A Study to Assess the Cardiovascular, Cognitive and Subjective Effects of Atomoxetine in Combination With Intravenous Methamphetamine
Overview
- Phase
- Phase 1
- Intervention
- Atomoxetine
- Conditions
- Continuous Methamphetamine Dependence
- Sponsor
- University of California, Los Angeles
- Enrollment
- 41
- Primary Endpoint
- Cardiovascular & Subjective Effects of Methamphetamine & Atomoxetine
- Status
- Completed
- Last Updated
- 9 years ago
Overview
Brief 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).
Investigators
Edythe London
Principal Investigator
University of California, Los Angeles
Eligibility Criteria
Inclusion Criteria
- •MA ABUSING PARTICIPANTS:
- •In order to participate in the study, MA-using subjects must:
- •Be fluently English-speaking volunteers who meet DSM-IV criteria for MA abuse or dependence.
- •Be between 18 and 50 years of age.
- •Be able to verbalize understanding of consent form, able to provide written informed consent, and verbalize willingness to complete study procedures.
- •Have smoked or injected methamphetamine for more than two years.
- •Produce a methamphetamine-positive urine prior to study entry.
- •Have vital signs as follows: resting pulse between 50 and 90 bpm, blood pressures between 105-150mm Hg systolic and 45-90mm Hg diastolic. Note: MA Abusing participants may present with elevated vital signs during the intake screening phase as a result of MA intoxication or anxiety and elevated vital signs may occur after inclusion to the study prior to administration or Methamphetamine or study compound. Participants must have vital signs within the aforementioned range on two timepoints (i.e., morning or night vital collection) during two consecutive days prior to randomization or participation will be terminated.
- •Have an ECG performed that demonstrates normal sinus rhythm, normal conduction, and no clinically significant arrhythmias.
- •Agree to abstain from MA during the study, evidenced by a MA-negative urine each morning of the study.
Exclusion Criteria
- •MA ABUSING PARTICIPANTS:
- •Exclusion Criteria:
- •A current or past history of seizure disorder, including alcohol- or stimulant-related seizure, febrile seizure, or significant family history of idiopathic seizure disorder.
- •A history of head trauma that resulted in neurological sequelae (e.g., with loss of consciousness \[LOC\] \> 15 minutes, or that required hospitalization. Also, individuals with 3 or more head injuries with LOC \> 5 minutes will be excluded).
- •Meet DSM-IV criteria (by SCID) for drug dependence other than meth, with the exception of nicotine and/or marajuna dependence.
- •Any previous medically serious adverse reaction to MA including loss of consciousness, chest pain, or epileptic seizure resulting in hospitalization.
- •Meeting diagnostic criteria or receiving psychopharmacological treatment for the following Axis I disorders within the last 6 months: anorexia nervosa, bulimia, psychosis, bipolar I disorder, organic brain disease, dementia, major depression, schizoaffective disorder, or schizophrenia.
- •Evidence of clinically significant heart disease, hypertension or significant medical illness.
- •Have any history of hypersensitivity to atomoxetine, glaucoma, motor tics or with a family history or diagnosis of Tourette's syndrome.
- •Have any preexisting severe gastrointestinal narrowing, small bowel inflammatory disease, intestinal adhesions, past history of peritonitis, or cystic fibrosis.
Arms & Interventions
Atomoxetine
Double-blind, Placebo controlled, 2-phase study the safety \& efficacy of Atomoxetine
Intervention: Atomoxetine
Placebo
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)
Intervention: Placebo
Outcomes
Primary Outcomes
Cardiovascular & Subjective Effects of Methamphetamine & Atomoxetine
Time Frame: 4 weeks
Participants will be followed for the duration of the study, an expected average of 4 weeks
Secondary Outcomes
- The effects of administration of atomoxetine on the preference of MA-using subjects for MA (0 and 15mg, IV) versus escalating doses of money, from $0.25 to $64 in a Multiple-Choice Procedure.(4 weeks)
- The effects of atomoxetine administration on cognitive function, as determined by measures of performance on cognitive tests, such as working memory tasks and reaction time tests(4 weeks)
- The effects of administration of atomoxetine on BOLD fMRI signals in the brain in MA users and normal controls.(4 weeks)