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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

The human brain is a complex system, whose activity exhibits flexible and continuous reorganization across space and time. The decomposition of whole-brain recordings into harmonic modes has revealed a repertoire of gradient-like activity patterns associated with distinct brain functions. However, the way these activity patterns are expressed over time with their changes in various brain states remains unclear. Here, we investigate healthy participants taking the serotonergic psychedelic N,N-dimethyltryptamine (DMT) with the Harmonic Decomposition of Spacetime (HADES) framework that can characterize how different harmonic modes defined in space are expressed over time. HADES demonstrates significant decreases in contributions across most low-frequency harmonic modes in the DMT-induced brain state. When normalizing the contributions by condition (DMT and non-DMT), we detect a decrease specifically in the second functional harmonic, which represents the uni- to transmodal functional hierarchy of the brain, supporting the leading hypothesis that functional hierarchy is changed in psychedelics. Moreover, HADES dynamic spacetime measures of fractional occupancy, life time and latent space provide a precise description of the significant changes of the spacetime hierarchical organization of brain activity in the psychedelic state.

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.

Psilocybin, a serotonergic psychedelic, is being increasingly researched in clinical studies for the treatment of psychiatric disorders. The relatively lengthy duration of oral psilocybins 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.

Mystical-like states of consciousness may arise through means such as psychedelic substances, but may also occur unexpectedly during near-death experiences (NDEs). So far, research studies comparing experiences induced by serotonergic psychedelics and NDEs, along with their enduring effects, have employed between-subject designs, limiting direct comparisons. We present results from an online survey exploring the phenomenology, attribution of reality, psychological insights, and enduring effects of NDEs and psychedelic experiences (PEs) in individuals who have experienced both at some point during their lifetime. We used frequentist and Bayesian analyses to determine significant differences and overlaps (evidence for null hypotheses) between the two. Thirty-one adults reported having experienced both an NDE (i.e. NDE-C scale total score ≥27/80) and a PE (intake of lysergic acid diethylamide, psilocybin/mushrooms, ayahuasca, N,N-dimethyltryptamine, or mescaline). Results revealed areas of overlap between both experiences for phenomenology, attribution of reality, psychological insights, and enduring effects. A finer-grained analysis of the phenomenology revealed a significant overlap in mystical-like effects, while low-level phenomena (sensory effects) were significantly different, with NDEs displaying higher scores of disembodiment and PEs higher scores of visual imagery. This suggests psychedelics as a useful model for studying mystical-like effects induced by NDEs, while highlighting distinctions in sensory experiences.

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.

Katrin Milger,1 Dirk Koschel,2 Dirk Skowasch,3 Hartmut Timmermann,4 Olaf Schmidt,5 Karl-Christian Bergmann,6 Claus Neurohr,7 Robert Lindner,8 Sebastian Heck,9 Johann Christian Virchow10 1Division of Pulmonology, Department of Internal Medicine, Medical University of Graz, Graz, Austria; 2Division of Pneumonology, Medical Department I, University Hospital Carl Gustav Carus, Dresden and Fachkrankenhaus Coswig, Lung Centre, Coswig, Germany; 3Department of Internal Medicine II – Pneumology, University Hospital Bonn, Bonn, Germany; 4Schwerpunktpraxis Colonnaden, Hamburg, Germany; 5Pneumologische Gemeinschaftspraxis und Studienzentrum KPPK, Koblenz, Germany; 6Institute for Allergology, Charité – Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Berlin, Germany; 7Abteilung für Pneumologie und Beatmungsmedizin, Robert-Bosch-Krankenhaus Lungenzentrum, Stuttgart, Germany; 8IQVIA Commercial GmbH & Co. OHG, Frankfurt Am Main, Germany; 9GlaxoSmithKline GmbH & Co. KG, Munich, Germany; 10Abteilung Pneumologie & Interdisziplinäre Internistische Intensivmedizin, Universitätsmedizin Rostock - Zentrum für Innere Medizin, Medizinische Klinik I, Rostock, GermanyCorrespondence: Katrin Milger, Division of Pulmonology, Department of Internal Medicine, Medical University of Graz, Auenbruggerplatz 15, Graz, 8036, Austria, Email katrin.milger-kneidinger@medunigraz.atPurpose: Asthma is affecting 4– 5% of all adults (10% of children) in Germany, ≥ half are inadequately controlled. In 2019 up to 54 thousand patients suffered from severe uncontrolled asthma, 52% were treated/co-treated by pneumonologists. 45% of them had continuous oral corticosteroid (OCS)- and short-acting β 2-agonist (SABA) overuse for ≥ 2 years. The aim of the current study was to analyze the main treatments, escalation schemes and the adherence to the GINA recommendations.Patients and Methods: Retrospective analysis in 2021 based on data from January to December 2019 in Germany, using the IQVIA™ LRx prescription database and the IQVIA™ Disease Analyzer database containing anonymized electronic medical records as the main data sources.Results: In 2019 25,200 patients with severe, uncontrolled asthma treated in a pneumonologist´s practice in Germany received GINA 3 (0,4%), GINA 4 (76%) or GINA 5 therapy (24%) during the study year compared to 59% GINA 5 therapy in the 5– 10% (1,500– 3,000) co-treated in a specialized outpatient department. In Pneumonologists` practices the most frequent choice in GINA 5 was OCS in 69% of patients (biologicals 37%, long-acting muscarinic antagonist (LAMA) 20%) compared to 66% biologicals, 55% OCS, and 25% LAMA in the outpatient department. 54,958 of 613,000 GINA 4/5 patients were treated with OCS, 9,725 even with doses above the so called “Cushing threshold” for prednisolone of 2700 mg/year. After introduction of a biological treatment, patients reduced their SABA prescriptions by 28%, OCS by 55%, and OCS overall exposure by 40%, one-third did not need OCS anymore.Conclusion: In 75% of patients with uncontrolled asthma for ≥ 2 years therapy was not escalated beyond GINA 4 or low dose OCS was used as the most frequent add-on treatment in GINA 5 contradictory to treatment recommendations. Use of biologics reduced on demand rescue medication and OCS use.Keywords: prescription database, disease analyzer, uncontrolled asthma, biological treatment, OCS use, Germany, guideline adherence

Abstract Background Status epilepticus (SE) is one of the most common neurological emergencies and an acutely life-threatening condition characterized by high mortality and morbidity. Despite the well-established staged therapy of status epilepticus, especially stages 1 and 2, more than one third of patients develop (super-) refractory SE. Despite a large variety of potential treatment options for super-refractory SE, there is an unmet clinical need of potential new treatment ideas in this often desperate clinical situation. A number of studies have demonstrated the safety and efficacy of stiripentol (STP) in patients with Dravet syndrome (DS) and in children with focal epilepsy and generalized epilepsies. Some smaller series and case reports have documented the use of STP in the treatment of status epilepticus in adult patients. Methods We retrospectively analyzed all patients who were admitted to the Department of Neurology at Marburg University Hospital between 2013 and 2023 with a diagnosis of (super)-refractory status epilepticus and who received additional treatment of SE with STP. All patients who received STP during the SE were included, regardless of previous medication. Results SE ceased in 64% of 25 patients (13 female and 12 male). The mean age was 58.6 ± 21.9 years (mean ± SD). 72% had a structural epilepsy. In 20% of patients, SE was terminated by the administration of STP alone in 32% of cases, while in a further 32% of patients, the simultaneous administration of multiple anti-seizure medications (ASMs) including STP was potentially responsible for the cessation of the SE, with valproic acid (VPA), benzodiazepines and STP, being the most frequently implicated ASMs. In 12% of patients, there was at least a temporary improvement in the electroencephalogram (EEG). Stiripentol had to be discontinued in three cases due to a reduction in vigilance or hypercalcemia. Conclusions Stiripentol may represent a promising additional treatment option for refractory and super-refractory status epilepticus. The tolerability of this treatment has already been demonstrated in previous studies, and was also reflected in these data. Further prospective investigation in larger patient populations are necessary to ascertain the efficacy of stiripentol in SE. Trial registration NCT06540378, retrospectively registered.

Abstract Unabated 21st-century climate change will accelerate Arctic-Subarctic permafrost thaw which can intensify microbial degradation of carbon-rich soils, methane emissions, and global warming. The impact of permafrost thaw on future Arctic-Subarctic wildfires and the associated release of greenhouse gases and aerosols is less well understood. Here we present a comprehensive analysis of the effect of future permafrost thaw on land surface processes in the Arctic-Subarctic region using the CESM2 large ensemble forced by the SSP3-7.0 greenhouse gas emission scenario. Analyzing 50 greenhouse warming simulations, which capture the coupling between permafrost, hydrology, and atmosphere, we find that projected rapid permafrost thaw leads to massive soil drying, surface warming, and reduction of relative humidity over the Arctic-Subarctic region. These combined processes lead to nonlinear late-21st-century regime shifts in the coupled soil-hydrology system and rapid intensification of wildfires in western Siberia and Canada.

The Marine Ice Sheet–Ocean Model Intercomparison Project – phase 2 (MISOMIP2) is a natural progression of previous and ongoing model intercomparison exercises that have focused on the simulation of ice-sheet and ocean processes in Antarctica. The previous exercises motivate the move towards realistic configurations, as well as more diverse model parameters and resolutions. The main objective of MISOMIP2 is to investigate the performance of existing ocean and coupled ice-sheet–ocean models in a range of Antarctic environments through comparisons to observational data. We will assess the status of ice-sheet–ocean modelling as a community and identify common characteristics of models that are best able to capture observed features. As models are highly tuned based on present-day data, we will also compare their sensitivity to prescribed abrupt atmospheric perturbations leading to either very warm or slightly warmer ocean conditions compared to the present day. The approach of MISOMIP2 is to welcome contributions of models as they are, including global and regional configurations, but we request standardized variables and common grids for the outputs. We target the analysis at two specific regions, the Amundsen Sea and the Weddell Sea, since they describe two different ocean environments and have been relatively well observed compared to other areas of Antarctica. An observational “MIPkit” synthesizing existing ocean and ice-sheet observations for a common period is provided to evaluate ocean and ice-sheet models in these two regions.

Abstract Isolated REM Sleep Behavior Disorder (iRBD) is considered a prodrome of Parkinson’s disease (PD). We investigate whether the potentially disease-modifying compound acetyl-DL-leucine (ADLL; 5 g/d) has an effect on prodromal PD progression in 2 iRBD-patients. Outcome parameters are RBD-severity sum-score (RBD-SS-3), dopamine-transporter single-photon emission computerized tomography (DAT-SPECT) and metabolic “Parkinson-Disease-related-Pattern (PDRP)”-z-score in 18F-fluorodeoxyglucose positron emission tomography (FDG-PET). After 3 weeks ADLL-treatment, the RBD-SS-3 drops markedly in both patients and remains reduced for >18 months of ADLL-treatment. In patient 1 (female), the DAT-SPECT putaminal binding ratio (PBR) decreases in the 5 years pretreatment from normal (1.88) to pathological (1.22) and the patient’s FDG-PET-PDRP-z-score rises from 1.72 to 3.28 (pathological). After 22 months of ADLL-treatment, the DAT-SPECT-PBR increases to 1.67 and the FDG-PET-PDRP-z-score stabilizes at 3.18. Similar results are seen in patient 2 (male): his DAT-SPECT-PBR rises from a pretreatment value of 1.42 to 1.72 (close to normal) and the FDG-PET-PDRP-z-score decreases from 1.02 to 0.30 after 18 months of ADLL-treatment. These results support exploration of whether ADLL may have disease-modifying properties in prodromal PD.

Calls for reframing the subject matter of Religious Education in schools include the tricky question of how to select from a world of potentially interesting and relevant material. Pedagogues have long questioned the educational logic that takes so-called substantive knowledge as its starting point and imagines education to follow a linear path from simple to complex. Scholars of Religious Studies have addressed similar questions of how to bring the subject matter to life through taking a more disciplinary orientation , though this approach is problematized by RE's multi-disciplinary foundations This paper brings together pedagogical and disciplinary perspectives to the question of exemplification in the production of curricular subject matter. Taking as its context RE in schools, the paper assumes the didactic principle that there is considerable difference between putative disciplinary knowledge and school subject matter and that the production of school subject matter requires considered processes of pedagogical transformation and reduction. The paper explores the logic governing this transformation by drawing on the pedagogical analysis of exemplarity offered by Martin Wagenschein alongside the more disciplinary analyses of the place of examples from Jonathan Z. Smith.

Thermally sprayed protective coatings are applied onto many mechanically stressed components such as support structures, shafts, turbine blades or heat exchangers. In addition to the static or cyclic load, a superimposition with corrosion processes occurs in many cases. Thermal sprayed ZnAl coatings are known for their performant corrosion protection properties. Within this context, the potential of ZnAl-based layer systems was analyzed regarding corrosion fatigue behavior. Therefore, a timeand cost-efficient testing strategy based on a corrosion-superimposed load increase procedure was used to estimate the effects of a corrosive attack during cyclic loading. The investigated coating systems were thermally sprayed and partially post-processed with a Machine Hammer Peening (MHP) operation. This treatment was identified as an appropriate technique for compressing and smoothing coated surfaces. The inter-relationships between the parametrization of the MHP process, the resulting surface integrity, and the estimated corrosion fatigue properties were analyzed. The investigations indicate a positive effect of MHP post-processing operations on the surface properties of the ZnAl-based coating system.

N,N-dimethyltryptamine (DMT) is a psychedelic compound that is being studied as a therapeutic option in various psychiatric disorders. Due to its short half-life, continuous infusion of DMT has been proposed to extend the psychedelic experience and potential therapeutic effects. The primary aim of this work was to design an infusion protocol for DMT based on a desired level of psychedelic intensity using population pharmacokinetic/pharmacodynamic modeling. As a secondary aim, the impact of choosing a continuous variable or a bounded integer pharmacokinetic/pharmacodynamic model to inform such an infusion protocol was investigated. A previously published continuous variable model and two newly developed bounded integer models were used to assess optimal doses for achieving a target response. Simulations were performed to identify an optimal combination of a bolus dose and an infusion rate. Based on the simulations, optimal doses to achieve intensity ratings between 7 and 9 (possible range = 0-10) were a bolus dose of 16 mg DMT fumarate followed by an infusion rate of 1.4 mg/min based on the continuous variable model and 14 mg with 1.2 mg/min for the two bounded integer models. However, the proportion within target was low (

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.