An inpatient safety study to characterize the cardiovascular and behavioral effects of cocaine administration in the presence of LCE. The proposed study involves an inpatient stay of 12 days during which participants will have two cocaine-administration sessions, each including five doses of smoked cocaine with ascending doses.

Cocaine dependence remains a serious public health problem; however no clearly effective pharmacological treatments have been identified to date. We hypothesize that identification of subgroups of cocaine-dependent patients will help to develop targeted and more effective treatments. We hypothesize that individuals who have difficulties in achieving abstinence have a deficit in dopaminergic functioning and correcting this deficit using dopaminergic medication levodopa in combination with carbidopa and entacapone (LCE) to increase availability and uptake of levodopa to synthesize dopamine in the brain will result in clinical improvement. We were unable to locate any clinical reports that might provide data on the interaction between cocaine and LCE. Therefore, we would like to conduct an inpatient safety study to characterize the cardiovascular and behavioral effects of cocaine administration in the presence of LCE. The proposed study involves an inpatient stay of 12 days during which participants will have two cocaine-administration sessions, each including five doses of smoked cocaine with ascending doses. Participants will be maintained on placebo capsules prior to the first study session and on the LCE prior to the second session. Physiological (HR, BP, ECG) as well as behavioral (subjective effects) effects of cocaine will be monitored during cocaine-administration sessions. Serial blood samples will also follow cocaine administration to assess whether the pharmacokinetics of cocaine is altered during treatment with LCE. All participants will also undergo two cognitive testing sessions, one on placebo and one on LCE, employing a computerized battery (Quarters, Gambling task, Drug Stroop, Threat Responsivity task). There will be an optional functional MRI (fMRI) component that will investigate behavioral and neural indicators of reward responsivity, thought to reflect dopaminergic transmission. Participants choosing to undergo fMRI testing will complete two sessions, on the same days as the cognitive task sessions. Data obtained in the present study will be used to inform the large, controlled trial of LCE in treatment seeking cocaine-dependent individuals.

Inclusion Criteria:

• Adult, age 21-50.
• Smokes cocaine on average at least 1x/week; currently spends at least $30/week on cocaine. Has been using cocaine for at least 6 months Urine toxicology positive for cocaine metabolites
• Has patterns of smoked cocaine use in terms of frequency and amount that parallels or exceed those administered in the study
• Able to give informed consent and comply with study procedures

Exclusion Criteria:

• Current DSM-IV criteria of substance use disorders with the exception of cocaine or nicotine dependence, or a history of alcohol or cannabis dependence.
• Request for drug treatment
• Unstable medical disorders, or medical disorders that might interfere with study participation, including current seizure disorder, heart disease or a history of serious adverse effects due to cocaine.
• Judged to be noncompliant with study protocol
• Concurrent use of any psychotropic medications
• Concurrent use of MAO inhibitors or epinephrine (patients must be off MAOIs for a minimum of 2 weeks)
• Clinical laboratory tests outside normal limits that are clinically unacceptable to the study physician (systolic BP > 140 and < 90, diastolic BP > 90 and < 60, and heart rate > 90; BUN, creatinine, LFTs > ULN; hematocrit < 34 for women, < 36 for men; pseudocholinesterase deficiency)
• Positive serum pregnancy test, lactation, or unwillingness to use a satisfactory method of birth control
• History of myocardial infarction or ischemia, clinically significant left ventricular hypertrophy, angina, clinically significant arrhythmia, or mitral valve prolapse
• History of narrow angle glaucoma or prostate cancer
• History of melanoma or current suspicious undiagnosed skin lesions
• Currently meeting DSM-IV criteria for all major psychiatric/psychotic disorders other than transient psychosis due to drug abuse
• History of allergic reaction or adverse reaction to study medications (levodopa/carbidopa/entacapone).
• Current parole or probation