Effects of 3,4-Methylenedioxymethamphetamine on Conditioned Fear Extinction and Retention in a Crossover Study in Healthy Subjects.
Effects of 3,4-Methylenedioxymethamphetamine on Conditioned Fear Extinction and Retention in a Crossover Study in Healthy Subjects.
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DOI：
10.3389/fphar.2022.906639
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发表时间：
2022
影响因子：
5.6
通讯作者：
Liechti, Matthias E.
中科院分区：
文献类型：
--
作者：
Vizeli, Patrick;Straumann, Isabelle;Duthaler, Urs;Varghese, Nimmy;Eckert, Anne;Paulus, Martin P.;Risbrough, Victoria;Liechti, Matthias E.
关键词：
背景：3，4-亚甲基二氧基甲基苯丙胺(MDMA)作为心理治疗创伤后应激障碍(PTSD)的辅助药物已显示出初步的前景。其有效性和安全性已在I-III期研究中得到证实。然而，MDMA治疗人类创伤后应激障碍的潜在效用的机制尚未得到彻底的研究。初步证据表明，MDMA可能促进恐惧消退回忆，这可能是通过释放催产素来实现的。为了验证这一假设，我们检验了急性MDMA治疗增强恐惧消退学习和回忆的有效性。方法：我们采用两阶段、双盲、随机、安慰剂对照的交叉设计，在30名健康男性受试者中接受安慰剂和单剂量MDMA(125 Mg)。使用两种不同的巴甫洛夫恐惧条件反射范式测试恐惧消退，一种使用皮肤电导反应(SCR)，另一种使用对条件线索的恐惧强化惊吓(FPS)。MDMA治疗在恐惧条件化后和消亡学习前2小时进行。在服用MDMA后23h进行消退回忆测试。其他结果测量包括主观效果、情绪识别任务、血浆催产素水平和药代动力学。结果：在两种恐惧消退范式下，恐惧条件反射和消退学习均获得成功(SCR的广义ETA平方：0.08；FPS：0.07)。与安慰剂治疗相比，在消退学习(GES=0.03)和回忆(GES=0.06)过程中，MDMA治疗显著降低了强化条件刺激(CS+)的SCR。在消退学习过程中，记忆的主观效应(良好效果、信任和开放性)的强度与回忆过程中CS+与安全刺激(CS−)的辨别度呈显著负相关。MDMA对条件性线索的FPS没有影响。在急性效应期间，MDMA使催产素浓度平均增加四倍，但与恐惧消退结果无关。结论：MDMA治疗促进了恐惧的快速消退和保持消退，这与动物研究中MDMA促进消退的动物研究相一致。然而，这种影响可能仅限于某些形式的获得性恐惧反应，因为在以惊吓反应为结果的灭绝模型中没有观察到这种影响。这项研究为MDMA治疗促进消退提供了进一步的证据，并表明这可能是与心理治疗相结合时其疗效的一个组成部分。临床试验注册：ClinicalTrials.gov标识：NCT03527316
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
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