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Thank you for visiting nature. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser or turn off compatibility mode in Internet Explorer. In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript. An Author Correction to this article was published on 07 October 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. Overall, Participants were ethnoracially diverse: 28 of There were no deaths or serious TEAEs. Managing PTSD is particularly complicated in individuals experiencing the dissociative subtype of PTSD, recurrent exposure to trauma and comorbidities, such as mood disorders and alcohol and substance use disorders 2 , 3 , 4. Together, these factors are associated with symptom exacerbation, treatment resistance and treatment discontinuation 3 , 5. Trauma-focused psychotherapies are the gold standard treatment for PTSD. However, many individuals have persisting symptomology, and dropout rates are high 6 , 7 , 8. More effective, therapeutic interventions are needed to address the immense individual, societal and economic burdens of PTSD 10 , MDMA, an entactogen that promotes monoamine reuptake inhibition and release primarily by inducing conformational change of pre-synaptic transporters 14 , 15 , 16 , 17 , effectively modulates fear memory reconsolidation, enhances fear extinction and promotes openness and prosocial behavior 18 , 19 , 20 , 21 , Due to disparities in trauma exposure, gender-diverse and transgender individuals, ethnoracial minorities, first responders, military personnel, veterans and victims of chronic sexual abuse have a disproportionately higher risk of developing PTSD 2 , 23 , 24 , 25 , 26 , 27 , However, these diverse populations are historically underrepresented in clinical trials Participants were recruited from 21 August to 18 May last participant visit on 2 November Overall, individuals were screened, and were enrolled. Of these, 17 individuals did not meet enrollment confirmation after initiation of preparation therapy, and were confirmed for randomization: 53 were assigned to MDMA-AT and 51 to placebo with therapy Fig. Baseline characteristics were generally similar between groups Table 1. In total, 74 of Participants were ethnically and racially diverse: 35 of The mean s. Overall, 28 of Source data. Improvements were observed across all domains, including family life, social life and work life Supplementary Table 4. By study end, 37 of 52 Furthermore, 24 of 52 The net number of participants needed to treat for each responder analysis group was as follows: responder, six; non-responder, six; loss of diagnosis, four; remission, four. Covariate analyses demonstrated similar responses to treatment regardless of disease severity, risk of hazardous alcohol or substance use disorder, severe adverse childhood experiences or dissociative subtype PTSD. A blinding survey conducted at study termination showed that 33 of 44 None had a serious TEAE. Two participants 3. These were mostly transient and of mild or moderate severity. Participants in the MDMA-AT group experienced temporary dose-dependent increases in mean blood pressure BP and pulse during experimental sessions compared to the placebo with therapy group Supplementary Table 8. Transient increases in heart rate and BP were expected and were observed during experimental sessions in a dose-dependent manner. These transient elevations did not require clinical intervention, including among the subset of participants with well-controlled hypertension. Because the current dosing regimen involves administering a single, split drug dose under observation, for a limited number of times, each after a lengthy washout, cardiovascular risk is likely to have been sufficiently mitigated by the study procedures and screening measures. No severe TEAEs of suicidal ideation or behavior were reported. Two participants in the placebo with therapy group had suicidality TEAESIs; one engaged in non-suicidal self-injurious behavior, and one had suicidal ideation and trichotillomania Supplementary Table 9. The number of participants reporting positive suicidal ideation varied throughout the study but collectively never exceeded baseline values in either group Supplementary Fig. Of these, one participant in the MDMA-AT group with no suicidal ideation at baseline had the emergence of active suicidal ideation with at least some intent to act. Notably, 45 of 52 In a historic first, to our knowledge, for psychedelic treatment studies, participants who identified as ethnically or racially diverse encompassed approximately half of the study sample. These findings confirm and extend the results observed in MAPP1 ref. Given the diverse population and degree of participant complexity, the replication of efficacy is particularly notable. In our study, A substantial proportion of participants displayed comorbid features associated with high treatment resistance 5 , such as major depression, multiple sources of trauma including childhood and combat trauma and dissociative subtype PTSD. In keeping with MAPP1, treatment was not significantly affected by disease severity, risk of hazardous alcohol or substance use disorder, severe adverse childhood experiences or dissociative subtype. Furthermore, there was no observed site-to-site variability and no differential effect if participants stayed overnight after the experimental session. MDMA simultaneously induces prosocial feelings and softens responses to emotionally challenging and fearful stimuli 19 , potentially enhancing the ability of individuals with PTSD to benefit from psychotherapy by reducing sensations of fear, threat and negative emotionality 18 , In contrast, a recent study comparing psychotherapies in veterans with PTSD reported dropout rates of The MAPP2 dropout rate was 1. The higher proportion of dropouts in the placebo with therapy group relative to MDMA-AT could be attributed to participants receiving less effective treatment and to disappointment from ineffective therapeutic blinding, although blinding survey data showed that not all participants correctly identified the treatment that they received. Consistent with MAPP1, no new major safety issues were reported. Consistent with PTSD, suicidal ideation was observed in both groups. MDMA did not appear to increase this risk, and no suicidal behavior was observed. C-SSRS scores varied throughout the study but never exceeded baseline values for either group. MAPP2 enrolled participants with a history of suicidality but excluded those with a current, serious imminent suicide risk; thus, special attention to this vulnerable population is warranted in future studies. In alignment with MAPP1 ref. Long-term data are also needed to assess the risk of MDMA abuse or misuse after study participation. To support these studies, data from the ongoing follow-up of participants from phase 2 and 3 studies ClinicalTrials. Several limitations may impact the integration of MDMA-AT into clinical care, including the exclusion of participants with high suicide risk, comorbid personality disorders and underlying cardiovascular disease. The notable effect seen in the placebo with therapy arm could suggest the standalone value of the manualized inner-directed therapy that was developed for use with MDMA. Additional head-to-head studies will need to be conducted to evaluate whether this form of manualized therapy provides greater value in the treatment of PTSD than the current first-line cognitive behavioral therapy and prolonged exposure therapy treatments Although treatment expectancy, per se, was not measured in this study, prospective treatment expectancy would likely have been high in both study arms, with random assignment expected to distribute this equally between groups. Although expectancy effects are a well-known issue in psychiatric clinical trials and are intertwined with the observation of treatment benefit during a trial 38 , several observations support expectancy mitigation in the current study: 1 the groups did not separate after the first experimental session; 2 placebo with therapy dropouts did not uniformly occur after the first experimental session; and 3 blinding survey data Supplementary Table 6 showed that not all participants correctly identified the treatment that they received. To ensure consistent clinical practice and to mitigate harm, it may be of benefit for prescribers to complete additional training and continuing education if MDMA-AT is approved for use by a regulatory agency. This confirmatory phase 3 trial showed consistent benefits of MDMA-AT in an ethnoracially diverse group of individuals with longstanding moderate to severe PTSD and numerous comorbidities. The dropout rate was low, and treatment was generally well tolerated. These findings represent the culmination of over two decades of research 39 , and, together with MAPP1, indicate that further consideration of this treatment in individuals with moderate to severe PTSD is warranted. Thirteen study sites 11 in the United States and two in Israel, both institutional and private participated. The trial was conducted in accordance with the Good Clinical Practice guidelines of the International Council for Harmonization and with the ethical principles of the Declaration of Helsinki. An independent data monitoring committee ensured that the study was conducted safely and had sufficient sample size. The review boards and institutions that approved the study protocol are listed in the Supplementary Methods. After written informed consent, participants were screened for eligibility. During the Preparation Period that preceded the Treatment Period, participants were tapered off all psychiatric medications before baseline to avoid potential drug interactions and confounding efficacy Supplementary Fig. Full inclusion and exclusion criteria are outlined in the Supplementary Methods. Participants were randomized in a allocation and in a blinded fashion to the MDMA-AT and placebo with therapy groups, stratified by clinical site. A central pool of blinded independent assessors was used to mitigate the risk of functional unblinding Assessors were trained and supervised by independent consultants with expertise in PTSD diagnostics and the CAPS-5 to ensure inter-rater reliability and validity of assessments. The independent assessors were blinded to the general study design, study visit, treatment assignment, number of treatments received and any safety data for the participant. Participants were instructed to withhold their opinion on treatment group assignment and the number of completed visits from the independent assessors. Each assessor conducted no more than one CAPS-5 assessment with each participant to reduce potential bias and expectancy effect from having conducted repeat CAPS-5s with a participant. To ensure that all site and sponsor staff were shielded from study outcomes, the blinded independent assessor pool collected and stored outcome measures in a dedicated database that was separate from the blinded clinical database. A blinding survey was conducted at study termination visit 20 to assess if participants thought that they received MDMA or placebo. Trial procedures were consistent with MAPP1 ref. The supplemental half dose was administered 1. Participants in both treatment groups received identical therapy. This dosing regimen also provides clinicians with the option of dose adjustments if needed. Within the MDMA-AT group, three participants did not undergo dose escalation in experimental sessions 2 and 3, and two participants experienced dose administration timing errors Supplementary Table 2. Each experimental session was followed by three min integration sessions to support participants in processing and understanding their experience Supplementary Fig. Full procedures, including details on therapy teams and training, are outlined in the Supplementary Methods. Exploratory outcome measurements included characterization of the treatment response and differences between the treatment groups by demographics and characteristics. Responder analyses were based on categorical diagnostic assessment data and the CAPS-5 total severity score assessment. Four responder categories were derived and compared at each post-experimental session visit using CAPS-5 scores. TEAEs were defined as any adverse event that occurred during the treatment period from the first experimental session to the last integration session. The severity of TEAEs was determined by the site physician as mild no limitation in normal daily activity , moderate some limitation in normal daily activity or severe unable to perform normal daily activity. A serious TEAE was defined as any unforeseen medical event at any dose of the drug that resulted in death; was life-threatening; required inpatient hospitalization; caused significant disability or incapacity; resulted in a congenital anomaly or birth defect; or required intervention to prevent permanent impairment or damage. Serious TEAEs also included any event, based on medical judgement, that jeopardized the participant or may have required intervention to prevent one of the events listed previously. With the exception of serious adverse event reporting, relatedness to study drug was not assessed by investigators, to preserve blinding. SAS version 9. Fixed effects were treatment, visit, treatment group by visit interaction and dissociative subtype; baseline CAPS-5 score was a covariate. Primary and secondary efficacy analyses used a de jure related to initially randomized treatment estimand and a supportive de facto treatment policy estimand of the modified intention-to-treat population, which required exposure to MDMA or placebo and at least one follow-up CAPS-5 assessment, as in MAPP1 ref. The de jure dataset included all available data, except for 12 one MDMA-AT and 11 placebo with therapy outcome measurements taken after treatment discontinuation in analysis of treatment efficacy Supplementary Table 3. Missed observations were considered missing at random MAR , and choice of this assumption was tested with a tipping point analysis Supplementary Methods. In additional exploratory analyses, 13 covariates were assessed in the model, with alpha set at 0. Analyses of primary or secondary outcomes by gender were not planned a priori; some exploratory analyses included sex as a covariate Supplementary Methods. TEAESIs involving cardiac function that could be indicative of QT prolongation or cardiac arrhythmias were collected, including torsade de pointes, sudden death, ventricular extrasystoles, ventricular tachycardia, ventricular fibrillation and flutter, non-postural syncope and seizures. Further information on research design is available in the Nature Portfolio Reporting Summary linked to this article. However, restrictions apply to the availability of these data, which were used under license for the current study and so are not publicly available. Data are, however, available from the authors upon reasonable request and with the permission of the sponsor. All requests for raw and analyzed data are promptly reviewed to verify if the request is subject to any confidentiality obligations. Participant-related data not included in the paper were generated as part of clinical trials and may be subject to participant confidentiality. Any data that can be shared will be released via a data use agreement. Source data are provided with this paper. Commercially available software SAS version 9. US Department of Veteran Affairs. How common is PTSD in adults? Prevalence of complex post-traumatic stress disorder in refugees and asylum seekers: systematic review. BJPysch Open 7 , e Article Google Scholar. Comorbidity in post-traumatic stress disorder: a population-based study from the two largest cities in Brazil. Hill, S. Dissociative subtype of posttraumatic stress disorder in women in partial and residential levels of psychiatric care. Trauma Dissociation 21 , — Article PubMed Google Scholar. Roberts, N. A systematic review and meta-analysis of psychological interventions for comorbid post-traumatic stress disorder and substance use disorder. Lewis, C. Dropout from psychological therapies for post-traumatic stress disorder PTSD in adults: systematic review and meta-analysis. Steenkamp, M. Psychotherapy for military-related PTSD: a review of randomized clinical trials. JAMA , — Mavranezouli, I. Psychological treatments for post-traumatic stress disorder in adults: a network meta-analysis. Alexander, W. Pharmacotherapy for post-traumatic stress disorder in combat veterans: focus on antidepressants and atypical antipsychotic agents. Google Scholar. Davis, L. The economic burden of posttraumatic stress disorder in the United States from a societal perspective. Psychiatry 83 , 21m Couette, M. Social cognition in post-traumatic stress disorder: a systematic review. Mitchell, J. Mithoefer, M. MDMA-assisted psychotherapy for treatment of PTSD: study design and rationale for phase 3 trials based on pooled analysis of six phase 2 randomized controlled trials. Nichols, D. Entactogens: how the name for a novel class of psychoactive agents originated. Psychiatry 13 , Mayer, F. Serotonin-releasing agents with reduced off-target effects. Psychiatry 28 , — Sandtner, W. Binding mode selection determines the action of ecstasy homologs at monoamine transporters. MDMA 3,4-methylenedioxymethamphetamine analogues as tools to characterize MDMA-like effects: an approach to understand entactogen pharmacology. Feduccia, A. Psychiatry 84 , — Kamilar-Britt, P. The prosocial effects of 3,4-methylenedioxymethamphetamine MDMA : controlled studies in humans and laboratory animals. Vizeli, P. Effects of 3,4-methylenedioxymethamphetamine on conditioned fear extinction and retention in a crossover study in healthy subjects. Maples-Keller, J. A randomized controlled trial of 3,4-methylenedioxymethamphetamine MDMA and fear extinction retention in healthy adults. Hysek, C. MDMA enhances emotional empathy and prosocial behavior. Brooks Holliday, S. Health 25 , — Goldstein, R. Psychiatry Psychiatr. Zimmerman, M. Psychiatric diagnoses among transgender and gender diverse patients compared to cisgender patients. Herman, J. Complex PTSD: a syndrome in survivors of prolonged and repeated trauma. Trauma Stress 5 , — Schein, J. Prevalence of post-traumatic stress disorder in the United States: a systematic literature review. Med Res. Lewis-Schroeder, N. Conceptualization, assessment, and treatment of traumatic stress in first responders: a review of critical issues. Psychiatry 26 , — Williams, C. Demographic and health behavior factors associated with clinical trial invitation and participation in the United States. JAMA Netw. Open 4 , e Ching, T. MDMA-assisted therapy for posttraumatic stress disorder: a pooled analysis of ethnoracial differences in efficacy and safety from two phase 2 open-label lead-in trials and a phase 3 randomized, blinded placebo-controlled trial. Schnurr, P. Comparison of prolonged exposure vs cognitive processing therapy for treatment of posttraumatic stress disorder among US veterans: a randomized clinical trial. Open 5 , e Jerome, L. Lester, S. Cardiovascular effects of 3,4-methylenedioxymethamphetamine: a double-blind, placebo-controlled trial. Safety pharmacology of acute MDMA administration in healthy subjects. Nicholas, C. Drug Alcohol Depend. Breakthrough for trauma treatment: safety and efficacy of MDMA-assisted psychotherapy compared to paroxetine and sertraline. Psychiatry 10 , Schenberg, E. Who is blind in psychedelic research? Letter to the editor regarding: blinding and expectancy confounds in psychedelic randomized controlled trials. Expert Rev. Doblin, R. Drugs 34 , — Weathers, F. Targum, S. Comparability of blinded remote and site-based assessments of response to adjunctive esketamine or placebo nasal spray in patients with treatment resistant depression. Res , 68—73 Download references. The authors thank all of the participants and their support networks. Medical writing assistance was provided by J. Carpenter and M. You can also search for this author in PubMed Google Scholar. All authors had full access to the trial data, contributed to the interpretation of the data and contributed to writing the manuscript. The authors attest to the accuracy and completeness of the reported data, accept responsibility to submit for publication and confirm that the trial conformed to the protocol and the statistical analysis plan available via Nature Medicine. Correspondence to Jennifer M. Nature Medicine thanks Matthias Liechti, Alimu Dayimu and the other, anonymous, reviewer s for their contribution to the peer review of this work. Primary handling editor: Jerome Staal, in collaboration with the Nature Medicine team. Reprints and permissions. Nat Med 29 , — Download citation. Received : 02 June Accepted : 24 August Published : 14 September Issue Date : October Anyone you share the following link with will be able to read this content:. Sorry, a shareable link is not currently available for this article. Provided by the Springer Nature SharedIt content-sharing initiative. Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily. Skip to main content Thank you for visiting nature. Download PDF. Subjects Drug development Trauma. This article has been updated. Abstract 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. Trauma-focused treatment for comorbid post-traumatic stress and substance use disorder Article 14 November Results Demographics and baseline characteristics Participants were recruited from 21 August to 18 May last participant visit on 2 November Full size image. Table 1 Demographics and clinical characteristics of participants at baseline Full size table. Table 2 Adverse events occurring during treatment Full size table. Participants After written informed consent, participants were screened for eligibility. Randomization and masking Participants were randomized in a allocation and in a blinded fashion to the MDMA-AT and placebo with therapy groups, stratified by clinical site. Statistical analysis SAS version 9. Reporting summary Further information on research design is available in the Nature Portfolio Reporting Summary linked to this article. Code availability Commercially available software SAS version 9. Article Google Scholar Hill, S. Google Scholar Davis, L. Article Google Scholar Schein, J. Article Google Scholar Weathers, F. Acknowledgements The authors thank all of the participants and their support networks. Author information Author notes A list of members and their affiliations appears in the Supplementary Information. Mitchell View author publications. View author publications. Ethics declarations Competing interests J. Peer review Peer review information Nature Medicine thanks Matthias Liechti, Alimu Dayimu and the other, anonymous, reviewer s for their contribution to the peer review of this work. Supplementary information. Reporting Summary. Source data Source Data Fig. Source Data Fig. About this article. Cite this article Mitchell, J. Copy to clipboard. Menkes Trials What should constitute a control condition in psychedelic drug trials? Liechti Neuropsychopharmacology Optimizing real-world benefit and risk of new psychedelic medications: the need for innovative postmarket surveillance Joshua C. Black Andrew A. Monte Richard C. 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The biggest unknown in psychedelic therapy is not the psychedelics

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But in-depth reporting is costly, so to continue this vital work, we have an ambitious goal to add 5, new members. We rely on readers like you to fund our journalism. Will you support our work and become a Vox Member today? To the surprise of almost everyone involved, therapy using MDMA — commonly known as ecstasy — will probably not become legal this year. There were lots of problems with the evidence about the drug itself. So, to what extent were those who got MDMA healing because they knew they were getting the real drug and expecting that it would help them? No one can tell. But there was another major question looming over Lykos previously known as MAPS public benefit corporation, the biggest force pushing psychedelics toward legalization over the past few decades. Therapy is not just one practice — there are many different approaches, from psychoanalysis to exposure therapy. Some types of therapy, like cognitive behavioral therapy , have plenty of evidence to back up their effectiveness when used on their own. Others, not so much. Lykos favors certain therapy modalities that have less of an evidence base and more of a New Age flavor. Holotropic breathwork is the brainchild of psychiatrist Stanislav Grof. Like many an ancient meditator before him, he found that intense breathing techniques can trigger something akin to a psychedelic trip. The Lykos treatment manual makes clear its intellectual debt to IFS. You might be thinking: So what? Many people feel like they do have a core self, and if that idea helps them heal, why not embrace it? Maybe the person is just triggered. In one case, therapist Veronika Gold touched a patient, Annie, who became distressed and physically struggled against her. Gold was not troubled. Get your fucking hands away from me! Over the course of the next several minutes, she pushed my hands with increasing vigor and force. In , Buisson — a sexual assault survivor who came in the hope of healing her PTSD — was pinned down and cuddled by her therapists, a married couple. Video footage shows the therapists continuing to touch her even after she reacts with distress. Later, the male therapist had sex with Buisson; in a lawsuit, she alleged that it was sexual assault. This gives therapists an unusual amount of latitude. If the patient complies, the Lykos logic enables the therapists to read that as the wise self talking. In fact, they can view themselves as getting the most authentic consent possible since the premise is that a patient is more able to access the true self during an MDMA trip than during regular life, when mental health issues obfuscate that inner wisdom. And if the patient resists? At its worst, the logic forms a tight, self-confirming loop, one that could increase risks to the patient rather than minimizing them. To some degree, the distinction is in the eye of the beholder. Former employees have also said that the company pushed ideological conformity. And other people will be able to do this as well. All of this really comes back to Stan Grof And we are coming forward to fulfill the promise. The psychedelic renaissance is here to help consciousness triumph. The declaration has the feel of apocalyptic logic. Found in many religious traditions, apocalypticism warns that catastrophe is looming and that humanity needs a tool to achieve salvation. To make such an omelet, there is surely no limit to the number of eggs that should be broken. But running psychotherapy studies is even harder than running drug trials. In , there was zero federal funding; since then, one study has been funded. That means most of the funding has had to come from industry or philanthropy. Among philanthropists, there may also be a feeling that the drug, not the therapy, is the exciting new thing. But the fact that the therapy component of MDMA therapy is so understudied is a major problem. That agency is set up to evaluate drugs; before the Lykos case, it had never attempted to evaluate therapy. With psychedelic treatments, the therapy component seems to be key to healing , so we should expect to see a growing number of applications for combined drug-therapy treatments — and that means the FDA itself may need to change. Understand the world with a daily explainer plus the most compelling stories of the day. AI is here to stay and the Nobels know it. Did they actually figure out why nations fail? The 11 policies that could help the cities of the future. The human mind is designed to predict, but uncertainty helps us thrive. The public did not consent to artificial general intelligence. In Sonoma County and Denver, activists are putting animal welfare on the ballot. Skip to main content The homepage Vox Vox logo. The homepage Vox Vox logo. Navigation Drawer. Become a Member. 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