Multicenter Trial of Combined Pharmacotherapy to Treat Cocaine Dependence

The investigators hypothesize that the combination of an agent that increased baseline
dopamine signaling (amphetamine) with one that reduced cocaine-induced dopamine release
(topiramate) will improve dopamine regulation and be associated with improved cocaine use
outcomes. 99 subjects at each of the two sites whom meet criteria for cocaine dependence, and
all other study inclusion and exclusion criteria will be assigned to the 14-week
double-blind, placebo-controlled treatment trial. Subjects will be randomized to receive
either placebo or MAS-ER and topiramate. This proposal will test the hypothesis that MAS-ER
and topiramate will promote cocaine abstinence. Participants who are randomized to the
combination medication arm will have their dose titrated to 60 mg MAS-ER daily (over 2 weeks)
and 200 mg topiramate a day (over 6 weeks) and maintained on this dose through week 13 of the
trial. During week 14, participants will be tapered off both medications. All participants
will receive a supportive behavioral treatment that emphasizes study procedure adherence.
Starting in week one, all patients will receive incentives for compliance with study
procedures on an escalating reinforcement schedule similar to that developed previously and
not contingent on urine results. The purpose of the lead-out is to blind patients to the
exact point of medication discontinuation and to provide naturalistic data on the effects of
medication discontinuation. Moreover, a 3 month follow-up will be conducted to determine what
happens to cocaine use after treatment discontinuation.

Inclusion Criteria:

- Men and women between the ages of 18-60 who meet DSM-IV criteria for cocaine
dependence.

- Used cocaine at least 9 days in the past 28 days with at least weekly cocaine use.

- Able of giving informed consent and capable of complying with study procedures.

Exclusion Criteria:

- Meets DSM-IV-TR criteria for bipolar disorder, schizophrenia or any psychotic disorder
other than transient psychosis due to drug abuse.

- Individuals with any current Axis I psychiatric disorder as defined by DSM-IV-TR
supported by the SCID-I/P that in the investigator's judgment are unstable, would be
disrupted by study medication, or are likely to require pharmacotherapy or
psychotherapy during the study period. Individuals who are currently stable on a
psychotropic medication for at least 3 months may be included if in the investigator's
opinion the psychotropic medication the patient is taking is compatible with the study
medication (mixed amphetamine salts plus topiramate) and does not entail serious risk
of adverse effects from the drug interactions. Individuals cannot be on any
psychostimulants or other contraindicated medications.

- Individuals with a history of seizures or unexplained loss of consciousness

- History of allergic reaction to candidate medications (amphetamine or topiramate).

- Individuals with significant current suicidal risk.

- Women who are pregnant, nursing, or failure in sexually active female patients to use
adequate contraceptive methods.

- Unstable physical disorders which might make participation hazardous such as
uncontrolled hypertension (SBP > 140, DBP> 90,or HR > 100 when sitting quietly), acute
hepatitis(patients with chronic mildly elevated transaminases < 3x upper limit of
normal are acceptable), or uncontrolled diabetes.

- Individuals with coronary vascular disease as indicated by history or suspected by
abnormal ECG, cardiac symptoms, fainting, open-heart surgery and/or arrhythmia, and
family history of ventricular tachycardia/sudden death.

- Individuals with use of carbonic anhydrase inhibitors

- History of glaucoma

- History of kidney stones

- Use of drugs that may be additive to the bicarbonate lowering effects of topiramate

- Body Mass Index (BMI) < 18kg/m2

- History of failure to respond to a previous adequate trial of either of the candidate
medications for cocaine dependence

- Individuals physiologically dependent on any other drugs (excluding nicotine or
cannabis) which require medical intervention

- Individuals who are legally mandated (e.g., to avoid incarceration, monetary or other
penalties,etc.) to participate in substance abuse treatment program

- Individuals with a current history (within the past 6 months) of amphetamine abuse or
dependence including amphetamines such as methamphetamine and MDMA.