A new study published in JAMA Network Open suggests that brain imaging could help identify who is most likely to benefit from MDMA as a treatment for trauma-related symptoms. In a randomized clinical trial at Stanford University, researchers found that participants with heightened brain reactivity to unconscious threat cues showed marked changes in neural activity after receiving MDMA. These changes included reduced responses in brain regions associated with fear and improved connectivity between areas involved in emotional regulation.
MDMA is a psychoactive compound best known as the recreational drug “ecstasy” or “molly,” but recent research has explored its use in treating mental health conditions like posttraumatic stress disorder. It has been shown to reduce defensiveness and enhance emotional openness, which may help people engage more effectively in therapy. While this approach shows promise, not everyone responds in the same way. The new study aimed to better understand the brain mechanisms involved in MDMA’s effects and to determine whether certain individuals might respond more strongly based on their brain activity before treatment.
The research team, led by scientists at the Stanford Center for Precision Mental Health and Wellness, focused on a specific brain circuit known as the “negative affect circuit,” which includes the amygdala and the subgenual anterior cingulate cortex. This network helps the brain detect and regulate responses to emotional threats, especially those outside of conscious awareness.
Overactivity in this system is common in people with trauma histories and has been linked to poor treatment outcomes. The team hypothesized that MDMA might help normalize this circuit, but that the effect could depend on a person’s baseline level of activity in these regions.
“We were motivated by a central question: Who is most likely to benefit from MDMA-based treatment—and why? MDMA is emerging as a fast-acting treatment for PTSD and is currently seeking FDA approval as part of MDMA-assisted therapy,” said study authors Xue Zhang and Leanne Williams.
Williams is the Vincent V.C. Woo Professor and Associate Chair of Psychiatry and Behavioral Sciences at Stanford University School of Medicine, where she directs the Center for Precision Mental Health and Wellness and the PanLab for Personalized and Translational Neuroscience. She also leads the Precision Medicine Core at the VA Palo Alto’s Mental Illness Research, Education, and Clinical Center and is the author of Precision Psychiatry. Zhang is a research scientist in Williams’ lab.
“While some individuals experience substantial benefits, others show little to no effect—suggesting that MDMA is not a one-size-fits-all solution,” the researchers said. “To understand this heterogeneity, we focused on the brain—specifically, how differences in neural circuit function might predict treatment response. PTSD is known to disrupt brain circuits involved in processing threat, including outside of conscious awareness.”
“We were particularly interested in whether individual variation in this ‘negative affect’ circuit might help identify who is more likely to benefit from MDMA. Our broader goal is to advance precision psychiatry based on personalized neuroscience: matching each person with the treatment most likely to work for them, based on their brain biotype.”
For their study, the researchers recruited 16 adults who had experienced early life trauma and were showing subclinical signs of posttraumatic stress. All participants had previously used MDMA but had not done so within the past six months. They did not meet the criteria for current psychiatric diagnoses. Each person completed four visits: one baseline session, one placebo session, and two sessions involving different doses of MDMA (80 and 120 milligrams), with the order randomized and spaced out over time.
During each visit, participants underwent functional MRI scans while completing a task designed to measure brain responses to nonconscious emotional threats. This involved briefly showing angry or fearful faces that were masked to prevent conscious recognition. The researchers also gathered behavioral data, such as how participants rated the likability of facial expressions and how quickly they responded to emotion recognition tasks. After each session, participants completed surveys about their emotional state and experiences.
Before examining the effects of MDMA, the researchers divided participants into two groups based on how reactive their amygdala was to nonconscious threats at the baseline visit. Eight participants showed high activity in this region (the NTNA+ group), while the other eight showed lower activity (the NTNA− group). This split allowed the team to compare how these subgroups responded differently to MDMA.
When participants in the NTNA+ group received the higher MDMA dose, their brain activity showed notable changes. The amygdala and subgenual anterior cingulate both became less active in response to threat cues. In addition, communication between these regions increased. These patterns suggest a shift toward a more balanced and regulated emotional response. In contrast, participants in the NTNA− group did not show the same neural changes after taking MDMA.
The NTNA+ group also showed behavioral changes that aligned with the brain data. After taking 120 milligrams of MDMA, they rated angry faces as more likable, suggesting a softening of their automatic negative reactions. Interestingly, while their brain reactivity decreased, these participants reported greater anxiety and less desire to be with others during the MDMA session compared to the NTNA− group. Their written descriptions indicated more introspective and emotionally complex experiences. Meanwhile, the NTNA− group tended to report more pleasant and euphoric effects.
“One striking finding was the consistency of brain circuit and behavioral findings within the negative affect biotype group,” Zhang and Williams told PsyPost. “Individuals with brain circuit hyperactivity also showed a stronger implicit threat bias, indicating that their brain activity disrupted their behavioral reaction time to respond to signals of threat that appeared outside of conscious awareness. This convergence between brain and behavior suggests that implicit behavioral responses might serve as surrogate markers of underlying brain biotypes—potentially allowing for stratification of individuals who are more likely to benefit from MDMA treatment using both behavior and brain-based measures.”
These results suggest that MDMA may work differently depending on how the brain processes emotional threats before treatment. For people with heightened baseline reactivity, MDMA appears to reduce brain responses linked to fear and increase connectivity in circuits involved in regulation. These effects could create a more open emotional state, potentially improving the effectiveness of therapy when combined with talk-based approaches. The study supports the idea that measuring brain activity could help match people with treatments tailored to their specific neural profiles.
“Our study shows that how the brain responds to threat—especially at a nonconscious level—can shape how someone responds to MDMA,” Zhang and Williams explained. “This supports the idea that treatments should be personalized, not one-size-fits-all, and that each person’s brain biotype really matters.”
“We identified a neural circuit-based biotype with elevated baseline activity in the negative affect circuit—a brain circuit that includes the amygdala and is involved in automatically detecting and responding to threat. Individuals in this negative affect biotype with high threat reactivity showed significant changes after a single 120 mg dose of MDMA: reduced circuit hyperactivity, more adaptive connectivity, and improved behavioral responses to threat-related cues.”
“These findings suggest that this biotype may be especially suited for MDMA-based therapies,” Zhang and Williams said. “More broadly, it highlights how brain circuit function could serve as an objective marker for treatment matching—bringing us closer to precision psychiatry.”
But it’s important to note that this was not a clinical trial of MDMA-assisted therapy. Instead, the study examined the effects of MDMA in a controlled setting without therapeutic guidance. While the results are promising, the small sample size and focus on healthy volunteers with subthreshold symptoms limit how broadly the findings can be applied. More research is needed in clinical populations, including people formally diagnosed with posttraumatic stress disorder.
“That’s the focus of our current neuroimaging study, led in collaboration with Dr. Trisha Suppes, and embedded in her clinical trial of MDMA-assisted cognitive processing therapy,” the researchers noted. “It will allow us to test whether the brain circuit biotypes we identified in our mechanistic trial can predict treatment response in real-world clinical settings.”
The study is part of a larger research effort funded by the National Institute on Drug Abuse to explore how fast-acting treatments like MDMA, ketamine, and psilocybin affect brain circuits.
“What set this MDMA study apart is that it’s the first to use a person’s pre-treatment brain circuit profile—what we call a biotype—to predict their acute response to the intervention,” Zhang and Williams said. “This circuit biotype-guided approach offers a promising way to improve future clinical trials and, ultimately, routine care. It could help stratify likely responders, rule out likely non-responders, minimize side effects, and streamline treatment – all key steps toward safer, more effective, and more accessible mental healthcare.”
In the long term, the researchers hope to build tools that use brain scans to guide personalized treatment decisions. By identifying “biotypes” based on brain activity, clinicians could better determine which interventions are most likely to help specific individuals. This could reduce the burden of trial-and-error approaches that are common in mental health care today.
“The next step is to validate our circuit-based biotype in individuals with PTSD, and we’re actively doing that in our ongoing neuroimaging trial,” Zhang and Williams explained. “Longer term, we aim to accelerate the clinical translation of our tools that use brain imaging to help match each person with the treatment most likely works for them. We also plan to expand the matching of biotypes to additional treatments, and determine which treatments are specific to each biotype. This precision medicine approach could lead to more effective, personalized care—dramatically reducing the burden of trial-and-error treatment.”
The study, “Negative Affect Circuit Subtypes and Neural, Behavioral, and Affective Responses to MDMA: A Randomized Clinical Trial,” was conducted by Xue Zhang, Laura M. Hack, Claire Bertrand, Rachel Hilton, Nancy J. Gray, Leyla Boyar, Jessica Laudie, Boris D. Heifets, Trisha Suppes, Peter J. van Roessel, Carolyn I. Rodriguez, Karl Deisseroth, Brian Knutson, and Leanne M. Williams.
