Cognitive effects of the acetylcholinesterase inhibitor, donepezil, in healthy, non-treatment seeking smokers: a pilot feasibility study

Drug Alcohol Depend. 2012 Nov 1;126(1-2):263-7. doi: 10.1016/j.drugalcdep.2012.04.019. Epub 2012 May 15.


Background: There is a need to identify medications to aid in smoking cessation. Reducing withdrawal-related cognitive deficits represents a pharmacological target for new pharmacotherapies. Endogenous acetylcholine levels, which are modulated by acetylcholinesterase inhibitors (AChEIs), play an important role in smoking behavior and cognition. This pilot feasibility study tested whether an AChEI, donepezil, enhanced cognitive performance among healthy smokers.

Methods: Eighteen non-treatment seeking daily smokers (6 female) received either donepezil (5 mg q.d) or placebo (double-blind; 2:1 allocation ratio) for 4 weeks. Smoking rate, side effects, and neurocognitive measures of working memory (Letter-N-back) and sustained attention (Penn Continuous Performance Task) were assessed weekly.

Results: For the working memory task, there was a significant group×load×time interaction (p=0.03) indicating that the donepezil group demonstrated an increase in true positives from baseline to week 4 at the highest working memory load (3-back). The placebo group showed no change in accuracy. For the sustained attention task, there was a marginal effect in the same direction for discriminability, or d', p=0.08. There were no significant effects on reaction time during either task. There was also a reduction in cigarettes per day in the placebo group, but not the donepezil group.

Conclusions: AChEIs, such as donepezil, may have pro-cognitive effects among healthy smokers while they continue to smoke as usual. Given the association between cognitive deficits and relapse, AChEIs should be explored as potential therapeutics for smoking cessation.

Publication types

  • Randomized Controlled Trial
  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Analysis of Variance
  • Attention / drug effects
  • Cholinesterase Inhibitors / adverse effects
  • Cholinesterase Inhibitors / pharmacology*
  • Cognition / drug effects*
  • Donepezil
  • Double-Blind Method
  • Feasibility Studies
  • Female
  • Humans
  • Indans / adverse effects
  • Indans / pharmacology*
  • Male
  • Medication Adherence
  • Neuropsychological Tests
  • Nootropic Agents / adverse effects
  • Nootropic Agents / pharmacology*
  • Pilot Projects
  • Piperidines / adverse effects
  • Piperidines / pharmacology*
  • Psychomotor Performance / drug effects
  • Reaction Time / drug effects
  • Smoking / psychology*


  • Cholinesterase Inhibitors
  • Indans
  • Nootropic Agents
  • Piperidines
  • Donepezil