Safety Interaction Trial Ibudilast and Methamphetamine

This study is designed to collect data to determine whether a medication, ibudilast, is safe
for use as a potential treatment for methamphetamine-dependent people. For 18 years in Japan
and South Korea, ibudilast has been used safely in humans as a treatment for asthma,
pulmonary, and cardiovascular disease. It is not known whether ibudilast is safe to use in
outpatient settings with people who have methamphetamine dependence. This would be the first
study to collect this information. This study is important because individuals with
methamphetamine dependence often relapse to meth use, even when in treatment; some number of
individuals who participate in an outpatient study will relapse to methamphetamine while
taking ibudilast. It is crucial to know whether there may be interactions between ibudilast
and methamphetamine before planning an outpatient clinical trial.

The study will be conducted at the Harbor-UCLA hospital to ensure the medical safety of
participants, especially if there are unexpected interactions between ibudilast and
methamphetamine on cardiovascular function. Methamphetamine can cause substantial increases
in heart rate and blood pressure that last for about 3 hours. This study will measure
whether people who are meth-dependent (and not looking for treatment) show increases in
their heart rate and blood pressures when given methamphetamine above what is expected by
methamphetamine alone and when at the recommended doses of ibudilast.

Ibudilast is an exciting medication candidate for treating methamphetamine dependence. When
individuals become abstinent from methamphetamine during early recovery, the body starts an
inflammatory process in neurons, especially glial cells. Glial cells are important in that
they provide support to the nerve cells that are involved in thought, movement, and other
human activities. By dampening inflammation in glial cells, ibudilast may preserve glial and
other nerve cells during early abstinence, which in turn may help individuals feel better
and think better during treatment.

The study specific aims are to determine whether ibudilast alters:

1. blood pressure and heart rate responses to methamphetamine;

2. the ratings of craving or other drug experiences from methamphetamine;

3. the reward/reinforcing effects of methamphetamine; and

4. the metabolism of methamphetamine.

Over an enrollment period of 24 months, 12 methamphetamine-dependent participants who are
not looking for treatment will complete this study. Each participant will complete
assessments of safety/tolerability, perceived effects of methamphetamine, and an assessment
where subjects make choices between different amounts of money and methamphetamine. Each
patient will stay in the hospital for a total of 27 nights. The first two days consist of
safety infusions to make sure methamphetamine is tolerable. Then, each subject will start
study medication and take a 7-day course of three conditions: placebo, ibudilast 20mg BID,
and ibudilast 50mg ibudilast. Low dose ibudilast always precedes high dose ibudilast. The
order of placebo being first or last is random.

Inclusion Criteria:

1. NOT seeking treatment for methamphetamine problems;

2. English-speaking;

3. Age 18-55;

4. Meet SCID criteria for MA dependence;

5. Self-reported history of MA use via injection or smoking AND at least one MA positive
urine drug screening during eligibility;

6. Resting heart rate 50-100BPM; Systolic BP 105-150 mm Hg; Diastolic BP 45-90 mm Hg
stabilized within 2 days of admission;

7. Baseline EKG demonstrating normal sinus rhythm, normal conduction, no clinically
significant arrhythmias;

8. Use of acceptable barrier method of birth control;

9. If female, not pregnant or lactating;

10. Have medical history and physical examination demonstrating no additional clinically
significant contraindications for study participation, in judgment of investigators.

Exclusion Criteria:

1. Current dependence on cocaine, opioids, marijuana, or alcohol;

2. Liver function tests GE 3x upper limit of normal, or kidney function tests GE 2x the
upper limit of normal;

3. Current or past history of seizure disorder;

4. History of head trauma;