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BackgroundPosttraumatic stress disorder is a prevalent mental health condition with substantial impact on daily functioning that lacks sufficient treatment options. Here we evaluate six phase 2 trials in a pooled analysis to determine the study design for phase 3 trials of MDMA-assisted psychotherapy for PTSD.MethodsSix randomized, double-blind, controlled clinical trials at five study sites were conducted from April 2004 to February 2017. Active doses of MDMA (75–125 mg, n = 72) or placebo/control doses (0–40 mg, n = 31) were administered to individuals with PTSD during manualized psychotherapy sessions in two or three 8-h sessions spaced a month apart. Three non-drug 90-min therapy sessions preceded the first MDMA exposure, and three to four followed each experimental session.ResultsAfter two blinded experimental sessions, the active group had significantly greater reductions in CAPS-IV total scores from baseline than the control group [MMRM estimated mean difference (SE) between groups − 22.0 (5.17), P < 0.001]. The between-group Cohen’s d effect size was 0.8, indicating a large treatment effect. After two experimental sessions, more participants in the active group (54.2%) did not meet CAPS-IV PTSD diagnostic criteria than the control group (22.6%). Depression symptom improvement on the BDI-II was greatest for the active group compared to the control group, although only trended towards significant group differences [MMRM, estimated mean difference (SE) between groups − 6.0 (3.03), P = 0.053]. All doses of MDMA were well tolerated, with some expected reactions occurring at greater frequency for the active MDMA group during experimental sessions and the 7 days following.ConclusionsMDMA-assisted psychotherapy was efficacious and well tolerated in a large sample of adults with PTSD. These studies supported expansion into phase 3 trials and led to FDA granting Breakthrough Therapy designation for this promising treatment.Trial registrationClinicalTrials.gov Identifier: NCT00090064, NCT00353938, NCT01958593, NCT01211405, NCT01689740, NCT01793610.

Rationale Standard therapeutic approaches to reduce social anxiety in autistic adults have limited effectiveness. Since 3,4-methylenedioxymethamphetamine (MDMA)-assisted psychotherapy shows promise as a treatment for other anxiety disorders, a blinded, placebo-controlled pilot study was conducted. Objectives To explore feasibility and safety of MDMA-assisted psychotherapy for reduction of social fear and avoidance that are common in the autistic population. Methods Autistic adults with marked to very severe social anxiety were randomized to receive MDMA (75 to 125 mg, n  = 8) or inactive placebo (0 mg, n  = 4) during two 8-h psychotherapy sessions (experimental sessions) in a controlled clinical setting. Double-blinded experimental sessions were spaced approximately 1 month apart with 3 non-drug psychotherapy sessions following each. The primary outcome was change in Leibowitz Social Anxiety Scale (LSAS) Total scores from Baseline to one month after the second experimental session. Outcomes were measured again six months after the last experimental session. Results Improvement in LSAS scores from baseline to the primary endpoint was significantly greater for MDMA group compared to the placebo group ( P  = 0.037), and placebo-subtracted Cohen’s d effect size was very large ( d  = 1.4, CI − 0.074, 2.874). Change in LSAS scores from baseline to 6-month follow-up showed similar positive results ( P  = 0.036), with a Cohen’s d effect size of 1.1 (CI − 0.307, 2.527). Social anxiety remained the same or continued to improve slightly for most participants in the MDMA group after completing the active treatment phase. Conclusions This pilot trial demonstrated rapid and durable improvement in social anxiety symptoms in autistic adults following MDMA-assisted psychotherapy. Initial safety and efficacy outcomes support expansion of research into larger samples to further investigate this novel treatment for social anxiety. Trial registration clinicaltrials.gov identifier, NCT02008396

RationalePosttraumatic stress disorder (PTSD) is a chronic condition that has wide-ranging negative effects on an individual’s health and interpersonal relationships. Treatments with long-term benefits are needed to promote the safety and well-being of those suffering from PTSD.ObjectivesTo examine long-term change in PTSD symptoms and additional benefits/harms after 3,4-methylenedioxymethamphetamine (MDMA)-assisted psychotherapy for treatment of PTSD.MethodsParticipants received two to three active doses of MDMA (75–125 mg) during blinded or open-label psychotherapy sessions with additional non-drug therapy sessions. PTSD symptoms were assessed using the Clinician-Administered PTSD Scale for DSM IV (CAPS-IV) at baseline, 1 to 2 months after the last active MDMA session (treatment exit), and at least 12 months post final MDMA session (LTFU). A mixed-effect repeated-measures (MMRM) analysis assessed changes in CAPS-IV total severity scores. The number of participants who met PTSD diagnostic criteria was summarized at each time point. Participants completed a long-term follow-up questionnaire.ResultsThere was a significant reduction in CAPS-IV total severity scores from baseline to treatment exit (LS mean (SE) = − 44.8 (2.82), p < .0001), with a Cohen’s d effect size of 1.58 (95% CI = 1.24, 1.91). CAPS-IV scores continued to decrease from treatment exit to LTFU (LS mean (SE) = − 5.2 (2.29), p < .05), with a Cohen’s d effect size of 0.23 (95% CI = 0.04, 0.43). The number of participants who no longer met PTSD criteria increased from treatment exit (56.0%) to LTFU (67.0%). The majority of participants reported benefits, including improved relationships and well-being, and a minority reported harms from study participation.ConclusionsPTSD symptoms were reduced 1 to 2 months after MDMA-assisted psychotherapy, and symptom improvement continued at least 12 months post-treatment. Phase 3 trials are investigating this novel treatment approach in a larger sample of participants with chronic PTSD.Trial registrationclinicaltrials.gov Identifier: NCT00090064, NCT00353938, NCT01958593, NCT01211405, NCT01689740, NCT01793610

The phenylethylamine, 3,4-methylenedioxymethamphetamine (MDMA, ‘ecstasy’), is the prototypical example of an entactogen. Its original placement in highly restrictive drug usage categories in the US and UK, led to an inevitable restriction on MDMA neuroscience research and treatment. The dominant pharmacological effects of MDMA are its properties of release and inhibition of reuptake of amine neurotransmitter transporters for dopamine, norepinephrine, and serotonin. MDMA is an agonist of a wide range of receptors; its mood-altering effects are mediated via 5-HT2A receptors; this receptor may also mediate its effects on body temperature, analgesia, and anxiolytic properties. The mechanisms underlying MDMA’s entactogenic properties of sociability and interpersonal closeness are not known but release and involvement of oxytocin, a peptide thought by some to be involved in social bonding, has been suggested. Adverse effects of MDMA are mostly transient; acute multiorgan adverse effects occurring during raves or crowded dance gatherings include dehydration, hyperthermia, seizures, rhabdomyolysis, disseminated intravascular coagulation, and acute renal failure. Deaths following MDMA taken by itself are rare compared to fatalities following coadministration with other drugs. A recent FDA-approved phase 3 clinical trial of MDMA for post-traumatic stress disorder (PTSD) led to the conclusion that MDMA-assisted therapy represents a potential breakthrough treatment meriting expedited clinical evaluation. Despite the ongoing deliberations by the FDA and EMA for approval of MDMA treatment of PTSD, the Australian Therapeutic Goods Administration (TGA) recently announced that after an evaluation of the therapeutic value, benefits, and risks of MDMA, it will permit its prescribing for the treatment of PTSD. Further examples of regulatory relaxation toward MDMA-assisted psychotherapy are underway. These include the FDA’s recently approved clinical trial to assess MDMA’s efficacy in the treatment of “asociality” in patients with schizophrenia and an open trial of MDMA treatment for alcohol-use disorder which showed decreased alcohol consumption. There are also ongoing studies on the little understood startle response, anxiety associated with life-threatening illness, and social anxiety in autistic adults.

MDMA-assisted psychotherapy (MDMA-AP) is a combined psychotherapeutic and pharmacologic intervention that shows promise in the treatment of posttraumatic stress disorder (PTSD). Although therapeutic alliance has been established as a key predictor across psychotherapies and is emphasised within MDMA-AP treatment manuals, research has not yet examined the relationship between therapeutic alliance and MDMA-AP treatment outcomes. Examine whether therapeutic alliance predicts changes in PTSD symptoms following MDMA-AP. Twenty-three individuals with chronic PTSD participated in a MDMA-AP clinical trial that included a randomised (MDMA vs. placebo) and open-label phase. The present analyses focused on participants who were administered MDMA over the course of the randomised and open-label phases (  = 22). Therapeutic alliance was assessed using the Working Alliance Inventory at sessions baseline (pre-session 3) and sessions 4 and 9. PTSD symptoms were assessed using the Clinician Administered PTSD Scale and the Impact of Events Scale-Revised. Controlling for baseline clinician-assessed PTSD severity, therapeutic alliance at sessions 4 and 9 (but not baseline) significantly predicted post-MDMA-AP clinician-assessed PTSD severity. Controlling for baseline self-reported PTSD severity, therapeutic alliance at baseline (although this did not survive correction for multiple comparisons) and sessions 4 and 9 predicted post-MDMA-AP self-reported PTSD severity. The present results provide the first preliminary evidence for the relationship between the therapeutic alliance and treatment outcomes within MDMA-AP for PTSD. These findings highlight the important role of psychotherapy, and common psychotherapeutic factors, within MDMA-AP. Replication in studies with larger and more diverse clinical samples remain necessary. ClinicalTrials.gov identifier: NCT00090064.

Background PTSD is a chronic condition with high rates of comorbidity, but current treatment options are limited and not always effective. One novel approach is MDMA-assisted psychotherapy for people diagnosed with treatment-resistant PTSD, where MDMA is used as a catalyst to facilitate trauma processing during psychotherapy. The aim was to review all current research into MDMA-assisted psychotherapy for PTSD. Methods Articles were identified through PubMed and Science Direct for items published up to 31st March 2019 using terms “treatments for PTSD”, “drug treatments for PTSD”, “MDMA”, “MDMA pathway”, “MDMA-assisted psychotherapy” and “MDMA-assisted psychotherapy for PTSD”. Articles were identified through Google Scholar and subject-specific websites. Articles and relevant references cited in those articles were reviewed. Results Small-scale studies have shown reduced psychological trauma, however there has been widespread misunderstanding of the aims and implications of this work, most commonly the notion that MDMA is a ‘treatment for PTSD’, which to date has not been researched. This has harmful consequences, namely dangerous media reporting and impeding research progression in an already controversial field. Conclusions MDMA-assisted psychotherapy may help people who have experienced psychological trauma and who have not been able to resolve their problems through existing treatments, however more research is needed. If this is to get appropriate research attention, we must report this accurately and objectively.

This chapter explores the complex and controversial path of MDMA-assisted therapy (MDMA-AT) for treating post-traumatic stress disorder (PTSD) and other behavioral disorders. It covers MDMA’s history from research to recreation to medicine, the pivotal trials, and the challenges faced by researchers. Despite recent setbacks for the clinical application of MDMA, the chapter argues that it holds potential for transforming psychiatry and discusses the uncertain future amidst ongoing debates over ethics, methodology, and political influence.

The present paper discusses the current literature with regard to substance-assisted psychotherapy with Methylenedioxymethamphetamine (MDMA) for posttraumatic stress disorder (PTSD). The aim of the paper is to give a comprehensive overview of the development from MDMA’s early application in psychotherapy to its present and future role in the treatment of PTSD. It is further attempted to increase the attention for MDMA’s therapeutic potential by providing a thorough depiction of the scientific evidence regarding its theorized mechanism of action and potential harms of its application in the clinical setting (e.g., misattribution of therapeutic gains to medication instead of psychological changes). Empirical support for the use of MDMA-assisted psychotherapy, including the randomized, double-blind, placebo-controlled trails that have been conducted since 2008, is discussed. Thus far, an overall remission rate of 66.2% and low rates of adverse effects have been found in the six phase two trials conducted in clinical settings with 105 blinded subjects with chronic PTSD. The results seem to support MDMA’s safe and effective use as an adjunct to psychotherapy. Even though preliminary studies may look promising, more studies of its application in a psychotherapeutic context are needed in order to establish MDMA as a potential adjunct to therapy.