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Updated: Sep 2, 2025
Extinction Training During the Reconsolidation Window Prevents Recovery of Fear
Published on: August 24, 2012
Effects of 3,4-Methylenedioxymethamphetamine on Conditioned Fear Extinction and Retention in a Crossover Study in
Patrick Vizeli1,2,3, Isabelle Straumann1,2, Urs Duthaler1,2
1Clinical Pharmacology and Toxicology, Department of Biomedicine and Department of Clinical Research, University Hospital Basel, Basel, Switzerland.
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. Clinical Trial registration: clinicaltrials.gov identifier: NCT03527316.
Insights
3,4-Methylenedioxymethamphetamine (MDMA) aids fear extinction recall in healthy adults, potentially enhancing psychotherapy for PTSD. This study shows MDMA reduces skin conductance responses to fear cues, suggesting a mechanism for its therapeutic effects.
Area of Science:
- Neuroscience
- Psychopharmacology
- Clinical Psychology
Background:
- 3,4-Methylenedioxymethamphetamine (MDMA) shows promise in treating posttraumatic stress disorder (PTSD) as an adjunct to psychotherapy.
- The precise mechanisms by which MDMA may exert therapeutic effects in PTSD remain under investigation.
- Preliminary research suggests MDMA might enhance fear extinction recall, possibly via oxytocin release.
Purpose of the Study:
- To investigate the efficacy of acute MDMA administration in enhancing fear extinction learning and recall in healthy human subjects.
- To explore the potential role of oxytocin in mediating MDMA's effects on fear extinction.
- To assess the impact of MDMA on subjective experiences, emotion recognition, and physiological fear responses.
Main Methods:
- A randomized, double-blind, placebo-controlled crossover study involving 30 healthy male participants.
- Participants received a placebo or a single 125 mg dose of MDMA.
- Fear extinction was assessed using Pavlovian conditioning paradigms measuring skin conductance response (SCR) and fear-potentiated startle (FPS).
- MDMA was administered after fear conditioning and 2 hours before extinction learning, with recall tested 23 hours later.
Main Results:
- MDMA significantly reduced SCRs to conditioned stimuli (CS+) during both extinction learning and recall compared to placebo.
- MDMA did not significantly affect fear-potentiated startle (FPS) responses.
- While MDMA increased plasma oxytocin levels, this increase was not directly correlated with fear extinction outcomes.
- Subjective effects of MDMA during extinction learning were negatively correlated with recall performance.
Conclusions:
- MDMA treatment facilitated rapid fear extinction and its retention, as evidenced by reduced SCRs to fear cues.
- The observed effect of MDMA on fear extinction may be specific to certain response modalities, as it was not seen with FPS.
- These findings provide further support for MDMA's role in facilitating extinction processes, potentially contributing to its efficacy in psychotherapy for PTSD.
