Negative Affect Circuit Subtypes and Neural, Behavioral, and Affective Responses to MDMA: A Randomized Clinical Trial

Abstract

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.

Trial registration: ClinicalTrials.gov Identifier: NCT04060108.

Figure 1.. Participant Flow Diagram

Figure 2.. Baseline Stratification and Validation of the High (NTN_A+) or Low (NTN_A-) Negative Affect Circuit Activity Subgroups Defined by Amygdala Activity Evoked by Nonconscious Threat

A, At the baseline visit, each participant was assessed by the negative affect circuit during facial expressions of emotion functional magnetic resonance imaging (fMRI) task, in which participants nonconsciously viewed facial expressions of emotion. Activity of the amygdala in response to threat faces relative to neutral faces was quantified and expressed in SD units relative to a separate healthy reference dataset (z scores). A median split was used to stratify all participants into NTN_A+ (n = 8) and NTN_A− (n = 8) negative affect circuit activity subgroups. Validating the stratification, the NTN_A+ subgroup had mean activity significantly above the mean of the healthy reference (mean z score, 1.09), while the NTN_A− subgroup had mean activity significantly below the mean of the healthy reference (mean z score, −0.57). B, Compared with the NTN_A− subgroup, the NTN_A+ subgroup had a nonconscious implicit bias toward threat at baseline, indicated by slowed reaction times on an implicit recognition test when primed by angry relative to neutral faces using the same facial expression stimuli as presented during the fMRI task. This implicit priming reaction time measure was also expressed as z score SD units relative to healthy reference norms. In both plots, the big solid dots indicate the mean; smaller dots, individual data points; and error bars, SEM. ^aP < .001. ^bP < .05.

Figure 3.. Baseline High (NTN_A+) and Low (NTN_A−) Negative Affect Circuit Activity Subgroups With Different Acute Neural Response to 3,4-Methylenedioxymethamphetamine (MDMA)

After acute administration of MDMA at a dose of 120 mg vs placebo, the NTN_A+ subgroup showed a greater activity reduction in the negative affect circuit in the right (R) amygdala (A) and the subgenual anterior cingulate cortex (sgACC [B]) and a greater increase in the circuit connectivity between sgACC and R amygdala (C), compared with the NTN_A− subgroup. In all plots, solid dots indicate the mean; error bars, SEM. ^aP < .05. ^bP < .01.