Study of Medical Treatment for Methamphetamine Addiction

Official Title: “Pharmacogenomics and Medication Development for Methamphetamine Dependence”

Currently there are no medications approved for the treatment of methamphetamine addiction.

Bupropion is an antidepressant that is approved by the Food and Drug Administration (FDA) for the treatment of depression and for cigarette smoking cessation but is not approved by the FDA for the treatment of methamphetamine addiction. Preliminary research studies suggest that bupropion may help people receiving treatment for methamphetamine addiction to reduce or to stop their methamphetamine use. But results of these studies also suggest that bupropion may help certain groups of patients more than others, such as men versus women and light versus heavy methamphetamine users, although the reasons for this difference are not known. One possibility is that a person's genetic make up may influence whether or not they respond to treatment with bupropion for methamphetamine addiction.

The purpose of the study is to determine if bupropion is can help people reduce or stop their methamphetamine use and to investigate whether genetic variations influence whether people respond to treatment with bupropion for methamphetamine addiction, which may help doctors and patients better decide if treatment with bupropion will be beneficial or not. To identify possible genetic variations that influence response to bupropion, we will perform genetic tests on blood or saliva specimens from participants receiving treatment with either bupropion or placebo (which is a pill that contains no medication) in conjunction with standard cognitive behavioral therapy drug counseling. We will compare methamphetamine use, as assessed with urine drug screens, among participants receiving bupropion versus those receiving placebo to determine if bupropion helps people to reduce or stop their methamphetamine use. We will then compare the results of the genetic tests among participants who respond and who do not respond to bupropion. In addition, since the amount of methamphetamine a person uses was associated with response to bupropion in preliminary studies, we will also compare the results of genetic testing among persons with heavy versus light methamphetamine use before entering treatment.

Results of this study have the potential to provide insights into the biology of methamphetamine addiction and help increase the understanding of how bupropion works. This information could be useful to develop effective medications for methamphetamine addiction and to improve the ability of clinicians to provide treatment to patients with methamphetamine addiction.

In order to assess the potential efficacy of bupropion for methamphetamine dependence and investigate potential genetics factors associated with response to bupropion and frequency of baseline MA use, we will perform a clinical trial to address the following aims:

1. To determine if bupropion results in greater reductions in methamphetamine use than placebo among methamphetamine dependent participants with low frequency of baseline MA use (MA use on 18 or fewer of the past 30 days at baseline) when provided in combination with cognitive behavioral therapy.

2. To determine whether genetic polymorphisms, including genes related to dopaminergic signaling (such as COMT, DAT, DRD2, and VMAT2) and/or metabolism of bupropion (CYP2B6) and methamphetamine (CYP2D6), are associated with response to bupropion among MA dependent participants with low frequency of baseline MA use (MA use on 18 or fewer of the past 30 days at baseline) who are randomized to receive bupropion or placebo, in combination with cognitive behavioral therapy.

3. To determine whether genetic polymorphisms, including genes related to dopaminergic signaling (such as COMT, DAT, DRD2, and VMAT2) are associated with baseline frequency of MA use among MA dependent participants.

4. To determine whether bupropion results in greater reductions in cigarette smoking compared to placebo among MA dependent participants with low frequency of baseline MA use (MA use on 18 or fewer of the past 30 days at baseline).

4a. To determine whether genetic polymorphisms, including genes related to dopaminergic (COMT, DAT, DRD2, and VMAT2) and cholinergic signaling (CHRNA3-CHRNA5-CHRNB4 gene cluster) as well as metabolism of bupropion (CYP2B6), are associated with reductions in cigarette smoking both overall and in response to treatment with bupropion.

In addition, we will perform exploratory analyses to investigate whether polymorphisms associated with baseline frequency of MA use and/or response to bupropion differ among male versus female participants. To address these aims, we will recruit and genotype 90 MA dependent participants with low frequency of baseline MA use (MA use on 18 or fewer of the past 30 days at baseline) who will be randomized to receive treatment with bupropion (n=45) or placebo (n=45) for 12 weeks, in combination with cognitive behavioral therapy.

Intervention(s) in this Clinical Trial

• Drug: Bupropion
  • Bupropion dose will start at 150 mg per day (one 150 mg sustained release tablet per day) for days 1-3 of the first week. The dose will then be increased to 300 mg per day (one 150 mg sustained release tablet twice daily) on day 4 and will remain 300 mg per day until the last week of the medication phase, when the dose will be decreased to 150 mg per day (one 150 mg sustained release tablet per day) for the last three days. The medication treatment phase is for 12 weeks.

Arms, Groups and Cohorts in this Clinical Trial

• Active Comparator: Bupropion
  • Bupropion dose will start at 150 mg per day (one 150 mg sustained release tablet per day) for days 1-3 of the first week. The dose will then be increased to 300 mg per day (one 150 mg sustained release tablet twice daily) on day 4 and will remain 300 mg per day until the last week of the medication phase, when the dose will be decreased to 150 mg per day (one 150 mg sustained release tablet per day) for the last three days.
• Placebo Comparator: Sugar Pill

Primary Measures

• Clinical phenotype of frequency of baseline MA use in 30 days preceding the baseline period using self-report and results of thrice weekly urine drug screens for MA metabolites during baseline.
  • Time Frame: Weekly
    Safety Issue?: No

Secondary Measures

• Clinical phenotype of treatment response to bupropion on MA use during the medication phase, as measured via self-reported MA use and thrice weekly urine screens for MA metabolites.
  • Time Frame: 12 weeks
    Safety Issue?: Yes

Inclusion Criteria:

• 1. 18 years of age or older;
• 2. meet DSM-IV criteria for methamphetamine dependence;
• 3. seeking treatment for MA problems;
• 4. specific range of methamphetamine use in the 30 days prior to study entry;
• 5. willing and able to comply with study procedures, including genotyping;
• 6. willing and able to provide written informed consent;
• 7. if female, not pregnant or lactating and willing to use an acceptable method of barrier birth control (e.g. condoms) during the trial.

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);
• 2. have a current neurological disorder (e.g., organic brain disease, dementia) or major psychiatric disorder not due to substance abuse (e.g., schizophrenia, bipolar disorder) as assessed by the SCID or 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;
• 3. currently on prescription medication that is contraindicated for use with bupropion;
• 4. have current dependence on cocaine, opiates, alcohol, or benzodiazepines as defined by DSM-IV-TR;
• 5. have a history of alcohol dependence within the past three years;
• 6. have a history of a seizure disorder;
• 7. have a medical condition (such as serious head injury) that is associated with increased risk of seizures or on a medication that lowers the seizure threshold;
• 8. have a history of anorexia or bulimia;
• 9. have current hypertension uncontrolled by medication, or any other circumstances that, in the opinion of the investigators, would compromise participant safety;
• 10. have a history of sensitivity to bupropion.

Gender Eligibility for this Clinical Trial: Both

Minimum Age for this Clinical Trial: 18 Years

Maximum Age for this Clinical Trial: N/A

Are Healthy Volunteers Accepted for this Clinical Trial?: No

Lead Investigator: National Institute on Drug Abuse (NIDA) NIH

Overall Clinical Trial Officials and Contacts

Keith G Heinzerling, MD MPH Principal Investigator UCLA Dept of Family Medicine  

Overall Contact: Javier Robles, BA 323 461 3106 jrobles@mednet.ucla.edu

Information obtained from ClinicalTrials.gov on February 12, 2012

Link to the current ClinicalTrials.gov record. http://clinicaltrials.gov/show/NCT00833443

Study ID Number: KH_K23

ClinicalTrials.gov Identifier: NCT00833443

Health Authority: United States: Food and Drug Administration

UCLA Substance Abuse Pharmacotherapy Unit

UCLA Center for Health Promotion and Disease Prevention