Imaging the Neurobiology of Behavioral and Medication Treatment for Cocaine Dependence

Cocaine dependence remains a serious public health problem; however no clearly effective
pharmacological treatments have been identified to date. The investigators hypothesize that
identification of subgroups of cocaine-dependent patients will help to develop targeted and
more effective treatments. The investigators have observed that 30-40% of cocaine-dependent
patients who enter our medication trials achieve abstinence during the lead-in period (the
two weeks prior to starting medication). Initial abstinence is strongly predictive of
abstinence during the subsequent medication trial. The investigators have also observed that
a low dopamine release in the striatum is associated with greater choice of cocaine in
volunteers and failure of cocaine-dependent patients to respond to behavioral treatment. The
investigators hypothesize that individuals who have difficulties in achieving abstinence have
a deficit in dopaminergic functioning and correcting this deficit using dopaminergic
medication LCE (levodopa in combination with carbidopa and entacapone) will result in
clinical improvement.

The proposed study will consist of three consecutive phases: 1) the 2-week outpatient lead-in
phase during which behavioral therapy will be administered; 2) the 15-21 day inpatient phase
(during which participants will start study medication and will undergo brain imaging; one
PET and two fMRI scan sessions); and 3) the 24 weeks outpatient treatment trial.

Study medication (LCE or placebo) will be administered in a double-blind, placebo controlled
manner for one week during inpatient phase followed by 12 weeks of the outpatient trial.
During the remaining 12 weeks of the outpatient trial participants will receive therapy only.

The purpose of the lead-in phase is to identify patients who do not achieve abstinence in
response to behavioral treatment. Subsequently, two matched subgroups of participants (half
who achieved abstinence and half who did not achieve abstinence) will undergo the [11C]
raclopride displacement PET brain imaging procedure. This procedure allows the measurement of
dopamine release in response to a single dose of methylphenidate, and the investigators will
determine if failure to achieve abstinence during the lead-in period is associated low
dopamine transmission.

All participants in the proposed study will also undergo a functional MRI with the
Motivational Incentive Delay task (fMRI/MID). This task is thought to reflect dopaminergic
transmission in the brain-reward system but is safer and more feasible than PET. The
investigators hypothesize that fMRI/MID will correlate strongly with results from the PET
procedure, thereby suggesting that it also reflects the status of striatal dopamine
functioning. In addition, a group of healthy controls will undergo one fMRI scan in order to
validate the procedure and to assess if a deficit can be detected in cocaine-dependent
participants. Cocaine-dependent participants will undergo two fMRI/MID, one at baseline and
another after a week of treatment with LCE to assess if treatment with LCE may reverse
baseline deficits and if this change is associated with clinical improvement.

Inclusion Criteria:

- Adult, age 21-50.

- Meets DSM-IV criteria for current cocaine dependence, supported by a positive urine
for cocaine metabolites

- Voluntarily seeking treatment for cocaine dependence

- Absence of other medical or psychiatric disorders that are unstable and would
interfere with participation.

- Absence of any suspicious skin changes, suggestive of melanoma, during the full body
exam

- Able to give informed consent.

Exclusion Criteria:

- Current DSM-IV criteria of other substance use disorders with the exception of
nicotine dependence, and mild to moderate alcohol or cannabis abuse or dependence.
Alcohol or cannabis abuse or dependence may be included provided that cocaine is the
predominant problem, and medical detoxification is not indicated; alcohol and cannabis
use are common among cocaine dependent patients and their categorical exclusion would
impede recruitment and result in a sample of limited generalizability; secondary
analyses will explore whether they exert any moderating effects on the main findings.

- Active psychiatric disorder which might interfere with participation or make
participation hazardous, including DSM-IV organic mental disorder, psychotic disorder,
bipolar disorder, recurrent severe MDD, OCD, or eating disorder. Participants with
depressive disorder (provided that the score on the Hamilton Depression Scale is less
than 20) and those with ADHD symptoms may be included, since these are common, often
reflect effects of chronic drug use, and may improve with behavioral treatment and
cessation or reduction of drug use.

- Unstable medical disorders, or medical disorders that might interfere with study
participation, including seizure disorder.

- Significant current suicidal risk or 1 or more suicide attempts within the past year

- Concurrent treatment with psychotropic medications

- Positive serum pregnancy test, lactation, or unwillingness to use a satisfactory
method of birth control

- Baseline systolic BP of > 140 and < 100, diastolic BP > 90 and < 60 and baseline HR
greater than 90.

- Any clinically significant heart abnormality or cardiovascular disease

- History of glaucoma

- History of melanoma or current suspicious undiagnosed skin lesions

- History of allergic reaction or adverse reaction to study medications
(levodopa/carbidopa/entacapone; methylphenidate; raclopride).

- Metal implants or paramagnetic objects contained within the body which may interfere
with the MRI scan as determined in consultation with a neuroradiologist and according
to the guidelines set forth in the following reference book commonly used by
neuroradiologists: "Guide to MR procedures and metallic objects" by Shellock

- Lifetime exposure to radiation in the workplace, or history of participation in
nuclear medicine procedures, including research protocols

- Individuals who are predominantly left handed. Based on a score <50 on the Edinburg
Handed Inventory (E.H.I.).

Inclusion Criteria(fMRI study-healthy controls):

- Adult, age 21-50.

- No current DSM-IV psychiatric or substance use disorders

- Absence of other medical disorders that are unstable and would interfere with
participation.

- Able to give informed consent.

Exclusion Criteria (fMRI study-healthy controls):

- Current or recent DSM-IV psychiatric or substance use disorders

- Past history of any major Axis I disorder (e.g., psychotic disorders, bipolar
disorder, recurrent major depressive disorder, OCD or eating disorders).

- Unstable medical disorders, or medical disorders that might interfere with study
participation.

- Concurrent treatment with psychotropic medications

- Positive serum pregnancy test, lactation, or unwillingness to use a satisfactory
method of birth control *

- Baseline systolic BP of > 140 and < 100, diastolic BP > 90 and < 60 and baseline HR
greater than 90.

- Any clinically significant heart abnormality or cardiovascular disease

- History of allergic reaction or adverse reaction to study medications
(methylphenidate; raclopride).

- Metal implants or paramagnetic objects contained within the body which may interfere
with the MRI scan as determined in consultation with a neuroradiologist and according
to the guidelines set forth in the following reference book commonly used by
neuroradiologists: "Guide to MR procedures and metallic objects" by Shellock

- Individuals who are predominantly left handed. Based on a score <50 on the Edinburg
Handed Inventory (E.H.I.).