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Midomafetamine (3,4-methylenedioxymethamphetamine [MDMA]) is under the U.S. Food and Drug Administration review for treatment of post-traumatic stress disorder in adults. MDMA is metabolized by CYP2D6 and is a strong inhibitor of CYP2D6, as well as a weak inhibitor of renal transporters MATE1, OCT1, and OCT2. A pharmacokinetic phase I study was conducted to evaluate the effects of food on MDMA pharmacokinetics. The results of this study, previously published pharmacokinetic data, and in vitro data were combined to develop and verify MDMA population pharmacokinetic and physiologically based pharmacokinetic models. The food effect study demonstrated that a high-fat/high-calorie meal did not alter MDMA plasma concentrations, but delayed T max . The population pharmacokinetic model did not identify any clinically meaningful covariates, including age, weight, sex, race, and fed status. The physiologically based pharmacokinetic model simulated pharmacokinetics for the proposed 120 and 180 mg MDMA HCl clinical doses under single- and split-dose (2 h apart) conditions, indicating minor differences in overall exposure, but lower AUC within the first 4 h and delayed T max when administered as a split dose compared to a single dose. The physiologically based pharmacokinetic model also investigated the drug-drug interaction magnitude by varying the fraction metabolized by a representative CYP2D6 substrate (atomoxetine) and evaluated inhibition of renal transporters. The simulations confirm MDMA is a potent CYP2D6 inhibitor, but likely has no meaningful impact on the pharmacokinetics of drugs sensitive to renal transport. This model-informed drug development approach was employed to inform drug-drug interaction potential and predict pharmacokinetics of clinically relevant dosing regimens of MDMA., (© 2024 Lykos Therapeutics. CPT: Pharmacometrics & Systems Pharmacology published by Wiley Periodicals LLC on behalf of American Society for Clinical Pharmacology and Therapeutics.)

This multi-site, randomized, double-blind, confirmatory phase 3 study evaluated the efficacy and safety of 3,4-methylenedioxymethamphetamine-assisted therapy (MDMA-AT) versus placebo with identical therapy in participants with moderate to severe post-traumatic stress disorder (PTSD). Changes in Clinician-Administered PTSD Scale for DSM-5 (CAPS-5) total severity score (primary endpoint) and Sheehan Disability Scale (SDS) functional impairment score (key secondary endpoint) were assessed by blinded independent assessors. Participants were randomized to MDMA-AT (n = 53) or placebo with therapy (n = 51). Overall, 26.9% (28/104) of participants had moderate PTSD, and 73.1% (76/104) of participants had severe PTSD. Participants were ethnoracially diverse: 28 of 104 (26.9%) identified as Hispanic/Latino, and 35 of 104 (33.7%) identified as other than White. Least squares (LS) mean change in CAPS-5 score (95% confidence interval (CI)) was -23.7 (-26.94, -20.44) for MDMA-AT versus -14.8 (-18.28, -11.28) for placebo with therapy (P < 0.001, d = 0.7). LS mean change in SDS score (95% CI) was -3.3 (-4.03, -2.60) for MDMA-AT versus -2.1 (-2.89, -1.33) for placebo with therapy (P = 0.03, d = 0.4). Seven participants had a severe treatment emergent adverse event (TEAE) (MDMA-AT, n = 5 (9.4%); placebo with therapy, n = 2 (3.9%)). There were no deaths or serious TEAEs. These data suggest that MDMA-AT reduced PTSD symptoms and functional impairment in a diverse population with moderate to severe PTSD and was generally well tolerated. ClinicalTrials.gov identifier: NCT04077437 ., (© 2023. This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply.)

Post-traumatic stress disorder (PTSD) presents a major public health problem for which currently available treatments are modestly effective. We report the findings of a randomized, double-blind, placebo-controlled, multi-site phase 3 clinical trial (NCT03537014) to test the efficacy and safety of 3,4-methylenedioxymethamphetamine (MDMA)-assisted therapy for the treatment of patients with severe PTSD, including those with common comorbidities such as dissociation, depression, a history of alcohol and substance use disorders, and childhood trauma. After psychiatric medication washout, participants ( n = 90) were randomized 1:1 to receive manualized therapy with MDMA or with placebo, combined with three preparatory and nine integrative therapy sessions. PTSD symptoms, measured with the Clinician-Administered PTSD Scale for DSM-5 (CAPS-5, the primary endpoint), and functional impairment, measured with the Sheehan Disability Scale (SDS, the secondary endpoint) were assessed at baseline and at 2 months after the last experimental session. Adverse events and suicidality were tracked throughout the study. MDMA was found to induce significant and robust attenuation in CAPS-5 score compared with placebo ( P < 0.0001, d = 0.91) and to significantly decrease the SDS total score ( P = 0.0116, d = 0.43). The mean change in CAPS-5 scores in participants completing treatment was -24.4 (s.d. 11.6) in the MDMA group and -13.9 (s.d. 11.5) in the placebo group. MDMA did not induce adverse events of abuse potential, suicidality or QT prolongation. These data indicate that, compared with manualized therapy with inactive placebo, MDMA-assisted therapy is highly efficacious in individuals with severe PTSD, and treatment is safe and well-tolerated, even in those with comorbidities. We conclude that MDMA-assisted therapy represents a potential breakthrough treatment that merits expedited clinical evaluation. Appeared originally in Nat Med 2021; 27:1025-1033 ., (Copyright © 2023 by the American Psychiatric Association.)

Unsuccessfully treated posttraumatic stress disorder (PTSD) is a serious and life-threatening disorder. Two medications, paroxetine hydrochloride and sertraline hydrochloride, are approved treatments for PTSD by the Food and Drug Administration (FDA). Analyses of pharmacotherapies for PTSD found only small to moderate effects when compared with placebo. The Multidisciplinary Association for Psychedelic Studies (MAPS) obtained Breakthrough Therapy Designation (BTD) from the FDA for 3,4-methylenedioxymethamphetamine (MDMA)-assisted psychotherapy for treatment of PTSD on the basis of pooled analyses showing a large effect size for this treatment. This review covers data supporting BTD. In this treatment, MDMA is administered with psychotherapy in up to three monthly 8-h sessions. Participants are prepared for these sessions beforehand, and process material arising from the sessions in follow-up integrative psychotherapy sessions. Comparing data used for the approval of paroxetine and sertraline and pooled data from Phase 2 studies, MAPS demonstrated that MDMA-assisted psychotherapy constitutes a substantial improvement over available pharmacotherapies in terms of safety and efficacy. Studies of MDMA-assisted psychotherapy had lower dropout rates compared to sertraline and paroxetine trials. As MDMA is only administered under direct observation during a limited number of sessions, there is little chance of diversion, accidental or intentional overdose, or withdrawal symptoms upon discontinuation. BTD status has expedited the development of MAPS phase 3 trials occurring worldwide, leading up to a planned submission seeking FDA approval in 2021. Appeared originally in Front Psychiatry 2019 ; 10:650 ., (Copyright © 2023 by the American Psychiatric Association.)

Background: Previous research has demonstrated that epigenetic changes in specific hypothalamic-pituitary-adrenal (HPA) genes may predict successful psychotherapy in post-traumatic stress disorder (PTSD). A recent Phase 3 clinical trial reported high efficacy of 3,4-methylenedioxymethamphetamine (MDMA)-assisted therapy for treating patients with severe PTSD compared to a therapy with placebo group (NCT03537014). This raises important questions regarding potential mechanisms of MDMA-assisted therapy. In the present study, we examined epigenetic changes in three key HPA axis genes before and after MDMA and placebo with therapy. As a pilot sub-study to the parent clinical trial, we assessed potential HPA epigenetic predictors for treatment response with genomic DNA derived from saliva (MDMA, n = 16; placebo, n = 7). Methylation levels at all 259 CpG sites annotated to three HPA genes ( CRHR1 , FKBP5 , and NR3C1 ) were assessed in relation to treatment response as measured by the Clinician-Administered PTSD Scale (CAPS-5; Total Severity Score). Second, group (MDMA vs. placebo) differences in methylation change were assessed for sites that predicted treatment response., Results: Methylation change across groups significantly predicted symptom reduction on 37 of 259 CpG sites tested, with two sites surviving false discovery rate (FDR) correction. Further, the MDMA-treatment group showed more methylation change compared to placebo on one site of the NR3C1 gene., Conclusion: The findings of this study suggest that therapy-related PTSD symptom improvements may be related to DNA methylation changes in HPA genes and such changes may be greater in those receiving MDMA-assisted therapy. These findings can be used to generate hypothesis driven analyses for future studies with larger cohorts., Competing Interests: BY-K and CH received payment for full-time employment from the MAPS or the MAPS Public Benefit Corporation throughout their work on the parent trial. JT is the Executive Director of Modern Spirit, the non-profit organization that funded this study. BC is on the Board of Directors for Modern Spirit. 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., (Copyright © 2023 Lewis, Tafur, Spencer, Green, Harrison, Kelmendi, Rabin, Yehuda, Yazar-Klosinski and Cahn.)

Introduction: 3,4-methylenedioxymethamphetamine-assisted therapy (MDMA-AT) for post-traumatic stress disorder (PTSD) has demonstrated promise in multiple clinical trials. MDMA is hypothesized to facilitate the therapeutic process, in part, by decreasing fear response during fear memory processing while increasing extinction learning. The acute administration of MDMA in healthy controls modifies recruitment of brain regions involved in the hyperactive fear response in PTSD such as the amygdala, hippocampus, and insula. However, to date there have been no neuroimaging studies aimed at directly elucidating the neural impact of MDMA-AT in PTSD patients., Methods: We analyzed brain activity and connectivity via functional MRI during both rest and autobiographical memory (trauma and neutral) response before and two-months after MDMA-AT in nine veterans and first-responders with chronic PTSD of 6 months or more., Results: We hypothesized that MDMA-AT would increase amygdala-hippocampus resting-state functional connectivity, however we only found evidence of a trend in the left amygdala-left hippocampus ( t = -2.91, uncorrected p = 0.0225, corrected p = 0.0901). We also found reduced activation contrast (trauma > neutral) after MDMA-AT in the cuneus. Finally, the amount of recovery from PTSD after MDMA-AT correlated with changes in four functional connections during autobiographical memory recall: the left amygdala-left posterior cingulate cortex (PCC), left amygdala-right PCC, left amygdala-left insula, and left isthmus cingulate-left posterior hippocampus., Discussion: Amygdala-insular functional connectivity is reliably implicated in PTSD and anxiety, and both regions are impacted by MDMA administration. These findings compliment previous research indicating that amygdala, hippocampus, and insula functional connectivity is a potential target of MDMA-AT, and highlights other regions of interest related to memory processes. More research is necessary to determine if these findings are specific to MDMA-AT compared to other types of treatment for PTSD., Clinical Trial Registration: https://clinicaltrials.gov/ct2/show/NCT02102802, identifier NCT02102802., Competing Interests: MM was paid as a contractor by MAPS PBC. AE, AC, and JW received salary support for full-time employment with MAPS PBC. BY-K and RD received salary support for full-time employment with MAPS. MM is on the Clinical Advisory Board of Awakn Life Sciences. 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., (Copyright © 2023 Singleton, Wang, Mithoefer, Hanlon, George, Mithoefer, Mithoefer, Coker, Yazar-Klosinski, Emerson, Doblin and Kuceyeski.)

Introduction: Increasing evidence demonstrates 3,4-methylenedioxymethamphetamine (MDMA)-assisted therapy (MDMA-AT) may be a safe and effective treatment for post-traumatic stress disorder (PTSD). There is growing interest in MDMA-AT to address a range of other health challenges. Chronic pain and PTSD are frequently comorbid, reciprocally interdependent conditions, though the possible role of MDMA-AT in treating chronic pain remains under-investigated. The present analysis examined the impact of manualized MDMA-AT on chronic pain severity among participants with PTSD who were enrolled in a Phase 2 clinical trial investigating MDMA-AT for PTSD (NCT03282123)., Materials and Methods: Exploratory data from a subset of participants who completed chronic pain measures ( n = 32) were drawn from a Phase 2 open-label study sponsored by the Multidisciplinary Association for Psychedelic Studies (MAPS). Multivariable analysis of variance (ANOVA) was utilized to compare pre- vs. post-treatment Chronic Pain Grade Scale (CPGS) values, adjusting for demographics (age, sex, and ethnicity). K-means clustering was then used to group the sample into three clusters to denote high ( n = 9), medium ( n = 11), and low ( n = 12) baseline pain severity, and the same analysis was repeated for each cluster., Results: Among the 32 participants included in this analysis, 59% ( n = 19) were women, 72% ( n = 23) were white, and median age was 38 years [interquartile range (IQR) = 31-47]. Overall, 84% ( n = 27) reported having pain, and 75% ( n = 24) reported disability associated with their pain. Significant reductions in CPGS subscales for pain intensity and disability score , and overall CPGS severity grade were observed among participants in the highest pain cluster ( n = 9, p < 0.05), and for pain intensity in the medium pain cluster ( n = 11, p < 0.05) post- vs. pre-treatment., Discussion: Findings demonstrate a high prevalence of chronic pain in this sample of people with severe PTSD and that chronic pain scores among medium and high pain subgroups were significantly lower following MDMA-AT. While these data are preliminary, when considered alongside the frequency of comorbid chronic pain and PTSD and promising efficacy of MDMA-AT for treating PTSD, these findings encourage further research exploring the role of MDMA-AT for chronic pain., Competing Interests: Author BY-K was employed by the company MAPS Public Benefit Corporation. Author WS was employed by Will Siu, MD Inc. Authors EA and DC were part-time consultants, and PK was a Clinical Advisor, to Numinus Wellness Inc. 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., (Copyright © 2022 Christie, Yazar-Klosinski, Nosova, Kryskow, Siu, Lessor and Argento.)

Background: Limited ethnoracial diversity in previous ±3,4-methylenedioxymethamphetamine-assisted therapy (MDMA-AT) trials for posttraumatic stress disorder (PTSD) has prompted questions concerning whether Black, Indigenous, and People of Color (BIPOC) also benefit from this treatment., Methods: Secondary analysis was conducted using a modified intent-to-treat sample pooled from two Phase 2 open-label trials and a Phase 3 randomized, blinded placebo-controlled trial to compare efficacy and safety of MDMA-AT for PTSD between BIPOC and non-Hispanic White participants. Four subgroups were of interest: MDMA-AT, BIPOC ( n  = 20); MDMA-AT, non-Hispanic White ( n  = 63); Placebo-assisted therapy (Placebo-AT), BIPOC ( n  = 17); and Placebo-AT, non-Hispanic White ( n  = 27). Planned comparisons tested subgroup differences in changes in Clinician-Administered PTSD Scale for DSM-5 (CAPS-5) scores from baseline to primary endpoint, controlling for study type and baseline scores. Adverse events (AEs) on the day of (day 0) to 2 days post-dosing were reported for each subgroup., Results: In the MDMA-AT group, no significant ethnoracial difference in CAPS-5 change scores was observed. In the Placebo-AT group, BIPOC participants trended toward greater reductions in CAPS-5 scores than non-Hispanic Whites. Among non-Hispanic Whites, MDMA-AT was accompanied by significantly greater reductions in CAPS-5 scores than Placebo-AT. No treatment difference emerged among BIPOC participants. AEs were mostly rated as mild or moderate across subgroups., Conclusions: These findings provide preliminary support for the efficacy and safety of MDMA-AT for treating PTSD across ethnoracial groups. There was also a trend toward greater efficacy with Placebo-AT among BIPOC participants. There was an imbalance in subgroups, highlighting the need for culturally responsive recruitment strategies to diversify future studies.

Background: Post-traumatic stress disorder (PTSD) is commonly associated with alcohol and substance use disorders (ASUD). A randomized, placebo-controlled, phase 3 trial demonstrated the safety and efficacy of MDMA-assisted therapy (MDMA-AT) for the treatment of severe PTSD. This analysis explores patterns of alcohol and substance use in patients receiving MDMA-AT compared to placebo plus therapy (Placebo+Therapy)., Methods: Adult participants with severe PTSD (n = 90) were randomized to three blinded trauma-focused therapy sessions with either MDMA-AT or Placebo+Therapy. Eligible participants met DSM-5 criteria for severe PTSD and could meet criteria for mild (current) or moderate (early remission) alcohol or cannabis use disorder; other SUDs were excluded. The current analyses examined outcomes on standardized measures of hazardous alcohol (i.e., Alcohol Use Disorder Identification Test; AUDIT) and drug (i.e., Drug Use Disorder Identification Test; DUDIT) use at baseline prior to randomization and at study termination., Results: There were no treatment group differences in AUDIT or DUDIT scores at baseline. Compared to Placebo+therapy, MDMA-AT was associated with a significantly greater reduction in mean (SD) AUDIT change scores (Δ = -1.02 (3.52) as compared to placebo (Δ = 0.40 (2.70), F (80, 1) = 4.20, p = 0.0436; Hedge's g= .45). Changes in DUDIT scores were not significantly different between treatment groups., Conclusions: MDMA-AT for severe PTSD may also lead to subclinical improvements in alcohol use. MDMA-AT does not appear to increase risk of illicit drug use. These data provide preliminary evidence to support the development of MDMA-AT as an integrated treatment for co-occurring PTSD and ASUD., (Copyright © 2022 The Authors. Published by Elsevier B.V. All rights reserved.)

MDMA is increasingly used in clinical research, but no cGMP process has yet been reported. We describe here the first fully validated cGMP synthesis of up to 5 kg (≈30 000 patient doses) of MDMA in a four-step process beginning with a noncontrolled starting material. The overall yield was acceptable (41-53%, over four steps), and the chemical purity of the final product was excellent, exceeding 99.9% of the peak area by HPLC in each of the four validation trials. The availability of cGMP-compliant MDMA will facilitate ongoing clinical trials and provide for future therapeutic use, if encouraging results lead to FDA approval., Competing Interests: The authors declare no competing financial interest., (© 2021 The Authors. Published by American Chemical Society.)

3,4 Methylenedioxymethamphetamine (MDMA)-assisted therapy has been recently found to be highly effective for treatment of posttraumatic stress disorder (PTSD). Previous studies have been inconclusive in elucidating potential MDMA genotoxicity. We performed three regulatory compliant studies to investigate the potential of genotoxic effects of MDMA treatment in humans: (1) an in vitro bacterial reverse mutation (Ames) assay, (2) an in vitro chromosome aberration test in Chinese hamster ovary cells, and (3) an in vivo micronucleus study in male Sprague Dawley rats. MDMA was found to not have genotoxic effects in any of the assays at or above clinically relevant concentrations.

Post-traumatic stress disorder (PTSD) presents a major public health problem for which currently available treatments are modestly effective. We report the findings of a randomized, double-blind, placebo-controlled, multi-site phase 3 clinical trial (NCT03537014) to test the efficacy and safety of 3,4-methylenedioxymethamphetamine (MDMA)-assisted therapy for the treatment of patients with severe PTSD, including those with common comorbidities such as dissociation, depression, a history of alcohol and substance use disorders, and childhood trauma. After psychiatric medication washout, participants (n = 90) were randomized 1:1 to receive manualized therapy with MDMA or with placebo, combined with three preparatory and nine integrative therapy sessions. PTSD symptoms, measured with the Clinician-Administered PTSD Scale for DSM-5 (CAPS-5, the primary endpoint), and functional impairment, measured with the Sheehan Disability Scale (SDS, the secondary endpoint) were assessed at baseline and at 2 months after the last experimental session. Adverse events and suicidality were tracked throughout the study. MDMA was found to induce significant and robust attenuation in CAPS-5 score compared with placebo (P < 0.0001, d = 0.91) and to significantly decrease the SDS total score (P = 0.0116, d = 0.43). The mean change in CAPS-5 scores in participants completing treatment was -24.4 (s.d. 11.6) in the MDMA group and -13.9 (s.d. 11.5) in the placebo group. MDMA did not induce adverse events of abuse potential, suicidality or QT prolongation. These data indicate that, compared with manualized therapy with inactive placebo, MDMA-assisted therapy is highly efficacious in individuals with severe PTSD, and treatment is safe and well-tolerated, even in those with comorbidities. We conclude that MDMA-assisted therapy represents a potential breakthrough treatment that merits expedited clinical evaluation.

Importance: There is a pressing need for development of novel pharmacology for the treatment of Posttraumatic Stress Disorder (PTSD). Given increasing use of medical cannabis among US military veterans to self-treat PTSD, there is strong public interest in whether cannabis may be a safe and effective treatment for PTSD., Objective: The aim of the present study was to collect preliminary data on the safety and potential efficacy of three active concentrations of smoked cannabis (i.e., High THC = approximately 12% THC and < 0.05% CBD; High CBD = 11% CBD and 0.50% THC; THC+CBD = approximately 7.9% THC and 8.1% CBD, and placebo = < 0.03% THC and < 0.01% CBD) compared to placebo in the treatment of PTSD among military veterans., Methods: The study used a double-blind, cross-over design, where participants were randomly assigned to receive three weeks of either active treatment or placebo in Stage 1 (N = 80), and then were re-randomized after a 2-week washout period to receive one of the other three active treatments in Stage 2 (N = 74). The primary outcome measure was change in PTSD symptom severity from baseline to end of treatment in Stage 1., Results: The study did not find a significant difference in change in PTSD symptom severity between the active cannabis concentrations and placebo by the end of Stage 1. All three active concentrations of smoked cannabis were generally well tolerated., Conclusions and Relevance: The present study is the first randomized placebo-controlled trial of smoked cannabis for PTSD. All treatment groups, including placebo, showed good tolerability and significant improvements in PTSD symptoms during three weeks of treatment, but no active treatment statistically outperformed placebo in this brief, preliminary trial. Additional well-controlled and adequately powered studies with cannabis suitable for FDA drug development are needed to determine whether smoked cannabis improves symptoms of PTSD., Trial Registration: Identifier: NCT02759185; ClinicalTrials.gov., Competing Interests: Author MBM is an employee of Canopy Growth Corporation, during which time he has received stock options, serves on the Board of Directors for AusCann Group Holdings Limited, was a prior employee of Zynerba Pharmaceuticals, and has received consulting fees from Tilray Inc. Author ML serves on the scientific advisory board for FSD Pharma and has received consulting fees from Greenwich Biosciences, Zynerba Pharmaceuticals, and Tilray Inc in the past two years. Authors RD, BY, JW, BS, CH, RM, and AE receive salary from the Multidisciplinary Association for Psychedelic Studies (MAPS), a 501(c)(3) non-profit research and educational organization. Author SS receives salary from the Scottsdale Research Institute, which is a private LLC and has no shareholders. The Academic Editor, BLF, co-authored "The state of clinical outcome assessments for cannabis use disorder clinical trials: A review and research agenda" (https://pubmed.ncbi.nlm.nih.gov/32360455/) with one of the authors, MBM. This article was a result of a meeting where a large number of investigators came together to discuss clinical trial outcomes with representative from NIH and FDA. No other relationship between this author and the Academic Editor exists. This does not alter our adherence to PLOS ONE policies on sharing data and materials.

Cognitive-behavioural conjoint therapy (CBCT) for PTSD has been shown to improve PTSD, relationship adjustment, and the health and well-being of partners. MDMA (3,4-methylenedioxymethamphetamine) has been used to facilitate an individual therapy for PTSD. This study was an initial test of the safety, tolerability, and efficacy of MDMA-facilitated CBCT. Six couples with varying levels of baseline relationship satisfaction in which one partner was diagnosed with PTSD participated in a condensed version of the 15-session CBCT protocol delivered over 7 weeks. There were two sessions in which both members of the couple were administered MDMA. All couples completed the treatment protocol, and there were no serious adverse events in either partner. There were significant improvements in clinician-assessed, patient-rated, and partner-rated PTSD symptoms (pre- to post-treatment/follow-up effect sizes ranged from d = 1.85-3.59), as well as patient depression, sleep, emotion regulation, and trauma-related beliefs. In addition, there were significant improvements in patient and partner-rated relationship adjustment and happiness ( d =.64-2.79). These results are contextualized in relation to prior results from individual MDMA-facilitated psychotherapy and CBCT for PTSD alone. MDMA holds promise as a facilitator of CBCT to achieve more robust and broad effects on individual and relational functioning in those with PTSD and their partners., (© 2020 Informa UK Limited, trading as Taylor & Francis.)

The success of modern medicine creates a growing population of those suffering from life-threatening illnesses (LTI) who often experience anxiety, depression, and existential distress. We present a novel approach; investigating MDMA-assisted psychotherapy for the treatment of anxiety in people with an LTI. Participants with anxiety from an LTI were randomized in a double-blind study to receive MDMA (125 mg, n = 13) or placebo (n = 5) in combination with two 8-h psychotherapy sessions. The primary outcome was change in State-Trait Anxiety Inventory (STAI) Trait scores from baseline to one month post the second experimental session. After unblinding, participants in the MDMA group had one open-label MDMA session and placebo participants crossed over to receive three open-label MDMA sessions. Additional follow-up assessments occurred six and twelve months after a participant's last experimental session. At the primary endpoint, the MDMA group had a greater mean (SD) reduction in STAI-Trait scores, - 23.5 (13.2), indicating less anxiety, compared to placebo group, - 8.8 (14.7); results did not reach a significant group difference (p = .056). Hedges' g between-group effect size was 1.03 (95% CI: - 5.25, 7.31). Overall, MDMA was well-tolerated in this sample. These preliminary findings can inform development of larger clinical trials to further examine MDMA-assisted psychotherapy as a novel approach to treat individuals with LTI-related anxiety.Trial Registration: clinicaltrials.gov Identifier: NCT02427568, first registered April 28, 2015.

Background: Chronic posttraumatic stress disorder (PTSD) is a disabling condition that generates considerable morbidity, mortality, and both medical and indirect social costs. Treatment options are limited. A novel therapy using 3,4-methylenedioxymethamphetamine (MDMA) has shown efficacy in six phase 2 trials. Its cost-effectiveness is unknown., Methods and Findings: To assess the cost-effectiveness of MDMA-assisted psychotherapy (MAP) from the health care payer's perspective, we constructed a decision-analytic Markov model to portray the costs and health benefits of treating patients with chronic, severe, or extreme, treatment-resistant PTSD with MAP. In six double-blind phase 2 trials, MAP consisted of a mean of 2.5 90-minute trauma-focused psychotherapy sessions before two 8-hour sessions with MDMA (mean dose of 125 mg), followed by a mean of 3.5 integration sessions for each active session. The control group received an inactive placebo or 25-40 mg. of MDMA, and otherwise followed the same regimen. Our model calculates net medical costs, mortality, quality-adjusted life-years (QALYs), and incremental cost-effectiveness ratios. Efficacy was based on the pooled results of six randomized controlled phase 2 trials with 105 subjects; and a four-year follow-up of 19 subjects. Other inputs were based on published literature and on assumptions when data were unavailable. We modeled results over a 30-year analytic horizon and conducted extensive sensitivity analyses. Our model calculates expected medical costs, mortality, quality-adjusted life-years (QALYs), and incremental cost-effectiveness ratio. Future costs and QALYs were discounted at 3% per year. For 1,000 individuals, MAP generates discounted net savings of $103.2 million over 30 years while accruing 5,553 discounted QALYs, compared to continued standard of care. MAP breaks even on cost at 3.1 years while delivering 918 QALYs. Making the conservative assumption that benefits cease after one year, MAP would accrue net costs of $7.6 million while generating 288 QALYS, or $26,427 per QALY gained., Conclusion: MAP provided to patients with severe or extreme, chronic PTSD appears to be cost-saving while delivering substantial clinical benefit. Third-party payers are likely to save money within three years by covering this form of therapy., Competing Interests: The authors have declared that no competing interests exist.

Rationale: Posttraumatic 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., Objectives: To examine long-term change in PTSD symptoms and additional benefits/harms after 3,4-methylenedioxymethamphetamine (MDMA)-assisted psychotherapy for treatment of PTSD., Methods: Participants 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., Results: There 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., Conclusions: PTSD 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 Registration: clinicaltrials.gov Identifier: NCT00090064, NCT00353938, NCT01958593, NCT01211405, NCT01689740, NCT01793610.

3,4-Methylenedioxymethamphetamine (MDMA)-assisted psychotherapy for posttraumatic stress disorder (PTSD) has been shown to significantly reduce clinical symptomatology, but posttraumatic growth (PTG), which consists of positive changes in self-perception, interpersonal relationships, or philosophy of life, has not been studied with this treatment. Participant data (n = 60) were pooled from three Phase 2 clinical studies employing triple-blind crossover designs. Participants were required to meet DSM-IV-R criteria for PTSD with a score higher than 50 on the Clinician-Administered PTSD Scale (CAPS-IV) as well as previous inadequate response to pharmacological and/or psychotherapeutic treatment. Data were aggregated into two groups: an active MDMA dose group (75-125 mg of MDMA; n = 45) or placebo/active control (0-40 mg of MDMA; n = 15). Measures included the Posttraumatic Growth Inventory (PTGI) and the CAPS-IV, which were administered at baseline, primary endpoint, treatment exit, and 12-month follow-up. At primary endpoint, the MDMA group demonstrated more PTG, Hedges' g = 1.14, 95% CI [0.49, 1.78], p < .001; and a larger reduction in PTSD symptom severity, Hedges' g = 0.88, 95% CI [-0.28, 1.50], p < .001, relative to the control group. Relative to baseline, at the 12-month follow-up, within-subject PTG was higher, p < .001; PTSD symptom severity scores were lower, p < .001; and two-thirds of participants (67.2%) no longer met criteria for PTSD. MDMA-assisted psychotherapy for PTSD resulted in PTG and clinical symptom reductions of large-magnitude effect sizes. Results suggest that PTG may provide a new mechanism of action warranting further study., (© 2020 Multidisciplinary Association for Psychedelic Studies, Inc. Journal of Traumatic Stress published by Wiley Periodicals, Inc. on behalf of International Society for Traumatic Stress Studies.)

Unsuccessfully treated posttraumatic stress disorder (PTSD) is a serious and life-threatening disorder. Two medications, paroxetine hydrochloride and sertraline hydrochloride, are approved treatments for PTSD by the Food and Drug Administration (FDA). Analyses of pharmacotherapies for PTSD found only small to moderate effects when compared with placebo. The Multidisciplinary Association for Psychedelic Studies (MAPS) obtained Breakthrough Therapy Designation (BTD) from the FDA for 3,4-methylenedioxymethamphetamine (MDMA)-assisted psychotherapy for treatment of PTSD on the basis of pooled analyses showing a large effect size for this treatment. This review covers data supporting BTD. In this treatment, MDMA is administered with psychotherapy in up to three monthly 8-h sessions. Participants are prepared for these sessions beforehand, and process material arising from the sessions in follow-up integrative psychotherapy sessions. Comparing data used for the approval of paroxetine and sertraline and pooled data from Phase 2 studies, MAPS demonstrated that MDMA-assisted psychotherapy constitutes a substantial improvement over available pharmacotherapies in terms of safety and efficacy. Studies of MDMA-assisted psychotherapy had lower dropout rates compared to sertraline and paroxetine trials. As MDMA is only administered under direct observation during a limited number of sessions, there is little chance of diversion, accidental or intentional overdose, or withdrawal symptoms upon discontinuation. BTD status has expedited the development of MAPS phase 3 trials occurring worldwide, leading up to a planned submission seeking FDA approval in 2021. Clinical Trial Registration: www.ClinicalTrials.gov, identifiers NCT00090064, NCT00353938, NCT01958593, NCT01211405, NCT01689740, NCT01793610., (Copyright © 2019 Feduccia, Jerome, Yazar-Klosinski, Emerson, Mithoefer and Doblin.)

Background: Posttraumatic 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., Methods: Six 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., Results: After 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., Conclusions: MDMA-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 Registration: ClinicalTrials.gov Identifier: NCT00090064, NCT00353938, NCT01958593, NCT01211405, NCT01689740, NCT01793610.

Background: Posttraumatic stress disorder often does not resolve after conventional psychotherapies or pharmacotherapies. Pilot studies have reported that 3,4-methylenedioxymethamphetamine (MDMA) combined with psychotherapy reduces posttraumatic stress disorder symptoms., Aims: This pilot dose response trial assessed efficacy and safety of MDMA-assisted psychotherapy across multiple therapy teams., Methods: Twenty-eight people with chronic posttraumatic stress disorder were randomized in a double-blind dose response comparison of two active doses (100 and 125 mg) with a low dose (40 mg) of MDMA administered during eight-hour psychotherapy sessions. Change in the Clinician-Administered PTSD Scale total scores one month after two sessions of MDMA served as the primary outcome. Active dose groups had one additional open-label session; the low dose group crossed over for three open-label active dose sessions. A 12-month follow-up assessment occurred after the final MDMA session., Results: In the intent-to-treat set, the active groups had the largest reduction in Clinician-Administered PTSD Scale total scores at the primary endpoint, with mean (standard deviation) changes of -26.3 (29.5) for 125 mg, -24.4 (24.2) for 100 mg, and -11.5 (21.2) for 40 mg, though statistical significance was reached only in the per protocol set ( p=0.03). Posttraumatic stress disorder symptoms remained lower than baseline at 12-month follow-up ( p<0.001) with 76% ( n=25) not meeting posttraumatic stress disorder criteria. There were no drug-related serious adverse events, and the treatment was well-tolerated., Conclusions: Our findings support previous investigations of MDMA-assisted psychotherapy as an innovative, efficacious treatment for posttraumatic stress disorder.

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.

Background: Post-traumatic stress disorder (PTSD) is prevalent in military personnel and first responders, many of whom do not respond to currently available treatments. This study aimed to assess the efficacy and safety of 3,4-methylenedioxymethamphetamine (MDMA)-assisted psychotherapy for treating chronic PTSD in this population., Methods: We did a randomised, double-blind, dose-response, phase 2 trial at an outpatient psychiatric clinic in the USA. We included service personnel who were 18 years or older, with chronic PTSD duration of 6 months or more, and who had a Clinician-Administered PTSD Scale (CAPS-IV) total score of 50 or greater. Using a web-based randomisation system, we randomly assigned participants (1:1:2) to three different dose groups of MDMA plus psychotherapy: 30 mg (active control), 75 mg, or 125 mg. We masked investigators, independent outcome raters, and participants until after the primary endpoint. MDMA was administered orally in two 8-h sessions with concomitant manualised psychotherapy. The primary outcome was mean change in CAPS-IV total score from baseline to 1 month after the second experimental session. Participants in the 30 mg and 75 mg groups subsequently underwent three 100-125 mg MDMA-assisted psychotherapy sessions in an open-label crossover, and all participants were assessed 12 months after the last MDMA session. Safety was monitored through adverse events, spontaneously reported expected reactions, vital signs, and suicidal ideation and behaviour. This study is registered with ClinicalTrials.gov, number NCT01211405., Findings: Between Nov 10, 2010, and Jan 29, 2015, 26 veterans and first responders met eligibility criteria and were randomly assigned to receive 30 mg (n=7), 75 mg (n=7), or 125 mg (n=12) of MDMA plus psychotherapy. At the primary endpoint, the 75 mg and 125 mg groups had significantly greater decreases in PTSD symptom severity (mean change CAPS-IV total scores of -58·3 [SD 9·8] and -44·3 [28·7]; p=0·001) than the 30 mg group (-11·4 [12·7]). Compared with the 30 mg group, Cohen's d effect sizes were large: 2·8 (95% CI 1·19-4·39) for the 75 mg group and 1·1 (0·04-2·08) for the 125 mg group. In the open-label crossover with full-dose MDMA (100-125 mg), PTSD symptom severity significantly decreased in the group that had previously received 30 mg (p=0·01), whereas no further significant decreases were observed in the group that previously achieved a large response after 75 mg doses in the blinded segment (p=0·81). PTSD symptoms were significantly reduced at the 12-month follow-up compared with baseline after all groups had full-dose MDMA (mean CAPS-IV total score of 38·8 [SD 28·1] vs 87·1 [16·1]; p<0·0001). 85 adverse events were reported by 20 participants. Of these adverse events, four (5%) were serious: three were deemed unrelated and one possibly related to study drug treatment., Interpretation: Active doses (75 mg and 125 mg) of MDMA with adjunctive psychotherapy in a controlled setting were effective and well tolerated in reducing PTSD symptoms in veterans and first responders., Funding: Multidisciplinary Association for Psychedelic Studies., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Background: The psychoactive indole alkaloid ibogaine has been associated with encouraging treatment outcomes for opioid dependence. The legal status of ibogaine in New Zealand provides a unique opportunity to evaluate durability of treatment outcomes., Objective: To examine longitudinal treatment effects over a 12-month period among individuals receiving legal ibogaine treatment for opioid dependence., Method: This observational study measured addiction severity as the primary outcome in 14 participants (50% female) over 12 months post-treatment using the Addiction Severity Index-Lite (ASI-Lite) following a single ibogaine treatment by either of two treatment providers. Secondary effects on depression were assessed via the Beck Depression Inventory-II (BDI-II). The Subjective Opioid Withdrawal Scale (SOWS) was collected before and immediately after treatment to measure opioid withdrawal symptoms., Results: Nonparametric comparisons via Friedman Test between baseline and 12-month follow-up for participants completing all interviews (n = 8) showed a significant reduction for the ASI-Lite drug use (p = 0.002) composite score. Reductions in BDI-II scores from baseline to 12-month follow-up were also significant (p < 0.001). Significant reductions in SOWS scores for all participants (n = 14) were also observed acutely after treatment (p = 0.015). Patients with partial data (n = 4) also showed reductions in ASI-Lite drug use scores and family/social status problems. One patient enrolled in the study died during treatment., Conclusion: A single ibogaine treatment reduced opioid withdrawal symptoms and achieved opioid cessation or sustained reduced use in dependent individuals as measured over 12 months. Ibogaine's legal availability in New Zealand may offer improved outcomes where legislation supports treatment providers to work closely with other health professionals.

A growing body of research suggests that traumatic events lead to persisting personality change characterized by increased neuroticism. Relevantly, enduring improvements in Post-Traumatic Stress Disorder (PTSD) symptoms have been found in response to 3,4-methylenedioxymethamphetamine (MDMA)-assisted psychotherapy. There is evidence that lasting changes in the personality feature of "openness" occur in response to hallucinogens, and that this may potentially act as a therapeutic mechanism of change. The present study investigated whether heightened Openness and decreased Neuroticism served as a mechanism of change within a randomized trial of MDMA-assisted psychotherapy for chronic, treatment-resistant PTSD. The Clinician-Administered PTSD Scale (CAPS) Global Scores and NEO PI-R Personality Inventory (NEO) Openness and Neuroticism Scales served as outcome measures. Results indicated that changes in Openness but not Neuroticism played a moderating role in the relationship between reduced PTSD symptoms and MDMA treatment. Following MDMA-assisted psychotherapy, increased Openness and decreased Neuroticism when comparing baseline personality traits with long-term follow-up traits also were found. These preliminary findings suggest that the effect of MDMA-assisted psychotherapy extends beyond specific PTSD symptomatology and fundamentally alters personality structure, resulting in long-term persisting personality change. Results are discussed in terms of possible mechanisms of psychotherapeutic change.

The heterodimeric transcription elongation factor Spt4/Spt5 (Spt4/5) tightly associates with RNAPII to regulate both transcriptional elongation and co-transcriptional pre-mRNA processing; however, the mechanisms by which Spt4/5 acts are poorly understood. Recent studies of the human and Drosophila Spt4/5 complexes indicate that they can bind nucleic acids in vitro. We demonstrate here that yeast Spt4/5 can bind in a sequence-specific manner to single stranded RNA containing AAN repeats. Furthermore, we show that the major protein determinants for RNA-binding are Spt4 together with the NGN domain of Spt5 and that the KOW domains are not required for RNA recognition. These findings attribute a new function to a domain of Spt4/5 that associates directly with RNAPII, making significant steps towards elucidating the mechanism behind transcriptional control by Spt4/5., (© 2016 The Protein Society.)

The first study of 3,4-methylenedioxymethamphetamine (MDMA)-assisted therapy for the treatment of social anxiety in autistic adults commenced in the spring of 2014. The search for psychotherapeutic options for autistic individuals is imperative considering the lack of effective conventional treatments for mental health diagnoses that are common in this population. Serious Adverse Events (SAEs) involving the administration of MDMA in clinical trials have been rare and non-life threatening. To date, MDMA has been administered to over 1133 individuals for research purposes without the occurrence of unexpected drug-related SAEs that require expedited reporting per FDA regulations. Now that safety parameters for limited use of MDMA in clinical settings have been established, a case can be made to further develop MDMA-assisted therapeutic interventions that could support autistic adults in increasing social adaptability among the typically developing population. As in the case with classic hallucinogens and other psychedelic drugs, MDMA catalyzes shifts toward openness and introspection that do not require ongoing administration to achieve lasting benefits. This infrequent dosing mitigates adverse event frequency and improves the risk/benefit ratio of MDMA, which may provide a significant advantage over medications that require daily dosing. Consequently, clinicians could employ new treatment models for social anxiety or similar types of distress administering MDMA on one to several occasions within the context of a supportive and integrative psychotherapy protocol., (Copyright © 2015 Elsevier Inc. All rights reserved.)

A double-blind, randomized, active placebo-controlled pilot study was conducted to examine safety and efficacy of lysergic acid diethylamide (LSD)-assisted psychotherapy in 12 patients with anxiety associated with life-threatening diseases. Treatment included drug-free psychotherapy sessions supplemented by two LSD-assisted psychotherapy sessions 2 to 3 weeks apart. The participants received either 200 μg of LSD (n = 8) or 20 μg of LSD with an open-label crossover to 200 μg of LSD after the initial blinded treatment was unmasked (n = 4). At the 2-month follow-up, positive trends were found via the State-Trait Anxiety Inventory (STAI) in reductions in trait anxiety (p = 0.033) with an effect size of 1.1, and state anxiety was significantly reduced (p = 0.021) with an effect size of 1.2, with no acute or chronic adverse effects persisting beyond 1 day after treatment or treatment-related serious adverse events. STAI reductions were sustained for 12 months. These results indicate that when administered safely in a methodologically rigorous medically supervised psychotherapeutic setting, LSD can reduce anxiety, suggesting that larger controlled studies are warranted.

We report follow-up data evaluating the long-term outcomes for the first completed trial of 3,4-methylenedioxymethamphetamine (MDMA)-assisted psychotherapy for chronic, treatment-resistant post-traumatic stress disorder (PTSD) (Mithoefer et al., 2011). All of the 19 subjects who received MDMA-assisted treatment in the original trial participated in the long-term follow-up (LTFU), with 16 out of 19 completing all of the long-term outcome measures, which were administered from 17 to 74 months after the original study's final MDMA session (mean = 45.4; SD = 17.3). Our primary outcome measure used was the Clinician-Administered PTSD Scale (CAPS). Secondary outcome measures were the Impact of Events Scale-Revised (IES-R) and the Neuroticism Extroversion Oppenness Personality Inventory-Revised (NEO PI-R) Personality Inventory. We also collected a long-term follow-up questionnaire. Results for the 16 CAPS completers showed there were no statistical differences between mean CAPS score at LTFU (mean = 23.7; SD = 22.8) (t (matched) = 0.1; df = 15, p = 0.91) and the mean CAPS score previously obtained at Study Exit (mean = 24.6, SD = 18.6). On average, subjects maintained statistically and clinically-significant gains in symptom relief, although two of these subjects did relapse. It was promising that we found the majority of these subjects with previously severe PTSD who were unresponsive to existing treatments had symptomatic relief provided by MDMA-assisted psychotherapy that persisted over time, with no subjects reporting harm from participation in the study.