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      Bedside to bench: the outlook for psychedelic research

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          Abstract

          There has recently been a resurgence of interest in psychedelic compounds based on studies demonstrating their potential therapeutic applications in treating post-traumatic stress disorder, substance abuse disorders, and treatment-resistant depression. Despite promising efficacy observed in some clinical trials, the full range of biological effects and mechanism(s) of action of these compounds have yet to be fully established. Indeed, most studies to date have focused on assessing the psychological mechanisms of psychedelics, often neglecting the non-psychological modes of action. However, it is important to understand that psychedelics may mediate their therapeutic effects through multi-faceted mechanisms, such as the modulation of brain network activity, neuronal plasticity, neuroendocrine function, glial cell regulation, epigenetic processes, and the gut-brain axis. This review provides a framework supporting the implementation of a multi-faceted approach, incorporating in silico, in vitro and in vivo modeling, to aid in the comprehensive understanding of the physiological effects of psychedelics and their potential for clinical application beyond the treatment of psychiatric disorders. We also provide an overview of the literature supporting the potential utility of psychedelics for the treatment of brain injury (e.g., stroke and traumatic brain injury), neurodegenerative diseases (e.g., Parkinson’s and Alzheimer’s diseases), and gut-brain axis dysfunction associated with psychiatric disorders (e.g., generalized anxiety disorder and major depressive disorder). To move the field forward, we outline advantageous experimental frameworks to explore these and other novel applications for psychedelics.

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          Ingestion of Lactobacillus strain regulates emotional behavior and central GABA receptor expression in a mouse via the vagus nerve.

          There is increasing, but largely indirect, evidence pointing to an effect of commensal gut microbiota on the central nervous system (CNS). However, it is unknown whether lactic acid bacteria such as Lactobacillus rhamnosus could have a direct effect on neurotransmitter receptors in the CNS in normal, healthy animals. GABA is the main CNS inhibitory neurotransmitter and is significantly involved in regulating many physiological and psychological processes. Alterations in central GABA receptor expression are implicated in the pathogenesis of anxiety and depression, which are highly comorbid with functional bowel disorders. In this work, we show that chronic treatment with L. rhamnosus (JB-1) induced region-dependent alterations in GABA(B1b) mRNA in the brain with increases in cortical regions (cingulate and prelimbic) and concomitant reductions in expression in the hippocampus, amygdala, and locus coeruleus, in comparison with control-fed mice. In addition, L. rhamnosus (JB-1) reduced GABA(Aα2) mRNA expression in the prefrontal cortex and amygdala, but increased GABA(Aα2) in the hippocampus. Importantly, L. rhamnosus (JB-1) reduced stress-induced corticosterone and anxiety- and depression-related behavior. Moreover, the neurochemical and behavioral effects were not found in vagotomized mice, identifying the vagus as a major modulatory constitutive communication pathway between the bacteria exposed to the gut and the brain. Together, these findings highlight the important role of bacteria in the bidirectional communication of the gut-brain axis and suggest that certain organisms may prove to be useful therapeutic adjuncts in stress-related disorders such as anxiety and depression.
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            The global, regional, and national burden of inflammatory bowel disease in 195 countries and territories, 1990–2017: a systematic analysis for the Global Burden of Disease Study 2017

            Summary Background The burden of inflammatory bowel disease (IBD) is rising globally, with substantial variation in levels and trends of disease in different countries and regions. Understanding these geographical differences is crucial for formulating effective strategies for preventing and treating IBD. We report the prevalence, mortality, and overall burden of IBD in 195 countries and territories between 1990 and 2017, based on data from the Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) 2017. Methods We modelled mortality due to IBD using a standard Cause of Death Ensemble model including data mainly from vital registrations. To estimate the non-fatal burden, we used data presented in primary studies, hospital discharges, and claims data, and used DisMod-MR 2.1, a Bayesian meta-regression tool, to ensure consistency between measures. Mortality, prevalence, years of life lost (YLLs) due to premature death, years lived with disability (YLDs), and disability-adjusted life-years (DALYs) were estimated. All of the estimates were reported as numbers and rates per 100 000 population, with 95% uncertainty intervals (UI). Findings In 2017, there were 6·8 million (95% UI 6·4–7·3) cases of IBD globally. The age-standardised prevalence rate increased from 79·5 (75·9–83·5) per 100 000 population in 1990 to 84·3 (79·2–89·9) per 100 000 population in 2017. The age-standardised death rate decreased from 0·61 (0·55–0·69) per 100 000 population in 1990 to 0·51 (0·42–0·54) per 100 000 population in 2017. At the GBD regional level, the highest age-standardised prevalence rate in 2017 occurred in high-income North America (422·0 [398·7–446·1] per 100 000) and the lowest age-standardised prevalence rates were observed in the Caribbean (6·7 [6·3–7·2] per 100 000 population). High Socio-demographic Index (SDI) locations had the highest age-standardised prevalence rate, while low SDI regions had the lowest age-standardised prevalence rate. At the national level, the USA had the highest age-standardised prevalence rate (464·5 [438·6–490·9] per 100 000 population), followed by the UK (449·6 [420·6–481·6] per 100 000). Vanuatu had the highest age-standardised death rate in 2017 (1·8 [0·8–3·2] per 100 000 population) and Singapore had the lowest (0·08 [0·06–0·14] per 100 000 population). The total YLDs attributed to IBD almost doubled over the study period, from 0·56 million (0·39–0·77) in 1990 to 1·02 million (0·71–1·38) in 2017. The age-standardised rate of DALYs decreased from 26·5 (21·0–33·0) per 100 000 population in 1990 to 23·2 (19·1–27·8) per 100 000 population in 2017. Interpretation The prevalence of IBD increased substantially in many regions from 1990 to 2017, which might pose a substantial social and economic burden on governments and health systems in the coming years. Our findings can be useful for policy makers developing strategies to tackle IBD, including the education of specialised personnel to address the burden of this complex disease. Funding Bill & Melinda Gates Foundation.
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              Neuropathological alterations in Alzheimer disease.

              The neuropathological hallmarks of Alzheimer disease (AD) include "positive" lesions such as amyloid plaques and cerebral amyloid angiopathy, neurofibrillary tangles, and glial responses, and "negative" lesions such as neuronal and synaptic loss. Despite their inherently cross-sectional nature, postmortem studies have enabled the staging of the progression of both amyloid and tangle pathologies, and, consequently, the development of diagnostic criteria that are now used worldwide. In addition, clinicopathological correlation studies have been crucial to generate hypotheses about the pathophysiology of the disease, by establishing that there is a continuum between "normal" aging and AD dementia, and that the amyloid plaque build-up occurs primarily before the onset of cognitive deficits, while neurofibrillary tangles, neuron loss, and particularly synaptic loss, parallel the progression of cognitive decline. Importantly, these cross-sectional neuropathological data have been largely validated by longitudinal in vivo studies using modern imaging biomarkers such as amyloid PET and volumetric MRI.
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                Author and article information

                Contributors
                Journal
                Front Pharmacol
                Front Pharmacol
                Front. Pharmacol.
                Frontiers in Pharmacology
                Frontiers Media S.A.
                1663-9812
                02 October 2023
                2023
                : 14
                : 1240295
                Affiliations
                [1] 1 Center for Brain Injury and Repair , Department of Neurosurgery , Perelman School of Medicine , University of Pennsylvania , Philadelphia, PA, United States
                [2] 2 Center for Neurotrauma, Neurodegeneration and Restoration , Corporal Michael J. Crescenz Veterans Affairs Medical Center , Philadelphia, PA, United States
                [3] 3 Department of Bioengineering , School of Engineering and Applied Science , University of Pennsylvania , Philadelphia, PA, United States
                [4] 4 Penn Psychedelics Collaborative , University of Pennsylvania , Philadelphia, PA, United States
                [5] 5 Department of Microbiology , Perelman School of Medicine , University of Pennsylvania , Philadelphia, PA, United States
                Author notes

                Edited by: Marco Scarselli, University of Pisa, Italy

                Reviewed by: Letizia Biso, University of Pisa, Italy

                Nathan Emmerich, Australian National University, Australia

                *Correspondence: D. Kacy Cullen, dkacy@ 123456pennmedicine.upenn.edu
                Article
                1240295
                10.3389/fphar.2023.1240295
                10588653
                37869749
                5bf4a263-413c-4784-a7a5-c20e291ee586
                Copyright © 2023 Acero, Cribas, Browne, Rivellini, Burrell, O’Donnell, Das and Cullen.

                This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

                History
                : 14 June 2023
                : 30 August 2023
                Funding
                This work was partially supported by the National Science Foundation Graduate Research Fellowship Program (VPA, Grant No. DGE-1845298), the Department of Veterans Affairs, Rehabilitation Research, and Development (JO, IK2-RX003376) and the National Institutes of Health (DKC, Grant No. R01-NS117757).
                Categories
                Pharmacology
                Review
                Custom metadata
                Translational Pharmacology

                Pharmacology & Pharmaceutical medicine
                psychedelics,psilocybin,salvinorin,ketamine,mechanism of action (moa),mdma,dmt,ayahuasca

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