Comparative and interactive human psychopharmacologic effects of ketamine and amphetamine: implications for glutamatergic and dopaminergic model psychoses and cognitive function.
BACKGROUND
In healthy individuals, ketamine hydrochloride and amphetamine sulfate produce cognitive, behavioral, and subjective effects resembling endogenous psychoses. Studying the comparative and interactive effects of these agents may provide insights into the roles of the glutamate and monoamine systems in psychosis and cognition.


OBJECTIVE
To directly compare the effects of ketamine and amphetamine and to explore their interactive effects within individuals.


METHODS
Placebo-controlled, randomized, double-blind psychopharmacologic trial.


METHODS
Forty-one healthy individuals recruited from the community who completed up to 4 test days.


METHODS
On each test day, participants received amphetamine (a 1-minute infusion of amphetamine sulfate, 0.25 mg/kg, or saline) and ketamine (a 1-minute intravenous infusion of ketamine, 0.23 mg/kg, followed by a 1-hour infusion of 0.5 mg/kg or an identical saline bolus and infusion). The order of amphetamine and ketamine infusions was randomized.


RESULTS
At the doses studied, ketamine and amphetamine produced positive symptoms and euphoria. However, perceptual changes were produced only by ketamine, and hostility, grandiosity, and somatic concern were stimulated only by amphetamine. Amphetamine and ketamine produced conceptual disorganization, but only ketamine produced concrete ideation and unusual mannerisms. Ketamine produced negative symptoms and disrupted delayed recall. Ketamine and amphetamine showed 3 types of interactive effects: (1) amphetamine attenuated the impairment of working memory produced by ketamine; (2) amphetamine and ketamine had additive effects on thought disorder, arousal, and euphoria; and (3) amphetamine and ketamine had less-than-additive effects on psychosis.


CONCLUSIONS
These findings implicate N-methyl-D-aspartate glutamate receptors and dopamine systems in psychosis. However, glutamate and dopamine may differentially contribute to psychosis, thought disorder, and euphoria. Regarding medication development for cognitive dysfunction, the pattern of the interactive effects of ketamine and amphetamine is consistent with the hypothesis that facilitation of prefrontal cortical dopamine levels would attenuate some cognitive impairments associated with deficits in N-methyl-D-aspartate receptor function.
Krystal
John H
JH
Department of Psychiatry and Division of Biostatistics, Department of Epidemiology and Public Health, Yale University School of Medicine, New Haven, Conn. 06516, USA. john.krystal@yale.edu
Perry
Edward B
EB
Gueorguieva
Ralitza
R
Belger
Aysenil
A
Madonick
Steven H
SH
Abi-Dargham
Anissa
A
Cooper
Thomas B
TB
Macdougall
Lisa
L
Abi-Saab
Walid
W
D'Souza
D Cyril
DC
D000661:Amphetamine / Q000494:pharmacology*; D003071:Cognition / Q000187:drug effects* / Q000502:physiology; D004298:Dopamine / Q000502:physiology*; D004311:Double-Blind Method; D004347:Drug Interactions; D005973:Glutamine / Q000187:drug effects* / Q000502:physiology*; D006801:Humans; D007649:Ketamine / Q000494:pharmacology*; D010919:Placebos; D017397:Prefrontal Cortex / Q000187:drug effects / Q000503:physiopathology; D011605:Psychoses, Substance-Induced / Q000209:etiology* / Q000503:physiopathology / Q000523:psychology; D016194:Receptors, N-Methyl-D-Aspartate / Q000187:drug effects / Q000502:physiology
D010919:Placebos; D016194:Receptors, N-Methyl-D-Aspartate; D005973:Glutamine; D007649:Ketamine; D000661:Amphetamine; D004298:Dopamine