This randomised, double-blind, placebo-controlled clinical trial (n=16) examines MDMA’s (80-120mg) effects on neural circuits in individuals with subthreshold PTSD symptoms and early life trauma. The study finds that participants with higher baseline amygdala reactivity (emotional experiences) showed significant reductions in amygdala and sgACC (emotional processing) activity, increased sgACC-amygdala connectivity, and increased likability of threat expressions after 120mg MDMA compared to those with lower baseline reactivity.
Abstract of Negative Affect Circuit Subtypes and Neural, Behavioral, and Affective Responses to MDMA
“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 (NTNA+ [n = 8] and NTNA- [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 NTNA+ 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 NTNA- 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.”
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
Summary of Negative Affect Circuit Subtypes and Neural, Behavioral, and Affective Responses to MDMA
Post‑traumatic stress disorder (PTSD) often co‑occurs with major depressive disorder and shows striking clinical and neurobiological diversity. Conventional “one‑size‑fits‑all” prescribing leaves many patients undertreated, so precision psychiatry seeks biomarkers that match individuals to the most effective interventions. Neuro‑imaging work has repeatedly shown that hyper‑reactivity of the amygdala to subliminal (non‑conscious) threat and dysregulated modulation by the subgenual anterior cingulate cortex (sgACC) form a negative‑affect circuit that predicts poor outcomes with first‑line drugs and psychotherapy. Building on this, the authors reasoned that a medicine such as MDMA—which reliably dampens threat responsiveness while enhancing affiliative emotions—might normalise this circuit, but only in those whose baseline reactivity is high.
Earlier research examining MDMA‑assisted therapy hinted at reduced amygdala reactivity and strengthened limbic connectivity months after treatment, yet the acute neural mechanisms of MDMA alone remained unclear. The present randomised clinical trial therefore asked whether baseline stratification by negative‑affect circuit activity could differentiate immediate neural, behavioural and affective responses to MDMA.
Methods
Participants
Find this paper
https://doi.org/10.1001/jamanetworkopen.2025.7803
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Cite this paper (APA)
Zhang, X., Hack, L. M., Bertrand, C., Hilton, R., Gray, N. J., Boyar, L., ... & Williams, L. M. (2025). Negative Affect Circuit Subtypes and Neural, Behavioral, and Affective Responses to MDMA: A Randomized Clinical Trial. JAMA Network Open, 8(4), e257803-e257803.
Study details
Compounds studied
MDMA
Topics studied
Healthy Subjects
PTSD
Study characteristics
Original
Placebo-Controlled
Within-Subject
Randomized
Participants
16
Humans
Compound Details
The psychedelics given at which dose and how many times
MDMA 80 - 120mg | 2x
Linked Clinical Trial
Stanford Reward Circuits of the Brain Study - MDMAThis study is a biomarker study designed to characterize how MDMA impacts the reward circuits of the human brain.