Safety Study to Assess Atomoxetine With MA Abusers and Healthy Controls
Condition: Continuous Methamphetamine Dependence; Methamphetamine Dependence in Remission
Study type: Interventional
Phase: Phase 1

Summary: 
      Methamphetamine (MA) abuse is a national public health concern. People who are dependent on
      MA have problems with mental functions (e.g., learning, remembering, focusing attention,
      solving problems). Such problems can interfere with their treatment for MA abuse, and thereby
      may promote continued drug use. While the effects of MA have been studied in rodents and
      non-human primates, its effects on the human brain have not been well characterized.

      This is a study of nontreatment seeking individuals who use MA compared to individuals who do
      not use MA(control participants). The study has three goals: 1. it aims to identify the brain
      regions and pathways that may contribute to the problems of MA abusers in performing mental
      tasks; 2. it will serve as a double-blind, placebocontrolled,within-subjects study to
      determine the safety and tolerability, and positive effects of MA in MA-abusing volunteers
      treated with atomoxetine or placebo; 3. It aims to compare the brain activity as measured by
      structuraland functional magnetic resonance imaging (fMRI). These are noninvasive brain
      imaging procedures, that will be used to study brain function while control and MA using
      participants take atomoxetine or placebo and perform tests of memory and concentration.

      MA abusing participants will undergo a 1-day outpatient screening and if it is safe for the
      participants to proceed with the study they will participate in two inpatient phases of the
      study that will occur in the UCLA research setting, the General Clinical Research Center. The
      first inpatient stay will be 15 days, and the second will be a 9 days stay that includes drug
      administration and assessments. There will be at least a two week interval between inpatient
      phases. During the inpatient phases participants will receive alternating study drugs;
      atomoxetine or placebo and four sessions of IV MA administration or placebo.

      The study schedule for control participants will include a 1-day outpatient screening and two
      phases of outpatient administration of atomoxotime or placebo with a two week study drug free
      interval between the phases. Four to five of the outpatient study visits will involve
      cognitive tests and brain imaging studies.
    

Detailed description: 
      As a preliminary step, the investigators will screen the experimental data for normality and
      for potential associations between outcome variables with demographic variables at baseline.
      In cases of strong deviations from normality, log or power transformations will be used as
      appropriate. For the subjective effects questionnaires, the peak effect will be identified
      for each subject and used as the dependent variable. The primary analytical technique will be
      linear mixed effects regression. The general linear mixed model (GLMM) is equivalent to
      repeated measures ANOVA when all subjects have complete data but automatically handles
      missing observations, producing unbiased estimates as long as the values are missing at
      random. This approach will allow use of the data from subjects who complete only part of the
      protocol or who have invalid measurements on some tests, greatly enhancing our power.

      The sample size is as large or greater than those in the previous human laboratory studies
      assessing safety and initial efficacy of agonist-like pharmacotherapies for stimulant
      dependence. For example, these previous studies used samples of 7 (Herin et al., 2010; Stoops
      et al., 2008; Dackis et al., 2003), and 10 (Sofuoglu et al., 2009) subjects to obtain
      significant reductions in subjective effects of d-amphetamine by atomoxetine and those of
      cocaine by modafinil.

      To be conservative, the investigators base power estimates on completers but will use
      available data from all 30 subjects in GLMM analyses. This should substantially increase
      power (power for GLMM and repeated measures ANOVA are equivalent except that ANOVA cannot
      utilize incomplete data, while a GLMM can).
    

Intervention name(s): Atomoxetine; Placebo
Intervention type(s): Drug; Other
Intervention description(s): MA Group: Dispense 1 cap @ 8 AM on Treatment day 9 and 10 (total daily dose 40mg or 0); 1 cap SID @ 8 AM and 4 PM on day 11,12, and 13 (total daily dose 80mg or 0); 1 cap @ 8 AM on day 14 (total daily dose, 40mg or 0).
Control Group Schedule:
Day 1: 40mg @ 8:00am
Day 2: 40mg @ 8:00am
Day 3: 40mg @ 8:00am, 40mg @ 8:00pm
Day 4: 40mg @ 8:00am, 40mg @ 8:00pm
Day 5: 40mg @ 8:00am, 40mg @ 8:00pm
Day 6: 40mg @ 8:00am = Testing day (fMRI scan & cognitive testing session); Control Group: Day 1: 40mg @ 8am Day 2: 40mg @ 8am Day 3: 40mg @ 8am, 40mg @ 8pm Day 4: 40 mg @ 8am, 40mg @ 8pm Day 5: 40mg @ 8am, 40 mg @ 8pm Day 6: 40 mg @ 8am = Testing day (fMRI scan & cognitive testing session)
Other intervention name(s): Strattera
Intervention MeSH terms: Atomoxetine Hydrochloride
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Triple (Participant, Investigator, Outcomes Assessor)
Primary purpose: Treatment
Keywords: Methamphetamine, Atomoxetine, Clinical Pharmacology