Baclofen in the Treatment of Patients With Alcohol Use Disorder and Other Mental Health Disorders

A limited number of medications are approved to treat Alcohol Use Disorder (AUD). Furthermore, the magnitude of their therapeutic effect is relatively modest, suggesting the potential for subtypes of patients who respond to a specific medication. The use of these medications is also limited in clinical practice by a series of contraindications such as medical comorbidities and/or concurrent use of other medications. In recent years, animal and human studies have been conducted to evaluate the efficacy of baclofen, a GABAB receptor agonist approved for clinical use as a muscle relaxant, in the treatment of AUD. However, these studies have yielded contrasting results. Despite this discrepancy, baclofen is often used off-label to treat AUD, especially in some European countries and Australia. Recently, several factors have been considered to try to shed light on the potential reasons and mechanisms underlying the inconsistent results obtained until now. The presence of a psychiatric comorbidity may be amongst the abovementioned factors playing a role in explaining different responses to baclofen treatment in terms of alcohol drinking outcomes. Therefore, the aim here was to conduct a narrative review of the scientific literature related to the use of baclofen in AUD, both in patients with and without concomitant psychiatric disorders. All clinical studies (randomized and controlled, open-label, retrospective, human laboratory studies, and case reports) were analyzed and discussed, bearing in mind other potential factors that may have influenced baclofen response, including dose administered, severity of AUD, use of other psychosocial therapies, and the presence of physical disorders. This review indicates that the most frequent psychiatric comorbidities in patients affected by AUD undergoing baclofen treatment are anxiety and mood disorders. Unfortunately, no definitive conclusions can be drawn due to the lack of specific analyses on whether baclofen efficacy is different in AUD patients with comorbid psychiatric disorders vs. those without. Therefore, it will be critical that psychiatric comorbidities are considered in the planning of future studies and in the analysis of the data, with the ultimate goal of understanding whether subtypes of AUD patients may respond best to baclofen

The Effects of Naltrexone Among Alcohol Non-Abstainers: Results from the COMBINE Study

These analyses of the COMBINE Study examined the effects of naltrexone among non-abstainers. Given that one of the most well-established mechanisms of action of naltrexone involves blunting of alcohol reward, it is hypothesized that naltrexone should be more effective among individuals who drank during treatment. Participants were 952 (78% of the total COMBINE Study sample) treatment-seeking alcohol-dependent men and women who received pharmacotherapy for alcoholism and drank at least once during the 16-week trial. Mixed model analyses revealed that individuals who drank more regularly during the trial seemed to benefit most from naltrexone and the effects of naltrexone on heavy drinking was significant in treatment months 2 through 4 among individuals who reported drinking on 81, 68, and 60% or more of days, respectively. Those drinking frequencies were observed in 11, 15, and 19% of the sample. Similar effects were not observed for drinks per drinking day. These results suggest that a small subgroup of non-abstainers, composed primarily of very regular drinkers, appears to benefit from naltrexone in reducing heavy drinking days. Naltrexone may be effective in the context of controlled-drinking approaches, even among very frequent drinkers

Psychosocial Findings in Alcohol-Dependent Patients Before and After Three Months of Total Alcohol Abstinence

Alcohol use disorders (AUDs) may be associated with several psychological and affective disorders. It is controversial, however, if these symptoms are a cause or rather a consequence of alcohol dependence. There are few data testing simultaneously psychosocial and affective disorders before and after a period of alcohol abstinence. The aim of this study was to perform multiple psychometric evaluations in alcohol-dependent patients before and after 12 weeks of abstinence. Twenty-five alcohol-dependent patients were included in the study. The following psychometric tests were administered at baseline (T0) and after 12 weeks (T1): addiction severity index (ASI), brief psychiatric rating scale (BPRS), social behavior scale (SBS), Sheehan disability scale (DISS), aggression questionnaire (AQ). At T1, 16 (64%) patients were abstinent, 5 (20%) patients dropped out and 4 (16%) patients relapsed. Compared to T0, patients totally abstinent at T1 showed a significant reduction of the scores related to BPRS, BPRS-E and its subscales (except BPRS 5), ASI 1, ASI 2, ASI 3, ASI 6, ASI 7, BSM, AQ, DISS 1, DISS 2, DISS 3 (p < 0.05). No significant changes in ASI 4, ASI 5, DISS 4, and DISS 5, BPRS 5 scores were found at T1 compared to T0. The present study indicates that total alcohol abstinence improves psychometric features, such as alcohol addiction severity, psychiatric rating, social behavior, aggressiveness, and disability. Larger controlled studies are needed to confirm these findings

Effects of oral, smoked, and vaporized cannabis on endocrine pathways related to appetite and metabolism: a randomized, double-blind, placebo-controlled, human laboratory study.

As perspectives on cannabis continue to shift, understanding the physiological and behavioral effects of cannabis use is of paramount importance. Previous data suggest that cannabis use influences food intake, appetite, and metabolism, yet human research in this regard remains scant. The present study investigated the effects of cannabis administration, via different routes, on peripheral concentrations of appetitive and metabolic hormones in a sample of cannabis users. This was a randomized, crossover, double-blind, placebo-controlled study. Twenty participants underwent four experimental sessions during which oral cannabis, smoked cannabis, vaporized cannabis, or placebo was administered. Active compounds contained 6.9 ± 0.95% (~50.6 mg) ∆9-tetrahydrocannabinol (THC). Repeated blood samples were obtained, and the following endocrine markers were measured: total ghrelin, acyl-ghrelin, leptin, glucagon-like peptide-1 (GLP-1), and insulin. Results showed a significant drug main effect (p = 0.001), as well as a significant drug × time-point interaction effect (p = 0.01) on insulin. The spike in blood insulin concentrations observed under the placebo condition (probably due to the intake of brownie) was blunted by cannabis administration. A significant drug main effect (p = 0.001), as well as a trend-level drug × time-point interaction effect (p = 0.08) was also detected for GLP-1, suggesting that GLP-1 concentrations were lower under cannabis, compared to the placebo condition. Finally, a significant drug main effect (p = 0.01) was found for total ghrelin, suggesting that total ghrelin concentrations during the oral cannabis session were higher than the smoked and vaporized cannabis sessions. In conclusion, cannabis administration in this study modulated blood concentrations of some appetitive and metabolic hormones, chiefly insulin, in cannabis users. Understanding the mechanisms underpinning these effects may provide additional information on the cross-talk between cannabinoids and physiological pathways related to appetite and metabolism

Toward a consensus nomenclature for ghrelin, its non-acylated form, liver expressed antimicrobial peptide 2 and growth hormone secretagogue receptor

The stomach-derived octanoylated peptide ghrelin was discovered in 1999 and recognized as an endogenous agonist of the growth hormone secretagogue receptor (GHSR). Subsequently, ghrelin has been shown to play key roles in controlling not only growth hormone secretion, but also a variety of other physiological functions including, but not limited to, food intake, reward-related behaviors, glucose homeostasis and gastrointestinal tract motility. Importantly, a non-acylated form of ghrelin, desacyl-ghrelin, can also be detected in biological samples. Desacyl-ghrelin, however, does not bind to GHSR at physiological levels, and its physiological role has remained less well-characterized than that of ghrelin. Ghrelin and desacyl-ghrelin are currently referred to in the literature using many different terms, highlighting the need for a consistent nomenclature. The variability of terms used to designate ghrelin can lead not only to confusion, but also to miscommunication, especially for those who are less familiar with the ghrelin literature. Thus, we conducted a survey among experts who have contributed to the ghrelin literature aiming to identify whether a consensus may be reached. Based on the results of this consensus, we propose using the terms “ghrelin” and “desacyl-ghrelin” to refer to the hormone itself and its non-acylated form, respectively. Based on the results of this consensus, we further propose using the terms “GHSR” for the receptor, and “LEAP2” for liver-expressed antimicrobial peptide 2, a recently recognized endogenous GHSR antagonist/inverse agonist.Fil: Perello, Mario. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - La Plata. Instituto Multidisciplinario de Biología Celular. Provincia de Buenos Aires. Gobernación. Comisión de Investigaciones Científicas. Instituto Multidisciplinario de Biología Celular. Universidad Nacional de La Plata. Instituto Multidisciplinario de Biología Celular; ArgentinaFil: Dickson, Suzanne L.. The Sahlgrenska Academy at the University of Gothenburg; SueciaFil: Zigman, Jeffrey M.. UT Southwestern Medical Center; Estados UnidosFil: Leggio, Lorenzo. National Institutes of Health; Estados Unido

Transcranial magnetic stimulation of dorsolateral prefrontal cortex reduces cocaine use: A pilot study

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Effects of naltrexone on cortisol levels in heavy drinkers

The primary objectives of this study were to: (a) examine the neuroendocrine effects of naltrexone vs. placebo by comparing serum cortisol levels; and (b) test the biobehavioral correlates of naltrexone-induced changes in cortisol. Non-treatment seeking heavy drinkers (n = 37) completed two intravenous alcohol administrations, one after naltrexone (50 mg) and one after placebo. Cortisol levels were measured at baseline and after alcohol intake (BrAC = 0.06 g/dl) on both sessions, as were subjective responses to alcohol. Analyses revealed that naltrexone significantly raised overall cortisol levels compared to placebo. Cortisol levels decreased during alcohol administration and a stronger decrease was observed in the naltrexone condition. Cortisol levels were, in turn, inversely related to some of alcohol&apos;s the reinforcing effects (i.e., alcohol &apos;high,&apos; vigor) and positively associated with some of its unpleasant effects (i.e., sedation and subjective intoxication). These results suggest that naltrexone alters cortisol levels in heavy drinkers and that its effects on subjective responses to alcohol may be related, in part, to naltrexone&apos;s ability to activate the HPA-axis

Role of the α1 blocker doxazosin in alcoholism: a proof-of-concept randomized controlled trial

Evidence suggests that the norepinephrine system represents an important treatment target for alcohol dependence (AD) and the α1-blocker prazosin may reduce alcohol drinking in rodents and alcoholic patients. The α1-blocker doxazosin demonstrates a more favorable pharmacokinetic profile than prazosin, but has never been studied for AD. A double-blind placebo-controlled randomized clinical trial was conducted in AD individuals seeking outpatient treatment. Doxazosin or matched placebo was titrated to 16 mg/day (or maximum tolerable dose). Drinks per week (DPW) and heavy drinking days (HDD) per week were the primary outcomes. Family history density of alcoholism (FHDA), severity of AD and gender were a priori moderators. Forty-one AD individuals were randomized, 30 (doxazosin = 15) completed the treatment phase and 28 (doxazosin = 14) also completed the follow-up. There were no significant differences between groups on DPW and HDD per week. With FHDA as a moderator, there were significant FHDA × medication interactions for both DPW (pcorrected = 0.001, d = 1.18) and HDD (pcorrected = 0.00009, d = 1.30). Post hoc analyses revealed that doxazosin significantly reduced alcohol drinking in AD patients with high FHDA and by contrast increased drinking in those with low FHDA. Doxazosin may be effective selectively in AD patients with high FHDA. This study provides preliminary evidence for personalized medicine using α1-blockade to treat AD. However, confirmatory studies are required

Association of the 5-HTT Gene-Linked Promoter Region (5-HTTLPR) Polymorphism with Psychiatric Disorders: Review of Psychopathology and Pharmacotherapy

Serotonin (5-HT) regulates important biological and psychological processes including mood, and may be associated with the development of several psychiatric disorders. An association between psychopathology and genes that regulate 5-HT neurotransmission is a robust area of research. Identification of the genes responsible for the predisposition, development, and pharmacological response of various psychiatric disorders is crucial to the advancement of our understanding of their underlying neurobiology. This review highlights research investigating 5-HT transporter (5-HTTLPR) polymorphism, because studies investigating the impact of the 5-HTTLPR polymorphism have demonstrated significant associations with many psychiatric disorders. Decreased transcriptional activity of the S allele (“risk allele”) may be associated with a heightened amygdala response leading to anxiety-related personality traits, major depressive disorder, suicide attempts, and bipolar disorder. By contrast, increased transcriptional activity of the L allele is considered protective for depression but is also associated with completed suicide, nicotine dependence, and attention deficit hyperactivity disorder. For some disorders, such as post-traumatic stress disorder and major depressive disorder, the research suggests that treatment response may vary by allele (such as an enhanced response to serotonin specific reuptake inhibitors in patients with major depressive disorder and post-traumatic stress disorder with L alleles), and for alcohol dependence, the association and treatment for S or L alleles may vary with alcoholic subtype. While some studies suggest that 5-HTTLPR polymorphism can moderate the response to pharmacotherapy, the association between 5-HTTLPR alleles and therapeutic outcomes is inconsistent. The discovery of triallelic 5-HTTLPR alleles (LA/LG/S) may help to explain some of the conflicting results of many past association studies, while concurrently providing more meaningful data in the future. Studies assessing 5-HTTLPR as the solitary genetic factor contributing to the etiology of psychiatric disorders continue to face the challenges of statistically small effect sizes and limited replication