Ibudilast and Withdrawal-Related Dysphoria
Condition: Alcohol Use Disorder
MeSH terms: Alcoholism; Alcohol Drinking
Intervention: Ibudilast; Placebo
Intervention description: Ibudilast (IBUD) is a neuroimmune modulator that inhibits phosphodiesterase-4 and -10 and macrophage migration inhibitory factor.; Placebo is matched to ibudilast active medication.
Intervention MeSH terms: Ibudilast
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Double (Participant, Investigator)
Enrollment: 52.0
Sex: All
Minimum age: 21 Years
Maximum age: 45 Years
Healthy volunteers: No

Summary:

      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.
    

Eligibility criteria:

        Inclusion Criteria:

          1. Age between 21 and 45

          2. Meet DSM-5 criteria for current Moderate-to-Severe AUD

          3. 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

          4. Have reliable internet access

        Exclusion Criteria:

          1. Currently receiving or seeking treatment for AUD*

          2. Past year DSM-5 diagnosis of any substance use disorder other than alcohol or nicotine

          3. A lifetime diagnosis of schizophrenia, bipolar disorder, or any psychotic disorder

          4. Current use of drugs, other than marijuana, verified by a urine toxicology screen*

          5. Pregnant, nursing, or refusal to use reliable birth control (if female)*

          6. 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)

          7. Self-reported recent (i.e. past 30 day) use of medications that are contraindicated
             with ibudilast*

          8. Non-removable ferromagnetic objects in body

          9. Claustrophobia

         10. 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.