Summary: A randomized clinical trial from UCLA found that ibudilast, a neuroimmune-modulating drug once considered a promising treatment for alcohol use disorder (AUD), did not outperform placebo overall. All participants reduced their drinking during the trial, but a subgroup—women taking ibudilast—showed a larger decrease in drinks per drinking day, suggesting a possible sex-specific benefit. Baseline depressive symptoms also modified outcomes: people with greater depressive symptoms showed better responses on placebo. The findings point toward the potential role of immune and inflammatory processes in AUD and the need for targeted trials.
Those involved in the study emphasize that future research should investigate immune-based approaches tailored to individual characteristics such as sex, depressive symptoms, pain, and baseline inflammation.
Key Facts:
- Overall result: Ibudilast did not reduce heavy drinking days more than placebo.
- Sex differences: Women taking ibudilast reduced drinks per drinking day more than women on placebo.
- Depression effect: Participants with higher baseline depressive symptoms experienced greater benefits on placebo.
- Inflammation markers: Ibudilast did not significantly reduce peripheral markers of inflammation over 12 weeks.
Source: UCLA
Overview
Ibudilast is an anti-inflammatory neuroimmune modulator approved in Japan for asthma and post-stroke dizziness. Because inflammation is increasingly recognized as a contributor to psychiatric conditions, including depression and AUD, researchers tested whether ibudilast could reduce drinking in adults seeking treatment for moderate to severe alcohol use disorder.
The randomized, double-masked phase 2 trial enrolled 102 adults and compared ibudilast 50 mg taken twice daily for 12 weeks with matched placebo. Participants were followed for an additional four weeks after treatment. Primary and secondary outcomes included percentage of heavy drinking days, drinks per drinking day, drinks per day, and percentage of days abstinent. The trial also measured depressive symptoms and circulating markers of inflammation to test whether baseline characteristics moderated medication effects.
On average, participants started the study consuming about seven drinks per drinking day and reduced that to roughly three to four drinks per drinking day by the end of treatment. Because both medication and placebo groups showed substantial improvement, the overall comparison did not support superiority of ibudilast over placebo for the primary outcome (percentage of heavy drinking days) or for the registered secondary drinking outcomes. Peripheral biomarkers of inflammation did not differ significantly between groups.
Subgroup findings and moderators
Exploratory moderators provided important nuance. Women receiving ibudilast experienced a greater reduction in drinks per drinking day compared with women on placebo, a difference the investigators considered strong enough to recommend further trials focused on females. By contrast, participants who entered the study with higher depressive symptoms reduced their drinking more and had more abstinent days when assigned to placebo rather than ibudilast. Statistical moderation analyses indicated potential interactions of baseline depressive symptomology (for drinks per drinking day) and sex with treatment effects.
“While ibudilast was not superior to the placebo, we saw that some individuals did better and some did worse with the drug,” said Lara Ray, UCLA psychology professor and first author of the study. “Female study participants did better, but both men and women who came in with higher levels of depression did worse, which are results we can use to guide further research.”
Interpretation and next steps
The large improvements seen across both groups reflect a common challenge in AUD medication trials: participants often reduce drinking simply by engaging in treatment and being regularly monitored, which can make it difficult to detect additional medication effects. The study team notes that longer follow-up periods (for example, six months) might help separate the influence of the treatment context from medication-specific benefits.
Investigators also plan further analyses to identify which subgroups may benefit from neuroimmune therapies—candidates include people reporting co-occurring pain or those with higher baseline inflammatory markers. The trial was supported by the National Institute on Alcohol Abuse and Alcoholism, and the authors stress the need for continued funding to advance personalized treatment strategies for AUD, a condition affecting millions of adults in the United States.
“Our lab is uncovering novel treatments for substance use disorders, and we’re excited that all the people who came into our study improved,” Ray added. “People are coming to our lab because they trust UCLA. They’re reporting on their drinking regularly, and that, in and of itself, is causing pretty significant changes in their behavior.”
About this psychopharmacology and AUD research news
Author: Holly Ober
Source: UCLA
Contact: Holly Ober – UCLA
Image: The image is credited to Neuroscience News
Original Research: Open access. “A Neuroimmune Modulator for Alcohol Use Disorder” by Lara Ray et al., JAMA Network Open
Abstract
A Neuroimmune Modulator for Alcohol Use Disorder
Importance
The neuroimmune system is a promising target for new medications to treat alcohol use disorder. Ibudilast selectively inhibits phosphodiesterases (PDE3, PDE4, PDE10, PDE11) and macrophage migration inhibitory factor (MIF), and has shown preclinical and early clinical potential.
Objective
To test the efficacy of ibudilast versus placebo for reducing alcohol use in adults with moderate to severe AUD.
Design, Setting, and Participants
This double-masked, randomized phase 2 clinical trial took place at an academic research center from October 2018 to April 2023. Eligible participants were adults seeking treatment for moderate or severe AUD. The treatment phase lasted 12 weeks, followed by a 4-week follow-up.
Interventions
Ibudilast 50 mg taken twice daily for 12 weeks versus matched placebo.
Main Outcomes and Measures
Primary outcome: percentage of heavy drinking days. Secondary outcomes: drinks per day, drinks per drinking day, and percentage of days abstinent. Registered exploratory analyses evaluated moderation by baseline depressive symptoms and whether ibudilast reduced circulating proinflammatory markers. A post hoc analysis tested sex as a moderator.
Results
Of 102 participants (mean [SD] age, 44.3 [10.8] years; 61 male [59.8%]; 24 Black [23.5%], 32 Hispanic [31.4%], 52 White [51.0%]), baseline characteristics were balanced across treatment arms. There was no significant difference between ibudilast and placebo on percentage of heavy drinking days (β = 0.06, SE = 0.08 [95% CI, −0.09 to 0.21]; P = .46) or on registered secondary drinking outcomes. No significant effects were observed on peripheral inflammatory markers. Moderation analyses suggested that baseline depressive symptoms (for drinks per drinking day: β = 0.25, SE = 0.11 [95% CI, 0.03 to 0.48]; P = .03) and sex (β = −2.48, SE = 1.07 [95% CI, −4.59 to −0.37]; P = .02) may influence treatment response.
Conclusions and Relevance
In this randomized clinical trial, ibudilast did not demonstrate overall efficacy over placebo for treating AUD and did not reduce measured peripheral inflammation. However, sex and baseline depressive symptoms may moderate response, underscoring the need for targeted trials of novel molecular treatments.
Trial Registration
ClinicalTrials.gov Identifier: NCT03594435