Search

Disclosure: B. Grant: None. J. Kean: None. N.L. de Silva: None. O. Quinton: None. P. Bassett: None. J. McVeigh: None. A. Lingford-Hughes: None. S. Minhas: None. S. Bhasin: None. W.S. Dhillo: None. C.N. Jayasena: None. Context: Anabolic-androgenic steroids (AAS) are misused by millions of men worldwide to boost muscle size and physical performance. Recent studies have quantified the recovery of cardiovascular markers and testicular function following AAS cessation. Qualitative studies demonstrate that low mood, anxiety, suicidal ideation, and sexual dysfunction are also common following AAS cessation. However, no previous study has focused on quantifying symptoms within the first year of AAS cessation, nor investigated independently associated factors for these symptoms. Methods: Cross-sectional, observational study of 165 men in 3 groups; non-AAS (n=43); current-AAS (n=76); past-AAS ≤1 year (n=46). All participants completed questions on substance misuse, Beck Depression Inventory-II (BDI-II), International Index Erectile Function-15 (IIEF-15), General Anxiety Disorder (GAD-7), Quality-of-life (SF-36), and underwent fasting, morning blood sampling with urine toxicology. Results: As expected, current-AAS had lower gonadotropins and elevated serum total testosterone compared with past-AAS and non-AAS. Sexual function measured using IIEF-15 was impaired in men stopping AAS <1year (past-AAS) compared with current AAS users: (1) total: 69.0 [95% CI 64.0, 71.0], current-AAS; 61.0 [95% CI 56.0, 66.0], past-AAS; p=0.077; (2) erectile function: 30.0 [95% CI 29.0, 30.0], current-AAS; 28 [95% CI 21.0, 29.0], past-AAS; p=0.015; (3) sexual desire: 9.0 [95% CI 8.0, 10.0], current-AAS; 6.0 [95% CI 5.0, 8.0], past-AAS; p<0.0001; (4) overall satisfaction: 10.0 [95% CI 8.0, 10.0], current-AAS; 7.0 [95% CI 7.0, 8.0], past-AAS; p=0.002. Multivariable analysis suggested that psychiatric comorbidity (coefficient -6.5 [95% CI -13.0, -1.3] p=0.03) and AAS cessation (coefficient -10.8 [95%

There is a growing interest in early phase dose-finding clinical trials studying combinations of several treatments. While the majority of dose finding designs for such setting were proposed for oncology trials, the corresponding designs are also essential in other therapeutic areas. Furthermore, there is increased recognition of recommending the patient-specific doses/combinations, rather than a single target one that would be recommended to all patients in later phases regardless of their characteristics. In this paper, we propose a dose-finding design for a dual-agent combination trial motivated by an opiate detoxification trial. The distinguishing feature of the trial is that the (continuous) dose of one compound is defined externally by the clinicians and is individual for every patient. The objective of the trial is to define the dosing function that for each patient would recommend the optimal dosage of the second compound. Via a simulation study, we have found that the proposed design results in high accuracy of individual dose recommendation and is robust to the model misspecification and assumptions on the distribution of externally defined doses. © 2021 The Authors. Pharmaceutical Statistics published by John Wiley & Sons Ltd.

Alcohol is one of the most widely consumed psychoactive drugs globally. Hazardous drinking, defined by quantity and frequency of consumption, is associated with acute and chronic morbidity. Alcohol use disorders (AUDs) are psychiatric syndromes characterized by impaired control over drinking and other symptoms. Contemporary aetiological perspectives on AUDs apply a biopsychosocial framework that emphasizes the interplay of genetics, neurobiology, psychology, and an individuals social and societal context. There is strong evidence that AUDs are genetically influenced, but with a complex polygenic architecture. Likewise, there is robust evidence for environmental influences, such as adverse childhood exposures and maladaptive developmental trajectories. Well-established biological and psychological determinants of AUDs include neuroadaptive changes following persistent use, differences in brain structure and function, and motivational determinants including overvaluation of alcohol reinforcement, acute effects of environmental triggers and stress, elevations in multiple facets of impulsivity, and lack of alternative reinforcers. Social factors include bidirectional roles of social networks and sociocultural influences, such as public health control strategies and social determinants of health. An array of evidence-based approaches for reducing alcohol harms are available, including screening, pharmacotherapies, psychological interventions and policy strategies, but are substantially underused. Priorities for the field include translating advances in basic biobehavioural research into novel clinical applications and, in turn, promoting widespread implementation of evidence-based clinical approaches in practice and health-care systems., Funding Agencies|Peter Boris Chair in Addictions Research; Tier 1 Canada Research Chair in Translational Addiction Research; Canadian Institutes of Health Research, Health Canada; National Institutes of Health (NIH) [R01AA024930, R01AA025911, R21 AA027679, R01AA025849]; NIH [R01AA025849, K24AA026876, K24AA022136, P50DA037844, R01AA02628, R01AA029688, K24AA025704]; Swedish Research Council [2013-07434, 2019-01138]; Knut and Alice Wallenberg Foundation; National Institute on Drug Abuse and the National Institute on Alcohol Abuse and Alcoholism

OBJECTIVE: To determine the most effective interventions in recently detoxified, alcohol dependent patients for implementation in primary care. DESIGN: Systematic review and network meta-analysis. DATA SOURCES: Medline, Embase, PsycINFO, Cochrane CENTRAL, ClinicalTrials.gov, and the World Health Organization's International Clinical Trials Registry Platform. STUDY SELECTION: Randomised controlled trials comparing two or more interventions that could be used in primary care. The population was patients with alcohol dependency diagnosed by standardised clinical tools and who became detoxified within four weeks. DATA EXTRACTION: Outcomes of interest were continuous abstinence from alcohol (effectiveness) and all cause dropouts (as a proxy for acceptability) at least 12 weeks after start of intervention. RESULTS: 64 trials (43 interventions) were included. The median probability of abstinence across placebo arms was 25%. Compared with placebo, the only intervention associated with increased probability of abstinence and moderate certainty evidence was acamprosate (odds ratio 1.86, 95% confidence interval 1.49 to 2.33, corresponding to an absolute probability of 38%). Of the 62 included trials that reported all cause dropouts, interventions associated with a reduced number of dropouts compared with placebo (probability 50%) and moderate certainty of evidence were acamprosate (0.73, 0.62 to 0.86; 42%), naltrexone (0.70, 0.50 to 0.98; 41%), and acamprosate-naltrexone (0.30, 0.13 to 0.67; 17%). Acamprosate was the only intervention associated with moderate confidence in the evidence of effectiveness and acceptability up to 12 months. It is uncertain whether other interventions can help maintain abstinence and reduce dropouts because of low confidence in the evidence. CONCLUSIONS: Evidence is lacking for benefit from interventions that could be implemented in primary care settings for alcohol abstinence, other than for acamprosate. More evidence from high quality randomised

Positron emission tomography (PET) enables non-invasive estimation of neurotransmitter fluctuations in the living human brain. While these methods have been applied to dopamine and some other transmitters, estimation of 5-hydroxytryptamine (5-HT; Serotonin) release has proved to be challenging. Here we demonstrate the utility of the novel 5-HT2A receptor agonist radioligand, [11C]CIMBI-36, and a d-amphetamine challenge to evaluate synaptic 5-HT changes in the living human brain. Seventeen healthy male volunteers received [11C]CIMBI-36 PET scans before and 3 h after an oral dose of d-amphetamine (0.5 mg/kg). Dynamic PET data were acquired over 90 min, and the total volume of distribution (VT) in the frontal cortex and the cerebellum derived from a kinetic analysis using MA1. The frontal cortex binding potential (BPNDfrontal) was calculated as (VTfrontal/VTcerebellum) - 1. ∆BPNDfrontal = 1 - (BPNDfrontal post-dose/BPNDfrontal baseline) was used as an index of 5-HT release. Statistical inference was tested by means of a paired Students t-test evaluating a reduction in post-amphetamine [11C]CIMBI-36 BPNDfrontal. Following d-amphetamine administration, [11C]CIMBI-36 BPNDfrontal was reduced by 14 ± 13% (p = 0.002). Similar effects were observed in other cortical regions examined in an exploratory analysis. [11C]CIMBI-36 binding is sensitive to synaptic serotonin release in the human brain, and when combined with a d-amphetamine challenge, the evaluation of the human brain serotonin system in neuropsychiatric disorders, such as major depression and Parkinson's disease is enabled.

Background: The US National Institutes of Mental Health Research Domain Criteria (RDoC) seek to stimulate research into biologically validated neuropsychological dimensions across mental illness symptoms and diagnoses. The RDoC framework comprises 39 functional constructs designed to be revised and refined, with the overall goal of improving diagnostic validity and treatments. This study aimed to reach a consensus among experts in the addiction field on the 'primary' RDoC constructs most relevant to substance and behavioural addictions. Methods: Forty-four addiction experts were recruited from Australia, Asia, Europe and the Americas. The Delphi technique was used to determine a consensus as to the degree of importance of each construct in understanding the essential dimensions underpinning addictive behaviours. Expert opinions were canvassed online over three rounds (97% completion rate), with each consecutive round offering feedback for experts to review their opinions. Results: Seven constructs were endorsed by ≥ 80% of experts as 'primary' to the understanding of addictive behaviour: five from the Positive Valence System (reward valuation, expectancy, action selection, reward learning, habit); one from the Cognitive Control System (response selection/inhibition); and one expert-initiated construct (compulsivity). These constructs were rated to be related differentially to stages of the addiction cycle, with some linked more closely to addiction onset and others more to chronicity. Experts agreed that these neuropsychological dimensions apply across a range of addictions. Conclusions: The study offers a novel and neuropsychologically informed theoretical framework, as well as a cogent step forward to test transdiagnostic concepts in addiction research, with direct implications for assessment, diagnosis, staging of disorder, and treatment.

Application of metabolic magnetic resonance imaging measures such as cerebral blood flow in translational medicine is limited by the unknown link of observed alterations to specific neurophysiological processes. In particular, the sensitivity of cerebral blood flow to activity changes in specific neurotransmitter systems remains unclear. We address this question by probing cerebral blood flow in healthy volunteers using seven established drugs with known dopaminergic, serotonergic, glutamatergic and GABAergic mechanisms of action. We use a novel framework aimed at disentangling the observed effects to contribution from underlying neurotransmitter systems. We find for all evaluated compounds a reliable spatial link of respective cerebral blood flow changes with underlying neurotransmitter receptor densities corresponding to their primary mechanisms of action. The strength of these associations with receptor density is mediated by respective drug affinities. These findings suggest that cerebral blood flow is a sensitive brain-wide in-vivo assay of metabolic demands across a variety of neurotransmitter systems in humans.

Background: The US National Institutes of Mental Health Research Domain Criteria (RDoC) seek to stimulate research into biologically validated neuropsychological dimensions across mental illness symptoms and diagnoses. The RDoC framework comprises 39 functional constructs designed to be revised and refined, with the overall goal of improving diagnostic validity and treatments. This study aimed to reach a consensus among experts in the addiction field on the ‘primary’ RDoC constructs most relevant to substance and behavioural addictions. Methods: Forty-four addiction experts were recruited from Australia, Asia, Europe and the Americas. The Delphi technique was used to determine a consensus as to the degree of importance of each construct in understanding the essential dimensions underpinning addictive behaviours. Expert opinions were canvassed online over three rounds (97% completion rate), with each consecutive round offering feedback for experts to review their opinions. Results: Seven constructs were endorsed by ≥ 80% of experts as ‘primary’ to the understanding of addictive behaviour: five from the Positive Valence System (reward valuation, expectancy, action selection, reward learning, habit); one from the Cognitive Control System (response selection/inhibition); and one expert-initiated construct (compulsivity). These constructs were rated to be related differentially to stages of the addiction cycle, with some linked more closely to addiction onset and others more to chronicity. Experts agreed that these neuropsychological dimensions apply across a range of addictions. Conclusions: The study offers a novel and neuropsychologically informed theoretical framework, as well as a cogent step forward to test transdiagnostic concepts in addiction research, with direct implications for assessment, diagnosis, staging of disorder, and treatment.

Copyright © 2018 The Authors, some rights reserved. Preliminary studies have suggested that -aminobutyric acid type A (GABAA) receptors, and potentially the GABAA 5 subtype, are deficient in autism spectrum disorder (ASD). However, prior studies have been confounded by the effects of medications, and these studies did not compare findings across different species. We measured both total GABAA and GABAA 5 receptor availability in two positron emission tomography imaging studies. We used the tracer [11C]flumazenil in 15 adults with ASD and in 15 control individuals without ASD and the tracer [11C]Ro15-4513 in 12 adults with ASD and in 16 control individuals without ASD. All participants were free of medications. We also performed autoradiography, using the same tracers, in three mouse models of ASD: the Cntnap2 knockout mouse, the Shank3 knockout mouse, and mice carrying a 16p11.2 deletion. We found no differences in GABAA receptor or GABAA 5 subunit availability in any brain region of adults with ASD compared to those without ASD. There were no differences in GABAA receptor or GABAA 5 subunit availability in any of the three mouse models. However, adults with ASD did display altered performance on a GABA-sensitive perceptual task. Our data suggest that GABAA receptor availability may be normal in adults with ASD, although GABA signaling may be functionally impaired.

In 2013, illegal drug use was responsible for 1.8% of years of life lost in the European Union, alcohol was responsible for 8.2% and tobacco for 18.2%, imposing economic burdens in excess of 2.5% of GDP. No single European country has optimal governance structures for reducing the harm done by nicotine, illegal drugs and alcohol, and existing ones are poorly designed, fragmented, and sometimes cause harm. Reporting the main science and policy conclusions of a transdisciplinary five-year analysis of the place of addictions in Europe, researchers from 67 scientific institutions addressed these problems by reframing an understanding of addictions. A new paradigm needs to account for evolutionary evidence which suggests that humans are biologically predisposed to seek out drugs, and that, today, individuals face availability of high drug doses, consequently increasing the risk of harm. New definitions need to acknowledge that the defining element of addictive drugs is 'heavy use over time', a concept that could replace the diagnostic artefact captured by the clinical term 'substance use disorder', thus opening the door for new substances to be considered such as sugar. Tools of quantitative risk assessment that recognize drugs as toxins could be further deployed to assess regulatory approaches to reducing harm. Re-designed governance of drugs requires embedding policy within a comprehensive societal well-being frame that encompasses a range of domains of well-being, including quality of life, material living conditions and sustainability over time; such a frame adds arguments to the inappropriateness of policies that criminalize individuals for using drugs and that continue to categorize certain drugs as illegal. A health footprint, modelled on the carbon footprint, and using quantitative measures such as years of life lost due to death or disability, could serve as the accountability tool that apportions responsibility for who and what causes drug-related harm.

In 2013, illegal drug use was responsible for 1.8% of years of life lost in the European Union, alcohol was responsible for 8.2% and tobacco for 18.2%, imposing economic burdens in excess of 2.5% of GDP. No single European country has optimal governance structures for reducing the harm done by nicotine, illegal drugs and alcohol, and existing ones are poorly designed, fragmented, and sometimes cause harm. Reporting the main science and policy conclusions of a transdisciplinary five-year analysis of the place of addictions in Europe, researchers from 67 scientific institutions addressed these problems by reframing an understanding of addictions. A new paradigm needs to account for evolutionary evidence which suggests that humans are biologically predisposed to seek out drugs, and that, today, individuals face availability of high drug doses, consequently increasing the risk of harm. New definitions need to acknowledge that the defining element of addictive drugs is 'heavy use over time', a concept that could replace the diagnostic artefact captured by the clinical term 'substance use disorder', thus opening the door for new substances to be considered such as sugar. Tools of quantitative risk assessment that recognize drugs as toxins could be further deployed to assess regulatory approaches to reducing harm. Re-designed governance of drugs requires embedding policy within a comprehensive societal well-being frame that encompasses a range of domains of well-being, including quality of life, material living conditions and sustainability over time; such a frame adds arguments to the inappropriateness of policies that criminalize individuals for using drugs and that continue to categorize certain drugs as illegal. A health footprint, modelled on the carbon footprint, and using quantitative measures such as years of life lost due to death or disability, could serve as the accountability tool that apportions responsibility for who and what causes drug-related harm.