PMID- 35910354 OWN - NLM STAT- PubMed-not-MEDLINE LR - 20230209 IS - 1663-9812 (Print) IS - 1663-9812 (Electronic) IS - 1663-9812 (Linking) VI - 13 DP - 2022 TI - Effects of 3,4-Methylenedioxymethamphetamine on Conditioned Fear Extinction and Retention in a Crossover Study in Healthy Subjects. PG - 906639 LID - 10.3389/fphar.2022.906639 [doi] LID - 906639 AB - 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. CI - Copyright (c) 2022 Vizeli, Straumann, Duthaler, Varghese, Eckert, Paulus, Risbrough and Liechti. FAU - Vizeli, Patrick AU - Vizeli P AD - Clinical Pharmacology and Toxicology, Department of Biomedicine and Department of Clinical Research, University Hospital Basel, Basel, Switzerland. AD - Department of Pharmaceutical Sciences, University of Basel, Basel, Switzerland. AD - Department of Psychiatry, University of California, San Diego, La Jolla, CA, United States. FAU - Straumann, Isabelle AU - Straumann I AD - Clinical Pharmacology and Toxicology, Department of Biomedicine and Department of Clinical Research, University Hospital Basel, Basel, Switzerland. AD - Department of Pharmaceutical Sciences, University of Basel, Basel, Switzerland. FAU - Duthaler, Urs AU - Duthaler U AD - Clinical Pharmacology and Toxicology, Department of Biomedicine and Department of Clinical Research, University Hospital Basel, Basel, Switzerland. AD - Department of Pharmaceutical Sciences, University of Basel, Basel, Switzerland. FAU - Varghese, Nimmy AU - Varghese N AD - Psychiatric University Hospital, University of Basel, Basel, Switzerland. AD - Transfaculty Research Platform Molecular and Cognitive Neuroscience, University of Basel, Basel, Switzerland. FAU - Eckert, Anne AU - Eckert A AD - Psychiatric University Hospital, University of Basel, Basel, Switzerland. AD - Transfaculty Research Platform Molecular and Cognitive Neuroscience, University of Basel, Basel, Switzerland. FAU - Paulus, Martin P AU - Paulus MP AD - Laureate Institute for Brain Research, Tulsa, OK, United States. FAU - Risbrough, Victoria AU - Risbrough V AD - Department of Psychiatry, University of California, San Diego, La Jolla, CA, United States. AD - Center of Excellence for Stress and Mental Health, San Diego, CA, United States. FAU - Liechti, Matthias E AU - Liechti ME AD - Clinical Pharmacology and Toxicology, Department of Biomedicine and Department of Clinical Research, University Hospital Basel, Basel, Switzerland. AD - Department of Pharmaceutical Sciences, University of Basel, Basel, Switzerland. LA - eng SI - ClinicalTrials.gov/NCT03527316 GR - I01 BX004312/BX/BLRD VA/United States PT - Journal Article DEP - 20220713 PL - Switzerland TA - Front Pharmacol JT - Frontiers in pharmacology JID - 101548923 PMC - PMC9326355 OTO - NOTNLM OT - MDMA and fear extinction paradigms OT - fear extinction OT - fear-potentiated startle OT - healthy subjects OT - oxytocin OT - skin conductance response COIS- ML is a consultant for Mind Medicine, Inc. Knowhow and data associated with this work and owned by the University Hospital Basel were licensed by Mind Medicine, Inc. MP is supported by the William K Warren Foundation and receives grant support from the NationalInstitute on Drug Abuse (U01 DA041089), and the National Institute of General Medical Sciences Center Grant Award Number (1P20GM121312). MP is an advisor to Spring Care, Inc., a behavioral health startup; he has received royalties for an article about methamphetamine in UpToDate. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. EDAT- 2022/08/02 06:00 MHDA- 2022/08/02 06:01 PMCR- 2022/07/13 CRDT- 2022/08/01 03:29 PHST- 2022/03/28 00:00 [received] PHST- 2022/06/02 00:00 [accepted] PHST- 2022/08/01 03:29 [entrez] PHST- 2022/08/02 06:00 [pubmed] PHST- 2022/08/02 06:01 [medline] PHST- 2022/07/13 00:00 [pmc-release] AID - 906639 [pii] AID - 10.3389/fphar.2022.906639 [doi] PST - epublish SO - Front Pharmacol. 2022 Jul 13;13:906639. doi: 10.3389/fphar.2022.906639. eCollection 2022.