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In the United States (US), there are almost 5 million alcohol-related visits to Emergency Departments (EDs) per year (1). Many of these visits involve patients with alcohol use disorder (AUD) who h...

Given the high coexistence of anxiety symptoms in people with alcohol use disorder (AUD), we aimed to determine the influence of anxiety symptoms on outcomes in patients with AUD treated with the GABAB receptor agonist baclofen. A meta-analysis of 13 comparisons (published 2010-2020) including baseline and outcome data on alcohol consumption and anxiety after 12 weeks was undertaken. There were significantly higher rates of abstinent days in patients treated with baclofen compared to placebo (p = 0.004; high certainty evidence); specifically in those with higher baseline anxiety levels (p < 0.00001; high certainty evidence) compared to those with lower baseline anxiety levels (p = 0.20; moderate certainty evidence). The change in anxiety ratings over 12 weeks did not differ between those treated with baclofen or placebo (p = 0.84; moderate certainty evidence). This may be due to different anxiety constructs being measured by scales not validated in this patient group, or that anxiety is not a biobehavioral mechanism by which baclofen may reduce alcohol drinking. Given the prevalence of anxiety symptoms in AUD all these factors warrant further research.

Background and AimsThe Brief Scale for Anxiety (BSA) and the State–Trait Anxiety Inventory Form Y‐2 (STAI‐Y‐2) are self‐report scales used to gauge anxiety symptoms in clinical settings. Co‐occuring anxiety is common in alcohol use disorder (AUD); however, no studies have assessed the validity of the BSA and STAI‐Y‐2 compared with a clinical diagnostic tool of anxiety in alcohol treatment programs. We aimed to examine the validity of the BSA and STAI‐Y‐2 to predict a clinical diagnosis of an anxiety disorder (via the Structured Clinical Interview for DSM [SCID]) in AUD patients.DesignParticipants were administered the BSA (n = 1005) on day 2 and the STAI‐Y‐2 (n = 483) between days 2 and 10 of the detoxification program. SCID‐based clinical diagnoses of AUD and anxiety were made approximately on day 10.Setting and participantsIndividuals seeking treatment for AUD admitted to an inpatient unit at the National Institutes of Health (NIH) Clinical Center in Bethesda, MD, USA (n = 1010).MeasurementsInclusion criteria included a current diagnosis of alcohol dependence (AD) according to DSM‐IV‐TR or moderate to severe AUD according to DSM‐5‐RV, as well as available baseline BSA and/or STAI Y‐2 data. Empirical receiver operating characteristic (ROC) curves were generated using estimates of sensitivity, 1‐specificity and positive and negative predictive values for each cut‐point to determine the accuracy of scale outcomes in relation to SCID diagnoses.FindingsThe BSA demonstrated low accuracy relative to a clinical diagnosis of anxiety with an area under the curve (AUC) of 0.67 at the optimal cut‐point of ≥ 10. The STAI‐Y‐2 had moderate accuracy relative to a clinical diagnosis of anxiety with an AUC of 0.70 at the optimal cut‐point of ≥ 51. The accuracy of the STAI‐Y‐2 increased (AUC = 0.74) when excluding post‐traumatic stress disorder and obsessive–compulsive disorder from anxiety disorder classification.ConclusionsUse of the Brief Scale for Anxiety (BSA) and/or State–Trait Anxiety Inventory Form Y‐2 (STAI‐Y‐2) does not appear to be a reliable substitute for clinical diagnoses of anxiety disorder among inpatients with alcohol use disorder. The BSA and STAI‐Y‐2 could serve as a screening tool to reject the presence of anxiety disorders rather than for detecting an anxiety disorder.

Living in an enriched environment (EE) produces a notable impact on several rodent behaviors, including those motivated by drugs of abuse. This picture is somewhat less clear when referring to alcohol-motivated behaviors. With the intent of contributing to this research field with data from one of the few rat lines selectively bred for excessive alcohol consumption, the present study investigated the effect of EE on operant oral alcohol self-administration in Sardinian alcohol-preferring (sP) rats. Starting from Postnatal Day (PND) 21, male sP rats were kept under 3 different housing conditions: impoverished environment (IE; single housing in shoebox-like cages with no environmental enrichment); standard environment (SE; small colony cages with 3 rats and no environmental enrichment); EE (large colony cages with 6 rats and multiple elements of environmental enrichment, including 2 floors, ladders, maze, running wheels, and shelter). From PND 60, rats were exposed to different phases of shaping and training of alcohol self-administration. IE, SE, and EE rats were then compared under (i) fixed ratio (FR) 4 (FR4) schedule of alcohol reinforcement for 20 daily sessions and (ii) progressive ratio (PR) schedule of alcohol reinforcement in a final single session. Acquisition of the lever-responding task (shaping) was slower in EE than IE and SE rats, as the likely consequence of a "devaluation" of the novel stimuli provided by the operant chamber in comparison to those to which EE rats were continuously exposed in their homecage or an alteration, induced by EE, of the rat "emotionality" state when facing the novel environment represented by the operant chamber. Training of alcohol self-administration was slower in EE than IE rats, with SE rats displaying intermediate values. A similar ranking order (IESEEE) was also observed in number of lever-responses for alcohol, amount of self-administered alcohol, and breakpoint for alcohol under FR4 and PR schedules of reinforcement. These data suggest that living in a complex environment reduced the reinforcing and motivational properties of alcohol in sP rats. These results are interpreted in terms of the reinforcing and motivational properties of the main components of EE (i.e., social interactions, physical activities, exploration, novelty) substituting, at least partially, for those of alcohol.

Alcohol and other xenobiotics may limit the therapeutic effects of medications. We aimed at investigating alcohol-medication interactions (AMI) after the exclusion of confounding effects related to other xenobiotics. We performed a systematic review and meta-analysis of controlled studies comparing the effects induced by alcohol versus placebo on pharmacodynamic and/or pharmacokinetic parameters of approved medications. Certainty in the evidence of AMI was assessed when at least 3 independent studies and at least 200 participants were available. We included 107 articles (3097 participants): for diazepam, cannabis, opioids, and methylphenidate, we found significant AMI and enough data to assign the certainty of evidence. Alcohol consumption significantly increases the peak plasma concentration of diazepam (low certainty; almost 290 participants), cannabis (high certainty; almost 650 participants), opioids (low certainty; 560 participants), and methylphenidate (moderate certainty; 290 participants). For most medications, we found some AMI but not enough data to assign them the certainty grades; for some medications, we found no differences between alcohol and placebo in any outcomes evaluated. Our results add further evidence for interactions between alcohol and certain medications after the exclusion of confounding effects related to other xenobiotics. Physicians should advise patients who use these specific medications to avoid alcohol consumption. Further studies with appropriate control groups, enough female participants to investigate sex differences, and elderly population are needed to expand our knowledge in this field. Short phrases suitable for indexing terms • Among participants taking diazepam, those who consumed alcohol achieved higher peak plasma concentration (low certainty; almost 290 participants) and area under the curve (very low certainty; 270 participants) of this medication compared to those who consumed placebo • Among participants taking cannabis, those who consumed alcohol achieved higher peak plasma concentration (high certainty; almost 650 participants), in a shorter time (very low certainty; more than 300 participants), and have a longer elimination half-life (moderate certainty; almost 250 participants) of Delta (9)-tetrahydrocannabinol (THC) compared to those who consumed placebo • Among participants taking opioids, those who consumed alcohol achieved higher peak plasma concentration (low certainty; 560 participants) and in a shorter time (moderate certainty; 554 participants) of opioids compared to those who received placebo • Among participants taking methylphenidate, those who consumed alcohol achieved higher peak plasma concentration (moderate certainty; 290 participants) and area under the curve of this medication compared to those who consumed placebo

Background: Pharmacotherapy for Alcohol Dependence (AD) is underutilized. Barriers preventing the use of AD medications include high prices, lack of access to prescribing physicians, and a limited number of available medications. Objective: The study evaluated the use of AD medications in a sample of Italian outpatients who received these medications free of charge, had access to physicians during office hours, and for whom substitution therapy [gamma-hydroxybutyrate (GHB)] was available. We also evaluated the rate of patients who received a combination of non-pharmacological and pharmacological treatments among participants who were still drinking. Methods: SCID for AD and questionnaire were filled by to AD outpatients during a face-to-face interview. Results & Discussion: 345 AD outpatients were interviewed: 58.8% were currently receiving at least one AD medication (GHB: 34.3%, disulfiram: 29.6%, acamprosate: 5.9%; naltrexone: 2.5%; more than one medication: 16.7%). Less than 30% of participants who were still drinking, received a combination of non-pharmacological and pharmacological treatments. Nonetheless, we found higher use of AD medications compared to previous studies conducted in other countries. This higher use of AD medications may be due to access to free medications, prescribing physicians’ style, and a larger number of available medications. Conclusion: Our results confirm the underutilization of AD medications, as less than 60% of AD outpatients received medications, and less than 30% of those who were still drinking, received a combination of non-pharmacological and pharmacological treatments. These findings may be useful in improving our knowledge of the barriers that prevent the use of AD medications in clinical practice.

We are particularly pleased that Alcohol and Alcoholism has dedicated this special collection to ‘Sex and Gender differences in Alcohol Use Disorder’. To date, a series of preclinical and clinical studies have tried to shed light on the similarities and differences in the field of alcohol research between men and women (Agabio et al., 2016a and 2017; Salvatore et al., 2017; McHugh et al., 2018; Ait-Daoud et al., 2019; Becker and Chartoff, 2019). However, our understanding of the complexities on this topic remains limited.

This study aims to provide a picture of University of Cagliari students’ alcohol-related behaviour and to explore factors associated with it. Data were collected by administering a questionnaire to 992 freshmen university students from different programs consisting of twelve closed questions, including three questions from the Alcohol Use Disorders Identification Test for Consumption (AUDIT-C short form). Three subgroups of alcohol-related behaviour were distinguished (risky drinkers, social drinkers and abstainers). In order to explore factors associated with patterns of alcohol consumption, a multivariate logistic regression was performed. The prevalence of risky drinkers was 35%. A binge-drinking behaviour at least once in the last twelve months was declared by 65% (more widespread in men and in students living away from their parents). Risky consumption is significantly associated with age of onset of alcohol use, living away from parents’ home, drinking outside meals and attending health courses. Regarding the levels of daily alcohol consumption perceived as a health risk, 66% of men and 88% of women indicate values higher than those recommended. The results underline the need for tailored prevention measures. University could be a promising setting to implement actions according to a health promotion perspective, to empower students to control their alcohol consumption.

Preclinical Research Δ9 -Tetrahydrocannabinol (THC) is a hydrophobic compound that has a potent antinociceptive effect in animals after intrathecal (IT) or intracerebroventricular (ICV) administration. The lack of a suitable solvent precludes its IT administration in humans. 2-Hydroxypropyl-β-cyclodextrin (HPβCD) increases the water solubility of hydrophobic drugs and is approved for IT administration in humans. To investigate whether HPβCD might be a suitable carrier for ICV administration of THC in rats, two formulations containing THC complexed with HPβCD (30 and 135 μg of THC per animal) and vehicle were administered to Wistar rats. The antinociceptive effect (using the tail flick test), locomotor activity, and body temperature were evaluated. ICV injection of 135 μg of THC/HPβCD complex increased tail flick latency, reduced locomotor activity, and had a dual effect on body temperature. The 30 μg THC/HPβCD formulation only produced a hyperthermic effect. All animals appeared healthy, with no difference between the groups. These results were similar to those obtained in other preclinical studies in which THC was administered centrally using solvents that are unsuitable for IT administration in humans because of their toxicity. Our findings suggest that HPβCD may be a useful carrier for IT administration of THC in humans. Drug Dev Res 78 : 411-419, 2017. © 2017 Wiley Periodicals, Inc.

The poor implementation of alcohol use disorder treatment programs has been well documented in many countries. Among the barriers have been identified in health professionals and patients, lack of awareness about existing medications and perceived lack of efficacy seem to deter physicians from offering pharmacotherapy to their patients. Indeed, existing registered medications are only modestly effective. Therefore, there is an urgent need to develop more effective treatments in this area, ideally targeting new mechanisms of action. The efficacy of GABAB agonists has been explored for some time, as they are believed to reduce alcohol craving, possibly through alcohol mimicking effects. In particular, two drugs, both decades-long marketed for other purposes, have been tested: baclofen and sodium oxybate. Sodium oxybate is approved for the treatment of alcohol use disorder in several countries, and efforts or currently been made to obtain an approval at the European level. This medication has showed medium to large treatment effects in patients with severe alcohol dependence [1] . Baclofen has recently been labeled for the treatment of alcohol use disorder in France, the only country so far having officially approved baclofen in this indication. Off-label Baclofen prescription for alcohol use disorder substantially increased a decade ago, leading to a regulatory recognition named a “temporary recommendation for use” in 2014, and eventually a full approval in 2018, despite the lack of consistent evidence of efficacy [2] . At the international level, a number of experts meeting in Cagliari succeeded in publishing a consensual statement regarding baclofen for the treatment of alcohol use disorder [3] . The aim of this session is to provide a scientific and historical background on the development of GABA-B agonists in alcohol use disorders, state of the art regarding baclofen efficacy and safety, and to elucidate the singularity of the French experience with baclofen that eventually permitted it's official approval.

There are conflicting results about sex differences in the response to opioids for pain control and the role of potential influencing factors of these differences has not been investigated. We meta-analyzed differences and similarities between men and women in opioid response for pain control and investigated the potential influence of baseline pain intensity, age, body weight, and other factors in these findings. PubMed, Scopus, and Cochrane CENTRAL were searched through January 15, 2019, for clinical studies in which opioids were administered for pain control. We included clinical studies in which (a) opioids were used to treat acute or chronic pain, (b) the response to opioids was broken down for men and women, and (c) the response to opioids was reported as (i) difference between baseline and final Visual Analog Scale of Pain Intensity (VASPI) score 30 min after opioid administration (Delta-VASPI at 30′), or daily dose of opioids (ii) self-administered by patients (patient-controlled analgesia PCA), or (iii) administered by physicians. Risk of bias was evaluated using ROBINS-I and the overall quality of evidence for primary outcomes was evaluated using the GRADE system. Globally, we included 40 comparisons (6794 patients). Regarding acute pain, we found moderate quality of evidence that women and men do not differ in their response to opioids 30 min after their administration [Delta-VASPI at 30′: mean difference, MD = 0.42 (−0.07; 0.91)]. We also found moderate quality of evidence that women self-administer lower daily amounts of opioids [daily PCA: standardized mean difference, SMD = −0.30 (−0.41; −0.18)]. Regarding chronic pain, we found low quality of evidence that women receive lower daily doses for non-cancer pain [MD = −36.42 (−57.86; –14.99)]. By contrast, we found very low quality of evidence that women and men do not differ in the daily dose of opioids for cancer pain [MD = −16.09 (−40.13; 7.94)]. Age, comorbid mental disorders, type of administration, type of opioids, type of patients, and body weight significantly modified these results. In conclusion, the results of the present meta-analysis suggest that men and women may differ in the response to opioids for pain relief, but these differences as well as similarities are significantly influenced by factors like age and comorbid mental disorders. However, the role of these factors is not usually evaluated in the prescription of opioids for pain control. There is an urgent need to conduct clinical trials on the use of opioid medications for pain, in which information about all possible influencing factors are provided and broken down for men and women.

Although sex differences in several aspects of substance use disorders (SUDs) have been identified, less is known about the importance of possible sex differences in side effects induced by substances of abuse or by medications used to treat SUDs. In the SUD field, the perception of certain subjective effects are actively sought, while all other manifestations might operationally be considered side effects. This article was aimed at reviewing sex differences in side effects induced by alcohol, nicotine, heroin, marijuana and cocaine and by medications approved for alcohol, nicotine and heroin use disorders. A large body of evidence suggests that women are at higher risk of alcohol-induced injury, liver disease, cardiomyopathy, myopathy, brain damages and mortality. The risk of tobacco-induced coronary heart disease, lung disease and health problems is higher for women than for men. Women also experience greater exposure to side effects induced by heroin, marijuana and cocaine. In addition, women appear to be more vulnerable to the side effects induced by medications used to treat SUDs. Patients with SUDs should be advised that the risk of developing health problems may be higher for women than for men after consumption of the same amount of substances of abuse. Doses of medications for SUD women should be adjusted at least according to body weight. The sex differences observed also indicate an urgent need to recruit adequate numbers of female subjects in pre-clinical and clinical studies to improve our knowledge about SUDs in women.

Alcohol Use Disorder (AUD) is a common mental disorder with severe medical, psychological and social consequences [1] . AUD leads up to 3- and 4-fold increases in the risk of mortality in men and women, respectively [2] . Nevertheless, less than 10% of people with AUD seek and receive treatment for their disorder and less than 4% receive any pharmacological intervention [3] . The identification of new medications is crucial to increase the number of people with AUD who receive effective treatment. Baclofen, a GABAB receptor agonist approved for clinical use as a muscle relaxant, has emerged as a promising drug for AUD [4] . Preclinical studies have provided consistent evidence that baclofen administration dose-dependently reduces alcohol consumption in validated animal models of AUD [5] . On the other hand, clinical studies have yielded less consistent results [6] . Some randomized controlled trials (RCTs) found that AUD patients treated with baclofen significantly reduced alcohol consumption compared to patients treated with placebo, whereas other RCTs found no differences between AUD patients treated with baclofen or placebo [6] . In addition, recent meta-analyses report there is insufficient evidence of effectiveness to support the use of baclofen to treat AUD [7] , [8] , [9] , [10] . Several methodological differences among these RCTs may have contributed to these contrasting results, including (i) the daily dose of baclofen (ranging from 30 to 300 mg), (ii) prescribing regimes (fixed doses or titration until the desired clinical effect was achieved), and (iii) presence/absence of comorbid medical (e.g. liver disease) or psychiatric diseases (e.g. anxiety disorders) [6] , [11] . Nevertheless, baclofen is used off-label to treat AUD in several countries, and in France baclofen was officially approved for AUD treatment in October 2018 [6] . In May 2018, during the GABAB Receptor Conference, held in Cagliari, Italy, a group of international experts in the clinical use of baclofen for AUD met and combined their expertise to provide concise and well-balanced information regarding this controversial topic. This group included 26 researchers and physicians who had contributed to the majority of RCTs (both positive and negative) on baclofen and AUD as well as studies focused on the side effects of baclofen in patients with AUD. A modified Delphi method was used. Each statement was discussed, modified, and rated until consensus was reached by the entire group. The final draft included 18 statements and was recently published as “the Cagliari Statement” in Lancet Psychiatry [12] . This Consensus paper is intended as a helpful tool for clinicians deciding whether or not prescribe baclofen off-label to their patients with AUD and to researchers planning investigations with baclofen. The Cagliari Statement may be particularly useful clinicians in France, where baclofen has been officially approved for AUD treatment [6] .

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 chronic use of alcohol can lead to the onset of an alcohol use disorder (AUD). About 50% of subjects with an AUD may develop alcohol withdrawal syndrome (AWS) when they reduce or discontinue their alcohol consumption and, in 3-5% of them, convulsions and delirium tremens (DTs), representing life-threatening complications, may occur. Unfortunately, few physicians are adequately trained in identifying and treating AWS. The Italian Society on Alcohol has, therefore, implemented a task force of specialists to draw up recommendations for the treatment of AWS with the following main results: (1) while mild AWS may not require treatment, moderate and severe AWS need to be pharmacologically treated; (2) out-patient treatment is appropriate in patients with mild or moderate AWS, while patients with severe AWS need to be treated as in-patients; (3) benzodiazepines, BDZs are the "gold standard" for the treatment of AWS and DTs; (4) alpha-2-agonists, beta-blockers, and neuroleptics may be used in association when BDZs do not completely resolve specific persisting symptoms of AWS; (5) in the case of a refractory form of DTs, the use of anaesthetic drugs (propofol and phenobarbital) in an intensive care unit is appropriate; (6) alternatively to BDZs, sodium oxybate, clomethiazole, and tiapride approved in some European Countries for the treatment of AWS may be employed for the treatment of moderate AWS; (7) anti-convulsants are not sufficient to suppress AWS, and they may be used only in association with BDZs for the treatment of refractory forms of convulsions in the course of AWS.

BACKGROUND: Alcohol dependence is a major public health problem characterized by recidivism, and medical and psychosocial complications. The co‐occurrence of major depression in people entering treatment for alcohol dependence is common, and represents a risk factor for morbidity and mortality, which negatively influences treatment outcomes. OBJECTIVES: To assess the benefits and risks of antidepressants for the treatment of people with co‐occurring depression and alcohol dependence. SEARCH METHODS: We searched the Cochrane Drugs and Alcohol Group Specialised Register (via CRSLive), Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, and Embase from inception to July 2017. We also searched for ongoing and unpublished studies via ClinicalTrials.gov (www.clinicaltrials.gov) and the World Health Organization (WHO) International Clinical Trials Registry Platform (ICTRP) (apps.who.int/trialsearch/). All searches included non‐English language literature. We handsearched references of topic‐related systematic reviews and the included studies. SELECTION CRITERIA: Randomized controlled trials and controlled clinical trials comparing antidepressants alone or in association with other drugs or psychosocial interventions (or both) versus placebo, no treatment, and other pharmacological or psychosocial interventions. DATA COLLECTION AND ANALYSIS: We used standard methodological procedures as expected by Cochrane. MAIN RESULTS: We included 33 studies in the review (2242 participants). Antidepressants were compared to placebo (22 studies), psychotherapy (two studies), other medications (four studies), or other antidepressants (five studies). The mean duration of the trials was 9.9 weeks (range 3 to 26 weeks). Eighteen studies took place in the USA, 12 in Europe, two in Turkey, and one in Australia. The antidepressant included in most of the trials was sertraline; other medications were amitriptyline, citalopram, desipramine, doxepin, escitalopram, fluoxetine, fluvoxamine, imipramine, mianserin, mirtazepine, nefazodone, paroxetine, tianeptine, venlafaxine, and viloxazine. Eighteen studies were conducted in an outpatient setting, nine in an inpatient setting, and six in both settings. Psychosocial treatment was provided in 18 studies. There was high heterogeneity in the selection of outcomes and the rating systems used for diagnosis and outcome assessment. Comparing antidepressants to placebo, low‐quality evidence suggested that antidepressants reduced the severity of depression evaluated with interviewer‐rated scales at the end of trial (14 studies, 1074 participants, standardized mean difference (SMD) ‐0.27, 95% confidence interval (CI) ‐0.49 to ‐0.04). However, the difference became non‐significant after the exclusion of studies with a high risk of bias (SMD ‐0.17, 95% CI ‐0.39 to 0.04). In addition, very low‐quality evidence supported the efficacy of antidepressants in increasing the response to the treatment (10 studies, 805 participants, risk ratio (RR) 1.40, 95% Cl 1.08 to 1.82). This result became non‐significant after the exclusion of studies at high risk of bias (RR 1.27, 95% CI 0.96 to 1.68). There was no difference for other relevant outcomes such as the difference between baseline and final score, evaluated using interviewer‐rated scales (5 studies, 447 participants, SMD 0.15, 95% CI ‐0.12 to 0.42). Moderate‐quality evidence found that antidepressants increased the number of participants abstinent from alcohol during the trial (7 studies, 424 participants, RR 1.71, 95% Cl 1.22 to 2.39) and reduced the number of drinks per drinking days (7 studies, 451 participants, mean difference (MD) ‐1.13 drinks per drinking days, 95% Cl ‐1.79 to ‐0.46). After the exclusion of studies with high risk of bias, the number of abstinent remained higher (RR 1.69, 95% CI 1.18 to 2.43) and the number of drinks per drinking days lower (MD ‐1.21 number of drinks per drinking days, 95% CI ‐1.91 to ‐0.51) among participants who received antidepressants compared to those who received placebo. However, other outcomes such as the rate of abstinent days did not differ between antidepressants and placebo (9 studies, 821 participants, MD 1.34, 95% Cl ‐1.66 to 4.34; low‐quality evidence). Low‐quality evidence suggested no differences between antidepressants and placebo in the number of dropouts (17 studies, 1159 participants, RR 0.98, 95% Cl 0.79 to 1.22) and adverse events as withdrawal for medical reasons (10 studies, 947 participants, RR 1.15, 95% Cl 0.65 to 2.04). There were few studies comparing one antidepressant versus another antidepressant or antidepressants versus other interventions, and these had a small sample size and were heterogeneous in terms of the types of interventions that were compared, yielding results that were not informative. AUTHORS' CONCLUSIONS: We found low‐quality evidence supporting the clinical use of antidepressants in the treatment of people with co‐occurring depression and alcohol dependence. Antidepressants had positive effects on certain relevant outcomes related to depression and alcohol use but not on other relevant outcomes. Moreover, most of these positive effects were no longer significant when studies with high risk of bias were excluded. Results were limited by the large number of studies showing high or unclear risk of bias and the low number of studies comparing one antidepressant to another or antidepressants to other medication. In people with co‐occurring depression and alcohol dependence, the risk of developing adverse effects appeared to be minimal, especially for the newer classes of antidepressants (such as selective serotonin reuptake inhibitors). According to these results, in people with co‐occurring depression and alcohol dependence, antidepressants may be useful for the treatment of depression, alcohol dependence, or both, although the clinical relevance may be modest.

The aim of this study was to evaluate whether the number of women recruited for studies to establish the efficacy of medications approved for treatment of alcohol dependence (AD) and of alcohol withdrawal syndrome (AWS) is sufficient to reveal possible gender differences in the response to these medications and in suggesting the use of different doses in female patients. Our results show that the rates of women recruited for studies evaluating the efficacy of disulfiram (1%), benzodiazepines (3%), and anticonvulsants (13%) were too low to establish possible gender differences. The rates of women recruited for studies evaluating the efficacy of acamprosate (22%), naltrexone (23%), and nalmefene (30%) were higher and allowed evaluation of data obtained for female patients. Women receive medications for treatment of AD and/or AWS for which efficacy has been demonstrated in studies in which men were more largely represented.

Fibromyalgia is a pain disorder associated with frequent comorbid mood, anxiety, and sleep disorders. Despite the frequent use of a complex, poly-drug pharmacotherapy, treatment for fibromyalgia is of limited efficacy. Oxytocin has been reported to reduce the severity of pain, anxiety, and depression, and improve the quality of sleep, suggesting that it may be useful to treat fibromyalgia. To evaluate this hypothesis, 14 women affected by fibromyalgia and comorbid disorders, assuming a complex pharmacotherapy, were enrolled in a double-blind, crossover, randomized trial to receive oxytocin and placebo nasal spray daily for 3 weeks for each treatment. Order of treatment (placebo-oxytocin or oxytocin-placebo) was randomly assigned. Patients were visited once a week. At each visit, the following instruments were administered: an adverse drug reaction record card, Visual Analog Scale of Pain Intensity, Spielberger State Anxiety Inventory, Zung Self-rating Depression Scale, and SF-12. Women self-registered painkiller assumption, pain severity, and quality of sleep in a diary. Unlikely, oxytocin nasal spray (80 IU a day) did not induce positive therapeutic effects but resulted to be safe, devoid of toxicity, and easy to handle.

Background: Alcohol use disorder (AUD) is a common and disabling mental disorder associated with a significant burden of medical consequences and high socioeconomic costs. Although a growing number of studies support the existence of sex differences in several aspects of alcohol consumption and AUD, the majority of investigations have been conducted in men. Objective: This article was aimed at reviewing sex differences in AUD, focusing on epidemiology, neurobiology, pharmacokinetics, susceptibility to medical consequences, and treatment. Results: Although AUD is more prevalent in men, the number of women with AUD is rapidly increasing, especially in adolescents. Women show a higher vulnerability to medical consequences induced by alcohol consumption, including alcohol-related liver disease, cardiomyopathy, and breast cancer. This observation is only partly explained by the sex differences observed in the pharmacokinetics of alcohol. Women also show an accelerated progression from the first use of alcohol to the onset of AUD and appear to be at higher risk of alcohol–medication interactions. Although AUD women are less likely to seek treatment than men, they achieve better results through dedicated programs taking into account the special needs of female patients. However, findings on the efficacy and safety of medications used to treat AUD mostly come from studies in which women were largely underrepresented. Conclusion: The sex differences observed suggest the urgent need to conduct studies recruiting adequate numbers of female subjects, to increase knowledge of sex differences in AUD, and to develop personalized and evidence-based approaches of prevention and treatment of AUD in women.

Although sex differences in several aspects of substance use disorders (SUDs) have been identified, less is known about the importance of possible sex differences in side effects induced by substances of abuse or by medications used to treat SUDs. In the SUD field, the perception of certain subjective effects are actively sought, while all other manifestations might operationally be considered side effects. This article was aimed at reviewing sex differences in side effects induced by alcohol, nicotine, heroin, marijuana and cocaine and by medications approved for alcohol, nicotine and heroin use disorders. A large body of evidence suggests that women are at higher risk of alcohol-induced injury, liver disease, cardiomyopathy, myopathy, brain damages and mortality. The risk of tobacco-induced coronary heart disease, lung disease and health problems is higher for women than for men. Women also experience greater exposure to side effects induced by heroin, marijuana and cocaine. In addition, women appear to be more vulnerable to the side effects induced by medications used to treat SUDs. Patients with SUDs should be advised that the risk of developing health problems may be higher for women than for men after consumption of the same amount of substances of abuse. Doses of medications for SUD women should be adjusted at least according to body weight. The sex differences observed also indicate an urgent need to recruit adequate numbers of female subjects in pre-clinical and clinical studies to improve our knowledge about SUDs in women.

Accumulating lines of experimental and clinical evidence suggest that the prototypic, orthosteric GABA type B (GABAB) receptor agonist, baclofen, may possess therapeutic potential for treatment of alcohol use disorder (AUD). At preclinical level, acute or repeated treatment with nonsedative doses of baclofen has repeatedly been reported to suppress several alcohol-motivated behaviors, including alcohol drinking, in rats and mice. At clinical level, administration of doses of baclofen ranging from low to extremely high doses has been found to suppress alcohol consumption, craving for alcohol, and alcohol withdrawal signs and symptoms in patients affected by AUD, confirming that baclofen may represent a promising option for treatment of AUD. A more recent avenue of research is represented by generalization of baclofen effects to the positive allosteric modulators of the GABAB receptor: preclinical data collected to date suggest that these compounds reproduce, with a much higher therapeutic index, several suppressing effects of baclofen on alcohol-motivated behaviors.

Background Preclinical studies suggest that the neuropeptide oxytocin reduces food intake and body weight, but only a few clinical studies have investigated the translatability of these findings in humans. The present study investigated the safety and efficacy of oxytocin nasal spray in patients affected by binge eating disorder and obesity. Methods Seventeen outpatients affected by binge eating disorder and obesity participated in a 8 week double-blind trial and received oxytocin (n=8; 24 IU, four times a day, 20 min before each of three meals and before going to bed) or placebo (n=9) with an energy-restricted diet. Primary outcomes included adverse events and the number of binge eating episodes per week. Secondary measures included body weight, BMI, severity of BED, craving for food, quality of sleep, quality of life, anxiety, and depressive symptoms. Results One patient of oxytocin group discontinued prematurely the trial before the first post-randomization efficacy measure. Among the other 16 participants, 13 (81.2%) completed the trial, and 3 (18.8%) discontinued [3 in the oxytocin group; 0 in the placebo group (p=0.0625, Fisher’s exact test)]. No significant difference between groups was found in any outcome evaluated. Patients of the placebo group performed slightly better than patients of the oxytocin group in some secondary outcomes, but these differences were not significant. Conclusion Oxytocin nasal spray resulted to be safe, including in women of childbearing age but did not significantly reduce the number of binge eating episodes per week in outpatients affected by binge eating disorder and obesity. These findings are discussed in light of the human oxytocin literature.

The National Institute on Alcohol Abuse and Alcoholism (NIAAA) has developed a two-question tool for the detection of unhealthy drinking (NIAAA-2Q) that investigates excessive alcohol consumption per single occasion. NIAAA-2Q can be commuted into a four-question tool (NIAAA-4Q) by the addition of two questions aimed at investigating excessive weekly alcohol intake. NIAAA-2Q and NIAAA-4Q may prove useful in busy settings such as an anesthesiological environment. However, to date, no study has evaluated their efficacy in a surgical setting. The purpose of this study was to evaluate the accuracy of NIAAA-2Q and NIAAA-4Q in detecting unhealthy drinking among surgical patients using the more complex Alcohol Use Disorders Identification Test (AUDIT) comprising 10 questions as the criterion method.NIAAA-4Q and AUDIT were administered to 200 surgical patients by three anesthetists.A total of 23.5%, 12.5%, and 28.5% surgical patients were unhealthy drinkers according to AUDIT, NIAAA-2Q, and NIAAA-4Q, respectively. NIAAA-2Q negative and positive predictive values were 0.78 and 0.36, respectively, and positive and negative likelihood ratios were 1.80 and 0.90, respectively. NIAAA-4Q negative and positive predictive values were 0.93 and 0.65, respectively, and positive and negative likelihood ratios were 6.00 and 0.24, respectively.NIAAA-4Q demonstrated a better satisfactory agreement than NIAAA-2Q with AUDIT in detecting unhealthy alcohol drinking among surgical patients. These results suggest that the detection of unhealthy alcohol drinking may be increased by the administration of questions aimed at assessing the weekly average of alcohol intake. The modest time required for NIAAA-4Q administration is a major advantage in clinical practice with respect to AUDIT. Further research will compare NIAAA-2Q and NIAAA-4Q with other brief alcohol screening tests.

Aims: (i) To evaluate the prevalence of alcohol use disorders, and at risk-drinking among outpatients admitted to the Division of Psychiatry, University of Cagliari, Italy, for mood disorders, and (ii) to compare the sensitivity and specificity of the questionnaires used. Methods: Fifty-six patients affected by mood disorders answered to the questions of (i) The NIAAA Guide for identification of at-risk drinking, (ii) AUDIT questionnaire, (iii) The CAGE questionnaire and, (iv) SCID-I application forms for mood and alcohol use disorders. Results: Fourteen subjects (25%) met the criteria for alcohol use disorders according to SCID-I; 17 (30.4%) achieved a score ≥ 1 in CAGE questionnaire; 12 (21.4%) reached AUDIT scores of ≥8 and 4 for men and women, respectively; 12 (21.4%) provided positive answers to NIAAA Guide. Despite these prevalence rates, no diagnosis of alcohol use disorders had previously been registered in their medical records. The CAGE questionnaire achieved the highest values of sensitivity and specificity in detecting alcohol use disorders tested against that of the SCID-I. Conclusions: Alcohol use disorders and at-risk drinking are frequent in patients affected by mood disorders, although often underestimated; this underestimation was virtually absolute in the sample of patients investigated. Combination of the CAGE questionnaire plus the first questions in the NIAAA Guide may be an effective tool for use in the identification of psychiatric patients with possible alcohol use disorders or at-risk drinking.

Tekst ten podsumowuje dane eksperymentalne i kliniczne wskazujące na potencjał terapeutyczny agonisty receptora GABAB, baklofenu w leczeniu zaburzeń związanych z używaniem alkoholu (AUD) oraz zaburzeń związanych z używaniem substancji psychoaktywnych (SUD). W wielu badaniach przedklinicznych wykazano zdolność baklofenu do zmniejszania picia alkoholu (w tym picia ciągami i nawrotów spożycia alkoholu), instrumentalnego doustnego samopodawania alkoholu, samopodawania dożylnego kokainy, nikotyny, amfetaminy, metamfetaminy, morfiny i heroiny u gryzoni. Niektóre randomizowane, kontrolowane badania kliniczne (RCT) oraz opisy przypadków potwierdzają skuteczność baklofenu w zakresie hamowania spożycia alkoholu, odczuwania głodu alkoholu oraz symptomatologii zespołu abstynencyjnego u pacjentów uzależnionych od alkoholu. Dane z badań z randomizacją i badań otwartych oceniających skuteczność baklofenu w SUD są mniej jednoznaczne. Ostatnio pojawiło się zainteresowanie podawaniem wysokich dawek baklofenu u pacjentów z AUD i SUD. Badania przedkliniczne pozwoliły ustalić, że "antyuzależniające" właściwości baklofenu są również cechą pozytywnych allosterycznych modulatorów receptora GABAB (PAM GABAB). W świetle ich bardziej korzystnego profilu działań niepożądanych (w stosunku do baklofenu), PAM GABAB mogą stanowić istotny krok naprzód w farmakoterapii AUD i SUD opartej o ligandy receptora GABAB.

Summary Recent preclinical and clinical studies have suggested that baclofen, the prototypic γ-aminobutyric acid B (GABAB) 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.

Cancer patients submitted to gastrointestinal surgery are at risk of thiamine deficiency (TD) and Wernicke's encephalopathy (WE). Although permanent neurological damage and death could be prevented by a timely replacement therapy, they often remain undiagnosed and untreated. We hypothesized that WE remains unrecognized because most cases may manifest several months after hospital discharge.WE frequency was investigated in a sample of cancer patients who underwent gastrointestinal surgery, by using the diagnostic criteria proposed to improve diagnosis among alcoholics. Patients were evaluated at discharge through the examination of medical records and 6 months after by telephonic interview.Forty-five patients were selected. Signs of WE resulted in 4.4% at discharge. At 6 months, 21 patients were interviewed. Among them, 90.4% had signs of WE. The number of affected patients was significantly higher 6 months after discharge than at discharge (90.4 vs 9.5%, p 0.0001).Further studies with larger samples are needed to establish the prevalence of TD and related WE in cancer patients after gastrointestinal surgery. This study suggests that the problem is understated. Even in absence of symptoms of TD, the use of prophylactic thiamine supplementation should be taken in consideration, as consequences of misdiagnosis can be severe.

Recent studies have demonstrated that treatment with the gamma-aminobutyric acid (GABA(B)) receptor agonist, baclofen, reduces alcohol intake in selectively bred Sardinian alcohol-preferring rats tested under the homecage two-bottle "alcohol versus water" choice regimen. This study was designed to investigate whether baclofen also reduces alcohol-reinforcing effects in Sardinian alcohol-preferring rats. To this aim, sP rats were trained to lever press for oral alcohol (15%, vol/vol) or sucrose (0.3%, wt/vol; included as alternative reinforcer to evaluate the specificity of baclofen effect on alcohol reinforcement) under a fixed ratio schedule of 4. Once steady levels of alcohol or sucrose self-administration behavior were established, the effects of acutely administered baclofen (0, 1.7, and 3 mg/kg, intraperitoneal [ip]) and naloxone (0, 1, and 3 mg/kg, ip; included as reference compound) on alcohol- or sucrose-reinforced responding were evaluated. Baclofen administration dose dependently, although not specifically, reduced alcohol-reinforced responding to an extent comparable to that of naloxone. Baclofen also produced a dose-dependent and specific delay in the onset of alcohol-reinforced responding, suggesting that it suppressed the rats' motivation to start drinking alcohol. These data are discussed in terms of adding further support to the hypothesized involvement of the GABA(B) receptor in the neural system mediating alcohol reinforcement. These data are also in agreement with the results of recent preliminary clinical studies suggesting that baclofen may have therapeutic efficacy in the treatment of alcohol dependence.

The present paper describes the results of recent preclinical and clinical studies conducted in this laboratory in order to characterize the anti-alcohol properties of the GABA(B) receptor agonist, baclofen. At a preclinical level, the repeated administration of non-sedative doses of baclofen dose-dependently suppressed the acquisition and maintenance of alcohol drinking behavior in selectively bred Sardinian alcohol-preferring (sP) rats tested under the homecage, 2-bottle "alcohol vs water" choice regimen. Acute injection of baclofen completely blocked the temporary increase in voluntary alcohol intake occurring after a period of alcohol abstinence (the so-called alcohol deprivation effect, which models alcohol relapses in human alcoholics). Acute treatment with baclofen also dose-dependently suppressed extinction responding for alcohol (an index of motivation to consume alcohol) in sP rats trained to lever-press for oral alcohol self-administration. Taken together, these results suggest the involvement of the GABA(B) receptor in the neural substrate mediating alcohol intake and alcohol motivational properties in an animal model of excessive alcohol consumption. Further, acutely administered baclofen dose-dependently reduced the severity of alcohol withdrawal signs in Wistar rats made physically dependent upon alcohol. Preliminary clinical surveys suggest that the anti-alcohol properties of baclofen observed in rats may generalize to human alcoholics. Indeed, a double-blind survey demonstrated that repeated daily treatment with baclofen was associated, when compared to placebo, with a higher percentage of subjects totally abstinent from alcohol and a higher number of days of total abstinence. Treatment with baclofen also suppressed the number of daily drinks and decreased the obsessive and compulsive components of alcohol craving. Finally, a single non-sedative dose of baclofen resulted in the rapid disappearance of alcohol withdrawal symptomatology, including delirium tremens, in alcohol-dependent patients. In both clinical studies, baclofen was well tolerated with minimal side effects. These results suggest that baclofen may represent a potentially effective medication in the treatment of alcohol-dependent patients.

Alcohol withdrawal syndrome is a distressing and at times life-threatening condition in alcohol-dependent patients (1). Usually, symptoms develop within 6 –24 hours after the last drink (2). Early symptoms include raised blood pressure and pulse rate, tremor, hyperreflexia, and anxiety with increased irritability. Clinical management is aimed at symptom relief, prevention of seizures and delirium, and a smooth transition to a treatment program to maintain long-term abstinence from alcohol (3). Benzodiazepines are presently the drug of choice (4). We recently found that baclofen, a -aminobutyric acid (GABA)B receptor agonist used to control spasticity (5), reduced voluntary alcohol intake in alcohol-preferring rats (6), as well as alcohol craving and intake, up to complete alcohol abstinence, in alcohol-dependent patients (7). Furthermore, baclofen suppressed the intensity of alcohol withdrawal syndrome in rats who were physically dependent on alcohol (6). We therefore studied the effects of oral administration of baclofen in patients with severe alcohol withdrawal syndrome.

Background: Alcohol use in adolescents constitutes a major public health concern. Europe is the heaviest drinking region of the world. Several school-based alcohol prevention programs have been developed but it is not clear whether they are really effective. The present study was aimed at identifying the typology with the best evidence of effectiveness in European studies. Methods: A systematic search of meta-analyses and/or randomized controlled trials (RCTs) on interventions school-based prevention programs aimed at preventing alcohol consumption or changing the attitudes to consume alcohol. Results: A meta-analysis published in 2011 and 12 RCTs more recently published were identified. The meta-analysis evaluated 53 RCTs but only 11.3% of them were conducted in Europe. Globally, 23 RCTs (43.4%) showed some evidence of effectiveness, and 30 RCTs (56.6%) did not find significant difference between the groups. According to the conclusions of the meta-analysis, the Unplugged program should be considered as a practice option in Europe. Among the other 12 RCTs, 42% were conducted in Europe. Globally, 7 studies (58.3%) achieved positive results, and 5 studies (41.7%) did not find significant differences or produced a mixed pattern of results. Three of the 5 European trials (60%) used the Unplugged program with positive results. Conclusion: Even if further studies should be conducted to confirm these results, Unplugged appears to be the prevention project with the best evidence of effectiveness in European studies.

To evaluate the efficacy and safety of disulfiram for treatment of binge eating disorder.Two hundred and fifty milligrams per day of disulfiram was administered to 12 patients affected by binge eating disorder for 16 weeks; the number of binge eating episodes per week and the number of participants who reported side effects were evaluated.Nine participants (75.0%) completed the trial, while the other 3 (25.0%) discontinued prematurely. Disulfiram significantly decreased the mean frequency of binge eating episodes per week from 7.9±1.2 to 0.9±0.6 (p.001). All patients (100.0%) reduced the frequency of binge eating episodes, and 7 participants (58.3%) achieved remission of binge eating. Eleven participants (91.7%) reported side effects [drowsiness (N=9), headache (N=7), dysgeusia (N=3), tachycardia (N=3), dizziness (N=2), and nausea (N=2)].While disulfiram reduced the frequency of binge eating episodes, side effects were observed in the majority of participants. Longer-term placebo-controlled studies are warranted to exclude the contribution of a placebo response from these results and to evaluate drugs with similar pharmacological activity but improved tolerability.

The present paper summarizes the preclinical and clinical studies conducted to define the “anti-alcohol” pharmacological profile of the prototypic GABAB receptor agonist, baclofen, and its therapeutic potential for treatment of alcohol use disorder (AUD). Numerous studies have reported baclofen-induced suppression of alcohol drinking (including relapse- and binge-like drinking) and alcohol reinforcing, motivational, stimulating, and rewarding properties in rodents and monkeys. The majority of clinical surveys conducted to date – including case reports, retrospective chart reviews, and randomized placebo-controlled studies – suggest the ability of baclofen to suppress alcohol consumption, craving for alcohol, and alcohol withdrawal symptomatology in alcohol-dependent patients. The recent identification of a positive allosteric modulatory binding site, together with the synthesis of in vivo effective ligands, represents a novel, and likely more favorable, option for pharmacological manipulations of the GABAB receptor. Accordingly, data collected to date suggest that positive allosteric modulators of the GABAB receptor reproduce several “anti-alcohol” effects of baclofen and display a higher therapeutic index (with larger separation – in terms of doses – between “anti-alcohol” effects and sedation).

Alcohol abuse and alcoholism are major medical and social problems worldwide. Unfortunately, pharmacotherapies currently available to physicians do not appear to possess relevant therapeutic efficacy. New medications are needed for the enhancing of abstinence and preventing relapse in alcoholics, as well as for reducing alcohol drinking. Relevant improvements in the pharmacotherapy of alcoholism are conceived to derive from elucidation of the elusive mechanisms of alcohol action in brain. Indeed, only a complete knowledge of how alcohol acts in brain and why drinking is so pleasurable and compelling in some individuals will allow the rational design and development of selective drugs capable of correcting the neurochemical alterations underlying alcohol dependence. The present paper reviews the research advances, at both preclinical and clinical levels, published in the scientific literature as well as the most recent (1998-2001) patent literature.

Background and Objectives Clinical research has proposed that initial sensitivity to ethanol may be negatively correlated with levels of subsequent ethanol intake; consistently, alcohol-preferring P rats were found to be less sensitive to the ataxic and sedative/hypnotic effects of ethanol than -nonpreferring NP rats. The present study investigated the initial sensitivity to the ataxic and sedative/hypnotic effects of ethanol and to the sedative/hypnotic effects of pentobarbital and diazepam in selectively bred Sardinian alcohol-preferring sP and -nonpreferring sNP rats. Methods: In experiment 1, time to lose (onset) and regain (sleep time) the righting reflex after the acute intraperitoneal (ip) administration of 3.0 and 3.5 g/kg ethanol were measured in sP and sNP rats. In experiment 2, sP and sNP rats were required to perform a motor coordination task on a Rota-Rod after the acute intragastric administration of 2.0, 2.5, and 3.0 g/kg ethanol. Experiment 3 assessed onset and sleep time in sP and sNP rats after the acute injection of pentobarbital (40 mg/kg; ip) and diazepam (15 and 20 mg/kg; ip). Results: In experiment 1, sP rats took shorter times to lose the righting reflex and regained this reflex over longer periods of time and at lower blood ethanol levels than sNP rats. In experiment 2, ethanol affected motor coordination to a greater extent in sP than sNP rats. In contrast, results from experiment 3 showed that sP and sNP rats were not differentially sensitive to the sedative/hypnotic effects of pentobarbital and diazepam. Conclusions: The results of experiments 1 and 2 suggest that sP rats possess a genetically determined, greater sensitivity to the motor impairing and sedative/hypnotic effects of ethanol than sNP rats. Although caution should be adopted before hypothesizing any comparison to humans, these results may feature sP rats as an experimental model of those subsets of human alcoholics with initial high sensitivity to ethanol challenges. Finally, the results of experiment 3 suggest a minimal involvement of the benzodiazepine and barbiturate recognition sites in the differential sensitivity to ethanol of sP and sNP rats.

The present paper briefly reviews the most relevant experimental data on the reducing effect of some medicinal herbs on voluntary alcohol intake in animal models of alcoholism. Pueraria lobata, Tabernanthe iboga, Panax ginseng, Salvia miltiorrhiza and Hypericum perforatum proved to be effective in decreasing alcohol consumption. Reduction of alcohol absorption from the gastrointestinal system appears to be a common feature among most of the above plants. These data suggest that medicinal plants may constitute novel and effective pharmacotherapies for alcoholism.

The possible presence of a functional interaction in the constipating effect of opioids and cannabinoids has been assessed. We have measured the ability of the opioid receptor antagonist, naloxone, to antagonize the inhibitory effect of the cannabinoid receptor agonist, WIN 55,212-2, and also, the ability of the cannabinoid CB1-receptor antagonist, SR 141716A, to antagonize the inhibitory effect of morphine, on transit of an orally administered, non-absorbable marker (carmine) in the mouse small intestine. Naloxone failed to alter the reducing effect of WIN 55,212-2 on the propulsive activity; conversely, pretreatment with SR 141716A did not prevent morphine-induced inhibition of marker transit. These results suggest that the constipating effect of opioids and cannabinoids occur through independent and unrelated mechanisms. We assessed also the possible existence of an interaction between CB1 and dopamine D2 receptor systems. The effect of the D2-receptor antagonist, S(-)-sulpiride, on the inhibiting effect of WIN 55,212-2 and of SR 141716A on the inhibiting effect of the D2 agonist, bromocriptine, on intestinal propulsion were assessed. Combination of 50 mg kg−1S(-)-sulpiride and 0.5 mg kg−1 WIN 55,212-2, but not higher doses, resulted in the blockade of WIN 55,212-2 effect; similarly, combination of 0.1 mg kg−1 SR 141716A abolished bromocriptine-induced decrease in intestinal motility. These results suggest the existence of a functional interaction between the CB1 and D2 receptors in mouse intestinal motility.

The present paper reviews the drug discrimination studies, both from the literature and from this laboratory, conducted to investigate the pharmacological profile of the discriminative stimulus effects of gamma-hydroxybutyric acid. Collectively, the results of these studies suggest that: (1) the discriminative stimulus effects of gamma-hydroxybutyric acid are composed of different cues, each one being the effect of gamma-hydroxybutyric acid on a specific receptor system; (2) the proportion of each component cue varies as the training dose of gamma-hydroxybutyric acid is increased; (3) the gamma-aminobutyric acid B-mediated cue is a major ingredient of the mixed stimulus of gamma-hydroxybutyric acid, but it is more prominent at high training doses than at low training doses of gamma-hydroxybutyric acid; and (4) positive modulation of the gamma-aminobutyric acid A receptor is a relevant part of the discriminative stimulus effects of low gamma-hydroxybutyric acid doses. Finally, data indicating symmetrical generalization between the discriminative stimulus effects of a specific range of doses of gamma-hydroxybutyric acid and those of ethanol are discussed in regard to their further support of the hypothesis that gamma-hydroxybutyric acid may exert its antialcohol effects through a substitution mechanism.

Background: The similarities between the pharmacological effects of the γ-aminobutyric acid receptor agonist, baclofen, and the alcohol-substituting agent, γ-hydroxybutyric acid, led us to investigate whether baclofen was capable of reducing (a) ethanol withdrawal syndrome in ethanol-dependent rats and (b) voluntary ethanol intake in ethanol-preferring rats. Methods: In experiment 1, Wistar rats were rendered physically dependent on ethanol by the repeated administration of intoxicating doses of ethanol for 6 consecutive days. Baclofen was acutely administered intraperitoneally at doses of 10, 20, and 40 mg/kg. In experiment 2, baclofen (0, 2.5, 5, and 10 mg/kg, intraperitoneally) was administered once a day for 14 consecutive days to ethanol-preferring sP rats that had continuous access to ethanol (10%, v/v) and water under the two-bottle free choice regimen. Results: In experiment 1, baclofen dose-dependently decreased the intensity of ethanol withdrawal signs; furthermore, 20 mg/kg of baclofen protected from audiogenic seizures in ethanol-withdrawn rats. In experiment 2, baclofen selectively and dose-dependently reduced voluntary ethanol intake; a compensatory increase in water intake left total fluid intake virtually unchanged. Conclusions: These results are in close agreement with those of a preliminary clinical study and suggest that baclofen may constitute a novel therapeutic agent for alcoholism.

studies [8–10]. The first study found that 32 IU of oxytocin nasal spray induced better results in patients with chronic migraine if they had not taken NSAIDs [8]. However, this study failed to report the number of patients and statistical evaluation. The second study found that 40 IU of oxytocin (twice a day, for 13 weeks) reduced abdominal discomfort but not constipation in 59 women with refractory constipation [9]. However, this study did not report whether NSAIDs were used or not [1, 9]. The third study found that oxytocin dose dependently reduced the severity of headache in 112 patients not taking analgesic medications [10]. However, the doses of oxytocin were not specified. It is reported that patients received six puffs of a solution containing different concentrations of oxytocin (100, 200 or 400 ng) without specifying whether these concentrations were referred to 1 ml, to 1 puff, or to 6 puffs. Considering that usually 1 puff consists of 0.1 ml of solution, and 1 IU corresponds to 2 μg of oxytocin [11], we calculated the maximum dose of oxytocin expressed in IU. If the highest dose (400 ng) was referred to 1 ml, each patient received 0.12 IU (400 ng/ml; each patient received 0.6 ml; 0.6 ml contains 240 ng, corresponding to 0.12 IU); if the dose was referred to 1 puff, each patient received 1.2 IU (400 ng/ puff; 400 ng × 6 = 2,400 ng corresponding to 1.2 IU); if it referred to the total of 6 puffs, each patient received 0.2 IU (400 ng/6 puffs corresponding to 0.2 IU). Accordingly, the maximum dose administered (1.2 IU) would be much lower than those usually administered. For instance, 27 and 33 times lower than that used in the first (32 IU) and in the second study (40 IU), respectively [8, 9]. The limits of these studies did not allow any conclusions to be drawn on the possible influence of NSAIDs on the effects induced by oxytocin. It has been observed that NSAID administration reduces the secretion of endogenous oxytocin [12], although this effect should not influence response We read with interest the Commentary of Drs. Kwong and Chan on the lack of analgesic effects induced by the administration of oxytocin nasal spray to fibromyalgic patients [1–3]. We agree with them that these negative results are very disappointing, particularly as the inverse relationship between plasma oxytocin levels and the severity of pain found by other studies persuaded us to conduct our study [4]. We also agree with them on the possibility that the severity of pain may change throughout the menstrual cycle of fertile women. Indeed, in fibromyalgic patients, the severity of pain is higher in the luteal than in the follicular phase [5], and, in healthy fertile women, plasma oxytocin levels are lower during the luteal than the follicular phase [6]. The expression of brain oxytocin receptors is modulated by estrogen and progesterone [7]. However, in our study, patients included seven postmenopausal and seven premenopausal women, most of the latter with irregular cycles (n = 5). This sample was not adequate to investigate possible swing of fibromyalgic symptoms throughout the menstrual cycle. Finally, we read with great interest the hypothesis that the lack of efficacy of oxytocin may be due to the use of nonsteroidal anti-inflammatory drugs (NSAIDs) [1]. This hypothesis was based on the results of three clinical

Experiment 1 in the present study investigated the time course and dose range of gamma-hydroxybutyric acid (GHB) to reduce voluntary ethanol intake in selectively bred Sardinian ethanol-preferring (sP) rats. Ethanol (10%, v/v) and tap water were offered under the two-bottle free choice regimen with unlimited access. GHB (200, 300, and 400 mg/kg, i.p.) was administered 15 20 min prior to the start of the dark phase of the light-dark cycle. Ethanol and water intakes were recorded at different time intervals during the dark phase. GHB significantly reduced ethanol intake at doses of 300 and 400 mg/kg; statistical significance occurred only at the 15-min and 30-min observation times. The GHB dose of 300 mg/kg was devoid of any sedative effect, as demonstrated in Experiment 2 by the lack of any impairment of spontaneous locomotor activity. Finally, this dose of GHB was also found to exert a robust anxiolytic effect in sP rats tested on the elevated plus maze (Experiment 3). Collectively, the results of the present study demonstrate that a non-sedative and anxiolytic dose of GHB effectively reduced voluntary ethanol intake in sP rats. The rapid onset of the reducing effect of GHB on ethanol intake, as well as its anxiolytic effect, are discussed in terms of adding further support to the hypothesis that GHB may control alcohol craving and consumption in humans by substituting for ethanol's reinforcing effects.

The effect of the cannabinoid CB1 receptor antagonist, SR 141716, on food intake and body weight was assessed in adult, non-obese Wistar rats. The daily administration of SR 141716 (2.5 and 10 mg/kg; i.p.) reduced dose-dependently both food intake and body weight. Tolerance to the anorectic effect developed within 5 days; in contrast, body weight in SR 141716-treated rats remained markedly below that of vehicle-treated rats throughout the entire treatment period (14 days). The results suggest that brain cannabinoid receptors are involved in the regulation of appetite and body weight.