Imperial College London

Professor Robin Carhart-Harris

Faculty of MedicineDepartment of Brain Sciences

Visiting Professor
 
 
 
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Contact

 

+44 (0)20 7594 7992r.carhart-harris

 
 
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Assistant

 

Miss Bruna Cunha +44 (0)20 7594 7992

 
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Location

 

Burlington DanesHammersmith Campus

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Summary

 

Publications

Publication Type
Year
to

238 results found

Copa D, Erritzoe D, Giribaldi B, Nutt D, Carhart-Harris R, Tagliazucchi Eet al., 2024, Predicting the outcome of psilocybin treatment for depression from baseline fMRI functional connectivity., J Affect Disord, Vol: 353, Pages: 60-69

BACKGROUND: Psilocybin is a serotonergic psychedelic drug under assessment as a potential therapy for treatment-resistant and major depression. Heterogeneous treatment responses raise interest in predicting the outcome from baseline data. METHODS: A machine learning pipeline was implemented to investigate baseline resting-state functional connectivity measured with functional magnetic resonance imaging (fMRI) as a predictor of symptom severity in psilocybin monotherapy for treatment-resistant depression (16 patients administered two 5 mg capsules followed by 25 mg, separated by one week). Generalizability was tested in a sample of 22 patients who participated in a psilocybin vs. escitalopram trial for moderate-to-severe major depression (two separate doses of 25 mg of psilocybin 3 weeks apart plus 6 weeks of daily placebo vs. two separate doses of 1 mg of psilocybin 3 weeks apart plus 6 weeks of daily oral escitalopram). The analysis was repeated using both samples combined. RESULTS: Functional connectivity of visual, default mode and executive networks predicted early symptom improvement, while the salience network predicted responders up to 24 weeks after treatment (accuracy≈0.9). Generalization performance was borderline significant. Consistent results were obtained from the combined sample analysis. Fronto-occipital and fronto-temporal coupling predicted early and late symptom reduction, respectively. LIMITATIONS: The number of participants and differences between the two datasets limit the generalizability of the findings, while the lack of a placebo arm limits their specificity. CONCLUSIONS: Baseline neurophysiological measurements can predict the outcome of psilocybin treatment for depression. Future research based on larger datasets should strive to assess the generalizability of these predictions.

Journal article

Peill J, Marguilho M, Erritzoe D, Barba T, Greenway KT, Rosas F, Timmermann C, Carhart-Harris Ret al., 2024, Psychedelics and the 'inner healer': Myth or mechanism?, J Psychopharmacol

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 body, for example, after sickness or injury. AIMS: Here, we sought to test and critique this idea by devising a single subjective rating item pertaining to perceived 'inner healing' effects. METHODS: The item was issued to 59 patients after a single high (25 mg, n = 30) or 'placebo' (1 mg, n = 29) dose of psilocybin in a double-blind randomised controlled trial of psilocybin for depression. RESULTS: Inner healer scores were higher after the high versus placebo dose of psilocybin (t = 3.88, p < 0.001). Within the high-dose sub-sample only, inner healer scores predicted improved depressive symptomatology at 2 weeks post-dosing. CONCLUSIONS: The principle of activating inner healing mechanisms via psychedelics is scientifically nascent; however, this study takes a positivist and pragmatic step forward, asking whether it warrants further examination.

Journal article

Luppi AI, Rosas FE, Noonan MP, Mediano PAM, Kringelbach ML, Carhart-Harris RL, Stamatakis EA, Vernon AC, Turkheimer FEet al., 2024, Oxygen and the Spark of Human Brain Evolution: Complex Interactions of Metabolism and Cortical Expansion across Development and Evolution., Neuroscientist, Vol: 30, Pages: 173-198

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 evolutionary expansion of human transmodal association cortices exceeded the capacity of oxygen delivery by the vascular system, which led these brain tissues to rely on nonoxidative glycolysis for additional energy supply. We draw a link between the resulting lower oxygen tension and its effect on cytoarchitecture, which we posit as a key driver of genetic developmental programs for the human brain-favoring lower intracortical myelination and the presence of biosynthetic materials for synapse turnover. Across biological and temporal scales, this protracted capacity for neural plasticity sets the conditions for cognitive flexibility and ongoing learning, supporting complex group dynamics and intergenerational learning that in turn enabled improved nutrition to fuel the metabolic costs of further cortical expansion. Our proposed model delineates explicit mechanistic links among metabolism, molecular and cellular brain heterogeneity, and behavior, which may lead toward a clearer understanding of brain development and its disorders.

Journal article

Erritzoe D, Barba T, Spriggs MJ, Rosas FE, Nutt DJ, Carhart-Harris Ret al., 2024, Effects of discontinuation of serotonergic antidepressants prior to psilocybin therapy versus escitalopram for major depression., J Psychopharmacol

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 on efficacy, participants enrolling in psychedelic trials are usually required to discontinue SNRI/SNRIs prior to enrolling. AIMS: Using data from a recent clinical trial examining the comparative efficacy the psychedelic drug psilocybin (P) combined with approximately 20 h of psychological support to a 6-week (daily) course of the SSRI escitalopram plus matched psychological support for major depressive disorder, we explored the effects of discontinuing SSRI/SNRIs prior to study enrolment on study outcomes. METHODS: Exploratory post hoc analyses using linear mixed effects model were performed to investigate the discontinuation effect on various validated depression symptom severity scales and well-being. The impact of SSRI/SNRIs discontinuation on the acute psychedelic experience was also explored. RESULTS/OUTCOMES: In the psilocybin group, there was a reduced treatment effect on all outcome measures for SSRI/SNRIs discontinuers compared with unmedicated patients at trial entry. However, no effects of discontinuation on measures of the acute psychedelic experience were found. CONCLUSION: Discontinuation of SSRI/SNRIs before psilocybin might diminish response to treatment; however, as we did not test SSRI/SNRI continuation in our trial, we cannot infer such causation. Moreover, the exploratory nature of the analyses makes them hypothesis generating, and not confirmatory. A controlled trial of SSRI/SNRI discontinuation versus continuation prior to psilocybin is urgently required.

Journal article

Jones G, Herrmann F, Bear A, Carhart-Harris R, Kettner Het al., 2024, The Relationship Between Changes in Mindfulness and Subsequent Changes in Well-Being Following Psychedelic Use: Prospective Cohort Study., JMIR Form Res, Vol: 8

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.

Journal article

Kusudo K, Tani H, Yonezawa K, Nakajima S, Nour MM, Carhart-Harris R, Uchida Het al., 2024, Development of the Japanese version of the Ego-Dissolution Inventory (EDI)., Neuropsychopharmacol Rep, Vol: 44, Pages: 292-297

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 for measuring this phenomenon, no Japanese version has been available. This study aimed to develop a Japanese version of the EDI. METHODS: We adhered to the "Guidelines for Best Practices in the Translation and Cultural Modification Process for Patient-Reported Outcomes Instruments: Document from the ISPOR Committee on Translation and Cultural Modification" during our translation approach. Two Japanese psychiatrists independently conducted initial translations, and a consolidated version was achieved via mutual agreement. This version was then back-translated to English and assessed by the original authors for consistency. The repetitive modification process was conducted in continuous dialogues with the original authors until they accepted the concluding back-translated version. RESULTS: The finalized, approved back-translated version of the EDI is presented in the accompanying figure. In addition, the authorized Japanese version of the EDI is included in the Appendix. CONCLUSIONS: In this study, we successfully developed the Japanese version of the EDI. This instrument will assist in assessing ego-dissolution experiences associated with psychedelic-assisted therapy among Japanese speakers. Additional studies are necessary to evaluate the reliability and validity of this newly translated instrument.

Journal article

Marrocu A, Kettner H, Weiss B, Zeifman RJ, Erritzoe D, Carhart-Harris RLet al., 2024, Psychiatric risks for worsened mental health after psychedelic use., J Psychopharmacol, Vol: 38, Pages: 225-235

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 increase in prevalence, so does the importance of understanding associated risks. Cases of prolonged negative psychological responses to psychedelic therapy seem to be rare; however, studies are limited by biases and small sample sizes. The current analytical approach was motivated by the question of whether rare but significant adverse effects have been under-sampled in psychedelic research studies. METHODS: A "bottom margin analysis" approach was taken to focus on negative responders to psychedelic use in a pool of naturalistic, observational prospective studies (N = 807). We define "negative response" by a clinically meaningful decline in a generic index of mental health, that is, one standard error from the mean decrease in psychological well-being 4 weeks post-psychedelic use (vs pre-use baseline). We then assessed whether a history of diagnosed mental illness can predict negative responses. RESULTS: We find that 16% of the cohort falls into the "negative responder" subset. Parsing the sample by self-reported history of psychiatric diagnoses, results revealed a disproportionate prevalence of negative responses among those reporting a prior personality disorder diagnosis (31%). One multivariate regression model indicated a greater than four-fold elevated risk of adverse psychological responses to psychedelics in the personality disorder subsample (b = 1.425, p < 0.05). CONCLUSION: We infer that the presence of a personality disorder may represent an elevated risk for psychedelic use and hypothesize that the importance of psychological support and good therapeutic alliance may be increased in this population.

Journal article

Timmermann Slater CB, Zeifman R, Erritzoe D, Nutt D, Carhart-Harris Ret al., 2024, Effects of DMT on mental health outcomes in healthy volunteers, Scientific Reports, Vol: 14, ISSN: 2045-2322

Psilocybin, a serotonergic psychedelic, is being increasingly researched in clinical studies for the treatment of psychiatric disorders. The relatively lengthy duration of oral psilocybin’s acute effects (4–6 h) may have pragmatic and cost-effectiveness limitations. Here, we explored the effects of intravenous (IV) N,N-Dimethyltryptamine (DMT), a closely related, but faster-acting psychedelic intervention, on mental health outcomes in healthy volunteers. Data is reported from two separate analyses: (1) A comparison of mental health-related variables 1 week after 7, 14, 18, and 20 mg of IV DMT versus IV saline placebo (n = 13) and, (2) A prospective dataset assessing effects before versus 2 weeks after 20 mg of IV DMT (n = 17). Mental health outcomes included measures of depression severity (QIDS-SR16), trait anxiety (STAI-T), Neuroticism (NEO-FFI), wellbeing (WHO-5), meaning in life (MLQ), optimism (LOT-R), and gratitude (GQ-6). In both the prospective and placebo-controlled datasets, significant improvements in scores of depression were found 1–2 weeks after DMT administration. Significant reductions in trait Neuroticism were only found for the placebo-controlled sample. Finally, changes in depression and trait anxiety correlated with acute peak experiences (assessed via ‘Oceanic Boundlessness’). While the use of two separate cohorts in pooled analysis limits the generalizability of these correlational findings, these results suggest that DMT may reduce depressive symptomatology by inducing peak experiences. The short half-life of IV DMT and its potential for flexible dosing via controlled infusions makes it an appealing candidate for psychedelic medicine. Further research in clinical samples is needed to corroborate the therapeutic potential of DMT.

Journal article

Barba T, Kettner H, Radu C, Peill J, Roseman L, Nutt D, Erritzoe D, Carhart-Harris R, Cunha Bet al., 2024, Psychedelics and sexual functioning: a mixed-methods study, Scientific Reports, Vol: 14, ISSN: 2045-2322

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

Journal article

Mediano PAM, Rosas FE, Timmermann C, Roseman L, Nutt DJ, Feilding A, Kaelen M, Kringelbach ML, Barrett AB, Seth AK, Muthukumaraswamy S, Bor D, Carhart-Harris RLet al., 2024, Effects of External Stimulation on Psychedelic State Neurodynamics., ACS Chem Neurosci, Vol: 15, Pages: 462-471

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

Journal article

Barbut Siva J, Barba T, Kettner H, Kuc J, Nutt DJ, Carhart-Harris R, Erritzoe Det al., 2024, Interactions between classic psychedelics and serotonergic antidepressants: Effects on the acute psychedelic subjective experience, well-being and depressive symptoms from a prospective survey study., J Psychopharmacol, Vol: 38, Pages: 145-155

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 acute psychedelic effects and subsequent changes in well-being and depressive symptoms among 'SRI -' individuals (not on psychiatric medication) and 'SRI +' individuals (undergoing SRI treatment). METHODS: Using prospective survey data, the study employs multivariate analysis of covariance (MANCOVA) and linear mixed effect models to analyse subjective differences and changes in well-being and depressive symptoms pre- and post-psychedelic experiences. RESULTS: Results indicate that 'SRI -' participants experience significantly more intense subjective effects compared to 'SRI +' participants (F = 3.200, p = 0.016) in MANCOVA analysis. Further analysis reveals 'SRI -' individuals report stronger mystical (18.2% higher, p = 0.048), challenging (50.9% higher, p = 0.001) and emotional breakthrough experiences (31.9% higher, p = 0.02) than 'SRI +' individuals. No differences are observed in drug-induced visual effects (p = 0.19). Both groups exhibited similar improvements in well-being and depressive symptoms after the psychedelic experience. CONCLUSION: Individuals presumed to be on serotonergic antidepressants during psychedelic use display reduced subjective effects but similar antidepressant effects compared to those not undergoing SRI treatment. Further controlled research is needed to comprehend the interplay between serotonergic antidepressants and psychedelics, illuminating potential therapeutic benefits and limitations in clinical contexts.

Journal article

Szigeti B, Weiss B, Rosas FE, Erritzoe D, Nutt D, Carhart-Harris Ret al., 2024, Assessing expectancy and suggestibility in a trial of escitalopram v. psilocybin for depression., Psychol Med, Pages: 1-8

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, parallel-group, randomized head-to-head comparison trial of escitalopram and investigational drug, COMP360, psilocybin. Mixed linear models were used to investigate the association between pre-treatment efficacy-related expectations, as well as baseline trait suggestibility and absorption, and therapeutic response to both escitalopram and COMP360 psilocybin. RESULTS: Patients had significantly higher expectancy for psilocybin relative to escitalopram; however, expectancy for escitalopram was associated with improved therapeutic outcomes to escitalopram, expectancy for psilocybin was not predictive of response to psilocybin. Separately, we found that pre-treatment trait suggestibility was associated with therapeutic response in the psilocybin arm, but not in the escitalopram arm. CONCLUSIONS: Overall, our results suggest that psychedelic therapy may be less vulnerable to expectancy biases than previously suspected. The relationship between baseline trait suggestibility and response to psilocybin therapy implies that highly suggestible individuals may be primed for response to this treatment.

Journal article

Weiss B, Ginige I, Shannon L, Giribaldi B, Murphy-Beiner A, Murphy R, Baker-Jones M, Martell J, Nutt DJ, Carhart-Harris RL, Erritzoe Det al., 2024, Personality change in a trial of psilocybin therapy vs escitalopram treatment for depression, Psychological Medicine, Vol: 54, Pages: 178-192, ISSN: 0033-2917

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 decreases in neuroticism (B = −0.38), disagreeableness (B = −0.26), impulsivity (B = −0.35), and increases in openness (B = 0.28) at week 6, with neuroticism (B = −0.46) remaining decreased at month 6. No significant between-condition differences were observed.Conclusions:Personality changes across both conditions were in a direction consistent with improved mental health. With the possible exception of trait absorption, there were no compelling between-condition differences warranting conclusions regarding a selective action of PT (v. ET) on personality; however, post-ET changes in personality were significantly moderated by pre-trial positive expectancy for escitalopram, whereas expectancy did not moderate response to PT.

Journal article

Weiss B, Roseman L, Giribaldi B, Nutt DJ, Carhart-Harris RL, Erritzoe Det al., 2024, Unique Psychological Mechanisms Underlying Psilocybin Therapy Versus Escitalopram Treatment in the Treatment of Major Depressive Disorder, International Journal of Mental Health and Addiction, ISSN: 1557-1874

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

Journal article

Luppi AI, Girn M, Rosas FE, Timmermann C, Roseman L, Erritzoe D, Nutt DJ, Stamatakis EA, Spreng RN, Xing L, Huttner WB, Carhart-Harris RLet al., 2024, A role for the serotonin 2A receptor in the expansion and functioning of human transmodal cortex, Brain: a journal of neurology, Vol: 147, Pages: 56-80, ISSN: 0006-8950

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 that the anatomical and functional organization of the cortex follows a unimodal-to-transmodal gradient. Situated at the apex of this processing hierarchy - where it plays a central role in the integrative processes underpinning complex, human-defining cognition - the transmodal cortex has disproportionately expanded across human development and evolution. Notably, the adult human transmodal cortex is especially rich in 5-HT2AR expression, and recent evidence suggests that, during early brain development, 5-HT2AR signaling on neural progenitor cells stimulates their proliferation - a critical process for evolutionarily-relevant cortical expansion. Drawing on multimodal neuroimaging and cross-species investigations, we argue that, by contributing to the expansion of the human cortex, and being prevalent at the apex of its hierarchy in the adult brain, 5-HT2AR signaling plays a major role in both human cortical expansion and functioning. Due to its unique excitatory and downstream cellular effects, neuronal 5-HT2AR agonism promotes neuroplasticity, learning, and cognitive and psychological flexibility in a context-(hyper)sensitive manner with therapeutic potential. Overall, we delineate a dual role of 5-HT2ARs in enabling both the expansion and modulation of the human transmodal cortex.

Journal article

Luan LX, Eckernäs E, Ashton M, Rosas FE, Uthaug MV, Bartha A, Jagger S, Gascon-Perai K, Gomes L, Nutt DJ, Erritzøe D, Carhart-Harris RL, Timmermann Cet al., 2024, Psychological and physiological effects of extended DMT., J Psychopharmacol, Vol: 38, Pages: 56-67

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 mental health conditions. In a within-subjects, placebo-controlled study, we investigated a novel method of DMT administration involving a bolus injection paired with a constant-rate infusion, with the goal of extending the DMT experience. Pharmacokinetic parameters of DMT estimated from plasma data of a previous study of bolus intravenous DMT were used to derive dose regimens necessary to keep subjects in steady levels of immersion into the DMT experience over an extended period of 30 min, and four dose regimens consisting of a bolus loading dose and a slow-rate infusion were tested in eleven healthy volunteers (seven male, four female, mean age ± SD = 37.09 ± 8.93 years). The present method is effective for extending the DMT experience in a stable and tolerable fashion. While subjective effects were maintained over the period of active infusion, anxiety ratings remained low and heart rate habituated within 15 min, indicating psychological and physiological safety of extended DMT. Plasma DMT concentrations increased consistently starting 10 min into DMT administration, whereas psychological effects plateaued into the desired steady state, suggesting the development of acute psychological tolerance to DMT. Taken together, these findings demonstrate the safety and effectiveness of continuous IV DMT administration, laying the groundwork for the further development of this method of administration for basic and clinical research.

Journal article

Weiss B, Ginige I, Shannon L, Giribaldi B, Murphy-Beiner A, Murphy R, Baker-Jones M, Martell J, Nutt DJ, Carhart-Harris RL, Erritzoe Det al., 2024, Personality Change in a Trial of Psilocybin Therapy vs Escitalopram Treatment for Depression - CORRIGENDUM., Psychol Med, Vol: 54

Journal article

Vohryzek J, Cabral J, Lord L-D, Fernandes HM, Roseman L, Nutt DJ, Carhart-Harris RL, Deco G, Kringelbach MLet al., 2024, Brain dynamics predictive of response to psilocybin for treatment-resistant depression., Brain Commun, Vol: 6

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

Journal article

Delli Pizzi S, Chiacchiaretta P, Sestieri C, Ferretti A, Tullo MG, Della Penna S, Martinotti G, Onofrj M, Roseman L, Timmermann C, Nutt DJ, Carhart-Harris RL, Sensi SLet al., 2023, LSD-induced changes in the functional connectivity of distinct thalamic nuclei., Neuroimage, Vol: 283

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

Journal article

Savoldi R, Roazzi A, Escobar JAC, Nour MM, Carhart-Harris Ret al., 2023, The Structural Organization and Construct Validity Evidence of the Brazilian Versions of the Mysticism Scale and the Ego-Dissolution Inventory in a Major Religion of the Ayahuasca, International Journal of Latin American Religions, Vol: 7, Pages: 521-549

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 (EDI)-8 through two psychometric techniques: the smallest space analysis technique and the factorial analysis. Design: a cross-sectional survey. The sample consisted of 1414 members of the União do Vegetal religion. The smallest space analysis (SSA) identified three distinct regions in HMS: introversive mysticism, extroversive mysticism, and interpretation. The SSA for EDI-8 suggests four distinct regions, which were conceptualized as (1) loss of ego, (2) total dissolution, (3) ego quiet, and (4) internal–external unity. In addition, a confirmatory factor analysis (CFA) was used to test the factorial replicability of the HMS and EDI-8. The CFA presented acceptable support for the dimensional structures tested. Conclusion: Results show good reliability and validity indicators, which endorse the Portuguese HMS and EDI-8 application in future research.

Journal article

Bremler R, Katati N, Shergill P, Erritzoe D, Carhart-Harris Ret al., 2023, Case analysis of long-term negative psychological responses to psychedelics, Scientific Reports, Vol: 13, Pages: 1-15, ISSN: 2045-2322

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 intentionally focusing exclusively on negative outcomes, defined as self-perceived ‘negative’ psychological responses lasting for at least 72 h 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. Via advertisements posted on social media, individuals were recruited who reported experiencing negative psychological responses to psychedelics (defined as classic psychedelics plus MDMA) lasting for greater than 72 h since using. Volunteers were directed to an online questionnaire requiring quantitative and qualitative input. A key second phase of this study involved reviewing all of the submitted cases, identifying the most severe—e.g., where new psychiatric diagnoses were made or pre-existing symptoms made worse post psychedelic-use—and inviting these individuals to participate in a semi-structured interview with two members of our research team, during which participant experiences and backgrounds were examined in greater depth. Based on the content of these interviews, a brief summary of each case was compiled, and an explorative thematic analysis was used to identify salient and consistent themes and infer common causes. 32 individuals fully completed an onboarding questionnaire (56% male, 53% < age 25); 37.5% of completers had a psychiatric diagnosis that emerged after their psychedelic experience, and anxiety symptoms arose or worsened in 87%.

Journal article

Eckernas E, Koomen J, Timmermann C, Carhart-Harris R, Roshammar D, Ashton Met al., 2023, Optimized infusion rates for N,N-dimethyltryptamine to achieve a target psychedelic intensity based on a modeling and simulation framework, CPT-PHARMACOMETRICS & SYSTEMS PHARMACOLOGY, ISSN: 2163-8306

Journal article

Simonsson O, Carlbring P, Carhart-Harris R, Davis AK, Nutt DJ, Griffiths RR, Erritzoe D, Goldberg SBet al., 2023, Assessing the risk of symptom worsening in psilocybin-assisted therapy for depression: A systematic review and individual participant data meta-analysis, PSYCHIATRY RESEARCH, Vol: 327, ISSN: 0165-1781

Journal article

Dougherty RF, Clarke P, Atli M, Kuc J, Schlosser D, Dunlop BW, Hellerstein DJ, Aaronson ST, Zisook S, Young AH, Carhart-Harris R, Goodwin GM, Ryslik GAet al., 2023, Psilocybin therapy for treatment resistant depression: prediction of clinical outcome by natural language processing., Psychopharmacology (Berl)

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 psilocybin, in participants with treatment-resistant depression. OBJECTIVE: While the phase-IIb results are promising, the treatment works for a portion of the population and early prediction of outcome is a key objective as it would allow early identification of those likely to require alternative treatment. METHODS: Transcripts were made from audio recordings of the psychological support session between participant and therapist 1 day post COMP360 administration. A zero-shot machine learning classifier based on the BART large language model was used to compute two-dimensional sentiment (valence and arousal) for the participant and therapist from the transcript. These scores, combined with the Emotional Breakthrough Index (EBI) and treatment arm were used to predict treatment outcome as measured by MADRS scores. (Code and data are available at https://github.com/compasspathways/Sentiment2D .) RESULTS: Two multinomial logistic regression models were fit to predict responder status at week 3 and through week 12. Cross-validation of these models resulted in 85% and 88% accuracy and AUC values of 88% and 85%. CONCLUSIONS: A machine learning algorithm using NLP and EBI accurately predicts long-term patient response, allowing rapid prognostication of personalized response to psilocybin treatment and insight into therapeutic model optimization. Further research is required to understand if language data from earlier stages in the therapeutic process hold similar predictive power.

Journal article

Zeifman RJ, Kettner H, Pagni BA, Mallard A, Roberts DE, Erritzoe D, Ross S, Carhart-Harris RLet al., 2023, Co-use of MDMA with psilocybin/LSD may buffer against challenging experiences and enhance positive experiences, Scientific Reports, Vol: 13, Pages: 1-11, ISSN: 2045-2322

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 psilocybin/LSD anecdotally reduces challenging experiences and enhances positive experiences associated with psilocybin/LSD. However, limited research has investigated the acute effects of co-use of MDMA and psilocybin/LSD. In a prospective convenience sample (N = 698) of individuals with plans to use psilocybin/LSD, we examined whether co-use of MDMA with psilocybin/LSD (n = 27) is associated with differences in challenging or positive experiences. Challenging experiences were measured using the Challenging Experiences Questionnaire and positive experiences were measured using the Mystical Experience Questionnaire and single-item measures of self-compassion, compassion, love, and gratitude. Potentially confounding variables were identified and included as covariates. Relative to psilocybin/LSD alone, co-use of psilocybin/LSD with a self-reported low (but not medium–high) dose of MDMA was associated with significantly less intense total challenging experiences, grief, and fear, as well as increased self-compassion, love and gratitude. Co-use of psilocybin/LSD and MDMA was not associated with differences in mystical-type experiences or compassion. Findings suggest co-use of MDMA with psilocybin/LSD may buffer against some aspects of challenging experiences and enhance certain positive experiences. Limitations include use of a convenience sample, small sample size, and non-experimental design. Additional studies (including controlled dose–response studies) that examine the effects and safety of co-administering MDMA with psilocybin/LSD (in healthy controls and clinical samples) are warranted an

Journal article

Zeifman RJ, Wagner AC, Monson CM, Carhart-Harris RLet al., 2023, How does psilocybin therapy work? An exploration of experiential avoidance as a putative mechanism of change., J Affect Disord, Vol: 334, Pages: 100-112

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 examined experiential avoidance as a mechanism underlying psilocybin therapy's therapeutic effects. METHOD: Data was used from a double-blind randomized controlled trial that compared psilocybin therapy (two 25 mg psilocybin session plus daily placebo for six weeks) with escitalopram (two 1 mg psilocybin sessions plus 10-20 mg daily escitalopram for six weeks) among individuals with major depressive disorder (N = 59). All participants received psychological support. Experiential avoidance, connectedness, and treatment outcomes were measured at pre-treatment and at a 6 week primary endpoint. Acute psilocybin experiences and psychological insight were also measured. RESULTS: With psilocybin therapy, but not escitalopram, improvements in mental health outcomes (i.e., well-being, depression severity, suicidal ideation, and trait anxiety) occurred via reductions in experiential avoidance. Exploratory analyses suggested that improvements in mental health (except for suicidal ideation) via reduction in experiential avoidance were serially mediated through increases in connectedness. Additionally, experiences of ego dissolution and psychological insight predicted reductions in experiential avoidance following psilocybin therapy. LIMITATIONS: Difficulties inferring temporal causality, maintaining blindness to condition, and reliance upon self-report. CONCLUSIONS: These results provide support for the role of reduced experiential avoidance as a putative mechanism underlying psilocybin therapy's positive therapeutic outcomes. The present findings may help to tailor, refine, and optimize psilocybin therapy and i

Journal article

Szigeti B, Nutt D, Carhart-Harris R, Erritzoe Det al., 2023, The difference between 'placebo group' and 'placebo control': a case study in psychedelic microdosing, Scientific Reports, Vol: 13, Pages: 1-10, ISSN: 2045-2322

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 expectancy bias’ (AEB) and show that AEB can inflate estimates of treatment effects and create false positive findings. To counteract AEB, we introduce the Correct Guess Rate Curve (CGRC), a statistical tool that can estimate the outcome of a perfectly blinded trial based on data from an imperfectly blinded trial. To demonstrate the impact of AEB and the utility of the CGRC on empirical data, we re-analyzed the ‘self-blinding psychedelic microdose trial’ dataset. Results suggest that observed placebo-microdose differences are susceptible to AEB and are at risk of being false positive findings, hence, we argue that microdosing can be understood as active placebo. These results highlight the important difference between ‘trials with a placebo-control group’, i.e., when a placebo control group is formally present, and ‘placebo-controlled trials’, where patients are genuinely blind. We also present a new blinding integrity assessment tool that is compatible with CGRC and recommend its adoption.

Journal article

Wall MB, Lam C, Ertl N, Kaelen M, Roseman L, Nutt DJ, Carhart-Harris RLet al., 2023, Increased low-frequency brain responses to music after psilocybin therapy for depression, JOURNAL OF AFFECTIVE DISORDERS, Vol: 333, Pages: 321-330, ISSN: 0165-0327

Journal article

Delli Pizzi S, Chiacchiaretta P, Sestieri C, Ferretti A, Onofrj M, Della Penna S, Roseman L, Timmermann C, Nutt DJ, Carhart-Harris RL, Sensi SLet al., 2023, Spatial Correspondence of LSD-Induced Variations on Brain Functioning at Rest With Serotonin Receptor Expression, BIOLOGICAL PSYCHIATRY-COGNITIVE NEUROSCIENCE AND NEUROIMAGING, Vol: 8, Pages: 768-776, ISSN: 2451-9022

Journal article

Weiss B, Erritzoe D, Giribaldi B, Nutt DJ, Carhart-Harris RLet al., 2023, A critical evaluation of QIDS-SR-16 using data from a trial of psilocybin therapy versus escitalopram treatment for depression, JOURNAL OF PSYCHOPHARMACOLOGY, Vol: 37, Pages: 717-732, ISSN: 0269-8811

Journal article

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