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

December 15, 2011
December 17, 2013
February 2012
May 2013   (final data collection date for primary outcome measure)
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
Same as current
Complete list of historical versions of study NCT01495195 on ClinicalTrials.gov Archive Site
How well the study medications are tolerated [ Time Frame: 33 days of dosing ] [ Designated as safety issue: Yes ]
Laboratory and self-reported adverse events
Same as current
Not Provided
Not Provided
 
Combined Donepezil and Selegiline Effects on Cocaine-Reinforced Behavior
Not Provided

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.

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.

Interventional
Phase 2
Allocation: Randomized
Endpoint Classification: Efficacy Study
Intervention Model: Parallel Assignment
Masking: Single Blind (Subject)
Primary Purpose: Treatment
Cocaine Use Disorders
  • Drug: High-dose donepezil
    Donepezil titrated to 22.5 mg daily
    Other Name: Aricept
  • Drug: Low-dose donepezil
    Donepezil titrated to 10 mg daily
    Other Name: Aricept
  • Drug: Selegiline
    Transdermal selegiline, 6 mg daily
    Other Name: EMSAM
  • Drug: Placebo
    microcrystalline cellulose
  • Experimental: Donepezil, high-dose
    Titration of donepezil to 22.5 mg daily
    Intervention: Drug: High-dose donepezil
  • Experimental: Selegiline & low-dose donepezil
    Low-Dose Donepezil [titrated to 10 mg daily] and transdermal selegiline [6 mg daily]
    Interventions:
    • Drug: Low-dose donepezil
    • Drug: Selegiline
  • Experimental: Selegiline & high-dose donepezil
    High-Dose Donepezil [titrated to 22.5 mg daily] and transdermal selegiline [6 mg daily]
    Interventions:
    • Drug: High-dose donepezil
    • Drug: Selegiline
  • Placebo Comparator: Sugar pill
    Inert pill for comparison
    Intervention: Drug: Placebo
Grasing K, Mathur D, Newton TF, DeSouza C. Donepezil treatment and the subjective effects of intravenous cocaine in dependent individuals. Drug Alcohol Depend. 2010 Feb 1;107(1):69-75.

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Completed
12
May 2013
May 2013   (final data collection date for primary outcome measure)

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
Both
21 Years to 50 Years
No
Contact information is only displayed when the study is recruiting subjects
United States
 
NCT01495195
NCT01406522B, R21DA029787
Yes
KENNETH GRASING, Midwest Biomedical Research Foundation
Midwest Biomedical Research Foundation
National Institute on Drug Abuse (NIDA)
Not Provided
Midwest Biomedical Research Foundation
December 2013

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP