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Tacrine Effects on Cocaine Self-Administration and Pharmacokinetics

This study has been withdrawn prior to enrollment.
(One of the study medications, tacrine, is no longer clinically available)
Sponsor:
Information provided by (Responsible Party):
KENNETH GRASING, Midwest Biomedical Research Foundation
ClinicalTrials.gov Identifier:
NCT01406522
First received: July 28, 2011
Last updated: December 17, 2013
Last verified: December 2013

July 28, 2011
December 17, 2013
October 2012
September 2013   (final data collection date for primary outcome measure)
Decreased cocaine-reinforced behavior [ Time Frame: Day 9 of treatment ] [ Designated as safety issue: No ]
participants will make a series of choices between vouchers with an ascending monetary value and intravenous injections of cocaine
Same as current
Complete list of historical versions of study NCT01406522 on ClinicalTrials.gov Archive Site
Changes in cocaine pharmacokinetics [ Time Frame: Day 9 of treatment ] [ Designated as safety issue: No ]
Plasma levels of cocaine and metabolites will be determined by liquid chromatography-tandem mass spectrometry
Same as current
Not Provided
Not Provided
 
Tacrine Effects on Cocaine Self-Administration and Pharmacokinetics
Tacrine Effects on Cocaine Self-Administration and Pharmacokinetics

No medications are currently available for treatment of psychostimulant addiction, a compulsive preoccupation with use of cocaine and related compounds. Tacrine, a medication that is currently prescribed for Alzheimer's disease, can decrease the amount of cocaine injections that laboratory animals choose to inject by vein. This project will determine if tacrine can also decrease cocaine-motivated behavior for human subjects in a laboratory setting.

Background Reinforcing effects of cocaine are believed to arise through release of dopamine (DA) at the nucleus accumbens by neurons in the ventral tegmental area. Activation of cholinergic receptors on the cell bodies of these neurons can enhance DA release. Elevated levels of acetylcholine (ACh) in the nucleus accumbens may also serve to inhibit appetitive behaviors. Cholinesterase inhibitors such as tacrine increase synaptic levels of ACh by preventing its inactivation by acetylcholinesterase (AChE) or butyrylcholinesterase (BuChE), and can improve learning and memory. In animals, cholinesterase inhibitors can attenuate cocaine self-administration and conditioned place preference. Tacrine is a centrally acting, reversible inhibitor of AChE and BuChE that is approved for treatment of Alzheimer's disease. In addition to its effects on the cholinergic system, tacrine can potentiate the actions of monoamines, including DA. Although use of tacrine has declined because of requirements for monitoring of potential liver toxicity and pharmacokinetics that necessitate multiple daily doses, it is more potent than other cholinesterase inhibitors in attenuating cocaine self-administration in animals. Pretreatment with tacrine can produce long-lasting reductions in cocaine-reinforced behavior in rats, described as persistent attenuation (cocaine self-administration is decreased by more than 80% over a period of three days during which no additional cholinesterase inhibitor is administered, see Figure 1). No previous studies have evaluated whether tacrine can modify the effects of cocaine in humans.

Rationale To our knowledge, tacrine is the only compound that can produce persistent attenuation in rats treated with clinically relevant doses. If similar effects were observed in humans, this would lead to an important paradigm shift for substance abuse treatment, in that large reductions in cocaine-reinforced behavior could be produced without the need for continuous dosing with a medication. This scenario could remove the requirement for continued compliance with oral dosing in some patients with its associated potential for toxicity.

Specific Aims:

  1. Evaluate whether tacrine treatment causes persistent attenuation of cocaine-reinforced behavior in humans.
  2. Determine the effectiveness of pretreatment with tacrine in attenuating cocaine-induced craving.
  3. Evaluate plasma levels of cocaine and characterize the bioavailability of tacrine in individual patients.

Methods This is a randomized, double-blind, double-dummy, placebo-controlled, inpatient, single-center, parallel-group evaluation of the potential for oral tacrine to modify cocaine self-administration, cocaine-induced craving, and the pharmacokinetics of cocaine and tacrine. To evaluate the occurrence of persistent attenuation, the subjective and reinforcing effects of intravenous cocaine will be determined during oral treatment and three days following its discontinuation.

Interventional
Phase 2
Allocation: Randomized
Endpoint Classification: Pharmacodynamics Study
Intervention Model: Parallel Assignment
Masking: Double Blind (Subject, Investigator)
Primary Purpose: Treatment
Cocaine Dependence
  • Drug: Oral tacrine
    Tacrine, 160 mg per day, four times daily
  • Drug: Oral placebo
    Microcrystalline cellulose
  • Placebo Comparator: Oral placebo
    Inactive treatment
    Intervention: Drug: Oral placebo
  • Experimental: Oral tacrine
    Oral tacrine
    Intervention: Drug: Oral tacrine

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Withdrawn
0
November 2013
September 2013   (final data collection date for primary outcome measure)

Inclusion Criteria:

  • Meets DSM-IV-TR criteria for cocaine abuse or dependence, with at least one cocaine-positive urine specimen within the six weeks prior to enrollment.
  • Has used cocaine for a duration of at least 6 months, with at least weekly use during the last 30 days by a rapid route of administration (either smoked or intravenous injection).
  • Is male or female, between 21 and 50 years old.

Exclusion Criteria:

  • Has a history of a medical adverse reaction to cocaine or other psychostimulants, including loss of consciousness, chest pain, cardiac ischemia, or seizure.
  • Has any current Axis I psychiatric disorder other than drug abuse or dependence.
  • Meets DSM-IV-TR criteria for dependence on opiates, benzodiazepines, alcohol, or other sedative-hypnotics.
Both
21 Years to 50 Years
No
Contact information is only displayed when the study is recruiting subjects
United States
 
NCT01406522
R21DA029787
Yes
KENNETH GRASING, Midwest Biomedical Research Foundation
Midwest Biomedical Research Foundation
Not Provided
Principal Investigator: Kenneth W Grasing, M.D. Kansas City VA Medical Center
Midwest Biomedical Research Foundation
December 2013

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP