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.

Keywords: alcohol use disorder; anti-inflammatory; choline; cytokine; ibudilast; magnetic resonance spectroscopy.

Figure 1.. Consort Diagram.

Subject flow through the trial.

Figure 2.. MRS Acquisition Volume Prescription and Data Quality From a Representative Participant.

Panel A features two sagittal (upper) and one transverse (lower) T1w MRI of the human brain showing position of the 8×8 subarray (“excitation box”; white-border) from which usable spectra are acquired within the 16×16 proton magnetic resonance spectroscopy (MRS) voxel grid (yellow). MRS was acquired with stimulated-echo acquisition mode (STEAM; TR/TE/TM=2000/20/20 ms, voxels 10×10×10 mm³, 4 excitation). Sample voxels from single voxels in the pregenual anterior cingulate cortex (pACC), superior frontal white matter (SFWM), and superior frontal cortex (SFC) target volumes-of-interest (VOIs) are indicated. Panel B shows raw (red) and fit (green) spectra across the excitation grid with spectra from the three sample voxels magnified in Panel C. NAA=N-acetyl-compounds, Cr=creatine-compounds, Cho=choline-compounds, MI=myo-inositol.

Figure 3.. Magnetic Resonance Spectroscopy Results.

Ibudilast-treated participants had lower inflammatory neurometabolite levels relative to placebo-treated participants. In Panel A, participants treated with ibudilast had significantly lower choline levels in the superior frontal white matter relative to placebo-treated participants. In Panel B, participants treated participants had trend level lower levels of myo-inositol in the pregenual anterior cingulate cortex relative to placebo treated participants. * = p<0.05; ^ = p<0.08.

Figure 4.. Inflammatory Marker Results.

Panel A shows the CRP levels over the course of the study by medication group. There was a trend-level interaction between medication and time, such that the ibudilast-treated participants had lower CRP levels at visit 2, whereas the placebo-treated participants had higher CRP levels at visit 2. Panel B shows the TNF-α/IL-10 ratio over the course of the study by medication group. Ibudilast-treated participants had lower ratios than placebo-treated participants across time at trend-level. Panel C shows the IL-8 levels over the course of the study by medication group. Participants treated placebo had lower IL-8 levels across time relative to ibudilast-treated participants. Figures are converged baselines and estimated marginal means ± SE’s controlling for baseline levels, age, sex, smoking, BMI, and pre-trial drinking.

Figure 5.. Clinical Prediction.

Superior frontal white matter choline levels at visit 1 were predictive of subsequent drinking in the ibudilast group only. Individuals who were treated with ibudilast who had low levels of choline in the superior frontal white matter had the fewest drinks per drinking day in the subsequent week.