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Background: Alcohol use disorder (AUD) is among the leading causes of morbidity and mortality worldwide, and over 95 million people live with alcohol dependence globally. The estimated heritability of AUD is 50-60 %, and multiple genes are thought to contribute to various endophenotypes of the disease. Previous clinical trials support a precision medicine approach using ondansetron (AD04, a 5-HT3 antagonist) by segregating AUD populations by the bio-genetic endophenotype of specific serotonergic genotypes and the bio-psychosocial endophenotype of the severity of drinking or both. By targeting the modulation of biogenetic signaling within the biopsychosocial context of AUD, low-dose AD04 holds promise in reducing alcohol consumption among affected individuals while minimizing adverse effects., Methods: This was a phase III, 6-month, 25-site, randomized, placebo-controlled clinical trial using AD04 to treat DSM-V-categorized AUD individuals who were pre-stratified into the endophenotypes of heavy or very heavy drinking individuals and possessed a pre-defined profile of genetic variants related to the serotonin transporter and serotonin-3AB receptor. Participants (N = 303) presented moderate to severe AUD, >80 % were men, mostly in their fifties, and >95 % were of European descent. Low-dose AD04 (approx. 033 mg twice daily) or a matching placebo was administered twice daily for 6 months. Brief Behavioral Compliance Enhancement Treatment (BBCET [53]) was administered every two weeks to enhance medication compliance and clinic attendance., Results: There was a significant reduction in the monthly percentage of heavy drinking days, PHDD (-46·7 % (2·7 %), 95 %CI: -52·1 % to -41·2 % vs. -38·1 % (2·9 %), 95 %CI: -43·8 % to -32·5 %, respectively; LS mean difference=-8·5 %; p = 0.03) among AD04-treated vs. placebo-receiving heavy drinking individuals at month 6. Heavy drinking individuals were also less likely to be diagnosed with AUD [Month 1: -32·0 % (2·8 %), 95 %CI: -37·5 % to -26·5 % vs. -23·2 % (2·9 %), 95 %CI: -28·9 to -17·5 %; LS mean difference= -8·8 %; p = 0·026)], and improved on the WHO quality of life BREF scale with a significant effect for at least a 1-level downward shift (OR = 3.4; 95 % CI: 1·03-11·45, p = 0·044). Importantly, heavy drinking individuals, as distinct from very heavy drinking individuals, were the bio-psychosocial endophenotype more predictive of therapeutic response to AD04. AD04 had an exceptional safety and tolerability profile, like the placebo's., Conclusions: In this Phase 3 clinical trial, AD04 was shown to be a promising treatment for currently drinking heavy drinking individuals with AUD who also possess a specific genotypic profile in the serotonin transporter and serotonin-3AB receptor complex. Using AD04 to reduce the harm of AUD in heavy drinking individuals who are currently drinking, without the necessity of abstinence or detoxification from alcohol use, is an important advance in the field of precision medicine. AD04's adverse events profile, which was like placebo, should enhance accessibility and acceptance of modern medical treatment for AUD by lowering the incorrect but commonly perceived stigma of personal failure., Competing Interests: Declaration of competing interest All authors are paid consultants of Adial Pharmaceuticals Inc. Vinzant Schuyler and Bankole Johnson are officers of Adial Pharmaceuticals Inc., (Copyright © 2024. Published by Elsevier B.V.)

Emerging treatments for alcohol dependence reveal an intricate interplay of neurobiological, psychological, and circumstantial factors that contribute to Alcohol Use Disorder (AUD). The approved strategies balancing these factors involve extensive manipulations of neurotransmitter systems such as GABA, Glutamate, Dopamine, Serotonin, and Acetylcholine. Innovative developments are engaging mechanisms such as GABA reuptake inhibition and allosteric modulation. Closer scrutiny is placed on the role of Glutamate in chronic alcohol consumption, with treatments like NMDA receptor antagonists and antiglutamatergic medications showing significant promise. Complementing these neurobiological approaches is the progressive shift towards Personalized Medicine. This strategy emphasizes unique genetic, epigenetic and physiological factors, employing pharmacogenomic principles to optimize treatment response. Concurrently, psychological therapies have become an integral part of the treatment landscape, tackling the cognitive-behavioral dimension of addiction. In instances of AUD comorbidity with other psychiatric disorders, Personalized Medicine becomes pivotal, ensuring treatment and prognosis are closely defined by individual characteristics, as exemplified by Lesch Typology models. Given the high global prevalence and wide distribution of AUD, a persistent necessity exists for development and improvement of treatments. Current research efforts are steadily paving paths towards more sophisticated, effective typology-based treatments: a testament to the recognized imperative for enhanced treatment strategies. The potential encapsulated within the ongoing research suggests a promising future where the clinical relevance of current strategies is not just maintained but significantly improved to effectively counter alcohol dependence., (Copyright © 2024. Published by Elsevier Inc.)

Alcohol-associated liver disease (ALD) is the most common cause of cirrhosis and liver-related mortality in many regions worldwide. Around 75% of patients with cirrhosis are unaware of their disease until they are referred to the emergency department. An innovative, noninvasive screening approach is required for an earlier diagnosis of liver fibrosis. In patients with ALD the physician is inevitably dealing with 2 major disorders: the liver disease itself and the alcohol use disorder (AUD). Focus only on the liver disease will inevitably lead to failure because transient improvements in liver function are rapidly overturned if the patient returns to alcohol consumption. For this reason, integrated models of care provided by hepatologists and addiction specialists are an effective approach, which are, however, not widely available. There are multiple pharmacologic and non-pharmacologic therapies for AUD. Progress has recently been made in the management of patients with severe AH who have improved survival through better understanding of the concept of response to medical treatment, improved survival prediction, and the advent of early liver transplantation. The emerging concept is that listing for transplantation a patient with severe ALD could lead to adjusting the duration of abstinence according to the severity and evolution of liver dysfunction and the patient's addictive profile., (Crown Copyright © 2023. Published by Elsevier Inc. All rights reserved.)

Aims: The estimated effect of sodium oxybate (SMO) in the treatment of alcohol dependence is heterogeneous. Population severity and treatment duration have been identified as potential effect modifiers. Population severity distinguishes heavy drinking patients with <14 days of abstinence before treatment initiation (high-severity population) from other patients (mild-severity population). Treatment duration reflects the planned treatment duration. This study aimed to systematically investigate the effect of these potential effect moderators on SMO efficacy in alcohol-dependent patients., Methods: Network meta-regression allows for testing potential effect modifiers. It was selected to investigate the effect of the above factors on SMO efficacy defined as continuous abstinence (abstinence rate) and the percentage of days abstinent (PDA). Randomized controlled trials for alcohol dependence with at least one SMO group conducted in high-severity and mild-severity populations were assigned to a high-severity and mild-severity group of studies, respectively., Results: Eight studies (1082 patients) were retained: four in the high-severity group and four in the mild-severity group. The high-severity group was associated with larger SMO effect sizes than the mild-severity group: abstinence rate risk ratio (RR) 3.16, P = 0.004; PDA +26.9%, P < 0.001. For PDA, longer treatment duration was associated with larger SMO effect size: +11.3% per extra month, P < 0.001. In the high-severity group, SMO showed benefit: abstinence rate RR 2.91, P = 0.03; PDA +16.9%, P < 0.001. In the mild-severity group, SMO showed benefit only in PDA for longer treatment duration: +23.9%, P < 0.001., Conclusions: In the retained studies with alcohol-dependent patients, high-severity population and longer treatment duration were associated with larger SMO effect sizes., (© The Author(s) 2023. Medical Council on Alcohol and Oxford University Press.)

Acute alcohol intoxication (AAI) is a harmful clinical condition, potentially life-threatening, secondary to the intake of large amounts of alcohol. Clinical manifestations of AAI are characterized by behavioural and neurological symptoms, even if its effects involve several organs and apparatus. Moreover, severe alcohol intoxication can produce a global neurological impairment leading to autonomic dysfunction, respiratory depression, coma and cardiac arrest. The evaluation of blood alcohol concentrations (BAC) is useful to confirm the suspicion of intoxication, both for clinical and legal reasons. Most of patients with AAI are referred to Emergency Departments due to behavioural, social, traumatic or clinical complications. Patient's stabilization is the first step in the management of AAI, in order to support vital functions and to prevent complications. Metadoxine represents a useful drug to increase ethanol metabolism and elimination. Given that AAI could represent a sentinel event of chronic alcohol abuse, patients presenting with acute intoxication should be screened for the presence of an underlying alcohol use disorder and referred to and an alcohol addiction unit to start a multidisciplinary treatment to achieve long term alcohol abstinence. The present review will focus on clinical features, diagnostic criteria and treatment strategies of AAI., Competing Interests: Conflict of Interest None., (Copyright © 2022 European Federation of Internal Medicine. Published by Elsevier B.V. All rights reserved.)

Alcohol use disorder (AUD) is one of the main causes of global death and disability. The liver represents the main target of alcohol damage, and alcohol-associated liver disease (ALD) represents the first cause of liver cirrhosis in Western countries. Alcohol abstinence is the main goal of treatment in AUD patients with ALD, as treatments for ALD are less effective when drinking continues. Moreover, the persistence of alcohol consumption is associated with higher mortality, increased need for liver transplantation, and graft loss. The most effective treatment for AUD is the combination of psychosocial interventions, pharmacological therapy, and medical management. However, the effectiveness of these treatments in patients with ALD is doubtful even because AUD patients with ALD are usually excluded from pharmacological trials due to concerns on liver safety. This narrative review will discuss the treatment options for AUD-ALD patients focusing on controversies in pharmacological therapy., Competing Interests: None declared., (Thieme. All rights reserved.)

Aim: People experiencing homelessness are often excluded from treatment programs for alcohol use disorder (AUD). The goal of this study was to describe the impact of a multidisciplinary treatment program on alcohol consumption and social reintegration in individuals with AUD experiencing homelessness., Methods: Thirty-one individuals with AUD experiencing homelessness were admitted to an inpatient unit for 5-6 days for clinical evaluation and to treat potential alcohol withdrawal syndrome. A group of volunteers, in collaboration with the Community of Sant'Egidio, provided social support aimed to reintegrate patients. After inpatient discharge, all patients were followed as outpatients. Alcohol intake (number drinks/day), craving and clinical evaluation were assessed at each outpatient visit. Biological markers of alcohol use were evaluated at enrollment (T0), at 6 months (T1) and 12 months (T2)., Results: Compared with T0, patients at T1 showed a significant reduction in alcohol consumption [10 (3-24) vs 2 (0-10); P = 0.015] and in γ-glutamyl-transpeptidase [187 (78-365) vs 98 (74-254); P = 0.0021]. The reduction in alcohol intake was more pronounced in patients with any housing condition [10 (3-20) vs 1 (0-8); P = 0.008]. Similarly, compared with T0, patients at T2 showed significant reduction in alcohol consumption [10 (3-24) vs 0 (0-15); P = 0.001], more pronounced in patients with any housing condition [10 (3-20) vs 0 (0-2); P = 0.006]. Moreover, at T2 patients showed a significant reduction in γ-glutamyl-transpeptidase [187 (78-365) vs 97 (74-189); P = 0.002] and in mean cell volume [100.2 (95-103.6) vs 98.3 (95-102); P = 0.042]., Conclusion: Patients experiencing homelessness may benefit from a multidisciplinary treatment program for AUD. Strategies able to facilitate and support their social reintegration and housing can improve treatment outcomes., (© The Author(s) 2020. Medical Council on Alcohol and Oxford University Press. All rights reserved.)

Background & Aims: Alcohol use disorder (AUD) represents the most common cause of liver disease. The gut microbiota plays a critical role in the progression of alcohol-related liver damage. Aim of this study was to characterize the gut microbial composition and function in AUD patients with alcohol-associated liver disease (AALD)., Methods: This study included 36 AUD patients (14 with cirrhosis) who were active drinkers and an equal number of matched controls. Stool microbial composition, serum levels of lipopolysaccharide, cytokines/chemokines and gut microbiota functional profile were assessed., Results: AUD patients had a decreased microbial alpha diversity as compared to controls (0.092 vs 0.130, P = .047) and a specific gut microbial signature. The reduction of Akkermansia and the increase in Bacteroides were able to identify AUD patients with an accuracy of 93.4%. Serum levels of lipopolysaccharide (4.91 vs 2.43, P = .009) and pro-inflammatory mediators (tumour necrosis factor alpha 60.85 vs 15.08, P = .001; interleukin [IL] 1beta 4.43 vs 1.72, P = .0001; monocyte chemoattractant protein 1 225.22 vs 16.43, P = .006; IL6 1.87 vs 1.23, P = .008) were significantly increased in AUD patients compared to controls and in cirrhotic patients compared to non-cirrhotic ones (IL6 3.74 vs 1.39, P = .019; IL8 57.60 vs 6.53, P = .004). The AUD-associated gut microbiota showed an increased expression of gamma-aminobutyric acid (GABA) metabolic pathways and energy metabolism., Conclusions: AUD patients present a specific gut microbial fingerprint, associated with increased endotoxaemia, systemic inflammatory status and functional alterations that may be involved in the progression of the AALD and in the pathogenesis of AUD., (© 2020 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Alcohol use disorder which includes alcohol abuse and dependence represents one of the leading risk factors for premature mortality in Europe and it is responsible of over 200 conditions, including neuropsychiatric disorders, chronic diseases, cancers and accidents leading to permanent disability. Alcohol use disorder represents the most common cause of liver damage in the Western world, with a wide spectrum of diseases ranging from steatosis, steatohepatitis, fibrosis, cirrhosis and cancer. The present clinical practice guidelines by the Italian Association for the Study of the Liver (AISF) are focused on the current knowledge about epidemiology, pathophysiology, clinical features, diagnosis and treatment of alcohol associated liver disease, aiming to provide practical recommendations on the management of this complex pathological condition., (Copyright © 2019 Editrice Gastroenterologica Italiana S.r.l. Published by Elsevier Ltd. All rights reserved.)

Introduction : Sodium oxybate (SMO) has been approved in Italy and in Austria for the treatment of alcohol use disorder (AUD). This study describes the cumulative postmarketing and clinical safety experience with SMO in AUD. Areas covered : Safety data for SMO at approved posology in AUD were identified from: (i) the clinical trial registries of the US National Institutes of Health (NIH) and the European Medicines Agency (EMA), (ii) reports from the biomedical literature and (iii) available pharmacovigilance safety information from the EMA. Expert opinion : Safety data from 3 recent large randomized clinical studies (520 participants) and 43 earlier clinical studies (2547 participants) showed that SMO has a good safety profile in AUD patients. The safety profile was confirmed by pharmacovigilance data resulting from 299 013 patients exposed to SMO in Austria and Italy. Main adverse events were transitory dizziness and vertigo. Serious adverse events were rare. No death attributable to SMO has been reported. Risks of abuse or dependence are low in patients without psychiatric comorbidities or poly-drug use. The adverse events of SMO are transitory and do not require discontinuation of treatment. SMO abuse or dependence are extremely rare in patients without psychiatric comorbidities or poly-drug use.

Alcohol use disorder is the most common cause of advanced liver disease in the Western world. Diagnosis of alcohol use disorder can be difficult because patients with liver disease tend to deny alcohol intake for the fear of being excluded from treatment and because available biomarkers of alcohol intake have poor specificity in these patients. Alcohol abstinence is the cornerstone of the therapy in these patients. However, pharmacological treatments for alcohol use disorders have not been formally tested in patients with advanced liver disease, except for baclofen. Psychosocial intervention became crucial in these patients considering the limited pharmacological choice. However, psychosocial approach and an appropriate team to manage these patients are not still well defined. In this review, we critically discuss the diagnosis and the management of alcohol use disorder in patients with liver disease.

Alcohol use disorders (AUDs) are one of the leading causes of mortality and morbidity worldwide. In spite of significant advances in understanding the neural underpinnings of AUDs, therapeutic options remain limited. Recent studies have highlighted the potential of repetitive transcranial magnetic stimulation (rTMS) as an innovative, safe, and cost-effective treatment for AUDs. Here, we summarize the fundamental principles of rTMS and its putative mechanisms of action via neurocircuitries related to alcohol addiction. We will also discuss advantages and limitations of rTMS, and argue that Hebbian plasticity and connectivity changes, as well as state-dependency, play a role in shaping some of the long-term effects of rTMS. Visual imaging studies will be linked to recent clinical pilot studies describing the effect of rTMS on alcohol craving and intake, pinpointing new advances, and highlighting conceptual gaps to be filled by future controlled studies., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Medication development for alcohol relapse prevention or reduction of consumption is highly challenging due to methodological issues of pharmacotherapy trials. Existing approved medications are only modestly effective with many patients failing to benefit from these therapies. Therefore, there is a pressing need for other effective treatments with a different mechanism of action, especially for patients with very high (VH) drinking risk levels (DRL) because this is the most severely affected population of alcohol use disorder patients. Life expectancy of alcohol-dependent patients with a VH DRL is reduced by 22 years compared with the general population and approximately 90 000 alcohol-dependent subjects with a VH DRL die prematurely each year in the EU (Rehm et al. ). A promising new medication for this population is sodium oxybate, a compound that acts on GABA B receptors and extrasynaptic GABA A receptors resulting in alcohol-mimetic effects. In this article, a European expert group of alcohol researchers and clinicians summarizes data (a) from published trials, (b) from two new-as yet unpublished-large clinical trials (GATE 2 (n = 314) and SMO032 (n = 496), (c) from post hoc subgroup analyses of patients with different WHO-defined DRLs and (d) from multiple meta-analyses. These data provide convergent evidence that sodium oxybate is effective especially in a subgroup of alcohol-dependent patients with VH DRLs. Depending on the study, abstinence rates are increased up to 34 percent compared with placebo with risk ratios up to 6.8 in favor of sodium oxybate treatment. These convergent data are supported by the clinical use of sodium oxybate in Austria and Italy for more than 25 years. Sodium oxybate is the sodium salt of γ-hydroxybutyric acid that is also used as a recreational (street) drug suggestive of abuse potential. However, a pharmacovigilance database of more than 260 000 alcohol-dependent patients treated with sodium oxybate reported very few adverse side effects and only few cases of abuse. We therefore conclude that sodium oxybate is an effective, well-tolerated and safe treatment for withdrawal and relapse prevention treatment, especially in alcohol-dependent patients with VH DRL., (© 2018 Society for the Study of Addiction.)

Aldosterone regulates electrolyte and fluid homeostasis through binding to the mineralocorticoid receptors (MRs). Previous work provides evidence for a role of aldosterone in alcohol use disorders (AUDs). We tested the hypothesis that high functional activity of the mineralocorticoid endocrine pathway contributes to vulnerability for AUDs. In Study 1, we investigated the relationship between plasma aldosterone levels, ethanol self-administration and the expression of CYP11B2 and MR (NR3C2) genes in the prefrontal cortex area (PFC) and central nucleus of the amygdala (CeA) in monkeys. Aldosterone significantly increased after 6- and 12-month ethanol self-administration. NR3C2 expression in the CeA was negatively correlated to average ethanol intake during the 12 months. In Study 2, we measured Nr3c2 mRNA levels in the PFC and CeA of dependent and nondependent rats and the correlates with ethanol drinking during acute withdrawal. Low Nr3c2 expression levels in the CeA were significantly associated with increased anxiety-like behavior and compulsive-like drinking in dependent rats. In Study 3, the relationship between plasma aldosterone levels, alcohol drinking and craving was investigated in alcohol-dependent patients. Non-abstinent patients had significantly higher aldosterone levels than abstinent patients. Aldosterone levels positively correlated with the number of drinks consumed, craving and anxiety scores. These findings support a relationship between ethanol drinking and the aldosterone/MR pathway in three different species.

The treatment of alcohol use disorder still remains a challenge. The efficacy of the combined pharmacological treatment for alcohol use disorder has been widely investigated with controversial results. The aim of our case series was to investigate the effect of nalmefene in patients not responding to sodium oxybate therapy. We describe seven cases of consecutive patients affected by alcohol use disorder, and treated with sodium oxybate (50 mg/kg per day) who did not achieve complete alcohol abstinence after at least one month of pharmacological treatment. Then, in partial- and non-responder patients to sodium oxybate treatment, administration of nalmefene, 18 mg as needed, was commenced. Our data show that, during the first month of the combined treatment of sodium oxybate plus nalmefene, patients were able to achieve alcohol abstinence (two patients), to suppress (five cases) or reduce (two patients) episodes of heavy drinking days, and to suppress the onset of craving for sodium oxybate (one patient). Likely, nalmefene may act in modulating the excessive reward effect of sodium oxybate, which may be responsible for the persistence of alcohol intake and for the onset of craving for sodium oxybate. However, controlled clinical trials to confirm the safety and efficacy of sodium oxybate plus nalmefene in treating alcohol use disorder are warranted., (© The Author(s) 2016.)

The treatment of alcohol use disorder (AUD) with sodium oxybate (SMO) or gamma-hydroxybutyric acid (GHB) was introduced in Italy and Austria more than 20 years and 15 years ago, respectively, and it is now widely employed to treat alcohol withdrawal syndrome (AWS) and to maintain alcohol abstinence. These indications derive from its similar structure to the inhibitory neurotransmitter γ-amino-butyric acid (GABA), exerting an ethanol-mimicking effect, because it binds to GABAB receptors. Craving for, and abuse of, SMO remain a controversial issue; even though these unfavorable effects are evident in poly-drug addicted patients and in those with psychiatric diagnosis of borderline personality disorder. In addition, despite cases of severe intoxication and deaths being widely documented when GHB is used as "street drug"; its clinical use remains safe. Thus, the aim of the present review is to examine the role of SMO in the treatment of AUD, its possible implications in reducing alcohol consumption, and cases of abuse, and severe intoxication due to SMO during its clinical use in the treatment of AUD.

Symptoms of alcohol withdrawal syndrome (AWS) may develop within 6-24 h after the abrupt discontinuation or decrease of alcohol consumption. Symptoms can vary from autonomic hyperactivity and agitation to delirium tremens. The gold-standard treatment for AWS is with benzodiazepines (BZDs). Among the BZDs, different agents (i.e., long-acting or short-acting) and different regimens (front-loading, fixed-dose or symptom-triggered) may be chosen on the basis of patient characteristics. Severe withdrawal could require ICU admission and the use of barbiturates or propofol. Other drugs, such as α2-agonists (clonidine and dexmetedomidine) and β-blockers can be used as adjunctive treatments to control neuroautonomic hyperactivity. Furthermore, neuroleptic agents can help control hallucinations. Finally, other medications for the treatment for AWS have been investigated with promising results. These include carbamazepine, valproate, sodium oxybate, baclofen, gabapentin and topiramate. The usefulness of these agents are discussed.

In Europe between 30 and 50% of all liver transplantations (LTX) are done within the context of chronic end-stage alcoholic liver disease (ALD). However, post-operatively 20-25% of these patients lapse or relapse into heavy alcohol use. Thus, assessment of alcohol relapse risk before enlisting and therapeutic follow-up during and after LTX is of utmost importance. However, as yet there are enormous differences between European countries and between transplant centers, with regard to the assessment methods and criteria and the implementation of therapeutic follow-up. Only the so-called '6-month abstinence' rule is widely used. However, there are not much scientific data validating its use in predicting relapse. Thus, there is a clear need of a more homogeneous approach, which was the focus of a symposium of the European Federation of Addiction Societies during the 14th conference of the European Society for Biomedical Research on Alcoholism, 2013 (ESBRA), entitled 'Liver transplantation: A European perspective'. In a follow-up on this symposium, the authors aim to sum up the evidence of psychiatric assessment criteria and psychiatric treatment interventions relevant in the context of patient selection and patient follow-up within ALD transplantation procedures. Based upon these findings, we propose elements of a procedure that can serve as a first step toward a model of good practice regarding addiction-specialist input within the pre- and post-transplantation period., (© The Author 2015. Medical Council on Alcohol and Oxford University Press. All rights reserved.)

Aim: To conduct a double-blind, placebo-controlled randomized clinical trial of baclofen in the treatment of alcohol dependence., Methods: Out of 69 participants consecutively screened, 42 alcohol-dependent patients were randomized to receive placebo, baclofen 30 mg/day or baclofen 60 mg/day for 12 weeks. All subjects were offered BRENDA, a structured psychosocial therapy for alcohol dependence that seeks to improve motivation for change, enhance strategies to prevent relapse and encourage compliance with treatment., Results: Intention-to-treat analyses revealed that alcohol consumption (heavy drinking days, drinks per drinking day) significantly reduced across all three groups during the treatment period. There were no statistically significant advantages to treatment on time to first heavy drinking day (relapse) (P = 0.08), nor time to first drink (lapse) (P = 0.18). A post hoc analysis stratifying according to whether there had been a comorbid anxiety disorder, revealed a beneficial effect of baclofen 30 mg/day versus placebo on time to lapse and relapse (P < 0.05). There was also a beneficial effect for baclofen 60 mg/day relative to placebo on time to relapse in this comorbid group (P < 0.05). Both doses of baclofen were well tolerated. There were no serious adverse events., Conclusions: In spite of the small sample for a 3-arm clinical trial, this study suggests a specific role of baclofen in alcohol-dependent individuals with comorbid anxiety. Replication in larger, fully-powered studies is required., (© The Author 2014. Medical Council on Alcohol and Oxford University Press. All rights reserved.)

Almost 10% of the world's population is affected by alcohol use disorders, and the treatment of alcohol dependence (AD) still remains a challenge. Patients with AD can differ in many traits. Three drugs (disulfiram, naltrexone, and acamprosate) have been approved by the FDA for the treatment of AD, and in some European countries sodium oxybate is also approved for this purpose. Combined pharmacological therapy has not provided such convincing results. Considering the fact that the "ideal" and effective drug for all types of alcoholic patients does not exists, the future challenge will be to identify a personalized approach. Recent data has shown that this objective can be achieved by investigating the genetic variability of the patient. Moreover, the use of replacement molecules can probably be considered an advantageous therapeutic opportunity (i.e. sodium oxybate). In addition, reduction of alcohol consumption is increasingly accepted as a viable treatment goal, and the use of nalmefene "as-needed" (a pharmacological approach similar to naltrexone, but, possibly, with lower hepatotoxicity) may help in the treatment of AD. Thus, it is important to stress that a pharmacological approach to treat AD should be preceded by the definition of patient characteristics; this may help in the choice of the most appropriate drug and it can be done more easily when more pharmacological options approved for the treatment of AD are also available., (© 2013 Published by Elsevier B.V. and ECNP.)

Background: Many concerns about liver transplantation in alcoholic patients are related to the risk of alcohol recidivism. Starting from 2002, an Alcohol Addiction Unit (AAU) was formed within the liver transplant center for the management of alcoholic patients affected by end-stage liver disease and included in the waiting list for transplantation. We evaluated retrospectively the impact of the AAU on alcohol recidivism after transplantation. The relationship between alcohol recidivism and the duration of alcohol abstinence before transplant was evaluated as well., Methods: Between 1995 and 2010, 92 cirrhotic alcoholic patients underwent liver transplantation. Clinical evaluation and management of alcohol use in these patients was provided by psychiatrists with expertise in addiction medicine not affiliated to the liver transplant center before 2002 (n = 37; group A), or by the clinical staff of the AAU within the liver transplant center starting from 2002 (n = 55; group B)., Results: Group B, as compared with group A, showed a significantly lower prevalence of alcohol recidivism (16.4 vs. 35.1%; p = 0.038) and a significantly lower mortality (14.5 vs. 37.8%; p = 0.01). Furthermore, an analysis of group B patients with either ≥6 or <6 months of alcohol abstinence before transplantation showed no difference in the rate of alcohol recidivism (21.1 vs. 15.4%; p = ns)., Conclusions: The presence of an AAU within a liver transplant center reduces the risk of alcohol recidivism after transplantation. A pretransplant abstinence period <6 months might be considered, at least in selected patients managed by an AAU., (Copyright © 2013 by the Research Society on Alcoholism.)

Alcohol dependence represents a chronic and relapsing disease affecting nearly 10 % of the general population both in the USA and in Europe, with a widespread burden of morbidity and mortality. Alcohol dependence represents the most common cause of liver damage in the Western world. Although alcoholic liver disease is associated primarily with heavy drinking, continued alcohol consumption, even in low doses after the onset of liver disease, increases the risk of severe consequences, including mortality. Consequently, the ideal treatment of patients affected by alcohol dependence and alcoholic liver disease should aim at achieving long-term total alcohol abstinence and preventing relapse. The aim of the present review is to provide an update on the management of alcohol dependence in patients with alcoholic liver disease. Increasing evidence suggests the usefulness of psychosocial interventions and medications combined in order to reduce alcohol intake, promote abstinence and prevent relapse in alcohol-dependent patients. Disulfiram, naltrexone and acamprosate have been approved for this indication; gamma-hydroxybutyric acid (GHB) is approved in Italy and Austria. However, these drugs have not been tested in patients with advanced liver disease. Amongst other emerging pharmacotherapies for alcoholism, topiramate, ondansetron, and baclofen seem the most promising ones. Both topiramate and ondansetron have a safe profile in alcoholic patients; however, none of them has been tested in alcoholic patients with advanced liver disease. To date, baclofen represents the only anti-craving medication formally tested in a randomized clinical trial in alcoholic patients affected by liver cirrhosis, although additional confirmatory studies are warranted.

Animal studies suggest that the gut-brain peptide ghrelin plays an important role in the neurobiology of alcohol dependence (AD). Human studies show an effect of alcohol on ghrelin levels and a correlation between ghrelin levels and alcohol craving in alcoholics. This investigation consisted of two studies. Study 1 was a 12-week study with alcohol-dependent subjects, where plasma ghrelin determinations were assessed four times (T0-T3) and related to alcohol intake and craving [Penn Alcohol Craving Score (PACS) and Obsessive Compulsive Drinking Scale (OCDS)]. Serum growth hormone levels and assessment of the nutritional/metabolic status were also performed. Study 2 was a pilot case-control study to assess ghrelin gene polymorphisms (Arg51Gln and Leu72Met) in alcohol-dependent individuals. Study 1 showed no significant differences in ghrelin levels in the whole sample, while there was a statistical difference for ghrelin between non-abstinent and abstinent subjects. Baseline ghrelin levels were significantly and positively correlated with the PACS score at T1 and with all craving scores both at T2 and T3 (PACS, OCDS, obsessive and compulsive OCDS subscores). In Study 2, although there was a higher frequency of the Leu72Met ghrelin gene polymorphism in alcohol-dependent individuals, the distribution between healthy controls and alcohol dependent individuals was not statistically significant. This investigation suggests that ghrelin is potentially able to affect alcohol-seeking behaviors, such as alcohol drinking and craving, representing a new potential neuropharmacological target for AD., (© 2011 The Authors, Addiction Biology © 2011 Society for the Study of Addiction.)

Drug addiction represents a major social problem where addicts and alcoholics continue to seek and take drugs despite adverse social, personal, emotional, and legal consequences. A number of pharmacological compounds have been tested in human addicts with the goal of reducing the level or frequency of intake, but these pharmacotherapies have often been of only moderate efficacy or act in a sub-population of humans. Thus, there is a tremendous need for new therapeutic interventions to treat addiction. Here, we review recent interesting studies focusing on gamma-aminobutyric acid receptors, voltage-gated ion channels, and transcranial magnetic stimulation. Some of these treatments show considerable promise to reduce addictive behaviors, or the early clinical studies or pre-clinical rationale suggest that a promising avenue could be developed. Thus, it is likely that within a decade or so, we could have important new and effective treatments to achieve the goal of reducing the burden of human addiction and alcoholism.

Aims: To explore the effect of baclofen in a dose of 20 mg three times per day, compared with the already studied dose of 10 mg three times per day, in the treatment of alcohol dependence., Methods: We present a secondary analysis of a 12-week double-blind, placebo-controlled, randomized clinical trial with two doses of baclofen, specifically 10 mg t.i.d. and 20 mg t.i.d. Out of 94 subjects consecutively screened, 42 were randomized into the study. Fourteen of the 42 patients were randomly allocated to placebo, 14 to the group treated with baclofen 10 mg t.i.d. (B10 mg) and 14 to the group treated with baclofen 20 mg t.i.d. (B20 mg)., Results: Compared with patients allocated to placebo, patients allocated to the B10 mg group had a 53% reduction in the number of drinks per day (P < 0.0001) and patients allocated to the B20 mg group had a 68% reduction in the number of drinks per day (P < 0.0001), with respect to the number of drinks per day during the 28 days before randomization. The effect of baclofen 20 mg t.i.d. was greater than that of baclofen 10 mg t.i.d. (P = 0.0214, Wald test) showing a dose-effect relationship. Both doses of baclofen were well tolerated., Conclusion: This is provisional evidence of a dose-response effect for baclofen in the treatment of alcohol dependence.

Objectives: Excessive alcohol consumption often results in intestinal damage, mediated by inflammatory processes, mainly characterized by an increased influx of leukocytes. Fecal calprotectin is a granulocyte cytosolic protein, representing as a promising marker of subclinical intestinal inflammation. In this study, we assessed fecal calprotectin concentrations (FCCs) in current drinking alcoholics, both at the baseline, and then during a subsequent 84-day period. Moreover, FCCs in the alcoholics were compared with the FCCs in healthy controls., Methods: Twenty-eight, active-drinking alcoholics were enrolled in this study and compared with 40 healthy volunteers as the control group. In alcoholics, FCCs were determined at the beginning of the study (baseline; T0) and then every 2 weeks (T1-T6) during the following 84-day period. Potential differences in FCCs were analyzed between alcoholics and healthy controls, and during the 84-day period within the group of alcoholics. In addition, an analysis of FCCs was conducted in three subgroups of alcoholics, considering their drinking status during the 84-day period (abstinent, relapsed, and active)., Results: At baseline, no significant differences in median FCCs were found between alcoholics and controls. No significant changes of median FCCs were found, comparing baseline FCCs and FCCs during the 84-day period (T1-T6) in the whole group of alcoholics, nor in the three subgroups of alcoholics., Conclusion: FCCs in active-drinking alcoholics are not significantly different, compared with the healthy controls. Moreover, FCCs do not significantly differ according to the alcohol drinking status. These results may suggest the absence of a subclinal intestinal inflammation involving neutrophils in the alcoholics.

Preclinical studies show that antagonism of the GABA(B) receptor may represent an effective neuropharmacological approach to treat alcohol dependence. Consistent with preclinical evidence, the majority of the human studies have demonstrated that the prototype GABA(B) receptor antagonist baclofen may represent an effective mediation to treat alcohol-dependent individuals. Specifically, baclofen has shown to reduce alcohol withdrawal symptoms, as well as to reduce alcohol craving and intake, and to promote alcohol abstinence. Notably, baclofen has shown a safe profile when administered to alcoholics, including those with liver cirrhosis. In summary, baclofen represents a safe and effective medication to treat alcohol dependence, thus holding promise as a new pharmacotherapy. However, large studies are needed to confirm the present findings.

Alcoholism and stress share some common neurobiological circuits, including the GABAergic system. In particular, the GABA(B) receptor seems to play an important role. The GABA(B) receptor agonist baclofen has been studied as a treatment for alcohol-dependent subjects. Baclofen administration in alcohol-dependent patients was able to promote abstinence, inducing the remission of withdrawal symptoms, reducing alcohol craving, and reducing alcohol intake. Baclofen also reduced anxiety in alcohol-dependent subjects, probably acting on brain stress circuitry and/or on other neuroendocrine systems. Baclofen also showed excellent safety and tolerability, even in alcohol-dependent patients with advanced liver disease (i.e., cirrhosis). Future studies should investigate which alcoholic subtype may better benefit of the administration of baclofen in the treatment of alcohol dependence.

There is an increasing interest in studying the role of GABAergic medications in the treatment of alcohol dependence. The GABAergic drug gamma-hydroxybutyric acid (GHB) has been investigated in Europe as a possible treatment for alcohol dependence. In some European Countries, GHB has been approved as a treatment for alcohol dependence. However, this drug has also shown addictive properties, therefore raising questions about its safety in treating alcohol-dependent subjects. More recent research is focusing on the possibility of identifying alcohol-dependent subtypes without risk of developing GHB abuse. Finally, GHB and naltrexone combined together represent a possible approach deserving future investigations.

Aims: Subjects with chronic alcohol abuse can present several metabolic and nutritional alterations. The hypothalamic-pituitary-adrenal (HPA) axis may play a role in these nutritional and metabolic disorders. The goal of this study was to investigate if there is any relationship between HP-hormones and metabolic and nutritional parameters in alcoholic subjects., Methods: Sixteen alcoholics were considered before and after 3 months of total alcohol abstinence. HP-related hormones were determined. Nutritional and metabolic parameters were assessed by dual-energy X-ray absorptiometry (DXA) and indirect calorimetry., Results: At baseline, a significant negative correlation was found between fat mass (FM) and cortisol (r = -0.54, P = 0.03). During abstinence, a significant increase of both body mass index (BMI) (P < 0.0001) and FM (P < 0.0001) was found at 12 weeks compared to baseline. A significant decrease of both plasma cortisol (P = 0.044) and aldosterone (P = 0.023) was found at 12 weeks compared to baseline. At 12 weeks, the significant correlation between cortisol and FM disappeared., Conclusions: A higher HPA-axis activation-reflected by higher cortisol levels-was associated with a lower FM in alcoholics. Conversely, during total abstinence a reduced HPA-axis activity can play a role in the parallel nutritional recovery. The present results suggest a role of the HPA axis throughout cortisol both in the etiology of the alcohol-related nutritional alterations and in their recovery after a period of total alcohol abstinence.

There is growing evidence for a role of appetite-related peptides and volume-regulating hormones in alcoholism. In particular, recent evidence has suggested that hormones, such as ghrelin, insulin and leptin and volume-regulating hormones, could play a role in alcohol-seeking behaviour. The goal of this review is to discuss the results of recent preclinical and clinical investigations on this topic. The findings indicate that neuroendocrinological mechanisms are potentially involved in the neurobiology of alcohol craving. Accordingly, research on this topic could lead to possible development of new therapeutic approaches in the treatment of patients with alcohol problems.

Background: A relationship between some hypothalamic-pituitary-related hormones and craving for alcohol has been suggested, leading to hypothesize a role of some hormones in the neurobiology of alcohol dependence. Investigating this association in alcohol-dependent (AD) patients was the aim of this preliminary and exploratory study., Methods: Cortisol, adrenocorticotropic hormone, prolactin, thyroid-stimulating hormone (TSH), free T3, free T4, growth hormone, follicle-stimulating hormone, luteinizing hormone as well as administering the Obsessive-Compulsive Drinking Scale (OCDS) and Penn Alcohol Craving Scale (PACS) were assessed at baseline and after 12 weeks in 25 current AD patients. Patients were treated with baclofen (10 mg t.i.d.) for these 12 weeks. Sixteen patients remained totally abstinent for 12 weeks., Results: At baseline, a significant inverse correlation was found between TSH and PACS (r = -0.46; p = 0.022) and OCDS scores (r = -0.53; p = 0.007). A significant direct correlation was found between free T3 and OCDS score (r = 0.44; p = 0.026). In the 16 abstinent patients, craving scores were significantly decreased at 12 weeks (p < 0.01). At 12 weeks, no significant correlation was found between TSH and craving, but free T3 remained directly correlated with OCDS score (r = 0.60; p = 0.013)., Conclusions: A relationship between alcohol craving and free T3 and TSH was demonstrated in AD patients, suggesting the potential involvement of the hypothalamic-pituitary-thyroid axis in the neurobiology of alcohol craving.

Both animal and human studies suggest that volume-regulating hormones could play a role in alcohol dependence as well as in alcohol craving. The role of the volume-regulating hormones, renin, aldosterone, and the N-terminal pro B-type natriuretic peptide (NT-proBNP) in alcohol craving was therefore evaluated in the present study. Twenty-five actively drinking alcohol-dependent patients satisfied the inclusion criteria and were enrolled into the study. The volume-regulating hormones, renin, aldosterone, and the NT-proBNP, and craving measurements--Obsessive-Compulsive Drinking Scale (OCDS) and Penn Alcohol Craving Scale (PACS)--were performed at baseline and after 12 weeks. Sixteen patients remained totally abstinent for the entire 12 weeks and were available for the second assessments. At baseline, no correlations between hormones and craving scores were found with either the 25 patients initially enrolled or the 16 abstinent patients. At 12 weeks, a significant increase of renin and a significant decrease of aldosterone were observed. Aldosterone showed a significant direct correlation with the obsessive OCDS subscore (r=0.59, P=.016) and a trend toward a significant direct correlation with the PACS score (r=0.48, P=.057). Renin demonstrated a significant direct correlation with the obsessive OCDS subscore (r=0.51, P=.041) and with the PACS score (r=0.56, P=.025). The NT-proBNP never correlated with craving measurements. In conclusion, the renin-aldosterone axis could play a role in craving in medium-term abstinent patients and thereby leading to the hypothesis that alcohol craving could be influenced by the fluid volume intake.

Cloninger proposed a neurochemical model of alcoholism suggesting that type 2 alcoholics have serotonergic deficits with intact dopaminergic system, whereas the type 1 alcoholics have defected dopaminergic system. The work by Storvik and colleagues recently published on Alcohol and Alcoholism shows some interesting differences on the SERT brain density between the type I and type II alcoholic subtypes. Critically, these findings on different serotonergic role in subtypes of alcohol-dependence revive the concept that alcohol addiction is a heterogeneous disorder associated with varying neurochemical abnormalities. Studies testing serotonergic medications in alcohol-dependent patients classified according to subtypes have shown interesting findings. Accordingly, the identification and standardization of alcoholic subtypes could be useful in guiding research on treatment. New developments in the neurobiological understanding of subtypes of alcoholic patients, could led to get the basis for a more personalized pharmacological therapy.

Background: Preclinical data suggest that brain insulin and insulin growth factor-1 (IGF-1) may contribute to the development of addiction. The aim of this clinical study was to evaluate the relationships between insulin and IGF-1 plasma concentrations and alcohol craving., Methods: The correlations between insulin and craving in actively drinking alcoholics were evaluated in the experiment 1 retrospectively and in the experiment 2 in a case-control study. Experiment 3 evaluated the correlations between insulin and craving in 12-weeks abstinent alcoholics in a longitudinal study. C-peptide and IGF-1 were also investigated in experiments 2-3. Alcohol craving was evaluated by the Obsessive-Compulsive Drinking Scale (OCDS)., Results: Significant positive correlations between insulin concentrations and craving scores were found in actively drinkers (p < 0.05). Specifically, in the first experiment insulin significantly correlated with the compulsive scores. In the second experiment and in an analysis of experiments 1-2 together, insulin plasma concentration correlated with total OCDS craving (p < 0.05) and compulsive craving (p < 0.05) and showed a trend of correlation with the obsessive craving. At 12 weeks no correlation was found between insulin and craving scores. In all the experiments the correlations between C-peptide and craving were close to the ones between insulin and craving while IGF-1 never correlated with craving., Conclusions: This study suggests that insulin could be involved in the neurobiology of alcohol craving and addiction. This characteristic seems specific of insulin since similar data were found on C-peptide but not on IGF-1. Future confirming studies on larger samples are needed, also to investigate possible therapeutic implications.

Background: Intervention to achieve alcohol abstinence represents the most effective treatment for alcohol-dependent patients with liver cirrhosis; however, anticraving drugs might worsen liver disease. We aimed to investigate the effectiveness and safety of baclofen in achieving and maintaining alcohol abstinence in patients with liver cirrhosis., Methods: Between October, 2003, and November, 2006, 148 alcohol-dependent patients with liver cirrhosis were referred to the Institute of Internal Medicine, Rome, Italy. 84 were randomly allocated either oral baclofen or placebo for 12 weeks. Primary outcome was proportion of patients achieving and maintaining alcohol abstinence. Measures of this outcome were total alcohol abstinence and cumulative abstinence duration, which were assessed at outpatient visits. Relapse was defined as alcohol intake of more than four drinks per day or overall consumption of 14 or more drinks per week over a period of at least 4 weeks. Analysis was by intention to treat. This study is registered with ClinicalTrials.gov, number NCT00525252., Findings: Of 42 patients allocated baclofen, 30 (71%) achieved and maintained abstinence compared with 12 (29%) of 42 assigned placebo (odds ratio 6.3 [95% CI 2.4-16.1]; p=0.0001). The number of dropouts (termination of treatment) did not differ between the baclofen (6/42 [14%]) and placebo (13/42 [31%]) groups (p=0.12). Cumulative abstinence duration was about twofold higher in patients allocated baclofen than in those assigned placebo (mean 62.8 [SE 5.4] vs 30.8 [5.5] days; p=0.001). No hepatic side-effects were recorded., Interpretation: Baclofen is effective at promoting alcohol abstinence in alcohol-dependent patients with liver cirrhosis. The drug is well tolerated and could have an important role in treatment of these individuals.

Background: Ghrelin is a peptide produced mainly by the gut and hypothalamus. Ghrelin is able to stimulate food-seeking behavior. Alcohol-craving and food-seeking behavior could share common neural circuits. Ghrelin is related to nutritional status, but few data are available in alcoholic patients on the relationship between ghrelin and nutritional disorders., Methods: Plasma ghrelin was evaluated in 15 current alcoholic male patients compared with 15 healthy male volunteers. Craving was evaluated by the Obsessive-Compulsive Drinking Scale. Body composition was assessed by dual-energy X-ray absorptiometry. Energy substrate utilization was evaluated by indirect calorimetry., Results: Ghrelin was significantly reduced in alcohol-dependent patients with respect to healthy subjects (p=0.0278). A significant positive correlation was found between ghrelin and craving (r=0.55; p=0.034). A preferential utilization of lipids as an energy substrate with a reduction of the fat mass (p=0.01) and an increase of the free fat mass (p=0.0091) was found in alcoholic patients., Conclusions: Within our sample showing low ghrelin levels probably related to the impaired nutritional status; patients with higher levels of ghrelin showed higher levels of alcohol craving. These preliminary data indicate that ghrelin could be implicated in the neurobiological mechanisms of alcohol craving, other than a hormone influenced by the nutritional status.

Recent preclinical and clinical studies have suggested that baclofen, the prototypic gamma-aminobutyric acid B (GABA(B)) receptor agonist, is a promising pharmacological compound for use in the treatment of alcohol dependence. In particular, baclofen has been found to suppress symptoms of alcohol withdrawal syndrome with an efficacy comparable with that of the 'gold standard' diazepam. Moreover, baclofen has proven effective in the prevention of relapse due to its ability to reduce alcohol intake and craving in alcoholic patients. Baclofen proved to be manageable, producing no significant side effects and displaying no addictive properties. The efficacy of the drug in the management of both alcohol withdrawal syndrome and relapse prevention should entail a vastly simplified pharmacotherapy of alcohol dependence.

Craving plays an important role in the pathogenesis of alcohol dependence and relapse. In this review we have tried to analyse how many contrasting theories have been formulated in order to clarify the concept of craving. Many complex neurobiochemical mechanisms are implicated in the etiology of craving; these mechanisms involve several neurotransmitters, such us dopamine, opioids, glutamate, and serotonin. On the other hand comportamental and/or cognitive aspects could also play a role in the etiology of craving. The coexistence of many and often contrasting theories can indicate that different subtypes of patients could have different mechanisms at the basis of alcohol craving, suggesting that it could be advisable to personalize the anti-craving therapy.

In the last decade, craving has increasingly been considered an important target for the treatment of patients with alcohol problems, and several drugs able to interfere with the neurotransmitters involved in craving mechanisms have been experimented. However, different subtypes of patients could have different mechanisms at the basis of alcohol craving. In this review, the main drugs currently used in the treatment of patients with alcohol problems are described. A hypothesis of pharmacological treatment of the different types of craving is also discussed., (Copyright 2005 S. Karger AG, Basel.)

Alcohol abuse and alcoholism are responsible for a wide variety of medical problems. The pharmaco-therapeutic aspect of alcoholism includes the use of drugs, with different actions and objectives. Among them, metadoxine seems to be of interest. Metadoxine is able to accelerate the elimination of alcohol from the blood and tissues, to help restore the functional structure of the liver and to relieve neuro-psychological disorders associated with alcohol intoxication. Metadoxine also seems to be safe; in more than 15 years of post-marketing surveillance only minor aspecific and reversible events were monitored in patients exposed to the treatment. In this review the preclinical and clinical results obtained using metadoxine in acute and chronic alcohol intoxication are reported.

Aims: The gamma-aminobutyric acid (GABA(B)) receptor agonist, baclofen, has recently been shown to reduce alcohol intake in alcohol-preferring rats and alcohol consumption and craving for alcohol in an open study in humans. The present study was aimed at providing a first evaluation of the efficacy of baclofen in inducing and maintaining abstinence and reducing craving for alcohol in alcohol-dependent patients in a double-blind placebo-controlled design., Methods: A total of 39 alcohol-dependent patients were consecutively enrolled in the study. After 12-24 h of abstinence from alcohol, patients were randomly divided into two groups. Twenty patients were treated with baclofen and 19 with placebo. Drug and placebo were orally administered for 30 consecutive days. Baclofen was administered at the dose of 15 mg/day for the first 3 days and 30 mg/day for the subsequent 27 days, divided into three daily doses. Patients were monitored as out-patients on a weekly basis. At each visit alcohol intake, abstinence from alcohol, alcohol craving and changes in affective disorders were evaluated., Results: A higher percentage of subjects totally abstinent from alcohol and a higher number of cumulative abstinence days throughout the study period were found in the baclofen, compared to the placebo, group. A decrease in the obsessive and compulsive components of craving was found in the baclofen compared to the placebo group; likewise, alcohol intake was reduced in the baclofen group. A decrease in state anxiety was found in the baclofen compared to the placebo group. No significant difference was found between the two groups in terms of current depressive symptoms. Baclofen proved to be easily manageable and no patient discontinued treatment due to the presence of side-effects. No patient was affected by craving for the drug and/or drug abuse., Conclusions: Baclofen proved to be effective in inducing abstinence from alcohol and reducing alcohol craving and consumption in alcoholics. With the limits posed by the small number of subjects involved, the results of this preliminary double-blind study suggest that baclofen may represent a potentially useful drug in the treatment of alcohol-dependent patients and thus merits further investigations.

Background: Accumulating evidence shows the efficacy of the gamma-aminobutyric acid (GABA(B)) receptor agonist baclofen in reducing alcohol intake in rats, but no studies have been performed in alcoholics. In the present preliminary study we investigated the effect of short-term baclofen administration on craving for alcohol, ethanol intake, and abstinence from alcohol in alcoholic individuals., Methods: Ten male current alcoholic individuals were admitted to the study. Baclofen was orally administered for 4 weeks, at a dose of 15 mg/day refracted in three times per day for the first 3 days, with the dose increased to 30 mg/day for the remaining 27 days. Each subject was checked as an outpatient every week for the 4 weeks; at each visit (T0-T4) craving level was evaluated by the Alcohol Craving Scale (ACS), and abstinence from alcohol was assessed based on the individual's self-evaluation, family member interview, and the main biological markers of alcohol abuse. A self-reported alcohol intake was recorded as the mean number of standard drinks consumed per day., Results: Nine subjects completed the study; of these, two subjects continued to drink alcohol although they substantially reduced their daily drinks in the first week of treatment, whereas seven maintained abstinence throughout the experimental period. Craving was significantly reduced from the first week of the drug administration (p < 0.01) and remained so throughout the entire treatment period. Participants also reported that obsessional thinking about alcohol disappeared. Values of gamma-glutamyltranspeptidase, alanine aminotransferase, and mean cellular volume significantly decreased by the end of the study. Tolerability was fair in all participants; headache, vertigo, nausea, constipation, diarrhea, abdominal pain, hypotension, increased sleepiness, and tiredness were present as side effects in the first stage of the treatment. No participants showed craving for the drug., Conclusions: With the limitations of the low number of individuals evaluated and the open design, this preliminary clinical study supports the preclinical evidence on the effect of baclofen in reducing alcohol intake. The anticraving properties of the drug suggest a possible role of baclofen in the treatment of individuals with alcohol problems.