scholarly journals Effects of topiramate on neural responses to alcohol cues in treatment-seeking individuals with alcohol use disorder: preliminary findings from a randomized, placebo-controlled trial

2021 ◽  
Author(s):  
Reagan R. Wetherill ◽  
Nathaniel Spilka ◽  
Kanchana Jagannathan ◽  
Paige Morris ◽  
Danielle Romer ◽  
...  
Keyword(s):  
Alcohol Use ◽  
Alcohol Use Disorder ◽  
Controlled Trial ◽  
Cue Reactivity ◽  
A Priori ◽  
Heavy Drinking ◽  
Double Blind ◽  
Alcohol Cues ◽  
Brain Responses ◽  
The Right

AbstractTopiramate, a GABA/glutamate modulator, is efficacious in reducing alcohol consumption, though the mechanisms underlying this effect are not well characterized. This study analyzed functional magnetic resonance imaging (fMRI) data from 22 heavy drinkers enrolled in a 12-week placebo-controlled, randomized clinical trial of topiramate to examine the effects of topiramate on alcohol cue-elicited brain responses, craving, and heavy drinking in individuals with DSM-5 alcohol use disorder. Patients were randomized to receive either topiramate (maximal daily dosage of 200 mg/day) or placebo and were administered an fMRI alcohol cue-reactivity task at baseline (before starting medication) and after 6 weeks of double-blind treatment. Analyses compared the topiramate (n = 12) and placebo (n = 8) groups on (1) the change in brain responses during alcohol cue exposure (vs non-alcohol cues) within five a priori regions of interest related to reward—the bilateral and medial orbitofrontal cortex (OFC) and bilateral ventral striatum (VS) and (2) change in craving and heavy drinking days (HDDs) from baseline and scan 2. Topiramate, relative to placebo, reduced alcohol cue-elicited activation of the left VS, bilateral OFC, and medial OFC, alcohol cue-elicited craving, and HDDs between baseline and 6 weeks of treatment. The reduction in alcohol cue-elicited activation in the medial OFC correlated with reductions in craving, and reduced activation in the right VS, right OFC, and medial OFC correlated with the reduction in HDD. This preliminary study provides evidence that topiramate’s attenuation of alcohol cue-elicited brain activation and craving are key elements of the drug’s neurobiological mechanism of action in reducing heavy drinking.

scholarly journals Nalmefene attenuates neural alcohol cue-reactivity in the ventral striatum and subjective alcohol craving in patients with alcohol use disorder

2021 ◽  
Author(s):  
Damian Karl ◽  
J. Malte Bumb ◽  
Patrick Bach ◽  
Christina Dinter ◽  
Anne Koopmann ◽  
...  
Keyword(s):  
Alcohol Use ◽  
Alcohol Use Disorder ◽  
Ventral Striatum ◽  
Neuronal Response ◽  
Cue Reactivity ◽  
Treatment Options ◽  
A Priori ◽  
Dorsal Striatum ◽  
Region Of Interest ◽  
Double Blind

Abstract Rationale Alcohol use disorder is a common and devastating mental illness for which satisfactory treatments are still lacking. Nalmefene, as an opioid receptor modulator, could pharmacologically support the reduction of drinking by reducing the (anticipated) rewarding effects of alcohol and expanding the range of treatment options. It has been hypothesized that nalmefene acts via an indirect modulation of the mesolimbic reward system. So far, only a few imaging findings on the neuronal response to nalmefene are available. Objectives We tested the effect of a single dose of 18 mg nalmefene on neuronal cue-reactivity in the ventral and dorsal striatum and subjective craving. Methods Eighteen non-treatment-seeking participants with alcohol use disorder (67% male, M = 50.3 ± 13.9 years) with a current high-risk drinking level (M = 76.9 ± 52 g of pure alcohol per day) were investigated using a cue-reactivity task during functional magnetic resonance imaging (fMRI) in a double-blind, placebo-controlled, cross-over study/design. In addition, self-reported craving was assessed before and after exposure to alcohol cues. Results An a priori defined region of interest (ROI) analysis of fMRI data from 15 participants revealed that nalmefene reduced alcohol cue-reactivity in the ventral, but not the dorsal striatum. Additionally, the subjective craving was significantly reduced after the cue-reactivity task under nalmefene compared to placebo. Conclusion In the present study, reduced craving and cue-reactivity to alcohol stimuli in the ventral striatum by nalmefene indicates a potential anti-craving effect of this drug via attenuation of neural alcohol cue-reactivity.

scholarly journals Ibudilast, a neuroimmune modulator, reduces heavy drinking and alcohol cue-elicited neural activation: a randomized trial

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Erica N. Grodin ◽  
Spencer Bujarski ◽  
Brandon Towns ◽  
Elizabeth Burnette ◽  
Steven Nieto ◽  
...  
Keyword(s):  
Macrophage Migration Inhibitory Factor ◽  
Alcohol Use Disorder ◽  
Cue Reactivity ◽  
Negative Mood ◽  
Heavy Drinking ◽  
Neural Activation ◽  
Daily Diary Study ◽  
Alcohol Cues ◽  
To Receive ◽  
The Brain

AbstractIbudilast, a neuroimmune modulator which selectively inhibits phosphodiesterases (PDE)-3, -4, -10, and -11, and macrophage migration inhibitory factor (MIF), shows promise as a novel pharmacotherapy for alcohol use disorder (AUD). However, the mechanisms of action underlying ibudilast’s effects on the human brain remain largely unknown. Thus, the current study examined the efficacy of ibudilast to improve negative mood, reduce heavy drinking, and attenuate neural reward signals in individuals with AUD. Fifty-two nontreatment-seeking individuals with AUD were randomized to receive ibudilast (n = 24) or placebo (n = 28). Participants completed a 2-week daily diary study during which they filled out daily reports of their past day drinking, mood, and craving. Participants completed an functional magnetic resonance imaging (fMRI) alcohol cue-reactivity paradigm half-way through the study. Ibudilast did not have a significant effect on negative mood (β = −0.34, p = 0.62). However, ibudilast, relative to placebo, reduced the odds of heavy drinking across time by 45% (OR = 0.55, (95% CI: 0.30, 0.98)). Ibudilast also attenuated alcohol cue-elicited activation in the ventral striatum (VS) compared to placebo (F(1,44) = 7.36, p = 0.01). Alcohol cue-elicited activation in the VS predicted subsequent drinking in the ibudilast group (F(1,44) = 6.39, p = 0.02), such that individuals who had attenuated ventral striatal activation and took ibudilast had the fewest number of drinks per drinking day in the week following the scan. These findings extend preclinical and human laboratory studies of the utility of ibudilast to treat AUD and suggest a biobehavioral mechanism through which ibudilast acts, namely, by reducing the rewarding response to alcohol cues in the brain leading to a reduction in heavy drinking.

scholarly journals Efficacy and tolerability of baclofen in a U.S. community population with alcohol use disorder: a dose-response, randomized, controlled trial

2021 ◽  
Author(s):  
James C. Garbutt ◽  
Alexei B. Kampov-Polevoy ◽  
Cort Pedersen ◽  
Melissa Stansbury ◽  
Robyn Jordan ◽  
...  
Keyword(s):  
Alcohol Use ◽  
Alcohol Use Disorder ◽  
Controlled Trial ◽  
Treatment Options ◽  
Double Blind ◽  
Randomized Controlled ◽  
Main Effect ◽  
Dsm Iv ◽  
Drop Outs ◽  
Positive Effect

AbstractIdentification of new medications for alcohol use disorder (AUD) is important for improving treatment options. Baclofen, a GABAB agonist, has been identified as a potential pharmacotherapy for AUD. In a 16-week double-blind, randomized, placebo-controlled trial, we investigated 30 and 90 mg/day of baclofen compared to placebo and examined effects of dose, sex, and level of pretreatment drinking. One hundred and twenty participants with DSM-IV alcohol dependence (age 46.1 (sd = 10.1) years, 51.7% male) were randomized after exclusion for unstable medical/psychiatric illness and/or dependence on drugs other than nicotine. Seventy-three participants completed the trial. A main effect of baclofen was found [%HDD (F(2,112) = 4.16, p = 0.018, d = 0.51 95%CI (0.06–0.95), 13.6 fewer HDD) and %ABST (F(2,112) = 3.68, p = 0.028, d = 0.49 95%CI (0.04–0.93), 12.9 more abstinent days)] and was driven by the 90 mg/day dose. A sex × dose interaction effect was present for both %HDD (F(2,110) = 5.48, p = 0.005) and %ABST (F(2,110) = 3.19, p = 0.045). Men showed a marginally positive effect for 90 mg/day compared to PBO (%HDD t(110) = 1.88, p = 0.063, d = 0.36 95%CI (−0.09–0.80), 15.8 fewer HDD days; %ABST t(110) = 1.68 (p = 0.096, d = 0.32 95%CI (−0.12–0.76), 15.7 more ABST)) with no effect for 30 mg/day. Women showed a positive effect for 30 mg/day (%HDD, t(110) = 3.19, p = 0.002, d = 0.61 95%CI (0.16–1.05), 26.3 fewer HDD days; %ABST t(110) = 2.73, p = 0.007, d = 0.52 95%CI (0.07–0.96), 25.4 more ABST days) with marginal effects for 90 mg/day on %ABST (p = 0.06) with drop-outs/dose reduction from sedative side-effects of 59% in women at 90 mg/day compared to 5% for men. These findings support the hypothesis that baclofen has efficacy in AUD and suggest that dose and sex be further explored as potential moderators of baclofen response and tolerability.

A 6-Month Randomized Trial of a Smartphone Application, UControlDrink, in Aiding Recovery in Alcohol Use Disorder

2021 ◽  
pp. 1-12
Author(s):  
Conor Farren ◽  
Aoife Farrell ◽  
Aisling Hagerty ◽  
Cliodhna McHugh
Keyword(s):  
Alcohol Use ◽  
Text Messaging ◽  
Alcohol Use Disorder ◽  
Positive Impact ◽  
Controlled Trial ◽  
Intervention Group ◽  
Heavy Drinking ◽  
Smartphone Application ◽  
Smartphone App ◽  
Control Group

<b><i>Background and Aims:</i></b> Alcohol use disorder (AUD) is a substantial problem, causing early death and great economic burden. Research has highlighted the potential positive impact of technological interventions, such as smartphone applications (app) in treatment of AUD. The aim of this study was to explore the effectiveness of a smartphone app, incorporating computerized cognitive behavioural therapy and text messaging support, on alcohol outcomes over 6 months in a post-rehabilitation setting. <b><i>Methods:</i></b> A total of 111 participants with AUD were recruited into this randomized controlled trial, following completion of a 30-day rehabilitation programme. The intervention group (<i>n</i> = 54) used the smartphone app “UControlDrink” (UCD) over 6 months with treatment as usual (TAU), and the control group (<i>n</i> = 57) received TAU. All subjects suffered from AUD as the primary disorder, with other major psychiatric disorders excluded. All intervention subjects used the UCD smartphone app in the treatment trial, and all subjects underwent TAU consisting of outpatient weekly support groups. Drinking history in the previous 90 days was measured at baseline and at 3- and 6-month follow-ups. Additional measurements were made to assess mood, anxiety, craving, and motivation. Results were analysed using intention-to-treat analyses. <b><i>Results:</i></b> Retention in the study was 72% at 3 months and 52% at 6 months. There was a significant reduction in heavy drinking days in the intervention group relative to TAU over the 6 months, <i>p</i> &#x3c; 0.02. <b><i>Conclusions:</i></b> The UCD smartphone app demonstrates a significant benefit to reducing heavy drinking days over a 6-month post-rehabilitation period in AUD.

scholarly journals Ibudilast for Alcohol Use Disorder: Study protocol for a phase II randomized clinical trial

2020 ◽  
Author(s):  
Elizabeth M. Burnette ◽  
Wave-Ananda Baskerville ◽  
Erica N. Grodin ◽  
Lara A. Ray
Keyword(s):  
Clinical Trial ◽  
Alcohol Use ◽  
Randomized Clinical Trial ◽  
Alcohol Use Disorder ◽  
Safety Data ◽  
Heavy Drinking ◽  
Phosphodiesterase Inhibitor ◽  
Neural Activation ◽  
Double Blind ◽  
Clinical Safety

Abstract 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 (50mg 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 July 20, 2018.

scholarly journals Ibudilast for alcohol use disorder: study protocol for a phase II randomized clinical trial

Trials ◽  
2020 ◽  
Vol 21 (1) ◽  
Author(s):  
Elizabeth M. Burnette ◽  
Wave-Ananda Baskerville ◽  
Erica N. Grodin ◽  
Lara A. Ray
Keyword(s):  
Clinical Trial ◽  
Alcohol Use ◽  
Randomized Clinical Trial ◽  
Alcohol Use Disorder ◽  
Safety Data ◽  
Heavy Drinking ◽  
Phosphodiesterase Inhibitor ◽  
Neural Activation ◽  
Double Blind ◽  
Clinical Safety

Abstract 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.

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