D-Cycloserine and Cue Exposure in Cocaine-Dependent Individuals

Cocaine dependence remains a serious problem in the US today and in spite of two decades of
intense research, efficacious pharmacotherapeutic treatments have not been identified.
Cocaine-associated environmental cues can elicit drug craving and exposure to cocaine-related
cues is likely to be involved in relapse. Emerging data supports the role of glutamate in
extinction of associative learning in animal models of rear-conditioning and clinical studies
of exposure treatment for anxiety disorders. A recent study demonstrated DCS acceleration of
cocaine-induced conditioned place preference in rats. Exploration of DCS in facilitating
extinction of response to drug-related cues in humans is needed. The proposed study will
extend these innovative and promising findings from the basic science arena and anxiety
disorders field in a proof of concept investigation of DCS facilitation of extinction of
response to cocaine-related cues in a human laboratory paradigm.

Inclusion Criteria:

1. Subjects must be able to provide informed consent and function at an intellectual
level sufficient to allow accurate completion of all assessment instruments.

2. Subjects must meet DSM-IV criteria for current cocaine dependence. Subjects may meet
criteria for abuse, but not dependence on any other substance within the past 60 days
with the exception of nicotine. Because of the high comorbidity of cocaine and
nicotine dependence, excluding nicotine dependence would seriously compromise the
feasibility of recruitment. Nicotine use immediately prior to the testing session will
be controlled. Alcohol has also been known to affect HPA function, however to enhance
recruitment efforts individuals with alcohol dependence or abuse will be included in
the study if they do not require medically supervised detoxification.

3. Use of one of the following methods of birth control by female subjects: barrier
methods (diaphragm or condoms with spermicide or both), surgical sterilization, use of
an intra-uterine contraceptive device, or complete abstinence from sexual intercourse.

4. Subjects must live within a 50-mile radius of our research program and have reliable
transportation.

5. Subjects must consent to remain abstinent from all drugs of abuse (except nicotine or
alcohol) for 24 hours immediately prior to the GCRC admission.

6. Subjects must consent to random assignment to the DCS vs. placebo conditions.

Exclusion Criteria:

1. Women who are pregnant, nursing or of childbearing potential and not practicing an
effective means of birth control.

2. Subjects with evidence of or a history of significant hematological, endocrine,
cardiovascular, pulmonary, renal, gastrointestinal, or neurological disease including
diabetes, as these conditions may affect heart rate or skin conductance measurement.

3. Individuals with creatinine clearance of 1.2 or greater as DCS is renally excreted.

4. Subjects with a history of or current psychotic disorder, current major depressive
disorder, bipolar affective disorder or a severe anxiety disorder as these may impact
cue reactivity.

5. Subjects who are unwilling or unable to maintain abstinent from alcohol and other
drugs of abuse (except nicotine) for 24 hours days prior to the cue procedure.

6. Subjects meeting DSM-IV criteria for substance dependence (other than nicotine or
cocaine as appropriate) within the past 60 days.

7. Subjects currently taking B-blockers, anti-arrythmic agents, psychostimulants or any
other agents known to interfere with heart rate and skin conductance monitoring.

8. Known or suspected hypersensitivity to DCS.

9. Individuals taking medications that could adversely interact with study medications,
including, but not limited to ethionamide, isoniazid, or amino acid supplements.

10. Subjects with a history of epilepsy or seizure disorder.

11. Subjects with significant liver impairment as DCS may increase serum transaminases.