Combined Donepezil and Selegiline Effects on Cocaine-Reinforced Behavior (SDC)

This study has been completed.
Sponsor:
Collaborator:
Information provided by (Responsible Party):
KENNETH GRASING, Midwest Biomedical Research Foundation
ClinicalTrials.gov Identifier:
NCT01495195
First received: December 15, 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. Donepezil is a medication that is currently prescribed for Alzheimer's disease, and selegiline is a medication used for treatment of Parkinson's Disease. Both of these medications can decrease the amount of cocaine injections that laboratory animals choose to inject by vein. This project will determine if combined treatment with donepezil and selegiline can also decrease cocaine-motivated behavior for human subjects in a laboratory setting.


Condition Intervention Phase
Cocaine Use Disorders
Drug: High-dose donepezil
Drug: Low-dose donepezil
Drug: Selegiline
Drug: Placebo
Phase 2

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Efficacy Study
Intervention Model: Parallel Assignment
Masking: Single Blind (Subject)
Primary Purpose: Treatment

Resource links provided by NLM:


Further study details as provided by Midwest Biomedical Research Foundation:

Primary Outcome Measures:
  • Changes in cocaine-reinforced behavior [ Time Frame: days 2 and 24 of dosing ] [ 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:
  • How well the study medications are tolerated [ Time Frame: 33 days of dosing ] [ Designated as safety issue: Yes ]
    Laboratory and self-reported adverse events


Enrollment: 12
Study Start Date: February 2012
Study Completion Date: May 2013
Primary Completion Date: May 2013 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Donepezil, high-dose
Titration of donepezil to 22.5 mg daily
Drug: High-dose donepezil
Donepezil titrated to 22.5 mg daily
Other Name: Aricept
Experimental: Selegiline & low-dose donepezil
Low-Dose Donepezil [titrated to 10 mg daily] and transdermal selegiline [6 mg daily]
Drug: Low-dose donepezil
Donepezil titrated to 10 mg daily
Other Name: Aricept
Drug: Selegiline
Transdermal selegiline, 6 mg daily
Other Name: EMSAM
Experimental: Selegiline & high-dose donepezil
High-Dose Donepezil [titrated to 22.5 mg daily] and transdermal selegiline [6 mg daily]
Drug: High-dose donepezil
Donepezil titrated to 22.5 mg daily
Other Name: Aricept
Drug: Selegiline
Transdermal selegiline, 6 mg daily
Other Name: EMSAM
Placebo Comparator: Sugar pill
Inert pill for comparison
Drug: Placebo
microcrystalline cellulose

Detailed Description:

Background:

We have recently shown that pretreatment with certain cholinesterase inhibitors can produce large reductions in cocaine-reinforced behavior in rats (drug self-administration is decreased by more than 70% over a period of three days during which no additional cholinesterase inhibitor is administered). Because the reductions persist over a period two or more weeks, they have been described as persistent attenuation. Similar reductions have been observed after rats receive pretreatment with the cholinesterase inhibitors donepezil or tacrine, but not rivastigmine. The key difference leading to persistent attenuation may be effects of donepezil or tacrine on catecholamine neurotransmitters. Specifically, our hypothesis is that persistent attenuation is caused by a combination of 1.) Cholinesterase inhibition, which increases brain levels of acetylcholine (ACh); and 2.) Increased brain levels of dopamine and serotonin. Although well-tolerated, pretreatment with low doses of the cholinesterase inhibitor donepezil have not modified either the positive subjective effects of cocaine in humans, or cocaine use in outpatients. This may reflect the relatively low doses of donepezil administered (up to 10 mg daily). Transdermal selegiline is a well-tolerated, nonselective monoamine oxidase inhibitor that potentiates actions of dopamine and serotonin in the central nervous system.

Rationale Persistent attenuation may be achieved in humans by administering donepezil at higher doses, or in combination with a centrally-acting inhibitor of monoamine oxidase (MAO). Inhibition of MAO increases brain levels of dopamine and serotonin. If persistent attenuation can be accomplished 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. Determine whether donepezil can be safely advanced over a 17-day period to an individualized dose of up to 22.5 mg daily (or the highest dose tolerated by each participant).
  2. Evaluate whether high-dose donepezil attenuates cocaine-reinforced behavior in humans.
  3. Determine whether combined donepezil and selegiline produces greater reductions in cocaine-reinforced behavior than observed for donepezil alone.

Methods This is a randomized, single-blind, placebo-controlled, research-unit, single-center evaluation of the potential for oral donepezil, with or without transdermal selegiline to modify cocaine self-administration in a laboratory setting. Up to 32 non-treatment-seeking, regular cocaine users will be assigned to receive one of four treatments: 1.) Oral placebo; 2.) High-Dose Donepezil [titrated to 22.5 mg daily]; and 3.) Low-Dose Donepezil [titrated to 10 mg daily] and transdermal selegiline [6 mg daily]; and 4.) High-Dose Donepezil [titrated to 22.5 mg daily] and transdermal selegiline [6 mg daily]. For participants who receive donepezil, it will be advanced to either a target dose (low or high), or a lower dose that is tolerated by individual participants. To evaluate the occurrence of persistent attenuation, cocaine use will be measured over a nine-day follow-up period, through urine drug screens and the timeline-follow-back method. As noncontingent infusions of cocaine are administered, the pharmacokinetics of cocaine and donepezil will be determined.

  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
  • At least one cocaine-positive urine within 6 weeks prior to enrollment
  • Has used cocaine for a duration of at least 6 months
  • At least weekly cocaine use during the last 30 days

Exclusion Criteria:

  • History of a medical adverse reaction to cocaine or other psychostimulants
  • Any current Axis I psychiatric disorder other than drug abuse or dependence
  • Dependence on abused substances other than cocaine
  • Current or past history of seizure disorder
  • Heart or lung disease
  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: NCT01495195

Locations
United States, Missouri
Kansas City VA Medical Center
Kansas City, Missouri, United States, 64128
Sponsors and Collaborators
Midwest Biomedical Research Foundation
  More Information

Additional Information:
Publications:
Responsible Party: KENNETH GRASING, Director, Substance Abuse Research Laboratory, Kansas City VA Medical Center, Midwest Biomedical Research Foundation
ClinicalTrials.gov Identifier: NCT01495195     History of Changes
Other Study ID Numbers: NCT01406522B, R21DA029787
Study First Received: December 15, 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:
Substance-Related Disorders
Chemically-Induced Disorders
Mental Disorders
Donepezil
Central Nervous System Agents
Cholinergic Agents
Cholinesterase Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Neurotransmitter Agents
Nootropic Agents
Pharmacologic Actions
Physiological Effects of Drugs
Therapeutic Uses

ClinicalTrials.gov processed this record on October 30, 2014