Can ketamine and other glutamate receptor modulators be considered entactogens?

Subanesthetic-dose ketamine has recently been reported to improve hedonic pleasures associated with social interactions and altruism in individuals with treatment-resistant depression. However, whether ketamine-among other glutamate receptor modulators-also improves empathy and/or prosocial behavior in humans remains unknown. Under a framework grounded in neurobiology that proposes that prosocial behavior is preceded by empathy, this systematic review sought to: (1) explore the entactogenic effects of glutamate receptor modulators observed in clinical trials (as either primary or secondary outcomes), and (2) synthesize the findings regarding which glutamate receptor modulators produce entactogenic effects. Thirty studies that included self-reported ratings, neuroimaging, and/or behavioral task outcomes met inclusion criteria suggesting potential entactogenic effects associated with ketamine and, to less convincing extent, d-cycloserine (DCS). The findings suggest that ketamine and DCS may modulate self- and other-perception, involving changes in activity in brain regions involved in empathetic concerns and mentalizing, the ability to understand one's own and others' thoughts and feelings. These findings may guide potential therapeutic interventions for neuropsychiatric conditions associated with impaired empathy and prosocial behavior, including mood disorders, neurodevelopmental disorders, psychotic disorders, and personality disorders.