A phase 2 clinical trial testing ibudilast for alcohol use disorder has failed to demonstrate superiority over placebo in the overall patient population, though the study revealed intriguing gender-specific effects that may guide future research directions. The randomized, double-masked trial, conducted by UCLA researchers and published in JAMA Network Open, enrolled 102 adults with moderate or severe alcohol use disorder.
Trial Design and Patient Population
The study recruited participants seeking treatment for alcohol use disorder between October 2018 and April 2023. Participants received either ibudilast 50 mg or placebo twice daily for 12 weeks, followed by a 4-week follow-up period. The study population had a mean age of 44.3 years, with 59.8% male participants and diverse ethnic representation including 23.5% Black, 31.4% Hispanic, and 51.0% White participants.
Researchers tracked multiple drinking outcomes including percentage of heavy drinking days (primary endpoint), drinks per day, drinks per drinking day, and percentage of days abstinent. The study also monitored depressive symptoms and inflammatory markers throughout the treatment period.
Primary Efficacy Results
The trial failed to meet its primary endpoint, showing 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). Similarly, no significant differences were observed for registered secondary outcomes.
"While ibudilast was not superior to the placebo, we saw that some individuals did better and some did worse with the drug," said UCLA psychology professor and study first author Lara Ray. Both treatment groups showed substantial improvements, with participants reducing their average consumption from seven drinks per drinking day at baseline to approximately three to four drinks per drinking day by treatment end.
Gender-Specific Treatment Response
Post hoc exploratory analysis revealed a significant sex-based moderation effect (β = −2.48, SE = 1.07 [95% CI, −4.59 to −0.37]; P = .02). Women who received ibudilast demonstrated greater reductions in drinks per drinking day compared to placebo, an effect strong enough to warrant further investigation in female-specific trials.
"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," Ray explained. The researchers hypothesize this gender difference may relate to baseline inflammation levels, as women generally exhibit higher inflammatory markers.
Depression as Treatment Moderator
The study identified baseline depressive symptomatology as a significant moderator of treatment response (β = 0.25, SE = 0.11 [95% CI, 0.03 to 0.48]; P = .03 for drinks per drinking day). Participants with higher depression levels at study entry showed better responses to placebo than to ibudilast, both in terms of reduced drinks per day and increased abstinent days.
Immune System Targeting Approach
Ibudilast, approved in Japan for asthma and post-stroke dizziness, functions as a neuroimmune modulator by selectively inhibiting phosphodiesterases 3, 4, 10, and 11, as well as macrophage migration inhibitory factor. The drug represents part of a broader research strategy targeting immune responses and inflammation in addiction treatment.
"We think that there's a strong immune contribution to psychiatric disorders, especially depression and alcohol use disorder," Ray noted. "Women generally have higher inflammation levels, and the fact that ibudilast works better for them and worse for people with more depressive symptoms suggests that we may be on the right track."
However, the study found no significant effects of ibudilast on peripheral markers of inflammation compared to placebo, raising questions about the drug's mechanism of action in this patient population.
Clinical Trial Challenges
The researchers highlighted a common challenge in alcohol use disorder trials: the pronounced placebo effect observed across treatment settings. "One of the challenges in alcohol use disorder trials is that all participants usually improve their drinking across the board," Ray explained. "Participants are responding to the whole treatment setting, and regardless of medication, we see a very pronounced beneficial effect on alcohol use disorder."
This phenomenon complicates the ability to distinguish active medication effects from the therapeutic benefits of the clinical trial environment itself.
Future Research Directions
The UCLA Addictions Lab plans to conduct longer-duration studies to better separate treatment context effects from active medication benefits. "One of the challenges going forward is to follow people a little bit longer, say, in a six-month trial, so that we can get more of a separation between the treatment context and the active medication effect," Ray said.
Ongoing analyses will focus on identifying specific patient subgroups who may benefit from ibudilast treatment, including individuals with co-occurring pain conditions and those with elevated baseline inflammation levels.
The research addresses a significant public health need, as alcohol use disorder affects nearly 30 million adults in the United States. The trial was funded by the National Institute on Alcohol Abuse and Alcoholism, with continued federal support required for developing novel treatment approaches in this therapeutic area.
