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

Grodin, Erica N.; Bujarski, Spencer; Towns, Brandon; Burnette, Elizabeth; Nieto, Steven J.; Lim, Aaron C.; Lin, Johnny Wei‐Bing; Miotto, Karen; Gillis, Artha; Irwin, Michael R.; Evans, Christopher J.; Ray, Lara A.

doi:10.1038/s41398-021-01478-5

Cited by 54 publications

(54 citation statements)

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“…Considering its immunomodulatory actions, ibudilast may reduce the acute and chronic proinflammatory effects of alcohol, either indirectly through suppression of peripheral inflammation or directly by altering cAMP signaling pathways and suppressing cytokine expression and in the brain (e.g., rewards regions relevant to craving) (Avila et al, 2017). In return, acute alcohol-induced increases Continuing, previous results from our group implicate ibudilast in the reduction in tonic craving (Ray et al, 2017) and neural alcohol-cue reactivity, as evidenced by attenuation of cue-elicited activation in the ventral striatum compared with placebo (Grodin et al, 2021). It is thus plausible that reductions in alcohol craving and reward, across these contexts, represent a primary mechanism of action of ibudilast for AUD.…”

Section: Discussionmentioning

confidence: 59%

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

Meredith

Grodin

Montoya

et al. 2022

Alcoholism Clin & Exp Res

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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.

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Section: Discussionmentioning

confidence: 59%

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

Meredith

Grodin

Montoya

et al. 2022

Alcoholism Clin & Exp Res

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“…Notably, drugs that reduce neuroinflammation to reduce drinking, such as phosphodiesterases, may be promising approaches for novel treatment options for AUD. Recently published randomized controlled trials suggest that a phosphodiesterase inhibitor reduces heavy drinking whereas an antibiotic compound was not effective [ 63 , 64 ]. A deeper understanding of the underlying mechanisms will enhance the discovery of drug targets and drive forward the development of precision medicine within this field.…”

Section: Discussionmentioning

confidence: 99%

Multi-omics signatures of alcohol use disorder in the dorsal and ventral striatum

et al. 2022

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Alcohol Use Disorder (AUD) is a major contributor to global mortality and morbidity. Postmortem human brain tissue enables the investigation of molecular mechanisms of AUD in the neurocircuitry of addiction. We aimed to identify differentially expressed (DE) genes in the ventral and dorsal striatum between individuals with AUD and controls, and to integrate the results with findings from genome- and epigenome-wide association studies (GWAS/EWAS) to identify functionally relevant molecular mechanisms of AUD. DNA-methylation and gene expression (RNA-seq) data was generated from postmortem brain samples of 48 individuals with AUD and 51 controls from the ventral striatum (VS) and the dorsal striatal regions caudate nucleus (CN) and putamen (PUT). We identified DE genes using DESeq2, performed gene-set enrichment analysis (GSEA), and tested enrichment of DE genes in results of GWASs using MAGMA. Weighted correlation network analysis (WGCNA) was performed for DNA-methylation and gene expression data and gene overlap was tested. Differential gene expression was observed in the dorsal (FDR < 0.05), but not the ventral striatum of AUD cases. In the VS, DE genes at FDR < 0.25 were overrepresented in a recent GWAS of problematic alcohol use. The ARHGEF15 gene was upregulated in all three brain regions. GSEA in CN and VS pointed towards cell-structure associated GO-terms and in PUT towards immune pathways. The WGCNA modules most strongly associated with AUD showed strong enrichment for immune response and inflammation pathways. Our integrated analysis of multi-omics data sets provides further evidence for the importance of immune- and inflammation-related processes in AUD.

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“…The current sample is culled from seven separate clinical and experimental psychopharmacology neuroimaging studies with similar inclusion and recruitment methods, all conducted in the Addictions Laboratory at the University of California, Los Angeles. The study sample was drawn from studies examining the neural correlates of risk-taking and alcohol administration (Courtney et al, 2013;Courtney & Ray, 2014), the neural correlates of alcohol prediction error (Cservenka et al, 2017), the effect of a brief intervention on neural response to alcohol taste cues (Grodin et al, 2019), and four pharmacotherapy trials investigating the effect of naltrexone (Lim et al, 2019), the combination of and naltrexone and varenicline (Ray et al, 2015(Ray et al, , 2021, and ibudilast (Grodin et al, 2021). Although some studies involved pharmacological manipulations, all demographic and clinical characteristics analyzed herein were collected at a baseline assessment visit (prior to medication randomization or any experimental procedures).…”

Section: Methods Data Source and Samplementioning

confidence: 99%

Effect of alcohol, tobacco, and cannabis co-use on gray matter volume in heavy drinkers.

Grodin¹,

Burnette²,

Towns³

et al. 2021

Psychology of Addictive Behaviors

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Objective: Alcohol, tobacco, and cannabis are the three most frequently used drugs in the United States and co-use is common. Alcohol, tobacco, and cannabis use has been separately associated with altered brain structure, and alcohol and tobacco co-use results in decreases in gray matter volume. Less is known about the effect of alcohol and cannabis co-use, and alcohol, tobacco, and cannabis tri-use. Therefore, this study examined the effect of co- and tri-use on gray matter volume, a measure of brain cell density, in heavy drinkers. Method: Heavy drinkers (n = 237; 152m/85f; age = 32.52; white = 111; black = 28; Latino = 9; American Indian = 2; Pacific Islander = 4; Asian = 59; mixed = 15; other = 9) were classified into four groups based on their alcohol, tobacco, and cannabis use: alcohol only users (n = 70), alcohol and tobacco co-users (n = 90), alcohol and cannabis co-users (n = 35), and alcohol, tobacco, and cannabis tri-users (n = 42). All participants completed a structural MRI scan. Voxel-based morphometry was conducted to evaluate the effect of co-use on gray matter volume, with alcohol only users as the reference group. Age, sex, and scanner were included as covariates. Results: Alcohol and tobacco co-users had significantly decreased left orbitofrontal gray matter volume relative to alcohol only users (Cohen’s d = .79). There were no differences in gray matter volume between the alcohol only and alcohol and cannabis co-users, or between the alcohol only and tri-user groups. Conclusion: The additive effect of tobacco co-use on gray matter volumes in heavy drinkers was limited and localized. The effect of tri-use of alcohol, tobacco, and cannabis may have interacted, such that overlapping cannabis and tobacco use masked volume differences present in separate co-using groups.

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

Cited by 54 publications

References 51 publications

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

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

Multi-omics signatures of alcohol use disorder in the dorsal and ventral striatum

Effect of alcohol, tobacco, and cannabis co-use on gray matter volume in heavy drinkers.

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