Effects of 3,4-Methylenedioxymethamphetamine on Conditioned Fear Extinction and Retention in a Crossover Study in Healthy Subjects

This double-blind placebo-controlled study (n=30) found that MDMA (125mg), administrated to healthy subjects, helped reduce fear conditioning in a lab test (versus the placebo). The results were not dependent on the level of oxytocin (which MDMA increased fourfold). This study could help explain why MDMA is effective in combination with psychotherapy, e.g. for PTSD.

Abstract

“Background: 3,4-Methylenedioxymethamphetamine (MDMA) has shown initial promise as an adjunct in psychotherapy to treat posttraumatic stress disorder (PTSD). Its efficacy and safety have been demonstrated across phase I–III studies. However, the mechanism underlying the potential utility of MDMA to treat PTSD in humans has not yet been thoroughly investigated. Preliminary evidence suggests that MDMA may facilitate fear extinction recall, which may be through the release of oxytocin. To test this hypothesis, we examined the efficacy of acute MDMA treatment to enhance fear extinction learning and recall.

Methods: We used a two-period, double-blind, randomized, placebo-controlled crossover design in 30 healthy male subjects who received a placebo and a single dose of MDMA (125 mg). Fear extinction was tested using two separate Pavlovian fear conditioning paradigms, one using skin conductance response (SCR), and the other fear-potentiated startle (FPS) to conditioned cues. MDMA treatment occurred after fear conditioning and 2 h before extinction learning. Extinction recall was tested 23 h after MDMA intake. Additional outcome measures included subjective effects, emotion recognition tasks, plasma levels of oxytocin, and pharmacokinetics.

Results: Fear conditioning and extinction learning were successful in both fear extinction paradigms (generalized eta–squared [ges] for SCR: 0.08; FPS: 0.07). Compared to placebo treatment, MDMA treatment significantly reduced SCRs to the reinforced conditioned stimulus (CS+) during extinction learning (ges = 0.03) and recall (ges = 0.06). Intensity of the subjective effects of MDMA (good effect, trust, and openness) during extinction learning negatively correlated with the discrimination between CS+ and the safety stimulus (CS−) during recall. MDMA did not influence FPS to conditioned cues. Oxytocin concentration was increased fourfold on average by MDMA during acute effects but was not associated with fear extinction outcomes.

Conclusions: MDMA treatment facilitated rapid fear extinction and retention of extinction as measured by SCR to fear cues, in line with animal studies of MDMA facilitation of extinction. However, this effect may be limited to certain forms of learned fear responses, as it was not observed in the extinction model using startle reactivity as the outcome. This study provides further evidence for the facilitation of extinction with MDMA treatment and suggests this may be a component of its efficacy when paired with psychotherapy.”

Authors: Patrick Vizeli, Isabelle Straumann, Urs Duthaler, Nimmy Varghese, Anne Eckert, Martin P. Paulus, Victoria Risbrough & Matthias E. Liechti

Summary

3,4-Methylenedioxymethamphetamine (MDMA) is being investigated for use as an adjunctive treatment to psychotherapy for patients with PTSD and social anxiety. It produces subjective pleasurable effects and alters emotion processing and social cognition. MDMA stimulates the release of oxytocin, which is known to enhance emotional empathy, reduce amygdala response to negative emotional stimuli, and increase the salience of positive versus negative facial expressions. Oxytocin may also contribute to the therapeutic effects of MDMA in a patient with PTSD.

MDMA is thought to promote fear extinction learning in mice, potentially through its serotonin transporter reversal effects and subsequent activation of serotonin 2 A receptors. MDMA treatment in rats does not facilitate fear extinction learning but instead disrupts fear memory reconsolidation.

Although the effects of MDMA on conditioned fear learning and extinction were relatively weak, this study tested the hypothesis that MDMA enhanced extinction recall through its effects on oxytocin release.

Study Design

The study used a double-blind, placebo-controlled, crossover design and was approved by the Ethics Committee of Northwest Switzerland. It was conducted from 30 October 2019 to 23 December 2020.

Participants

Thirty healthy male participants were recruited through a flyer on the online notice board of the University of Basel or by word of mouth. All provided written informed consent and were paid for their participation. Subjects had to exhibit a baseline skin conductance level of 2 – 20 S during screening and show a positive response to physiologic stimuli (holding breath).

Study Procedures

The study included a screening visit, two 8-h test sessions, a 2-h follow-up session 22 h after drug intake, and an end-of-study visit. It was conducted in a neutral hospital room, and only one research subject and one investigator were present during each test session.

Study Drugs

Participants received five capsules containing either five times 25 mg of pharmaceutically pure MDMA or five times 25 mg of mannitol. The average dose was 1.69 mg/kg.

Subjective Drug Effects and Effect Durations

Subjective alterations in consciousness over time were assessed using visual analog scales. These scales were presented as 100-mm horizontal lines labeled “not at all” on the left side and “extremely” on the right side.

The Adjective Mood Rating Scale (AMRS) and state-trait anxiety inventory (STAI-S) were used to assess mood and anxiety levels before and after drug administration.

Facial Emotion Recognition Task

The facial emotion recognition task assessed the recognition of basic emotions. Participants had to indicate the correct emotion from a series of 160 faces.

Oxytocin Concentrations

Oxytocin levels were measured before and after MDMA administration. Analyses were performed blinded at the end of the study in one batch.

3,4-Methylenedioxymethamphetamine Concentrations

Blood samples were collected using lithium heparin tubes, centrifuged at 4°C at 3,000 rpm for 10 min, and stored at 80°C until analysis. MDMA, MDA, and HMMA concentrations were determined after enzymatic deglucuronidation.

Pharmacokinetic Analyses

Pharmacokinetic parameters were estimated using noncompartmental methods. The terminal elimination rate constant (z) could not be determined in 17 individuals, so the AUC to infinity was calculated using the AUC24.

Skin Conductance Response

Fear conditioning using skin conductance response (SCR) was as previously described (Sehlmeyer et al., 2011; Ball et al., 2017). Participants were presented with two sets of each two complex fractal pictures as either CS+ or CS.

Fractal pictures were presented to participants in two runs of 8 min each. The acquisition phase consisted of five presentations of each CS with no instances of the US, and the extinction phase and recall phase consisted of 25 and 15 presentations of each CS with no instances of the US, respectively. Two electrodermal activity (EDA) finger electrodes were placed on the middle and index fingers of the nondominant hand and data was recorded and analyzed with AcqKnowlege 5.0.1 software. Five subjects with no valid responses in the placebo session were considered nonresponders and excluded from the within-subject analysis.

Fear-Potentiated Startle

The fear conditioning and extinction task is comprised of three phases: the acquisition phase was conducted before dosing, the extinction learning phase was conducted 2.5 h after dosing, and the extinction recall was performed the next day, 23.5 h after drug administration.

Participants were presented with a symbol (CS+) and an aversive stimulus (air puff) for acquisition and extinction. They were also presented with a baseline startle measurement (NA trials) between the CS+ and CS presentations. Startle data was initially processed by averaging responses to CS+, CS, and NA trials within each phase into blocks of two trials each. Standardized potentiated startle values were then obtained by subtracting NA blocks from CS+ and CS blocks and dividing by the SD of NA trials within each phase.

Statistical Data Analysis

Subjective and autonomous maximum (Emax) and minimum (Emin) effects were determined directly from the observed data. Main effects and interactions were followed by Tukey posthoc comparisons, and Pearson correlations and paired t-tests were performed in the statistical analysis software R.

Fear Induced Skin Conductance Response vs. Fear-Potentiated Startle

During conditioning, SCR responses were greater to CS+ than to CS, and the response decreased over the session likely reflecting some habituation. During extinction learning, a main effect for trial type was observed as well as an interaction of drug x trial type. SCRs across trial types were only different in the placebo condition (p = 0.004), but not under the influence of MDMA (p = 0.80). Baseline SC levels were higher during acute MDMA treatment than placebo (p = 0.001). The results showed that the participants were engaged in the task in both drug conditions, as evidenced by 99 % accuracy in the simple low-level continuous performance task, and that there was a significant main effect of trial type during the extinction recall phase.

MDMA treatment did not affect participants’ fear response to the US (air puff) during acquisition, extinction learning or extinction recall. There was a main effect for time in the extinction learning and extinction recall, but not in the acquisition phase.

Autonomic and Subjective Effects

MDMA moderately increased vital parameters and produced higher ratings in subjective effects, such as any drug effect, “good” drug effect, liking, and talkative, compared to placebo. MDMA also produced significantly lower minimum scores on the real-time anxiety index STAI compared to placebo. Subjective effects, such as any drug and good drug effect, openness and trust during the extinction learning phase, negatively correlated with the CS+ and CS z-score in early extinction recall.

Oxytocin

MDMA produced significantly higher blood plasma oxytocin levels compared to placebo, and the levels of oxytocin at the time of the emotion task (3 h) did not correlate with the emotion recognition or fear extinction learning results.

Facial Emotion Recognition Task

MDMA impaired the recognition of faces displaying negatively valanced emotions, such as “anger”, “sad” and “fear”, but not “happy” or “neutral”. Most emotions that were not correctly identified were misclassified as “neutral”, but the fewest trials were misclassified as “happy”.

Order and Sequence Effects

In the nonstandardized data, an order effect was observed in the SCR and EMG FPS measurements, but no drug / trial / order interaction was observed.

DISCUSSION

This study provides the first within-subject comparison of fear extinction learning and recall between MDMA and placebo. MDMA treatment increased extinction recall as measured using SCR, but not in the FPS paradigm.

Participants showed stronger fear extinction recall the day after MDMA treatment, compared to participants after placebo. The acquisition of conditioned fear was successful, and the subsequent extinction of the conditioned fear was successful. Studies with MDMA in mice and oxytocin in humans suggest immediate enhancement of fear extinction learning and recall, but rats did not freeze after high MDMA injections during extinction learning.

The effects of MDMA on self-reports of feelings of trust and openness were correlated with the fear extinction retention.

MDMA’s subjective effects have been associated with decreased blood flow in the right amygdala and hippocampus, which could be a predictor of treatment efficacy for PTSD.

We did not find significant changes in fear-related priming (FPS) after MDMA treatment, but we did find an increase in extinction retainers (fear associations that are resistant to drug effects on extinction). The results of this study are comparable to the results of the study by Maples-Keller et al. (2022b) because both studies demonstrated the feasibility of experimental extinction research under the influence of MDMA (100 and 125 mg), and because both studies found no clear facilitation of fear extinction learning per se.

MDMA has been shown to increase trust and openness, which are important for the therapist-patient relationship. Antidepressant drugs may decrease the treatment responsiveness to MDMA, which is consistent with previous findings of SSRIs blocking MDMA-induced subjective effects in humans and fear extinction enhancement in mice.

MDMA is thought to increase the ability to recognize positive feelings in others, but we found no correlation between oxytocin concentration and facial emotion recognition, nor a correlation between peripheral oxytocin levels and fear extinction. Many studies have not found a relationship between oxytocin concentration and the subjective, emotional, empathic, or prosocial effects of MDMA. However, the use of an oxytocin receptor antagonist may be required to investigate this further. The study has certain limitations, such as only observing drug effects in the SCR task, and not observing any drug effects in the FPS task. However, future studies could investigate the feasibility of other compounds with a less stimulating profile than MDMA in fear extinction. The study had several limitations, including a crossover design, a possibility of self-unblinding, and the absence of females due to concerns that hormonal influences on fear extinction might reduce the power to detect drug effects on extinction.

Recent studies indicate that there are no sex differences in response to MDMA effects on extinction or PTSD symptoms, but future research should investigate the impact of menstrual hormones in fear extinction learning, especially in people with fear extinction deficits, such as patients with PTSD.

CONCLUSION

MDMA facilitated fear extinction in the SCR model, but not in the FPS test. Further research is needed to determine the full range of MDMA’s supportive effects.