Effects of ibudilast on central and peripheral markers of inflammation in alcohol use disorder: A randomized clinical trial

Abstract

Ibudilast, a neuroimmune modulator, shows promise as a pharmacotherapy for alcohol use disorder (AUD). In vivo administration of ibudilast reduces the expression of pro‐inflammatory cytokines in animal models, but its effects on markers of inflammation in humans are unknown. This preliminary study examined the effect of ibudilast on peripheral and potential central markers of inflammation in individuals with AUD. This study also explored the predictive relationship of neurometabolite markers with subsequent drinking in the trial. Non‐treatment‐seeking individuals with an AUD (n = 52) were randomized to receive oral ibudilast (n = 24) or placebo (n = 28) for 2 weeks. Plasma levels of peripheral inflammatory markers were measured at baseline and after 1 and 2 weeks of medication. At study mid‐point, proton magnetic resonance spectroscopy was performed to measure potential neurometabolite markers of inflammation: choline‐compounds (Cho), myo‐inositol (MI) and creatine + phosphocreatine (Cr) in frontal and cingulate cortices from 43 participants (ibudilast: n = 20; placebo: n = 23). The treatment groups were compared on peripheral and central markers. Ibudilast‐treated participants had lower Cho in superior frontal white matter and nominally lower MI in pregenual anterior cingulate cortex. Ibudilast‐treated participants had nominally lower C‐reactive protein levels at visit 2 and nominally lower TNF‐α/IL‐10 ratios, relative to placebo. C‐reactive protein and Cho levels were correlated, controlling for medication. Superior frontal white matter Cho predicted drinking in the following week. Micro‐longitudinal ibudilast treatment may induce peripheral and putative central anti‐inflammatory responses in patients with AUD. The neurometabolite responses may be associated with reduction in drinking, suggesting an anti‐inflammatory component to the therapeutic action of ibudilast.

A Narrative Review of Current and Emerging Trends in the Treatment of Alcohol Use Disorder

“…The ibudilast group exhibited lower inflammation markers in their brains and bodies. Interestingly, a link was observed between C-reactive protein and choline compound (Cho) levels, and Cho levels in the brain predicted drinking behavior in the following week [ 87 ].…”

Biochemical, Hematological, Inflammatory, and Gut Permeability Biomarkers in Patients with Alcohol Withdrawal Syndrome with and without Delirium Tremens

“…Recently, there has been increased interest in the repurposing of drugs for the treatment of inflammatory and autoimmune diseases for the therapy of AUD and related conditions [71]. Such drugs with anti-inflammatory effects include ibudilast, apremilast, exenatide, semaglutide, liraglutide, metformin, and others, which have shown to reduce craving and the amount of alcohol drunk in animal models and randomized clinical trials in humans [71][72][73]. However, there is a need to develop criteria for stratifying patients by inflammation level for personalized anti-inflammatory therapy.…”

Ibudilast Protects Retinal Bipolar Cells from Excitotoxic Retinal Damage and Activates the mTOR Pathway

“…Recently, ibudilast was found to have neuroprotective effects in a variety of neurological disorders (Egashira et al, 2021; Fujita et al, 2018; Zhang et al, 2022). It is in clinical trials in the United States for evaluation as a neuroprotective agent in amyotrophic lateral sclerosis (Oskarsson et al, 2021) and multiple sclerosis (Bermel et al, 2021; Fox et al, 2018; MediciNova, Health, Disorders, Stroke, & Society, 2013; MediciNova & System, 2014; Oskarsson et al, 2021) as well as in drug addiction (Grodin et al, 2022) and pain (Egashira et al, 2021).…”

“…The copyright holder for this preprint this version posted March 20, 2024. ; https://doi.org/10.1101/2024.03.18.585556 doi: bioRxiv preprint MediciNova & System, 2014;Oskarsson et al, 2021) as well as in drug addiction (Grodin et al, 2022) and pain (Egashira et al, 2021).…”