Development of the Neuroimmune Modulator Ibudilast for the Treatment of Alcoholism: A Randomized, Placebo-Controlled, Human Laboratory Trial

Abstract

Current directions in medication development for alcohol use disorder (AUD) emphasize the need to identify novel molecular targets and efficiently screen new compounds aimed at those targets. Ibudilast (IBUD) is a neuroimmune modulator that inhibits phosphodiesterase-4 and -10 and macrophage migration inhibitory factor and was recently found to reduce alcohol intake in rats by ∼50%. To advance medication development for AUD, the present study consists of a randomized, crossover, double-blind, placebo-controlled laboratory study of IBUD in nontreatment-seeking individuals with current (ie, past month) mild-to-severe AUD. This study tested the safety, tolerability, and initial human laboratory efficacy of IBUD (50 mg b.i.d.) on primary measures of subjective response to alcohol as well as secondary measures of cue- and stress-induced changes in craving and mood. Participants (N=24) completed two separate 7-day intensive outpatient protocols that included daily visits for medication administration and testing. Upon reaching a stable target dose of IBUD (or matched placebo), participants completed a stress-exposure session (day 5; PM), an alcohol cue-exposure session (day 6; AM), and an i.v. alcohol administration session (day 6; PM). Participants stayed overnight after the alcohol administration, and discharge occurred on day 7 of the protocol. Medication conditions were separated by a washout period that was ⩾7 days. IBUD was well tolerated; however, there were no medication effects on primary measures of subjective response to alcohol. IBUD was associated with mood improvements on the secondary measures of stress exposure and alcohol cue exposure, as well as reductions in tonic levels of craving. Exploratory analyses revealed that among individuals with higher depressive symptomatology, IBUD attenuated the stimulant and mood-altering effects of alcohol as compared with placebo. Together, these findings extend preclinical demonstrations of the potential utility of IBUD for the treatment of AUD and suggest that depressive symptomatology should be considered as a potential moderator of efficacy for pharmacotherapies with neuroimmune effects, such as IBUD.

Figures

Figure 1

Flowchart of study design.

Figure 2

Positive mood during the stressful imagery paradigm (n=24). Positive mood was found to return to baseline levels following the stressful imagery more quickly while on IBUD relative to placebo (p=0.06).

Figure 3

Stimulation (a), positive mood (b), and negative mood (c) in response to alcohol is affected by the administration of IBUD and levels of depressive symptomatology. For ease of presentation, means and SEs are presented based on a median split of depressive symptomatology (n=12 per group); however, the analyses examined depressive symptomatology (ie, log-transformed BDI-II scores) as a continuous predictor.

Figure 4

Alcohol ‘Liking’ and ‘Wanting’ in response to alcohol is affected by the administration of IBUD and levels of depressive symptomatology. For ease of presentation, means and SEs are presented based on a median split of depressive symptomatology (n=12 per group); however, the analyses examined depressive symptomatology (ie, log-transformed BDI-II scores) as a continuous predictor.

Figure 5

Tonic levels of craving for alcohol on day 1 and day 7 of medication administration (n=24). Alcohol craving decreased significantly more sharply on IBUD relative to placebo (p<0.05).