Neuroimaging studies of cannabidiol and potential neurobiological mechanisms relevant for alcohol use disorders: a systematic review.

The underlying neurobiological mechanisms of cannabidiol's (CBD) management of alcohol use disorder (AUD) remains elusive.Aim We conducted a systematic review of neuroimaging literature investigating the effects of CBD on the brain in healthy participants. We then theorise the potential neurobiological mechanisms by which CBD may ameliorate various symptoms of AUD.Methods This review was conducted according to the PRISMA guidelines. Terms relating to CBD and neuroimaging were used to search original clinical research published in peer-reviewed journals.Results Of 767 studies identified by our search strategy, 16 studies satisfied our eligibility criteria. The results suggest that CBD modulates γ-Aminobutyric acid and glutamate signaling in the basal ganglia and dorso-medial prefrontal cortex. Furthermore, CBD regulates activity in regions associated with mesocorticolimbic reward pathways; salience, limbic and fronto-striatal networks which are implicated in reward anticipation; emotion regulation; salience processing; and executive functioning.Conclusion CBD appears to modulate neurotransmitter systems and functional connections in brain regions implicated in AUD, suggesting CBD may be used to manage AUD symptomatology.

Hypothalamic-pituitary-adrenocortical response in alcohol-dependent patients during baclofen treatment and association with clinical outcome: Preliminary results.

Baclofen has been shown to reduce alcohol consumption in some individuals with alcohol use disorder. This preliminary study aimed to evaluate i) the effect of baclofen versus placebo on hypothalamic-pituitary-adrenocortical activity (HPA axis), as measured by cortisol, and ii) the relationship between clinical outcomes such as alcohol consumption on a randomized controlled trial of baclofen (BAC) versus placebo (PL) (Kirsten C. Morley et al., 2018; K. C. Morley, Leung, Baillie, & Haber, 2013). We hypothesized that baclofen will reduce HPA-axis activity following a mild stressor in patients with alcohol dependence. Plasma cortisol levels were taken from N = 25 alcohol-dependent patients at two time points, approximately 60 (pre-MRI scan: PreCortisol) and 180 min (post MRI scan: PostCortisol) following administration of PL, BAC 10 mg, or BAC 25 mg. Participants were followed up for the remaining 10 weeks as part of the trial for clinical outcome (percentage days abstinent). Mixed models revealed a significant main effect of medication on cortisol levels (F = 3.88, p = 0.037), no significant effect of time (F = 0.04, p = 0.84), and a significant time × medication interaction (F = 3.54, p = 0.049). Linear regression (F = 6.98, p = 0.01, R2 = 0.66) revealed that abstinence at follow-up, weighted by gender, was predicted by blunted cortisol response (ß = -0.48 p = 0.023), in addition to medication (ß = 0.73 p = 0.003). In conclusion, our preliminary data suggest that baclofen moderates HPA-axis activity, as measured by blood cortisol, and that these alterations may play a role in long-term treatment response.

Central markers of neuroinflammation in alcohol use disorder: A meta-analysis of neuroimaging, cerebral spinal fluid, and postmortem studies.

INTRODUCTION AND AIMS: There is emerging evidence that heavy long-term alcohol consumption may alter the neuroimmune profile. We conducted a meta-analysis of the association between alcohol use disorder (AUD) and the extent of neuroinflammation using cerebrospinal (CSF), PET (Positron Emission Tomography), and postmortem studies. DESIGN AND METHODS: A comprehensive search of electronic databases was conducted using the Preferred Reporting Items for Systematic Review and Meta-Analysis Protocols (PRISMA-P) for AUD-related terms in combination with neuroinflammatory markers and cytokine- and chemokine-related terms for CSF, PET, and postmortem studies. Participants had to meet established criteria for AUD and/or heavy alcohol consumption with dependence features and be compared with healthy controls. Papers retrieved were assessed for inclusion criteria and a critical appraisal was completed using the Newcastle-Ottawa Scale. A meta-analysis was conducted on postmortem and PET studies. RESULTS: Eleven papers met the inclusion criteria with CSF, PET, and postmortem studies included in the final analysis. Postmortem studies demonstrate significant heterogeneity (𝑄 (14) = 62.02, 𝑝 < 0.001), with the alcohol group showing higher levels of neuroimmune markers than controls (𝑑 = 1.50 [95% CI 0.56, 2.45]). PET studies demonstrated a lower [11 C] PBR28 total volume of distribution (V T ) for translocator protein in the hippocampus (g = -1.95 [95% CI -2.72, -1.18], p < 0.001) of the alcohol group compared to controls. CONCLUSION: There is emerging evidence across multiple diagnostic modalities that alcohol impacts neuroimmune signaling in the human brain.

Assessing the validity of the Wechsler Adult Intelligence Scale (WAIS-IV) in predicting completion in a long-term residential rehabilitation for substance use problems.

BACKGROUND: We aimed to examine the predictive validity of the Weschler Adult Intelligence Scale (WAIS-IV) in predicting treatment completion, over and above educational status. METHODS: One hundred and ninety-six (N = 196) individuals from the Odyssey House Residential Rehabilitation Program, NSW, Australia between 2010 and 2016 were administered a structured interview including substance use disorders and the Verbal Comprehension (VCI), Perceptual Reasoning (PRI), Working Memory (WMI), and Processing Speed (PSI) domains of the WAIS-IV. RESULTS: There were significant differences between our clinical sample and the population norm with respect to the proportion below the mean for PSI (z = 12.27, p < .001), VCI (z = 2.33, p < .02) but not for WMI (z = 1.67, p < .10) or PRI (z = -1.76, p < .08). The WAIS-IV subscales did not significantly predict treatment completion (p's > .16) over and above educational status (p < .01). CONCLUSIONS: Our findings suggest that in clients in drug and alcohol rehabilitation settings a combination of skills may be impacted including Verbal Comprehension and Processing Speed. Moreover, our findings also suggest that WAIS-IV subscales do not predict treatment completion in a drug and alcohol residential setting, over and above a brief assessment of educational status.

Sex as a Potential Moderator for Baclofen Response in the Treatment of Alcohol Dependence.

Background and Aims: Recent studies indicate that sex may moderate the response to baclofen in the treatment of alcohol use disorder (AUD). We conducted a secondary analysis of a double-blind randomized controlled trial, Baclofen in the treatment of Alcohol Liver Disease (BacALD), to examine the moderating role of sex on treatment response to baclofen in reducing alcohol consumption. Methods: Alcohol-dependent patients (n = 104 including 74 men and 30 women) were treated for 12 weeks with baclofen (30 mg/day or 75 mg) or placebo. Predefined primary outcomes included time to lapse (any drinking) and relapse (≥ 5 drinks per day in men and ≥ 4drinks per day in women). Other outcomes included drinks per drinking day, the number of heavy drinking days, and percentage of days abstinent. We also examined the frequency of adverse events with an exploratory dose-response analysis. Results: There was a main effect of baclofen for days to first lapse for women (Log Rank: χ2 = 6.23, p = 0.01, d = 0.49) but not for men (Log Rank: χ2 = 2.48, p = 0.12, d = 0.22) and a marginal effect of baclofen for days to first relapse for women (Log Rank: χ2 = 3.15, p = 0.08, d = 0.27) but not for men (Log Rank: χ2 = 2.03, p = 0.16, d = 0.17). There were no significant effects of sex on the frequency of adverse events reported for the combined-dose or between-dose analysis (all p > 0.44). Conclusion: Baclofen significantly delayed the time to lapse for women but not male participants. These findings provide some support for the hypothesis that sex may be a potential moderator of baclofen response in the treatment of AUD. Trial Registration: https://clinicaltrials.gov/ct2/show/NCT01711125, identifier: NCT01711125.

Alcohol-related suicide across Australia: a geospatial analysis.

BACKGROUND: The acute effects of alcohol consumption are a major risk factor for suicide. Positive blood alcohol concentrations are present in almost one-third of all suicides at time of death. These suicides are defined as alcohol-related suicides. This cross-sectional study examines the geospatial distribution/clustering of high proportions of alcohol-related suicides and reports on socioeconomic and demographic risk factors. METHODS: National Coronial Information System (NCIS) data were used to calculate proportions of suicides with alcohol present at the time of death for each level 3 statistical areas (SA3) in Australia. A density analysis and hotspot cluster analysis were used to visualise and establish statistically significant clustering of areas with higher (hotspots) and lower (coldspots) proportions. Subsequently, socioeconomic and demographic risk factors for alcohol use and suicide were reported on for hot and cold spots. RESULTS: Significant clustering of areas with higher proportions of alcohol-related suicide occurred in northern Western Australia, the Northern Territory and Queensland, as well as inland New South Wales and inland Queensland. Clustering of SA3s with significantly lower proportions occurred in major city and inner regional Sydney and Melbourne. Conclusion and implications for public health: Results from this study identify areas in which prevention strategies should target alcohol use and can be used to inform prevention strategy design. Additionally, hotspots and coldspots identified in this study can be used for further analysis to better understand contextual risk factors for alcohol-related suicide.

New approved and emerging pharmacological approaches to alcohol use disorder: a review of clinical studies.

introduction: The number of medications approved for AUD is small and they generally have limited efficacy. We need new pharmacotherapies for the management of AUD.Areas covered: In this review, the authors aim to synthesise literature for new approved and emerging pharmacotherapies for AUD. Recently approved medications include nalmefene, which was approved in Europe and Australia for the purposes of controlled drinking. Baclofen has also been approved in France but not in other countries. Off label medications including topiramate and gabapentin have received significant attention with multiple RCTs and meta-analyses and have widespread use in several countries including the USA. Several novel medications have emerged over the last decade but further work is required to determine their efficacy and safety for the widespread management of AUD.Expert opinion: Despite significant advances in our understanding of the neurobiological basis of factors that contribute to the development and maintenance of AUD, there have been few new AUD medications approved for almost 20 years. There are many challenges to the development and introduction of new pharmacotherapies for AUD. Strategies for improving the translational pipeline include drug repurposing and utilisation of human acute laboratory models.

Psychosocial Interventions for Reducing Suicidal Behaviour and Alcohol Consumption in Patients With Alcohol Problems: A Systematic Review of Randomized Controlled Trials.

OBJECTIVE: We aimed to provide a synthesis and evaluation of psychosocial interventions to prevent suicide and reduce self-harm, as well as alcohol intake, for patients with alcohol problems. METHODS: The systematic review was carried out according to the PRISMA guidelines and considered articles published in English from all countries. Terms relating to suicidality and alcohol problems were used to search Medline, EMBASE and PsycINFO databases. Randomized controlled trials of psychosocial interventions targeted for outpatient settings were included. RESULTS: Six studies with a total of 400 participants were included. Two investigated dialectic behavioural therapy (DBT), one internet-delivered DBT, one dynamic deconstructivist psychotherapy (DDP) and two integrated cognitive behavioural therapy (CBT). Face to face and online DBT was significantly associated with abstinence and reductions in consumption with only a trend for a reduction in suicide attempts in one study relative to treatment at usual (TAU). DDP yielded significant reductions in alcohol consumption and suicide attempts versus community care. CBT was significantly effective relative to TAU in reducing alcohol use and suicide attempts in one trial with adolescents but not in another trial in an adult population. CONCLUSION: Integrated CBT has promise for adolescents, DBT may be helpful for alcohol patients with borderline personality disorder and iDBT may be useful for the wider community with heavy alcohol use. However, given the paucity of studies and the exploratory nature of these trials, there is currently no strong evidence for an effective psychosocial intervention to reduce alcohol consumption and suicidal behaviour in adults with problematic alcohol use.

Reporting of alcohol as a contributor to death in Australian national suicide statistics and its relationship to post-mortem alcohol concentrations.

AIM: To describe the assignment of International Classification of Disease (ICD)-10 alcohol codes as underlying or contributory causes of death by the Australian Bureau of Statistics during mortality coding for suicides according to the blood alcohol concentration (BAC) detected at autopsy. DESIGN: Population-based case-series descriptive analysis. SETTING AND PARTICIPANTS: Data for all alcohol-related (Alc+) suicide deaths (aged 15+) in Australia from 2010-2015 (n = 3132) from the National Coronial Information System. MEASUREMENTS: Alc+ suicides were categorised as those with a post-mortem BAC ≥0.05 g/100 mL. The outcome variable was whether the case was assigned an ICD-10 alcohol code (F10.0-F10.9, R78.0, T51, X45 and/or X65). We estimated OR for the assignment of codes in Alc+ suicides using BAC as the key predictor. We also examined several covariates that have been implicated in the risk of Alc+ suicides. FINDINGS: An ICD-10 alcohol code was assigned during the mortality coding process in 47.6% (n = 1491) of Alc+ suicides. Higher BAC was associated with higher odds of having a code assigned; cases with a BAC over 0.20 g/100 mL over were twice as likely to have an alcohol code assigned (adjusted OR [AOR] = 2.06, 95% CI = 1.59, 2.67) compared with cases with a BAC of 0.050-0.075 g/100 mL. Compared with New South Wales, higher likelihood of code assignment was found in Northern Territory (AOR = 3.85, 95% CI = 2.32, 6.63) and Western Australia (AOR = 2.89, 95% CI = 2.27, 3.68). Compared with 15-24 year olds, 25-44 (AOR = 0.79, 95% CI = 0.63, 0.99) and 65-84 year olds (AOR = 0.63, 95% CI = 0.43, 0.93) were less likely to have a code assigned. CONCLUSIONS: An ICD-10 alcohol code was not assigned as an underlying or contributory cause of death in over half of suicides in Australia (2010-2015) with a BAC ≥0.05 g/100 mL. The higher the BAC detected at autopsy, the more likely cases were to be assigned an alcohol code during the mortality coding process.