The Effect of Brief Potent Glutamatergic Modulation on Cocaine Dependence

This project will evaluate the effect of a single sub-anesthetic dose of ketamine on the time to first cocaine use and abstinence rates in 60 treatment-seeking cocaine-dependent individuals receiving mindfulness-based relapse prevention (MBRP) therapy, using a 5 week combined laboratory-inpatient and outpatient double-blind, randomized, controlled trial.

he study will begin with an inpatient phase (phase 1) of 5 days, during which abstinence is achieved, followed by a 4 week outpatient phase (phase 2). A single infusion of ketamine or midazolam will occur on day 3 of Phase 1. In addition to measures of mindfulness and impulsivity, stress sensitivity tests are incorporated into the design in order to elucidate mechanisms of action. The study hypotheses are:

1. ketamine and MBRP will significantly increase the time to first use compared to placebo and MBRP in cocaine-dependent individuals.
2. ketamine and MBRP is significantly more likely to lead to abstinence from cocaine (no use over one week) as compared to placebo and MBRP.
3. ketamine and MBRP will significantly reduce subjective, endocrine, and physiological responses to stress (including cue exposure) as compared to placebo and MBRP.
4. ketamine and MBRP will significantly increase mindfulness, as assessed by the Five Facet Mindfulness Questionnaire (FFMQ), as compared to placebo and MBRP.

Eligibility Criteria:
Inclusion Criteria:

* Active cocaine dependence with at least 8 days of use or at least 4 binges of large amounts (\>$200/occasion) over the past 30 days, and displaying at least one positive utox during screening
* Physically healthy
* No adverse reactions to study medications
* 21-60 years of age
* Capacity to consent and comply with study procedures, including sufficient proficiency in English
* Seeking treatment

Exclusion Criteria:

* Meets DSM IV criteria for current major depression, bipolar disorder, schizophrenia, any psychotic illness, including substance induced psychosis, and current substance-induced mood disorder with HAMD score \> 12.
* Physiological dependence on another substance requiring medical management, such as alcohol, opioids, or benzodiazepines, excluding caffeine, nicotine, and cannabis
* Delirium, Dementia, Amnesia, Cognitive Disorders, or Dissociative disorders
* Current suicide risk or a history of suicide attempt within the past year
* Pregnant or interested in becoming pregnant during the study period
* Heart disease as indicated by history, abnormal ECG, previous cardiac surgery.
* Unstable physical disorders which might make participation hazardous such as end-stage AIDS, hypertension (\>140/90), WBC \< 3.5, active hepatitis or other liver disease with elevated transaminase levels (\< 2-3 X upper limit of normal will be considered acceptable if PT/PTT is normal), renal failure (creatinine \> 2, BUN \>40), or untreated diabetes
* Previous history of ketamine or benzodiazepine misuse or abuse, and a history of an adverse reaction/experience with prior exposure to ketamine or benzodiazepine
* Recent history of significant violence (past 2 years)
* First degree relative with a psychotic disorder (bipolar disorder, schizophrenia, schizoaffective disorder, or psychosis NOS)
* BMI \> 32, or a history of documented obstructive sleep apnea
* On psychotropic or other medications whose effect could be disrupted by participation in the study
* Patients who cannot comply with study procedures during the initial hospitalization phase