Reward, relief, and habit drinking profiles in treatment seeking individuals with an AUD.

AIMS: This study aimed to compare reward, relief, and habit treatment-seeking individuals on recent drinking, alcohol use disorder (AUD) phenomenology, and mood. The second aim of the study was to evaluate the predictive validity of reward, relief, and habit profiles. METHOD: Treatment-seeking individuals with an AUD (n = 169) were recruited to participate in a medication trial for AUD (NCT03594435). Reward, relief, and habit drinking groups were assessed using the UCLA Reward Relief Habit Drinking Scale. Group differences at baseline were evaluated using univariate analyses of variance. A subset of participants were enrolled in a 12-week, double-blind, placebo-controlled medication trial (n = 102), and provided longitudinal drinking and phenomenology data. The predictive validity of group membership was assessed using linear regression analyses. RESULTS: At baseline, individuals who drink primarily for relief had higher craving and negative mood than those who drink for reward and habit. Prospectively, membership in the relief drinking group predicted greater alcohol use, greater heavy drinking, and fewer days abstinent compared to those in the reward drinking group. Membership in the relief drinking group also predicted greater alcohol craving, more alcohol-related consequences, and more anxiety symptoms over 12 weeks compared to those in the reward drinking group. CONCLUSIONS: This study provides support for reward and relief drinking motive profiles in treatment-seeking individuals with an AUD. Membership in the relief drinking motive group was predictive of poorer drinking outcomes and more negative symptomology over 12 weeks, indicating that individuals who drink for relief may be a particularly vulnerable sub-population of individuals with AUD.

Development, implementation, and acceptability of a bedside mindfulness intervention for adults with sickle cell disease.

Acute and chronic pain are the most frequent complications of sickle cell disease (SCD), often severely reducing quality of life and requiring management with long-term pharmacological interventions. A biopsychosocial approach conceptualizing pain in SCD as the result of complex biological, psychological, and social factors could facilitate targeted behavioral interventions. Mindfulness is one procedure for management of pain in individuals with chronic pain/illness. The goal of the current project was to design and implement a bedside mindfulness intervention to help patients with SCD enhance self-efficacy of pain management and reduce distress. As part of a quality improvement project in SCD clinics in a large health system, we developed a bedside mindfulness intervention to be provided during infusion sessions for patients presenting for acute vaso-occlusive episodes (VOE). The approach to development and implementation involved engagement of professionals working directly with patients. Concept planning meetings with these professionals along with qualitative patient and provider feedback informed feasibility, design, and intervention application. During a quantitative phase, patients completed validated surveys items on acceptability. Interview data (N = 11) supported patient interest in mindfulness skills and highlighted a need for tailored, person-centered interventions and non-pharmacological treatment strategies. On quantitative items, participants (N = 14) liked the intervention and agreed mindfulness skills would help manage disease-related distress. Following the interventions, participants reported increased mindfulness (p = .005). While preliminary, these results provide support for the continued development of evidence-based, mindfulness-oriented services to help individuals with SCD manage pain and other psychological difficulties.

Baseline C-reactive protein levels are predictive of treatment response to a neuroimmune modulator in individuals with an alcohol use disorder: a preliminary study.

Background: Inflammation is implicated in alcohol use disorder (AUD). Ibudilast, a neuroimmune modulator, shows promise for the treatment of AUD. Elevated inflammation, indicated by high levels of C-reactive protein (CRP), represents a possible subtype of AUD, which may be associated with treatment response to ibudilast.Objectives: The current study evaluated CRP as a predictor of treatment response to ibudilast; hypothesizing that ibudilast would be more effective at reducing drinking and alcohol cue-reactivity in individuals with higher CRP levels.Methods: This is a secondary analysis of a clinical trial of ibudilast for AUD, which found that ibudilast reduced heavy drinking in individuals with AUD. Fifty-one individuals were randomized to receive ibudilast (n = 24 [16 M/8F]) or placebo (n = 27 [18 M/9F]) for two weeks. Participants provided blood samples at baseline to assess CRP levels, completed daily assessments of alcohol use, and an fMRI alcohol cue-reactivity task at study mid-point. Models tested the effects of medication, CRP levels, and their interaction on drinks per drinking day and alcohol cue-reactivity.Results: There was a significant interaction between medication and CRP (F = 3.80, p = .03), such that the ibudilast high CRP group had fewer drinks per drinking day compared to the ibudilast low CRP group. CRP moderated the effect of medication on brain activation in a cluster extending from the left inferior frontal gyrus to the right-dorsal striatum (Z = 4.55, p < .001). This interaction was driven by attenuated cue-reactivity in the ibudilast high CRP group relative to the ibudilast low CRP and placebo high CRP groups.Conclusions: This study serves as an initial investigation into predictors of clinical response to ibudilast treatment and suggests that a baseline proinflammatory profile may enhance clinical efficacy.

The effect of neuroimmune modulation on subjective response to alcohol in the natural environment.

BACKGROUND: Despite the promising implications for novel immune therapeutics, few clinical trials have tested these therapies to date. An understanding of how immune pharmacotherapies influence complex alcohol use disorder (AUD) profiles, including subjective response to alcohol, is very limited. Initial findings show that ibudilast, a neuroimmune modulator, reduces rates of heavy drinking and measures of alcohol craving. METHODS: This study is a secondary analysis of a 2-week clinical trial of ibudilast that enrolled a nontreatment-seeking sample with AUD. Eligible participants (N = 52) were randomized to receive ibudilast or matched placebo and completed daily diary assessments (DDAs) during the 2-week period. Each morning, participants reported on their mood and craving levels both before and during the previous day's drinking episode, as well as stimulation and sedation levels during the previous day's drinking episode. Multilevel models were used to compare the effects of ibudilast and placebo on subjective alcohol response. Exploratory analyses tested whether ibudilast moderated the relationship between daily stimulation/sedation and alcohol intake and whether withdrawal-related dysphoria moderated ibudilast's effects on subjective response. RESULTS: Ibudilast did not significantly alter mean levels of stimulation or sedation (p's > 0.05). It did, however, moderate the effect of daily stimulation on drinking (p = 0.045). Ibudilast attenuated alcohol-induced increases in craving compared with placebo (p = 0.047), but not other subjective response measures. Ibudilast significantly tempered daily alcohol-induced changes in urge to drink and positive mood only among individuals without withdrawal-related dysphoria. CONCLUSIONS: Ibudilast's effects on subjective alcohol responses appear to be nuanced and perhaps most salient for individuals drinking for positive reinforcement as distinguished from those who drink to feel normal. Consistent with previous findings, reductions in alcohol craving may represent a primary mechanism of ibudilast's effects on drinking. The ecologically valid nature of DDAs provide a clinically useful window into how individuals experience alcohol's effects while taking ibudilast.

Effects of ibudilast on central and peripheral markers of inflammation in alcohol use disorder: A randomized clinical trial.

Ibudilast, a neuroimmune modulator, shows promise as a pharmacotherapy for alcohol use disorder (AUD). In vivo administration of ibudilast reduces the expression of pro-inflammatory cytokines in animal models, but its effects on markers of inflammation in humans are unknown. This preliminary study examined the effect of ibudilast on peripheral and potential central markers of inflammation in individuals with AUD. This study also explored the predictive relationship of neurometabolite markers with subsequent drinking in the trial. Non-treatment-seeking individuals with an AUD (n = 52) were randomized to receive oral ibudilast (n = 24) or placebo (n = 28) for 2 weeks. Plasma levels of peripheral inflammatory markers were measured at baseline and after 1 and 2 weeks of medication. At study mid-point, proton magnetic resonance spectroscopy was performed to measure potential neurometabolite markers of inflammation: choline-compounds (Cho), myo-inositol (MI) and creatine + phosphocreatine (Cr) in frontal and cingulate cortices from 43 participants (ibudilast: n = 20; placebo: n = 23). The treatment groups were compared on peripheral and central markers. Ibudilast-treated participants had lower Cho in superior frontal white matter and nominally lower MI in pregenual anterior cingulate cortex. Ibudilast-treated participants had nominally lower C-reactive protein levels at visit 2 and nominally lower TNF-α/IL-10 ratios, relative to placebo. C-reactive protein and Cho levels were correlated, controlling for medication. Superior frontal white matter Cho predicted drinking in the following week. Micro-longitudinal ibudilast treatment may induce peripheral and putative central anti-inflammatory responses in patients with AUD. The neurometabolite responses may be associated with reduction in drinking, suggesting an anti-inflammatory component to the therapeutic action of ibudilast.

Immune treatments for alcohol use disorder: A translational framework.

While the immune system is essential for survival, an excessive or prolonged inflammatory response, such as that resulting from sustained heavy alcohol use, can damage the host and contribute to psychiatric disorders. A growing body of literature indicates that the immune system plays a critical role in the development and maintenance of alcohol use disorder (AUD). As such, there is enthusiasm for treatments that can restore healthy levels of inflammation as a mechanism to reduce drinking and promote recovery. In this qualitative literature review, we provide a conceptual rationale for immune therapies and discuss progress in medications development for AUD focused on the immune system as a treatment target. This review is organized into sections based on primary signaling pathways targeted by the candidate therapies, namely: (a) toll-like receptors, (b) phosphodiesterase inhibitors, (c) peroxisome proliferator-activated receptors, (d) microglia and astrocytes, (e) other immune pharmacotherapies, and (f) behavioral therapies. As relevant within each section, we examine the basic biological mechanisms of each class of therapy and evaluate preclinical research testing the role of the therapy on mitigating alcohol-related behaviors in animal models. To the extent available, translational findings are reviewed with discussion of completed and ongoing randomized clinical trials and their findings to date. An applied and clinically focused approach is taken to identify the potential clinical applications of the various treatments reviewed. We conclude by delineating the most promising candidate treatments and discussing future directions by considering opportunities for immune treatment development and personalized medicine for AUD.

Understanding low treatment seeking rates for alcohol use disorder: A narrative review of the literature and opportunities for improvement.

Despite a well-documented global burden of disease attributable to alcohol use disorder (AUD), treatment seeking rates remain low. In this qualitative literature review, we address treatment seeking for AUD from a host of perspectives and summarize the literature on key factors. First, we summarize the rates of alcohol treatment seeking across various epidemiological surveys, spanning decades. Second, we discuss the definition of treatment seeking and 'what' is typically considered formal treatment. Third, we consider timing and discuss 'when' individuals are most likely to seek treatment. Fourth, we review the literature on 'who' is most likely to seek treatment, including demographic and clinical correlates. Fifth, we address the critical question of 'why' so few people receive clinical services for AUD, relative to the number of individuals affected by the disorder, and review barriers to treatment seeking at the treatment- and person-levels of analysis. Finally, we identify opportunities to improve treatment seeking rates by focusing on tangible points of intervention. Specifically, we recommend a host of adaptations to models of care including efforts to make treatment more appealing across stages of AUD severity, accept a range of health-enhancing drinking goals as opposed to an abstinence-only model, educate providers and consumers about evidence-based behavioral and pharmacological treatments, and incentivize the delivery of evidence-based services.

Piloting of the Just Say Know prevention program: a psychoeducational approach to translating the neuroscience of addiction to youth.

BACKGROUND: Substance use during adolescence can have a number of negative consequences and interfere with normal brain development. Given limited time and resources, brief group- and school-based prevention programs are an efficient strategy for educating youth about the effects of substance use on health outcomes. OBJECTIVES: To determine if a science-based, interactive substance prevention program could improve student knowledge and influence students' attitudes toward future substance use behaviors. METHODS: The Just Say Know program was given to 1,594 middle and high school students. The facilitator engaged students in an interactive, hour-long session covering brain basics and effects of substance use. Students completed an eight-item pre- and post-knowledge-based test to measure learning outcomes along with feedback questions about youths' attitudes toward substance use and the program. RESULTS: After the program, 94% of students reported that it provided helpful information; 92% reported it may influence their approach to substance use, with 76% specifying that they would delay or cut back on substance use. Knowledge-based test performance increased by 78%, with high schoolers displaying significantly higher scores than middle schoolers, but both showing similar improvements in scores. Students who reported higher levels of friends' substance use had smaller improvements from pre- to posttest. CONCLUSION: Results suggest Just Say Know, a scientifically-based prevention program, is effective in increasing adolescents' program based-knowledge, has the potential to affect youths' attitudes toward substance use, and is well-received. These findings provide preliminary evidence that a cost-effective, neuroscience-informed group prevention program might reduce or delay adolescents' future substance use.

Alcohol Cue-Induced Ventral Striatum Activity Predicts Subsequent Alcohol Self-Administration.

BACKGROUND: Human laboratory paradigms are a pillar in medication development for alcohol use disorders (AUD). Neuroimaging paradigms, in which individuals are exposed to cues that elicit neural correlates of alcohol craving (e.g., mesocorticolimbic activation), are increasingly utilized to test the effects of AUD medications. Elucidation of the translational effects of these neuroimaging paradigms on human laboratory paradigms, such as self-administration, is warranted. The current study is a secondary analysis examining whether alcohol cue-induced activation in the ventral striatum is predictive of subsequent alcohol self-administration in the laboratory. METHODS: Non-treatment-seeking heavy drinkers of East Asian descent (n = 41) completed a randomized, placebo-controlled, double-blind, crossover experiment on the effects of naltrexone on neuroimaging and human laboratory paradigms. Participants completed 5 days of study medication (or placebo); on day 4, they completed a neuroimaging alcohol taste cue-reactivity task. On the following day (day 5), participants completed a 60-minute alcohol self-administration paradigm. RESULTS: Multilevel Cox regressions indicated a significant effect of taste cue-elicited ventral striatum activation on latency to first drink, Wald χ2  = 2.88, p = 0.05, such that those with higher ventral striatum activation exhibited shorter latencies to consume their first drink. Similarly, ventral striatum activation was positively associated with total number of drinks consumed, F(1, 38) = 5.90, p = 0.02. These effects were significant after controlling for alcohol use severity, OPRM1 genotype, and medication. Other potential regions of interest (anterior cingulate, thalamus) were not predictive of self-administration outcomes. CONCLUSIONS: Neuroimaging alcohol taste cue paradigms may be predictive of laboratory paradigms such as self-administration. Elucidation of the relationships among different paradigms will inform how these paradigms may be used synergistically in experimental medicine and medication development.

Inclusion of Cannabis Users in Alcohol Research Samples: Screening In, Screening Out, and Implications.

BACKGROUND: Alcohol and cannabis are frequently co-used, as 20-50% of those who drink alcohol report co-using cannabis. This study is based on the argument that alcohol researchers should enroll cannabis users in human laboratory studies of alcohol use disorder (AUD) to strengthen generalizability. This study examines how heavy drinking cannabis users differ from non-cannabis using heavy drinkers. METHODS: In a community sample of non-treatment-seeking heavy drinkers (n = 551, 35% female), cannabis users were identified through: (a) self-reported cannabis use in the past 6 months and (b) positive urine toxicology test for tetrahydrocannabinol (THC). Cannabis users, identified as described previously, were compared with non-cannabis users on demographic and clinical characteristics. RESULTS: Those who endorsed cannabis use in the past 6 months reported more binge drinking days. Participants who tested positive for THC had higher Alcohol Use Disorder Identification Test scores and more binge drinking days. Younger age and being a tobacco smoker were associated with an increased likelihood of cannabis use in the past 6 months, whereas male gender and being a tobacco use were associated with a greater likelihood of testing positive for THC. Individuals with cannabis use disorder (CUD) endorsed more depression and anxiety and had higher AUD symptom counts than cannabis users without CUD. CONCLUSIONS: The inclusion of cannabis users in AUD samples allows for increased clinical severity. Excluding cannabis users from AUD studies may limit representativeness and expend unnecessary study resources. Lastly, tobacco use may explain a large portion of the effects of cannabis use on sample characteristics. SHORT SUMMARY: Alcohol and cannabis are frequently co-used substances. In a sample of non-treatment-seeking heavy drinkers (n = 551, 35% female), cannabis users reported higher alcohol use and higher likelihood of tobacco use than non-cannabis users. Including cannabis users in alcohol research studies will improve representativeness and likely increase clinical severity.

Executive function moderates naltrexone effects on methamphetamine-induced craving and subjective responses.

Background: Emerging evidence suggests that opioid receptor antagonists, such as naltrexone, are effective pharmacotherapies for alcohol, opioid, and possibly stimulant use disorders. It is posited that naltrexone exerts its effects, in part, by increasing functional connectivity between neural reward circuitry and frontal systems implicated in executive function. Yet no studies had examined whether executive function moderates these effects. Objectives: This study examined whether a composite measure of executive function (EF) moderates the effect of naltrexone on craving for methamphetamine and subjective responses following infusion of the drug. Methods: Individuals with methamphetamine use disorder (N = 30; 27% female) completed baseline neurocognitive assessments of premorbid and executive function, and an executive function factor was computed. Participants then underwent a randomized, double-blind, cross-over study of titration with naltrexone and placebo. Participants then received a 30-mg intravenous methamphetamine infusion and completed subjective response questionnaires at 8 times in the 120 minutes post-infusion. Results: Multilevel mixed models indicated a significant EF × medication interaction, reflecting greater effects of naltrexone to decrease "desire to access the drug", "want more of the drug", "crave the drug", "feel drug effects" and "feel high" in participants with low EF compared to those with high EF (Bs = .36-1.29, SEs = .14-.17, ps<0.01). These effects remained significant after controlling for premorbid cognitive functioning, baseline responses to methamphetamine, severity of methamphetamine use, and methamphetamine-related functional problems. Conclusion: Naltrexone may be especially effective in methamphetamine-dependent individuals with low EF. Neuropsychological assessments may also provide predictive clinical utility not captured by traditional measures of substance use severity.

Leveraging meta-regression to test if medication effects on cue-induced craving are associated with clinical efficacy.

RATIONALE: The alcohol cue exposure paradigm is a common method for evaluating new treatments for alcohol use disorder (AUD); however, it is unclear if medication-related reductions in cue-induced craving in the human laboratory can predict the clinical success of those medications in reducing alcohol consumption during clinical trials. OBJECTIVES: To use a novel meta-analytic approach to test whether medication effect sizes on cue-induced alcohol craving are associated with clinical efficacy in clinical trials. METHOD: We searched the literature for medications tested for AUD treatment using both the alcohol cue-reactivity paradigm and randomized clinical trials (RCTs). For alcohol cue-reactivity studies, we computed medication effect sizes for cue-induced alcohol craving (k = 36 studies, 15 medications). For RCTs, we calculated medication effect sizes for heavy drinking and abstinence (k = 139 studies, 19 medications). Using medication as the unit of analysis, we applied the Williamson-York bivariate weighted least squares estimation to account for errors in both independent and dependent variables. We also conducted leave-one-out cross validation simulations to examine the predictive utility of cue-craving medication effect sizes on RCT heavy drinking and abstinence endpoints. RESULTS: There was no significant relationship between medication effects on cue-induced alcohol craving in the human laboratory and medication effects on heavy drinking ( ß ^ = 0.253, SE = 0.189, p = 0.090) and abstinence ( ß ^ = 0.829, SE = 0.747, p = 0.133) in RCTs. CONCLUSIONS: The preliminary results of the current study challenge the assumption that alcohol cue-reactivity alone can be used as an early efficacy indicator for AUD pharmacotherapy development. These findings suggest that a wider range of early efficacy indicators and experimental paradigms be considered for Phase II testing of novel compounds.

Adolescent Neurodevelopment Within the Context of Impulsivity and Substance Use.

Purpose of Review: The aim of the present review is to provide an update on recent studies examining adolescent neurodevelopment in the context of impulsivity and substance use. We provide a review of the neurodevelopmental changes in brain structure and function related to impulsivity, substance use, and their intersection. Recent Findings: When examining brain structure, smaller gray matter volume coupled with lower white matter integrity is associated with greater impulsivity across three components: trait impulsivity, choice impulsivity, and response inhibition. Altered functional connectivity in networks including the inhibitory control network and reward processing network confers risk for greater impulsivity and substance use. Summary: Across brain structure and function, there is evidence to suggest that overlapping areas involved in the rise in impulsivity during adolescence contribute to early substance use initiation and escalation. These overlapping neurodevelopmental correlates have promising implications for prevention and early intervention efforts for adolescent substance use.

Are medication effects on subjective response to alcohol and cue-induced craving associated? A meta regression study.

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.

Testing pharmacotherapies for alcohol use disorder with cue exposure paradigms: A systematic review and quantitative synthesis of human laboratory trial methodology.

Alcohol cue exposure is a widely used experimental paradigm for screening pharmacotherapies for alcohol use disorder (AUD). Medication-related reductions in cue-reactivity signal early efficacy and inform medications development. Yet, across trials, the design of cue exposure, parameter testing, and outcome reporting is heterogeneous. This systematic review is a quantitative synthesis of trial methodologies and effect size estimation for AUD medication-related craving and psychophysiological outcomes under the cue exposure paradigm. A PubMed search was conducted on January 3, 2022 based on identified pharmacotherapies for peer-reviewed articles reported in English. Study-level characteristics, including sample descriptors, paradigm design, analytic approach, and Cochrane Risk of Bias, along with descriptive statistics for cue-exposure outcomes, were coded by two independent raters. Study-level effect sizes were estimated for craving and psychophysiological outcomes separately and sample-level effect sizes were calculated for each medication. Thirty-six trials, comprising 1640 participants and testing 19 different medications satisfied eligibility criteria. All studies reported on biological sex (71% male participants on average). The exposure paradigms implemented used in vivo (n = 26), visual (n = 8), and audio script (n = 2) cues. Some trials included means for craving by medication condition in text (k = 7) or figures (k = 18). The quantitative synthesis included 63 effect sizes (craving kes = 47; psychophysiological kes = 16) from 28 unique randomized trials testing 15 medications for effects on cue reactivity. For cue-induced craving, eight medications (kes range: 1-12) demonstrated small-to-medium effects (Cohen's d range: |0.24-0.64|) compared to placebo, with individuals randomized to receive medication reporting lower craving following cue exposure. Recommendations are provided to promote further consilience, so that the utility of cue exposure paradigms can be maximized in the development of effective AUD pharmacotherapies. Future work should explore the predictive utility of medication-related reductions in cue-reactivity on clinical outcomes.

Implementation of Specialty Tobacco Use Disorder Services in a Community Health Setting: Support for Enhanced Prescription Practices.

OBJECTIVES: Although public efforts to reduce tobacco use have been successful, millions of US adults currently smoke tobacco. Reducing the public health burden of tobacco use disorder (TUD) and eliminating disparities experienced by underresourced communities requires increased accessibility to services. The goal of this study was to assess whether prescriptions for evidence-based medications for tobacco treatment showed steeper growth rates among community health clinics providing specialty TUD services as compared with treatment as usual. METHODS: Clinic-wide data on prescriptions for smoking cessation pharmacotherapy at 18 primary care or mental health community clinics operated by Los Angeles County were retrieved for 4 years of an ongoing implementation trial. Specialty services included behavioral counseling and medications for tobacco treatment. Descriptive statistics characterized prescriptions rates across clinics and time. Analyses compared the slopes of the changes between intervention groups across time for primary care and mental health sites. RESULTS: Within primary care clinics, the most commonly prescribed smoking cessation medications were nicotine patches, nicotine gum, and varenicline. Throughout the trial, all clinics displayed increased rates of prescribing smoking cessation medications. Analytic results supported overall steeper increases in prescription rates for these medications among clinics randomized to specialty services versus treatment as usual within primary care ( P = 0.020) and mental health sites ( P = 0.004). CONCLUSIONS: This work provides support for the effectiveness of community-based implementation interventions that promote prescribing smoking cessation medications with the potential to reduce health disparities among communities at greater risk for TUD and its consequences.

Ibudilast moderates the effect of mood on alcohol craving during stress exposure.

Neuroinflammation is implicated in the development and maintenance of alcohol use disorder (AUD) and neuroimmune therapeutics show promise in treating AUD. Proinflammatory signaling contributes to progressive elevations in the dysfunction of mood and alcohol craving. The current study sought to examine potential biobehavioral mechanisms of neuroimmune modulation in AUD under experimental conditions. In a community sample of individuals with AUD who completed a placebo-controlled crossover trial of ibudilast, we tested the effect of ibudilast on the relationship between mood states and alcohol craving. Multilevel modeling analyses tested the hypothesis that ibudilast would moderate the effect of positive and negative mood states on alcohol craving during stress and cue exposures. Results revealed that after stress-induction, participants' feelings of depression and happiness were more strongly predictive of their craving for alcohol while taking ibudilast as compared with placebo (ps < .03). These results suggest that with neuroimmune modulation, positive and negative mood states may have a stronger influence on one's desire to drink, such that craving may be more mood dependent. No moderating effect of ibudilast on mood states and craving were observed after alcohol cue exposure. Given the potential of anti-inflammatory treatments to reduce depressive symptomatology, this strengthened relationship between mood and craving under ibudilast might reduce the likelihood of stress-related craving and subsequent drinking over time. Moreover, ibudilast may enhance the benefits of happiness, such that maintaining positive mood in the face of acute stress may attenuate craving. Future trials directly testing the clinical implications of these mechanistic findings are warranted. (PsycInfo Database Record (c) 2022 APA, all rights reserved).

Novel Agents for the Pharmacological Treatment of Alcohol Use Disorder.

Alcohol use disorder (AUD) is a highly prevalent but severely under-treated disorder, with only three widely-approved pharmacotherapies. Given that AUD is a very heterogeneous disorder, it is unlikely that one single medication will be effective for all individuals with an AUD. As such, there is a need to develop new, more effective, and diverse pharmacological treatment options for AUD with the hopes of increasing utilization and improving care. In this qualitative literature review, we discuss the efficacy, mechanism of action, and tolerability of approved, repurposed, and novel pharmacotherapies for the treatment of AUD with a clinical perspective. Pharmacotherapies discussed include: disulfiram, acamprosate, naltrexone, nalmefene, topiramate, gabapentin, varenicline, baclofen, sodium oxybate, aripiprazole, ondansetron, mifepristone, ibudilast, suvorexant, prazosin, doxazosin, N-acetylcysteine, GET73, ASP8062, ABT-436, PF-5190457, and cannabidiol. Overall, many repurposed and novel agents discussed in this review demonstrate clinical effectiveness and promise for the future of AUD treatment. Importantly, these medications also offer potential improvements towards the advancement of precision medicine and personalized treatment for the heterogeneous AUD population. However, there remains a great need to improve access to treatment, increase the menu of approved pharmacological treatments, and de-stigmatize and increase treatment-seeking for AUD.

Sex-dependent effects of alcohol administration on the urge to use cannabis.

Alcohol and cannabis couse is highly prevalent and associated with various negative consequences. The likelihood of same day couse is high, especially among men, however, underlying mechanisms to their couse and its sex-dependent nature remain poorly understood. This study aims to elucidate the effects of controlled alcohol administration on the urge to use cannabis and considers sex-dependent effects. A community sample of non-treatment-seeking heavy drinkers (N = 37, 46% female) reporting cannabis use in the past 6 months completed an alcohol administration paradigm. Participants rated their urge to use cannabis and drink alcohol at baseline and at rising levels of breath alcohol concentration (BrAC). Mixed model analyses examined the effects of BrAC, sex, and their interaction on craving for cannabis. The relationships across urge for cannabis, urge for alcohol, and subjective responses to alcohol were also tested. There was a significant BrAC × Sex interaction on the urge to use cannabis, such that males reported increases in the urge to use cannabis at rising BrACs but females did not. Urge for alcohol significantly predicted urge for cannabis across rising levels of BrAC and this relationship was stronger in males than in females. Lastly, stimulation, but not sedation, during alcohol administration was positively associated with the urge for cannabis. Overall, these results suggest that the pharmacological effects of alcohol on the urge to use cannabis are sex-dependent and that the stimulant effects of alcohol are associated with a higher urge for cannabis. (PsycInfo Database Record (c) 2021 APA, all rights reserved).

Preliminary study of alcohol problem severity and response to brief intervention.

BACKGROUND: Findings have been mixed as to whether brief intervention (BI) is appropriate and effective for individuals with more severe alcohol use problems. Motivation to change drinking has been supported as a mechanism of behavior change for BI. This exploratory study examined aspects of motivation as mechanisms of clinical response to BI and alcohol problem severity as a moderator of treatment effects. METHODS: Non-treatment-seeking heavy drinkers (average age = 35 years; 57% male) were randomized to receive BI (n = 27) or attention-matched control (n = 24). Three indices of motivation to change were assessed at baseline and post-intervention: importance, confidence, and readiness. Moderated mediation analyses were implemented with treatment condition as the focal predictor, changes in motivation as mediator, 1-month follow-up drinks per day as the outcome, and an alcohol severity factor as second-stage moderator. RESULTS: Analysis of importance displayed a significant effect of intervention condition on importance (p < 0.003) and yielded a significant index of moderated mediation (CI - 0.79, - 0.02), indicating that the conditional indirect effect of treatment condition on drinking through importance was stronger for those with higher alcohol severity. For all motivation indices, alcohol severity moderated the effect of post-intervention motivation levels on drinking (p's < 0.05). The direct effect of treatment condition on drinking was not significant in any model. CONCLUSIONS: Findings highlight the relevance of considering one's degree of alcohol problem severity in BI and alcohol screening efforts among non-treatment seeking heavy drinkers. These nuanced effects elucidate both potential mechanisms and moderators of BI response. Trial registration Clinicaltrials.gov: NCT04710095. Registered January 14, 2021-retrospectively registered, https://clinicaltrials.gov/ct2/show/study/NCT04710095 .