A recent study published in Science Advances investigated the effects of 3,4-Methylendioxymethamphetamine (MDMA), commonly known as ecstasy, on empathy in mice. The findings provide evidence that MDMA enhances empathy-like behaviors through the release of serotonin in the nucleus accumbens, a brain region associated with reward and social behaviors. The discovery provides valuable insights into the potential mechanisms by which MDMA could be used therapeutically for conditions such as post-traumatic stress disorder and autism spectrum disorder.
“MDMA has been reported to promote prosocial behavior in humans and mice, and it has been suggested as a potential ’empathogen’ (i.e. increasing empathy), though we did not have direct mechanistic evidence for this,” explained study author Monique Smith, a T. Denny Sanford Institute for Empathy and Compassion Professor and an assistant professor at the University of California San Diego in the Departments of Neurobiology and Neurosciences.
“Since studying the neurobiology of empathy-related behaviors in rodents is relatively new, the effect of MDMA on empathy-related behaviors had not been previously explored in rodents. We have what we believe is now a well-validated model of emotional contagion (empathy-related behavior), in mice and wanted to see if MDMA had the ability to impact this behavior, and if so, what the underlying neural mechanisms might be.”
“This research is translationally relevant because MDMA is currently being used in several human clinical trials for treatment of a variety of deficits seen in neuropsychiatric disorders (e.g. alcohol use disorder, obsessive compulsive disorder, social anxiety in autism spectrum disorder), though not yet for the treatment of empathy-related dysregulation.”
The researchers found that MDMA significantly enhanced empathy-like behaviors in male mice using two behavioral paradigms: the social transfer of pain and the social transfer of analgesia. In the social transfer of pain paradigm, bystander mice exhibited increased pain sensitivity after interacting with a demonstrator mouse that was experiencing inflammatory pain.
Male bystander mice injected with MDMA before this interaction displayed significantly reduced mechanical thresholds, indicating heightened pain sensitivity. This hypersensitivity persisted for over 24 hours, demonstrating that MDMA robustly facilitates the social transfer of pain. In contrast, bystander mice injected with saline showed no change in mechanical thresholds.
In the social transfer of analgesia paradigm, bystander mice gained pain relief after interacting with a DEM mouse that had both inflammatory pain and received morphine analgesia. Bystander mice treated with MDMA exhibited significantly higher pain thresholds (indicating reduced pain sensitivity) after interacting with a DEM mouse under analgesia. This effect was observed at 1 and 6 hours post-interaction but had returned to baseline by 24 hours. These results indicate that MDMA not only enhances the social transfer of pain but also facilitates the social transfer of analgesia.
The nucleus accumbens, a brain region involved in social and reward-related behaviors, emerged as a critical site for MDMA’s empathogenic effects. Local infusion of MDMA directly into the nucleus accumbens replicated the systemic effects observed with MDMA injection, enhancing both the social transfer of pain and analgesia. This finding suggests that MDMA’s action in the nucleus accumbens alone is sufficient to produce its empathogenic effects.
Further investigation revealed that optogenetic stimulation of serotonin inputs in the nucleus accumbens also enhanced empathy-like behaviors. When researchers activated serotonin-releasing neurons in the nucleus accumbens using optogenetics, bystander mice displayed similar enhancements in the social transfer of pain and analgesia as those observed with MDMA administration. These results indicate that MDMA’s effects are mediated by serotonin release in the nucleus accumbens, pinpointing a specific neurobiological mechanism for the drug’s action.
“We show that MDMA does enhance emotional contagion in mice, and this effect might require serotonin signaling the nucleus accumbens,” Smith told PsyPost. “Importantly, we can see enhanced pain and pain relief depending on the state of the social partner. This might suggest that enhancement of the effect of increasing empathy might lead to positive or negative outcomes depending on the and social environmental social context. This also highlights inform why MDMA is successful primarily as an adjunct to cognitive behavioral therapy (as seen in many of the clinical trials).”
An intriguing aspect of the study was the sex-specific effect of MDMA. While MDMA significantly enhanced empathy-like behaviors in male mice, it did not have the same effect in female mice. This finding aligns with human reports suggesting that MDMA enhances emotional empathy primarily in males.
The researchers ruled out differences in pharmacological action as a cause for this discrepancy, as both male and female mice exhibited equivalent increases in serotonin levels in the nucleus accumbens following MDMA administration. The underlying reasons for these sex differences remain unclear. Smith said she was particularly surprised by “the lack of effect of MDMA in enhancing social transfer in female mice. This is something we are actively exploring.”
The researchers also explored the effects of MDMA in Shank3-deficient mice, a genetic model for autism spectrum disorder. Shank3-deficient mice typically do not exhibit empathy-like behaviors such as the social transfer of pain or analgesia. However, administration of MDMA restored these behaviors in Shank3-deficient mice, indicating that the drug can reverse empathy deficits in this autism model.
Optogenetic activation of serotonin inputs in the nucleus accumbens also rescued empathy-like behaviors in Shank3-deficient mice, further supporting the role of serotonin release in the nucleus accumbens as a key mechanism underlying MDMA’s effects.
“We also show deficits in emotional contagion in a mouse model of autism that can be rescued by MDMA treatment and serotonin release in the nucleus accumbens,” Smith said. “This could inform future clinical trials for treating empathy dysregulation in neurodevelopmental conditions.”
The researchers are investigating how serotonin signaling and specific receptors affect MDMA’s ability to enhance social behaviors, and they are also exploring other brain chemicals like oxytocin and developing better ways to measure empathy in different situations.
“Specifically with regard to this project, we are interested in other neuromodulators that might contribute to the social transfer of pain (e.g. oxytocin),” Smith explained. “More broadly, we are interested in developing more sophisticated behavioral assays and measurements for empathy behaviors (i.e. prosocial consolation), and measuring empathy and pain behavior in different contexts (e.g. during birth and maternal care).”
“We are recruiting PhD students and postdocs to explore these questions and others,” Smith added. “We are also very interested in finding clinical colleagues that might be interested in a clinical trial!”
The study, “MDMA enhances empathy-like behaviors in mice via 5-HT release in the nucleus accumbens“, was authored by Ben Rein, Kendall Raymond, Cali Boustani, Sabrena Tuy, Jie Zhang, Robyn St. Laurent, Matthew B. Pomrenze, Parnaz Boroon, Boris Heifets, Monique L. Smith, and Robert C. Malenka.
