A randomized controlled trial of 3,4-methylenedioxymethamphetamine (MDMA) and fear extinction retention in healthy adults

This double-blind placebo-controlled trial (n=34) assessed the effects of MDMA (100mg) following a fear acquisition session, an extinction training session and retention in healthy subjects. There was no difference between extinction training and retention between groups. However, significantly more participants in the MDMA group retained extinction learning compared to the placebo group (p = 0.007).

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 a 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 the 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 a compelling rationale to continue to explore the potential for MDMA to impact extinction retention.”

Authors: Jessica L. Maples-Keller, Seth D. Norrholm, Mark Burton, Collin Reiff, Callan Coghlan, Tanja Jovanovic, Carly Yasinski, Kathleen Jarboe, Jeffery Rakofsky, Shelia Rauch, Boadie W. Dunlop & Barbara O. Rothbaum

Notes

PTSD is a multifaceted disorder. One of the well-known features of the disorder relates to a persons fear response. In general, people respond to fear through subjective feelings, physiological responses, and overt behaviour. Simply put, fear is best described as an urge to get out of whatever situation one may be in. In people with PTSD, their fear extinction is impaired i.e the ability to cope with the fearful stimuli. Thus, one of the most widely used forms of therapy in the treatment of PTSD is prolonged exposure therapy (PET). At the root of PET lies fear extinction learning and retention.

In PET patients are exposed to anxiety-provoking thoughts and images which the therapist helps them to process in a safe environment. As MDMA, is proving to be an effective treatment for PTSD, this study investigated MDMA’s impact on fear extinction learning and retention which could better determine MDMA’s potential to enhance outcomes of PET for PTSD through its action on fear circuitry and resulting behaviour.

The present study is the first study to investigate the acute administration of MDMA on fear learning in humans. Healthy study participants (n=34) were exposed to 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 were randomized 1:1 to receive either MDMA (100mg) or a placebo.

The effects on fear:

  • All participants successfully acquired and then extinguished conditioned fear
  • Re-extinction training administration of MDMA, and its associated experiential and physiological effects, did not interfere with participants’ ability to learn to extinguish recently acquired conditioned fear such that both groups demonstrated extinction learning
  • Acute MDMA administration did not overall enhance within-session extinction learning nor enhance extinction retention
  • Notably, there was a significantly greater number of participants who retained extinction learning in the MDMA versus placebo group

Overall, the results of the present study suggest that MDMA does not impair the extinction of learned fear nor does it directly improve extinction learning in human subjects. The authors acknowledge limitations to the study including difficulties in maintaining blinding in the MDMA group, while the timing of MDMA administration (2hrs prior to extinction training) may have been an issue.

Study details

Compounds studied
MDMA

Topics studied
Healthy Subjects PTSD

Study characteristics
Original Placebo-Controlled Double-Blind Randomized

Participants
34 Humans

Institutes

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Compound Details

The psychedelics given at which dose and how many times

MDMA 100 mg | 1x

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