Spironolactone as a potential new pharmacotherapy for alcohol use disorder: convergent evidence from rodent and human studies.

Evidence suggests that spironolactone, a nonselective mineralocorticoid receptor (MR) antagonist, modulates alcohol seeking and consumption. Therefore, spironolactone may represent a novel pharmacotherapy for alcohol use disorder (AUD). In this study, we tested the effects of spironolactone in a mouse model of alcohol drinking (drinking-in-the-dark) and in a rat model of alcohol dependence (vapor exposure). We also investigated the association between spironolactone receipt for at least 60 continuous days and change in self-reported alcohol consumption, using the Alcohol Use Disorders Identification Test-Consumption (AUDIT-C), in a pharmacoepidemiologic cohort study in the largest integrated healthcare system in the US. Spironolactone dose-dependently reduced the intake of sweetened or unsweetened alcohol solutions in male and female mice. No effects of spironolactone were observed on drinking of a sweet solution without alcohol, food or water intake, motor coordination, alcohol-induced ataxia, or blood alcohol levels. Spironolactone dose-dependently reduced operant alcohol self-administration in dependent and nondependent male and female rats. In humans, a greater reduction in alcohol consumption was observed among those who received spironolactone, compared to propensity score-matched individuals who did not receive spironolactone. The largest effects were among those who reported hazardous/heavy episodic alcohol consumption at baseline (AUDIT-C ≥ 8) and those exposed to ≥ 50 mg/day of spironolactone. These convergent findings across rodent and human studies demonstrate that spironolactone reduces alcohol use and support the hypothesis that this medication may be further studied as a novel pharmacotherapy for AUD.

Barriers to the management of alcohol use disorder and alcohol-associated liver disease: strategies to implement integrated care models.

Despite its increased recognition as a major public health issue, alcohol use disorder is mostly underdiagnosed and undertreated. The undertreatment and underdiagnosis of alcohol use disorder is most concerning in the management of patients with alcohol-associated liver disease, which is one of the main medical consequences of chronic and excessive alcohol use. Dual pathology (alcohol use disorder and alcohol-associated liver disease) requires multidisciplinary care involving hepatologists and addiction specialists. Such integrated care models are widely accepted as optimal care for treating comorbid medical and mental health conditions. However, the implementation of such models in clinical practice is challenging and often represents the exception, rather than the rule, in managing patients with alcohol use disorder and alcohol-associated liver disease. Barriers at the patient, clinician, and system levels are encountered in treating patients with alcohol use disorder and alcohol-associated liver disease. In this Viewpoint, we synthesise the emerging literature on the potential barriers encountered in caring for patients with alcohol-associated liver disease and alcohol use disorder and focus on how integrated models of care could overcome these barriers. We provide our perspective on why these barriers exist and propose strategies to overcome them.

Interventions and Manipulations of Interoception.

Interoceptive pathways may be manipulated at various levels to develop interventions to improve symptoms in a range of disorders. Primarily through the lens of the respiratory system, we outline various pathways that can be manipulated at neural, behavioral, and psychological levels to change the representation of and attention to interoceptive signals, which can alter interconnected physiological systems and improve functioning and adaptive behavior. Interventions can alter interoception via neuromodulation of the vagus nerve, slow breathing to change respiratory rate and depth, or awareness processes such as mindfulness-based interventions. Aspects of this framework may be applied to other physiological systems and future research may integrate interventions across multiple levels of manipulation or bodily systems.

The CRF1 Antagonist Verucerfont in Anxious Alcohol-Dependent Women: Translation of Neuroendocrine, But not of Anti-Craving Effects.

Blockade of corticotropin-releasing factor receptor 1 (CRF1) suppresses stress-induced alcohol seeking in rodents, but clinical translation remains. Here, we first showed that the CRF1 antagonist verucerfont potently blocks hypothalamic-pituitary adrenal (HPA) axis activation in adrenalectomized rats. We then evaluated verucerfont for its ability to block HPA axis activation and reduce stress-induced alcohol craving in alcohol-dependent patients. Anxious, alcohol-dependent women (age 21-65 years, n=39) were admitted to the NIH Clinical Center and completed withdrawal treatment before enrollment if needed. One-week single-blind placebo was followed by randomized double-blind verucerfont (350 mg per day) or placebo for 3 weeks. Verucerfont effects on the HPA axis were evaluated using the dexamethasone-CRF test. Craving was evaluated using two established protocols, one that combines a social stressor with physical alcohol cue exposure, and one that uses guided imagery to present personalized stress, alcohol, or neutral stimuli. An fMRI session examined brain responses to negative affective stimuli and alcohol cues. In contrast to our recent observations with another CRF1 antagonist, pexacerfont, verucerfont potently blocked the HPA axis response to the dexamethasone-CRF test, but left alcohol craving unaffected. Right amygdala responses to negative affective stimuli were significantly attenuated by verucerfont, but responses to alcohol-associated stimuli were increased in some brain regions, including left insula. Discontinuation rates were significantly higher in the verucerfont group. Our findings provide the first translational evidence that CRF1 antagonists with slow receptor dissociation kinetics may have increased efficacy to dampen HPA axis responses. The findings do not support a clinical efficacy of CRF1 blockade in stress-induced alcohol craving and relapse.

Treatments for alcohol-related disorders in China: a developing story.

AIMS: Alcohol-related disorders (ARDs) have become an increasing mental health and social challenge in China. Research from China may provide important clinical information for researchers and clinicians around the world. However, most of the Chinese research on ARDs has only been published in Chinese language journals. This article summarizes publications related to treatments for ARDs found in the Chinese literature. METHODS: A descriptive study based on literature identified from searches of the China National Knowledge Infrastructure (1979-2012), Pubmed databases and hand-picked references with emphasis on traditional Chinese medicine (TCM). RESULTS: More than 1500 Chinese language papers on treatment for ARDs were found and ~110 were selected. Many medications used in the Western countries (e.g. disulfiram and acamprosate) are not available in China, and no drugs have been officially approved for alcohol dependence. TCM approaches (including acupuncture, electroacupunture and herbals) have played a role in treatment for ARDs with some positive results. These unique methods are reviewed and the need for additional controlled studies is noted. CONCLUSION: Currently, very limited facilities, medications or programs are available for patients with ARDs in China, thus much improvement is needed in the field, including setting up intervention/treatment programs.

Turning the clock ahead: potential preclinical and clinical neuropharmacological targets for alcohol dependence.

Treating alcohol use disorders represents a main goal in public health, but the effect of current medications is modest. Thus, in the last few years, research has been focusing on identifying new neuropharmacological targets for alcohol dependence. This review will summarize recent research, which has identified new targets to treat alcohol dependence. A variety of systems have been investigated, such as the endocannabinoid system, modulators of glutamatergic transmission, corticotropin-releasing factor (CRF), neuropeptide Y (NPY), nociceptin, glial cell line-derived neurotrophic factor (GDNF), acetaldehyde (ACD), substance P and Neurokinin 1 (NK1) receptor, nicotinic acetylcholine receptors (nAchRs), alpha-adrenergic receptor, and many others. Compared to preclinical studies, only a few clinical studies have been conducted so far. Thus, there is a critical need to translate successful preclinical results into human clinical trials. However, since some clinical studies have failed to replicate preclinical findings, future research will have not only to identify more efficacious medications, but also delineate the best match between a particular pharmacotherapy with a specific alcoholic subtype.

Complementary medicine for alcohol dependence in Italian services: a mail questionnaire.

It is well known that Complementary Medicine (CM) is extensively used in western countries for the treatment of many afflictions. CM has been recently promoted in addiction treatment. To evaluate CM use in alcohol dependence we planned a mail questionnaire for Italian alcohol services. We sent out 612 questionnaires. Health services that were unable to respond to the questionnaire within a 20-day limit period were contacted by phone and if we obtained agreement to participate in the study the questionnaire was sent by fax. We obtained 312 (51.82%) completed questionnaires. Only 16.50% of Italian services use CM for alcohol dependence treatment and acupuncture is utilized more frequently than other methods (phytotherapy, homeopathy, etc.). In Italian alcohol services CM is identified as an instrument incorporated into traditional alcohol treatments (self-help groups, drug treatment, etc.) and not an alternative method. In fact, health services that use it as a principal method of treatment were a rare event in our study (1%). CM plays an integrated role with traditional forms of alcohol treatment in Italian alcohol services and this utilization could be useful to reduce drop-outs and improve alcohol treatment compliance.