Gene and cell therapy on the acquisition and relapse-like binge drinking in a model of alcoholism: translational options.

Studies reviewed show that lentiviral gene therapy directed either at inhibiting the synthesis of brain acetaldehyde generated from ethanol or at degrading brain acetaldehyde fully prevent ethanol intake by rats bred for their high alcohol preference. However, after animals have chronically consumed alcohol, the above gene therapy did not inhibit alcohol intake, indicating that in the chronic ethanol intake condition brain acetaldehyde is no longer the compound that generates the continued alcohol reinforcement. Oxidative stress and neuroinflammation generated by chronic ethanol intake are strongly associated with the perpetuation of alcohol consumption and alcohol relapse "binge drinking". Mesenchymal stem cells, referred to as guardians of inflammation, release anti-inflammatory cytokines and antioxidant products. The intravenous delivery of human mesenchymal stem cells or the intranasal administration of mesenchymal stem cell-generated exosomes reverses both (i) alcohol-induced neuro-inflammation and (ii) oxidative stress, and greatly (iii) inhibits (80-90%) chronic alcohol intake and relapse binge-drinking. The therapeutic effect of mesenchymal stem cells is mediated by increased levels of the brain GLT-1 glutamate transporter, indicating that glutamate signaling is pivotal for alcohol relapse. Human mesenchymal stem cells and the products released by these cells may have translational value in the treatment of alcohol-use disorders.

Intravenous administration of anti-inflammatory mesenchymal stem cell spheroids reduces chronic alcohol intake and abolishes binge-drinking.

Chronic alcohol intake leads to neuroinflammation and astrocyte dysfunction, proposed to perpetuate alcohol consumption and to promote conditioned relapse-like binge drinking. In the present study, human mesenchymal stem cells (MSCs) were cultured in 3D-conditions to generate MSC-spheroids, which greatly increased MSCs anti-inflammatory ability and reduced cell volume by 90% versus conventionally 2D-cultured MSCs, enabling their intravenous administration and access to the brain. It is shown, in an animal model of chronic ethanol intake and relapse-drinking, that both the intravenous and intra-cerebroventricular administration of a single dose of MSC-spheroids inhibited chronic ethanol intake and relapse-like drinking by 80-90%, displaying significant effects over 3-5 weeks. The MSC-spheroid administration fully normalized alcohol-induced neuroinflammation, as shown by a reduced astrocyte activation, and markedly increased the levels of the astrocyte Na-glutamate (GLT-1) transporter. This research suggests that the intravenous administration of MSC-spheroids may constitute an effective new approach for the treatment of alcohol-use disorders.

Computer-Facilitated Screening and Brief Advice to Reduce Adolescents' Heavy Episodic Drinking: A Study in Two Countries.

PURPOSE: A computer-facilitated screening and brief advice (cSBA) intervention was previously shown to reduce drinking among U.S. adolescents but not among Czech youth. The purpose of this study was to assess cSBA effect on heavy episodic drinking (HED). METHODS: Participants were 12- to 18-year-olds at nine U.S. primary care offices (N = 2,096) and 10 Czech pediatrician-generalist offices (N = 589) who completed measurements only during an 18-month treatment-as-usual (TAU) phase. We then initiated the cSBA protocol for all participants and recruited the 18-month cSBA phase. Generalized Estimating Equations logistic regression compared past-90-day HED for cSBA versus TAU at 3- and 12-months, controlling for baseline HED and other covariates. RESULTS: Baseline past-90-day HED rates were 11% for U.S. and 28% for Czech youth. At 3 months, among Czech baseline non-HED, the adjusted relative risk ratio for cSBA versus TAU was .52 (95% confidence interval .29, .92). The effect dissipated by 12 months. CONCLUSIONS: cSBA shows promise for short-term prevention of adolescent HED.

HealthCall delivered via smartphone to reduce co-occurring drug and alcohol use in HIV-infected adults: A randomized pilot trial.

AIMS: Co-occurrence of drug and alcohol use among people living with HIV is linked to poor medication adherence and lack of viral suppression. HealthCall, a technological enhancement of brief Motivational Interviewing (MI), involves brief daily self-monitoring, positive reinforcement, and personalized feedback. This randomized pilot study among people living with HIV investigated the feasibility and efficacy of reducing non-injection drug and alcohol use with MI+HealthCall as adapted for smartphone technology. DESIGN: An urban, largely-minority community sample of adults living with HIV were screened for eligibility: last 30 day use of non-injection drugs (≥4days of crack/cocaine, methamphetamine, or heroin use) and binge drinking (≥1day of 4+ standard drinks). Those eligible were randomized to one of two groups: MI-only (n=21) and MI+HealthCall-S (n=21). Trained counselors delivered the brief MI at baseline. Drug and alcohol use assessments were completed at baseline, 30 and 60days (end of treatment). Primary outcomes derived from a Timeline Follow Back (TLFB) of the past 30 days included (1) total number of days used primary drug (NumDU) (2) total quantity of primary drug used (dollar amount spent per day; QuantU), (3) total number of drinking days (NumDD) and (4) mean number of drinks per day (QuantDD). Feasibility was determined by HealthCall use rates, patient satisfaction questionnaire (1-5 scale, 5 being best), and retention. FINDINGS: The median daily use rate for HealthCall was 95%, patient satisfaction was excellent (4.5) and retention was high (93%). Both treatment groups reduced drug and alcohol use by end of treatment, with MI+Healthcall-S showing significantly greater reductions than MI-only in QuantU (p=0.01) and NumDU (p=0.046). P-values for reductions in alcohol quantity and frequency in the MI+Healthcall group were 0.09-0.11. CONCLUSIONS: This proof-of-concept randomized trial indicates that HealthCall on the smartphone is a highly feasible intervention in urban, minority individuals with HIV, and suggests efficacy in reducing co-occurring drug and alcohol use. Results suggest opportunities for brief behavioral intervention that may be enhanced through interactive mobile technology to address complex alcohol and drug use patterns that interfere with HIV care, medication adherence and ultimately, viral suppression. A larger randomized trial is warranted to replicate and extend present results.

The effect of varenicline on binge-like ethanol consumption in mice is ß4 nicotinic acetylcholine receptor-independent.

BACKGROUND: Our laboratory has previously shown that the smoking-cessation agent varenicline, an agonist/partial agonist of α4ß2*, α3ß4*, α3ß2*, α6ß2* (* indicates the possibility of additional subunits) and α7 subunits of nicotinic acetylcholine receptors (nAChRs), reduces ethanol consumption in rats only after long-term exposure (12 weeks). As compounds having partial agonistic activity on α3ß4* nAChRs were shown to decrease ethanol consumption in rodents, we assessed here the involvement of the ß4 subunit in the effect of varenicline in the reduction of short- and long-term binge-like ethanol drinking in mice. METHODS: We used the well-validated drinking-in-the-dark (DID) paradigm to model chronic binge-like ethanol drinking in ß4-/- and ß4+/+ littermate mice and compare the effect of intraperitoneal injection of varenicline (2mg/kg) on ethanol intake following short- (4 weeks) or long-term (12 weeks) exposure. RESULTS: Drinking pattern and amounts of ethanol intake were similar in ß4-/- and ß4+/+ mice. Interestingly, our results showed that varenicline reduces ethanol consumption following short- and long-term ethanol exposure in the DID. Although the effect of varenicline on the reduction of ethanol consumption was slightly more pronounced in ß4-/- mice than their ß4+/+ littermates no significant differences were observed between genotypes. CONCLUSION: In mice, varenicline reduces binge-like ethanol consumption both after short- and long-term exposure in the DID and this effect is independent of ß4 nAChR subunit.

The long-term effect of a population-based life-style intervention on smoking and alcohol consumption. The Inter99 Study--a randomized controlled trial.

AIMS: To examine whether improvements in smoking and alcohol consumption throughout the 5-year course of a population-based multi-factorial life-style intervention were sustained 5 years after its discontinuation. DESIGN: Population-based randomized controlled trial. SETTING: Suburbs of Copenhagen, Denmark. PARTICIPANTS: A total of 9415 people aged 30-60 years were randomized to an intervention group (n = 6091) and an assessment-only control group (n = 3324). INTERVENTION: All participants in the intervention group received screening, risk assessment and individual life-style counselling; participants at high risk of ischaemic heart disease-according to pre-specified criteria-were also offered group-based counselling. MEASUREMENTS: Self-reported point abstinence from smoking as well as changes in the average alcohol consumption per week and binge drinking in the past week from baseline to 10-year follow-up were investigated using random-effects modelling. FINDINGS: At 10-year follow up, people in the intervention group reported a higher smoking abstinence rate [odds ratio (OR) = 1.84, 95% confidence interval (CI) = 1.02-3.33, P = 0.043] and a greater reduction in binge drinking (net change = -0.08 days with binge drinking in the last week, 95% CI = -0.16 to -0.01, P = 0.028) than in the control group. There were no detectable long-term intervention effects on the average alcohol consumption per week. CONCLUSIONS: A population-based multi-factorial life-style intervention of 5 years' duration in Denmark had sustained beneficial effects on smoking abstinence and binge drinking 5 years after its discontinuation.

Do therapist behaviors differ with Hispanic youth? A brief look at within-session therapist behaviors and youth treatment response.

Brief addiction treatments, including motivational interviewing (MI), have shown promise with youth. One underexamined factor in this equation is the role of therapist behaviors. We therefore sought to assess whether and how therapist behaviors differ for Hispanic versus non-Hispanic youth and how that may be related to treatment outcome. With 80 substance-using adolescents (M age = 16 years; 65% male; 59% Hispanic; 41% non-Hispanic), we examined the relationship between youth ethnicity and therapist behaviors across two brief treatments (MI and alcohol/marijuana education [AME]). We then explored relationships to youth 3-month treatment response across four target outcomes: binge drinking days, alcohol-related problems, marijuana use days, and marijuana-related problems. In this study, therapists showed significantly more MI skills within the MI condition and more didactic skills in the AME condition. With respect to youth ethnicity, across both conditions (MI and AME), therapists used less MI skills with Hispanic youth. Contrary to expectations, therapists' use of MI skills was not connected to poorer outcomes for Hispanic youth across the board (e.g., for binge drinking days, marijuana use days, or marijuana-related problems). Rather, for Hispanic youth, therapists' use of lower MI skills was related only to poorer treatment outcomes in the context of alcohol-related problems. The observed relationships highlight the importance of investigating salient treatment interactions between therapist factors and youth ethnicity to guide improvements in youth treatment response.

SBIRT goes to college: interdisciplinary screening for alcohol use.

Although risky/harmful drinking, in the form of binge drinking, remains a national problem, only recently have health services in universities systematically screened for drinking, drug use, and smoking. This article recounts "lessons learned" in two nurse-directed, interdisciplinary health services, which adapted the National College Depression Partnership model to include screening and brief intervention (SBIRT) for risky/harmful alcohol use in the form of binge drinking. Using a planned change model, nurse leaders worked with university administrators, providers, and health service staff to screen all students seeking health services for risky drinking. The outcomes suggest that this process may increase staff and student awareness of the importance of alcohol consumption to health, show the ease of using SBIRT screening along with standard screening tools, and yield information on the normalization of high-risk drinking in collegiate settings. Project findings indicate that common perceptions in college students minimize negative outcomes and stress the importance of additional quality assurance initiatives that review the efficacy of combinations of standardized screening tools.