Glutamatergic Modulation of Cocaine-related Deficits

• Sponsor: New York State Psychiatric Institute (Other)
• Overall Status: Completed
• CT.gov ID: NCT01790490
• Collaborator: (none)
• Enrollment: 8
• Location: 1
• Arms: 3
• Duration (Months): 12.9
• Patients Per Site Per Month: 0.6

Study Details

Study Description

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.

Condition or Disease	Intervention/Treatment	Phase
Cocaine Dependence	Drug: Ketamine 0.41 mg/kg; Drug: Ketamine 0.71 mg/kg; Drug: Lorazepam 2 mg	Phase 2

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.

Study Design

• Study Type: Interventional
• Actual Enrollment: 8 participants
• Allocation: Randomized
• Intervention Model: Crossover Assignment
• Masking: Triple (Participant, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: The Effect of Ketamine on Reducing Cue Reactivity in Cocaine Users
• Study Start Date: Feb 1, 2011
• Actual Primary Completion Date: Mar 1, 2012
• Actual Study Completion Date: Mar 1, 2012

Arms and Interventions

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

Outcome Measures

Primary Outcome Measures

1. 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.

2. 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.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 21 Years to 52 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

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

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	NYSPI	New York	New York	United States	10032

Sponsors and Collaborators

• New York State Psychiatric Institute

Investigators

• Principal Investigator: Elias Dakwar, MD, NYSPI/Columbia College of Physicians and Surgeons
• Study Chair: Carl Hart, PhD, NYSPI/Columbia College of Physicians and Surgeons

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Elias Dakwar, Assistant Professor Clinical Psychiatry, New York State Psychiatric Institute
• ClinicalTrials.gov Identifier: NCT01790490
• Other Study ID Numbers: #6162
• First Posted: Feb 13, 2013
• Last Update Posted: Apr 30, 2019
• Last Verified: Apr 1, 2019

• Additional relevant MeSH terms: Cocaine-Related Disorders; Ketamine; Lorazepam

Study Results

Participant Flow

Recruitment Details	Participants were recruited using advertisements and were seen at NYSPI.
Pre-assignment Detail	Participants were excluded if they could not comply with study procedures or if they were found to be ineligible.

Arm/Group Title	K1, LZP, and K2	LZP, K1, and K2	K1, K2, and LZP
Arm/Group Description	Ketamine 0.41 (K1) followed by lorazepam (LZP) and then ketamine 0.71. Infusions are separated by 48 hours. This ordering allows for comparison between K1 and LZP, and between the post-K1 additive effects of LZP and K2.	LZP followed by K1 and then K2. Infusions are separated by 48 hours. This order allows for comparison between LZP and K1.	K1 followed by K2 and then LZP. Infusions are separated by 48 hours. This allows for within-subject comparison of the post-K1 additive effects of K2 and LZP.
Period Title: Overall Study
STARTED	3	3	2
COMPLETED	3	3	2
NOT COMPLETED	0	0	0

Baseline Characteristics

Arm/Group Title	K1, LZP, and K2	LZP, K1, and K2	K1, K2, and LZP	Total
Arm/Group Description	Ketamine 0.41 (K1) followed by lorazepam (LZP) and then ketamine 0.71. Infusions are separated by 48 hours. This ordering allows for comparison between K1 and LZP, and between the post-K1 additive effects of LZP and K2.	LZP followed by K1 and then K2. Infusions are separated by 48 hours. This order allows for comparison between LZP and K1.	K1 followed by K2 and then LZP. Infusions are separated by 48 hours. This allows for within-subject comparison of the post-K1 additive effects of K2 and LZP.	Total of all reporting groups
Overall Participants	3	3	2	8
Age (Count of Participants)
<=18 years	0 0%	0 0%	0 0%	0 0%
Between 18 and 65 years	3 100%	3 100%	2 100%	8 100%
>=65 years	0 0%	0 0%	0 0%	0 0%
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	46.8 (9)	48.2 (6.1)	44.2 (8.2)	47.5 (5.5)
Sex: Female, Male (Count of Participants)
Female	1 33.3%	0 0%	0 0%	1 12.5%
Male	2 66.7%	3 100%	2 100%	7 87.5%
Region of Enrollment (participants) [Number]
United States	3 100%	3 100%	2 100%	8 100%

Outcome Measures

1. Primary Outcome

Title	Change in Cue Reactivity
Description	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

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Ketamine Infusion 0.41 mg/kg Over 52 Minutes (K1)	Ketamine Infusion 0.71 mg/kg Over 52 Minutes (K2)	Lorazepam Infusion 2 mg/kg Over 52 Minutes (LZP)
Arm/Group Description	Ketamine 0.41 mg/kg infused over 52 min (K1) Ketamine 0.41 mg/kg: 52 minute iv infusion of ketamine 0.41 mg/kg	Ketamine 0.71 mg/kg infused over 52 min (K2) Ketamine 0.71 mg/kg: 52 minute iv infusion of ketamine 0.71 mg/kg. This dose follows K1 in all 3 orderings.	Lorazepam 2 mg infused over 52 minutes (LZP) Lorazepam 2 mg: 52 minute infusion of lorazepam 2 mg. This serves as an active control.
Measure Participants	8	8	8
Median (Standard Error) [units on a scale (0-200), high is worse]	126 (66)	18 (13)	16 (12)

2. Primary Outcome

Title	Change in Motivation to Quit
Description	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

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Ketamine Infusion 0.41 mg/kg Over 52 Minutes (K1)	Lorazepam Infusion 2 mg/kg Over 52 Minutes (LZP)	Lorazepam Infusion 2 mg/kg Over 52 Minutes (LZP) Following K1
Arm/Group Description	Ketamine 0.41 (K1) followed by lorazepam (LZP) and then ketamine 0.71. Infusions are separated by 48 hours. This ordering allows for comparison between K1 and LZP, and between the post-K1 additive effects of LZP and K2.	LZP followed by K1 and then K2. Infusions are separated by 48 hours. This order allows for comparison between LZP and K1.	Infusions are separated by 48 hours. This allows for within-subject comparison of the post-K1 additive effects of K2 and LZP.
Measure Participants	3	3	2
Mean (Full Range) [units on a scale]	4.35	3.2	4.2

Adverse Events

Arm/Group Title	Ketamine 0.41 (K1)		Lorazepam 2 mg (LZP)		Ketamine 0.71 (K2)
Arm/Group Description	Ketamine 0.41 (K1) over 52 minutes		Lorazepam 2 mg (LZP) over 52 minutes		Ketamine 0.71 mg/kg over 52 minutes (K2)
All Cause Mortality
	Ketamine 0.41 (K1)		Lorazepam 2 mg (LZP)		Ketamine 0.71 (K2)
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)		/ (NaN)
Serious Adverse Events
	Ketamine 0.41 (K1)		Lorazepam 2 mg (LZP)		Ketamine 0.71 (K2)
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/8 (0%)		0/8 (0%)		0/8 (0%)
Other (Not Including Serious) Adverse Events
	Ketamine 0.41 (K1)		Lorazepam 2 mg (LZP)		Ketamine 0.71 (K2)
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/8 (0%)		0/8 (0%)		0/8 (0%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.