Predictors of Substance Use Initiation by Early Adolescence.

OBJECTIVE: Substance use initiation during early adolescence is associated with later development of substance use and mental health disorders. This study used various domains to predict substance use initiation, defined as trying any nonprescribed substance (e.g., alcohol, tobacco, cannabis), by age 12, using a large longitudinal data set. METHODS: Substance-naive youths from the Adolescent Brain Cognitive Development Study (ages 9-10; N=6,829) were followed for 3 years. A total of 420 variables were examined as predictors of substance use initiation, using a penalized logistic regression with elastic net; domains spanned demographic characteristics, self and peer involvement with substance use, parenting behaviors, mental and physical health, culture and environment, hormones, neurocognitive functioning, and structural neuroimaging. RESULTS: By age 12, 982 (14.4%) children reported substance initiation, with alcohol being the most common. Models with only self-report predictors had similar prediction performance to models adding hormones, neurocognitive factors, and neuroimaging predictors (AUCtest=0.66). Sociodemographic factors were the most robust predictors, followed by cultural and environmental factors, physical health factors, and parenting behaviors. The top predictor was a religious preference of Mormon (coefficient=-0.87), followed by a religious preference for Jewish (coefficient=0.32), and by Black youths (coefficient=-0.32). CONCLUSIONS: Sociodemographic variables were the most robust predictors of substance use initiation. Adding resource-intensive measures, including hormones, neurocognitive assessment, and structural neuroimaging, did not improve prediction of substance use initiation. The application of these large-scale findings in clinical settings could help to streamline and tailor prevention and early intervention efforts.

Adolescent alcohol use is associated with differences in the diversity and composition of the oral microbiome.

BACKGROUND: Adolescence is a sensitive stage of oral microbial development that often coincides with the initiation and escalation of alcohol use. Thus, adolescents may be particularly susceptible to alcohol-induced alterations in the oral microbiome, though minimal research has been done in this area. Understanding the connection between the oral microbiome and alcohol use during adolescence is important to understand fully the biological consequences of alcohol use to mitigate potential adverse outcomes. METHODS: Saliva samples were collected from adolescents aged 17-19 who used alcohol heavily (n = 21, 52.4% female) and those who did not use alcohol or any other substances (n = 18, 44.4% female). We utilized 16S rRNA sequencing to examine differences in microbial diversity and composition between the groups. RESULTS: For alpha diversity, evenness was significantly lower in the drinking group than the control group as indicated by Pielou's evenness, Shannon, and Simpson indices. There were no statistically significant findings for beta diversity. Differential abundance analyses revealed higher abundances of Rothia and Corynebacterium in the alcohol-using group using both centered-log-ratio and relative abundance normalization. These genera are known for their high capacity to convert alcohol into acetaldehyde, a toxic metabolite reported to play a role in the neurobiological effects of alcohol. An unclassified Clostridia UCG-014, Streptobacillus, Comamonas, unclassified Lachnospiraceae, and Parvimonas were also identified as significantly different between groups when using only one of the normalization techniques. CONCLUSIONS: This is the first study designed specifically to compare the oral microbiome of adolescents who use alcohol with that of control participants. Our findings reveal distinct alcohol-related differences in microbial composition and taxon abundance, emphasizing the importance of understanding the impact on the oral microbiome of alcohol use during adolescence. Because the oral microbiome is malleable, this study provides foundational work for future prevention and intervention studies.

Multi-modal neuroimaging reveals differences in alcohol-cue reactivity but not neurometabolite concentrations in adolescents who drink alcohol.

BACKGROUND: The objective of this multi-modal neuroimaging study was to identify neuroscience-informed treatment targets for adolescent alcohol use disorder (AUD) by examining potential neural alterations associated with adolescent alcohol use. METHODS: Adolescents (ages 17-19) who heavily used (n=49) or did not use alcohol (n=22) were recruited for a multi-modal neuroimaging protocol, including proton magnetic resonance spectroscopy within the dorsal anterior cingulate cortex (dACC) and an fMRI alcohol cue-reactivity task. The alcohol cue-reactivity task was analyzed across 11 a priori regions-of-interest (ROI), including the dACC, and in an exploratory whole-brain approach. Correlations were run between neurometabolite levels and alcohol cue-reactivity in the dACC. RESULTS: There were no significant group differences in absolute neurometabolite concentrations. Compared to the control group, the alcohol-using group exhibited heightened alcohol cue reactivity in the left amygdala ROI (p=0.04). The whole-brain approach identified higher alcohol cue reactivity in the alcohol-using group compared to controls in the amygdala and occipital regions, and lower reactivity in the parietal lobe. Whole-brain sex effects were noted, with females displaying higher reactivity regardless of group. No significant correlations were found between neurometabolite levels and alcohol cue-reactivity in the dACC. CONCLUSIONS: The null neurometabolic findings may be due to age, relatively low severity of alcohol use, and non-treatment-seeking status of the participants. Females showed overall higher reactivity to alcohol cues, indicating a sex effect regardless of alcohol use history. Higher amygdala reactivity in alcohol-using adolescents suggests that emotional processing related to alcohol cues may be a useful target for future adolescent AUD interventions.

The adolescent and young adult microbiome and its association with substance use: a scoping review.

AIMS: The microbiome is a critical factor in health throughout human development. The aims of this scoping review are to (i) elucidate the differences between the youth (post-natal day 21-65 for rodents, 2-7 years for non-human primates, and 10-25 years for humans) microbiome with other life stages and (ii) identify youth-specific microbial changes associated with substance use. METHODS: Peer-reviewed studies published up to May 2023 were identified in PubMed and SCOPUS and included gut and oral microbiome studies from rodents, non-human primates, and humans (N = 1733). Twenty-six articles were determined eligible based on inclusion criteria (aim 1: n = 19, aim 2: n = 7). RESULTS: The adolescent and young adult oral and gut microbiomes are distinct compared to other life stages, within both non-human and human models. While there is limited research in this area, the microbiome appears to be vulnerable to substance use exposure earlier in life, including substances commonly initiated and escalated during adolescence and young adulthood (i.e. alcohol, cannabis, and tobacco). CONCLUSIONS: Studies across the lifespan indicate that adolescence and young adulthood are distinct periods of development, where the microbiome is sensitive to exposures, including substance use. There is a need for more studies focused on the adolescent and young adult microbiome and substance use, as well as focused on the oral microbiome during this developmental period. Understanding the gut and oral microbiome during adolescence and young adulthood may provide insight into the pathophysiology of substance use disorders.

Pairwise comparisons of three medication adherence outcomes in adolescents who use alcohol.

BACKGROUND: Accurate assessment of medication adherence is important for understanding pharmacotherapy outcomes across all phases of adolescent substance use disorder (SUD) clinical trials. The objective of this study was to describe and assess the pairwise concordance between three commonly used non-biological medication adherence assessment methods in adolescents who use alcohol to inform the selection of medication adherence measures for use in future youth SUD trials. METHODS: Participants (N = 32, 17-19-years-old) took N-acetylcysteine and placebo, in a randomized cross-over design, for 10 days each. Medication adherence was assessed (20 days total) via pill count, medication videos submitted twice daily, and the Medication Event Monitoring System (MEMS®). Lin's Concordance Correlation Coefficient (CCC) assessed concordance and Bland-Altman plots are reported. Linear mixed-effects models with main effects of medication, treatment block (first medication, second medication), and sequence were also run. RESULTS: Medication videos yielded the lowest (64%) and pill count yielded the highest (89%) adherence estimates. CCC values indicated poor correspondence, except between pill count and MEMS. The Bland-Altman plots showed good pairwise agreement between all methods. Linear mixed-effects models indicated a difference between the first and second cross-over medication, with adherence estimates being lower for the second medication, regardless of whether it was N-acetylcysteine or placebo. CONCLUSIONS: The study yielded important and practical information. First, incorporating more than one method of adherence assessment may capture estimated floor and ceiling adherence in the absence of a biological marker. This is particularly relevant for remote or hybrid studies where bio-marker collection is challenging. Selection of the assessment methods will depend on study goals. Second, the continuation of medication adherence research can benefit each phase of clinical trials and inform rigorous pharmacotherapy evaluation.

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.

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.

N-acetylcysteine does not alter neurometabolite levels in non-treatment seeking adolescents who use alcohol heavily: A preliminary randomized clinical trial.

Current treatments for adolescent alcohol use disorder (AUD) are mainly psychosocial and limited in their efficacy. As such, pharmacotherapies are being investigated as potential adjunctive treatments to bolster treatment outcomes. N-acetylcysteine is a promising candidate pharmacotherapy for adolescent AUD because of its tolerability and demonstrated ability to modulate glutamatergic, GABAergic, and glutathione systems. The primary objective of this double-blind, placebo-controlled, within-subjects crossover preliminary investigation was to measure potential changes within glutamate + glutamine (Glx), GABA, and glutathione levels in the dorsal anterior cingulate cortex (dACC) using proton magnetic resonance spectroscopy during 10-days of N-acetylcysteine (1200 mg twice daily) compared to 10-days of placebo in non-treatment seeking adolescents who use alcohol heavily (N = 31; 55% female). Medication adherence was confirmed via video. Effects on alcohol use were measured using Timeline Follow-Back as an exploratory aim. Linear mixed effects models controlling for baseline metabolite levels, brain tissue composition, alcohol use, cannabis use, and medication adherence found no significant differences in Glx, GABA, or glutathione levels in the dACC after N-acetylcysteine compared to placebo. There were also no measurable effects on alcohol use; however, this finding was underpowered. Findings were consistent in the subsample of participants who met criteria for AUD (n = 19). The preliminary null findings in brain metabolite levels may be due to the young age of participants, relatively low severity of alcohol use, and non-treatment seeking status of the population investigated. Future studies can use these findings to conduct larger, well-powered studies within adolescents with AUD.

ADHD symptoms and smoking outcomes in a randomized controlled trial of varenicline for adolescent and young adult tobacco cessation.

BACKGROUND: Most adult daily smokers try their first cigarette during adolescence. Attention-Deficit Hyperactivity Disorder (ADHD) in adolescents is associated with increased risk for cigarette smoking. The impact of ADHD symptoms on smoking cessation among adolescents has been less well-studied. The present secondary data analysis from a clinical trial of varenicline examined ADHD symptoms as a moderator of smoking cessation in adolescents and young adults. METHODS: The double-blind, placebo-controlled trial included treatment-seeking daily cigarette smokers ages 14 - 21 (N = 157) randomized to receive a 12-week course of varenicline or placebo, added to weekly smoking cessation counseling. At pre-treatment assessment, participants were administered a self-report measure of ADHD symptoms, the ADHD - Rating Scale (ADHD-RS). High (≥5) versus low (<5) and continuous ADHD-RS symptom counts in both hyperactive/impulsive (HI) and inattention (IA) domains were examined as predictors of smoking outcomes. RESULTS: Participants with high IA symptoms at baseline were less likely to achieve 7-day point prevalence abstinence (PPA) at weekly visits (p = .001) during active treatment and end-of-treatment (p = .002) compared to those with low IA symptoms. In contrast, high HI symptoms did not predict differences in 7-day PPA or end-of-treatment abstinence versus low symptoms (p's ≥ .07). These findings were not modified by varenicline versus placebo treatment assignment. CONCLUSIONS: ADHD IA symptoms were associated with poorer cessation outcomes among adolescent smokers. These findings warrant additional investigation into how ADHD symptoms may be accounted for in smoking cessation interventions for adolescents and young adults.

Characteristics associated with treatment seeking for smoking cessation among heavy-drinking research participants.

Objective: Treatment seeking for smoking cessation has tremendous clinical implications with the potential to reduce tobacco-related morbidity and mortality. The present study seeks to elucidate clinical variables that distinguish treatment seeking versus non-treatment seeking status for smoking cessation in a large sample of heavy drinking smokers using data-driven methods. Materials and methods: This secondary data analysis examines n = 911 (n = 267 female) individuals who were daily smokers and heavy drinkers (≥ 7 drinks per week for women, ≥ 14 for men) that were enrolled in either a treatment-seeking study (N = 450) or a non-treatment seeking study (N = 461) using identical pharmacotherapies. Participants completed measures of demographics, alcohol and cigarette use, alcohol craving, the Barratt Impulsiveness Scale (BIS-11), and the Wisconsin Inventory of Smoking Dependence Motives (WISDM-68). These measures were used in a random forest model to identify predictors of treatment seeking status. Results: The top variables of importance in identifying treatment seeking status were: age, drinks per drinking day, cigarettes per smoking day, BIS-11 cognitive impulsivity, WISDM social environmental goads, WISDM loss of control, WISDM craving, and WISDM tolerance. Age and drinks per drinking day were two of the most robust predictors, followed by measures of nicotine craving and tolerance. Conclusion: Individuals who are daily smokers and consume more drinks per drinking day are less likely to belong to the smoking cessationtreatment-seeking group. Targeting heavy drinking smokers, particularly younger individuals, may be necessary to engage this group in smoking cessation efforts and to reduce the burden of disease of nicotine dependence earlier in the lifespan.

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).

Brain metabolite alterations related to alcohol use: a meta-analysis of proton magnetic resonance spectroscopy studies.

Alcohol misuse and alcohol use disorder (AlUD) have neurobiological consequences. This meta-analysis of proton magnetic resonance spectroscopy (MRS) studies aimed to assess the differences in brain metabolite levels in alcohol misuse and AUD relative to controls (PROSPERO registration: CRD42020209890). Hedge's g with random-effects modeling was used. Sub-group and meta-regression techniques explored potential sources of demographic and MRS parameter heterogeneity. A comprehensive literature review identified 43 studies, resulting in 69 models across gray and white matter (GM, WM). Lower N-acetylaspartate levels were found in frontal, anterior cingulate cortex (ACC), hippocampal, and cerebellar GM, and frontal and parietal WM, suggesting decreased neuronal and axonal viability. Lower choline-containing metabolite levels (all metabolites contributing to choline peak) were found in frontal, temporal, thalamic, and cerebellar GM, and frontal and parietal WM, suggesting membrane alterations related to alcohol misuse. Lower creatine-containing metabolite levels (Cr; all metabolites contributing to Cr peak) were found in temporal and occipital cortical GM, while higher levels were noted in midbrain/brainstem GM; this finding may have implications for using Cr as an internal reference. The lack of significant group differences in glutamate-related levels is possibly related to biological and methodological complexities. The few studies reporting on GABA found lower levels restricted to the ACC. Confounding variables were age, abstinence duration, treatment status, and MRS parameters (echo time, quantification type, data quality). This first meta-analysis of proton MRS studies consolidates the numerous individual studies to identify neurometabolite alterations within alcohol misuse and AUD. Future studies can leverage this new formalized information to investigate treatments that might effectively target the observed disturbances.

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 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. Target effect sizes were calculated for each outcome and a meta-regression was conducted to test the effects of required pre-trial abstinence, required pre-trial AUD diagnosis, and their interaction on effect sizes. A sub-analysis was conducted on trials, which included FDA-approved medications for AUD. RESULTS: In total, 118 studies testing 19 medications representing 21,032 treated participants were included in the meta-regression analysis. There was no significant effect of either predictor on abstinence or no heavy drinking outcomes in the full analysis or in the sub-study of FDA-approved medications. CONCLUSION: By examining these design features in a quantitative, rather than qualitative, fashion the present study advances the literature and shows that requiring AUD diagnosis or requiring pre-trial abstinence do not impact the likelihood of a significant medication effect in the trial.

The relationship between drinking and smoking in a clinical trial for smoking cessation and drinking reduction.

Heavy drinking smokers experience poorer smoking cessation outcomes. Less is known about the relationship between drinking and smoking among those who are trying to reduce or abstain from both substances. The present study used data from 115 heavy drinking smokers who completed a 12-week clinical trial comparing varenicline alone (1 mg/bid) versus varenicline (1 mg/bid) plus naltrexone (50 mg/day) for smoking cessation and drinking reduction. We tested whether drinking outcomes mediated the relationship between medication and cigarettes per smoking day (CPSD) during the active medication phase (Week 4, 8, and 12) and follow-up phase (Week 16 and 26). CPSD and drinking variables predicted respective use at subsequent time points (p's < .0001). Results revealed a nonsignificant mediation effect of our primary mediator drinks per drinking day (DPDD) at Week 12: 95% CI = [-1.03, .58] and Week 26: 95% CI = [-.09, .51], and our secondary mediators of percent heavy drinking days (PHDDs) and percent days abstinent (PDA) at Week 12: 95% CI = [-.14, .35] and Week 26: 95% CI = [-.15, .41]. Cross-lagged effects (e.g., Week 4 drinking predicting Week 8 smoking) were nonsignificant between DPDD and CPSD (p's ≥ .07), and PHDD and PDA and CPSD that met our a priori cutoff (p's ≥ .02). There was a significant relationship between drinking and smoking concurrently indicated by fixed error covariances (CPSD and DPDD: p < .01; CPSD and PDA p = .01). Our findings highlight an association between drinking and smoking behaviors, respectively, across the span of 6 months. (PsycInfo Database Record (c) 2022 APA, all rights reserved).

Alcohol use disorder severity moderates clinical response to varenicline.

BACKGROUND: In a multisite clinical trial, varenicline was effective in reducing drinking in both smoking and non-smoking patients with alcohol dependence. Because alcohol use disorder (AUD) is heterogeneous, research aimed at characterizing features associated with treatment response could advance personalized pharmacotherapy. The current study examined the utility of a multidimensional assessment of AUD severity to identify responders to varenicline treatment. METHODS: The study utilized data from a 13-week, Phase 2, randomized, double-blind, placebo-controlled, multisite trial of varenicline in 200 alcohol-dependent patients. Four hypothesized measures of AUD severity (i.e., DSM-IV criterion count, withdrawal, craving, and alcohol-related consequences) were combined into a single severity factor. A series of multilevel models that included the severity factor were conducted to examine its effects on treatment outcomes. RESULTS: All hypothesized indices of AUD severity loaded significantly onto a singular severity factor. Among low-severity groups, varenicline treatment significantly reduced drinking (i.e., percent heavy drinking days, drinks per day, and drinks per drinking day) and, in the lowest severity group, it improved the mental health component of quality of life more than placebo. The most severe group showed no differences between the varenicline and placebo groups on drinking or quality of life measures. CONCLUSIONS: Treatment response to varenicline may be greater among individuals with less-severe AUD, as evidenced by both reductions in drinking outcomes and improvements in psychosocial functioning.

Combined varenicline and naltrexone attenuates alcohol cue-elicited activation in heavy drinking smokers.

BACKGROUND: There is a strong bidirectional relationship between the use of alcohol and cigarettes which results in various challenges for treating those who co-use both substances. While varenicline and naltrexone each have FDA-approval for nicotine and alcohol use disorder, respectively, there is evidence that their clinical benefit may extend across the two disorders. Critically, the effect of combined varenicline and naltrexone on neural reactivity to alcohol cues among heavy drinking smokers has not yet been studied. Probing the effect of the combination therapy on alcohol cue-reactivity may give insight to the mechanisms underlying its efficacy. METHODS: Forty-seven heavy drinking smokers enrolled in two medication studies were randomized to receive varenicline alone (n = 11), varenicline plus naltrexone (n = 11), or placebo (n = 25). Participants completed an fMRI alcohol cue-reactivity task and rated their in-scanner alcohol craving. Whole-brain analyses examined the effect of medication on alcohol cue-elicited neural response. RESULTS: Varenicline plus naltrexone attenuated alcohol cue-elicited activation in mesolimbic regions relative to varenicline alone and to placebo (Z > 2.3, p < 0.05). The combination varenicline and naltrexone group also endorsed lower in-scanner alcohol craving relative to varenicline alone group (p = 0.04). CONCLUSIONS: These findings provide evidence for the benefit of combined therapy of varenicline and naltrexone over varenicline alone for the attenuation of alcohol cue-elicited neural activation. This study provides a preliminary proof-of-mechanism for this combination pharmacotherapy and suggests that naltrexone may be driving the reductions in cue-elicited alcohol craving in the brain. Further clinical studies using the combined therapy to treat heavy drinking smokers are warranted.

Efficacy of Combining Varenicline and Naltrexone for Smoking Cessation and Drinking Reduction: A Randomized Clinical Trial.

OBJECTIVE: Pharmacological treatments that can concomitantly address cigarette smoking and heavy drinking stand to improve health care delivery for these highly prevalent co-occurring conditions. This superiority trial compared the combination of varenicline and naltrexone against varenicline alone for smoking cessation and drinking reduction among heavy-drinking smokers. METHODS: This was a phase 2 randomized double-blind clinical trial. Participants (N=165) who were daily smokers and drank heavily received either 2 mg/day of varenicline plus 50 mg/day of naltrexone or 2 mg/day of varenicline plus matched placebo pills for 12 weeks. Primary outcomes were 7-day point prevalence of nicotine abstinence (bioverified by a breath CO reading ≤5 ppm) at the 26-week follow-up and number of drinks per drinking day during the 12-week treatment phase. RESULTS: Smoking abstinence at week 26 was significantly higher in the varenicline plus placebo condition than in the varenicline plus naltrexone condition (N=37 [45.1%] compared with N=22 [26.5%]). For drinks per drinking day, there was a medication effect favoring the combination of varenicline and naltrexone over varenicline alone across the 12-week treatment phase, although it did not meet the significance threshold. CONCLUSIONS: These findings suggest that smoking cessation and drinking reduction can be concomitantly targeted with pharmacotherapy and that while varenicline alone may be sufficient as a smoking cessation aid in heavy-drinking smokers, the combination of varenicline and naltrexone may confer benefits with regard to drinking outcomes, particularly during the 12-week period of active medication treatment.