Modafinil vs Placebo for the Treatment of Methamphetamine Dependence

Modafinil is a non-amphetamine type stimulant that acts as a wakefulness-promoting drug, and is approved for managing symptoms of narcolepsy (i.e., daytime somnolence). Its precise mechanism of action in promoting wakefulness remains unclear. This trial is a placebo-controlled double-blind trial of modafinil, on a platform of contingency management (CM) and individual cognitive-behavioral (CBT) counseling, for the treatment of methamphetamine dependence. Participants in this study will complete a 2-week baseline screening period during which they will provide urine samples and complete physical and psychological assessments to establish their eligibility for the study. In addition, participants will be asked to provide a blood or saliva specimen for genetic testing in order to identify genetic variations that influence response to methamphetamine and to treatment with modafinil. Upon successful completion of screening, participants will be randomly assigned to receive either modafinil (400mg qd) or placebo during the 12 weeks of the study. Neither the participants nor study staff will know who is receiving active medication or placebo. Regardless of medication condition, all participants will receive CM and weekly individual CBT counseling sessions to help them stop using methamphetamine and prevent relapse. They will attend the clinical research site (either at the UCLA Hollywood Clinic, or the Rancho Cucamonga site) three times per week, providing urine samples at each visit, completing data measures, and receiving individual CBT counseling on one visit each week. At the end of the 12-week study, the medication or placebo will be discontinued. Participants will return to the research site approximately 30 days following medication discontinuation for a brief health check to assess any possible lingering side effects and complete brief data measures.

This application proposes a placebo-controlled double-blind trial of modafinil, on a platform of contingency management (CM) and individual cognitive-behavioral counseling (CBT once weekly individual session), for the treatment of methamphetamine dependence. Modafinil is a medication warranting evaluation as a treatment for MA dependence. It has a half-life of approximately 15 hours and reaches steady state in 2-4 days (Package insert) and will likely require once daily dosing, which reduces problems with medication adherence. Modafinil has potent psychiatric and behavioral effects that include brightening mood (Menza et al., 2000; Ninan et al., 2004), improving cognition (Turner et al., 2004a, b; 2003), improving impulse control (Turner et al., 2003; Turner et al., 2004a), and countering fatigue (Beusterien et al., 1999, Stahl et al., 2003). These effects neatly counterbalance effects produced by MA withdrawal (Newton et al., 2004) and may have particular value in ameliorating the negative reinforcing properties of MA, i.e., when MA is used to immediately relieve depressed mood due to recent abstinence (Peck et al., 2005b). CM is a behavioral intervention that effectively helps substance abusers to initiate abstinence, particularly from cocaine (Higgins et al., 1993; Higgins et al., 2000; Higgins et al., 1991) and from methamphetamine (Roll \& Shoptaw, in press; Shoptaw et al., 2005). As well, CM has been shown to reduce substance abuse and optimize the effects of medications in reducing substance abuse (Carroll, 2004; Shoptaw et al., 2002). The objective of this study is to determine whether modafinil reduces methamphetamine use and concomitant physical and psychological symptoms more effectively than placebo when administered in conjunction with CM and CBT. The purpose of this project is to evaluate whether methamphetamine abusers seeking outpatient treatment demonstrate significantly significant reductions of methamphetamine when randomly assigned to receive modafinil (400mg qd) in combination with CM and weekly CBT compared their peers randomly assigned to receive placebo in combination with CM and weekly CBT.

Research Hypotheses:

1. Participants receiving active experimental drug (modafinil 400mg) will demonstrate statistically significant reductions in methamphetamine use over participants receiving placebo. Methamphetamine use outcomes will be measured using urine samples and analyzed with the following indices: Treatment Effectiveness Score, the Joint Probability Index, self-report of methamphetamine use verified by urine drug screening, and the longest uninterrupted period of methamphetamine abstinence. Primary analyses will be conducted using modeling approaches (Generalized Estimation Equations, Markov Chain Transition Models) depending upon the structure of the dataset. Self-report of methamphetamine use will be analyzed using the Addiction Severity Index drug composite scale and Substance Use Inventory (SUI).
2. Participants receiving active experimental drug will remain in treatment for significantly longer periods compared to participants receiving placebo. Retention will be measured by the number of days in the protocol and analyzed using survival analysis.

   a. Specifically, participants with mild cognitive dysfunction (as measured as \<=1 SD below the published mean for the MicroCog assessments) receiving modafinil (400mg) will demonstrate significantly greater overall retention, and attendance to CBT sessions than those participants with cognitive function measured at greater than 1 SD below the mean for the MicroCog assessments who are receiving placebo.
3. Participants receiving active experimental drug (modafinil 400mg) will demonstrate statistically significant reductions in reported methamphetamine craving over participants receiving placebo. Craving outcomes will be measured using a visual analogue scale.
4. Participants receiving active experimental drug (modafinil 400mg) will demonstrate statistically significant reductions in withdrawal symptoms and somatic complaints compared to participants receiving placebo. These outcomes will be measured using the BSI, the Beck Depression Inventory-II, and the Quality of Well-Being scale.

Exploratory analyses will also be conducted to identify potential genetic variants associated with treatment response to modafinil for MA dependence. Candidate genes implicated by previous research as being involved in the pathogenesis of MA dependence and/or the molecular mechanism of modafinil (for example, genes for neurotransmitter receptors and transporters, including dopamine, norepinephrine, GABA, and glutamate, as well as genes for enzymes involved in the metabolism of these neurotransmitter, such as catechol-O-methyltransferase and monoamine oxidase A) will be sequenced in order to determine the frequency of known single nucleotide polymorphisms (SNPs), as well as potentially identify novel SNPs, in these genes among MA dependent participants. Initial analyses will focus on genes involved in the dopaminergic pathway, given the importance of dopamine in the neurobiology of MA dependence, but additional genes may also be assessed. SNPs associated with response to modafinil will be identified in order to generate hypotheses for future pharmacogenomic studies.

Eligibility Criteria:
Inclusion Criteria:

1. 18 years of age or older;
2. meet DSM-IV criteria for methamphetamine dependence;
3. willing and able to comply with study procedures;
4. willing and able to provide written informed consent;
5. if female, not pregnant or lactating and willing to use an acceptable method of barrier birth control (e.g. condoms) during the trial and for one month after discontinuation of study medication (modafinil may reduce the effectiveness of steroidal contraceptives both during administration and for one month after discontinuation).

Exclusion Criteria:

1. have 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, unstable diabetes, or elevated liver enzymes (SGOT or SGPT) greater than 4 times the upper limit of normal);
2. have a current neurological disorder (e.g., organic brain disease, dementia) or major psychiatric disorder not due to substance abuse (e.g., schizophrenia or bipolar illness) as assessed by the SCID and a medical history which would make study agent compliance difficult or which would compromise informed consent, or recent (past 30 days) history of suicide attempts and/or current serious suicidal intention or plan as assessed by the SCID and the BDI-II;
3. currently on prescription medication that is known to interact with the study drug;
4. have current dependence on cocaine, opiates, alcohol, or benzodiazepines, as defined by DSM-IV-TR criteria;
5. have a history of alcohol dependence within the past three years;
6. have a history of mitral valve prolapse, left ventricular hypertrophy, cardiac arrhythmias, angina, myocardial infarction, acute coronary syndrome (unstable angina), cardiac syncope or presyncope, or any EKG abnormalities that suggests the presence of one of these conditions;
7. have a systolic blood pressure greater than 160, a diastolic blood pressure greater than 100 (i.e. cutoffs for stage 2 hypertension), and a heart rate greater than 70% of the maximum heart rate expected for their age (0.70(220-age)) at any of the study visits.
8. any other circumstances that, in the opinion of the investigators, would compromise participant safety;
9. have a history of sensitivity to modafinil.