Altered brain activity and functional connectivity after MDMA-assisted therapy for post-traumatic stress disorder

In nine veterans and first-responders with chronic PTSD, MDMA-assisted therapy did not significantly increase amygdala-hippocampus resting-state functional connectivity as hypothesized, only showing a trend. After treatment, activation in the cuneus decreased when recalling traumatic versus neutral memories. The amount of PTSD recovery correlated with changes in four functional connections during autobiographical memory recall: left amygdala with left and right posterior cingulate cortex and left insula, and left isthmus cingulate with left posterior hippocampus. These findings suggest that MDMA-AT may alter functional connectivity in brain regions involved in memory and fear processing, but more research is needed to determine if these effects are specific to MDMA-AT compared to other PTSD treatments.

Study at a glance

Abstract

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. 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. 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. 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.