Rivastigmine and Huperzine A as Treatments for Cocaine Dependence

The purpose of this study is to evaluate the interactions between cocaine and oral
rivastigmine and between cocaine and oral huperzine A (HupA).

The following Specific Aims are proposed: 1. Among cocaine-dependent, non-treatment seeking
participants, to establish the ability of rivastigmine (3 or 6 mg, daily) or HupA (0.4 or
0.8 mg, daily), as compared to placebo, to reduce cocaine-induced craving (0, 20, and 40 mg,
IV) and to reduce reinforcing effects produced by cocaine (20 mg, IV/infusion). Hypothesis.
Relative to placebo-treated participants, treatment with rivastigmine or HupA will reduce
cocaine-induced craving and choices for cocaine.

2. To determine the safety of rivastigmine and HupA in cocaine-dependent participants who
receive cocaine in a laboratory setting. Hypothesis 2A. Relative to placebo-treated
participants, treatment with rivastigmine or HupA will not increase the adverse events
produced by cocaine. Hypothesis 2B. Relative to placebo-treated participants, treatment with
rivastigmine or HupA will reduce cocaine-induced increases in heart rate and blood pressure.

3. To determine the effects of AChE inhibition on plasma levels of cocaine and cocaine
metabolites. Hypothesis 3A. Relative to placebo-treated participants, treatment with
rivastigmine, but not HupA, will be associated with increased plasma levels of cocaine.
Hypothesis 3B. Relative to placebo-treated participants, treatment with rivastigmine, but
not HupA, will be associated with increased formation of ecgonine and benzoylecgonine, and
decreased formation of ecgonine methylester.

4. a) provide a more frequent measure of heart rate (15 sec vs. 5 minutes) and b) measure a
new dependent variable, physical activity, on days with and without cocaine exposure.

Public Health Significance: Cocaine abuse is an important health problem that is associated
with serious medical, psychiatric, social, and economic consequences. No medications are
currently available for prevention of relapse in patients who are addicted to cocaine, and
compounds such as rivastigmine and HupA are predicted to be useful for this indication. The
testing of HupA is particularly exciting since it has antioxidant and neuroprotective
properties that may also contribute to its efficacy as a treatment medication for cocaine
dependence.

Inclusion Criteria:

- Be a cocaine-dependent volunteer who is non-treatment-seeking

- Meets DSM-IV criteria for cocaine dependence as determined by SCID, and has provided
at least one cocaine-positive urine specimen within the 2 weeks prior to enrollment

- Be male or female, between 18 and 55 years old

- Be able to verbalize understanding of consent form, able to provide written informed
consent, and verbalize willingness to complete study procedures

- Female subjects must be non-nursing and postmenopausal, have had a hysterectomy,
undergone tubal ligation, or have a negative pregnancy test and agree to use one of
the birth control methods below

- Agreeable to conditions of the study and likely to complete schedule of interventions
and measures

- Has medical history, physical exam, and screening laboratory results that demonstrate
no contraindication to participation

Exclusion Criteria:

- Has a history of a medical adverse reaction to cocaine or other psychostimulants,
including loss of consciousness, chest pain, cardiac ischemia, or seizure

- Has a current psychiatric disorder other than cocaine abuse or dependence, including
major depression, bipolar disorder, schizoaffective disorder, schizophrenia, organic
brain disease, or dementia

- Meets DSM-IV criteria for dependence to opiates, benzodiazepines, alcohol, or other
sedative-hypnotics

- Receiving opiate-substitution therapy (methadone, LAAM, or buprenorphine) within 2
mo's of enrollment

- Has a current or past history of seizure disorder, including alcohol- or
psychostimulant- related seizures, febrile seizures, or family history of seizure
disorder

- Has a diagnosis of adult (i.e., 21 years or older) asthma, or chronic obstructive
pulmonary disease, including a history of acute asthma within the past two years, and
those with current or recent (with the past two years) treatment with an inhaled or
oral b-adrenergic agonist

- Has had head trauma that resulted in neurological sequelae (e.g., loss of memory for
greater than 5 min or that required hospitalization)

- Has an unstable medical condition, which, in the judgment of investigators, would
make participation hazardous, including, but not limited to, AIDS, acute hepatitis,
active TB, unstable cardiac disease, unstable diabetes, hepatic or renal
insufficiency (serum bilirubin or creatinine exceeding 1.5 the upper limit of normal,
respectively)

- Be pregnant or lactating (nursing), or a fertile woman not practicing adequate
methods of contraception or planning to become pregnant within one month of
conclusion of the study

- Has current suicidal ideation or plan as assessed by SCID or MINI interview

- Has clinically significant ECG abnormalities, including QTc interval prolongation
>450 ms in men or >480 ms in women

- In the opinion of the PI, be expected to fail to complete the study protocol due to
probable incarceration or relocation from the clinic area

- Has clinically significant laboratory values (outside of normal limits), in the
judgment of the PI

- Is on parole, probation or has any legal obligations