Glutamatergic Modulation of Cocaine-related Deficits

New York State Psychiatric Institute8 enrolled

Overview

Cocaine dependence involves problematic neuroadaptations, such as heightened reactivity to cocaine cues, that may be responsive to pharmacological modulation of glutamatergic circuits. Despite promising preclinical findings with n-methyl-d-aspartate receptor (NMDAr) modulators, studies with human subjects have been unsuccessful to date. The purpose of this investigation is to examine the effects of the NMDAr antagonist ketamine, recently found to have potent therapeutic effects in humans, on cue-induced craving and impaired motivation for quitting cocaine in cocaine dependent participants, 24-hours post-infusion.

In this study, volunteers will undergo a 9 day inpatient trial during which they will receive three counter-balanced infusions (two doses of ketamine and a dose of lorazepam) on three separate days in a within-subject, double-blind, controlled design. Of the various glutamate antagonists available for human use, ketamine will be utilized because its safety profile, pharmacokinetics, and range of tolerable sub-anesthetic dosings have been very well studied. Also, ketamine has shown promise in managing opiate and alcohol use disorders in certain studies, and may therefore be the most likely glutamate antagonist to dampen cue reactivity and increase motivation in cocaine users. If ketamine significantly improves these deficits, this would suggest that the drug should be investigated further for potential utility as a treatment for cocaine dependence.

Study Type

INTERVENTIONAL

Allocation

RANDOMIZED

Purpose

TREATMENT

Masking

TRIPLE

Enrollment

Conditions

Cocaine Dependence

Interventions

Ketamine 0.41 mg/kgDRUG

52 minute iv infusion of ketamine 0.41 mg/kg

Ketamine 0.71 mg/kgDRUG

52 minute iv infusion of ketamine 0.71 mg/kg. This dose follows K1 in all 3 orderings.

Lorazepam 2 mgDRUG

52 minute infusion of lorazepam 2 mg. This serves as an active control.

Eligibility

Sex: ALLMin age: 21 YearsMax age: 52 Years

Medical Language ↔ Plain English

Inclusion Criteria 1. Active free-base cocaine dependence (at least 4 days of use over the past month, with at least 1 use per week); if the participant uses through another route (IN, IV), then the FB route is dominant (\> 80% of occasions). 2. Physically healthy 3. No adverse reactions to study medications 4. 21-52 years of age 5. Normal body weight 6. Responsive to drug cues 7. Capacity to consent Exclusion Criteria: 1. Seeking treatment or abstinence 2. DSM IV criteria for substance dependence (other than methamphetamine, cocaine, cannabis, or nicotine), or DSM IV criteria for abuse of ketamine or lorazepam 3. DSM-IV criteria for other Axis I psychiatric illness that may make participation hazardous such as schizophrenia, schizoaffective disorder, psychosis NOS, MDD, psychosis secondary to substances, or bipolar disorder 4. Delirium, Dementia, Amnesia, Cognitive Disorders, or dissociative disorders 5. Current suicide risk or a history of suicide attempt within the past 2 years 6. Current use of prescribed psychotropic medication 7. Pregnancy, nursing, or had a baby within the past 6 mo. 8. Heart disease as indicated by history, abnormal ECG, previous cardiac surgery. 9. Unstable physical disorders which might make participation hazardous such as end-stage AIDS, hypertension (\>140/90), anemia, active hepatitis or other liver disease, or diabetes 10. "Bad" reaction/experience with prior exposure to ketamine or lorazepam 11. History of significant violence 12. First degree relative with a psychotic disorder

Locations (1)

NYSPI

New York, New York, United States

Outcomes

Primary Outcomes

Change in Cue Reactivity

Serial visual analogue scale (VAS) scores for craving elicited by cocaine cue: units on a scale (0-200), high is worse. Scores are obtained at baseline and at 24 hours after the infusion.

Time frame: Baseline and 24 hours after infusion

Change in Motivation to Quit

Motivation score obtained from the University of Rhode Island Change Assessment (URICA). Scores are obtained at baseline and at 24 hours after each infusion. The scores are 0-13, with higher scores indicating greater motivation. The analysis is within-subject. Scores included below are means; higher scores represent higher motivation to quit than do lower scores.

Time frame: Baseline and 24 hours post-infusion

Data from ClinicalTrials.gov

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