Can ketamine and other glutamate receptor modulators be considered entactogens?
Hiroe Hu, Alaina N Tillman, Miyu Fujita, Mayu Yoshikawa, Elizabeth D. Ballard, Yoojin Lee, Carlos A. Zarate
Psychiatry Research July 1, 2025 DOI: 10.1016/j.psychres.2025.116513 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Systematic review Peer reviewed |
|---|---|
| Sample size | 30 |
| Population | Studies including human participants with self-reported ratings, neuroimaging, and/or behavioral task outcomes |
| Interventions | Ketamine d-cycloserine |
| Topics | Ketamine Esketamine |
| Keywords | Entactogen Glutamate receptor modulators Prosocial behavior D-cycloserine Psychopharmacology psychotropic drugs Psychiatric medication Social cognition Therapeutic compounds pharmaceuticals Empathy emotional intelligence Social awareness |
| Citations | 2 |
| Key findings | Ketamine and d-cycloserine may modulate self- and other-perception through changes in brain activity related to empathy and mentalizing. |
Abstract
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.
Comparable studies
Other systematic reviews and meta-analyses on ketamine, most cited first.
| Study | Year | Design | Participants |
|---|---|---|---|
| The effect of a single dose of intravenous ketamine on suicidal ideation: a systematic review and individual participant data meta-analysis Depressed patients with suicidal ideation at baseline | 2017 | Systematic review and individual participant data meta-analysis | n = 167 |
| Ketamine use: a review Ketamine users | 2011 | Systematic review | |
| Ketamine and Other NMDA Antagonists: Early Clinical Trials and Possible Mechanisms in Depression Participants with major depression in placebo-controlled, double-blind, randomized... | 2015 | Systematic review and meta-analysis | |
| Ketamine and postoperative pain – a quantitative systematic review of randomised trials Surgical patients from 25 countries | 2004 | Systematic review | n = 2,839 |
| Side-effects associated with ketamine use in depression: a systematic review. Patients with depression | 2018 | Systematic review |
Citations in the library
Cites 28
- A Randomized Trial of an N-methyl-D-aspartate Antagonist in Treatment-Resistant Major Depression Archives of General Psychiatry August 1, 2006
- The Psychedelic State Induced by Ayahuasca Modulates the Activity and Connectivity of the Default Mode Network PLoS One February 18, 2015
- MDMA enhances emotional empathy and prosocial behavior Social Cognitive and Affective Neuroscience October 4, 2013
- Psilocybin therapy increases cognitive and neural flexibility in patients with major depressive disorder. Translational Psychiatry November 8, 2021
- Ketamine Decreases Resting State Functional Network Connectivity in Healthy Subjects: Implications for Antidepressant Drug Action PLoS One September 24, 2012
and 23 more in the library