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Journal articleVerroust V, Zafar R, Spriggs MJ, 2021,
Psilocybin in the treatment of anorexia nervosa: The English transition of a French 1959 case study
, Annales Medico Psychologiques, Vol: 179, Pages: 777-781, ISSN: 0003-4487Psilocybin is a psychotropic molecule that is a partial agonist of serotonin 2A receptors and is the main psychoactive compound in hallucinogenic mushrooms. After the observation in 1953 in Mexico of ritual practices involving ingestion of such mushrooms, psilocybin was chemically characterized and synthesized in 1958 thanks to the collaboration between the Muséum national d'Histoire naturelle in France and the Sandoz pharmaceutical laboratories in Switzerland. The interest of this substance in psychiatric therapy was then evaluated for the first time at the Sainte-Anne Hospital in Paris, by the team of Professor Jean Delay. Among the patients who received this substance was a 35-year-old woman who was hospitalized for compulsive manifestations emblematic of anorexia nervosa and who experienced an immediate and lasting improvement. The original 1959 article (published in the Annales de la Société Médico-Psychologique) gives details of the patient's family background, biography and clinical examination. It then outlines the observations after two injections of psilocybin four days apart, in particular the autobiographical verbal statements that allowed the patient to understand the psychogenesis of her illness. After a long hiatus, psilocybin is once again the subject of medical research, with clinical trials now underway assessing psilocybin in the treatment of anorexia nervosa (NCT04505189; NCT04052568; NCT04661514) and this 1959 case study, is the first known demonstration of the safety and efficacy of psilocybin treatment of anorexia nervosa. This case study thus provides an interesting insight into possible therapeutic mechanisms and is of great interest to the field moving forward.
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Journal articleSpriggs M, Douglass H, Park R, et al., 2021,
Study protocol for “Psilocybin as a Treatment for Anorexia Nervosa: A Pilot Study"
, Frontiers in Psychiatry, Vol: 12, Pages: 1-16, ISSN: 1664-0640Background: Anorexia nervosa (AN) is a serious and life-threatening psychiatric condition. With a paucity of approved treatments, there is a desperate need for novel treatment avenues to be explored. Here, we present 1) an overview of the ways through which Public Patient Involvement (PPI) has informed a trial of psilocybin-assisted therapy for AN and 2) aprotocol for a pilot study of psilocybin-assisted therapy in AN currently underway at Imperial College London. The study aims to assess the feasibility, brain mechanisms and preliminary outcomes of treating anorexia nervosa with psilocybin. Methods: 1) PPI: Across two online focus groups, eleven individuals with lived experience of AN were presented with an overview of the protocol. Their feedback not only identified solutions to possible barriers for future participants, but also helped the research team to better understand the concept of “recovery” from the perspective of those with lived experience. 2) Protocol: Over a 6-week period, twenty female participants (21-65 years old,body mass index (BMI) ³15kg/m2) will receive three oral doses of psilocybin (up to 25 mg) delivered in a therapeutic environment and enveloped by psychological preparation and integration. We will work with participant support networks (care teams and an identified support person) throughout and there will be an extended remote follow-up period of 12 months. Our twofold primary outcomes are 1) psychopathology (Eating Disorder Examination) across the 6-month follow-up and 2) readiness and motivation to engage in recovery (Readiness and Motivation Questionnaire) across the 6-week trial period. Neurophysiological outcome measures will be: 1) functional magnetic resonance imaging (fMRI) brain changes from baseline to 6-week endpoint and 2) post-acute changes in electroencephalography (EEG) activity, including an electrophysiological marker of neuronal plasticity. Discussion: The results of this pilot study will not only shed
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Journal articleCarhart-Harris R, Blemings A, Nutt DJ, 2021,
Psilocybin for Depression
, NEW ENGLAND JOURNAL OF MEDICINE, Vol: 385, Pages: 863-864, ISSN: 0028-4793- Cite
- Citations: 2
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Journal articleMans K, Kettner HS, Erritzoe D, et al., 2021,
Sustained, multifaceted improvements in mental well-being following psychedelic experiences in a prospective opportunity sample
, Frontiers in Psychiatry, Vol: 12, ISSN: 1664-0640In the last 15 years, psychedelic substances, such as LSD and psilocybin, have regained legitimacy in clinical research. In the general population as well as across various psychiatric populations, mental well-being has been found to significantly improve after a psychedelic experience. Mental well-being has large socioeconomic relevance, but it is a complex, multifaceted construct. In this naturalistic observational study, a comprehensive approach was taken to assessing well-being before and after a taking a psychedelic compound to induce a “psychedelic experience.” Fourteen measures of well-being related constructs were included in order to examine the breadth and specificity of change in well-being. This change was then analysed to examine clusters of measures changing together. Survey data was collected from volunteers that intended to take a psychedelic. Four key time points were analysed: 1 week before and 2 weeks, 4 weeks, and 2 years after the experience (N = 654, N = 315, N = 212, and N = 64, respectively). Change on the included measures was found to cluster into three factors which we labelled: 1) “Being well”, 2) “Staying well,” and 3) “Spirituality.” Repeated Measures Multivariate Analysis of Variance revealed all but the spirituality factor to be improved in the weeks following the psychedelic experience. Additional Mixed model analyses revealed selective increases in Being Well and Staying Well (but not Spirituality) that remained statistically significant up to 2 years post-experience, albeit with high attrition rates. Post-hoc examination suggested that attrition was not due to differential acute experiences or mental-health changes in those who dropped out vs. those who did not. These findings suggest that psychedelics can have a broad, robust and sustained positive impact on mental well-being in those that have a prior intention to use a psychedelic compound. Public policy implications are discussed.
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Journal articleDaws R, Timmerman C, Giribaldi B, et al., 2021,
Decreased brain modularity after psilocybin therapy for depression.
<title>Abstract</title> <p><bold>Importance </bold>Psilocybin therapy shows antidepressant potential; our data link its antidepressant effects to decreased brain network modularity post-treatment. <bold>Objective </bold>To assess the sub-acute impact of psilocybin on brain activity in patients with depression. <bold>Design </bold>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). <bold>Setting </bold>Study visits occurred at the NIHR Imperial Clinical Research Facility.<bold>Participants </bold>Adult male and female patients with TRD or MDD. <bold>Intervention(s) (for clinical trials) or Exposure(s) (for observational studies)</bold>Study 1: Two oral doses of psilocybin (10mg and 25mg, fixed order, 7 days apart). fMRI was recorded at baseline and one day after the 25mg dose. Study 2: either: 2 x 25mg oral psilocybin, 3 weeks apart, plus 6 weeks of daily placebo (‘psilocybin-arm’), or 2 x 1mg oral psilocybin, 3 weeks apart, plus 6 weeks of daily escitalopram [10-20mg] (‘escitalopram-arm’). fMRI was recorded at baseline and 3 weeks after the 2nd psilocybin dose, which was the final day of the 6-week daily capsule ingestion. <bold>Main Outcome(s) and Measure(s) </bold>Beck Depression Inventory and fMRI network modularity. <bold> </bold><bold>Results </bold>Study 1: In 16 adults (mean age [SD], 42.8 [10.1] years, 4 [25%] female), psilocybin therapy<underline> </underline>was associated with markedly decreased BDI scores at 1 week (mean difference, -21; 95% CI=[-27.3, -
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Journal articleSingleton SP, Luppi AI, Carhart-Harris RL, et al., 2021,
LSD and psilocybin flatten the brain’s energy landscape: insights from receptor-informed network control theory
<jats:title>Abstract</jats:title> <jats:p>Psychedelics like lysergic acid diethylamide (LSD) and psilocybin offer a powerful window into the function of the human brain and mind, by temporarily altering subjective experience through their neurochemical effects. A recent model postulates that serotonin 2a (5-HT2a) receptor agonism allows the brain to explore its dynamic landscape more readily, as reflected by more diverse (entropic) brain activity. We postulate that this increase in entropy may arise in part from a flattening of the brain’s control energy landscape, which can be observed using network control theory to quantify the energy required to transition between recurrent brain states measured using functional magnetic resonance imaging (fMRI) in individuals under LSD, psilocybin, and placebo conditions. We show that LSD and psilocybin reduce the amount of control energy required for brain state transitions, and, furthermore, that, across individuals, LSD’s reduction in control energy correlates with more frequent state transitions and increased entropy of brain state dynamics. Through network control analysis that incorporates the spatial distribution of 5-HT2a receptors from publicly available (non-drug) positron emission tomography (PET) maps, we demonstrate the specific role of this receptor in reducing control energy. Our findings provide evidence that 5-HT2a receptor agonist compounds allow for more facile state transitions and more temporally diverse brain activity. More broadly, by combining receptor-informed network control theory with pharmacological modulation, our work highlights the potential of this approach in studying the impacts of targeted neuropharmacological manipulation on brain activity dynamics.</jats:p> <jats:sec> <jats:title>Significance Statement</jats:title> <jats:p>We present a multi-modal framework for quantif
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Journal articleCarhart-Harris R, Giribaldi B, Watts R, et al., 2021,
Trial of Psilocybin versus Escitalopram for Depression
, NEW ENGLAND JOURNAL OF MEDICINE, Vol: 384, Pages: 1402-1411, ISSN: 0028-4793- Author Web Link
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- Citations: 902
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Journal articleStenbaek DS, Madsen MK, Ozenne B, et al., 2021,
Brain serotonin 2A receptor binding predicts subjective temporal and mystical effects of psilocybin in healthy humans
, JOURNAL OF PSYCHOPHARMACOLOGY, Vol: 35, Pages: 459-468, ISSN: 0269-8811- Cite
- Citations: 63
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Journal articleVarley TF, Carhart-Harris R, Roseman L, et al., 2020,
Serotonergic psychedelics LSD & psilocybin increase the fractal dimension of cortical brain activity in spatial and temporal domains
, NEUROIMAGE, Vol: 220, ISSN: 1053-8119- Cite
- Citations: 55
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Journal articleGirn M, Roseman L, Bernhardt B, et al., 2020,
Serotonergic psychedelic drugs LSD and psilocybin reduce the hierarchical differentiation of unimodal and transmodal cortex
<jats:title>Abstract</jats:title> <jats:p>LSD and psilocybin are serotonergic psychedelic compounds with potential in the treatment of mental health disorders. Past neuroimaging investigations have revealed that both compounds can elicit significant changes to whole-brain functional organization and dynamics. A recent proposal linked past findings into a unified model and hypothesized reduced whole-brain hierarchical organization as a key mechanism underlying the psychedelic state, but this has yet to be directly tested. We applied a non-linear dimensionality reduction technique previously used to map hierarchical connectivity gradients to pharmacological resting-state fMRI data to assess cortical organization in the LSD and psilocybin state. Results supported our primary hypothesis: The principal gradient of cortical connectivity, describing a hierarchy from unimodal to transmodal cortex, was significantly flattened under both drugs relative to their respective placebo conditions. Between-condition contrasts revealed that this was driven by a reduction of functional differentiation at both hierarchical extremes – default and frontoparietal networks at the upper end, and somatomotor at the lower. Gradient-based connectivity mapping confirmed that this was underpinned by increased unimodal-transmodal crosstalk. In addition, LSD-dependent principal gradient changes tracked changes in self-reported ego-dissolution. Results involving the second and third gradient, which respectively represent axes of sensory and executive differentiation, also showed significant alterations across both drugs. These findings provide support for a recent mechanistic model of the psychedelic state relevant to therapeutic applications of psychedelics. More fundamentally, we provide the first evidence that macroscale connectivity gradients are sensitive to a pharmacological manipulation, specifically highlighting an important relationship between cortic
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