Despite numerous clinical trials, no medication has been approved to treat methamphetamine (MA)dependence. Dysfunction in dopaminergic systems and cognitive dysfunction al'e hallmarks of stimulantdependence and predict poor response to behavioral treatment for cocaine and MA dependence. As a result,novel approaches to restoring dopaminergic functioning is a promising approach to developing medicationsfor MA dependence. Ibudiiast (IBUD) is a phosphodiesterase inhibitor and modulator of glial cell activationthat may be effective for MA dependence via reductions in neuroinflammation and/or induction ofneurotrophic factors such as GDNF. In preclinical studies, IBUD reduced MA-prime- and stress-inducedreinstatement of MA seeking in rats, suggesting IBUD is a promising candidate medication with potentialeffects in restoring dopaminergic functioning. The proposed study is a phase II randomized, double-blind,clinical trial of IBUD (N=60) versus placebo. (N=60) with cognitive behavioral therapy for 12 weeks todetenmine the safety and efficacy of IBUD for MA dependence. Primary aims will compare MA use andtreatment retention for IBUD versus placebo. The study has >80% power to detect a benefit for IBUD overplacebo on the FDA-preferred outcome in stimulant trials: urine drug screen confirmed MA abstinence duringthe final two weeks of treatment (yveeks 11/12). Effects of potential confounders including medicationsafety/tolerability, medication non-adherence, and ability to achieve MA abstinence with a contingencymanagement intervention during a two-week trial lead-in period, on outcomes will be assessed. Potentialmechanisms of IBUD in MA dependence will be probed in exploratory analyses examining any effects ofIBUD on cognitive function and changes in cognition during treatment, and associations between treatmentoutcomes and polymorphisms in dopaminergic genes, the gene for GDNF, and serum GDNF levels. A phaseI human safety-interaction study of IBUD in MA dependence is currently undenway at our Center and will becompleted prior to funding of this proposed study. The proposed trial is the result of a long-standing ,collaboration between our research Center and MediciNova, Inc. who are fully committed to seeing IBUDthrough the regulatory and marketing process for MA dependence. If unanticipated events precludeadvancing IBUD into phase II testing in time for this study, the bupropion-naltrexone combination formulationundergoing phase 1 testing in Project 1 of this proposal will be advanced to phase II testing instead.
(See Instructions):Methamphetamine dependence is a significant source of detrimental consequences to individual and publichealth including psychiatric distress (paranoia, suicidality, etc.), neurologic effects (neurological impairment,stroke, seizures), HIV and hepatitis C infection, and cardiovascular disease. Identification of an effectivepharmacotherapy for MA dependence would have a significant public health impact.
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