Development of Ibudilast for Alcohol Use Disorder

Alcohol dependence (AD) is a chronic and relapsing condition affecting 10 million Americans.
To date, only four pharmacotherapies are approved by the FDA for the treatment of alcoholism
and their efficacy is modest. Therefore, medication development for AD represents a high
priority area. Ibudilast (IBUD) is a glial cell modulator that inhibits phosphodiesterases
(PDE) -4 and -10 and macrophage migration inhibitory factor (MIF). Preclinical data suggest
that neuroimmune modulation is critical to the rewarding properties of drugs of abuse,
including alcohol. Further, IBUD has been shown to enhance GDNF release in vivo and GDNF
modulation has been implicated in alcohol reinstatement in animals, while PDE inhibition has
been shown to reduce alcohol intake in mice. Together, these findings suggest that
neuroimmune modulation constitutes a novel target for the treatment of alcoholism. The
objective of this study is to advance medication development for alcoholism by conducting an
initial Phase II study of IBUD for AD. Specifically, the proposed study consists of a
randomized, double-blind, placebo-controlled within-subject crossover design to determine
the safety, tolerability, and initial human laboratory efficacy of IBUD in a sample of 24
non-treatment seeking individuals with either alcohol abuse or dependence treated with IBUD
(50mg BID) and placebo. Participants will complete two separate 7-day inpatient stays at the
UCLA CTRC during which they will take the study medication, complete an IV alcohol
challenge, and take part in a stress-exposure and cue-exposure paradigms. Specific aims are
to test whether IBUD (a) is safe in the context of alcohol administration, (b) attenuates
alcohol-induced reinforcement, and (c) dampens stress-induced and cue-induced alcohol
craving. In sum, this study will efficiently evaluate safety and initial efficacy of IBUD
thereby screening novel medications for AD and elucidating potential mechanisms by which
IBUD may be clinically efficacious. Results from this study will inform whether a randomized
controlled trial of IBUD for alcoholism is warranted.

Inclusion Criteria:

- age between 21 and 65

- meet DSM-IV diagnostic criteria for alcohol abuse or dependence

- report drinking at least 48 standard drinks in a 30-day period, during the 90 days
before enrollment

Exclusion Criteria:

- current treatment for alcohol problems, a history of treatment in the 30 days before
enrollment or current treatment seeking;

- current (last 12 months) DSM-IV diagnosis of dependence on any psychoactive
substances other than alcohol and nicotine;

- lifetime DSM-IV diagnosis of schizophrenia, bipolar disorder, or any psychotic
disorder;

- positive urine screen for narcotics, amphetamines, or sedative hypnotics;

- serious alcohol withdrawal symptoms as indicated by a score ≥ 10 on the Clinical
Institute Withdrawal Assessment for Alcohol-Revised (CIWA-R);

- pregnancy, nursing, or refusal to use reliable method of birth control (if female);

- medical condition that may interfere with safe study participation (e.g., unstable
cardiac, renal, or liver disease, uncontrolled hypertension or diabetes);

- AST, ALT, or GGT ≥ 3 times upper normal limit;

- attempted suicide in the past 3 years and/or serious suicidal intention or plan in
the past year;

- currently on prescription medication that contraindicates use of IBUD;

- any other circumstances that, in the opinion of the investigators, compromises
participant safety