New study reveals how MDMA rewires serotonin and oxytocin systems in the brain

A new study published in the Journal of Psychopharmacology has found that MDMA’s mood-enhancing effects may be partly driven by changes in brain systems related to serotonin, oxytocin, and vasopressin—neurochemical pathways that are involved in emotional and social behavior. The results support the growing interest in MDMA as a possible treatment for mental health conditions.

MDMA, commonly known as ecstasy, is a synthetic stimulant with both energizing and hallucinogenic properties. In recent years, researchers have been exploring whether MDMA can be used in controlled therapeutic settings to help people with conditions like post-traumatic stress disorder or social anxiety. Its ability to reduce fear and increase feelings of connection makes it especially promising for patients who struggle with interpersonal difficulties. However, scientists still know relatively little about how MDMA produces these effects in the brain, or how these effects vary depending on dosage.

To explore these questions, researchers from the Medical University of Lublin and the International Institute of Molecular and Cell Biology in Poland tested the effects of MDMA on 3-week-old zebrafish. This developmental stage is roughly equivalent to adolescence in humans and represents a time when social behaviors are emerging and brain systems involved in emotion are still developing.

Zebrafish are small freshwater fish native to South Asia that have become widely used in biomedical research. They develop rapidly, are transparent in early stages, and share a high degree of genetic and physiological similarity with humans. Because their brains contain many of the same neurotransmitter systems as mammals, and their behavior can be easily observed and quantified, zebrafish are especially valuable for studying brain development, drug effects, and psychiatric disorders.

The researchers were particularly interested in how MDMA influences anxiety and sociability, and whether these effects could be linked to oxytocin—a hormone involved in social bonding and emotional regulation.

The scientists conducted several behavioral tests to assess anxiety and social behavior in the zebrafish. One test measured how closely the fish stuck to the edges of a new environment—a behavior known as thigmotaxis, which is often used as an indicator of anxiety in animals. Another test evaluated how much time the fish spent in a light versus dark area, since zebrafish tend to avoid darkness when they feel safe. Finally, a social preference test measured whether the fish were more likely to spend time near familiar conspecifics, or members of their species.

The zebrafish were divided into groups and exposed to various concentrations of MDMA. They were also treated with either an oxytocin receptor agonist, which mimics the effects of oxytocin, or an antagonist, which blocks those effects. For comparison, some fish were given diazepam, a known anti-anxiety medication. After behavioral testing, the researchers examined the expression of several genes in the fish’s brains, looking at those related to serotonin signaling, oxytocin, and vasopressin. They also analyzed how MDMA affected specific intracellular pathways involved in mood and behavior, such as AKT and ERK1/2 signaling.

The researchers found that MDMA had a dose-dependent effect on anxiety. At very low doses, it appeared to increase anxiety-like behavior. But at moderate doses, particularly 2.5 micromolar, MDMA reduced signs of anxiety. Fish at this dose spent more time in the center of a new environment and were quicker to explore dark areas—both behaviors associated with lower anxiety. However, at higher doses, MDMA began to reduce locomotion and showed signs of possible toxicity, suggesting that the therapeutic range is narrow.

In terms of social behavior, the lowest dose of MDMA (0.5 micromolar) increased the time fish spent near their peers, suggesting enhanced sociability. Interestingly, this prosocial effect was most noticeable at doses that increased anxiety, indicating a complex relationship between emotional and social responses. The oxytocin receptor agonist also promoted social interaction and showed anti-anxiety effects, but only under certain conditions.

In contrast, the antagonist had no noticeable effect on behavior, which may indicate that blocking the oxytocin system is not enough on its own to alter emotional or social responses in zebrafish.

On the molecular level, MDMA exposure led to reduced expression of genes involved in serotonin signaling, including two types of serotonin receptors and the serotonin transporter. These changes may reflect the compound’s action on serotonin release, which is known to be one of MDMA’s main effects in the brain.

At the same time, MDMA increased the expression of genes for oxytocin receptors and reduced the expression of vasopressin receptor genes. While MDMA did not appear to increase actual oxytocin levels in the brain, the changes in receptor expression suggest that it may make brain regions more sensitive to oxytocin’s effects.

The researchers also found that different doses of MDMA affected specific signaling pathways in the brain. At the lowest tested dose, MDMA reduced activation of the AKT pathway, which has been linked to social behavior in other animals. The oxytocin agonist, on the other hand, increased activity in the ERK1/2 pathway, which is known to be involved in anxiety regulation. These findings suggest that different aspects of MDMA’s effects—its influence on anxiety versus social behavior—may be driven by distinct biological mechanisms.

As with any study, there are caveats to consider. Most importantly, the study was conducted in zebrafish, whose brains are simpler than those of mammals and lack some structures found in humans. Although zebrafish share many of the same neurotransmitter systems and genetic pathways, findings in fish may not always translate directly to human biology. Additionally, the study only looked at the short-term effects of MDMA, and more work is needed to understand how repeated or long-term exposure might influence behavior or brain function.

Future research could build on these findings by examining how MDMA affects brain circuits at different developmental stages or by testing how the compound interacts with stress. The researchers also suggested that genetic tools such as CRISPR could be used to further investigate the role of specific receptors in mediating MDMA’s effects. As scientists work toward better treatments for conditions like social anxiety and post-traumatic stress, studies like this one offer a window into how compounds like MDMA could be used not just as recreational drugs, but as tools for healing.

The study, “Exploring the impact of MDMA and oxytocin ligands on anxiety and social responses: A comprehensive behavioural and molecular study in the zebrafish model,” was authored by Monika Maciag, Olga Doszyn, Artur Wnorowski, Justyna Zmorzynska, and Barbara Budzynska.