Combined Donepezil and Selegiline Effects on Cocaine-Reinforced Behavior

Cocaine Use Disorders Clinical Trial

— SDC  

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT01495195
• Other study ID #: NCT01406522B
• Secondary ID: R21DA029787
• Status: Completed
• Phase: Phase 2
• First received: December 15, 2011
• Last updated: December 17, 2013
• Start date: February 2012
• Est. completion date: May 2013

Study information

• Verified date: December 2013
• Source: Midwest Biomedical Research Foundation
• Contact: n/a
• Is FDA regulated: No
• Health authority: United States: Food and Drug Administration
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 12
• Est. completion date: May 2013
• Est. primary completion date: May 2013
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 21 Years to 50 Years

Eligibility

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

Study Design

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

Related Conditions & MeSH terms

• Cocaine Use Disorders
• Substance-Related Disorders

Intervention

Drug:
• High-dose donepezil
Donepezil titrated to 22.5 mg daily
• Low-dose donepezil
Donepezil titrated to 10 mg daily
• Selegiline
Transdermal selegiline, 6 mg daily
• Placebo
microcrystalline cellulose

Locations

Country	Name	City	State
United States	Kansas City VA Medical Center	Kansas City	Missouri

Sponsors (2)

Lead Sponsor	Collaborator
Midwest Biomedical Research Foundation	National Institute on Drug Abuse (NIDA)

Country where clinical trial is conducted

United States, 

References & Publications (2)

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. doi: 10.1016/j.drugalcdep.2009.09.010. — View Citation

Grasing K, Yang Y, He S. Reversible and persistent decreases in cocaine self-administration after cholinesterase inhibition: different effects of donepezil and rivastigmine. Behav Pharmacol. 2011 Feb;22(1):58-70. doi: 10.1097/FBP.0b013e3283428cd8. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Changes in cocaine-reinforced behavior	Participants will make a series of choices between vouchers with an ascending monetary value and intravenous injections of cocaine	days 2 and 24 of dosing	No
Secondary	How well the study medications are tolerated	Laboratory and self-reported adverse events	33 days of dosing	Yes

External Links

•   Principle Investigator Background
•   Sponsor