A randomized controlled trial of 3,4-methylenedioxymethamphetamine (MDMA) and fear extinction retention in healthy adults
In a randomised, placebo-controlled trial of 100 mg MDMA in 34 healthy adults, MDMA was well tolerated but produced no overall group-level facilitation of fear extinction retention between extinction training and retention sessions. However, a significantly greater proportion of participants in the MDMA group retained extinction learning compared with placebo (χ2 = 7.29, p = 0.007), supporting further investigation of MDMA’s effects on extinction retention.
Authors
- Katharine Dunlop
- Boadie Dunlop
- Jessica Maples-Keller
Published
Abstract
Background
Fear conditioning and extinction are well-characterized cross-species models of fear-related posttraumatic stress disorder (PTSD) symptoms, and recent animal data suggest that 3,4-methylenedioxymethamphetamine (MDMA) enhances fear extinction retention.
Aims
This study investigated the effect of MDMA on fear learning, extinction training, and retention in healthy humans.
Methods
The study involved a randomized placebo-controlled, two-group, parallel design trial in a sample of healthy adults, age 21–55 recruited from a major metropolitan area. The experimental paradigm included a fear acquisition session followed by an extinction training session 24 hours later, and 2 hours after study drug administration. Fear extinction retention was measured 48 hours after extinction training. Participants ( N = 34; 70.6% male and 29.4% female) were randomly assigned in 1:1 ratio to 100 mg MDMA or placebo. All randomized participants completed the trial and were included in primary analyses. Safety was monitored via adverse events and vital signs. MDMA was well-tolerated with no serious adverse events.
Results
Results indicated a significant main effect of session between extinction training and retention with no significant group differences. Significantly more participants in the MDMA group retained extinction learning compared to the placebo group (χ2 = 7.29, p = 0.007).
Conclusion
Although we did not observe the hypothesized facilitation of extinction retention, the findings from this initial human trial provide compelling rationale to continue to explore the potential for MDMA to impact extinction retention. Clinical Trials Registry Name and Identifier: Evaluation of MDMA on Startle Response (NCT0318176) https://clinicaltrials.gov/ct2/show/NCT03181763?term = MDMA&draw = 2&rank = 9
Research Summary of 'A randomized controlled trial of 3,4-methylenedioxymethamphetamine (MDMA) and fear extinction retention in healthy adults'
Introduction
Posttraumatic stress disorder (PTSD) is a disabling condition for which trauma-focused psychotherapies such as prolonged exposure (PE) are effective but not universally successful. Maples-Keller and colleagues note growing interest in MDMA-assisted psychotherapy as a potential treatment for PTSD; mechanistic work from animal models suggests that MDMA given before extinction training can enhance long-term extinction retention, an effect linked to amygdala and medial prefrontal cortical activity and increased BDNF expression in rodents. Extinction learning and extinction retention (the within-session reduction of conditioned fear and the later retrieval of that learning, respectively) are widely used translational models for fear-related symptoms of PTSD and are theorised to underlie PE's therapeutic effects. This randomised, placebo-controlled human trial tested whether acute MDMA administration would enhance extinction learning or, primarily, extinction retention in healthy adults. The investigators hypothesised that participants who received 100 mg MDMA prior to extinction training would show reduced fear-potentiated startle during an extinction retention test 48 hours later compared with placebo-treated participants. This study therefore aimed to translate preclinical findings into a human experimental fear-conditioning paradigm and to assess safety and tolerability of acute MDMA in this context.
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Study Details
- Study Typeindividual
- Journal
- Compound
- Topics
- Authors
- APA Citation
Maples-Keller, J. L., Norrholm, S. D., Burton, M., Reiff, C., Coghlan, C., Jovanovic, T., Yasinski, C., Jarboe, K., Rakofsky, J., Rauch, S., Dunlop, B. W., & Rothbaum, B. O. (2022). A randomized controlled trial of 3,4-methylenedioxymethamphetamine (MDMA) and fear extinction retention in healthy adults. Journal of Psychopharmacology, 36(3), 368-377. https://doi.org/10.1177/02698811211069124
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