Response to Letter to the Editors regarding 'A Meta-Regression of Trial Features Predicting the Effects of Alcohol Use Disorder Pharmacotherapies on Drinking Outcomes in Randomized Clinical Trials: A Secondary Data Analysis'.

The Letter to the Editors regarding our article was reviewed. The take-home message is that substantively, the authors of the letter are referencing a paper that asks a different research question in a different set of studies. When we ask different questions, we are not surprised when we reach different answers.

A Meta-Regression of Trial Features Predicting the Effects of Alcohol Use Disorder Pharmacotherapies on Drinking Outcomes in Randomized Clinical Trials: A Secondary Data Analysis.

Aims: To test whether two critical design features, inclusion criteria of required pre-trial abstinence and pre-trial alcohol use disorder (AUD) diagnosis, predict the likelihood of detecting treatment effects in AUD pharmacotherapy trials.

Methods: This secondary data analysis used data collected from a literature review to identify randomized controlled pharmacotherapy trials for AUD. Treatment outcomes were selected into abstinence and no heavy drinking.

Lifetime heavy drinking years predict alcohol use disorder severity over and above current alcohol use.

: Preclinical studies demonstrate that chronic and heavy alcohol use facilitates neuroadaptations that perpetuate addiction-like behaviors. In clinical studies, it is unclear whether the extent of heavy alcohol use over the lifetime contributes to alcohol use disorder (AUD) severity over and above current alcohol use patterns (i.e.

A meta-regression of methodological features that predict the effects of medications on the subjective response to alcohol.

Background: Alcohol administration paradigms have been used for early efficacy testing of novel compounds for alcohol use disorder (AUD). There has been an ongoing debate about sample characteristics and methodological features that affect the likelihood of detecting an early efficacy signal for AUD medications. We conducted a meta-regression to test whether the drinking level of the study sample and the peak breath alcohol concentration (BrAC) in the alcohol administration study predict the efficacy of AUD pharmacotherapies on the subjective responses to alcohol.

Ibudilast, a neuroimmune modulator, reduces heavy drinking and alcohol cue-elicited neural activation: a randomized trial.

Ibudilast, a neuroimmune modulator which selectively inhibits phosphodiesterases (PDE)-3, -4, -10, and -11, and macrophage migration inhibitory factor (MIF), shows promise as a novel pharmacotherapy for alcohol use disorder (AUD). However, the mechanisms of action underlying ibudilast's effects on the human brain remain largely unknown. Thus, the current study examined the efficacy of ibudilast to improve negative mood, reduce heavy drinking, and attenuate neural reward signals in individuals with AUD.

Do behavioral pharmacology findings predict clinical trial outcomes? A proof-of-concept in medication development for alcohol use disorder.

Behavioral pharmacology paradigms have been used for early efficacy testing of novel compounds for alcohol use disorder (AUD). However, the degree to which early efficacy in the human laboratory predicts clinical efficacy remains unclear. To address this gap in the literature we employed a novel meta-analytic approach.

Modeling motivation for alcohol in humans using traditional and machine learning approaches.

Given the significant cost of alcohol use disorder (AUD), identifying risk factors for alcohol seeking represents a research priority. Prominent addiction theories emphasize the role of motivation in the alcohol seeking process, which has largely been studied using preclinical models. In order to bridge the gap between preclinical and clinical studies, this study examined predictors of motivation for alcohol self-administration using a novel paradigm.

Sensitivity and specificity of a commercial urinary ethyl glucuronide (ETG) test in heavy drinkers.

Introduction: To advance the use of alcohol metabolites as biomarkers in the context of alcohol research, the present study tested the sensitivity and specificity of a commercially available urinary ethyl glucuronide (uEtG) test (DrugConfirm Advanced 80hr EtG) in a clinical research context.

Methods: A community sample of heavy drinkers (N = 68) completed the 30-day Timeline Follow-Back (TLFB) interview and provided a urine sample for uEtG analysis. Analyses of sensitivity and specificity of the uEtG assay were conducted using the following outcomes: (a) past day drinking, (b) past day binge drinking (defined as ≥4 drinks for women and ≥5 drinks for men), (c) past 3-day drinking, and (d) past 3-day binge drinking.

Capturing habitualness of drinking and smoking behavior in humans.

Background: Recent findings suggest that overreliance on habit may be common in individuals diagnosed with addiction. To advance our understanding of habit in clinical samples and from behavioral measures, this study examines the interrelations between self-reported habit index for smoking and drinking as well as behavioral measures of intraindividual variability in smoking and drinking.

Methods: Treatment-seeking heavy drinking smokers (N = 416) completed the Self-Report Habit Index (SRHI) adapted for both smoking and drinking.

Reward, Relief and Habit Drinking: Initial Validation of a Brief Assessment Tool.

Aims: Alcohol use disorder is highly heterogeneous. One approach to understanding this heterogeneity is the identification of drinker subtypes. A candidate classification consists of reward and relief subtypes.

Convergence between the Penn Alcohol Craving Scale and diagnostic interview for the assessment of alcohol craving.

Introduction: The Penn Alcohol Craving Scale (PACS) is one of the most widely used instruments to measure craving for alcohol. Recent research has suggested that scores on the PACS can be used as a "stand in" for the diagnostic criterion of alcohol craving with a proposed cutoff of >20 on the PACS indicating a "positive" alcohol craving symptom. The present study examined the convergence between the PACS and face-to-face diagnostic interview for the assessment of alcohol craving.

Neuroimaging findings from an experimental pharmacology trial of naltrexone in heavy drinkers of East Asian descent.

Background: Despite known genetic variation across races, studies examining pharmacogenetics of a single nucleotide polymorphism (SNP) of the mu-opioid receptor gene (OPRM1) on clinical response to naltrexone have been conducted in predominantly Caucasian samples. Evidence is mixed for pharmacogenetic OPRM1 and naltrexone effects on neural responses to alcohol cues. The current study tests the pharmacogenetic effects of naltrexone and OPRM1 on neural responses to alcohol taste cues in heavy drinkers of East Asian descent.

Naltrexone effects on subjective responses to alcohol in the human laboratory: A systematic review and meta-analysis.

Naltrexone (NTX) has been widely studied for the treatment of alcohol use disorder with overall support for its efficacy. The mechanisms of action of naltrexone are thought to involve attenuation of the hedonic effects of alcohol and potentiation of its aversive effects. In order to provide a quantitative estimate of the effects of naltrexone on subjective response to alcohol, the aims of this meta-analytic review are to examine the effects of naltrexone across four domains of subjective response.

The Interplay Between Subjective Response to Alcohol, Craving, and Alcohol Self-Administration in the Human Laboratory.

Background: Despite a rich literature on human laboratory paradigms of subjective response (SR) to alcohol, craving for alcohol, and alcohol self-administration, few studies have examined the interplay across these 3 constructs. The present study addresses this gap in the literature by examining the interplay between SR, craving, and self-administration in the human laboratory.

Methods: Data were culled from a medication study (NCT02026011) in which heavy drinking participants of East Asian ancestry completed 2 double-blinded and counterbalanced experimental sessions.

Naltrexone and alcohol effects on craving for cigarettes in heavy drinking smokers.

Naltrexone has been extensively studied for the treatment of alcohol use disorder. However, less is known about the effects of naltrexone on smoking outcomes in the context of alcohol use among East Asian individuals who have been suggested to differ in response to alcohol and to naltrexone. The present study is a secondary analysis that used a double-blind placebo-controlled design (n = 31) to examine the (a) effects of alcohol on basal craving for cigarettes, (b) effects of naltrexone on cigarette craving and alcohol craving during alcohol administration, and (c) relationship between craving for alcohol and cigarettes.

State-of-the-art behavioral and pharmacological treatments for alcohol use disorder.

Background: Alcohol use disorder (AUD) and its associated consequences remain significant public health concerns. Given that AUD represents a spectrum of severity, treatment options represent a continuum of care, ranging from single-session brief interventions to more intensive, prolonged, and specialized treatment modalities.

Objective: This qualitative literature review seeks to describe the best practices for AUD by placing a particular emphasis on identifying those practices which have received the most empirical support.

Overcoming the "Valley of Death" in Medications Development for Alcohol Use Disorder.

As the development of novel pharmacotherapies for alcohol use disorder (AUD) has been slow, the discovery and testing of more efficacious pharmacotherapies for AUD represent a high priority research area. In fact, the transition from preclinical to clinical testing of novel compounds has been termed the "valley of death" in medications development. One key obstacle consists of the lack of an articulated set of goals for each stage of medications development.

Differences in the subjective and motivational properties of alcohol across alcohol use severity: application of a novel translational human laboratory paradigm.

The Allostatic Model proposes that Alcohol Use Disorder (AUD) is associated with a transition in the motivational structure of alcohol drinking: from positive reinforcement in early-stage drinking to negative reinforcement in late-stage dependence. However, direct empirical support for this preclinical model from human experiments is limited. This study tests predictions derived from the Allostatic Model in humans.

Pharmacogenetic Effects of Naltrexone in Individuals of East Asian Descent: Human Laboratory Findings from a Randomized Trial.

Background: Genetic variation in the endogenous opioid system has been identified as 1 potential source of individual variability in naltrexone treatment outcomes. The majority of naltrexone pharmacogenetic studies have focused on a particular single nucleotide polymorphism (SNP) of the mu-opioid receptor gene (OPRM1; rs1799971; commonly known as the Asn40Asp SNP) in Caucasian samples with decidedly mixed results. The goal of this study was to test the pharmacogenetic effects of naltrexone on subjective response to alcohol and self-administration of alcohol in individuals of East Asian descent.

Differences between treatment-seeking and non-treatment-seeking participants in medication studies for alcoholism: do they matter?

Background: Medication development for alcoholism typically includes experimental pharmacology studies with non-treatment-seeking individuals with alcohol use disorder (AUD) paving the way for randomized controlled trials in treatment-seekers with AUD.

Objectives: The goal of this study is to provide a direct comparison between AUD treatment-seeking research participants and non-treatment-seeking participants on demographic and clinical variables and to test whether variables that differentiate the two groups are associated with clinical outcomes.

Method: Non-treatment-seeking AUD participants (n = 213; 76.

Naltrexone moderates the relationship between cue-induced craving and subjective response to methamphetamine in individuals with methamphetamine use disorder.

Rationale: Reductions in cue-induced craving and subjective response to drugs of abuse are commonly used as initial outcome measures when testing novel medications for the treatment of addiction. Yet neither the relationship between these two measures at the individual level nor the moderating effects of pharmacotherapies on this relationship has been examined.

Objective: This secondary data analysis sought to examine (1) the predictive relationship between cue-induced craving and subsequent acute subjective response to methamphetamine (MA) and (2) whether the opioid-receptor antagonist naltrexone moderated this association in a sample of non-treatment-seeking individuals who met DSM-IV criteria for MA use disorder (abuse or dependence).

Development of the Neuroimmune Modulator Ibudilast for the Treatment of Alcoholism: A Randomized, Placebo-Controlled, Human Laboratory Trial.

Current directions in medication development for alcohol use disorder (AUD) emphasize the need to identify novel molecular targets and efficiently screen new compounds aimed at those targets. Ibudilast (IBUD) is a neuroimmune modulator that inhibits phosphodiesterase-4 and -10 and macrophage migration inhibitory factor and was recently found to reduce alcohol intake in rats by ∼50%. To advance medication development for AUD, the present study consists of a randomized, crossover, double-blind, placebo-controlled laboratory study of IBUD in nontreatment-seeking individuals with current (ie, past month) mild-to-severe AUD.

Impulsivity Moderates Subjective Responses to Alcohol in Alcohol-Dependent Individuals.

Aims: Studies of social drinkers indicate that subjective response (SR) to alcohol and impulsivity are risk factors for the development of alcohol use disorder which may be related. It is unclear, however, whether there are significant relationships between SR and impulsivity among individuals with alcohol dependence. Using data from an intravenous (IV) alcohol challenge study, the present study is the first to explore the relationship between impulsivity and SR during alcohol administration among alcohol-dependent individuals.

Experimental psychopathology paradigms for alcohol use disorders: Applications for translational research.

In spite of high prevalence and disease burden, scientific consensus on the etiology and treatment of Alcohol Use Disorder (AUD) has yet to be reached. The development and utilization of experimental psychopathology paradigms in the human laboratory represents a cornerstone of AUD research. In this review, we describe and critically evaluate the major experimental psychopathology paradigms developed for AUD, with an emphasis on their implications, strengths, weaknesses, and methodological considerations.

Relationship between negative affect and smoking topography in heavy drinking smokers.

Heavy drinking smokers represent a sizeable subgroup of smokers for whom nicotine deprivation and alcohol use increases the urge to smoke in the laboratory and predicts lapses during smoking cessation. The manner in which individuals smoke a cigarette (i.e.