Combined Donepezil and Selegiline Effects on Cocaine-Reinforced Behavior
Condition: Cocaine Use Disorders
Study type: Interventional
Phase: Phase 2

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.
    

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.
    

Intervention name(s): High-dose donepezil; Low-dose donepezil; Selegiline; Placebo
Intervention type(s): Drug; Drug; Drug; Drug
Intervention description(s): Donepezil titrated to 22.5 mg daily; Donepezil titrated to 10 mg daily; Transdermal selegiline, 6 mg daily; microcrystalline cellulose
Other intervention name(s): Aricept; Aricept; EMSAM
Intervention MeSH terms: Selegiline; Donepezil
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Single (Participant)
Primary purpose: Treatment
Keywords: Acetylcholine; Cholinesterases; Cocaine; Self-Administration