Pilot study indicates that a gluten-free diet lowers oxidative stress for gluten-sensitive persons with schizophrenia.

One-third of people with schizophrenia have elevated levels of anti-gliadin antibodies (AGA IgG). A 5-week randomized double-blind pilot study was performed in 2014-2017 in an inpatient setting to test the effect of a gluten-free diet (GFD) on participants with schizophrenia or schizoaffective disorder who also had elevated AGA IgG (≥ 20 U) but were negative for celiac disease. This earlier pilot study reported that the GFD-group showed improved gastrointestinal and psychiatric symptoms, and also improvements in TNF-α and the inflammatory cytokine IL-23. Here, we performed measurements of these banked plasma samples to detect levels of oxidative stress (OxSt) using a recently developed iridium (Ir)-reducing capacity assay. Triplicate measurements of these samples showed an Intraclass Correlation Coefficient of 0.84 which indicates good reproducibility. Further, a comparison of the OxSt measurements at the baseline and 5-week end-point for this small sample size shows that the GFD-group (N = 7) had lowered OxSt levels compared to the gluten-containing diet group (GCD; N = 9; p = 0.05). Finally, we showed that improvements in OxSt over these 5 weeks were correlated to improvements in gastrointestinal (r = +0.64, p = 0.0073) and psychiatric (r = +0.52, p = 0.039) symptoms. Also, we showed a possible association between the decrease in OxSt and the lowered levels of IL-23 (r = +0.44, p = 0.087), although without statistical significance. Thus, the Ir-reducing capacity assay provides a simple, objective measure of OxSt with the results providing further evidence that inflammation, redox dysregulation and OxSt may mediate interactions between the gut and brain.

A reduction in cigarette smoking improves health-related quality of life and does not worsen psychiatric symptoms in individuals with serious mental illness.

INTRODUCTION: Individuals with serious mental illness (SMI) smoke cigarettes at a much higher rate than the general population, increasing their risk for medical illnesses and mortality. However, individuals with SMI do not get enough support to quit smoking, partially because of concerns from medical providers that reducing smoking may worsen their symptoms or quality of life. METHODS: Veterans with SMI and nicotine dependence (n = 178) completed a 12-week smoking cessation trial (parent trial dates: 2010-2014) including assessments of smoking status, psychiatric symptoms (Brief Psychiatric Rating Scale), and quality of life (Lehman Quality of Life Interview-Short Version) at up to four time points: baseline, post-treatment, three-month follow-up, and 9-month follow-up. Bayesian multilevel modeling estimated the impact of changes in the self-reported number of cigarettes per day in the past seven days on psychiatric symptoms and quality of life. RESULTS: Between subjects, each additional pack of cigarettes smoked per day was associated with a 0.83 point higher score (95%CI: 0.03 to 1.7) on a negative symptoms scale ranging from 0 to 35. Within subjects, each one-pack reduction in the number of cigarettes smoked per day was associated with an improvement of 0.32 (95%CI = 0.12 to 0.54) on the health-related quality of life scale, which ranges from 0 to 7 points. There were no other significant between- or within-subjects effects of smoking on psychiatric symptoms or quality of life. CONCLUSIONS: Individuals with SMI and their providers should pursue smoking cessation without fear of worsening psychiatric symptoms or quality of life.

Associations among Trauma Exposure, Post-Traumatic Stress Symptoms and Alcohol Use in Black/African American Treatment-Seeking Adults.

OBJECTIVE: Black/African American (AA) individuals are a group at risk for co-occurring posttraumatic stress disorder (PTSD) symptoms and alcohol use due to unique cultural and system-level barriers. Although associations between trauma exposure, PTSD symptoms, and alcohol use are well established across various populations, Black/AA individuals are underrepresented in this literature, and related findings in this population are inconclusive. Thus, the goal of this study was to examine the associations among trauma exposure, PTSD symptoms, and alcohol use in a sample of treatment-seeking, Black/AA adults. We hypothesized that trauma exposure and alcohol use would be positively associated and that this relationship would be mediated by PTSD symptoms. METHODS: This study conducted secondary analysis of screening data from a PTSD and alcohol use disorder clinical trial. Participants were 96 Black/AA adults (57.3% male; 2.0% Hispanic; M age = 44.73, SD = 11.83) who were seeking treatment for alcohol use and endorsed trauma exposure. Associations between trauma exposure, PTSD symptom severity, and quantity and frequency of alcohol use were tested using bivariate correlations and linear regressions. Hypothesized indirect effects were tested using IBM SPSS Statistics Version 27 PROCESS model 4 with bootstrapping. RESULTS: Findings illustrated a significant positive association between trauma exposure and PTSD symptoms and between PTSD symptoms and drinks per typical drinking day. PTSD symptoms were not significantly associated with number of drinking days. Tests of indirect effects were significant for trauma exposure on drinks per typical drinking day through PTSD symptoms. CONCLUSIONS: Results from the test of indirect effects suggest that among Black/AA adults with heavy alcohol use and trauma exposure, trauma exposure is associated with PTSD symptoms, which in turn is associated with quantity of alcohol use. These findings are consistent with research conducted with White/mixed groups and align with tenets of the self-medication model of PTSD-AUD comorbidity. These findings support current practices that highlight the importance of screening for and addressing PTSD and alcohol use in individuals exposed to trauma. Findings from this paper provide initial data on understudied relationships in an underserved sample and several suggestions are made to generate future research and improve clinical care for Black/AA adults. CLINICAL TRIALS REGISTRY NAME: Pharmacogenetic Treatment With Anti-Glutaminergic Agents for Comorbid PTSD & AUD; ClinicalTrials.gov Identifier: NCT02884908.

Examining the associations between PTSD symptom clusters and alcohol-related problems in a sample of low-SES treatment-seeking Black/African American adults.

Posttraumatic stress disorder (PTSD) and alcohol use disorder (AUD) often co-occur. This comorbidity negatively influences treatment outcomes, functioning, and quality of life. To better understand the relation between PTSD and AUD, research has begun to examine the influence of PTSD symptom clusters on alcohol-related problems. The current study is the first to analyze the associations between PTSD symptom clusters and alcohol consumption and AUD symptom severity in a treatment-seeking sample of Black/African American (AA) adults with co-occurring AUD and PTSD symptoms. Examination of these associations may help to facilitate greater recovery in this underserved population by identifying more precise targets for treatment. PTSD symptom clusters were identified from both the current 4-factor model identified in the DSM-5 and from a recently proposed 7-factor model. Participants were Black/AA adults (50.6% male) who endorsed trauma exposure and were seeking treatment for alcohol misuse. The majority (66%) were unemployed and almost half (45%) reported an income at or lower than $20,000. In the 4-factor model, results showed Cluster D symptoms of PTSD (i.e., negative alterations in cognitions and mood) were independently associated with alcohol consequences. Use of the 7-factor model, which divides Cluster D into symptoms of negative affect and anhedonia, further demonstrated that only anhedonic symptoms were independently associated with alcohol consequences. No symptom clusters were uniquely associated with alcohol consumption. Results suggest the absence of positive emotions, rather than the presence of negative emotions, are primarily associated with alcohol-related problems in a sample of trauma-exposed, Black/AA adults seeking treatment for alcohol misuse.

The Effects of Menstrual Cycle Hormones on Responses to Varenicline and Naltrexone Among Female Heavy Drinking Smokers.

AIMS: Women often experience poorer smoking cessation outcomes in comparison to men. Menstrual cycle phase and sex hormones may influence smoking behavior and alter response to opioid antagonist medications. Less is known about the effects of sex hormones in response to pharmacotherapy for female heavy drinking smokers. METHODS: This study is a secondary analysis of premenopausal female heavy drinking smokers who completed a 12-week randomized clinical trial comparing varenicline plus placebo versus varenicline plus naltrexone for smoking cessation and drinking reduction. Participants (n = 26; total observations = 66) provided saliva samples for assays of progesterone (P4) and estradiol (E2) post-randomization at Weeks 4, 8 and 12. We examined the effects of P4/E2 ratio and medication on smoking and drinking outcomes. RESULTS: For drinking outcomes, there was a significant interaction for percent days abstinent (b = 0.017, P = 0.05), suggesting that greater P4/E2 ratio is associated with greater percent days abstinent for women assigned to the varenicline plus naltrexone condition. There were no interaction effects for the remaining drinking outcomes (P's ≥ 0.12). Results found no significant interaction effect of P4/E2 ratio and medication on smoking abstinence (P = 0.19). CONCLUSION: Our results imply that when women show a greater P4/E2 ratio, typically observed during the luteal phase of the menstrual cycle, they experience an added benefit of naltrexone, versus placebo, for drinking outcomes as shown by greater percent days abstinent. Additional studies in larger samples are warranted as sex hormones offer important information above and beyond comparing women versus men.

A Scoping Review of Gender, Sex and Sexuality Differences in Polysubstance Use in Adolescents and Adults.

BACKGROUND: Polysubstance use is a common, problematic behavior that increases risk of harm to self and others. Research suggests that rates may vary based on gender, sex and sexuality. Understanding the current state of this literature may inform prevention and treatment of polysubstance use, leading to reduced public health burden. OBJECTIVES: This review aimed to synthesize research on gender, sex and sexuality differences in polysubstance use in adults and adolescents. METHODS: A scoping review was conducted using all EBSCO databases, PubMed and Google Scholar to identify articles examining the effects of gender, sex and sexuality on polysubstance use. Polysubstance use was defined broadly as the use of any combination of substances over any time period and included licit (alcohol, tobacco) and illicit substances, concurrent and simultaneous use, from lifetime to daily use and use at any frequency. Studies were considered if they were published in peer-reviewed journals between January 1990 and October 2020 and were written in English. Publicly available data sources were also utilized to fully capture prevalence data that has not been published elsewhere. RESULTS: Findings were mostly inconsistent and often conflicting. Only two findings were generally consistent: adult men were overall more likely to report polysubstance use than adult women, and sexual and gender minorities report more frequent polysubstance use than non-minorities. CONCLUSIONS: Research has been unable to clearly elucidate differences in polysubstance use prevalence and patterns according to gender, sex and sexuality. Several recommendations are offered to advance future research and address limitations of current research.

SIGH, what's in a name? An examination of the factor structure and criterion validity of the (Structured Interview Guide for the) Hamilton Anxiety scale (SIGH-A) in a sample of African American adults with co-occurring trauma experience and heavy alcohol use.

The Hamilton Anxiety Inventory (HAM-A) is one of the oldest and most commonly used anxiety rating scales in clinical research. Despite its ubiquity, no studies have examined the scale's underlying factor structure and criterion validity among Black and African American adults with psychopathology (Mage = 42.25, SD = 11.44). Therefore, we estimated a confirmatory factor analysis of the commercially available Structured Interview Guide for the Hamilton Anxiety scale (SIGH-A; Williams, 1996) among African American adults (n = 88; 43% female) with co-occurring heavy alcohol use and trauma-related symptoms. Next, we examined the criterion validity of its Psychic and Somatic factors and overall anxiety severity score from participants who completed a single screening session (i.e., cross-sectional analysis) for a larger study. Results indicated that a two-factor solution provided an adequate fit to the data. Regression analyses indicated that the total SIGH-A score, but not its subscales, significantly predicted posttraumatic stress disorder (PTSD) severity. Neither the SIGH-A subscales nor total scores were significant predictors of alcohol consumption. The current findings suggest that the SIGH-A factor structure among African American adults with alcohol and trauma-related conditions is similar to previous reports that have tested largely White samples but highlight potential shortcomings when its subscales are used independently. (PsycInfo Database Record (c) 2022 APA, all rights reserved).

A Narrative Literature Review of the Epidemiology, Etiology, and Treatment of Co-Occurring Panic Disorder and Opioid Use Disorder.

OBJECTIVE: Panic disorder is a debilitating psychiatric disorder that often co-occurs with substance use disorders. Given the current opioid epidemic, the high reported rates of comorbid panic disorder and opioid use disorder are particularly concerning. In this narrative review, we describe the literature on panic disorder and opioid use disorder co-occurrence. METHODS: 86 studies, 26 reviews, 2 commentaries, and 5 guidelines pertaining to opioid use disorder, panic disorder, and their comorbidity were identified using all EBSCO databases, PubMed, and Google Scholar. RESULTS: First, we review epidemiological literature on the prevalence of the comorbid condition above and beyond each disorder on its own. Additionally, we discuss the challenges that complicate the differential diagnosis of panic disorder and opioid use disorder and contribute to difficulties establishing rates of comorbidity. Second, we review three theoretical models that have been proposed to explain high rates of co-occurring panic disorder and opioid use disorder: the precipitation hypothesis, the self-medication hypothesis, and the shared vulnerability hypothesis. Third, we outline how co-occurring panic and opioid use disorder may impact treatment for each condition. CONCLUSION: Based on findings in the field, we provide recommendations for future research as well as treatment considerations for co-occurring panic and opioid use disorders.

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. METHODS: We computed the effects of 21 medications on alcohol-induced stimulation, sedation, negative mood, and craving during alcohol administration in 49 studies. RESULTS: Meta-regression analyses indicated a significant and positive effect of pre-study drinks per month on alcohol-induced stimulation (ß = 0.142, p < 0.0001), such that as drinking increases, the benefit of medication over placebo decreases. There was an effect of drinks per month on negative mood (ß = -0.164, p = 0.0248), such that at higher levels of drinks per month, the effects of medications on negative mood are stronger. For sedation, there was an effect of peak BrAC (ß = 0.119, p = 0.0002), such that at low levels of peak BrAC, the effects of medication on sedation were null. For craving, there was a peak BrAC × drinks per month interaction such that at low levels of BrAC, a heavier drinking sample is required to detect the effects of medication on craving. Sensitivity analyses comparing naltrexone studies and non-naltrexone studies suggested that naltrexone was less sensitive to drinks per month across subjective response domains. CONCLUSIONS: These analyses show that design features are critical in studies that test the effects of medications on the subjective responses to alcohol. By specifying the significance and directionality of these effects, as well as the specific points in BrAC or drinks per month at which medication effects are detectable, the study offers recommendations for design features of alcohol administration studies that aim to inform AUD medication development.

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. We searched the literature for medications tested for AUD using both behavioral pharmacology (i.e., alcohol administration) and randomized clinical trials (RCTs). For behavioral pharmacology, we computed medication effects on alcohol-induced stimulation, sedation, and craving during the alcohol administration (k = 51 studies, 24 medications). For RCTs, we computed medication effects on any drinking and heavy drinking (k = 118 studies, 17 medications). We used medication as the unit of analysis and applied the Williamson-York bivariate weighted least squares estimation to preserve the errors in both the independent and dependent variables. Results, with correction for publication bias, revealed a significant and positive relationship between medication effects on alcohol-induced stimulation (ß = 1.18 p < 0.05), sedation (ß = 2.38, p < 0.05), and craving (ß = 3.28, p < 0.001) in the laboratory, and drinking outcomes in RCTs, such that medications that reduced stimulation, sedation, and craving during the alcohol administration were associated with better clinical outcomes. A leave-one-out Monte Carlo analysis examined the predictive utility of these laboratory endpoints for each medication. The observed clinical effect size was within one standard deviation of the mean predicted effect size for all but three pharmacotherapies. This proof-of-concept study demonstrates that behavioral pharmacology endpoints of alcohol-induced stimulation, sedation, and craving track medication effects from the human laboratory to clinical trial outcomes. These results apply to alcohol administration phenotypes and may be especially useful to medications for which the mechanisms of action involve alterations in subjective responses to alcohol (e.g., antagonist medication). These methods and results can be applied to a host of clinical questions and can streamline the process of screening novel compounds for AUD. For instance, this approach can be used to quantify the predictive utility of cue-reactivity screening models and even preclinical models of medication development.

Lack of Association between Opioid-Receptor Genotypes and Smoking Cessation Outcomes in a Randomized, Controlled Naltrexone Trial.

AIMS: The present study examined how variation in mu- (OPRM1), kappa- (OPRK), and delta- (OPRD) opioid receptor genes may influence the efficacy of naltrexone in the context of a smoking cessation trial. METHODS: The study's primary objective was to examine the association of the Asn40Asp OPRM1 single nucleotide polymorphism (SNP) with naltrexone's effects on smoking quit rate, weight gain, and heavy drinking behavior during a double-blind, randomized clinical trial in 280 adult DSM-IV nicotine-dependent participants. The secondary goal of the study was to examine the relationship of 20 additional SNPs of OPRM1, OPRK, and OPRD with the aforementioned outcomes. RESULTS: Results indicated a null association between any opioid-receptor gene SNP and naltrexone's effects on smoking quit rate, weight gain, and heavy drinking behavior in this sample of nicotine dependent participants. CONCLUSIONS: In sum, these results do not suggest that genetic variation in opioid-receptors is related to treatment responses to naltrexone in a smoking cessation trial.

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. Meta-analyses of naltrexone effects on alcohol craving (k = 16, N = 686), stimulation (k = 15, N = 675), sedation (k = 18, N = 777), and negative mood (k = 9, N = 281) suggested that under laboratory conditions and compared with placebo, naltrexone reduces craving (Hedges g = -0.252; SE = 0.054; 95% CI, -0.375 to -0.130; P < 0.01), reduces stimulation (g = -0.223; SE = 0.067; 95% CI, -0.372 to -0.074; P < 0.01), increases sedation (g = 0.251; SE = 0.064; 95% CI, 0.112-0.389; P < 0.01), and increases negative mood (g = 0.227; SE = 0.047; 95% CI, 0.100-0.354; P < 0.01). Results were robust when drinks per month and alcohol dose were added to the models as covariates. The effects of naltrexone varied by severity of alcohol use with medication effects on craving and stimulation being observed in sample of both heavy drinkers and AUD individuals. These results are consistent with the hypothesized mechanisms of action of NTX, although the effects are of small magnitude. This meta-analysis aggregates across multiple human laboratory studies of NTX's effects on subjective response to alcohol, providing a comprehensive summary of a key mechanism of NTX efficacy, namely, alteration of the subjective experience of alcohol.

Distress Tolerance and Craving for Cigarettes Among Heavy Drinking Smokers.

OBJECTIVE: Heavy drinking smokers experience significant difficulties with smoking cessation. Craving is closely tied to relapses during cessation attempts, and alcohol consumption increases cigarette craving among heavy drinking smokers. To date, however, few moderators of the relationship between craving and relapse have been identified. Individuals' capacity for distress tolerance predicts smoking cessation outcomes and may be connected to craving. Relatedly, pharmacotherapies like varenicline and naltrexone reduce cigarette and alcohol cravings, respectively. No studies have examined the interrelationships among distress tolerance, craving, and pharmacotherapy effects. This study therefore examines distress tolerance as a moderator of the relationship between overnight abstinence-induced cigarette craving and subsequent alcohol- and cigarette-induced changes in craving among heavy drinking smokers. This study also examines the impact of varenicline and naltrexone on these relationships. METHOD: A total of 120 non-treatment-seeking heavy drinking smokers were randomized and titrated to one of the following conditions: (a) placebo, (b) varenicline, (c) naltrexone, or (d) varenicline + naltrexone. Participants then completed a laboratory paradigm after overnight abstinence that included consumption of alcohol (target .06 g/dl breath alcohol concentration) and one cigarette. Craving was assessed as abstinence-induced (Time 1), alcohol-induced (Time 2), and cigarette-induced (Time 3). RESULTS: Within varenicline + naltrexone, low distress tolerance individuals exhibited higher increases from abstinence- to alcohol-induced cigarette craving relative to high distress tolerance individuals. Across medications, low distress tolerance individuals reported flatter decreases from abstinence- to cigarette-induced cigarette craving relative to high distress tolerance individuals. CONCLUSIONS: Distress tolerance may differentially predict alcohol-induced cigarette craving when titrated to pharmacotherapy, as well as moderate decreases in craving after cigarette consumption. Future exploration of the identified interactive effects could elucidate specific conditions in which cravings are more proximally related to abstinence-induced smoking.

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. Specifically, this study tested whether alcohol use severity (1) independently predicts subjective responses to alcohol (SR; comprised of stimulation/hedonia, negative affect, sedation and craving domains), and alcohol self-administration and 2) moderates associations between domains of SR and alcohol self-administration. Heavy drinking participants ranging in severity of alcohol use and problems (N = 67) completed an intravenous alcohol administration paradigm combining an alcohol challenge (target BrAC = 60 mg%), with progressive ratio self-administration. Alcohol use severity was associated with greater baseline negative affect, sedation, and craving but did not predict changes in any SR domain during the alcohol challenge. Alcohol use severity also predicted greater self-administration. Craving during the alcohol challenge strongly predicted self-administration and sedation predicted lower self-administration. Neither stimulation, nor negative affect predicted self-administration. This study represents a novel approach to translating preclinical neuroscientific theories to the human laboratory. As expected, craving predicted self-administration and sedation was protective. Contrary to the predictions of the Allostatic Model, however, these results were inconsistent with a transition from positively to negatively reinforced alcohol consumption in severe AUD. Future studies that assess negative reinforcement in the context of an acute stressor are warranted.

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. We hypothesized that naltrexone, compared with placebo, would potentiate the aversive and sedative effects of alcohol and reduce alcohol self-administration to a greater extent in Asp40 carriers. METHODS: Participants (N = 77; Asn40Asn, n = 29; Asn40Asp, n = 34, and Asp40Asp, n = 14) completed 2 double-blinded and counterbalanced experimental sessions: one after taking naltrexone (50 mg/d) for 5 days and one after taking matched placebo for 5 days. In each experimental session, participants received a priming dose of intravenous alcohol up to the breath alcohol concentration target of 0.06 g/dl which was immediately followed by an alcohol self-administration period (1 hour). RESULTS: There were no pharmacogenetic effects observed for alcohol-induced stimulation, sedation, craving for alcohol, or alcohol self-administration in the laboratory. During the self-administration period, Asp40 carriers consumed fewer drinks and had a longer latency to first drink as compared to Asn40 homozygotes. CONCLUSIONS: These findings in East Asians add to the mixed literature on naltrexone pharmacogenetics from predominantly Caucasian samples and highlight the complexity of these effects and their overall limited replicability. It is plausible that a consistent pharmacogenetic effect in tightly controlled preclinical and experimental medicine models "fades" in more complex and heterogeneous settings and samples.

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; 76.3% male) who completed behavioral pharmacology studies were compared to treatment-seekers who completed the COMBINE Study (n = 1383; 69.1% male) on demographic and clinical variables. Analyses examined whether the variables that differentiated the two groups predicted treatment outcomes in the COMBINE Study. RESULTS: Analyses revealed that treatment-seeking participants were older, had more years of education, higher Alcohol Dependence Scale scores, higher Drinker Inventory of Consequences scores, higher Obsessive Compulsive Drinking Scale scores, a greater number of DSM-IV symptoms of AUD, longer duration of AUD, and consumed more standard drinks and more drinks per drinking day (i.e., in the past 30 days) compared to non-treatment-seeking participants. Nearly all characteristics that differed between the groups predicted at least one of the primary clinical outcomes of the COMBINE Study. CONCLUSIONS: This study highlights a host of clinical and demographic factors that differ between non-treatment-seeking and treatment-seeking research participants and the clinical significance of these variables. Differences between samples should be considered and addressed in order to promote greater consilience across stages of medication development.

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). METHODS: Participants (n = 30) completed two 4-day medication regimens (oral naltrexone 50 mg or placebo, in a randomized, counterbalanced, and double-blind fashion). On day 4 of each medication regimen, participants completed a cue-reactivity paradigm followed by intravenous MA administration. Methamphetamine craving was assessed after the cue-reactivity paradigm, and subjective response to MA was assessed during MA infusion. RESULTS: Cue-induced craving for MA was positively associated with post-infusion subjective MA effects, including positive (i.e., stimulation, good effects, feel drug, high), negative (i.e., anxious and depressed), and craving-related (i.e., want more, would like access to drug, crave) responses. Naltrexone, vs. placebo, significantly reduced the association between cue-induced craving and positive subjective response to MA. CONCLUSIONS: The findings indicate that naltrexone moderates the predictive relationship between cue-induced craving and positive subjective effects of MA, thereby suggesting a behavioral mechanism by which naltrexone may be efficacious in treating MA use disorder.