Glutamatergic Modulation of Cocaine-related Deficits

Study Overview
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Brief Summary
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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.

Detailed Description
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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.

Official Title
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The Effect of Ketamine on Reducing Cue Reactivity in Cocaine Users

Conditions
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Cocaine Dependence

Intervention / Treatment
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* Drug: Ketamine 0.41 mg/kg
* Drug: Ketamine 0.71 mg/kg
* Drug: Lorazepam 2 mg


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria 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). Physically healthy No adverse reactions to study medications 21-52 years of age Normal body weight Responsive to drug cues Capacity to consent Exclusion Criteria: Seeking treatment or abstinence DSM IV criteria for substance dependence (other than methamphetamine, cocaine, cannabis, or nicotine), or DSM IV criteria for abuse of ketamine or lorazepam 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 Delirium, Dementia, Amnesia, Cognitive Disorders, or dissociative disorders Current suicide risk or a history of suicide attempt within the past 2 years Current use of prescribed psychotropic medication Pregnancy, nursing, or had a baby within the past 6 mo. 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), anemia, active hepatitis or other liver disease, or diabetes Bad reaction/experience with prior exposure to ketamine or lorazepam History of significant violence First degree relative with a psychotic disorder

Ages Eligible for Study
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Minimum Age: 21 Years
Maximum Age: 52 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: K1<br>Ketamine 0.41 mg/kg infused over 52 min (K1) | Drug: Ketamine 0.41 mg/kg<br>* 52 minute iv infusion of ketamine 0.41 mg/kg<br>* Other names: K1;|
| Experimental: K2<br>Ketamine 0.71 mg/kg infused over 52 min (K2) | Drug: Ketamine 0.71 mg/kg<br>* 52 minute iv infusion of ketamine 0.71 mg/kg. This dose follows K1 in all 3 orderings.<br>* Other names: K2;|
| Experimental: LZP<br>Lorazepam 2 mg infused over 52 minutes (LZP) | Drug: Lorazepam 2 mg<br>* 52 minute infusion of lorazepam 2 mg. This serves as an active control.<br>* Other names: LZP;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. | 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. | Baseline and 24 hours post-infusion |