Trial of Ibudilast for Methamphetamine Dependence

Ibudilast (IBUD) is a macrophage migration inhibitory factor (MIF) and phosphodiesterase
(PDE)-4 and -10 inhibitor at peak clinical exposures (Rolan, Hutchinson et al. 2009) that
increases glial cell line-derived neurotrophic factor (GDNF) expression (Mizuno, Kurotani et
al. 2004) and reduces microglial activation (Suzumura, Ito et al. 1999; Suzumura, Ito et al.
2003), including HIV-induced glial activation (Kiebala and Maggirwar 2011). IBUD
significantly reduces methamphetamine (MA) prime- and stress-induced reinstatement of MA
seeking in rats (Beardsley, Shelton et al. 2010) and has multiple effects that may make it an
effective treatment for MA dependence including amelioration of dopaminergic and
neuroinflammatory dysfunction. Multiple studies implicate glial cells in a variety of
neurodegenerative diseases (Hirsch and Hunot 2009; Sidoryk-Wegrzynowicz, Wegrzynowicz et al.
2011) including MA dependence and HIV infection (Nath 2010). Activated glial cells secrete
pro-inflammatory mediators (Minghetti, Ajmone-Cat et al. 2005) that may exacerbate MA-induced
dopaminergic dysfunction. Glial cells also produce neurotrophic factors, including GDNF,
which may ameliorate dopaminergic dysfunction (Pascual, Hidalgo-Figueroa et al. 2008). Thus,
IBUD may be an effective medication for MA dependence due to its modulation of glial cell
activation resulting in amelioration of dopaminergic and neurocognitive dysfunction and
improved treatment outcomes in MA dependence. IBUD may also have unique effects in HIV
positive MA users as it may additionally block the degradation of neuronal integrity seen in
HIV infection (Chana, Everall et al. 2006; Dash, Gorantla et al. 2011).

Inclusion Criteria:

1. 18 years of age or older;

2. meet DSM-IV-TR criteria for MA dependence (SCID verified);

3. a MA-positive urine drug screen at one or more visit during the two week lead-in
period;

4. seeking treatment for MA problems;

5. willing and able to comply with study procedures;

6. provide written informed consent;

7. English speaking

8. reside within 35 miles of the clinical research site; and

9. if female of childbearing potential, not pregnant or lactating and willing to use a
medically reliable method of birth control during the trial (e.g., birth control
pills, Depo-Provera, and/or condoms with spermicide).

Exclusion Criteria:

1. a medical condition that, in the study physician's judgment, may interfere with safe
study participation (e.g., active TB; unstable cardiac, renal, or liver disease;
uncontrolled hypertension; unstable diabetes);

2. CD4 count < 50 cells/mm3 (suggestive of advanced HIV infection)

3. AST, ALT, or GGT > 3 times upper normal limit;

4. A corrected QT of > 450 msecs in men or > 460 msec in women on at least two ECGs
during the baseline period, or clinical risk factors for Torsades de Pointes (e.g.
(e.g., heart failure, hypokalemia, family history of Long QT Syndrome), or requiring
ongoing treatment with concomitant medication(s) with established risk of Torsades de
Pointes (e.g. Amiodarone, Arsenic trioxide, Astemizole, Bepridil, Chloroquine,
Chlorpromazine, Cisapride, Citalopram, Clarithromycin, Disopyramide, Dofetilide,
Domperidone, Droperidol, Erythromycin, Flecainide, Halofantrine, Haloperidol,
Ibutilide, Levomethadyl, Mesoridazine, Methadone, Moxifloxacin, Pentamidine, Pimozide,
Probucol, Procainamide, Quinidine, Sotalol, Sparfloxacin, Terfenadine, Thioridazine,
Vandetanib);

5. current ongoing treatment with psychotropic medications (e.g., antidepressants,
antipsychotics, antiepileptics, sedative/hypnotics, narcotic analgesics);

6. a neurological disorder (e.g., organic brain disease, dementia) or a medical condition
which would make study agent compliance difficult or which would compromise informed
consent;

7. a major psychiatric disorder not due to substance abuse (e.g., schizophrenia, bipolar
disorder) as assessed by the SCID;

8. attempted suicide in the past 3 years and/or serious suicidal intention or plan in the
past year as assessed by the C-SSRS;

9. currently on prescription medication that is contraindicated for use with IBUD
including alpha or beta agonists, theophylline, or other sympathomimetics;

10. current dependence on cocaine, opiates, alcohol, or benzodiazepines as defined by
DSM-IV-TR;

11. alcohol dependence within the past year;

12. greater than one urine specimens during the lead-in with a riboflavin concentration of
< 900 ng/ml as assessed via UV fluorescence;

13. a history of sensitivity to IBUD; or

14. any other circumstances that, in the opinion of the investigators, would compromise
participant safety;

15. current participation in another clinical trial.