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  • 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
    Nutt DJ, Peill JM, Weiss B, Godfrey K, Carhart-Harris RL, Erritzoe Det al., 2023,

    Psilocybin and Other Classic Psychedelics in Depression.

    , Curr Top Behav Neurosci, ISSN: 1866-3370

    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 hallucinations and out of body experiences, insightful and emotional breakthroughs as well as mystical-type experiences. When coupled with psychological support, effects can produce a rapid improvement in mood among people with depression that can last for months. In this chapter, we summarise the scientific studies to date that explore the use of psychedelics in depressed individuals, highlighting key clinical, psychological and neuroimaging features of psychedelics that may account for their therapeutic effects. These include alterations in brain entropy that disrupt fixed negative ruminations, a period of post-treatment increased cognitive flexibility, and changes in self-referential psychological processes. Finally, we propose that the brain mechanisms underlying the therapeutic effect of serotonergic psychedelics might be distinct from those underlying classical serotonin reuptake-blocking antidepressants.

  • Journal article
    Nutt DJ, 2023,

    Pharmacological Dissection of Antipsychotics

    , BIOLOGICAL PSYCHIATRY, Vol: 94, Pages: 524-525, ISSN: 0006-3223
  • Journal article
    Wall MB, Harding R, Zafar R, Rabiner EA, Nutt DJ, Erritzoe Det al., 2023,

    Neuroimaging in psychedelic drug development: past, present, and future

    , MOLECULAR PSYCHIATRY, ISSN: 1359-4184
  • 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
    Garel N, Drury J, Levesque JT, Goyette N, Lehmann A, Looper K, Erritzoe D, Dames S, Turecki G, Rej S, Richard-Devantoy S, Greenway KTet al., 2023,

    The Montreal model: an integrative biomedical-psychedelic approach to ketamine for severe treatment-resistant depression

    , FRONTIERS IN PSYCHIATRY, Vol: 14, ISSN: 1664-0640
  • Journal article
    Murphy RJ, Sumner R, Evans W, Ponton R, Ram S, Godfrey K, Forsyth A, Cavadino A, Naga VK, Smith T, Hoeh NR, Menkes DB, Muthukumaraswamy Set al., 2023,

    Acute Mood-Elevating Properties of Microdosed Lysergic Acid Diethylamide in Healthy Volunteers: A Home-Administered Randomized Controlled Trial

    , BIOLOGICAL PSYCHIATRY, Vol: 94, Pages: 511-521, ISSN: 0006-3223
  • 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

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