Effects of Vigabatrin on Cocaine Self-Administration

The objective of this study is to determine if vigabatrin will decrease cocaine self-administration, cardiovascular effects, subjective effects and craving compared to placebo.

Two recent open label clinical trials have reported that the anticonvulsant, gamma vinyl-GABA (GVG; vigabatrin), decreases relapse to cocaine use (Brodie et al., 2003, 2005). Vigabatrin increases neural GABA levels by irreversibly inhibiting the primary GABA degradation enzyme, GABA-transaminase; the hypothesized mechanism by which vigabatrin decreases cocaine relapse is by increasing GABA levels, thereby decreasing the effects of cocaine and cocaine-associated environmental cues on extracellular dopamine concentrations in the mesolimbic dopaminergic pathway (Morgan and Dewey, 1998). We are proposing to use our model of repeated dose cocaine self-administration to assess the interaction between vigabatrin and smoked cocaine under controlled laboratory conditions. This 57-day outpatient/inpatient /outpatient/inpatient protocol will evaluate the effects of vigabatrin maintenance (0, 3 g/day) on cocaine craving, subjective effects, and self-administration using a within-subjects design. Non-treatment seeking cocaine-dependent volunteers will be maintained outpatient for 14 days of vigabatrin maintenance prior to beginning each inpatient study phase. During the inpatient phases, volunteers will live on a hospital clinical research unit and will participate in laboratory sessions in which they will have the opportunity to purchase doses of smoked cocaine (0, 12, 25, 50 mg; $5/administration). In addition to measuring cocaine self-administration, we will measure the cardiovascular and subjective effects of repeated cocaine administration and cocaine craving under each vigabatrin maintenance condition. Determining vigabatrin's effects on a range of smoked cocaine doses will provide essential data on the mechanism of the vigabatrin-cocaine interaction.

Eligibility Criteria:
Inclusion Criteria:

* Meets DSM-IV criteria for current cocaine abuse
* Average use of smoked cocaine is at least 2x/week for past 6 mos; currently spends at least $70 per week on cocaine
* Has patterns of smoked cocaine use in terms of frequency and amounts which parallel or exceed those administered in the study
* Age 21-45
* Able to give informed consent, and comply with study procedures
* Agrees to practice an effective form of contraception

Exclusion Criteria:

* Current seizure disorder or heart disease
* Currently meeting DSM-IV criteria for all major psychiatric/psychotic disorders. Volunteers with a history of depression or psychosis will also be excluded (p. 43, Investigator's brochure)
* Dependence on substances other than cocaine or nicotine
* Request for drug treatment
* Judged to be noncompliant with study protocol
* Clinical laboratory tests outside normal limits that are unacceptable to the study physician (e.g., BP \> 140/90; BUN, creatinine, LFTs \> 1.5 ULN; hematocrit \< 34 for women, \< 36 for men; pseudocholinesterase deficiency)
* Current parole or probation
* Recent history of significant violent or suicidal behavior
* Pregnancy or lactation
* Baseline visual field defects