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Background Alcohol dependence is a devastating illness affecting a large population, and new pharmacological treatments with good efficacy are greatly needed. One potential candidate is varenicline, a smoking cessation agent with partial agonist action at α4β2 nicotinic acetylcholine receptors. Methods A total of 160 subjects, 30 to 70 years of age, fulfilling DSM- IV criteria for alcohol dependence without any serious physical or mental disorders, were recruited through advertisement at 3 university clinics in Sweden during March 2009 to January 2011. After a 2-week placebo run-in period, subjects received 2 mg varenicline daily (titrated from 0.5 mg during first week) or placebo for 12 weeks in a double-blind manner. Results The primary outcome was the proportion of heavy drinking days, measured by self-reported alcohol consumption. Primary and secondary outcomes were calculated as a mean over the 10-week steady-state active treatment period. In the primary outcome analysis, no effect of varenicline over placebo was found ( p = 0.73 for the intention to treat [ ITT] and 0.92 for per protocol [ PP]). Secondary outcome analysis found a significant reduction of specific alcohol marker phosphatidylethanol ( PEth) in the blood in the varenicline group compared to placebo ( p = 0.02 ITT). Craving ( p = 0.048 PP) and Alcohol Use Disorders Identification Test ( AUDIT) scores ( p = 0.015 ITT) were also reduced in the active treatment group. PEth more strongly correlated with self-reported alcohol consumption than carbohydrate-deficient ttransferrin and γ-glutamyl transferase, and correlation coefficients were higher in the varenicline group than in the placebo group for all markers. Conclusions Although the results of the main outcome of this study did not support an effect of varenicline in alcohol-dependent individuals, the secondary analyses of PEth, craving and AUDIT score support an effect of varenicline on alcohol consumption. The disclosure of a treatment effect and the lack of a clear placebo effect when using PEth as outcome variable, together with a nonsymmetric bias associated with self-reported data, strongly argue for using the specific biomarker PEth in studies of treatments of alcohol dependence. [ABSTRACT FROM AUTHOR]

Background: Extracellular dopamine (DA) levels in the nucleus accumbens (nAc) increase after ethanol (EtOH) administration in the rat, a response that may be involved in the positive reinforcing effects of EtOH. The mechanisms underlying this DA activation and how they relate to EtOH reinforcement remain to be elucidated, but recent data indicate that glycine receptors (GlyRs) in the nAc may be involved. Here this hypothesis was further challenged by examining the influence of bilateral accumbal application of glycine (a GlyR agonist), strychnine (a GlyR competitive antagonist), or Ringer on EtOH intake and preference, as well as on the concomitant DA output in the nAc, in EtOH high-preferring male Wistar rats. Methods: EtOH high-preferring male Wistar rats [EtOH preference >60% during continuous access to a bottle of EtOH (6% v/v) and a bottle of water] were limited to drink 1 hr/day (limited access drinking). Thereafter, the animals were equipped bilaterally with microdialysis probes aimed at the mAc, and were subjected to in vivo microdialysis (coupled to high-pressure liquid chromatography with electrochemical detection) and reversed microdialysis (for drug application) during two experimental days (balanced study), during which the animals were allowed a choice between EtOH and water. Results: The EtOH consumption in rats that were perfused with Ringer in the nAc was ∼0.9 g/kg/hr and associated with a significant increase in extracellular accumbal DA levels. In a subpopulation of rats, bilateral accumbal glycine (100 μM)perfusion produced a significant increase in accumbal DA output and a decrease in EtOH preference and intake. In these glycine responders, the EtOH consumed (∼0.7 g/kg/hr) did not produce a further increase of DA levels. In other rats, bilateral glycine perfusion did not change the accumbal DA output, and voluntary EtOH intake was not altered. In these glycine nonresponders, EtOH tended to increase accumbal DA levels. Bilateral accumbal strychnine (20 M) perfusion significantly decreased DA output in the nAc, and the DA levels remained decreased despite a statistically significant increase of EtOH intake. Finally, the increase in accumbal DA levels observed after EtOH consumption in Ringer-treated rats was significantly larger in glycine responders than in glycine nonresponders. Conclusions: The present findings suggest that glycine and strychnine alter extracellular DA levels in the nAc, probably via GlyR stimulation and blockade, respectively, and concomitantly glycine and strychnine reciprocally alter also EtOH consumption in EtOH high-preferring male Wistar rats. The possibility of developing selective GlyR agonists and/or antagonists should be explored. Such agents could prove of value in the treatment of alcoholism. [ABSTRACT FROM AUTHOR]

BACKGROUND: Targeting pituitary adenylate cyclase-activating polypeptide (PACAP) is a new avenue for treating migraine. The efficacy and safety of intravenous Lu AG09222, a humanized monoclonal antibody directed against the PACAP ligand, for migraine prevention are unclear. METHODS: In a phase 2, double-blind, randomized, placebo-controlled trial, we enrolled adult participants (18 to 65 years of age) with migraine for whom two to four previous preventive treatments had failed to provide a benefit. The trial included a 4-week treatment period and an 8-week follow-up period. Participants were randomly assigned in a 2:1:2 ratio to receive a single-dose baseline infusion of 750 mg of Lu AG09222, 100 mg of Lu AG09222, or placebo. The primary end point was the mean change from baseline in the number of migraine days per month, during weeks 1 through 4, in the Lu AG09222 750-mg group as compared with the placebo group. RESULTS: Of 237 participants enrolled, 97 received 750 mg of Lu AG09222, 46 received 100 mg of Lu AG09222, and 94 received placebo. The mean number of baseline migraine days per month was 16.7 in the overall population, and the mean change from baseline over weeks 1 through 4 was -6.2 days in the Lu AG09222 7 50-mg group, as compared with -4.2 days in the placebo group (difference, -2.0 days; 95% confidence interval, -3.8 to -0.3; P=0.02). Adverse events with a higher incidence in the Lu AG09222 750-mg group than in the placebo group during the 12-week observation period included coronavirus disease 2019 (7% vs. 3°/o), nasopharyngitis (7% vs. 4%), and fatigue (5% vs. 1%). CONCLUSIONS: In a phase 2 trial, a single intravenous infusion of 750 mg of Lu AG09222 showed superiority over placebo in reducing migraine frequency over the subsequent 4 weeks. [ABSTRACT FROM AUTHOR]