Glutamatergic Modulation of Cocaine-related Deficits

Phase 2

Completed

Interventions: Drug: Ketamine 0.41 mg/kg
Drug: Ketamine 0.71 mg/kg
Drug: Lorazepam 2 mg

Brief Summary: 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: 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.

Recruitment & Eligibility

Inclusion Criteria

Not provided

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

Arm && Interventions

Group	Intervention	Description
K1	Ketamine 0.41 mg/kg	Ketamine 0.41 mg/kg infused over 52 min (K1)
K2	Ketamine 0.71 mg/kg	Ketamine 0.71 mg/kg infused over 52 min (K2)
LZP	Lorazepam 2 mg	Lorazepam 2 mg infused over 52 minutes (LZP)

Primary Outcome Measures

Name	Time	Method
Change in Cue Reactivity	Baseline and 24 hours after infusion	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.
Change in Motivation to Quit	Baseline and 24 hours post-infusion	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.

Secondary Outcome Measures