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

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ClinicalTrials.gov Identifier: NCT01495195
Recruitment Status : Completed
First Posted : December 19, 2011
Last Update Posted : December 18, 2013
National Institute on Drug Abuse (NIDA)
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. 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 or disease Intervention/treatment Phase
Cocaine Use Disorders Drug: High-dose donepezil Drug: Low-dose donepezil Drug: Selegiline Drug: Placebo Phase 2

Detailed Description:


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.

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 12 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Single (Participant)
Primary Purpose: Treatment
Study Start Date : February 2012
Actual Primary Completion Date : May 2013
Actual Study Completion Date : May 2013

Resource links provided by the National Library of Medicine

Arm Intervention/treatment
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

Primary Outcome Measures :
  1. Changes in cocaine-reinforced behavior [ Time Frame: days 2 and 24 of dosing ]
    Participants will make a series of choices between vouchers with an ascending monetary value and intravenous injections of cocaine

Secondary Outcome Measures :
  1. How well the study medications are tolerated [ Time Frame: 33 days of dosing ]
    Laboratory and self-reported adverse events

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
  • 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

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 ClinicalTrials.gov identifier (NCT number): NCT01495195

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United States, Missouri
Kansas City VA Medical Center
Kansas City, Missouri, United States, 64128
Sponsors and Collaborators
Midwest Biomedical Research Foundation
National Institute on Drug Abuse (NIDA)
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Responsible Party: KENNETH GRASING, Director, Substance Abuse Research Laboratory, Kansas City VA Medical Center, Midwest Biomedical Research Foundation
ClinicalTrials.gov Identifier: NCT01495195    
Other Study ID Numbers: NCT01406522B
R21DA029787 ( U.S. NIH Grant/Contract )
First Posted: December 19, 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:
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Cholinesterase Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Cholinergic Agents
Neurotransmitter Agents
Physiological Effects of Drugs
Nootropic Agents
Antidepressive Agents
Psychotropic Drugs
Antiparkinson Agents
Anti-Dyskinesia Agents
Monoamine Oxidase Inhibitors
Neuroprotective Agents
Protective Agents