Separating the agony from ecstasy: R(-)-3,4-methylenedioxymethamphetamine has prosocial and therapeutic-like effects without signs of neurotoxicity in mice
This mouse study (n=52) compared the two enantiomers R-MDMA of S-MDMA, and their racemic mixture (5.6 -; 7.8 mg/kg) with respect to their prosocial therapeutic effects and adverse neurotoxicity, in mice. Due to a lower potency to release dopamine, R-MDMA exerted fewer adverse effects than SR/S-MDMA, but increased prosocial behavior to a similar magnitude.
Abstract
Introduction
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.
Methods
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.
Results
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.
Discussion
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.
Research Summary of 'Separating the agony from ecstasy: R(-)-3,4-methylenedioxymethamphetamine has prosocial and therapeutic-like effects without signs of neurotoxicity in mice'
Introduction
SR-MDMA (racemic MDMA) is a substituted phenethylamine with stimulant and entactogenic properties that has been investigated both recreationally and as an adjunct to psychotherapy. Earlier clinical research reported marked prosocial effects in humans and promising therapeutic outcomes in PTSD, including a small placebo-controlled trial in which SR-MDMA–assisted psychotherapy produced sustained clinical responses in a large proportion of treated patients. Nonetheless, concerns about acute harms (notably hyperthermia) and possible long-term neurotoxicity have limited enthusiasm for wider clinical use and motivated search for safer alternatives. Curry and colleagues set out to test whether the R-enantiomer of MDMA (R-MDMA) retains the prosocial and extinction-facilitating effects attributed to SR-MDMA while producing fewer adverse effects. The study therefore compared SR-MDMA, R-MDMA and S-MDMA across a battery of assays in mice: social interaction, locomotor activity, Pavlovian fear conditioning and extinction, thermoregulation, and markers of neurotoxicity (reactive astrogliosis, tissue monoamine content, and dopamine transporter expression). The authors also probed whether dopamine D1 receptor signalling contributes to SR-MDMA–induced hyperthermia.
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Study Details
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- APA Citation
Curry, D. W., Young, M. B., Tran, A. N., Daoud, G. E., & Howell, L. L. (2018). Separating the agony from ecstasy: R(-)-3,4-methylenedioxymethamphetamine has prosocial and therapeutic-like effects without signs of neurotoxicity in mice. Neuropharmacology, 128, 196-206. https://doi.org/10.1016/j.neuropharm.2017.10.003
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