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



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



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.



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.



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.
Maryland Psychiatric Research Center, University of Maryland School of Medicine, P.O. Box 21247, Baltimore, MD, 21228, USA.
Marie B
MB
Yuille
Maryland Psychiatric Research Center, University of Maryland School of Medicine, P.O. Box 21247, Baltimore, MD, 21228, USA.
Cory K
CK
Olmstead
Maryland Psychiatric Research Center, University of Maryland School of Medicine, P.O. Box 21247, Baltimore, MD, 21228, USA.
Ashleigh K
AK
Wells
Maryland Psychiatric Research Center, University of Maryland School of Medicine, P.O. Box 21247, Baltimore, MD, 21228, USA. bhahn@mprc.umaryland.edu.
Britta
B
Hahn
D000328:Adult; D001288:Attention / Q000187:drug effects; D003071:Cognition / Q000187:drug effects*; D004311:Double-Blind Method; D005260:Female; D006801:Humans; D008297:Male; D008464:Mecamylamine / Q000494:pharmacology*; D008570:Memory, Short-Term / Q000187:drug effects; D008875:Middle Aged; D009483:Neuropsychological Tests; D018733:Nicotinic Antagonists / Q000494:pharmacology*; D018697:Nootropic Agents / Q000494:pharmacology*; D055815:Young Adult
D018733:Nicotinic Antagonists; D018697:Nootropic Agents; D008464:Mecamylamine
Antagonist; Attention; Cognition; Human; Mecamylamine; Memory; Nicotinic
Pharmacol Biochem Behav. 2011 Aug;99(2):130-45
21463652
Ann N Y Acad Sci. 2012 Feb;1248:89-106
22129082
J Pharmacol Exp Ther. 2009 Feb;328(2):364-70
19023041
Eur J Nucl Med Mol Imaging. 2011 Mar;38(3):515-25
21069319
Neuropsychopharmacology. 1998 Jul;19(1):60-9
9608577
Psychopharmacology (Berl). 1996 Sep;127(1):31-8
8880941
Behav Brain Res. 2000 Dec 20;117(1-2):197-208
11099773
Neuroimage. 2006 Aug 15;32(2):842-53
16757180
Med Res Rev. 1995 Jan;15(1):47-72
7898169
IDrugs. 2004 Dec;7(12):1096-103
15599803
Curr Top Med Chem. 2010;10(2):144-52
20166959
Psychopharmacology (Berl). 2011 Sep;217(1):75-82
21432025
Prog Neurobiol. 2008 Apr;84(4):329-42
18242816
Neurobiol Aging. 1992 Mar-Apr;13(2):313-8
1522945
Curr Opin Pharmacol. 2004 Feb;4(1):36-46
15018837
Pharmacol Ther. 2013 Jan;137(1):22-54
22925690
Pharmacol Biochem Behav. 1997 Feb;56(2):181-7
9050073
Front Biosci. 2007 May 01;12:4755-72
17485411
Curr Pharm Des. 2010 Jan;16(3):309-22
20109141
IDrugs. 2006 Mar;9(3):205-17
16523387
Psychopharmacology (Berl). 2004 Jun;174(1):54-64
15205879
Neurobiol Learn Mem. 2006 Jul;86(1):117-22
16632386
Curr Drug Targets CNS Neurol Disord. 2002 Aug;1(4):423-31
12769614
Eur J Pharmacol. 2013 Feb 28;702(1-3):269-74
23399762
J Neurosci. 2007 Mar 28;27(13):3477-89
17392464
Biol Psychiatry. 2013 Sep 15;74(6):436-43
23660272
Clin Ther. 2001 Apr;23(4):532-65
11354389
Psychopharmacology (Berl). 1998 Feb;135(3):305-10
9498735
Hum Psychopharmacol. 2009 Jun;24(4):309-17
19475630
Psychopharmacology (Berl). 2010 Jul;210(4):453-69
20414766
Neuropsychopharmacology. 2010 Jun;35(7):1429-39
20393456
Behav Neural Biol. 1987 Sep;48(2):206-12
2823791
J Neurobiol. 2002 Dec;53(4):457-78
12436413
Psychopharmacology (Berl). 1992;108(4):480-4
1410163
Neurobiol Learn Mem. 1999 Nov;72(3):230-43
10536100
Psychopharmacology (Berl). 1984;82(3):147-50
6425892
Brain Res. 1997 Sep 12;768(1-2):49-56
9369300
Neuropsychopharmacology. 2004 Jan;29(1):108-16
12955099
Eur J Pharmacol. 2000 Mar 30;393(1-3):215-22
10771016
Psychopharmacologia. 1973;28(3):247-59
4691000
J Abnorm Psychol. 2012 Feb;121(1):119-28
21604825
Psychol Bull. 1971 Jun;75(6):424-9
5580548