Nicotine fails to attenuate ketamine-induced cognitive deficits and negative and positive symptoms in humans: implications for schizophrenia

Biol Psychiatry. 2012 Nov 1;72(9):785-94. doi: 10.1016/j.biopsych.2012.05.009. Epub 2012 Jun 19.


Background: The uncompetitive N-methyl-D-aspartate receptor (NMDAR) antagonist, ketamine, induces a range of symptoms resembling those seen in schizophrenia. Enhancement of nicotinic acetylcholine receptor (nAChR) function may have potential as a treatment for the cognitive deficits and negative symptoms of schizophrenia. Accordingly, we examined the modulatory effects of brain nAChR systems on NMDAR antagonist-induced effects.

Methods: The interactive effects of ketamine and nicotine were evaluated in 37 healthy subjects in a randomized, placebo-controlled, double-blind, crossover counterbalanced, 2 (intravenous ketamine or placebo) × 2 (intravenous nicotine or placebo) design. Verbal and visual memory, sustained attention, working memory, response inhibition, emotion recognition, executive function, reaction time, motor function, and speed of processing were assessed once per test day, while negative and positive symptoms, perceptual alterations, and a number of feeling states were measured several times before and after administration of drugs.

Results: Ketamine induced cognitive deficits and negative and positive symptoms. Nicotine worsened immediate recall, auditory working memory, response inhibition, and executive function and serial processing. Nicotine decreased (improved) reaction time on the sustained attention and choice reaction time tasks. Nicotine did not reduce ketamine-induced cognitive deficits or negative and positive symptoms.

Conclusions: At blood levels comparable with tobacco smoking, nicotine infusion does not appear to alleviate the ketamine-induced transient cognitive and behavioral effects in healthy subjects that resemble those seen in schizophrenia. The lack of an effect of nicotine on a spectrum of ketamine effects suggests that the consequences of NMDAR antagonism are not likely under the direct influence of nAChR.

Trial registration: NCT00690170.

Publication types

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

MeSH terms

  • Adolescent
  • Adult
  • Attention / drug effects
  • Cognition / drug effects*
  • Cognition Disorders / chemically induced*
  • Cognition Disorders / psychology
  • Cross-Over Studies
  • Double-Blind Method
  • Drug Interactions
  • Executive Function / drug effects
  • Humans
  • Inhibition, Psychological
  • Ketamine / antagonists & inhibitors
  • Ketamine / pharmacokinetics
  • Ketamine / pharmacology*
  • Memory / drug effects
  • Middle Aged
  • Motor Skills / drug effects
  • Nicotine / pharmacokinetics
  • Nicotine / pharmacology*
  • Psychiatric Status Rating Scales / statistics & numerical data
  • Psychomotor Performance / drug effects
  • Reaction Time / drug effects
  • Recognition, Psychology / drug effects
  • Schizophrenia / chemically induced*
  • Schizophrenia / diagnosis


  • Ketamine
  • Nicotine

Associated data