UCLA

Background: Excessive alcohol consumption is a major public health burden. Yet less than 8% of individuals with past-year alcohol use disorder (AUD) received treatment. To support individuals in reducing drinking, treatments must target factors sustaining alcohol use from the molecular to psychosocial level. One emerging feature of AUD is alterations in immune signaling and neuroinflammation. Immune treatments that can restore healthy immune functioning may serve to promote recovery from AUD. Methods: This dissertation project focused on the application of immune interventions as treatments for AUD. Chapter 1 comprised a qualitative literature review on preclinical and clinical studies testing immune compounds for AUD. The subsequent chapters utilized empirical data collected during two clinical trials on a neuroimmune compound to explore its clinical mechanisms. In the first trial, 52 participants with AUD were randomized to ibudilast or matched placebo for two weeks and completed daily diary assessments on alcohol, mood, and craving. Chapter 2 tested whether ibudilast modulated acute alcohol-induced changes in craving and mood. In a larger clinical trial, 102 treatment-seeking participants with AUD were randomized to ibudilast or placebo and took study medication for 12 weeks. Chapter 3 tested for differences in monthly change rates among clinical measures of alcohol craving, depression, and anxiety between the medication groups. In Chapter 4, exploratory analyses assessed whether ibudilast improved neurocognition, compared to placebo. Results: In Chapter 1, we highlighted translational findings with an emphasis on safety and clinical implications from randomized controlled trials testing immune treatments for AUD. Results from naturalistic reports in Chapter 2 showed that ibudilast reduced daily alcohol-induced craving but not mood. Similarly, linear growth models from Chapter 3 showed that the ibudilast group had steeper reductions in tonic alcohol craving than placebo but there were no treatment group differences in rates of change for depression or anxiety symptoms. Lastly, as outlined in Chapter 4, ibudilast did not improve neurocognitive functioning compared to placebo. Conclusion: This dissertation used a translational framework combining neuroimmunology, pharmacology, and experimental psychology to better characterize the clinical application of immune treatments for AUD. Mitigation of craving may be a central clinical mechanism of ibudilast.