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Byline: B Sessa (Psychopharmacology Unit, Bristol University, Bristol, UK); D Nutt (Psychopharmacology Unit, Bristol University, Bristol, UK) 457 Reply to Letter to the EditorsReply to letter by Green, Marsden and [...]

A letter to the editor is presented in response to the article related to pharmacology and psychotherapy, which appeared in the previous issue.

Psychedelics were used in the treatment of psychiatric conditions prior to their prohibition in the late 1960s. In the past three decades, there is a revived research interest in the therapeutic potential of psychedelic drugs with expected FDA approvals for treatment of various conditions. Given the exponential scientific growth of this field, we sought to characterize, analyze, and visualize trends in its top-cited articles. Bibliometric analyses are quantitative approaches to characterize a scientific field, including evaluation of the impact of academic literature. The bibliometric analysis and visualizations were conducted with R-tools for comprehensive science mapping. The top-cited 100 articles were cited between 82 and 668 times (median 125; mean 158). Fifty-four percent of the T100 articles were produced in the past decade (2010-2020). Network and author impact analysis highlighted key figures and primary collaboration networks within the top 100 publications. UK, USA, Switzerland, Spain, and Brazil lead the field. Results are discussed in terms of research growth, access, diversity, and the distribution of knowledge and experience in the field. These aggregated data and insights on the second wave of psychedelic research facilitate research evaluation, data-driven funding policies, and a practical map for researchers and clinicians entering the field.

Objective: Reports have indicated possible uses of ayahuasca for the treatment of conditions including depression, addictions, post-traumatic stress disorder, anxiety and specific psychoneuroendocrine immune system pathologies. The article assesses potential ayahuasca and N,N-dimethyltryptamine (DMT) integration with contemporary healthcare. The review also seeks to provide a summary of selected literature regarding the mechanisms of action of DMT and ayahuasca; and assess to what extent the state of research can explain reports of unusual phenomenology., Design: A narrative review., Results: Compounds in ayahuasca have been found to bind to serotonergic receptors, glutaminergic receptors, sigma-1 receptors, trace amine-associated receptors, and modulate BDNF expression and the dopaminergic system. Subjective effects are associated with increased delta and theta oscillations in amygdala and hippocampal regions, decreased alpha wave activity in the default mode network, and stimulations of vision-related brain regions particularly in the visual association cortex. Both biological processes and field of consciousness models have been proposed to explain subjective effects of DMT and ayahuasca, however, the evidence supporting the proposed models is not sufficient to make confident conclusions. Ayahuasca plant medicine and DMT represent potentially novel treatment modalities., Conclusions: Further research is required to clarify the mechanisms of action and develop treatments which can be made available to the general public. Integration between healthcare research institutions and reputable practitioners in the Amazon is recommended., (© 2022 The Authors. Human Psychopharmacology: Clinical and Experimental published by John Wiley & Sons Ltd.)

Background: Incorporating 3,4-methylenedioxymethamphetamine (MDMA) as an adjunct to psychotherapy has shown promise in recent years for treating various mental health conditions, particularly those involving trauma. However, concerns about declines in mood and cognition during the days following dosing, also known as 'Blue Mondays', have been raised as limitations to its clinical use. Although these changes have been well-documented among recreational users, there are critical confounds to these reports that limit generalizability to clinically administered MDMA., Aims: Here, we aimed to evaluate the evidence basis for the negative side effects associated with MDMA as well as inform our understanding of the drug's post-acute effects in a clinical context with an open-label study., Methods: The current open-label study examined MDMA therapy for alcohol use disorder (AUD; N = 14) and measured mood, sleep quality, illicit MDMA consumption and anecdotal reports after the acute drug effects had worn off., Results: Participants maintained a positive mood during the week following drug administration in a clinical context. Relative to baseline, self-reported sleep quality improved at the 3- and 6-month follow-ups. Finally, no participants reported using or desiring to use illicit MDMA, and the anecdotal reports indicated that they perceived the treatment favourably., Conclusion: The results support the overall safety and tolerability of clinically administered MDMA and, importantly, suggest that the 'come downs' previously associated with the substance may be explained by confounds in research relating to the illicit sourcing of the drug and specific environmental setting for recreational consumption.

Objectives: (1) To investigate whether a contrast-free biparametric MRI (bp-MRI) including T2-weighted images (T2W) and diffusion-weighted images (DWI) can be considered an accurate alternative to the standard multiparametric MRI (mp-MRI), consisting of T2, DWI, and dynamic contrast-enhanced (DCE) imaging for the muscle-invasiveness assessment of bladder cancer (BC), and (2) to evaluate how the diagnostic performance of differently experienced readers is affected according to the type of MRI protocol., Methods: Thirty-eight patients who underwent a clinically indicated bladder mp-MRI on a 3-T scanner were prospectively enrolled. Trans-urethral resection of bladder was the gold standard. Two sets of images, set 1 (bp-MRI) and set 2 (mp-MRI), were independently reviewed by four readers. Descriptive statistics, including sensitivity and specificity, were calculated for each reader. Receiver operating characteristic (ROC) analysis was performed, and the areas under the curve (AUCs) were calculated for the bp-MRI and the standard mp-MRI. Pairwise comparison of the ROC curves was performed., Results: The AUCs for bp- and mp-MRI were respectively 0.91-0.92 (reader 1), 0.90 (reader 2), 0.95-0.90 (reader 3), and 0.90-0.87 (reader 4). Sensitivity was 100% for both protocols and specificity ranged between 79.31 and 89.66% and between 79.31 and 83.33% for bp-MRI and mp-MRI, respectively. No significant differences were shown between the two MRI protocols (p > 0.05). No significant differences were shown accordingly to the reader's experience (p > 0.05)., Conclusions: A bp-MRI protocol consisting of T2W and DWI has comparable diagnostic accuracy to the standard mp-MRI protocol for the detection of muscle-invasive bladder cancer. The experience of the reader does not significantly affect the diagnostic performance using VI-RADS., Key Points: • The contrast-free MRI protocol shows a comparable accuracy to the standard multiparametric MRI protocol in the bladder cancer muscle-invasiveness assessment. • VI-RADS classification helps non-expert radiologists to assess the muscle-invasiveness of bladder cancer. • DCE should be carefully interpreted by less experienced readers due to inflammatory changes representing a potential pitfall.

Background: 3,4-methylenedioxymethamphetamine (MDMA) therapy has qualities that make it potentially well suited for patients with addictions, but this has never been explored in a research study. We present data from the Bristol Imperial MDMA in Alcoholism (BIMA) study. This is the first MDMA addiction study, an open-label safety and tolerability proof-of-concept study investigating the potential role for MDMA therapy in treating patients with alcohol use disorder (AUD)., Aims: This study aimed to assess if MDMA-assisted psychotherapy can be delivered safely and can be tolerated by patients with AUD post detoxification. Outcomes regarding drinking behaviour, quality of life and psychosocial functioning were evaluated., Methods: Fourteen patients with AUD completed a community alcohol detoxification and received an eight-week course of recovery-based therapy. Participants received two sessions with MDMA (187.5 mg each session). Psychological support was provided before, during and after each session. Safety and tolerability were assessed alongside psychological and physiological outcome measures. Alcohol use behaviour, mental well-being and functioning data were collected for nine months after alcohol detoxification., Results: MDMA treatment was well tolerated by all participants. No unexpected adverse events were observed. Psychosocial functioning improved across the cohort. Regarding alcohol use, at nine months post detox, the average units of alcohol consumption by participants was 18.7 units per week compared to 130.6 units per week before the detox. This compares favourably to a previous observational study (the 'Outcomes' study) by the same team with a similar population of people with AUD., Conclusions: This study provides preliminary support for the safety and tolerability of a novel intervention for AUD post detox. Further trials to examine better the therapeutic potential of this approach are now indicated.

Background: The Vesical Imaging Reporting and Data System (VI-RADS) was recently introduced as a standardized approach to reporting multiparametric magnetic resonance imaging (mpMRI) for bladder cancer. We aimed to prospectively analyze its routine use and its diagnostic performance in discriminating non-muscle-invasive bladder cancer (NMIBC) and muscle-invasive bladder cancer (MIBC)., Patients and Methods: A total of 38 patients with diagnosis of suspect bladder cancer at cystoscopy underwent bladder mpMRI before transurethral resection of the bladder (TURB). Bladder tumors were categorized according to the VI-RADS. After TURB, the VI-RADS score was compared with histological report for each lesion separately. Receiving operating characteristic and decision curve analyses were used to assess its accuracy and clinical utility., Results: A total of 68 lesions were included, of which 7 (10.3%) were MIBC. The pooled accuracy was 90.0% (95% confidence interval [CI], 75.4%-98.7%). The best threshold was estimated as VI-RADS 4, showing a sensitivity of 85.7% (95% CI, 57.1%-100%) and a specificity of 86.9% (95% CI, 78.7%-95.1%). Decision curve analyses showed that using VI-RADS ≥4 improved the net benefit compared with any default strategy for threshold probabilities of MIBC up to ∼40%, which is a reasonable clinical threshold for planning further treatments., Conclusions: Our prospective study shows that the use of VI-RADS as a standardized reporting method is appealing and could be considered in clinical practice owing to its high accuracy., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Objective: Research into psychedelic therapy models has shown promise for the treatment of specific psychiatric conditions. Mystical-type experiences occasioned by psilocybin have been correlated with therapeutic benefits and long-term improvements in positive mental outlook and attitudes. This article aims to provide an overview of the topic, highlight strengths and weaknesses in current research, generate novel perspectives and discussion, and consider future avenues for research., Design: This narrative review was designed to summarise and assess the state of research on psilocybin occasioned mystical-type experiences and applications for the treatment of specific psychiatric conditions., Results: Contemporary methods on the quantification of mystical-type experiences and their acute subjective effects are discussed. Recent studies provide some understanding of the pharmacological actions of psychedelics although the neurological similarities and differences between spontaneous and psychedelic mystical-type experiences are not well described. Applicability to modern clinical settings is assessed. Potential novel therapeutic applications include use in positive psychology interventions in healthy individuals., Conclusions: Since 2006 significant advancements in understanding the therapeutic potential of psilocybin-assisted psychotherapy have been made; however, more work is required to understand the neuromechanistic processes and applicability in modern clinical settings. Despite promising results in recent studies, funding issues for clinical trials, legal concerns and socio-cultural resistance provide a counterpoint to experimental evidence., (© The Authors. Human Psychopharmacology: Clinical and Experimental published by John Wiley & Sons Ltd.)

Purpose: To compare tumor detectability and conspicuity of standard b = 1000 s/mm 2 (b1000) versus ultrahigh b = 2000 s/mm 2 (b2000) diffusion-weighted imaging (DWI) in rectal cancer., Methods: Fifty-five patients for a total of 81 3T DWI-MR scans were retrospectively evaluated by two differently experienced readers. A comparison between b1000 and b2000 for tumor detectability and conspicuity was performed. The conspicuity was qualitatively and quantitatively assessed by using three-point scale and whole tumor volume manual delineation, respectively. Receiver-operating characteristic curve (ROC) with area under the curve (AUC) analysis provided diagnostic accuracy in tumor detectability of restaging MR scans. Qualitative scores and quantitative features including mean signal intensity, variance, 10th percentile and 90th percentile, were compared using the Wilcoxon test. Interobserver agreement (IOA) for qualitative and quantitative data was calculated using Cohen's Kappa and intraclass correlation coefficient (ICC) respectively., Results: Diagnostic accuracy was comparable between b1000 and b2000 for both readers (p > 0.05). Overall quality scores were significantly better for b2000 than b1000 (2.29 vs 1.65 Reader 1, p = 0.01; 2.18 vs 1.69 Reader 2, p = 0.04). IOA was equally good for both b values (k = 0.86 b1000, k = 0.86 b2000). Quantitative analysis revealed more uniform signal (measured in variance) of b2000 in both healthy surrounding tissue (p < 0.05) and tumor (p < 0.05), with less outliers (measured using 10th and 90th percentile). Additionally, b2000 offered lower mean signal intensity in tissue sorrounding the tumor (p < 0.05). Finally, ICC improved from 0.92 (b1000) to 0.97 (b2000)., Conclusion: Ultrahigh b value (b2000) may improve rectal cancer conspicuity and introbserver agreement maintaining comparable diagnostic accuracy to standard b1000.

We present the preliminary data in an ongoing open-label safety and tolerability proof of concept study exploring the potential role for 3,4-methylenedioxymethamphetamine (MDMA)-assisted psychotherapy in treating patients with alcohol use disorder. At this stage, seven participants have completed the full 8-week MDMA-assisted psychotherapy course, including two therapy sessions each with MDMA. This paper focuses on the safety and tolerability of the therapeutic course for the first four participants to complete treatment. Longer-term outcomes of drinking behaviour will be presented later when the full project data are published. Results show all four participants have successfully tolerated the treatment. There have been no serious adverse events related to MDMA, no unexpected physiological responses to the MDMA sessions or changes to blood results or electrocardiograms, measured before and after the 8-week course. We conclude that the treatment is well- tolerated and are making plans to expand the project into a randomised placebo-controlled study., Competing Interests: Competing interests: None declared., (© BMJ Publishing Group Limited 2019. No commercial re-use. See rights and permissions. Published by BMJ.)

This paper provides a brief review of the history, proposed pharmacological mechanisms, safety issues, and clinical applications of the medicine 3,4-methylenedioxymethamphetamine (MDMA). Most clinical MDMA research in patients to date has focused on MDMA-assisted psychotherapy to treat posttraumatic stress disorder (PTSD). In this review paper other potential therapeutic applications for MDMA therapy are described, including contemporary studies treating anxiety associated with autism and the authors' ongoing study exploring the potential role for MDMA-assisted psychotherapy to treat alcohol use disorder. MDMA therapy for PTSD is now entering the final Phase 3 stage of drug development, with a target set for licensing by the FDA and EMA in 2021. This means that if clinical efficacy criteria are achieved, MDMA would become a medicine.

Alcohol use disorder represents a serious clinical, social and personal burden on its sufferers and a significant financial strain on society. Current treatments, both psychological and pharmacological are poor, with high rates of relapse after medical detoxification and dedicated treatment programs. The earliest historical roots of psychedelic drug-assisted psychotherapy in the 1950s were associated with Lysergic acid diethylamide (LSD)-assisted psychotherapy to treat what was then called, alcoholism. But results were varied and psychedelic therapy with LSD and other 'classical' psychedelics fell out of favour in the wake of socio-political pressures and cultural changes. A current revisiting of psychedelic clinical research is now targeting substance use disorders - and particularly alcohol use disorder - again. 3,4-Methylenedioxymethamphetamine (MDMA)-assisted psychotherapy has never been formally explored as a treatment for any form of substance use disorder. But in recent years MDMA has risen in prominence as an agent to treat posttraumatic stress disorder (PTSD). With its unique receptor profile and a relatively well-tolerated subjective experience of drug effects when used clinically, MDMA Therapy is ideally suited to allow a patient to explore and address painful memories without being overwhelmed by negative affect. Given that alcohol use disorder is so often associated with early traumatic experiences, the author is proposing in a current on-going UK-based study that patients with alcohol use disorder who have undergone a medical detoxification from alcohol might benefit from a course of MDMA-assisted psychotherapy. This article is part of the Special Issue entitled 'Psychedelics: New Doors, Altered Perceptions'., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

Given the plethora of new studies and published papers in the scientific press and the increasingly emerging presence of articles about positive psychedelic experiences appearing in the popular media, there is little doubt that we are in the midst of a Psychedelic Renaissance. The classical psychedelic drugs LSD and psilocybin and the entactogen MDMA are showing promise as tools to assist psychotherapy for a wide range of mental disorders, with multiple pilot studies demonstrating their safety and efficacy. In this article, the author describes how MDMA in particular has inherent characteristics that make it well suited for assisting trauma-focused psychotherapy in a population of patients who have experienced child abuse. But despite these advances, there remain many obstacles ahead of the widespread mainstream acceptance of psychedelic medicines. The author argues that the Misuse of Drugs Act 1971 is one such obstacle. Other impediments include a prevailing attitude of pseudoscience and rigidity from within the non-scientific psychedelic community itself. Resolution of these conflicts must be sought if medicine and society are to see psychedelics gaining a place in mainstream culture and science.