A phase III multisite randomised controlled trial to compare the efficacy of cannabidiol to placebo in the treatment of cannabis use disorder: the CBD-CUD study protocol.

BACKGROUND: Cannabis use disorder (CUD) is increasingly common and contributes to a range of health and social problems. Cannabidiol (CBD) is a non-intoxicating cannabinoid recognised for its anticonvulsant, anxiolytic and antipsychotic effects with no habit-forming qualities. Results from a Phase IIa randomised clinical trial suggest that treatment with CBD for four weeks reduced non-prescribed cannabis use in people with CUD. This study examines the efficacy, safety and quality of life of longer-term CBD treatment for patients with moderate-to-severe CUD. METHODS/DESIGN: A phase III multi-site, randomised, double-blinded, placebo controlled parallel design of a 12-week course of CBD to placebo, with follow-up at 24 weeks after enrolment. Two hundred and fifty adults with moderate-to-severe CUD (target 20% Aboriginal), with no significant medical, psychiatric or other substance use disorders from seven drug and alcohol clinics across NSW and VIC, Australia will be enrolled. Participants will be administered a daily dose of either 4 mL (100 mg/mL) of CBD or a placebo dispensed every 3-weeks. All participants will receive four-sessions of Cognitive Behavioural Therapy (CBT) based counselling. Primary endpoints are self-reported cannabis use days and analysis of cannabis metabolites in urine. Secondary endpoints include severity of CUD, withdrawal severity, cravings, quantity of use, motivation to stop and abstinence, medication safety, quality of life, physical/mental health, cognitive functioning, and patient treatment satisfaction. Qualitative research interviews will be conducted with Aboriginal participants to explore their perspectives on treatment. DISCUSSION: Current psychosocial and behavioural treatments for CUD indicate that over 80% of patients relapse within 1-6 months of treatment. Pharmacological treatments are highly effective with other substance use disorders but there are no approved pharmacological treatments for CUD. CBD is a promising candidate for CUD treatment due to its potential efficacy for this indication and excellent safety profile. The anxiolytic, antipsychotic and neuroprotective effects of CBD may have added benefits by reducing many of the mental health and cognitive impairments reported in people with regular cannabis use. TRIAL REGISTRATION: Australian and New Zealand Clinical Trial Registry: ACTRN12623000526673 (Registered 19 May 2023).

Substance use during hospitalisation requiring an urgent clinical response: an opportunity for intervention.

BACKGROUND: There are few reports on drug use in patients while hospitalised and none regarding management or clinical outcomes. AIMS: To describe cases of drug use by inpatients requiring an urgent clinical response. METHODS: We retrospectively reviewed cases at a teaching hospital in Sydney, Australia, from February 2019 to March 2021. RESULTS: Thirty cases were identified, with no deaths. Two patient groups were identified: (i) substance use disorders, using illicit drugs and (ii) self-harm history, using prescribed or over-the-counter drugs. Management involved cardiac monitoring (40%), intensive care (30%), charcoal (20%), antidotes (20%) and intubation (13%). Discharge was planned in 22 of 30 patients, against medical advice in four and directed by medical staff in four. CONCLUSIONS: Inpatient drug use requiring an urgent clinical response was infrequently recognised but presents a risk of harm to patients and staff and increases service utilisation and costs. Both harm reduction and systematic approaches guided by institutional policy are recommended. Using these events as reachable moments to address driving factors may modify patients' risk from future events.

Economic evaluations of alcohol pharmacotherapy: Systematic review of economic evaluations of pharmacotherapy for the treatment of alcohol use disorder.

OBJECTIVE: Alcohol use disorders confer a significant burden of disease and economic cost worldwide. However, the utilisation of pharmacotherapies to manage alcohol use disorder is poor. We aimed to conduct a systematic review of economic evaluation studies of alcohol use disorder pharmacotherapies. METHODS: A search was conducted in Embase, Medline, CINAHL, PsychINFO and EconLit (August 2019, updated September 2022). Full economic evaluations using pharmacotherapy to treat alcohol use disorders were included. Included studies were stratified by medication and summarised descriptively. The Consensus on Health Economic Criteria list was used to assess the methodological quality. RESULTS: A total of 1139 studies were retrieved, of which 15 met the inclusion criteria. All studies were conducted in high-income countries. Four studies analysed nalmefene, four studies assessed acamprosate, three for naltrexone and four for stand-alone and/or combinations of naltrexone and acamprosate. There were 21 interventions synthesised from 15 studies as some studies evaluated multiple interventions and comparators. More than half of the included studies (73%) reported pharmacotherapy as dominant (less costly and more effective than comparators). From healthcare payer perspectives, five studies found that pharmacotherapy added to psychosocial support was dominant or cost-effective, accruing additional benefits at a higher cost but under accepted willingness to pay thresholds. Three analyses from a societal perspective found pharmacotherapy added to psychosocial support was a dominant or cost-effective strategy. Quality scores ranged from 63% to 95%. CONCLUSION: Pharmacotherapy added to psychosocial support was cost-effective from both healthcare and societal perspectives, emphasising an increased role for pharmacotherapy to reduce the burden of alcohol use disorders.

No improvement in AUDIT-C screening and brief intervention rates among wait-list controls following support of Aboriginal Community Controlled Health Services: evidence from a cluster randomised trial.

BACKGROUND: While Aboriginal and Torres Strait Islander Australians are less likely to drink any alcohol than other Australians, those who drink are more likely to experience adverse alcohol-related health consequences. In a previous study, providing Aboriginal Community Controlled Health Services (ACCHSs) with training and support increased the odds of clients receiving AUDIT-C alcohol screening. A follow-up study found that these results were maintained for at least two years, but there was large variability in the effectiveness of the intervention between services. In this study, we use services that previously received support as a comparison group to test whether training and support can improve alcohol screening and brief intervention rates among wait-list control ACCHSs. METHODS: Design: Cluster randomised trial using routinely collected health data. SETTING: Australia. CASES: Twenty-two ACCHSs that see at least 1000 clients a year and use Communicare as their practice management software. Intervention and comparator: After initiating support, we compare changes in screening and brief intervention between wait-list control services and services that had previously received support. MEASUREMENT: Records of AUDIT-C screening and brief intervention activity in routinely collected data. RESULTS: During the reference period we observed 357,257 instances where one of 74,568 clients attended services at least once during a two-monthly data extraction period. Following the start of support, the odds of screening (OR = 0.94 [95% CI 0.67, 1.32], p = 0.74, [Formula: see text]≈ 0.002) and brief intervention (OR = 1.43 [95% CI 0.69, 2.95], p = 0.34, [Formula: see text]≈ 0.002) did not improve for the wait-list control group, relative to comparison services. CONCLUSIONS: We did not replicate the finding that support and training improves AUDIT-C screening rates with wait-list control data. The benefits of support are likely context dependent. Coincidental policy changes may have sensitised services to the effects of support in the earlier phase of the study. Then the COVID-19 pandemic may have made services less open to change in this latest phase. Future efforts could include practice software prompts to alcohol screening and brief intervention, which are less reliant on individual staff time or resources. TRIAL REGISTRATION: Retrospectively registered on 2018-11-21: ACTRN12618001892202.

Impaired Decision-Making and Skin Conductance Responses Are Associated with Reward and Punishment Sensitivity in Individuals with Severe Alcohol Use Disorder.

INTRODUCTION: Individuals with alcohol use disorder (AUD) have difficulties regulating alcohol consumption, despite adverse drinking-related consequences. This may be due to incapacity incorporating previous negative feedback from drinking, resulting in impaired decision-making. METHODS: We assessed whether decision-making is impaired in participants with AUD related to severity of AUD, indexed by severe negative drinking consequences using the Drinkers Inventory of Consequences (DrInC) and reward and punishment sensitivity with the Behavioural Inhibition System Behavioural Activation System (BIS BAS) scales. 36 treatment-seeking alcohol-dependent participants completed the Iowa gambling task (IGT) with skin conductance responses (SCRs) measured continuously as an index of somatic autonomic arousal to evaluate impaired expectancy of negative outcomes. RESULTS: Two-thirds of the sample showed behavioural impairment during the IGT, with greater AUD severity related to worse performance. BIS moderated IGT performance according to severity of AUD, with increased anticipatory SCRs for those with fewer reported DrInC severe consequences. Participants with more DrInC severe consequences showed IGT deficits and reduced SCRs regardless of BIS scores. BAS-Reward was associated with increased anticipatory SCRs to disadvantageous deck choices among those with lower AUD severity, while SCRs did not differ related to AUD severity for reward outcomes. DISCUSSION: Effective decision-making in the IGT and adaptive somatic responses were moderated by punishment sensitivity contingent on severity of AUD in these drinkers, with impairments in expectancy to negative outcomes from risky choices, including reduced somatic responses, resulting in poor decision-making processes that may help explain impaired drinking and worse drinking-related consequences.

N acetylcysteine in the treatment of alcohol use disorder: a randomized, double-blind, placebo-controlled trial.

N-acetyl cysteine (NAC) is a potent antioxidant that modulates glutamatergic signalling which is thought to play a role in alcohol use disorder (AUD). There have been no clinical trials investigating NAC for AUD. We aimed to conduct a 28 day double-blind, placebo-controlled (PL) randomized trial of NAC in the treatment of AUD (NCT03879759). A total of 42 participants with AUD (56% alcohol-related liver disease) were randomized to receive placebo or NAC 2400 mg/day. Feasibility outcomes included treatment retention and adverse events. Primary clinical outcomes included alcohol consumption (heavy drinking days, standard drinks per drinking day). Secondary clinical outcome measures included craving, liver tests, and psychological outcomes. There were no significant differences in overall retention between treatment groups (χ2(1) = 0.14, P = 0.71: 86% vs 76% for placebo and NAC, respectively). The most commonly reported adverse event in NAC-treated individuals included headache (14%). For standard drinks per drinking day, there was a significant overall effect of time (F = 9.18, P < 0.001), no significant effect of treatment (F = 0.75, P = 0.79), and a significant time x treatment (NAC vs PL) effect (F = 2.73, P < 0.05). For number of heavy drinks per day, there was a significant overall effect of time (F = 3.16, P < 0.05) but no significant effect of treatment or time x treatment (P = 0.17). There were no significant NAC vs PL effects on secondary clinical outcome measures. In the first trial of NAC for the management of AUD, NAC appears to be feasible and safe. Although there was a significant effect of NAC vs placebo on some alcohol measures such as drinks per drinking day, there does appear to be a variable pattern of effect across time suggesting that a larger trial incorporating a longer treatment duration is now required to determine efficacy.

A genetic risk score and diabetes predict development of alcohol-related cirrhosis in drinkers.

BACKGROUND & AIMS: Only a minority of excess alcohol drinkers develop cirrhosis. We developed and evaluated risk stratification scores to identify those at highest risk. METHODS: Three cohorts (GenomALC-1: n = 1,690, GenomALC-2: n = 3,037, UK Biobank: relevant n = 6,898) with a history of heavy alcohol consumption (≥80 g/day (men), ≥50 g/day (women), for ≥10 years) were included. Cases were participants with alcohol-related cirrhosis. Controls had a history of similar alcohol consumption but no evidence of liver disease. Risk scores were computed from up to 8 genetic loci identified previously as associated with alcohol-related cirrhosis and 3 clinical risk factors. Score performance for the stratification of alcohol-related cirrhosis risk was assessed and compared across the alcohol-related liver disease spectrum, including hepatocellular carcinoma (HCC). RESULTS: A combination of 3 single nucleotide polymorphisms (SNPs) (PNPLA3:rs738409, SUGP1-TM6SF2:rs10401969, HSD17B13:rs6834314) and diabetes status best discriminated cirrhosis risk. The odds ratios (ORs) and (95% CIs) between the lowest (Q1) and highest (Q5) score quintiles of the 3-SNP score, based on independent allelic effect size estimates, were 5.99 (4.18-8.60) (GenomALC-1), 2.81 (2.03-3.89) (GenomALC-2), and 3.10 (2.32-4.14) (UK Biobank). Patients with diabetes and high risk scores had ORs of 14.7 (7.69-28.1) (GenomALC-1) and 17.1 (11.3-25.7) (UK Biobank) compared to those without diabetes and with low risk scores. Patients with cirrhosis and HCC had significantly higher mean risk scores than patients with cirrhosis alone (0.76 ± 0.06 vs. 0.61 ± 0.02, p = 0.007). Score performance was not significantly enhanced by information on additional genetic risk variants, body mass index or coffee consumption. CONCLUSIONS: A risk score based on 3 genetic risk variants and diabetes status enables the stratification of heavy drinkers based on their risk of cirrhosis, allowing for the provision of earlier preventative interventions. LAY SUMMARY: Excessive chronic drinking leads to cirrhosis in some people, but so far there is no way to identify those at high risk of developing this debilitating disease. We developed a genetic risk score that can identify patients at high risk. The risk of cirrhosis is increased >10-fold with just two risk factors - diabetes and a high genetic risk score. Risk assessment using this test could enable the early and personalised management of this disease in high-risk patients.

Genome-wide Association Study and Meta-analysis on Alcohol-Associated Liver Cirrhosis Identifies Genetic Risk Factors.

BACKGROUND AND AIMS: Only a minority of heavy drinkers progress to alcohol-associated cirrhosis (ALC). The aim of this study was to identify common genetic variants that underlie risk for ALC. APPROACH AND RESULTS: We analyzed data from 1,128 subjects of European ancestry with ALC and 614 heavy-drinking subjects without known liver disease from Australia, the United States, the United Kingdom, and three countries in Europe. A genome-wide association study (GWAS) was performed, adjusting for principal components and clinical covariates (alcohol use, age, sex, body mass index, and diabetes). We validated our GWAS findings using UK Biobank. We then performed a meta-analysis combining data from our study, the UK Biobank, and a previously published GWAS. Our GWAS found genome-wide significant risk association of rs738409 in patatin-like phospholipase domain containing 3 (PNPLA3) (odds ratio [OR] = 2.19 [G allele], P = 4.93 × 10-17 ) and rs4607179 near HSD17B13 (OR = 0.57 [C allele], P = 1.09 × 10-10 ) with ALC. Conditional analysis accounting for the PNPLA3 and HSD17B13 loci identified a protective association at rs374702773 in Fas-associated factor family member 2 (FAF2) (OR = 0.61 [del(T) allele], P = 2.56 × 10-8 ) for ALC. This association was replicated in the UK Biobank using conditional analysis (OR = 0.79, P = 0.001). Meta-analysis (without conditioning) confirmed genome-wide significance for the identified FAF2 locus as well as PNPLA3 and HSD17B13. Two other previously known loci (SERPINA1 and SUGP1/TM6SF2) were also genome-wide significant in the meta-analysis. GeneOntology pathway analysis identified lipid droplets as the target for several identified genes. In conclusion, our GWAS identified a locus at FAF2 associated with reduced risk of ALC among heavy drinkers. Like the PNPLA3 and HSD17B13 gene products, the FAF2 product has been localized to fat droplets in hepatocytes. CONCLUSIONS: Our genetic findings implicate lipid droplets in the biological pathway(s) underlying ALC.

Setting foot in private spaces: extending the hepatitis C cascade of care to automatic needle/syringe dispensing machines, a mixed methods study.

BACKGROUND: Global commitment to achieving hepatitis C virus (HCV) elimination has enhanced efforts in improving access to direct-acting antiviral (DAA) treatments for people who inject drugs (PWID). Scale-up of efforts to engage hard-to-reach groups of PWID in HCV testing and treatment is crucial to success. Automatic needle/syringe dispensing machines (ADMs) have been used internationally to distribute sterile injecting equipment. ADMs are a unique harm reduction service, affording maximum anonymity to service users. This paper explores the feasibility and acceptability of extending the HCV cascade of care to sites where ADMs are located. METHODS: The ADM users into Treatment (ADMiT) study was undertaken in a metropolitan region in Sydney, Australia. This mixed methods study involved analysis of closed-circuit television footage, ethnographic methods (fieldwork observation and in-depth interviews) and structured surveys. Researchers and peers conducted fieldwork and data collection over 10 weeks at one ADM site, including offering access to HCV testing and treatment. RESULTS: Findings from 10 weeks of fieldwork observations, 70 survey participants and 15 interviews highlighted that there is scope for engaging with this population at the time they use the ADM, and enhanced linkage to HCV testing and treatment may be warranted. Most survey participants reported prior HCV testing, 61% in the last 12 months and 38% had received HCV treatment. However, fieldwork revealed that most people observed using the ADM were not willing to engage with the researchers. Field work data and interviews suggested that extending the HCV cascade of care to ADMs may encroach on what is a private space for many PWID, utilized specifically to avoid engagement. DISCUSSION: Enhanced linkage to HCV testing and treatment for people who use ADMs may be warranted. However, data suggested that extending the HCV cascade of care to ADMs may encroach on what is a private space for many PWID, utilized specifically to avoid engagement. The current study raises important public health questions about the need to ensure interventions reflect the needs of affected communities, including their right to remain anonymous.

Relationship between clinician-level attributes and implementation outcomes from the Pathways to Comorbidity Care training program.

BACKGROUND: The process of determining the best strategy for increasing the uptake of evidence-based practice might be improved through an understanding of relevant clinician-level factors. The Pathways to Comorbidity Care (PCC) training program (Louie E, et al., J Dual Diagnosis 17:304-12, 2021) aimed to facilitate integrated management of comorbid drug and alcohol and mental disorders amongst drug and alcohol clinicians. We hypothesised that uptake of integrated management of comorbidity following the implementation of the PCC program would be associated with clinician-level: (i) demographics (gender, education, experience), (ii) attitudes (evidence-based practice, therapist manuals, counselling self-efficacy), and (iii) organisational readiness to change. METHODS: Twenty clinicians participated in the 9-month PCC training program. Attitudes towards evidence-based practices and psychotherapist manuals, self-efficacy, and organisational readiness to change, along with demographics, were measured at baseline. At follow-up, change in Comorbidity Practice (CoP) scores related to integrated comorbidity management were obtained using a file audit checklist and categorised into high (at least 60% increase in CoP), medium or low (a decrease of - 20% or less in CoP). Clinician-level characteristics were examined across the implementation categories. RESULTS: There were no significant differences found between implementation groups on sociodemographic variables (p's > 0.30), attitudes to evidence-based practices, attitudes to therapist manuals, and self-efficacy (p's > 0.52). The high implementation group demonstrated significantly higher scores on leadership practices aspect of organisational readiness to change relative to the low and medium implementation group ((F(2, 16) = 3.63, p = 0.05; Cohen's d = .31) but not on the other subscales (p's > 0.07). CONCLUSIONS: Confidence that leadership will play a positive role in the implementation process may improve effectiveness of comorbidity training programs for drug and alcohol clinicians. On the other hand, contrary to our hypothesis, counselling self-efficacy, evidence-based practice attitudes, attitudes towards therapist manuals, gender, education and experience were not distinguishing factors.

Obesity, Diabetes, Coffee, Tea, and Cannabis Use Alter Risk for Alcohol-Related Cirrhosis in 2 Large Cohorts of High-Risk Drinkers.

INTRODUCTION: Sustained high alcohol intake is necessary but not sufficient to produce alcohol-related cirrhosis. Identification of risk factors, apart from lifetime alcohol exposure, would assist in discovery of mechanisms and prediction of risk. METHODS: We conducted a multicenter case-control study (GenomALC) comparing 1,293 cases (with alcohol-related cirrhosis, 75.6% male) and 754 controls (with equivalent alcohol exposure but no evidence of liver disease, 73.6% male). Information confirming or excluding cirrhosis, and on alcohol intake and other potential risk factors, was obtained from clinical records and by interview. Case-control differences in risk factors discovered in the GenomALC participants were validated using similar data from 407 cases and 6,573 controls from UK Biobank. RESULTS: The GenomALC case and control groups reported similar lifetime alcohol intake (1,374 vs 1,412 kg). Cases had a higher prevalence of diabetes (20.5% (262/1,288) vs 6.5% (48/734), P = 2.27 × 10-18) and higher premorbid body mass index (26.37 ± 0.16 kg/m2) than controls (24.44 ± 0.18 kg/m2, P = 5.77 × 10-15). Controls were significantly more likely to have been wine drinkers, coffee drinkers, smokers, and cannabis users than cases. Cases reported a higher proportion of parents who died of liver disease than controls (odds ratio 2.25 95% confidence interval 1.55-3.26). Data from UK Biobank confirmed these findings for diabetes, body mass index, proportion of alcohol as wine, and coffee consumption. DISCUSSION: If these relationships are causal, measures such as weight loss, intensive treatment of diabetes or prediabetic states, and coffee consumption should reduce the risk of alcohol-related cirrhosis.

New Australian guidelines for the treatment of alcohol problems: an overview of recommendations.

OF RECOMMENDATIONS AND LEVELS OF EVIDENCE: Chapter 2: Screening and assessment for unhealthy alcohol use Screening Screening for unhealthy alcohol use and appropriate interventions should be implemented in general practice (Level A), hospitals (Level B), emergency departments and community health and welfare settings (Level C). Quantity-frequency measures can detect consumption that exceeds levels in the current Australian guidelines (Level B). The Alcohol Use Disorders Identification Test (AUDIT) is the most effective screening tool and is recommended for use in primary care and hospital settings. For screening in the general community, the AUDIT-C is a suitable alternative (Level A). Indirect biological markers should be used as an adjunct to screening (Level A), and direct measures of alcohol in breath and/or blood can be useful markers of recent use (Level B). Assessment Assessment should include evaluation of alcohol use and its effects, physical examination, clinical investigations and collateral history taking (Level C). Assessment for alcohol-related physical problems, mental health problems and social support should be undertaken routinely (GPP). Where there are concerns regarding the safety of the patient or others, specialist consultation is recommended (Level C). Assessment should lead to a clear, mutually acceptable treatment plan which specifies interventions to meet the patient's needs (Level D). Sustained abstinence is the optimal outcome for most patients with alcohol dependence (Level C). Chapter 3: Caring for and managing patients with alcohol problems: interventions, treatments, relapse prevention, aftercare, and long term follow-up Brief interventions Brief motivational interviewing interventions are more effective than no treatment for people who consume alcohol at risky levels (Level A). Their effectiveness compared with standard care or alternative psychosocial interventions varies by treatment setting. They are most effective in primary care settings (Level A). Psychosocial interventions Cognitive behaviour therapy should be a first-line psychosocial intervention for alcohol dependence. Its clinical benefit is enhanced when it is combined with pharmacotherapy for alcohol dependence or an additional psychosocial intervention (eg, motivational interviewing) (Level A). Motivational interviewing is effective in the short term and in patients with less severe alcohol dependence (Level A). Residential rehabilitation may be of benefit to patients who have moderate-to-severe alcohol dependence and require a structured residential treatment setting (Level D). Alcohol withdrawal management Most cases of withdrawal can be managed in an ambulatory setting with appropriate support (Level B). Tapering diazepam regimens (Level A) with daily staged supply from a pharmacy or clinic are recommended (GPP). Pharmacotherapies for alcohol dependence Acamprosate is recommended to help maintain abstinence from alcohol (Level A). Naltrexone is recommended for prevention of relapse to heavy drinking (Level A). Disulfiram is only recommended in close supervision settings where patients are motivated for abstinence (Level A). Some evidence for off-label therapies baclofen and topiramate exists, but their side effect profiles are complex and neither should be a first-line medication (Level B). Peer support programs Peer-led support programs such as Alcoholics Anonymous and SMART Recovery are effective at maintaining abstinence or reductions in drinking (Level A). Relapse prevention, aftercare and long-term follow-up Return to problematic drinking is common and aftercare should focus on addressing factors that contribute to relapse (GPP). A harm-minimisation approach should be considered for patients who are unable to reduce their drinking (GPP). Chapter 4: Providing appropriate treatment and care to people with alcohol problems: a summary for key specific populations Gender-specific issues Screen women and men for domestic abuse (Level C). Consider child protection assessments for caregivers with alcohol use disorder (GPP). Explore contraceptive options with women of reproductive age who regularly consume alcohol (Level B). Pregnant and breastfeeding women Advise pregnant and breastfeeding women that there is no safe level of alcohol consumption (Level B). Pregnant women who are alcohol dependent should be admitted to hospital for treatment in an appropriate maternity unit that has an addiction specialist (GPP). Young people Perform a comprehensive HEEADSSS assessment for young people with alcohol problems (Level B). Treatment should focus on tangible benefits of reducing drinking through psychotherapy and engagement of family and peer networks (Level B). Aboriginal and Torres Strait Islander peoples Collaborate with Aboriginal or Torres Strait Islander health workers, organisations and communities, and seek guidance on patient engagement approaches (GPP). Use validated screening tools and consider integrated mainstream and Aboriginal or Torres Strait Islander-specific approaches to care (Level B). Culturally and linguistically diverse groups Use an appropriate method, such as the "teach-back" technique, to assess the need for language and health literacy support (Level C). Engage with culture-specific agencies as this can improve treatment access and success (Level C). Sexually diverse and gender diverse populations Be mindful that sexually diverse and gender diverse populations experience lower levels of satisfaction, connection and treatment completion (Level C). Seek to incorporate LGBTQ-specific treatment and agencies (Level C). Older people All new patients aged over 50 years should be screened for harmful alcohol use (Level D). Consider alcohol as a possible cause for older patients presenting with unexplained physical or psychological symptoms (Level D). Consider shorter acting benzodiazepines for withdrawal management (Level D). Cognitive impairment Cognitive impairment may impair engagement with treatment (Level A). Perform cognitive screening for patients who have alcohol problems and refer them for neuropsychological assessment if significant impairment is suspected (Level A). SUMMARY OF KEY RECOMMENDATIONS AND LEVELS OF EVIDENCE: Chapter 5: Understanding and managing comorbidities for people with alcohol problems: polydrug use and dependence, co-occurring mental disorders, and physical comorbidities Polydrug use and dependence Active alcohol use disorder, including dependence, significantly increases the risk of overdose associated with the administration of opioid drugs. Specialist advice is recommended before treatment of people dependent on both alcohol and opioid drugs (GPP). Older patients requiring management of alcohol withdrawal should have their use of pharmaceutical medications reviewed, given the prevalence of polypharmacy in this age group (GPP). Smoking cessation can be undertaken in patients with alcohol dependence and/or polydrug use problems; some evidence suggests varenicline may help support reduction of both tobacco and alcohol consumption (Level C). Co-occurring mental disorders More intensive interventions are needed for people with comorbid conditions, as this population tends to have more severe problems and carries a worse prognosis than those with single pathology (GPP). The Kessler Psychological Distress Scale (K10 or K6) is recommended for screening for comorbid mental disorders in people presenting for alcohol use disorders (Level A). People with alcohol use disorder and comorbid mental disorders should be offered treatment for both disorders; care should be taken to coordinate intervention (Level C). Physical comorbidities Patients should be advised that alcohol use has no beneficial health effects. There is no clear risk-free threshold for alcohol intake. The safe dose for alcohol intake is dependent on many factors such as underlying liver disease, comorbidities, age and sex (Level A). In patients with alcohol use disorder, early recognition of the risk for liver cirrhosis is critical. Patients with cirrhosis should abstain from alcohol and should be offered referral to a hepatologist for liver disease management and to an addiction physician for management of alcohol use disorder (Level A). Alcohol abstinence reduces the risk of cancer and improves outcomes after a diagnosis of cancer (Level A).

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.

Randomised controlled trial of integrated cognitive behavioural treatment and motivational enhancement for comorbid social anxiety and alcohol use disorders.

OBJECTIVE: Alcohol use disorder and social anxiety disorder are interconnected disorders that commonly co-occur. We report the first trial to assess whether integrated treatment for social anxiety and alcohol use disorder comorbidity improves outcomes relative to standard alcohol-focussed treatment. METHOD: Participants were recruited to a randomised controlled trial, and randomly allocated to one of two treatments, Integrated (n = 61) or Control (alcohol-focussed; n = 56). Assessment and treatment session were conducted at two sites in Sydney, Australia. Inclusion criteria were as follows: (1) clinical diagnosis of social anxiety disorder and (2) Diagnosis or sub-clinical symptoms of alcohol use disorder. Diagnoses were determined according to the Diagnostic and Statistical Manual of Mental Disorders (4th ed.). All participants (n = 117) received 10 sessions of cognitive behavioural treatment and motivational enhancement. The Integrated treatment simultaneously targeted social anxiety disorder, alcohol use disorder and the connections between these disorders. The Control treatment focussed on alcohol use disorder only. Outcomes were assessed at 6-month follow-up, with interim assessments at post-treatment and 3 months. Primary outcomes were social anxiety disorder severity (composite Social Phobia Scale and Social Interaction Anxiety Scale), alcohol use disorder severity (standard drinks per day and Severity of Alcohol Dependence Questionnaire) and quality of life (Short-Form Health survey) was assessed to capture the combined impairment of social anxiety and alcohol use disorder comorbidity. RESULTS: At 6-month follow-up, both conditions showed significant reductions in social anxiety and alcohol use disorder symptoms, and improved quality of life. There was no evidence of between-condition differences for alcohol outcomes, with mean consumption reduced by 5.0 (0.8) and 5.8 (1.0) drinks per day following Alcohol and Integrated treatments, respectively. Integrated treatment achieved greater improvements in social anxiety symptoms (mean difference = -14.9, 95% confidence interval = [-28.1, -1.6], d = 0.60) and quality of life (mean difference = 7.6, 95% confidence interval = [1.2, 14.0], d = 0.80) relative to alcohol-focused treatment. CONCLUSION: These results suggest that integrated social anxiety and alcohol use disorder treatment enhances quality of life and social anxiety disorder symptom improvement, but not alcohol outcomes, compared to treatment focussed on alcohol use disorder alone.

Implementation of a Multi-Modal Training Program for the Management of Comorbid Mental Disorders in Drug and Alcohol Settings: Pathways to Comorbidity Care (PCC).

OBJECTIVES: We aimed to evaluate the impact of the Pathways to Comorbidity Care (PCC) training program for alcohol and other drugs (AOD) clinicians to improve the management of comorbidity. METHODS: A controlled before-and-after study using PCC training was conducted across 6 matched sites in Australia including 35 clinicians. Controls received standard workplace training. PCC training included seminar presentations, workshops conducted by local "clinical champions," individual clinical supervision, and access to an online information portal. We examined (a) identification (screening, assessment) and treatment (treatment, referral) of comorbidity in practice (N = 10 clinical files per clinician), (b) self-efficacy, knowledge, and attitudes of clinicians. RESULTS: Significant improvements were observed in the PCC group but not the control sites with regards to the rate of clinical files showing identification of comorbidity (+50% v -12% change from baseline, respectively; [X2 (1, N = 340) = 35.29, p = .01] with only a trend for improvements in the rate of files demonstrating treatment of comorbidity [X2 (1, N = 340) = 10.45, p = .06]. There were significant improvements in the PCC relative to the control group for clinician self-efficacy, F(1,33) = 6.40, p = .02 and knowledge and attitudes of comorbidity monitoring, F(1,33) = 8.745, p = .01. CONCLUSIONS: The PCC training package may help improve identification of comorbidity, self-efficacy, and attitudes toward screening and monitoring of comorbidity in drug and alcohol settings.

Hepatitis C virus testing, liver disease assessment and treatment uptake among people who inject drugs pre- and post-universal access to direct-acting antiviral treatment in Australia: The LiveRLife study.

Gaps in hepatitis C virus (HCV) testing, diagnosis, liver disease assessment and treatment uptake among people who inject drugs (PWID) persist. We aimed to describe the cascade of HCV care among PWID in Australia, prior to and following unrestricted access to direct-acting antiviral (DAA) treatment. Participants enrolled in an observational cohort study between 2014 and 2018 provided fingerstick whole-blood samples for dried blood spot, Xpert HCV Viral Load and venepuncture samples. Participants underwent transient elastography and clinical assessment by a nurse or general practitioner. Among 839 participants (mean age 43 years), 66% were male (n = 550), 64% (n = 537) injected drugs in the previous month, and 67% (n = 560) reported currently receiving opioid substitution therapy. Overall, 45% (n = 380) had detectable HCV RNA, of whom 23% (n = 86) received HCV treatment within 12 months of enrolment. HCV treatment uptake increased from 2% in the pre-DAA era to 38% in the DAA era. Significant liver fibrosis (F2-F4) was more common in participants with HCV infection (38%) than those without (19%). Age 50 years or older (aOR, 2.88; 95% CI, 1.18-7.04) and attending a clinical follow-up with nurse (aOR, 3.19; 95% CI, 1.61-6.32) or physician (aOR, 11.83; 95% CI, 4.89-28.59) were associated with HCV treatment uptake. Recent injection drug use and unstable housing were not associated with HCV treatment uptake. HCV treatment uptake among PWID has increased markedly in the DAA era. Evaluation of innovative and simplified models of care is required to further enhance treatment uptake.

Alcohol use disorder and circulating cytokines: A systematic review and meta-analysis.

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.

Baclofen modulates cardiovascular responses to appetitive cues in treatment-seeking alcohol use disorder individuals.

OBJECTIVE: To assess whether baclofen-treated alcohol dependent participants show different subjective and psychophysiological responses to appetitive cues during an alcohol cue reactivity task compared to placebo, and whether these responses are associated with prospective drinking outcomes. METHODS: Forty-two alcohol dependent participants (placebo: n = 12, low-dose baclofen [30 mg/day] n = 18, high-dose baclofen [75 mg/day]: n = 12) completed an alcohol cue reactivity task, whereby water and alcohol beverage cues were presented, with subsequent recovery periods, and subjective alcohol craving and psychophysiological indices (skin conductance; cardiovascular measures: heart rate, high-frequency heart rate variability) were recorded. RESULTS: High-dose baclofen-treated participants showed both overall cue reactivity to water and alcohol cues and greater recovery effects during recovery periods, revealed by high-frequency heart rate variability, when compared to low-dose- and placebo-treated participants. There were no medication effects on subjective craving. In high-dose baclofen participants only, there was a predictive effect of lower baseline heart rate variability and fewer post-test percentage of heavy drinking days. CONCLUSION: There was a dose-specific rescuing effect of high-dose baclofen on the dynamic modulation of cardiovascular responses to eliciting cues. Investigation of treatment responses using psychophysiological techniques may elucidate baclofen's mechanisms of action, and identify subgroups amenable to treatment.

Brain GABA levels are reduced in alcoholic liver disease: A proton magnetic resonance spectroscopy study.

BACKGROUND AND AIMS: Baclofen, a selective γ-aminobutyric acid (GABA)B receptor agonist, has emerged as a potential treatment for alcohol use disorder with much unexplained variation in response to treatment efficacy and dose regimen. Several positive studies include patients with alcoholic liver disease (ALD) and/or history of heavy drinking. The aim of this paper was to examine the association of cortical GABA+ concentration with severity of liver disease (including markers of liver injury) and other clinical characteristics in alcohol patients. METHODS: Proton magnetic resonance spectroscopy (1 H-MRS), from the parietal lobe, was analyzed to yield absolute concentration of GABA in 24 alcohol-dependent individuals. Diagnosis of ALD, markers of liver injury, severity of liver disease (Model for End-Stage Liver Disease [MELD]), and alcohol history were assessed. Covariates included concurrent medication, age, and recent alcohol consumption. RESULTS: Multiple linear regression revealed that GABA+ concentration was significantly predicted by MELD scores (F = 5.02, R2  = 0.59, P = 0.01; MELD: B = -0.63, P = 0.02), when controlling for covariates concurrent medication, age, and recent alcohol consumption. CONCLUSION: Severity of ALD is associated with lower cortical concentrations of GABA+. These results may explain variations in response to the GABAB agonist, baclofen, in the alcohol-dependent population.

Evidence based models of care for the treatment of alcohol use disorder in primary health care settings: a systematic review.

BACKGROUND: Pharmacological and behavioural treatments for alcohol use disorders (AUDs) are effective but the uptake is limited. Primary care could be a key setting for identification and continuous care for AUD due to accessibility, low cost and acceptability to patients. We aimed to synthesise the literature regarding differential models of care for the management of AUD in primary health care settings. METHODS: We conducted a systematic review of articles published worldwide (1998-present) using the following databases; Medline, PsycINFO, Cochrane database of systematic reviews, Cochrane Central Register of Controlled Trials and Embase. The Grey Matters Tool guided the grey literature search. We selected randomised controlled trials evaluating the effectiveness of a primary care model in the management of AUD. Two researchers independently assessed and then reached agreement on the included studies. We used the Cochrane risk of bias tool 2.0 for the critical appraisal. RESULTS: Eleven studies (4186 participants) were included. We categorised the studies into 'lower' versus 'higher' intensity given the varying intensity of clinical care evaluated across the studies. Significant differences in treatment uptake were reported by most studies. The uptake of AUD medication was reported in 5 out of 6 studies that offered AUD medication. Three studies reported a significantly higher uptake of AUD medication in the intervention group. A significant reduction in alcohol use was reported in two out of the five studies with lower intensity of care, and three out of six studies with higher intensity of care. CONCLUSION: Our results suggest that models of care in primary care settings can increase treatment uptake (e.g. psychosocial and/or pharmacotherapy) although results for alcohol-related outcomes were mixed. More research is required to determine which specific patient groups are suitable for AUD treatment in primary health care settings and to identify which models and components are most effective. TRIAL REGISTRATION: PROSPERO: CRD42019120293 .