Comparative and Interactive Human Psychopharmacologic Effects of Ketamine and Amphetamine

Ketamine and amphetamine produce different patterns of psychotic and cognitive effects in healthy people. Ketamine causes perceptual changes, negative symptoms, and memory disruption, while amphetamine triggers hostility, grandiosity, and somatic concern. Both drugs produce positive symptoms and euphoria, but their interaction reveals three patterns: amphetamine reduces ketamine-induced working memory impairment; the drugs additively increase thought disorder, arousal, and euphoria; and their combined effect on psychosis is less than additive. These results suggest that glutamate and dopamine systems contribute differently to psychosis, thought disorder, and euphoria, and that boosting prefrontal dopamine may help cognitive problems linked to glutamate dysfunction.

Study at a glance

Abstract

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. OBJECTIVES: To directly compare the effects of ketamine and amphetamine and to explore their interactive effects within individuals. DESIGN: Placebo-controlled, randomized, double-blind psychopharmacologic trial. SETTING AND PARTICIPANTS: Forty-one healthy individuals recruited from the community who completed up to 4 test days. MAIN OUTCOME MEASURES: 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.