3,4-methylenedioxymethamphetamine (MDMA)-assisted psychotherapy for post-traumatic stress disorder in military veterans, firefighters, and police officers: a randomised, double-blind, dose-response, phase 2 clinical trial

Mithoefer, Michael C.; Mithoefer, Ann T; Feduccia, Allison A.; Jerome, Lisa; Wagner, Mark T.; Wymer, Joy H.; Holland, Julie; Hamilton, Scott; Yazar‐Klosinski, Berra; Emerson, Amy; Doblin, Rick

doi:10.1016/s2215-0366(18)30135-4

Cited by 366 publications

(353 citation statements)

References 27 publications

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“…This hypothesis is in good agreement with the positive effects obtained by injecting the anxiolytic drug propranolol in cocaine addicted 72 or PTSD 73 patients before their respective exposure to drug-craving stimuli or to PTSD cues. It is also consistent with the evaluation of the recent advancements in MDMA-assisted psychotherapy for PTSD 74,75 which points out that treatments that block pathological activation in brain regions implicated in the expression of fear during the memory malleability phase are likely to induce re-processing of traumatic memories. This new memory with a lower emotional component could therefore reduce the forthcoming impact of the trauma.…”

Section: Emotional Remodeling With Oxytocin: What Mechanisms?supporting

confidence: 86%

Emotional remodeling with oxytocin durably rescues trauma-induced behavioral and neuro-morphological changes in rats: a promising treatment for PTSD

et al. 2020

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Recent evidence indicates that reactivated memories are malleable and can integrate new information upon their reactivation. We injected rats with oxytocin to investigate whether the delivery of a drug which dampens anxiety and fear before the reactivation of trauma memory decreases the emotional load of the original representation and durably alleviates PTSD-like symptoms. Rats exposed to the single prolonged stress (SPS) model of PTSD were classified 15 and 17 days later as either resilient or vulnerable to trauma on the basis of their anxiety and arousal scores. Following 2 other weeks, they received an intracerebral infusion of oxytocin (0.1 µg/1 µL) or saline 40 min before their trauma memory was reactivated by exposure to SPS reminders. PTSD-like symptoms and reactivity to PTSD-related cues were examined 3-14 days after oxytocin treatment. Results showed that vulnerable rats treated with saline exhibited a robust PTSD syndrome including increased anxiety and decreased arousal, as well as intense fear reactions to SPS sensory and contextual cues. Exposure to a combination of those cues resulted in c-fos hypo-activation and dendritic arbor retraction in prefrontal cortex and amygdala neurons, relative to resilient rats. Remarkably, 83% of vulnerable rats subjected to oxytocin-based emotional remodeling exhibited a resilient phenotype, and SPS-induced morphological alterations in prelimbic cortex and basolateral amygdala were eliminated. Our findings emphasize the translational potential of the present oxytocin-based emotional remodeling protocol which, when administered even long after the trauma, produces deep reprocessing of traumatic memories and durable attenuation of the PTSD symptomatology.

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Section: Emotional Remodeling With Oxytocin: What Mechanisms?supporting

confidence: 86%

Emotional remodeling with oxytocin durably rescues trauma-induced behavioral and neuro-morphological changes in rats: a promising treatment for PTSD

et al. 2020

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“…Studies that have considered the efficacy of psychotherapeutic interventions following unsuccessful evidencebased PTSD treatment for veterans and other TR-PTSD populations are very scarce [51]. Results of multiple trials with 3,4-methylenedioxymethamphetamine (MDMA)assisted psychotherapy for TR-PTSD were encouraging with large effect sizes [52][53][54][55], and deep brain stimulation shows promise as well, with two positive case reports [56]. Considering that the current trial recruited veterans with, on average, 4 prior unsuccessful treatments and demonstrated a large effect size, 3MDR could prove to be a useful non-invasive, non-pharmacological addition to the toolbox of clinicians working with veterans with TR-PTSD.…”

Section: Interpretation and Comparison To Existing Studiesmentioning

confidence: 99%

Interactive Motion-Assisted Exposure Therapy for Veterans with Treatment-Resistant Posttraumatic Stress Disorder: A Randomized Controlled Trial

Gelderen

Nijdam

Haagen

et al. 2020

Psychother Psychosom

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Background: Veterans with posttraumatic stress disorder (PTSD) tend to benefit less from evidence-based treatments than other PTSD populations. A novel virtual reality and motion-assisted exposure therapy, called 3MDR, provides treatment in an immersive, personalized and activating context. Objective: To study the efficacy of 3MDR for veterans with treatment-resistant PTSD. Method: In a randomized controlled trial (n = 43) 3MDR was compared to a non-specific treatment component control group. Primary outcome was clinician-rated PTSD symptoms at baseline, after 3MDR, and at the 12-week and 16-week follow-up (primary end point). Intention-to-treat analyses of covariance and mixed models were applied to study differences between groups at the end point and over the course of intervention, controlling for baseline scores. Results: The decrease in PTSD symptom severity from baseline to end point was significantly greater for 3MDR as compared to the control group, with a large effect size (F[1, 37] = 6.43, p = 0.016, d = 0.83). No significant between-group difference was detected in the course of PTSD symptoms during treatment when including all time points. The dropout rate was low (7%), and 45% of the patients in the 3MDR group improved clinically. The number needed to treat was 2.86. Conclusions: In this trial, 3MDR significantly decreased PTSD symptoms in veterans with, on average, a history of 4 unsuccessful treatments. The low dropout rate may be indicative of high engagement. However, a lack of significant differences on secondary outcomes limits conclusions that can be drawn on its efficacy and underlines the need for larger phase III trials. These data show emerging evidence for 3MDR and its potential to progress PTSD treatment for veterans (Dutch Trial Register Identifier: NL5126).

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“…For example, greater psilocybin-induced mystical-type experiences and more pronounced and more positive acute alterations of consciousness were associated with lasting antidepressant responses in patients with depression [6,7]. 3,4-Methylenedioxymethamphetamine (MDMA) is the active compound in the recreational substance ecstasy and is currently investigated as an adjunct to psychotherapy to treat posttraumatic stress disorder (PTSD) [12,13]. MDMA not only exhibits some amphetamine-like properties but also shows hallucinogeniclike effects and can be considered an intermediate substance between a pure stimulant like D-amphetamine and a pure hallucinogenic drug like LSD.…”

Section: Introductionmentioning

confidence: 99%

Distinct acute effects of LSD, MDMA, and d-amphetamine in healthy subjects

Holze

Vizeli

Müller

et al. 2019

Neuropsychopharmacol.

181

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Lysergic acid diethylamide (LSD) is a classic psychedelic, 3,4-methylenedioxymethamphetamine (MDMA) is an empathogen, and D-amphetamine is a classic stimulant. All three substances are used recreationally. LSD and MDMA are being investigated as medications to assist psychotherapy, and D-amphetamine is used for the treatment of attention-deficit/hyperactivity disorder. All three substances induce distinct acute subjective effects. However, differences in acute responses to these prototypical psychoactive substances have not been characterized in a controlled study. We investigated the acute autonomic, subjective, and endocrine effects of single doses of LSD (0.1 mg), MDMA (125 mg), D-amphetamine (40 mg), and placebo in a randomized, doubleblind, cross-over study in 28 healthy subjects. All of the substances produced comparable increases in hemodynamic effects, body temperature, and pupil size, indicating equivalent autonomic responses at the doses used. LSD and MDMA increased heart rate more than D-amphetamine, and D-amphetamine increased blood pressure more than LSD and MDMA. LSD induced significantly higher ratings on the 5 Dimensions of Altered States of Consciousness scale and Mystical Experience Questionnaire than MDMA and D-amphetamine. LSD also produced greater subjective drug effects, ego dissolution, introversion, emotional excitation, anxiety, and inactivity than MDMA and D-amphetamine. LSD also induced greater impairments in subjective ratings of concentration, sense of time, and speed of thinking compared with MDMA and D-amphetamine. MDMA produced greater ratings of good drug effects, liking, high, and ego dissolution compared with D-amphetamine. D-Amphetamine increased ratings of activity and concentration compared with LSD. MDMA but not LSD or D-amphetamine increased plasma concentrations of oxytocin. None of the substances altered plasma concentrations of brain-derived neurotrophic factor. These results indicate clearly distinct acute effects of LSD, MDMA, and D-amphetamine and may assist the dose-finding in substance-assisted psychotherapy research.

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3,4-methylenedioxymethamphetamine (MDMA)-assisted psychotherapy for post-traumatic stress disorder in military veterans, firefighters, and police officers: a randomised, double-blind, dose-response, phase 2 clinical trial

Cited by 366 publications

References 27 publications

Emotional remodeling with oxytocin durably rescues trauma-induced behavioral and neuro-morphological changes in rats: a promising treatment for PTSD

Emotional remodeling with oxytocin durably rescues trauma-induced behavioral and neuro-morphological changes in rats: a promising treatment for PTSD

Interactive Motion-Assisted Exposure Therapy for Veterans with Treatment-Resistant Posttraumatic Stress Disorder: A Randomized Controlled Trial

Distinct acute effects of LSD, MDMA, and d-amphetamine in healthy subjects

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