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RATIONALE: Alcohol administration and cue-reactivity paradigms are frequently used to screen for the initial efficacy of medications for alcohol use disorder (AUD). While medication effects on the primary outcomes for these paradigms are assumed to be qualitatively related, there is a critical lack of quantitative evidence to support this hypothesis. OBJECTIVES: The study aims to test the relationship between medication effect sizes on subjective response to alcohol administration and medication effect sizes for cue-induced craving to cue exposure, using meta-analysis. METHODS: Systematic literature searches were conducted to identify randomized trials, wherein AUD medications were tested using the alcohol administration and/or cue-reactivity paradigms. From these studies, descriptive statistics were collected to compute medication effect sizes on the primary outcomes for each respective paradigm. With medication as the unit of analysis, medication effect sizes in alcohol administration studies were compared with medication effect sizes in cue-reactivity studies using the Williamson-York regression which allows for meta-regression across independent samples. RESULTS: Medication effect sizes on alcohol-induced stimulation and alcohol-induced craving were not significantly associated with medication effect sizes on cue-induced alcohol craving (k stimulation = 10 medications, [Formula: see text] and k craving = 11 medications, [Formula: see text] (SE = 0.237), [Formula: see text]), respectively. Medication effect sizes on alcohol-induced sedation were significantly associated with medication effects on cue-induced craving (k = 10 medications, [Formula: see text] (SE = 0.258), [Formula: see text]), such that medications that increased alcohol-induced sedation were more likely to reduce cue-induced alcohol craving. CONCLUSIONS: With the exception of alcohol-induced sedation, there is little quantitative evidence of medication effects on subjective response domains measured during alcohol administration parallel medication effects on cue-induced alcohol craving. To provide additional context to the current study, future work should examine whether cue-reactivity findings predict clinical trial outcomes.

Rationale: Alcohol administration and cue-reactivity paradigms are frequently used to screen for the initial efficacy of medications for alcohol use disorder (AUD). While medication effects on the primary outcomes for these paradigms are assumed to be qualitatively related, there is a critical lack of quantitative evidence to support this hypothesis. Objectives: The study aims to test the relationship between medication effect sizes on subjective response to alcohol administration and medication effect sizes for cue-induced craving to cue exposure, using meta-analysis. Methods: Systematic literature searches were conducted to identify randomized trials, wherein AUD medications were tested using the alcohol administration and/or cue-reactivity paradigms. From these studies, descriptive statistics were collected to compute medication effect sizes on the primary outcomes for each respective paradigm. With medication as the unit of analysis, medication effect sizes in alcohol administration studies were compared with medication effect sizes in cue-reactivity studies using the Williamson-York regression which allows for meta-regression across independent samples. Results: Medication effect sizes on alcohol-induced stimulation and alcohol-induced craving were not significantly associated with medication effect sizes on cue-induced alcohol craving (k stimulation = 10 medications, β ^ = 0.272 SE = 0.263 , p = 0.150 and k craving = 11 medications, β ^ = 0.217 (SE = 0.237), p = 0.181 ), respectively. Medication effect sizes on alcohol-induced sedation were significantly associated with medication effects on cue-induced craving (k = 10 medications, β ^ = - 0.600 (SE = 0.258), p = 0.010 ), such that medications that increased alcohol-induced sedation were more likely to reduce cue-induced alcohol craving. Conclusions: With the exception of alcohol-induced sedation, there is little quantitative evidence of medication effects on subjective response domains measured during alcohol administration parallel medication effects on cue-induced alcohol craving. To provide additional context to the current study, future work should examine whether cue-reactivity findings predict clinical trial outcomes. [ABSTRACT FROM AUTHOR]

Objective: Alcohol craving is a predictor of continued drinking and a diagnostic criterion for alcohol use disorder. Rewarding subjective effects potentiate craving, but it remains unclear if relations are expectancy-driven vs. alcohol-induced. In addition, it remains unclear if relations operate solely at the person level, or if there is also within-person dynamic change. Methods: Participants (N = 448) come from a placebo-controlled alcohol administration study. Participants in the alcohol condition reported subjective effects and alcohol craving on ascending (BAC =.068), peak (BAC =.079), and descending (BAC =.066) BAC limbs. Participants in the placebo condition were yoked to alcohol condition participants. Multilevel models tested whether (1) within-person deviations in subjective effects predicted within-person deviations in craving, (2) between-person levels of subjective effects predicted between-person levels of craving, and (3) effects were dependent upon experimental condition. Results: At the within-person level, increases in high arousal positive/stimulant effects were associated with within-person increases in alcohol craving, regardless of experimental condition. At the between-person level, interactions were observed between high arousal positive/stimulant (and low arousal positive/relaxing) effects and condition. Probing suggested that the association between person-level high arousal positive/stimulant effects and craving was statistically significant in the alcohol but not the placebo condition. Conversely, the association between person-level low arousal positive/relaxing effects and craving was positive and statistically significant in the placebo but negative in the alcohol condition. Conclusions: Findings suggest expectancy-like relations among high arousal positive/stimulant effects and craving within-person. However, alcohol-induced positive reinforcement (i.e., stimulation) facilitated heightened person-level craving, whereas expectancy-like negative reinforcement (i.e., relaxation) attenuated person-level craving. [ABSTRACT FROM AUTHOR]

Rationale: Proinflammatory processes have been implicated in alcohol addiction, craving, and relapse, while studies in experimental animals have suggested that activation of peroxisome proliferator-activated receptor gamma (PPARγ) inhibits proinflammatory signaling. Accordingly, it is hypothesized that medications with PPARγ activity may have therapeutic potential in alcohol dependence. Objectives: We conducted a double-blind, placebo-controlled mechanistic proof of principle study in alcohol-dependent inpatients to investigate the effect of pioglitazone on alcohol craving. Methods: Participants were treated for withdrawal, if needed, and then randomized to pioglitazone (target dose 45 mg/day) or placebo. Once at target dose, they completed two experimental manipulations: guided imagery, which used personalized auditory scripts to induce alcohol cravings, and a low-dose challenge with i.v. lipopolysaccharide (LPS; 0.8 ng/kg) or placebo, on two separate sessions, in counterbalanced order. Behavioral and endocrine responses as well as CSF levels of proinflammatory cytokines were evaluated. Results: The study was prematurely terminated after randomization of 16 subjects, following an independent review that established a high risk of myopathy in the active treatment group. Analysis of those who completed the study indicated that pioglitazone was associated with elevated, rather than suppressed alcohol cravings in response to alcohol-associated stimuli. LPS did not induce cravings for alcohol and thus did not lend itself to evaluating pioglitazone effects; however, pioglitazone increased the neuroendocrine stress response to LPS. CSF levels of IL-6, TNF-α, or MCP-1 were unaffected by pioglitazone treatment. Conclusions: Both safety and efficacy biomarker data suggest that pioglitazone lacks potential as a medication for the treatment of alcohol dependence. Clinical trial registration: NCT01631630 [ABSTRACT FROM AUTHOR]

BackgroundAlcoholics report persistent alcohol craving that is heightened by cognitive cues, stressful situations, and abstinence. The role of endogenous cannabinoids in human alcohol craving--though long suspected--remains elusive.Materials and methodsWe employed laboratory exposure to stress, alcohol cue, and neutral relaxed situations through guided imagery procedures to evoke alcohol desire and craving in healthy social drinkers (n = 11) and in treatment-engaged, recently abstinent alcoholic subjects (n = 12) and assessed alcohol craving, heart rate, and changes in circulating endocannabinoid levels. Subjective anxiety was also measured as a manipulation check for the procedures.ResultsIn healthy social drinkers, alcohol cue imagery increased circulating levels of the endocannabinoid anandamide, whereas neutral and stress-related imagery had no such effect. Notably, baseline and response anandamide levels in these subjects were negatively and positively correlated with self-reported alcohol craving scores, respectively. Cue-induced increases in heart rate were also correlated with anandamide responses. By contrast, no imagery-induced anandamide mobilization was observed in alcoholics, whose baseline anandamide levels were markedly reduced compared to healthy drinkers and were uncorrelated to either alcohol craving or heart rate.ConclusionsThe results suggest that plasma anandamide levels provide a marker of the desire for alcohol in social drinkers, which is suppressed in recently abstinent alcoholics.

Rationale: Clinical trials and human laboratory studies have established that varenicline can reduce rates of alcohol use among heavy drinkers. Less is known about the mechanisms by which varenicline has this effect on drinking behavior. Reactivity to alcohol cues is often cited as the primary cause of relapse among those being treated for alcohol use disorder, and several front-line treatments for alcohol use disorder work, at least in part, by minimizing cue-induced alcohol craving. Objective: The current double-blind, placebo-controlled human laboratory study tested the effects of varenicline on alcohol cue reactivity in a group of heavy-drinking adult smokers and nonsmokers. Methods: As part of a larger series of sequential human laboratory experiments testing the effects of varenicline on drinking outcomes, participants were assigned (between-participant) to receive either active varenicline (2 mg/day) or placebo. Following a titration period, participants ( n = 77) attended a laboratory session during which they were exposed to alcohol and neutral cues using a standard cue reactivity paradigm. Results: Alcohol cue exposure increased craving for alcohol in both medication groups. However, participants receiving varenicline showed a smaller increase in alcohol craving compared to participants receiving placebo. The medication effect did not differ between smokers and nonsmokers. Among smokers, alcohol cue exposure also increased tobacco craving. Varenicline did not attenuate this effect. Conclusions: Results support the use of varenicline for reducing alcohol use in heavy drinkers and identify a potential mechanism by which varenicline reduces drinking. Varenicline continues to show promise as a pharmacological treatment for alcohol use disorder. [ABSTRACT FROM AUTHOR]

Rationale: The available treatments for alcoholism are only modestly effective, and patients vary widely in their treatment response. Quetiapine, an atypical antipsychotic medication with antagonist activity at D1 and D2, 5-HT and 5-HT, H, and α1 and α2 receptors was shown to promote abstinence, reduce drinking days, and reduce heavy drinking days in a 12-week double-blind placebo-controlled trial. Objective: Although quetiapine represents one of the promising pharmacotherapies for the treatment of alcoholism, its mechanisms of action are poorly understood. The objective of this study is to elucidate the biobehavioral mechanisms of action of quetiapine for alcoholism, by examining its effects on subjective intoxication and craving. Method: A total of 20 non-treatment-seeking alcohol-dependent individuals were randomized to one of the following conditions in a double-blind, placebo-controlled design: (1) quetiapine (400 mg/day); or (2) matched placebo. Participants were on the target medication dose (or matched placebo) for 4 weeks during which they completed weekly assessments of drinking, sleep, mood, and anxiety. Participants completed two counterbalanced intravenous placebo-alcohol administration sessions as well as cue-reactivity assessments. Results: Analyses revealed a significant effect of quetiapine in reducing craving during the alcohol administration, the alcohol cue-exposure, and the weekly reports of alcohol craving. Quetiapine was also found to reduce subjective intoxication and alcohol-induced sedation during the alcohol administration paradigm. Conclusions: This study contributes critical new information about mechanisms of response to quetiapine for alcoholism, which, in turn, can inform larger-scale studies and ultimately, clinical practice. [ABSTRACT FROM AUTHOR]

Rationale: Varenicline, an approved smoking cessation pharmacotherapy, also shows promise as a potential treatment for alcohol dependence. However, varenicline has not been tested in heavy drinkers, and it remains to be determined whether varenicline could reduce alcohol craving and consumption in smokers who are trying to quit smoking. Objectives: We conducted a preliminary study to examine the effect of varenicline on drinking behavior and the effects of extended varenicline pretreatment on smoking. Methods: Thirty heavy drinking smokers received smoking cessation counseling and were randomly assigned to receive either an extended 4-week pretreatment with varenicline 2 mg daily or the usual 1-week pretreatment. Those in the extended pretreatment group received active medication for 8 weeks (i.e., 4 weeks of active pre-treatment followed by 4 weeks of active treatment), and participants in the usual pretreatment group received active medication after a placebo lead in (i.e., 3 weeks of placebo followed by active medication for 5 weeks). Results: Participants who received varenicline during the first 3 weeks reported significantly greater reductions in alcohol craving and numerically fewer heavy drinking days compared to those who received placebo, and these differences persisted during the open-label phase. Extended pretreatment was associated with numerically greater reductions in cigarette smoking over the entire study period. There were no differences, however, in smoking abstinence rates following the smoking quit date between the two groups. Conclusions: Findings from this preliminary study suggest that varenicline may be a promising strategy for concurrently reducing heavy drinking and promoting smoking changes in heavy drinkers. [ABSTRACT FROM AUTHOR]

Rationale. Alcohol effects in humans involve N-methyl-d-aspartate (NMDA) receptor-mediated glutamatergic neurotransmission. It has been proposed that NMDA receptor antagonists may be effective in the treatment of alcohol dependence. Objective. This study evaluated the acute effects of memantine, an NMDA receptor antagonist, on the subjective, physiological, and performance effects of alcohol in moderate (10–30 drinks per week) alcohol drinkers. Methods. Eighteen volunteers without alcohol dependence were tested using a double-blind design with three 3-day long inpatient phases separated by at least a 2-week wash-out period. Memantine (0, 15, and 30 mg) was administered 4 h before alcohol (1.5 g/l body water), which was given in four divided doses every 20 min. Results. Pretreatment with memantine attenuated the craving for alcohol before alcohol administration, but not after alcohol was given. Memantine increased the dissociative effects of alcohol, without altering its sedative, stimulant, and overall intoxicating effects. Memantine also did not affect alcohol-induced impairment in performance, physiological changes, or pharmacokinetics. Memantine increased subjective reports of dissociation, confusion, and stimulation, and impaired motor coordination on the balance task. Conclusions. Memantine was well tolerated in combination with alcohol. The findings suggest that NMDA receptor neurotransmission may be involved in alcohol craving and alcohol-induced subjective dissociative effects. [ABSTRACT FROM AUTHOR]