Tacrine Effects on Cocaine Self-Administration and Pharmacokinetics

December 17, 2013 updated by: KENNETH GRASING, Midwest Biomedical Research Foundation
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.

Study Overview

Status

Withdrawn

Conditions

Intervention / Treatment

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.

Study Type

Interventional

Phase

  • Phase 2

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

  • United States
    • Missouri
      • Kansas City, Missouri, United States, 64128
        • Kansas City VA Medical Center

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

19 years to 48 years (Adult)

Accepts Healthy Volunteers

No

Genders Eligible for Study

All

Description

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.

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Treatment
  • Allocation: Randomized
  • Interventional Model: Parallel Assignment
  • Masking: Double

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
Placebo Comparator: Oral placebo
Inactive treatment
Drug: Oral placebo
Microcrystalline cellulose
Experimental: Oral tacrine
Drug: Oral tacrine
Tacrine, 160 mg per day, four times daily

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Decreased cocaine-reinforced behavior
Time Frame: Day 9 of treatment
participants will make a series of choices between vouchers with an ascending monetary value and intravenous injections of cocaine
Day 9 of treatment

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Changes in cocaine pharmacokinetics
Time Frame: Day 9 of treatment
Plasma levels of cocaine and metabolites will be determined by liquid chromatography-tandem mass spectrometry
Day 9 of treatment

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Midwest Biomedical Research Foundation

Investigators

  • Principal Investigator: Kenneth W Grasing, M.D., Kansas City VA Medical Center

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start

October 1, 2012

Primary Completion (Anticipated)

September 1, 2013

Study Completion (Anticipated)

November 1, 2013

Study Registration Dates

First Submitted

July 28, 2011

First Submitted That Met QC Criteria

July 28, 2011

First Posted (Estimate)

August 1, 2011

Study Record Updates

Last Update Posted (Estimate)

December 18, 2013

Last Update Submitted That Met QC Criteria

December 17, 2013

Last Verified

December 1, 2013

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • R21DA029787 (U.S. NIH Grant/Contract)

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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