Effect of Zonisamide on Cocaine Reinforcement, Craving, and Relapse

This is a residential pilot trial to evaluate the effect of zonisamide (ZNS) on cocaine
reinforcement, craving and relapse. Cocaine addiction remains a major social and medical
problem that imposes a significant burden on our society, as more than a half million
cocaine dependent individuals are seeking treatment every year. Medications that act to
antagonize the glutamate system and/or increase the GABA-system are new targets in the
search towards effective cocaine treatment. ZNS is part of a new line of antiepileptic
agents that act both as glutamate antagonists and to enhance the GABA system. Topiramate, a
similar agent, showed a positive signal in a pilot trial for cocaine dependence. ZNS has
the advantages of a longer half-life requiring only once a day dosing and, being better
tolerated, it requires a shorter induction phase and can be administered at higher doses.
We hypothesize that ZNS in moderate to high doses will attenuate the central effect of
cocaine and improve the neural perturbations resulting from cocaine use, thus decreasing
cocaine craving. Healthy, adult cocaine dependent volunteers will be enrolled on our
residential unit for 44 days for this double-blind within subject study. The
pharmacodynamic interactions between ZNS and cocaine will be measured in cocaine
self-administration procedure offering alternative reinforcers with monetary values.
Cocaine reinforcing effect will be evaluated over a range of doses, and subjective and
objective outcomes on mood and behavior will be collected. In addition, the effect of ZNS
on ad-lib smoking will be studied on the days when no other procedure interferes with
smoking behaviors. Neurocognitive and psychomotor effects of ZNS treatment will also be
studied with an extensive test battery on the day of the week when no cocaine is
administered. This study will explore the potential therapeutic effect of ZNS for the
treatment of cocaine dependence while providing necessary safety assessments required for
possible future outpatient clinical trials.

Inclusion Criteria:

- Age at least 21 years old, not older than 45 years.

- Evidence of cocaine dependence.

- Not seeking treatment for cocaine abuse.

- Able and willing to be restricted to our unit for 6-7 weeks.

- Able to answer frequent questionnaires reliably and consistently.

- Smoker.

Exclusion Criteria:

- Allergy to Sulfonamide drugs (e.g. topiramate, zonisamide,
sulfamethoxazole/trimethoprim).

- Diabetes, respiratory insufficiency, renal tubular acidosis or renal insufficiency,
heart failure, liver insufficiency, chronic diarrhea, other chronic diseases
predisposing to acidosis.

- Renal insufficiency defined as serum creatine > 1.30 mg/DL for males or > 1.03 mg/DL
for females.

- History of nephrolithiasis, unexplained hematuria on screening urinalysis.

- History of head injury (with loss of consciousness longer than a few minutes).

- History of seizure, or use of antiepileptic medications.

- HIV positive individuals who meet AIDS by CDC criteria or are on antiretroviral
medications.

- BMI < 19 or BMI > 34.

- Total cholesterol > 240mg%.

- Serous psychiatric illness with psychosis, dementia.

- Glaucoma, family history of glaucoma, one-sided blindness.

- For female participants: being pregnant, lactating or not using an effective method
of contraception.

- Physical dependence on any drug other than cocaine, nicotine, or caffeine.