Ibudilast and Withdrawal-Related Dysphoria

Alcohol use disorder (AUD) is a prevalent and disabling psychiatric disorder with few, and only moderately efficacious, treatment options. Consequently, the identification of novel treatment targets and the development of rigorous laboratory paradigms to screen and optimize novel therapeutics represents a research priority. Ibudilast (IBUD) is a neuroimmune modulator that inhibits phosphodiesterase-4 and -10 and macrophage migration inhibitory factor. Recently in an AUD sample, IBUD was shown to decrease reactivity to a psychological stressor. Furthermore, IBUD was effective in blunting alcohol reward among participants with greater depressive symptoms, a hallmark symptom of protracted withdrawal. Recently, preclinical research in opiates has demonstrated that drug withdrawal is necessary for microglia activation and neuroinflammation in reward networks, suggesting that IBUD may be most effective among patients who experience withdrawal-related dysphoria. Therefore, this proposed study aims to examine withdrawal-related dysphoria as a moderator of IBUD efficacy in the natural environment measured using Daily Diary Assessment (DDA) approaches. To accomplish this aim, participants meeting criteria for AUD and balanced on the presence of withdrawal-related dysphoria will be enrolled in a double-blinded IBUD trial including consisting of two weeks randomized to medication and DDA assessment. The proposed research aims are: Aim 1: Test whether IBUD reduces basal negative affect in abstinence, and blunts alcohol-related negative reinforcement. It is hypothesized that IBUD will reduce basal levels of negative affect during alcohol abstinence, and in so doing will interfere with alcohol-induced blunting of negative affectivity as captured during naturalistic drinking episodes. Aim 2: Test whether IBUD attenuates neural alcohol cue-reactivity. It is hypothesized that IBUD will reduce BOLD activation to alcohol cues in mesocorticolimbic reward circuitry. Aim 3: Test whether withdrawal-related dysphoria moderates the effects of IBUD. It is hypothesized that IBUD will alleviate basal negative affect, interfere with alcohol-induced negative reinforcement and attenuate BOLD activation to alcohol cues only among participants who experience dysphoria in withdrawal. Aim 4: Test whether neural activation to alcohol cues is predictive of drinking outcomes. It is hypothesized that individuals with higher mesocorticolimbic activation to alcohol cues will report more drinking in the week following the neuroimaging session.

Ibudilast (IBUD) is a neuroimmune modulator that inhibits phosphodiesterase-4 and -10 and macrophage migration inhibitory factor.

Negative affect as measured by self-reported ratings of "Downhearted", "Discouraged", "Uneasy", and "Anxious". Each item was rated on a scale from 0 (not at all) to 4 (extremely). The 4 items were summed for the total negative affect score for each day, ranging from 0 - 16. Higher scores indicate more negative mood.

Medication effects on number of heavy drinking days. Heavy drinking is defined by the National Institute on Alcohol Abuse and Alcoholism (NIAAA) as ≥5 drinks/day for men and ≥4 drinks/day for women. Values indicate estimated probability of a heavy drinking day across time for each group.

Medication effects on number of days where any drinking was reported. . Values indicate estimated probability of a drinking day across time for each group.

Medication effect on alcohol cue-induced ventral striatal activation. Participants completed an fMRI alcohol cue-reactivity paradigm where they viewed pictures of alcoholic beverages, non-alcoholic beverages, blurred images, and a plus sign. The mean percent signal change between the ALC and BEV blocks was extracted from an a priori defined region of interest: bilateral ventral striatum (VS), 6 mm-radius sphere centered at ±12 6 9 in MNI space.

Inclusion Criteria: Age between 21 and 45 Meet DSM-5 criteria for current Moderate-to-Severe AUD Current Heavy Drinking (> 14 drinks per week for men; > 7 drinks per week for women), as indicated by self-reported drinking for the 30 days prior to screening Have reliable internet access Exclusion Criteria: Currently receiving or seeking treatment for AUD* Past year DSM-5 diagnosis of any substance use disorder other than alcohol or nicotine A lifetime diagnosis of schizophrenia, bipolar disorder, or any psychotic disorder Current use of drugs, other than marijuana, verified by a urine toxicology screen* Pregnant, nursing, or refusal to use reliable birth control (if female)* A medical condition that may interfere with safe participation (e.g., unstable cardiac, renal, or liver disease, uncontrolled hypertension, diabetes, or AST, ALT, or GGT ≥ 3 times upper normal limit) Self-reported recent (i.e. past 30 day) use of medications that are contraindicated with ibudilast* Non-removable ferromagnetic objects in body Claustrophobia Serious head injury or prolonged period of unconsciousness (>30 minutes) Participants who meet these criteria at any point during the course of the study (i.e. after randomization) will be withdrawn from the study for safety purposes.

Ray LA, Bujarski S, Shoptaw S, Roche DJ, Heinzerling K, Miotto K. Development of the Neuroimmune Modulator Ibudilast for the Treatment of Alcoholism: A Randomized, Placebo-Controlled, Human Laboratory Trial. Neuropsychopharmacology. 2017 Aug;42(9):1776-1788. doi: 10.1038/npp.2017.10. Epub 2017 Jan 16.

Burnette EM, Ray LA, Irwin MR, Grodin EN. Ibudilast attenuates alcohol cue-elicited frontostriatal functional connectivity in alcohol use disorder. Alcohol Clin Exp Res. 2021 Oct;45(10):2017-2028. doi: 10.1111/acer.14696. Epub 2021 Sep 29.