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This study has been withdrawn prior to enrollment.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
  Purpose

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.


Condition Intervention Phase
Cocaine Dependence
Drug: Oral tacrine
Drug: Oral placebo
Phase 2

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Pharmacodynamics Study
Intervention Model: Parallel Assignment
Masking: Double Blind (Subject, Investigator)
Primary Purpose: Treatment
Official Title: Tacrine Effects on Cocaine Self-Administration and Pharmacokinetics

Resource links provided by NLM:


Further study details as provided by Midwest Biomedical Research Foundation:

Primary Outcome Measures:
  • 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


Secondary Outcome Measures:
  • 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


Enrollment: 0
Study Start Date: October 2012
Estimated Study Completion Date: November 2013
Estimated Primary Completion Date: September 2013 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Placebo Comparator: Oral placebo
Inactive treatment
Drug: Oral placebo
Microcrystalline cellulose
Experimental: Oral tacrine
Oral tacrine
Drug: Oral tacrine
Tacrine, 160 mg per day, four times daily

Detailed Description:

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.

  Eligibility

Ages Eligible for Study:   21 Years to 50 Years
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

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.
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01406522

Locations
United States, Missouri
Kansas City VA Medical Center
Kansas City, Missouri, United States, 64128
Sponsors and Collaborators
Midwest Biomedical Research Foundation
Investigators
Principal Investigator: Kenneth W Grasing, M.D. Kansas City VA Medical Center
  More Information

Additional Information:
Publications:
Responsible Party: KENNETH GRASING, Director, Substance Abuse Research Laboratory, Midwest Biomedical Research Foundation
ClinicalTrials.gov Identifier: NCT01406522     History of Changes
Other Study ID Numbers: R21DA029787
Study First Received: July 28, 2011
Last Updated: December 17, 2013
Health Authority: United States: Food and Drug Administration

Keywords provided by Midwest Biomedical Research Foundation:
Acetylcholine
Cholinesterases
Cocaine
Self-Administration

Additional relevant MeSH terms:
Cocaine-Related Disorders
Substance-Related Disorders
Chemically-Induced Disorders
Mental Disorders
Cocaine
Tacrine
Anesthetics, Local
Anesthetics
Central Nervous System Depressants
Physiological Effects of Drugs
Pharmacologic Actions
Sensory System Agents
Peripheral Nervous System Agents
Central Nervous System Agents
Therapeutic Uses
Vasoconstrictor Agents
Cardiovascular Agents
Dopamine Uptake Inhibitors
Dopamine Agents
Neurotransmitter Agents
Molecular Mechanisms of Pharmacological Action
Neurotransmitter Uptake Inhibitors
Cholinesterase Inhibitors
Enzyme Inhibitors
Cholinergic Agents
Parasympathomimetics
Autonomic Agents
Nootropic Agents

ClinicalTrials.gov processed this record on August 28, 2014