Rationale

Alcohol use disorder (AUD) is associated with steeper delay discounting rates; however, it is unknown whether substance co-use, particularly cannabis use, has an additive effect on discounting rates among heavy drinkers. Furthermore, it is unclear whether substance co-use and delay discounting are independently associated with AUD severity.

Objectives

The purpose of this study was to determine whether alcohol, tobacco, and cannabis co-use impacts delay discounting rates. We also sought to determine whether substance co-use and delay discounting were associated with AUD symptom counts.

Methods

The study sample was culled from several human laboratory studies and consisted of 483 heavy drinking individuals who completed a baseline visit (prior to experimental procedures). Participants were divided into groups based on self-reported alcohol, tobacco, and cannabis use during the past 30 days: alcohol only (n = 184), alcohol + cigarettes (n = 89), alcohol + cannabis (n = 82), and tri-use (n = 128). We examined discounting rates across the 4 groups and used multiple linear regression to test whether co-use and delay discounting were associated with AUD symptoms.

Results

After adjusting for covariates, individuals in the alcohol + cannabis group and the tri-use group had steeper discounting rates relative to the alcohol-only group. In addition, tri-use and delay discounting rates were independently correlated with a greater number of AUD symptoms.

Conclusions

Delay discounting rates were significantly greater among subgroups reporting cannabis use providing partial support for an additive effect, while also highlighting the importance of co-use substance type. Both tri-use and delay discounting were associated with greater AUD severity, which may provide relevant intervention targets.

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.

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.

Background

Alcohol use disorder (AUD) is a chronic and relapsing condition for which current pharmacological treatments are only modestly effective. The development of efficacious medications for AUD remains a high research priority with recent emphasis on identifying novel molecular targets for AUD treatment and to efficiently screen new compounds aimed at those targets. Ibudilast, a phosphodiesterase inhibitor, has been advanced as a novel addiction pharmacotherapy that targets neurotrophin signaling and neuroimmune function.

Methods

This study will conduct a 12-week, double-blind, placebo controlled randomized clinical trial of ibudilast (50 mg BID) for AUD treatment. We will randomize 132 treatment-seeking men and women with current AUD. We will collect a number of alcohol consumption outcomes. Primary among these is percent heavy drinking days (PHDD); secondary drinking outcomes include drinks per day, drinks per drinking day, percent days abstinent, percent subjects with no heavy drinking days, and percent subjects abstinent, as well as measures of alcohol craving and negative mood. Additionally, participants will have the option to opt-in to a neuroimaging session in which we examine the effects of ibudilast on neural activation to psychosocial stress and alcohol cues. Finally, we will also collect plasma levels of proinflammatory markers, as well as subjective and biological (salivary cortisol) markers of stress response.

Discussion

This study will further develop ibudilast, a safe and promising novel compound with strong preclinical and clinical safety data for AUD, and will probe biological mechanisms underlying the effects of Ibudilast on stress, neuroinflammation, and alcohol cue-reactivity and craving. If ibudilast proves superior to placebo in this study, it will set the stage for a confirmatory multi-site trial leading to FDA approval of a novel AUD treatment.

Trial registration

ClinicalTrials.gov NCT03594435 "Ibudilast for the Treatment of Alcohol Use Disorder". Registered on 20 July 2018.

This study examines associations between two measures of impulsivity and brain response to alcohol taste cues. Impulsivity is both a risk factor for and a consequence of alcohol use and misuse. Frontostriatal circuits are linked to both impulsivity and addiction-related behaviors, including response to alcohol cues. Non-treatment-seeking heavy drinkers (n = 55) completed (i) an fMRI alcohol taste cue-reactivity paradigm; (ii) the monetary choice questionnaire (MCQ), a measure of choice impulsivity where participants choose between smaller, sooner rewards and larger, delayed rewards; (iii) and the UPPS-P Impulsive Behavior Scale, a self-report measure assessing five impulsivity factors. General linear models identified associations between neural alcohol taste cue-reactivity and impulsivity, adjusting for age, gender, and smoking status. Self-reported sensation seeking was positively associated with alcohol taste cue-elicited activation in frontostriatal regions, such that individuals who reported higher sensation seeking displayed greater neural response to alcohol taste cues. Conversely, delay discounting was negatively associated with activation in frontoparietal regions, such that individuals who reported greater discounting showed less cue-elicited activation. There were no significant associations between other self-reported impulsivity subscales and alcohol taste cue-reactivity. These results indicate that sensation seeking is associated with reward responsivity, while delay discounting is associated with recruitment of self-control circuitry.

Studies of inflammation in alcohol use disorder (AUD) are overwhelmingly preclinical, and translation to clinical samples is necessary. Endotoxin administration has been used successfully in humans to study mood disorders, offering a translational, reliable and safe model that may be validated in AUD research. We argue for the use of endotoxin challenge to elucidate the interplay between AUD and inflammation.

Background

Ibudilast, a novel neuroimmune modulator being studied to treat alcohol use disorder (AUD), was shown in a randomized controlled trial (NCT03489850) to reduce ventral striatum (VS) activation in response to visual alcohol cues. The present study extended this finding by probing the effects of ibudilast on alcohol cue-elicited functional connectivity (i.e., temporally correlated activation) with the VS seed. The study also tests the association between functional connectivity and alcohol use during the trial.

Methods

Non-treatment-seeking participants (n = 45) with current alcohol use disorder were randomized to receive twice-daily dosing with either ibudilast (50 mg; n = 20) or placebo (n = 25). Upon reaching the target dosagee of the medication or placebo, participants completed a functional neuroimaging alcohol cue reactivity paradigm. Drinks per drinking day were assessed at baseline and daily during the 2-week trial.

Results

Ibudilast reduced alcohol cue-elicited functional connectivity between the VS seed and reward-processing regions including the orbitofrontal and anterior cingulate cortices compared with placebo (p < 0.05). Cue-elicited functional connectivity was correlated with drinks per drinking day (R²  = 0.5351, p < 0.001), and ibudilast reduced this association in similar reward-processing regions compared with placebo.

Conclusions

Ibudilast's effects on drinking outcomes may be related to the attenuation of functional connectivity in frontostriatal circuits related to reward processing. These results provide an important proof of concept for this novel pharmacotherapy and support the clinical utility of incorporating neuroimaging-and especially functional connectivity-analyses into medication development.

Aims

The current study examined the association between pain catastrophizing and alcohol cue-elicited brain activation in individuals with alcohol use disorder (AUD).

Methods

Non-treatment seeking heavy drinkers with AUD (n = 45; 28 males) completed self-report measures of pain catastrophizing and alcohol use/problems as part of a clinical trial of the neuroimmune modulator ibudilast. Participants were randomized to either placebo (n = 25) or ibudilast (n = 20) and completed an functional magnetic resonance imaging (fMRI) scan to assess neural activation to alcohol cues 1 week into the medication trial. Multiple linear regression examined whether pain catastrophizing predicted cue-induced activation in a priori regions of interest, namely the dorsal and ventral striatum (VS). An exploratory whole-brain analysis was conducted to assess the relationship between pain catastrophizing and neural alcohol cue reactivity.

Results

Pain catastrophizing predicted greater cue-induced activation in the dorsal (b = 0.006; P = 0.03) but not VS controlling for medication. Pain catastrophizing was positively associated with neural activation to alcohol cues in regions including the bilateral thalamus, left precuneus and left frontal pole.

Conclusion

Greater pain catastrophizing is associated with greater cue-induced neural activation in brain regions sub-serving habits and compulsive alcohol use. These findings provide initial support for a neural mechanism by which pain catastrophizing may drive alcohol craving among individuals with AUD.

Background

Alcohol use disorder (AUD) is heterogenous. One approach to parsing this heterogeneity is to phenotype individuals by their underlying motivation to drink, specifically drinking for reward (i.e., positive reinforcement) or for relief (i.e., negative reinforcement/normalizing). Reward- versus relief-motivated behavior is thought to be associated with a shift from ventral to dorsal striatal (DS) signaling. The present study examined whether reward and relief drinking were differentially associated with other clinical characteristics and with alcohol cue-elicited activation of the ventral and dorsal striatum.

Methods

Non-treatment-seeking heavy drinkers (N = 184; 61 female, 123 male) completed the UCLA Reward, Relief, Habit Drinking Scale (RRHDS) and the Reasons for Heavy Drinking Questionnaire (RHDQ), to categorize drinking motivation. Measures of alcohol use, alcohol problems, mood, and craving were also collected. A subset of participants (N = 45; 17 female, 28 male) also completed a functional neuroimaging alcohol cue reactivity task.

Results

RRHDS-designated relief/habit drinkers scored lower than reward drinkers on the RHDQ Reinforcement subscale (p = 0.04) and higher on the RHDQ Normalizing subscale (p = 0.004). Relief/habit drinkers also demonstrated greater AUD severity on a host of clinical measures. Relief/habit drinkers displayed higher cue-elicited DS activation compared with reward drinkers (p = 0.04), while ventral striatal cue-elicited activation did not significantly differ between groups.

Conclusions

Our findings support and extend the differentiation of reward from relief/habit-motivated drinking and suggest that differences in DS response to conditioned alcohol cues may underlie this distinction. Elucidating neurobiological and clinical differences between these subtypes may facilitate treatment matching and precision medicine for AUD.

Background

Risky decision-making is an important facet of addiction. Individuals with alcohol dependence show abnormalities in gambling and other risk-taking tasks. In one such measure, the Balloon Analogue Risk Task (BART), participants sequentially choose to pump a virtual balloon to increase potential reward while the risk of explosion increases, or to cash-out and take earnings. In a prior study, alcohol-dependent participants differed from controls in brain activation during decision-making on the BART, but the relationship between risk/reward magnitude and brain activation was not studied, nor were participants compared to controls. Here we compared the degree to which risk and magnitude of reward influenced brain activation in alcohol-dependent participants vs. controls during decision-making on the BART.

Methods

Thirty-two participants (16 alcohol-dependent, 16 control; 5 females/group) performed the BART during fMRI. A parametric analysis tested for a relationship between risk/reward magnitude and activation in rDLPFC and bilateral striatum regions of interest when participants chose to take risk or to cash out. An exploratory whole-brain voxel-wise analysis of mean activation during pumping, cash-out, and explosion events was also conducted.

Results

Compared with controls, alcohol-dependent participants displayed less modulation of activation in the rDLPFC when taking risk. Exploratory analyses found that alcohol-dependent participants showed less activation than controls during explosions in a cluster including the insula. No differences were seen in striatal activation.

Conclusions

Insensitivity of the rDLPFC to risk and of the insula to loss may contribute to decision-making deficits in alcohol dependence.