Comparative and Interactive Human Psychopharmacologic Effects of Ketamine and Amphetamine
John H. Krystal, Edward Perry, Ralitza Gueorguieva, Ayşenil Belger, Steven Madonick, Anissa Abi‐dargham, Thomas B. Cooper, Lisa Macdougall, Walid Abi‐saab, Deepak Cyril D’souza
Archives of General Psychiatry September 1, 2005 DOI: 10.1001/archpsyc.62.9.985 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Randomized controlled trial Placebo-controlled Double-blind Peer reviewed |
|---|---|
| Sample size | 41 |
| Population | Healthy individuals recruited from the community |
| Interventions | Ketamine Amphetamine |
| Dose | amphetamine sulfate, 0.25 mg/kg; ketamine, 0.23 mg/kg bolus followed by 0.5 mg/kg infusion |
| Duration | Up to 4 test days |
| Topics | Ketamine Esketamine |
| Keywords | Amphetamine Pharmacology |
| Citations | 323 |
| Key findings | Ketamine and amphetamine produce distinct symptom profiles and interact in ways that suggest glutamate and dopamine systems differentially contribute to psychosis, thought disorder, and euphoria. |
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.