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

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.

Keywords: Fear extinction; MDMA; fear-potentiated startle; psychophysiology; randomized trial.

Figure 1.

Schematic illustration of the experimental design for assessing CS habituation, fear acquisition, extinction training, and extinction retention (also termed recall). NA = noise alone; CS = conditioned stimulus

Figure 2.

All participants, prior to any drug administration, displayed significant acquisition of fear-potentiated startle to the reinforced CS+ as compared to the noise probe alone. CSH = conditioned stimuli habituation; ACQ = acquisition; NA = noise alone; CS+ = reinforced conditioned stimuli; μV = microvolts; ** = significant block × trial type interaction, p = 0.012

Figure 3.

All participants, prior to any drug administration, showed successful discrimination between the reinforced CS+ and non-reinforced CS−. CSH = conditioned stimuli habituation; ACQ = acquisition; CS+ = reinforced conditioned stimuli; CS− = non-reinforced conditioned stimuli; fear-potentiated startle = [mean startle magnitude to CS] – [mean startle magnitude to noise alone]; μV = microvolts; ** = significant block × CS type interaction, p = 0.008.

Figure 4.

Participants assigned to either the placebo or drug administration exhibited a significant reduction in fear-potentiated startle to the CS+ across the blocks of extinction training to the previously reinforced CS+. In addition, both groups showed a significant return of fear at the extinction retention test. PBO = placebo; MDMA = 3,4-methylenedioxymethamphetamine; EXT = extinction; RET = extinction retention; fear-potentiated startle = [mean startle magnitude to CS] – [mean startle magnitude to noise alone]; μV = microvolts; *** = significant effect of block, p < 0.001.

Figure 5.

Extinction training and retention in MDMA group by retainers and non-retainers: (a) within the MDMA group, retainers (Ret) demonstrated full retention of extinction training from the end of extinction training (EXT4) to the extinction retention test (RET) with no return of fear via spontaneous recovery. The non-retainers (Non-Ret) demonstrated spontaneous recovery from EXT4 to RET (significant block × group interaction, F(1,15) = 9.34, p = 0.008). (b) Scatterplot demonstrating that there were no retainers (Ret) in the placebo (PBO) group but there were significantly more retainers (n = 6) in the MDMA group (χ² = 7.29, p = 0.007). PBO = Placebo; MDMA = 3,4-methylenedioxymethamphetamine; EXT = extinction; RET = extinction retention; fear-potentiated startle = [mean startle magnitude to CS] – [mean startle magnitude to noise alone]; μV = microvolts.