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The GABA B agonist, baclofen, has been shown to reduce alcohol consumption in patients with alcohol use disorder and also those with comorbid anxiety. This study aimed to evaluate the effect of baclofen versus placebo on the BOLD response during an anticipatory anxiety fMRI task in treatment seeking alcohol patients. Participants included 28 alcohol dependant individuals who had received daily baclofen 30 mg (n = 10), 75 mg (n = 8) or placebo (n = 10) for at least 2 week on a randomized controlled trial (Morley, Leung et al. 2013, Morley, Baillie et al. 2018). Using functional magnetic resonance imaging (fMRI), we examined threat cue-elicited neural activation during a threat reactivity task 120 min following administration of BAC (30 mg or 75 mg) or placebo. Whole-brain analyses revealed no significant differences between the combined BAC doses versus PL. However, there were significant decreases in anticipatory threat cue-elicited activation observed in BAC 75 mg/day compared to PL participants in the insula. In response to threat cues, high dose (75 mg/day) baclofen administration attenuates activation in the insula and inferior frontal gyrus, relative to placebo. These preliminary findings suggests that modulating emotional regulation and attentional allocation during high threat stimuli may be mediated by GABA B receptors and may be a potential mechanism of action for baclofen's beneficial treatment effects for alcohol use disorder., Competing Interests: Conflict of interest None., (Copyright © 2021. Published by Elsevier B.V.)

There has been emerging interest in the role of the immune system in the pathophysiology of alcohol use disorder (AUD) given alcohol consumption stimulates immune cells to secrete peripheral pro- and anti-inflammatory cytokines. We conducted a systematic review and meta-analysis to determine whether an abnormal inflammatory cytokine profile exists in AUD patients compared to controls and whether cytokine levels were correlated with behavioural and psychiatric variables. Using the PRISMA (Preferred Reporting Items for Systematic reviews and Meta-analyses) guidelines, a comprehensive search of electronic databases (MEDLINE, EMBASE, Web of Science Core Collection and the Cochrane Library) was conducted, for AUD-related terms in combination with cytokine-related terms. Patients had to meet established criteria for AUD and be compared with healthy controls. A critical appraisal was completed using the Newcastle-Ottawa Scale. Twenty-four papers met the inclusionary criteria with 46 serum or plasma cytokines measured without immune stimulation whereby 17 studies had sufficient data for inclusion in the meta-analysis. Collectively, AUD patients had greater cytokine concentrations than control patients g = 0.85 [ 95% CI 0.42, 1.29]. Differences in cytokine concentrations between AUD patients and controls varied within-study by stage of illness (R (2) 2  = 19.56%). The greatest differences were reported when AUD patients were engaging in active drinking g = 0.96 [0.49, 1.43] or were in alcohol withdrawal g = 1.25 [0.71, 1.80]. Baseline findings were moderated within and between studies by cytokine identity R (2) 2  = 51.10%; R (3) 2  = 44.89%. Cytokine concentrations were not significantly correlated with self-reported craving for alcohol, but were with alcohol consumption r = 0.22 [-0.05, 0.46]. The relationship between cytokine concentration and consumption was moderated by cytokine identity (R (2) 2  = 100.00%; R (3) 2  = 100.00%), and sample age (R (2) 2  = 0.00%; R (3) 2  = 95.76%). There is sufficient evidence to support the presence of an abnormal circulating cytokine profile in AUD which may vary with respect to the different stages of AUD illness., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Crown Copyright © 2020. Published by Elsevier Inc. All rights reserved.)

Background: Although the efficacy of alcohol pharmacotherapy has been widely investigated, little is known about real-world prescription patterns. Population-based dispensing data can provide an understanding of prescription patterns and characteristics of treatment in nonexperimental settings., Methods: A retrospective cohort study of patients (aged 15-84) treated with acamprosate or naltrexone between July 2009 and June 2013 was conducted using dispensing claims from the Australian Pharmaceutical benefits Scheme Database. Only individuals with prescriptions from September 2009 onwards were included., Results: We identified 61,904 individuals (40% female, 32% in 35-44 age bracket,) with a total number of 198,247 dispensings. There were 23,452 naltrexone-treated and 38,452 acamprosate-treated patients. For naltrexone, 42% of initial dispenses were followed by a second dispense with only 25% receiving at least 3 months of treatment. For acamprosate, 28% of dispenses were followed by a third dispense with only 15% receiving at least 3 months of treatment. Patients in older age groups were more likely to be dispensed a repeat script than those in younger age groups (e.g., for the 75-84 vs 15-24 age bracket OR's=2.27 and 2.98 for naltrexone and acamprosate respectively)., Conclusion: Current national guidelines in Australia recommend alcohol pharmacotherapy for a minimum period of 3 months yet only 15-25% are receive this duration of treatment. Naltrexone-treated patients were more likely to return for a second and third dispense than acamprosate-treated patients. Prevalence and prescribing patterns change with age., (Crown Copyright © 2016. Published by Elsevier Ireland Ltd. All rights reserved.)

Background: Effective treatments for alcohol use disorders in those with significant liver disease are critically lacking. The primary aim of the current study is to explore the effectiveness and biobehavioural basis of low and high dose baclofen in improving treatment outcomes for alcohol dependence in people with alcoholic liver disease (The BacALD study)., Methods: This double-blind, placebo-controlled study will randomize 180 participants to a 12-week regime of either baclofen (30 mg/day baclofen, 75 mg/day baclofen) or placebo. Participants must meet the ICD-10 criteria for alcohol dependence in addition to alcoholic liver disease (ALD) defined as the presence of symptoms and/or signs referable to liver disease or its complications with or without cirrhosis. Primary outcome measures will include total abstinence duration, and time to lapse and relapse. Furthermore, 60 of the ALD patients enrolled in the trial will also participate in a pharmacokinetic and cue-reactivity component, along with an additional 30 healthy volunteers matched for age and gender randomised to a 1 week regime of either 30 mg/day baclofen or 75 mg/day baclofen. At week 1, plasma levels of baclofen and β-p-chlorophenol-γ-hydroxybutric acid will be measured at 0, 1 and 4 h following baclofen administration and psychophysiological responses to alcohol-associated stimuli will be assessed in a cue reactivity paradigm. Recruitment commenced in late March 2013., Conclusions: This trial will demonstrate the efficacy and safety of two doses of baclofen in patients with alcoholic liver disease and will explore the biobehavioural mechanisms of the treatment effect., (© 2013.)

The current experiment investigated the effect of 3,4-methylenedioxymethamphetamine (MDMA; 'Ecstasy') preexposure on the acquisition of intravenous amphetamine self-administration and the reinstatement of amphetamine-seeking behavior by either MDMA or amphetamine. Rats were preexposed to a 5-HT depleting regime of MDMA (5 mg/kg every hour for 4 h on two consecutive days) or equivalent vehicle injections. Intravenous self-administration of low dose d-amphetamine (0.03 mg/kg/infusion) on a FR1 schedule was subsequently assessed. The rats were then given 2 weeks of extinction and tested for drug-seeking behavior with priming doses of amphetamine or MDMA. Brains were analysed for monoamine content using high-performance liquid chromatography (HPLC). MDMA-preexposed rats were initially slower to acquire amphetamine self-administration. However, by day 6 of acquisition, there was no difference from controls. Following extinction, amphetamine (1 mg/kg, i.p.) reinstated drug seeking and produced locomotor hyperactivity in both MDMA- and vehicle-pretreated animals. However, MDMA (5 mg/kg, i.p.) was only effective in producing amphetamine seeking and hyperactivity in MDMA-pretreated rats. MDMA pretreatment caused significant decreases in 5-hydroxy-indolacetic acid (5-HIAA) and 5-HT in several brain regions. These results suggest that 5-HT depletion induced by MDMA may initially slow the acquisition of amphetamine self-administration but that MDMA preexposure may also sensitize animals to the locomotor stimulating and priming effects of MDMA on drug-seeking behavior.