A Study to Assess the Cardiovascular, Cognitive, and Subjective Effects of Atomoxetine in Combination with Intravenous Methamphetamine

The Study to Assess the Cardiovascular, Cognitive, and Subjective Effects of Atomoxetine in Combination with Intravenous Methamphetamine started in 2007 and ended in 2011. It was a small pilot study that included methamphetamine abusing individuals and healthy control participants aged 18-50 years. Participants who qualified over the telephone were scheduled to visit the London Laboratory at the UCLA Semel Institute for Neuroscience and Human Behavior for the In-Person Screening Phase. The screening procedures, usually scheduled over two visits, determined if participants were eligible to complete the subsequent study visits. Both groups completed identical screening procedures, including a SCID diagnostic interview to rule out any major psychiatric disorders. Methamphetamine users also answered questionnaires specific to their drug use. Urine toxicology for marijuana, opiates, cocaine, methamphetamine, and benzodiazepines were monitored at the beginning and throughout the study. Additionally, participants had blood samples to test for Rapid Plasma Reagin (exposure to syphilis), purified protein derivative (PPD), HIV and Hepatitis-C (HCV). Positive test results were relayed by a study physician and resulted in termination from continuing in the study.

The inpatient portion of the study lasted a total of 24 days. To confirm compliance with abstinence from illicit and prescription drug use for the duration of the study, urine and breath alcohol testing was performed for both inpatient (methamphetamine users) and outpatient (healthy control) groups. Each subject was randomized to receive either atomoxetine (80 mg daily) or placebo. During inpatient days of the study, a study physician oversaw research subjects daily and experimental procedures were conducted in the General Clinical Research Center (GCRC). During drug administration sessions, heart rate and blood pressure were assessed at frequent intervals. Experimental sessions lasted around three hours and were conducted at approximately the same time of day for a given participant. Lunch was provided to participants at 11:30am with the prohibition of caffeine on study days involving methamphetamine administration. Participants were provided with smoke breaks as needed to assure that acute nicotine withdrawal did not negatively impact performance on cognitive testing. The following outlines the day to day procedures for a methamphetamine inpatient:

Phase I Inpatient Study (15 days total)
Days 1-3: On the day of admission, participants received blood tests and an EKG in order to determine that they had no occult medical conditions which would make their participation in the study medically contraindicated. A three day washout period was provided at the beginning of the study to establish an appropriate methamphetamine-free baseline for testing.
Days 4-6: Participants completed cognitive test batteries to assess inhibitory control including self-report measures and cognitive testing, as well as up to three MRI scanning sessions.
Day 7: On day 7, at 9AM and 1PM, participants received methamphetamine in a single-blinded condition. It was administered as two IV infusions of 15mg separated by a 60min break. The total dose of IV methamphetamine was 30mg. Participants were clinically evaluated by continuous cardiac telemetry, serial EKG and measurement of vital signs, during and after infusions, in order to determine the medical safety of methamphetamine infusion in the absence of study medication.
Day 8: On day 8 we evaluated the safety and residual effects of the methamphetamine administered on the previous day.
Days 9-10: After demonstrating medical and psychiatric stability of the initial methamphetamine infusion, participants were then randomized to receive placebo or atomoxetine (0 or 40mg) under double-blind conditions, which would be given at 8AM on both study days.
Days 11-12: On days 11 and 12, participants remained in the GCRC and took two doses of test compound atomoxetine (0 or 40mg) at 8AM and 8PM. On the morning of day 12, participants completed a series of cognitive testing.
Day 13: On day 13, participants remained in the GCRC, and took two doses of the test compound atomoxetine (0 or 40mg) at 8AM and 8PM. At 9AM and noon, they received methamphetamine under double-blind conditions administered non-contingently as two infusions of 0 or 15mg by IV (intravenously), with each infusion separated by 60min. The total dose of IV methamphetamine that each participant received was 30mg. As before, participants were clinically evaluated by continuous cardiac telemetry, serial EKG and measurement of vital signs, during and after infusions, in order to determine the medical safety of methamphetamine infusion in those participants receiving study medication.
Day 14: On day 14 at 8AM, participants received their final dosing of the first test compound (atomoxetine 0 or 40mg). At 9AM and 1PM, participants selected between methamphetamine infusion or money using double-blind conditions in a multiple-choice self-administration paradigm. Participants were able to take up to two infusions of 0 or 15mg of methamphetamine, separated by 60min. The total dose of IV methamphetamine that each participant received on day 14 was 30mg. Participants were clinically evaluated by continuous cardiac telemetry, serial EKG and measurement of vital signs, during and after infusions, in order to determine the medical safety of methamphetamine infusion in those participants receiving study medication. At 5pm on day 14 discharge laboratory studies were drawn.
Day 15: On day 15, a final EKG was performed as well as a review of discharge laboratory studies, including review of the EKG and continued medical and psychiatric stability. Upon clearance from a physician, participants were discharged on day 15. Participants spent at least 2 weeks (14 days) out of the hospital prior to returning to the UCLA GCRC for inpatient Phase II.

Phase II Inpatient Study (9 days total)
Day 1-2: On the day of re-admission, participants received blood tests and an EKG. A two day washout period was provided at the beginning of the study to establish an appropriate methamphetamine free condition for safe administration of the second test compound condition.
Days 3-4: On days 3 and 4, given medical stability, participants were then switched to the opposite test compound (atomoxetine 0 or 40mg) under double-blind conditions, in the same manner as in Days 9-10 in Phase I.
Days 5-6: Same procedure as in Days 11-12 in Phase I but with opposite medication condition.
Day 7: Same procedure as in Day13 in Phase I but with opposite medication condition.
Day 8: Same procedure as in Day14 in Phase I but with opposite medication condition.
Day 9: Same procedure as in Day14 in Phase I but with opposite medication condition.

For healthy control participants, the study consisted of 30 days or fewer of out-patient testing. Healthy control participants had an extensive screening, including a history and physical exam performed by a study physician, an EKG, and laboratory studies performed to assess for medical or psychiatric conditions. Control participants meeting criteria were invited back to UCLA to undergo cognitive testing, and some participants received fMRI scans. Participants were required to refrain from illicit and prescription drug use for the duration of the study, which was confirmed with urine toxicology and breath alcohol level testing on examination days. Caffeine was restricted on study days for least 2 hours prior to cognitive testing and MRI scans. Participants were permitted to drink their normal daily intake of caffeine, given the caveat above. On study days, cigarette smoking was permitted to match conditions used with methamphetamine users. The incorporation of smoke breaks during the test day assured that acute nicotine withdrawal did not negatively impact performance on cognitive tests or neuroimaging. The following outlines procedures for healthy control participants:

For normal controls, participation involved one day of outpatient screening, and one day of baseline cognitive testing and possible MRI scans. After these procedures were completed, participants were randomized to the first test compound (atomoxetine 40mg or placebo), to be taken once daily in the morning for 2 days. It was then increased to twice daily for the next 3 days, followed by a final dose (40mg or placebo) on the sixth day of study medication. Participants were also asked to bring their pill packages to assess compliance with the study medication. Additionally, control participants completed a series of repeated-measures cognitive testing (on placebo or atomoxetine, respectively) and possibly two fMRI sessions (separated by a short break).

After at least a four-day washout period, control participants were instructed to start the opposite test compound (atomoxetine 40mg or placebo), again to be taken once daily in the morning for two days, then twice daily for 3 days, reaching the final dose (40mg or placebo) of the second test compound in the morning. Participants were again asked to bring their pill packages to assess compliance and had blood drawn to assess atomoxetine levels. Control participants then completed another series of cognitive testing and fMRI testing sessions. They were subsequently discharged from the study. Normal control participants returned two weeks after completion of both study phases in order to complete assessments to their physical and psychological status following treatment.

• Study Design:
  • Case-Control
• Study Type:
  • Case-Control
• dbGaP estimated ancestry using GRAF-pop
• Subject Sample Telemetry Report (SSTR)

Inclusion Criteria:

1. Be fluently English-speaking volunteers.
2. Be between 18 and 50 years of age.
3. Be able to verbalize understanding of consent form, able to provide written informed consent, and verbalize willingness to complete study procedures.
4. If female, have a negative pregnancy test and agree to use one of the following methods of birth control, or be postmenopausal, have had a hysterectomy or have been sterilized.
1. oral contraceptives
2. barrier (diaphragm or condom) with spermicide, or condom only
3. intrauterine progesterone, or non-hormonal contraceptive system
4. levonorgestrel implant
5. medroxyprogesterone acetate contraceptive injection
6. complete abstinence from sexual intercourse
5. Control Subjects:
1. Must have vital signs as follows during two visits prior to medication administration: resting pulse between 50 and 90 bpm, blood pressures between 105-150mm Hg systolic and 45-90mm Hg diastolic.
2. Have an ECG performed that demonstrates normal sinus rhythm, normal conduction, and no clinically significant arrhythmias.
3. Agree to abstain from any and all substances of abuse during the study, evidenced by toxicology-negative urine each day prior to study procedures.
6. Methamphetamine Subjects:
1. Must meet DSM-IV criteria for methamphetamine abuse or dependence.
2. Have smoked or injected methamphetamine for more than two years.
3. Produce a methamphetamine-positive urine prior to study entry.
4. 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: Methamphetamine Abusing participants may present with elevated vital signs during the intake screening phase as a result of methamphetamine 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 was terminated.
5. Have an ECG performed that demonstrates normal sinus rhythm, normal conduction, and no clinically significant arrhythmias.
6. Agree to abstain from MA during the study, evidenced by a MA-negative urine each morning of the study.

Exclusion Criteria:

1. A current or past history of seizure disorder, including alcohol- or stimulant-related seizure, febrile seizure, or significant family history of idiopathic seizure disorder.
2. 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).
3. Evidence of clinically significant heart disease, hypertension or significant medical illness.
4. Have any history of hypersensitivity to atomoxetine, glaucoma, motor tics or with a family history or diagnosis of Tourette's syndrome.
5. Have any preexisting severe gastrointestinal narrowing, small bowel inflammatory disease, intestinal adhesions, past history of peritonitis, or cystic fibrosis.
6. Be pregnant or nursing.
7. Have a significant family history of early cardiovascular morbidity or mortality.
8. Have a diagnosis of adult asthma, including those with a history of acute asthma within the past two years, and those with current or recent (past 2 years) treatment with inhaled or oral beta-agonist or steroid therapy (due to potential serious adverse interactions with methamphetamine).
9. Be actively using albuterol or other beta agonist medications, regardless of formal diagnosis of asthma. (Inhalers are sometimes used by methamphetamine addicts to enhance methamphetamine delivery to the lungs.) If respiratory disease is excluded and the subject will consent to discontinue agonist use, s/he may be considered for inclusion.
10. For subjects suspected to have asthma, but without formal diagnosis, 1) have a history of coughing and/or wheezing, 2) have a history of asthma and/or asthma treatment two or more years before, 3) have a history of other respiratory illness, e.g., complications of pulmonary disease (exclude if on beta agonists), 4) use over-the-counter agonist or allergy medication for respiratory problems (e.g., Primatene Mist): a detailed history and physical exam, pulmonary consult, and pulmonary function tests should be performed prior to including or excluding from the study or 5) have an FEV1 <70 %.
11. Have any illness, condition, and/or use of medications that in the opinion of the site Principal Investigator and the admitting physician would preclude safe and/or successful completion of the study.
12. Have active syphilis that has not been treated or refuse treatment for syphilis. Note: Syphilis testing will not be performed as part of this study and the study will rely solely on subjects' self-report.
13. Be undergoing HIV treatment with antiviral and non-antiviral therapy (participants who are HIV positive may not be eligible for cognitive assessments or brain scans and may only participate in the safety aspect of the protocol.)
14. Have AIDS according to the current CDC criteria for AIDS - MMWR 1999;48 (#RR-13:29-31).
15. Have neurological disorders including Parkinson's disease.
16. Have evidence of significant liver or kidney dysfunction.
17. Have a history of urinary retention or bladder outlet obstruction.
18. Be UCLA students or staff.
19. Have evidence of active tuberculosis infection.
20. Only for MRI Procedures:
• We will exclude any participant from participating in MRI scans whose body contains a ferromagnetic implanted device that might produce a safety hazard during fMRI. We will follow guidelines found in the manual, Magnetic Resonance: Bioeffects, Safety, and Patient Management 72, supplemented by the current information published on the International MR Safety Web Site: http://www.mrisafety.com/SafetyInfog.asp
21. Control Subjects:
1. Meet criteria for abuse or dependence of either alcohol or other illicit substances (other than nicotine).
2. Have physiological dependence on alcohol or a sedative-hypnotic, (e.g., a benzodiazepine) that requires medical detoxification.
3. Meet the diagnostic criteria for the following Axis I disorders: psychosis, bipolar I disorder, organic brain disease, dementia, major depression, schizoaffective disorder, or schizophrenia.
22. Methamphetamine Subjects:
1. Meet DSM-IV criteria (by SCID) for drug dependence other than meth, with the exception of nicotine and/or marijuana abuse/dependence.
2. Any previous medically serious adverse reaction to methamphetamine including loss of consciousness, chest pain, or epileptic seizure resulting in hospitalization.
3. 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.

Criteria for Discontinuation Following Initiation:

1. Positive urine drug screen or breath test indicating illicit use of cocaine, methamphetamine, alcohol, opiates, or other abused drugs not delivered as part of this protocol;
2. Inability to comply with study procedures;
3. Methamphetamine Subjects: Meet discontinuation criteria due to exaggerated response to methamphetamine, described below.
• Participants must continue to meet inclusion criteria in order to remain in the protocol. Thus, MA administration procedures will not be initiated if there are clinically significant arrhythmias or if vital signs are outside of acceptable ranges:
• Resting Pulse: 50-90 beats per minute.
• Systolic Blood Pressure: 105-140mm Hg
• Diastolic Blood Pressure: 45-90mm Hg
• In addition, repeated doses of methamphetamine will not be administered (and the study physician or nurse practitioner will halt continued methamphetamine delivery) if there are behavioral manifestations of methamphetamine toxicity (agitation, psychosis, inability to cooperate with study procedures). Note that participants remain eligible to remain in the study provided that vital signs do not exceed the limits below.
• Systolic BP >200mm Hg sustained; Diastolic BP >110 mm Hg sustained; Heart rate > (220 - age) x 0.85 bpm.
• A clinically significant ECG abnormality, such as: ST segment elevations in two or more continuous ads of greater than 0.1 mV; ST segment depression of greater than 1 mm that are flat or down-sloping at 80 msec after the J point; New bundle branch block; Mobitz II 20 or 30 heart block; Atrial fibrillation or atrial flutter or activation of any tachyarrhythmia for greater than 10 sec; QTc >440 msec for males and > 450 msec for females; An uncorrected QT of 470 msec or a rate-corrected QTc of 500 msec or greater is observed and does not revert to baseline within 10 min; Three or more consecutive ectopic ventricular complexes at a rate of greater than 100/min.

• Primary Phenotype: Substance Abuse, Intravenous
• Sex/Gender Identity
• Ethnic Groups
• Age Groups
• Drug Users

• BioProject
• BioSample
• MeSH

• Principal Investigator
  • Edythe London, PhD. Department of Psychiatry and Biobehavioral Sciences, University of California Los Angeles, Los Angeles, CA, USA.
• Co-Investigator
  • Andrew Dean, PhD. Department of Psychiatry and Biobehavioral Sciences, University of California Los Angeles, Los Angeles, CA, USA.
• Funding Source- Gift
  • Edythe London, PhD. Laboratory of Molecular Neuroimaging Opportunity Funds-Department of Psychiatry and Biobehavioral Sciences, University of California Los Angeles, Los Angeles, CA, USA.
• Funding Source
  • 1K23DA027734; Neurobehavioral Predictors of Cognitive Decline in Methamphetamine Dependence. National Institute on Drug Abuse, National Institutes of Health, Betheda, MD, USA.