A test of the cognitive-enhancing potential of low-dose mecamylamine in healthy non-smokers

Abstract

Rationale: The beneficial effects of nicotinic acetylcholine receptor (nAChR) agonists on cognitive performance have been widely shown. Paradoxically, recent preclinical studies employing extremely low doses of nAChR antagonists have also found cognitive enhancement, perhaps pointing to a novel treatment mechanism for cognitive deficits.

Objectives: The aim was to test whether low doses of the nAChR antagonist mecamylamine would benefit performance in human volunteers.

Methods: The study employed a double-blind within-subject design. Over four separate days, healthy adult non-smokers (n = 23) were tested with placebo and three trace doses of mecamylamine (0.25-1 mg, p.o.), adjusted for body weight. Participants performed three computerized tasks: a task of spatial selective attention and stimulus detection, the rapid visual information processing task (RVIPT) taxing sustained attention and working memory, and a change detection short-term memory task. Subjective state and vital signs were assessed repeatedly.

Results: Mecamylamine did not improve performance in any of the tasks. Any trends that were observed instead pointed toward performance impairment. Mecamylamine also had no effects on subjective state or vital signs.

Conclusions: The present results do not support the hypothesized cognitive-enhancing potential of low doses of mecamylamine. Contrary to preclinical reports, these findings speak against low-dose nAChR antagonism as a novel avenue for treating cognitive deficits.

Keywords: Antagonist; Attention; Cognition; Human; Mecamylamine; Memory; Nicotinic.

Fig. 1

(A) Components of a trial in the Spatial Attentional Resource Allocation Task (B) Components of a trial in the Change Detection Task

Fig. 2

Effects of mecamylamine on reaction time (A) and omission errors (B) in the Spatial Attentional Resource Allocation Task. Bars reflect the mean performance in each dose condition. Error bars reflect SEMs, adjusted to remove between-subject variability in the average performance across dose levels (Cousineau 2007; Morey 2008) to yield variability related to interindividual differences in drug effect. Doses Small, Medium (Med), & Large refer to 0.2 mg, 0.4 mg, & 0.8 mg of mecamylamine for participants weighing <160 lbs; to 0.25 mg, 0.5 mg, & 1 mg for 160–200 lbs; and to 0.3 mg, 0.6 mg, & 1.2 mg for >200 lbs. Pla=Placebo. * P<0.05 in paired t-test comparing performance after mecamylamine to performance after vehicle

Fig. 3

Effects of mecamylamine on signal detection sensitivity (A) and reaction time (B) in the Rapid Visual Information Processing Task. Bars reflect the mean performance in each dose condition. Error bars reflect SEMs, adjusted to remove between-subject variability in the average performance across dose levels (Cousineau 2007; Morey 2008). Doses Small, Medium (Med), & Large refer to 0.2 mg, 0.4 mg, & 0.8 mg for participants weighing <160 lbs; to 0.25 mg, 0.5 mg, & 1 mg for 160–200 lbs; and to 0.3 mg, 0.6 mg, & 1.2 mg for >200 lbs. * P<0.05, ⁽*⁾ P=0.057 in paired t-tests comparing performance after mecamylamine to performance after vehicle