Negative Affect Circuit Subtypes and Neural, Behavioral, and Affective Responses to MDMA
Authors: 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, Leanne M. Williams
Journal: JAMA Network Open (2025)

Importance Rapidly acting therapeutics like 3,4-methylenedioxymethamphetamine (MDMA) are promising treatments for disorders such as posttraumatic stress disorder (PTSD). However, understanding who benefits most and the underlying neural mechanisms remains a critical gap. Stratifying individuals by neural circuit profiles could help differentiate neural, behavioral, and affective responses to MDMA, enabling personalized treatment strategies. Objective To investigate whether baseline stratification of individuals based on negative affect circuit profiles, particularly in response to nonconscious threat stimuli, can differentiate acute responses to MDMA. Design, Setting, and Participants This randomized clinical trial, implementing a double-blinded, within-participant, placebo- and baseline-controlled design, was conducted at Stanford University School of Medicine between November 2, 2021, and November 9, 2022, for wave 1 data collection. Participants had used MDMA on at least 2 prior occasions, but not in the past 6 months, and had subthreshold PTSD symptoms and early life trauma but no current psychiatric disorders. Data were analyzed from March 1, 2023, to January 1, 2024. Interventions Participants completed 4 visits: 1 baseline session followed by 1 placebo session and 2 MDMA sessions in a randomized order, totaling 64 visits. Baseline functional magnetic resonance imaging (fMRI) assessed the negative affect circuit using a nonconscious threat processing task (NTN). Main Outcomes and Measures Primary outcomes included activity and connectivity of amygdala and subgenual anterior cingulate cortex (sgACC) defining the negative affect circuit. Secondary outcomes were behavioral measures of implicit threat bias, likability of threat expressions, and affective assessments. Results Sixteen participants (10 [63%] female; mean [SD] age, 40.8 [7.6] years) were stratified into subgroups with high and low levels of NTN activity in the amygdala (NTN A+ [n = 8] and NTN A− [n = 8], respectively), based on a median split of baseline nonconscious threat-evoked fMRI responses. Following administration of the 120 mg of MDMA vs placebo, the NTN A+ subgroup showed significant reductions in amygdala (contrast estimate [CE], −1.43; 95% CI, −2.60 to −0.27; Cohen d , −1.22; P = .02) and sgACC activity (CE, −1.48; 95% CI, −2.42 to −0.54; Cohen d , −1.56; P = .004), increased sgACC-amygdala connectivity (CE, 0.65; 95% CI, 0.02-1.28; Cohen d , 1.02; P = .04), and increased likability of threat expressions (CE, 14.38; 95% CI, 1.46-27.29; Cohen d , 0.86; P = .03) compared with the NTN A− subgroup. Conclusions and Relevance In this randomized clinical trial of MDMA’s acute profiles, 120 mg of MDMA acutely normalized negative affect circuit reactivity in participants stratified by heightened amygdala reactivity at baseline, demonstrating the potential of neuroimaging to identify prospective biomarkers and guide personalized MDMA-based therapies. Trial Registration ClinicalTrials.gov Identifier: NCT04060108