The objective of this study is to test the safety and potential efficacy of ibudilast to treat methamphetamine dependence. The study hypotheses are that ibudilast will reduce methamphetamine use and increase treatment retention more than placebo among patients seeking treatment for methamphetamine dependence. As HIV infection is a common complication of methamphetamine dependence, half of the participants will be HIV positive and the study will assess whether ibudilast also improves HIV related outcomes (e.g. medication adherence, CD4 count, risk behaviors).

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.

12 week medication treatment period and 4 week post-treatment follow-up period

Study did not determine if ibudilast may help patients who have stopped methamphetamine use prior to starting medication