Tacrine Effects on Cocaine Self-Administration and Pharmacokinetics

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details. Identifier: NCT01406522
Recruitment Status : Withdrawn (One of the study medications, tacrine, is no longer clinically available)
First Posted : August 1, 2011
Last Update Posted : December 18, 2013
Information provided by (Responsible Party):
KENNETH GRASING, Midwest Biomedical Research Foundation

Brief Summary:
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 or disease Intervention/treatment Phase
Cocaine Dependence Drug: Oral tacrine Drug: Oral placebo Phase 2

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  (Clinical Trial)
Actual Enrollment : 0 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double (Participant, Investigator)
Primary Purpose: Treatment
Official Title: Tacrine Effects on Cocaine Self-Administration and Pharmacokinetics
Study Start Date : October 2012
Estimated Primary Completion Date : September 2013
Estimated Study Completion Date : November 2013

Resource links provided by the National Library of Medicine

Arm Intervention/treatment
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

Primary Outcome Measures :
  1. 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

Secondary Outcome Measures :
  1. 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

Information from the National Library of Medicine

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Ages Eligible for Study:   21 Years to 50 Years   (Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No

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.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its identifier (NCT number): NCT01406522

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

Additional Information:
Responsible Party: KENNETH GRASING, Director, Substance Abuse Research Laboratory, Midwest Biomedical Research Foundation Identifier: NCT01406522     History of Changes
Other Study ID Numbers: R21DA029787 ( U.S. NIH Grant/Contract )
First Posted: August 1, 2011    Key Record Dates
Last Update Posted: December 18, 2013
Last Verified: December 2013

Keywords provided by KENNETH GRASING, Midwest Biomedical Research Foundation:

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