Variations in alcohol craving and negative mood during a clinical trial of ibudilast for alcohol use disorder.

Background: Immune medications, including ibudilast, have shown early potential in mitigating alcohol intake in preclinical models and small-scale trials for alcohol use disorder (AUD). To elucidate clinical utility and clinical mechanisms of these novel treatments, research should carefully assess medication-related changes in AUD symptomatology, including craving and negative mood, over time.

Methods: This is a secondary analysis of a 12-week randomized clinical trial of ibudilast for AUD. Participants were 102 individuals (40% female, average age 44 years) seeking treatment for AUD and randomized to ibudilast (50 mg twice-daily) or matched placebo. Clinical symptom measures of alcohol craving, depression, and anxiety were collected monthly. Growth models compared rates of change in clinical symptomatology between treatment groups and tested whether changes were moderated by sex. A subsample (n = 25) completed a functional magnetic resonance imaging scan with an alcohol cue-reactivity task at week four to assess a brain-based craving marker.

Results: At pretreatment, participants reported moderate craving symptoms and nonclinically elevated negative mood symptoms, on average. Participants taking ibudilast showed significantly steeper reductions in craving during the trial, as compared with placebo (1.32 vs. 0.52 points lower per month; p = 0.035). At treatment endpoint, female participants taking ibudilast reported lower craving than female participants taking placebo (p < 0.001). Greater cue-elicited brain activation in bilateral insula, bilateral orbitofrontal cortex, and right precuneus (p's < 0.02) was detected among the placebo subsample, compared to ibudilast. Rates of change for depression and anxiety did not differ between medication conditions, nor were they moderated by sex. Depression symptoms decreased during the trial, while anxiety symptoms remained relatively stable.

Conclusions: Consistent with prior research, ibudilast reduced neurobiological and self-report markers of craving, with female participants showing a stronger treatment response by trial endpoint. Despite shared neuroimmune correlates between negative mood and addiction, ibudilast did not alleviate negative mood symptoms beyond placebo effects.