Separating the agony from ecstasy: R(−)-3,4-methylenedioxymethamphetamine has prosocial and therapeutic-like effects without signs of neurotoxicity in mice
D. Curry, M. B. Young, A‐nga T. Tran, Georges E. Daoud, L. Howell
Neuropharmacology October 6, 2017 DOI: 10.1016/j.neuropharm.2017.10.003 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Experimental study Peer reviewed |
|---|---|
| Population | Male Swiss Webster and C57BL/6 mice |
| Interventions | racemic MDMA selective dopamine D1 receptor antagonist |
| Topics | MDMA |
| Citations | 50 |
| Key findings | R-MDMA increased social interaction and facilitated fear-extinction learning in mice without producing hyperthermia, increased locomotor activity, or signs of neurotoxicity, unlike racemic MDMA. |
Abstract
ABSTRACT S,R(+/–)‐3,4‐methylenedioxymethamphetamine (SR‐MDMA) is an amphetamine derivative with prosocial and putative therapeutic effects. Ongoing clinical trials are investigating it as a treatment for post‐traumatic stress disorder (PTSD) and other conditions. However, its potential for adverse effects such as hyperthermia and neurotoxicity may limit its clinical viability. We investigated the hypothesis that one of the two enantiomers of SR‐MDMA, R‐MDMA, would retain the prosocial and therapeutic effects but with fewer adverse effects. Using male Swiss Webster and C57BL/6 mice, the prosocial effects of R‐MDMA were measured using a social interaction test, and the therapeutic‐like effects were assessed using a Pavlovian fear conditioning and extinction paradigm relevant to PTSD. Locomotor activity and body temperature were tracked after administration, and neurotoxicity was evaluated post‐mortem. R‐MDMA significantly increased murine social interaction and facilitated extinction of conditioned freezing. Yet, unlike racemic MDMA, it did not increase locomotor activity, produce signs of neurotoxicity, or increase body temperature. A key pharmacological difference between R‐MDMA and racemic MDMA is that R‐MDMA has much lower potency as a dopamine releaser. Pretreatment with a selective dopamine D1 receptor antagonist prevented SR‐MDMA‐induced hyperthermia, suggesting that differential dopamine signaling may explain some of the observed differences between the treatments. Together, these results indicate that the prosocial and therapeutic effects of SR‐MDMA may be separable from the stimulant, thermogenic, and potential neurotoxic effects. To what extent these findings translate to humans will require further investigation, but these data suggest that R‐MDMA could be a more viable therapeutic option for the treatment of PTSD and other disorders for which SR‐MDMA is currently being investigated. HIGHLIGHTSR‐MDMA increases prosocial behavior and facilitates fear‐extinction learning in mice.High doses of R‐MDMA do not produce hyperthermia or signs of neurotoxicity in mice.Lower dopamine release may explain why R‐MDMA lacks these adverse effects of SR‐MDMA.R‐MDMA may be a safer and more viable therapeutic than racemic MDMA.
Comparable studies
Other preclinical and animal studies on MDMA, most cited first.
Citations in the library
Cited by 34
- Hallucinogens in Mental Health: Preclinical and Clinical Studies on LSD, Psilocybin, MDMA, and Ketamine Journal of Neuroscience November 30, 2020
- Dark Classics in Chemical Neuroscience: 3,4-Methylenedioxymethamphetamine ACS Chemical Neuroscience July 12, 2018
- Therapeutic mechanisms of psychedelics and entactogens. Neuropsychopharmacology July 24, 2023
- Methylenedioxymethamphetamine (MDMA) in Psychiatry Journal of Clinical Psychopharmacology October 10, 2018
- MDMA and MDMA-Assisted Therapy. American Journal of Psychiatry 2025
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Cites 39
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