PTSDAnxiety DisordersHealthy VolunteersMDMA

MDMA-assisted psychotherapy for PTSD: are memory reconsolidation and fear extinction underlying mechanisms?

This review (2018) suggests how memory reconsolidation and fear extinction may play a significant role in the potent therapeutic effects of MDMA in the treatment of PTSD.

Authors

  • Michael Mithoefer
  • Anna Feduccia

Published

Progress in Neuro-Psychopharmacology and Biological Psychiatry
meta Study

Abstract

MDMA-assisted psychotherapy for treatment of PTSD has recently progressed to Phase 3 clinical trials and received Breakthrough Therapy designation by the FDA. MDMA used as an adjunct during psychotherapy sessions has demonstrated effectiveness and acceptable safety in reducing PTSD symptoms in Phase 2 trials, with durable remission of PTSD diagnosis in 68% of participants. The underlying psychological and neurological mechanisms for the robust effects in mitigating PTSD are being investigated in animal models and in studies of healthy volunteers. This review explores the potential role of memory reconsolidation and fear extinction during MDMA-assisted psychotherapy. MDMA enhances release of monoamines (serotonin, norepinephrine, dopamine), hormones (oxytocin, cortisol), and other downstream signaling molecules (BDNF) to dynamically modulate emotional memory circuits. By reducing activation in brain regions implicated in the expression of fear- and anxiety-related behaviors, namely the amygdala and insula, and increasing connectivity between the amygdala and hippocampus, MDMA may allow for reprocessing of traumatic memories and emotional engagement with therapeutic processes. Based on the pharmacology of MDMA and the available translational literature of memory reconsolidation, fear learning, and PTSD, this review suggests a neurobiological rationale to explain, at least in part, the large effect sizes demonstrated for MDMA in treating PTSD.

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Research Summary of 'MDMA-assisted psychotherapy for PTSD: are memory reconsolidation and fear extinction underlying mechanisms?'

Introduction

Posttraumatic stress disorder (PTSD) can follow a single traumatic event or repeated stressors and produces persistent symptoms that impair daily functioning. Exposure-based psychotherapies aim to extinguish conditioned fear by having patients recall traumatic events or confront trauma-related cues, but 40–60% of patients fail to respond adequately. Factors such as emotional detachment, memory fragmentation, and inability to tolerate re-experiencing may contribute to non-response and dropout. Pharmacological augmentation of psychotherapy has been explored previously (for example with D-cycloserine), and MDMA has emerged as a candidate because its acute pharmacology promotes release of monoamines and neurohormones that appear to enhance aspects of the therapeutic process, such as introspection and strengthened therapeutic alliance. Feduccia and colleagues set out to review translational and clinical evidence bearing on whether MDMA-assisted psychotherapy acts through processes of memory reconsolidation and/or fear extinction. The paper summarises animal studies, imaging and behavioural work in healthy volunteers, and outcomes from Phase 2 clinical trials to provide a neurobiological rationale for how MDMA might facilitate reprocessing of traumatic memories and durable symptom reduction in PTSD. The goal is to integrate pharmacology, circuitry, and learning theory to explain the large effect sizes observed in clinical studies and to indicate directions for future research.

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Study Details

References (13)

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