title: 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.
authors.affiliation: Department of Psychology, University of California, Los Angeles, CA, USA.|Department of Psychiatry and Biobehavioral Sciences, University of California, Los Angeles, CA, USA.
authors.forename: Lara A
authors.initials: LA
authors.lastname: Ray
authors.affiliation: Department of Psychology, University of California, Los Angeles, CA, USA.
authors.forename: Spencer
authors.initials: S
authors.lastname: Bujarski
authors.affiliation: Department of Psychiatry and Biobehavioral Sciences, University of California, Los Angeles, CA, USA.|Department of Family Medicine, University of California, Los Angeles, CA, USA.
authors.forename: Steve
authors.initials: S
authors.lastname: Shoptaw
authors.affiliation: Department of Psychology, University of California, Los Angeles, CA, USA.
authors.forename: Daniel Jo
authors.initials: DJ
authors.lastname: Roche
authors.affiliation: Department of Psychiatry and Biobehavioral Sciences, University of California, Los Angeles, CA, USA.|Department of Family Medicine, University of California, Los Angeles, CA, USA.
authors.forename: Keith
authors.initials: K
authors.lastname: Heinzerling
authors.affiliation: Department of Psychiatry and Biobehavioral Sciences, University of California, Los Angeles, CA, USA.
authors.forename: Karen
authors.initials: K
authors.lastname: Miotto
mesh_terms: D000328:Adult; D000339:Affect / Q000187:drug effects; D000427:Alcohol Deterrents / Q000627:therapeutic use*; D000437:Alcoholism / Q000188:drug therapy* / Q000523:psychology; D002492:Central Nervous System Depressants / Q000008:administration & dosage; D066249:Craving / Q000187:drug effects; D018592:Cross-Over Studies; D003863:Depression / Q000188:drug therapy; D004311:Double-Blind Method; D000431:Ethanol / Q000008:administration & dosage; D005260:Female; D006801:Humans; D008297:Male; D011725:Pyridines / Q000627:therapeutic use*; D012720:Severity of Illness Index; D016896:Treatment Outcome; D007212:Indolizines; D011720:Pyrazoles
chemical_list: D000427:Alcohol Deterrents; D002492:Central Nervous System Depressants; D000431:Ethanol; D011725:Pyridines; C038366:ibudilast; D007212:Indolizines; D011720:Pyrazoles