Altered brain activity and functional connectivity after MDMA-assisted therapy for post-traumatic stress disorder
S Parker Singleton1, Julie B Wang2, Michael Mithoefer2,3
1Department of Computational Biology, Cornell University, Ithaca, NY, United States.
Introduction:
3,4-methylenedioxymethamphetamine-assisted therapy (MDMA-AT) for post-traumatic stress disorder (PTSD) has demonstrated promise in multiple clinical trials. MDMA is hypothesized to facilitate the therapeutic process, in part, by decreasing fear response during fear memory processing while increasing extinction learning. The acute administration of MDMA in healthy controls modifies recruitment of brain regions involved in the hyperactive fear response in PTSD such as the amygdala, hippocampus, and insula. However, to date there have been no neuroimaging studies aimed at directly elucidating the neural impact of MDMA-AT in PTSD patients.
Methods:
We analyzed brain activity and connectivity via functional MRI during both rest and autobiographical memory (trauma and neutral) response before and two-months after MDMA-AT in nine veterans and first-responders with chronic PTSD of 6 months or more.
Results:
We hypothesized that MDMA-AT would increase amygdala-hippocampus resting-state functional connectivity, however we only found evidence of a trend in the left amygdala-left hippocampus (t = -2.91, uncorrected p = 0.0225, corrected p = 0.0901). We also found reduced activation contrast (trauma > neutral) after MDMA-AT in the cuneus. Finally, the amount of recovery from PTSD after MDMA-AT correlated with changes in four functional connections during autobiographical memory recall: the left amygdala-left posterior cingulate cortex (PCC), left amygdala-right PCC, left amygdala-left insula, and left isthmus cingulate-left posterior hippocampus.
Discussion:
Amygdala-insular functional connectivity is reliably implicated in PTSD and anxiety, and both regions are impacted by MDMA administration. These findings compliment previous research indicating that amygdala, hippocampus, and insula functional connectivity is a potential target of MDMA-AT, and highlights other regions of interest related to memory processes. More research is necessary to determine if these findings are specific to MDMA-AT compared to other types of treatment for PTSD.
Clinical Trial Registration:
https://clinicaltrials.gov/ct2/show/NCT02102802, identifier NCT02102802.
Insights
3,4-methylenedioxymethamphetamine-assisted therapy (MDMA-AT) shows promise for PTSD. Neuroimaging revealed changes in brain connectivity and activation, correlating with recovery, suggesting MDMA-AT impacts fear processing and memory networks.
Area of Science:
- Neuroscience
- Psychiatry
- Psychopharmacology
Background:
- Post-traumatic stress disorder (PTSD) is linked to hyperactive fear responses in brain regions like the amygdala, hippocampus, and insula.
- 3,4-methylenedioxymethamphetamine-assisted therapy (MDMA-AT) is a promising treatment for PTSD, hypothesized to reduce fear and enhance extinction learning.
- No prior neuroimaging studies have directly investigated the neural effects of MDMA-AT in PTSD patients.
Purpose of the Study:
- To investigate the neurobiological impact of MDMA-AT on brain activity and functional connectivity in individuals with chronic PTSD.
- To explore how changes in brain function after MDMA-AT correlate with clinical recovery from PTSD symptoms.
Main Methods:
- Functional MRI (fMRI) was used to analyze brain activity and resting-state functional connectivity before and two months after MDMA-AT.
- Nine veterans and first responders with chronic PTSD underwent fMRI scans during rest and while recalling autobiographical trauma and neutral memories.
- Statistical analyses examined changes in brain activation and connectivity, correlating these with PTSD symptom recovery.
Main Results:
- A trend towards increased resting-state functional connectivity was observed between the left amygdala and left hippocampus (p=0.0901).
- Reduced brain activation contrast between trauma and neutral memories was found in the cuneus post-MDMA-AT.
- Recovery from PTSD symptoms correlated with significant changes in functional connectivity, particularly involving the amygdala, posterior cingulate cortex, insula, and hippocampus.
Conclusions:
- MDMA-AT may modulate neural pathways involved in fear processing and memory, including amygdala-hippocampus and amygdala-insular circuits.
- Changes in functional connectivity, especially related to the amygdala and memory networks, are associated with therapeutic recovery in PTSD patients treated with MDMA-AT.
- Further research is needed to confirm these findings and differentiate the effects of MDMA-AT from other PTSD treatments.
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