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  • 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
    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.

    , J Affect Disord, Vol: 333, Pages: 321-330

    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: Brain responses to music were assessed before and after PT using functional Magnetic Resonance Imaging (fMRI) and ALFF (Amplitude of Low Frequency Fluctuations) analysis methods. Nineteen patients with treatment-resistant depression underwent two treatment sessions involving administration of psilocybin, with MRI data acquired one week prior and the day after completion of psilocybin dosing sessions. RESULTS: Comparison of music-listening and resting-state scans revealed significantly greater ALFF in bilateral superior temporal cortex for the post-treatment music scan, and in the right ventral occipital lobe for the post-treatment resting-state scan. ROI analyses of these clusters revealed a significant effect of treatment in the superior temporal lobe for the music scan only. Voxelwise comparison of treatment effects showed relative increases for the music scan in the bilateral superior temporal lobes and supramarginal gyrus, and relative decreases in the medial frontal lobes for the resting-state scan. ALFF in these music-related clusters was significantly correlated with intensity of subjective effects felt during the dosing sessions. LIMITATIONS: Open-label trial. Relatively small sample size. CONCLUSIONS: These data suggest an effect of PT on the brain's response to music, implying an elevated responsiveness to music after psilocybin therapy that was related to subjective drug effects felt during dosing.

  • Journal article
    Weiss B, 2023,

    Prevalence and therapeutic impact of adverse life event reexperiencing under ceremonial ayahuasca

    , Scientific Reports, ISSN: 2045-2322

    The present study examined the safety and efficacy of the ceremonial use of ayahuasca in relation to reports of heightened life event reexperiencing under psychedelics. The study examined (1) the prevalence of specific types of adverse life event reexperiencing, (2) characteristics predictive of reexperiencing, (3) the psychological character of reexperiencing, and (4) the impact of reexperiencing on mental health. Participants were recruited from three ayahuasca healing and spiritual centers in South and Central America (N = 33 military veterans, 306 non-veterans) using self-report data at three timepoints (Pre-retreat, Post-retreat, 3-months post-retreat). Reexperiencing adverse life events under ayahuasca was common, with women showing particularly high probability of reexperiencing sexual assault, veterans reexperiencing combat-related trauma, and individuals with a self-reported lifetime diagnosis of post-traumatic stress disorder exhibiting a substantively higher prevalence of reexperiencing. Reexperiencing was associated with states of reappraisal, psychological flexibility, and discomfort during ceremony, and incremental reductions in trait neuroticism. Clinical implications of these results for the application of psychedelics to mood and stress disorders are discussed.

  • Journal article
    Zafar R, 2023,

    Psychedelic therapy in the treatment of addiction: The past, present and future

    , Frontiers in Psychiatry, ISSN: 1664-0640

    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 (Nutt, Spriggs and Erritzoe, 2023). 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 imaging (fMRI) and positron emission tomography (PET), that can be applied to foster a mechanistic understanding of therapeutic mechanisms. A more granular understanding of the treatment effects of psychedelics will facilitate the optimisation of the psychedelic therapy drug development landscape, and ultimately improve patient outcomes.

  • Journal article
    Singleton SP, Timmermann C, Luppi AI, Eckernäs E, Roseman L, Carhart-Harris RL, Kuceyeski Aet al., 2023,

    Time-resolved network control analysis links reduced control energy under DMT with the serotonin 2a receptor, signal diversity, and subjective experience.

    , bioRxiv

    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 psilocybin flatten the brain's control energy landscape in a manner that covaries with more dynamic and entropic brain activity. Contrary to LSD and psilocybin, whose effects last for hours, the serotonergic psychedelic N,N-dimethyltryptamine (DMT) rapidly induces a profoundly immersive altered state of consciousness lasting less than 20 minutes, allowing for the entirety of the drug experience to be captured during a single resting-state fMRI scan. Using network control theory, which quantifies the amount of input necessary to drive transitions between functional brain states, we integrate brain structure and function to map the energy trajectories of 14 individuals undergoing fMRI during DMT and placebo. Consistent with previous work, we find that global control energy is reduced following injection with DMT compared to placebo. We additionally show longitudinal trajectories of global control energy correlate with longitudinal trajectories of EEG signal diversity (a measure of entropy) and subjective ratings of drug intensity. We interrogate these same relationships on a regional level and find that the spatial patterns of DMT's effects on these metrics are correlated with serotonin 2a receptor density (obtained from separately acquired PET data). Using receptor distribution and pharmacokinetic information, we were able to successfully recapitulate the effects of DMT on global control energy trajectories, demonstrating a proof-of-concept for the use of control models in predicting pharmacological intervention effects on brain dynamics.

  • Journal article
    Spriggs M, Bornemann J, Murphy-Beiner A, Murphy R, Thurgur H, Schlag AKet al., 2023,

    ARC: a framework for access, reciprocity and conduct in psychedelic therapies

    , Frontiers in Psychology, Vol: 14, Pages: 1-8, ISSN: 1664-1078

    The field of psychedelic assisted therapy (PAT) is growing at an unprecedented pace. The immense pressures this places on those working in this burgeoning field have already begun to raise important questions about risk and responsibility. It is imperative that the development of an ethical and equitable infrastructure for psychedelic care is prioritized to support this rapid expansion of PAT in research and clinical settings. Here we present Access, Reciprocity and Conduct (ARC); a framework for a culturally informed ethical infrastructure for ARC in psychedelic therapies. These three parallel yet interdependent pillars of ARC provide the bedrock for a sustainable psychedelic infrastructure which prioritized equal access to PAT for those in need of mental health treatment (Access), promotes the safety of those delivering and receiving PAT in clinical contexts (Conduct), and respects the traditional and spiritual uses of psychedelic medicines which often precede their clinical use (Reciprocity). In the development of ARC, we are taking a novel dual-phase co-design approach. The first phase involves co-development of an ethics statement for each arm with stakeholders from research, industry, therapy, community, and indigenous settings. A second phase will further disseminate the statements for collaborative review to a wider audience from these different stakeholder communities within the psychedelic therapy field to invite feedback and further refinement. By presenting ARC at this early stage, we hope to draw upon the collective wisdom of the wider psychedelic community and inspire the open dialogue and collaboration upon which the process of co-design depends. We aim to offer a framework through which psychedelic researchers, therapists and other stakeholders, may begin tackling the complex ethical questions arising within their own organizations and individual practice of PAT.

  • Journal article
    Weiss B, 2023,

    Personality change in a trial of psilocybin therapy vs escitalopram treatment for depression

    , Psychological Medicine, ISSN: 0033-2917
  • Journal article
    Girn M, Rosas FE, Daws RE, Gallen CL, Gazzaley A, Carhart-Harris RLet al., 2023,

    A complex systems perspective on psychedelic brain action.

    , Trends Cogn Sci, Vol: 27, Pages: 433-445

    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, findings have been largely inconsistent. We argue here that a perspective based on complexity science that foregrounds the distributed, interactional, and dynamic nature of brain function may render these inconsistencies intelligible. We propose that psychedelics induce a mode of brain function that is more dynamically flexible, diverse, integrated, and tuned for information sharing, consistent with greater criticality. This 'meta' perspective has the potential to unify past findings and guide intuitions toward compelling mechanistic models.

  • 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.

    , J Psychopharmacol

    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-SR16) did not. AIMS: The present study aims to (1) rationally and psychometrically account for discrepant results between outcome measures and (2) to overcome psychometric problems particular to individual measures by re-examining between-condition differences in depressive response using all outcome measures at item-, facet-, and factor-levels of analysis. METHOD: Four depression measures were compared on the basis of their validity for examining differences in depressive response between PT and ET conditions. RESULTS/OUTCOMES: Possible reasons for discrepant findings on the QIDS-SR16 include its higher variance, imprecision due to compound items and whole-scale and unidimensional sum-scoring, vagueness in the phrasing of scoring options for items, and its lack of focus on a core depression factor. Reanalyzing the trial data at item-, facet-, and factor-levels yielded results suggestive of PT's superior efficacy in reducing depressed mood, anhedonia, and a core depression factor, along with specific symptoms such as sexual dysfunction. CONCLUSION/INTERPRETATION: Our results raise concerns about the adequacy of the QIDS-SR16 for measuring depression, as well as the practice of relying on individual scales that tend not to capture the multidimensional structure or core of depression. Using an alternative approach that captures depression more granularly and comprehensively yielded specific insight into areas where PT therapy may be particularly useful to patients and clinicians.

  • Journal article
    Herzog R, Mediano PAM, Rosas FE, Lodder P, Carhart-Harris R, Perl YS, Tagliazucchi E, Cofre Ret al., 2023,

    A whole-brain model of the neural entropy increase elicited by psychedelic drugs.

    , Sci Rep, Vol: 13

    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 spontaneous neural activity, is thought to be of relevance to the psychedelic experience, mediating both acute alterations in consciousness and long-term effects. However, no clear mechanistic explanation for this entropy increase has been put forward so far. We sought to do this here by building upon a recent whole-brain model of serotonergic neuromodulation, to study the entropic effects of 5HT2A-R activation. Our results reproduce the overall entropy increase observed in previous experiments in vivo, providing the first model-based explanation for this phenomenon. We also found that entropy changes were not uniform across the brain: entropy increased in all regions, but the larger effect were localised in visuo-occipital regions. Interestingly, at the whole-brain level, this reconfiguration was not well explained by 5HT2A-R density, but related closely to the topological properties of the brain's anatomical connectivity. These results help us understand the mechanisms underlying the psychedelic state and, more generally, the pharmacological modulation of whole-brain activity.

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