Combined Donepezil and Selegiline Effects on Cocaine-Reinforced Behavior



Status:Recruiting
Conditions:Psychiatric
Therapuetic Areas:Psychiatry / Psychology
Healthy:No
Age Range:21 - 50
Updated:11/30/2013
Start Date:February 2012

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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.

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
We found this trial at
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Kansas City, Missouri 64128
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Kansas City, MO
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