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Models of addiction are based on neurobiological, behavioral, and pharmacological studies in animals, but translational support from human studies is limited. Studies are lacking in examining acute responses to alcohol in drinkers with alcohol use disorder (AUD), particularly in terms of relevant intoxicating doses and measurement of stimulating and rewarding effects throughout the breath alcohol concentration (BrAC) time curve. Participants were N = 60 AUD drinkers enrolled in the Chicago Social Drinking Project and examined in three random-order and blinded sessions for subjective and physiological responses to a beverage containing 0.0 g/kg, 0.8 g/kg, and 1.2 g/kg alcohol. BrAC in the alcohol sessions at 60 min was 0.09 g/dL and 0.13 g/dL, respectively. Both doses of alcohol produced significant biphasic effects on subjective measures of stimulation, euphoria, reward (liking and wanting), sedation, and neuroendocrine and cardiovascular factors. Increased pleasurable effects of alcohol were pronounced during the rising limb-to-peak BrAC and sedating effects emerged during the declining limb. Alcohol dose-dependently increased feel drug ratings and rewarding effects at peak BrAC or early declining limb, and physiological responses at the rising limb. Thus, rather than the notion of an overall tolerance, results show an alcohol response phenotype characterized by sensitivity to alcohol's stimulating, rewarding and physiological effects. The results of this study may aid in the conceptualization of alcohol addiction as a disorder characterized by the persistence of enhanced hedonic alcohol responses rather than chronic tolerance and reward deficiency.

INTRODUCTION: There remains a paucity of research quantifying alcohol’s effects in drinkers with alcohol use disorder (AUD), particularly responses to very high alcohol doses (≥0.8 g/kg). As drinkers with AUD frequently engage in very heavy drinking (8-10 drinks/occasion), doses of ≤0.8 g/kg may lack ecological validity. The present study examined the feasibility, tolerability, and safety of administering a very high alcohol dose (1.2 g/kg) to non-treatment seeking AUD participants. METHODS: Sixty-one young-adult AUD drinkers enrolled in the Chicago Social Drinking Project and completed three laboratory sessions at which they consumed a beverage with 1.2 g/kg, 0.8 g/kg, and 0.0 g/kg alcohol. Physiological responses (vital signs, nausea and vomiting, breath alcohol concentrations (BrAC)) were monitored throughout the sessions. After each session, participants completed a next-day survey of substance use, engagement in risky behaviors, and related consequences. RESULTS: Overall, the sample demonstrated good compliance with study procedures; 93% of participants adhered to pre-session alcohol abstinence requirements (indicated by BrAC

Aim The purpose of this brief narrative review is to address the complexities and benefits of extending animal alcohol addiction research to the human domain, emphasizing Allostasis and Incentive Sensitization, two models that inform many pre-clinical and clinical studies. Methods The work reviewed includes a range of approaches, including: a) animal and human studies that target the biology of craving and compulsive consumption; b) human investigations that utilize alcohol self-administration and alcohol challenge paradigms, in some cases across 10 years; c) questionnaires that document changes in the positive and negative reinforcing effects of alcohol with increasing severity of addiction; and d) genomic structural equation modeling based on data from animal and human studies. Results Several general themes emerge from specific study findings. First, positive reinforcement is characteristic of early stage addiction and sometimes diminishes with increasing severity, consistent with both Allostasis and Incentive Sensitization. Second, evidence is less consistent for the predominance of negative reinforcement in later stages of addiction, a key tenant of Allostasis. Finally, there are important individual differences in motivation to drink at a given point in time as well as person-specific change patterns across time. Conclusions Key constructs of addiction, like stage and reinforcement, are by necessity operationalized differently in animal and human studies. Similarly, testing the validity of addiction models requires different strategies by the two research domains. Although such differences are challenging, they are not insurmountable, and there is much to be gained in understanding and treating addiction by combining pre-clinical and clinical approaches.

The concurrent use of both tobacco and alcohol causes substantial disease and early mortality, and smokers who drink heavily tend to be less successful in smoking cessation than smokers who do not. Although varenicline combined with nicotine replacement therapy for smoking cessation has been examined among smokers who do not drink heavily, this combination treatment has not yet been examined among smokers who drink heavily.To determine whether combined treatment with varenicline tartrate and nicotine patch improves continuous abstinence from cigarette smoking among smokers who drink heavily.This double-blind, placebo-controlled, superiority randomized clinical trial evaluated combined treatment with varenicline and nicotine patch compared with placebo and nicotine patch for smoking cessation (primary outcome) and drinking behavior (secondary outcome) among smokers who drink heavily. The clinical trial was conducted at 2 outpatient sites in Chicago, Illinois, with enrollment from March 26, 2018, to February 14, 2020. The 122 participants were recruited from the community via social media and public transit advertisements and equally randomized to the 2 treatment groups, which were stratified by sex and smoking behavior. Eligible participants smoked between 5 and 30 cigarettes per day and drank heavily (14 drinks per week for men or7 drinks per week for women and ≥1 heavy drinking day [defined as5 drinks per occasion for men or4 drinks per occasion for women] per month for the past year) and had a desire to quit smoking.Varenicline tartrate, 1.0 mg, twice daily or matching placebo pills twice daily for 12 weeks. Nicotine patch at manufacturer-recommended doses for 10 weeks and brief individual smoking cessation counseling the week before the quit date and on the quit date.The primary outcome was self-reported continuous cigarette abstinence through weeks 9 to 12; abstinence was biochemically confirmed at the week 12 study visit. Secondary outcomes were the frequency of weekly drinking and weekly heavy drinking during the study period.Among 122 participants (mean [SD] age, 44.0 [12.4] years; 67 men [54.9%]), 61 were randomly assigned to receive combined treatment with varenicline and nicotine patch (varenicline group), and 61 were randomly assigned to receive placebo and nicotine patch (placebo group). A total of 54 participants (44.3%) self-identified as Black, 56 (45.9%) as White, and 12 (9.8%) as other races (including American Indian or Alaska Native, Asian,1 race, and unspecified race). A total of 8 participants (6.6%) self-identified as Hispanic and 114 (93.4%) as non-Hispanic ethnicity. Study retention to 12 weeks was 89%. The intention-to-treat analyses showed higher smoking cessation rates during weeks 9 to 12 in the varenicline group vs the placebo group (27 participants [44.3%] vs 17 participants [27.9%]; odds ratio, 2.20; 95% CI, 1.01-4.80; P = .047) and lower likelihood of relapse throughout treatment in the varenicline group relative to the placebo group (hazard ratio, 0.62; 95% CI, 0.40-0.96; P = .03). Both treatments were well tolerated; however, compared with participants in the placebo group, those in the varenicline group experienced more adverse effects, with 5 participants in the varenicline group discontinuing medication due to adverse effects.In this study, combined treatment with varenicline and nicotine patch was more effective than placebo and nicotine patch for smoking cessation among smokers who drink heavily. The combination treatment had no effect on alcohol consumption, with both groups showing significant reductions. Combination treatment with varenicline and nicotine patch may be a viable option for smokers who drink heavily.ClinicalTrials.gov Identifier: NCT02859142.

Objectives: In this study, we examined whether visual exposure to the heated tobacco product (HTP) IQOS, which was authorized for sale by the US Food and Drug Administration in 2019, acts as a cue to increase cigarette craving and smoking behavior among smokers. Methods: Young adult smokers (N = 105) were randomly assigned to view a video depicting use of either IQOS or bottled water. Main outcomes were changes in cigarette and e-cigarette desire and latency to smoke between the groups. We also examined participants' attitudes about the actors using IQOS and drinking water in the videos. Results: Exposure to the use of IQOS acutely increased observers' ratings of smoking urge and desire for a cigarette and an e-cigarette. The IQOS cue, compared with the water cue, also produced a marginally significant shorter latency to smoke. Participants perceived actors as less likeable and friendly when using IQOS than when drinking water. Conclusions: Results showed that exposure to IQOS produced smoking urge and behavior in young adult smokers, implicating IQOS use as a smoking and vaping cue. As HTPs gain popularity, product impact on passive observers should be included in their risk-benefit profile.

Background Cigarette smokers report increases in smoking urge in response to exposure to electronic nicotine delivery systems (ENDS) and dual users, i.e. smokers who also vape ENDS, may exhibit greater cue reactivity than exclusive smokers. The current investigation examined reactivity to a variety of ENDS cues across a large sample of cigarette smokers and dual ENDS users. Methods Young adult smokers (N = 345; > 5 cigarettes per day) were recruited between 2013–2019 for participation in a series of within-subjects laboratory-based studies. Participants completed surveys before and after exposure to a confederate-delivered control cue (water) and an active cue, including cigarette or ENDS cues ranging from first generation “cigalikes” to a fourth generation “pod-mod”. Main outcomes were post-cue changes in desire for combustible cigarettes and e-cigarettes, and smoking behavior as determined by the smoking latency portion of the Smoking Lapse Paradigm after cue exposure. Results Relative to smokers who do not use ENDS, dual users demonstrated higher baseline desire for ENDS and greater ENDS cue reactivity (across product types) in terms of post-cue increases in smoking urge and shorter latency to smoking choice. In contrast, reactivity to the cigarette cue was similar across groups. Conclusions Dual users show heightened ENDS cue reactivity on smoking urge and behavior relative to never users of ENDS, regardless of the type of ENDS cue. Given their reactivity to both cigarette and ENDS cues, it may be difficult for dual users to transition to exclusive vaping or quit tobacco product use altogether.

RATIONALE: Electronic nicotine delivery systems (ENDS or e-cigarettes) share salient features of combustible smoking, such as inhalation and exhalation behaviors, and evidence indicates that first and second-generation ENDS generalize as smoking cues. The present study examined whether newer, tank-based third-generation ENDS (“mods”) also evoke smoking urges, and whether enhancing the visibility of exhaled aerosol clouds - by increasing the e-liquid vegetable glycerin (VG) content - strengthens the cue salience of ENDS. OBJECTIVES: The objective was to assess the role of exhaled aerosol clouds on ENDS cue potency using a standardized laboratory paradigm designed to mimic real-world exposures METHODS: Using a mixed design, young adult smokers (n=50; mean age 26.5 yrs; ≥5 cigarettes/day) observed a study confederate drinking bottled water (control cue) and vaping an ENDS mod containing e-liquid with either high (73%) or low (0%) VG. Participants completed the Brief Questionnaire on Smoking Urges (BQSU) and visual analog scales (VAS) assessing cigarette and e-cigarette desire pre- and post-cue exposure. RESULTS: Increasing the e-liquid content of VG enhanced the size and visibility of the exhaled aerosol clouds and evoked a greater increase in smoking desire and a more sustained increase in e-cigarette desire relative to the low VG cue. Both cues elicited increases in smoking urges. These results remained after controlling for sex, prior ENDS experience, recent smoking behavior, and menthol preference. CONCLUSIONS: Observation of tank-based ENDS use generalizes as a smoking cue and its cue salience is strengthened by increasing the e-liquid content of VG to enhance the visibility of the exhaled aerosol cloud.

BackgroundExposure to the use of first, second and third generations of electronic cigarettes (e-cigarettes) elicits the desire to vape and smoke among observers, as well as facilitates smoking behaviour. Given the rapid rise in the popularity of the pod mod JUUL, we examined whether observing the use of this device would elicit similar responses in smokers. Exploratory analyses were also conducted to determine whether JUUL can act as a smoking cue for former smokers.MethodsThe sample consisted of 82 young adult participants (62 current smokers and 20 former smokers approximately 1 year smoke free). The study examined their response to observing use of bottled water (control cue) and JUUL (active cue) in a controlled laboratory paradigm. Both cues were delivered by a trained study confederate under the guise of a social interaction task, and participants completed mood and desire and urge surveys precue and postcue exposures.ResultsIn current smokers, exposure to the JUUL cue increased smoking urge and desire for a cigarette, mod/vape pen and JUUL, and two-thirds chose to smoke in the behavioural analogue task. In former smokers, the JUUL cue evoked modest and transient increases in desire for a cigarette and JUUL.ConclusionsThe use of JUUL affects the user and elicits responses in observers; this study is the first to demonstrate that exposure to JUUL use may act as a smoking cue and exposure to JUUL use may affect tobacco control efforts.

Introduction Passive exposure to the use of electronic nicotine delivery systems (ENDS or e-cigarettes) has been shown to generalize as a smoking cue. As young adult women in particular are increasingly targeted by ENDS distributors, the present study examined whether passive exposure to the use of a female-marketed ENDS product selectively enhanced smoking urge, cigarette and e-cigarette desire, and smoking behavior among women (vs men) smokers. Methods Using a mixed design, young adult smokers (n = 64; mean age 28.2 yrs.; ≥5 cigarettes/day) observed a study confederate drink bottled water (control cue) and then vape a female-marketed tank-based ENDS (active cue). Main measures were the Brief Questionnaire of Smoking Urges (BQSU) and visual analog scales (VAS) for cigarette and e-cigarette desire pre- and post-cue exposure, followed by a smoking latency task. Results Compared to the control cue, the female-marketed ENDS cue increased smoking urge and desire for cigarettes and e-cigarettes to a similar extent in women and men. It also affected subsequent smoking behavior similarly between the sexes, with 68% of men and 58% of women opting to smoke (vs. obtaining monetary reinforcers). Conclusions Both women and men were sensitive to the use of the female-marketed ENDS as a smoking cue. Consistent with prior work by our group, findings demonstrate the cue salience of ENDS, which may be attributable to the aspects of vaping that resemble traditional smoking (e.g. hand-to-mouth and inhalation and exhalation behaviors).

Striatal dopamine plays a critical role in the expression of goal-directed behaviors and in mediating the reinforcing effects of various drugs of abuse, including alcohol. Techniques such as microdialysis and fast-scan voltammetry, which enable monitoring molecules in the extracellular space of freely behaving animals, have permitted the study of ethanol’s effects on dopamine activity in striatal subregions. Animal models have demonstrated that alcohol produces differential effects on extracellular dopamine, depending on the route of administration, dose, and subregion. Clinical studies using positron emission tomography have generally supported the findings from animal models, showing that the striatal dopamine response to acute alcohol and alcohol-related cues varies by subregion and drinking status (e.g., social, heavy, or alcoholic). While decades of research have provided an abundance of data, the implications of alcohol’s effects on extracellular striatal dopamine continues to be investigated.

Background Preclinical and clinical evidence suggest that the neuropeptide oxytocin may be of value in treating alcohol use disorder, by either reducing the rewarding effects of alcohol or reducing negative affect induced by alcohol withdrawal. However, the effect of a single dose of oxytocin on subjective and psychomotor responses to alcohol in social drinkers is not known. Methods This study examined the effect of intranasal oxytocin on subjective, behavioral, and physiological responses to a moderate dose of alcohol (0.8 g/kg) in young adult social drinkers. Participants (N = 35) completed 2 study sessions at which they consumed beverages containing alcohol (ALC; N = 20) or placebo (NoALC; N = 15) in combination with intranasal oxytocin (40 IU with a 20 IU booster) or placebo. They received oxytocin at one session and placebo at the other session (order counterbalanced) 20 minutes before consuming beverages. Subjective mood and drug effects ratings, heart rate and blood pressure, and 4 behavioral tasks (flanker task, digit span, go/no-go, and pursuit rotor) were the primary outcome measures. Results ALC produced its expected subjective and behavioral effects; including feeling intoxicated and impaired performance on the digit span and go/no-go tasks. Oxytocin alone had no significant subjective or physiological effects, and it did not affect responses to alcohol on any measure. Conclusions We can conclude that, under these conditions, a single dose of intranasal oxytocin does not alter the effects of acute alcohol in healthy young adult social drinkers. Further research is needed to determine whether oxytocin alters responses to alcohol under different conditions, and to determine its potential as an aid in treatment for substance use disorders.