Bupropion-Enhanced Contingency Management (CM) for Cocaine Dependence

The efficacy of behavior therapies may be enhanced by certain medications, particularly those
that act on dopaminergic systems. The purpose of this project is to examine effects of
bupropion on initiation and maintenance of cocaine abstinence in a population of cocaine
dependent methadone maintenance patients. Bupropion appears to be the most promising
medication for this purpose because of its previously demonstrated efficacy and safety as
well as its pharmacological actions at dopamine systems.

Methadone maintained cocaine dependent patients will participate (N = 200). Volunteers will
be eligible for inclusion in the study if they are 1) enrolled in methadone maintenance
treatment, having previously met the criteria for opioid dependence; 2) between the ages of
18 and 65; 3) provide evidence of cocaine dependence (DSM-IV criteria, self-report, and/or
urine tests positive for cocaine during the intake process); and 4) are willing to take study
medications and adhere to reporting and data collection schedules.

Exclusion Criteria are: 1) history of epilepsy or seizure, including alcohol- or
cocaine-related seizure; 2) conditions with increased risk of seizure (e.g. head trauma with
loss of consciousness > 30 mins), 3) current use (past 30 days) of antidepressants,
antipsychotics, theophyllines, systemic steroids, MAO-A inhibitors, 4) recent use (past 30
days of any medication containing bupropion or budeprion (Wellbutrin®, Zyban®), 5) allergy to
bupropion or budeprion, 6) liver enzyme levels greater than 3x upper limit of normal (ULN);
7) uncontrolled diabetes mellitus (glucose > 200mg%); 8) severe psychiatric diagnosis:
schizophrenia, psychosis, major depression, mania, current suicidal ideation with plan;
cognitive impairment severe enough to preclude informed consent or valid responses on
questionnaires; 9) severe renal insufficiency (eGFR < 30 ml/min), 10) pregnant, breast
feeding or unwilling to use birth control, 11) medical illness that in the view of the
investigators would compromise participation in research, 12) advanced HIV infection
requiring HAART 13) current eating disorder (anorexia or bulimia), 14) uncontrolled
hypertension with blood pressure ( BP) >140/90.

Study participants who qualify and sign informed consent will be stratified according to
their initial response to an abstinence incentive (contingency management) procedure
targeting cocaine negative urines. Those who stop their cocaine use will enter a study that
examines effects of bupropion XL (300mg/day) versus placebo on relapse prevention. Those who
fail to stop cocaine use after initial exposure to the CM procedure will enter a parallel
study conducted concurrently that examines the effects of bupropion XL (300mg/day) on
abstinence initiation. Our hypothesis is that bupropion as compared to placebo treatment will
both enhance rates of abstinence initiation in those who have difficulty stopping cocaine and
retard rates of relapse in those who initially stopped their cocaine use.

Each study will involve a CM schedule that is uniquely tailored to the questions being asked
but that is equated on total amount that can be earned ($675). Both studies will track
outcomes over a 6-month time frame that includes assessment of drug use outcomes after
incentives have stopped. In addition, the project will provide novel information about
mechanisms of medication effects by measuring subjective drug effects, drug vs money choices,
and self-reports of pleasure derived from daily non-drug activities. The investigators
hypothesize that bupropion compared to placebo participants will report non-drug activities
as more pleasurable (reinforcing), will engage in more of them and that measures of non-drug
reinforcement will mediate abstinence outcomes.

Overall, this research will provide new and valuable information about combined
behavioral-pharmacological treatments and specifically the conditions under which medication
may enhance effects of CM. If hypothesized synergies can be demonstrated, the study will
point the way to a significant advance in improved treatment outcomes for this critical group
of drug abusers. The proposed study is compelling because it conceptually differentiates the
two key clinical issues in treatment of stimulant abusers- abstinence initiation and relapse
prevention. It uses a design that efficiently and effectively tests a combined treatment
approach for each clinical issue and as well examines cognitive function and
reinforcement-based mediators. The research will add to understanding of the interplay
between brain reinforcement systems and drug-seeking behavior. Finally, it will make an
important contribution to behavioral therapy development by exploring a novel solution to
limitations previously noted for CM that include lack of response in some patients and
relapse after withdrawal of incentives.

Inclusion Criteria:

- Enrolled in methadone maintenance

- Meets Diagnostic and Statistical Manual of Mental Disorders, Fifth edition (DSM V)
criteria for active cocaine use

- Submits one cocaine positive urine sample within 30 days of study start

- Agrees to study procedures

Exclusion Criteria:

- Healthy and without contra-indications to study medication

- Any history of epilepsy or seizure, including alcohol-, sedative-, or cocaine-related
seizure

- Any increased risk of seizure such as serious head trauma with a loss of consciousness
of more than an hour duration, brain tumor, or other brain pathology increasing risk
of seizure.

- Current eating disorder including anorexia or bulimia

- Current use (last 30 days) of antidepressants, antipsychotics, theophyllines, systemic
steroids, monoamine oxidase (MAO-A) inhibitors.

- Recent use (last 30 days) of budeprion, zyban®, wellbutrin®, aplenzin®, or any other
medication containing bupropion.

- Allergy to bupropion or budeprion

- Liver enzymes greater than 3x ULN (upper limit of normal)

- Uncontrolled diabetes mellitus, or h/o diabetic coma

- Uncontrolled hypertension with BP > 140/90.

- Current psychiatric diagnosis: schizophrenia, psychosis, major depression, mania,
current suicidal ideation as determined by MINI psychiatric interview, cognitive
impairment severe enough to preclude informed consent or valid responses on
questionnaires

- Severe renal insufficiency (eGFR < 30 ml/min)

- Pregnancy or current breast feeding,

- Medical illness that in the view of the investigators would compromise participation
in research, such as uncompensated congestive heart failure, recent history of
myocardial infarction (<1year), or urologic conditions that inhibit urine collection.

- Advanced HIV infection requiring the use of HAART (Highly Active Anti-Retroviral
Therapy), or with CD4 T cell count < 200/uL