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.

Summary

Posttraumatic stress disorder (PTSD) is a debilitating psychiatric illness associated with significant distress and difficulties in functioning. MDMA in combination with psychotherapy is effective in treating PTSD, and the effects of MDMA are likely responsible for the subjective effects in humans.

In six randomized trials, participants who took MDMA for two to three 8-hour sessions demonstrated a greater reduction in PTSD symptoms compared to placebo or control dose groups. The study also indicated a favorable safety profile.

This study investigated the impact of MDMA on fear extinction learning and retention, which could improve outcomes of PE for PTSD through its action on fear circuitry and resulting behavior.

Fear-related PTSD symptoms can occur following exposure to an extremely aversive event, and can involve conditioned fear responses, avoidance of trauma-related cues, and exaggerated fear responses that do not diminish over time due to a failure of fear extinction.

Fear extinction training involves repeated presentation of the conditioned stimulus without the unconditioned stimulus (US), resulting in a decreased conditioned fear response. Fear extinction retention is the ability to appropriately maintain this inhibition of fear.

MDMA enhanced long-term extinction in rodent models, and a recent preclinical study replicated this finding. MDMA reduced conditioned fear when administered during the consolidation phase, suggesting MDMA may act to disrupt reconsolidation of fear memories.

This study investigated the impact of MDMA on fear extinction training and retention in healthy humans. Participants who received MDMA demonstrated a decreased startle response to aversive stimuli during extinction retention compared to participants who received placebo.

Study design

A parallel-group, randomized, placebo-controlled trial was conducted at Emory University in Atlanta, Georgia, from March 2018 to July 2020. Adverse events were collected for duration of study participation.

Randomization

MDMA or placebo was randomly assigned at Visit 2 using a list generated by an independent biostatistician and sent directly to the unblinded study physician, who dispensed the study medication. All study personnel were blinded to group assignment.

Participants

Participants were recruited through community advertising, provided written informed consent, and were 21-55 years of age, ability to read and understand the English language, had previously used MDMA in recreational setting with no reported adverse experiences, and were required to use birth control through 10 days after study completion.

Procedure

Participants were prescreened by telephone for basic eligibility criteria, underwent a medical history and physical exam, and a screening laboratory test was completed to confirm study eligibility. After completion of the fear acquisition session, participants were instructed to refrain from alcohol, caffeine, and nicotine.

Participants completed a urine drug screen and pregnancy test if applicable, and were administered a white capsule containing either 100 mg MDMA or matching placebo. They remained in the treatment room for 6 hours after dosing.

Startle paradigm

The study used an EMG to measure the startle response of the right orbicularis oculi muscle to a 108 dB sound pressure level, 40 ms burst of broadband noise.

Visit 1 (fear acquisition) consisted of habituation blocks, three acquisition blocks, 12 reinforcement blocks, and 12 noise alone blocks. Stimuli were presented using SuperLab 4.5 for Windows and synchronized with psychophysiological data acquisition using DIO card.

Visit 2 (extinction training): 16 trials of each type (CS+, CS, NA) were administered with same ITI range (9 – 22 seconds).

Statistical analysis

In a study of conditioned fear, extinction training and extinction retention were tested using Repeated Measures Analysis of Variance (RM-ANOVA). The primary outcome measure was fear-potentiated startle magnitude during extinction retention.

The extinction retention of the previously reinforced CS+ was tested with RM-ANOVA with session and group as within-subjects variables and extinction retention as a between-subjects variable.

We conducted post hoc exploratory analyses to determine the proportion of participants in each group that showed a specific response to fear extinction and compared the amount of extinction retainers in MDMA and placebo groups.

Participants

Fifty-one people consented for the study, and thirty-four were randomized. No significant differences were identified across all demographic variables.

Fear acquisition

We conducted four blocks of conditioning, with a three-way interaction of block t trial type g and a block t trial type interaction g. Both groups showed higher startle magnitude to CS+ versus NA, and there were no significant differences between MDMA and placebo groups on any block.

The fear-potentiated startle response returned to the previously reinforced CS+ at the end of extinction training.

In our previous work, we classified individuals based on the degree to which they learn to extinguish fear during extinction learning sessions. In this study, we further explored this examination.

CS+/CS− discrimination

The discrimination between the CS+ and CS cues was quantified and analyzed per previously reported methods. There were no significant differences between MDMA and placebo groups during the acquisition session with regard to discriminative learning.

Extinction training

We examined whether baseline startle was affected by MDMA prior to extinction training. We observed no effect of MDMA versus placebo on baseline startle during the extinction session.

Extinction retention

Participants who showed no increase in fear-potentiated startle at the end of extinction training but increased fear-potentiated startle at the beginning of extinction retention were defined as “non-retainers”. The MDMA group demonstrated a full retention of extinction training across the retention session with no return of fear.

Tolerability and safety of MDMA

Adverse events were collected for the duration of the study protocol. The most common adverse events were elevated blood pressure, headache, anxiety, and tachycardia, which were mild to moderate in severity.

Physiological indices including pulse rate, blood pressure, and body temperature were assessed during the drug/placebo session. We found that the MDMA group displayed significantly higher pulse rate, higher blood pressure, and higher body temperature compared to the placebo group.

Discussion

MDMA-assisted psychotherapy has shown potential as a treatment for PTSD, and this study sought to translate pre-clinical evidence from rodent models to human fear learning paradigms. The results showed that MDMA did not enhance extinction retention, but did increase the number of participants who retained extinction learning.

Recently MDMA research has significantly increased with growing evidence for the safety and efficacy of MDMA-assisted therapy. A large analysis has shown that MDMA is safe and well tolerated. The effects of acute MDMA administration on extinction learning in healthy human adults was investigated. It was found that participants were able to successfully attend to and engage in this experimental paradigm, despite acute subjective effects and increase in physiological arousal. Extinction retention was the primary outcome for this study. MDMA did not enhance extinction retention in this study, and a higher dose of extinction training may be required to see higher rates of extinction retention.

The results of this study provide valuable new insight into the mechanisms by which MDMA may or may not elicit clinical gains in PTSD treatment. The MDMA group demonstrated significantly more participants who retained extinction learning compared to the placebo group.

Research indicates that MDMA may facilitate fear extinction in a subset of individuals. Further research should investigate the potential role of MDMA in fear extinction in larger sample sizes or in samples elected specifically for deficits in fear extinction learning.

MDMA administration prior to fear extinction training did not enhance the fear extinction memory, but administration during reconsolidation phase resulted in a reduction in conditioned fear. Imaging studies may be beneficial in further elucidating how MDMA may impact these distinct processes.

MDMA-assisted psychotherapy shows promise as a novel intervention for PTSD. However, a recent study suggests that MDMA does not impair the extinction of learned fear nor does it directly improve extinction learning in human subjects in this paradigm.

Limitations and future directions

In this study, MDMA was safe and well tolerated, and the effect of MDMA on fear extinction was objective. Future research may investigate the pharmacological specificity of MDMA’s impact on fear extinction, and whether MDMA may hold the greatest potential to rescue deficits in PTSD patients.