MDMA treatment paired with a trauma-cue promotes adaptive stress responses in a translational model of PTSD in rats
Shira Arluk, Michael A. Matar, Lior Carmi, Oded Arbel, Joseph Zohar, Doron Todder, Hagit Cohen
Translational Psychiatry May 3, 2022 DOI: 10.1038/s41398-022-01952-8 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Controlled prospective study Peer reviewed |
|---|---|
| Population | Rats exposed to predator-scent stress |
| Intervention | MDMA injection |
| Dose | 5 mg/kg |
| Duration | 14 days |
| Topics | MDMA PTSD |
| Citations | 19 |
| Key points | MDMA treatment paired with a trauma-cue attenuated stress behavioral responses and normalized dendritic cytoarchitecture in the dentate gyrus and basolateral amygdala, effects that were prevented by HPA axis or serotonin receptor blockade. |
Abstract
AbstractMDMA (3,4-methylenedioxymethamphetamine), a synthetic ring-substituted amphetamine, combined with psychotherapy has demonstrated efficacy for the treatment of chronic posttraumatic stress disorder (PTSD) patients. This controlled prospective study aimed to assess the bio-behavioral underpinnings of MDMA in a translational model of PTSD. Rats exposed to predator-scent stress (PSS) were subjected to a trauma-cue at day 7 shortly after single-dose MDMA injection (5 mg/kg). The elevated plus maze and acoustic startle response tests were assessed on day 14 and served for classification into behavioral response groups. Freezing response to a further trauma-reminder was assessed on Day 15. The morphological characteristics of the dentate gyrus (DG) and basolateral amygdala (BLA) were subsequently examined. Hypothalamic–pituitary–adrenal axis and 5-hydroxytryptamine involvement were evaluated using: (1) corticosterone measurements at 2 h and 4 h after MDMA treatment, (2) Lewis strain rats with blunted HPA-response and (3) pharmacological receptor-blockade. MDMA treatment was effective in attenuating stress behavioral responses only when paired with memory reactivation by a trauma-cue. The effects of the treatment on behavior were associated with a commensurate normalization of the dendritic cytoarchitecture of DG and BLA neurons. Pretreatment with RU486, Ketanserin, or Pindolol prevented the above improvement in anxiety-like behavioral responses. MDMA treatment paired with memory reactivation reduced the prevalence rate of PTSD-phenotype 14 days later and normalized the cytoarchitecture changes induced by PSS (in dendritic complexities) compared to saline control. MDMA treatment paired with a trauma-cue may modify or update the original traumatic memory trace through reconsolidation processes. These anxiolytic-like effects seem to involve the HPA axis and 5-HT systems.
Comparable studies
Other preclinical and animal studies on MDMA for PTSD, most cited first.
| Study | Year | Design | Participants |
|---|---|---|---|
| Psychedelics: A review of their effects on recalled aversive memories and fear/anxiety expression in rodents Rodents | 2024 | Review | |
| Examining the Role of Oxytocinergic Signaling and Neuroinflammatory Markers in the Therapeutic Effects of MDMA in a Rat Model for PTSD. Male rats | 2024 | Preclinical study | |
| MDMA administration attenuates hippocampal IL-β immunoreactivity and subsequent stress-enhanced fear learning: An animal model of PTSD Male rats | 2022 | Preclinical study | |
| Methylone is a rapid-acting neuroplastogen with less off-target activity than MDMA Rats | 2024 | Preclinical study | |
| Discriminative stimulus properties of α-ethyltryptamine (α-ET) in rats: α-ET-like effects of MDMA, MDA and aryl-monomethoxy substituted derivatives of α-ET. Rats | 2025 | Drug discrimination study |
Citations in the library
Cited by 14
- Therapeutic mechanisms of psychedelics and entactogens. Neuropsychopharmacology July 24, 2023
- Altered brain activity and functional connectivity after MDMA-assisted therapy for post-traumatic stress disorder. Frontiers in Psychiatry 2022
- Psychedelics: A review of their effects on recalled aversive memories and fear/anxiety expression in rodents Neuroscience & Biobehavioral Reviews September 20, 2024
- MDMA-assisted psychotherapy for PTSD: Growing evidence for memory effects mediating treatment efficacy. Progress in Neuro-Psychopharmacology and Biological Psychiatry January 10, 2024
- How Psychedelics Modulate Multiple Memory Mechanisms in Posttraumatic Stress Disorder. Drugs November 1, 2024
and 9 more in the library
Cites 29
- MDMA-assisted therapy for severe PTSD: a randomized, double-blind, placebo-controlled phase 3 study. Nature Medicine June 1, 2021
- The safety and efficacy of {+/-}3,4-methylenedioxymethamphetamine-assisted psychotherapy in subjects with chronic, treatment-resistant posttraumatic stress disorder: the first randomized controlled pilot study. Journal of Psychopharmacology July 19, 2010
- 3,4-methylenedioxymethamphetamine (MDMA)-assisted psychotherapy for post-traumatic stress disorder in military veterans, firefighters, and police officers: a randomised, double-blind, dose-response, phase 2 clinical trial. The Lancet Psychiatry May 1, 2018
- A randomized, controlled pilot study of MDMA (±3,4-Methylenedioxymethamphetamine)-assisted psychotherapy for treatment of resistant, chronic Post-Traumatic Stress Disorder (PTSD) Journal of Psychopharmacology October 31, 2012
- Durability of improvement in post-traumatic stress disorder symptoms and absence of harmful effects or drug dependency after 3,4-methylenedioxymethamphetamine-assisted psychotherapy: a prospective long-term follow-up study. Journal of Psychopharmacology 2013
and 24 more in the library