −0.38), disagreeableness (B = −0.47), impulsivity (B = −0.40), and increases in absorption (B = 0.32), conscientiousness (B = 0.30), and openness (B = 0.23) at week 6, with neuroticism (B = −0.47) and disagreeableness (B = −0.41) remaining decreased at month 6. Escitalopram Treatment (ET) was associated with decrea...
Background: Recent controversies have arisen regarding claims of uncritical positive regard and h... more Background: 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.Aim: The present study was motivated by a desire to address this alleged bias by intentionally focusing exclusively on negative outcomes, defined as self-perceived ‘negative’ psychological responses lasting for at least 72 hours after psychedelic use. A strong justification for this selective focus was that it might improve our ability to capture otherwise missed cases of negative response, enabling us to validate their existence and better examine their nature, as well as possible causes, which could inspire risk-mitigation strategies. Methods: Via advertisements posted on social media, individuals were recruited who reported experiencing negative psychological responses to psychedelics (defined as classic psychedelics p...
Classic psychedelics are compounds that target the 5-hydroxytryptamine receptor type 2A (5-HT2AR)... more Classic psychedelics are compounds that target the 5-hydroxytryptamine receptor type 2A (5-HT2AR), inducing profound changes in consciousness. Although these compounds most closely resemble the natural neurotransmitter serotonin, their therapeutic and psychoactive action is still not well understood. Therefore, a quantitative atomistic description of their interaction in the 5-HT2AR receptor is required to shed light into their mode of action. In this work, we performed a computational characterization of the orthosteric binding pocket for classical and photoswitchable psychedelics by means of semi-flexible molecular docking, classical molecular dynamics and binding free energy computations to identify the interactions with the key protein residues. Two nearly degenerate binding poses were observed inside the orthosteric pocket. 5-HT (5-hydroxytryptamine) and LSD (lysergic acid diethylamide) show a preference for the canonical crystallized pose of the 5-HT2AR-LSD structure, in contr...
Psychedelic therapy (PT) is an emerging paradigm with great transdiagnostic potential for treatin... more Psychedelic therapy (PT) is an emerging paradigm with great transdiagnostic potential for treating a range of psychiatric disorders, including depression, addiction, eating disorders, post-traumatic stress disorder, and others. ‘Classic’ serotonergic psychedelics, such as psilocybin, lysergic acid diethylamide (LSD), N, N-Dimethyltryptamine (DMT) and 5-methoxy-N,N-dimethyltryptamine (5-MeO-DMT), form the main focus of this movement, but other substances including ketamine, 3,4-Methylenedioxymethamphetamine (MDMA) and ibogaine also hold promise. The development of these novel treatment modalities in the early 21st century has occurred concurrently with the wider use of advanced human neuroscientific research methods; principally neuroimaging. This has enabled assessment of drug and therapy brain effects with greater precision and quantification than any previous novel development in psychiatric pharmacology. We outline some of the major trends in existing data and suggest that the mo...
Background: Across psychotherapeutic frameworks, the strength of the therapeutic alliance has bee... more 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 psychedelic experience and treatment outcomes.Methods: This 2-arm double-blind randomized controlled trial compared escitalopram with psychedelic-assisted therapy for moderate-severe depressive disorder (N = 59). This analysis focused on the psilocybin condition (n = 30), who received two oral doses of 25 mg psilocybin, 3-weeks apart, with psychological preparation, in-session support, and integration therapy. A new psychedelic therapy model, called “Accept-Connect-Embody” (ACE), was developed in this trial. The primary outcome was depression severity 6 weeks post treatment (Quick Inventory of Depressive Symptomatology, QIDS-SR-16). Path anal...
Healthful behaviors such as maintaining a balanced diet, being physically active, and refraining ... more 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 - is considerable. Consequently, interventions designed to promote healthy behaviors are increasingly being studied, e.g. using psychobiological models of behavioral regulation and change. In this article, we explore the notion that psychedelic substances such as psilocybin could be used to assist in promoting positive lifestyle change conducive to good overall health. Psilocybin has a low toxicity, is non-addictive, and has been shown to predict favorable changes in patients with depression, anxiety, and other conditions marked by rigid behavioral patterns, including substance (mis)use. While it is still early days for modern psychedelic sci...
Supplemental material, MDMA_Prosocial_Effects_Supplementary_revision_submission for Acute effects... more Supplemental material, MDMA_Prosocial_Effects_Supplementary_revision_submission for Acute effects of MDMA on trust, cooperative behaviour and empathy: A double-blind, placebo-controlled experiment by Anna Borissova, Bart Ferguson, Matthew B Wall, Celia JA Morgan, Robin L Carhart-Harris, Mark Bolstridge, Michael AP Bloomfield, Tim M Williams, Amanda Feilding, Kevin Murphy, Robin J Tyacke, David Erritzoe, Lorna Stewart, Kim Wolff, David Nutt, H Valerie Curran and Will Lawn in Journal of Psychopharmacology
Poor behavioral inhibition is a common feature of neurological and psychiatric disorders. Success... more Poor behavioral inhibition is a common feature of neurological and psychiatric disorders. Successful inhibition of a prepotent response in ‘NoGo ’ paradigms requires the integrity of both the inferior frontal gyrus (IFG) and the serotonergic system. We investigated individual differences in serotonergic regulation of response inhibition. In 24 healthy adults, we used 18F-altanserin positron emission tomography to assess cerebral 5-HT2A receptors, which have been related to impulsivity. We then investigated the impact of two acute manipulations of brain serotonin levels on behavioral and neural correlates of inhibition using intravenous citalopram and acute tryptophan depletion during functional magnetic resonance imaging. We adapted the NoGo paradigm to isolate effects on inhibition per se as opposed to other aspects of the NoGo paradigm. Successful NoGo inhibition was associated with greater activation of the right IFG compared to control trials with alternative responses, indicati...
The present study examines prospective changes in personality traits relevant to social functioni... more 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 acute subjective factors (e.g., emotional breakthrough experiences) influenced trajectories of personality and perceived social connectedness. Participants recruited online completed self-report measures of personality and social connectedness at three timepoints (baseline, 2weeks post-experience, 4weeks post-experience). Linear mixed models were used to examine changes in outcomes and the moderation of these outcomes by covariates. The most substantive changes were reductions in the personality domains Neuroticism, and increases in Agreeableness and social connectedness. Notably, reductions in Neuroticism and increases in Agreeableness cov...
Importance Psilocybin therapy shows antidepressant potential; our data link its antidepressant ef... more 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 da...
Healthful behaviours such as maintaining a balanced diet, being physically active and refraining ... more 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 considerable. Consequently, interventions designed to promote healthy behaviours are increasingly being studied, e.g., using psychobiological models of behavioural regulation and change. In this article, we explore the notion that psychedelic substances such as psilocybin could be used to assist in promoting positive lifestyle change conducive to good overall health. Psilocybin has a low toxicity, is non-addictive and has been shown to predict favourable changes in patients with depression, anxiety and other conditions marked by rigid behavioural patterns, including substance (mis)use. While it is still early days for modern psychedelic scienc...
Studying transitions in and out of the altered state of consciousness caused by intravenous (IV) ... more 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 particular...
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Papers by David Erritzoe