Main

PTSD is a common and debilitating condition with immeasurable social and economic costs that affects the lives of hundreds of millions of people annually. There are a number of environmental and biological risk factors that contribute to the development and maintenance of PTSD, and poor PTSD treatment outcomes are associated with several comorbid conditions that include childhood trauma, alcohol and substance use disorders, depression, suicidal ideation and dissociation. It is therefore imperative to identify a therapeutic that is beneficial in those individuals with the comorbidities that typically confer treatment resistance.The selective serotonin reuptake inhibitors (SSRIs) sertraline and paroxetine are Food and Drug Administration (FDA)-approved first-line therapeutics for the treatment of PTSD. However, an estimated 40–60% of patients do not respond to these compounds. Likewise, although evidenced-based trauma-focused psychotherapies such as prolonged exposure and cognitive behavioral therapy are considered to be the gold standard treatments for PTSD, many participants fail to respond or continue to have significant symptoms, and dropout rates are high. Novel cost-effective therapeutics are therefore desperately needed.The substituted amphetamine 3,4-methylenedioxymethamphetamine (MDMA) induces serotonin release by binding primarily to presynaptic serotonin transporters. MDMA has been shown to enhance fear memory extinction, modulate fear memory reconsolidation (possibly through an oxytocin-dependent mechanism), and bolster social behavior in animal models. Pooled analysis of six phase 2 trials of MDMA-assisted therapy for PTSD have now shown promising safety and efficacy findings. Here, we assess the efficacy and safety of MDMA-assisted therapy in individuals with severe PTSD. Participants were given three doses of MDMA or placebo in a controlled clinical environment and in the presence of a trained therapy team. Primary and secondary outcome measures (CAPS-5 and SDS, respectively) were assessed by a centralized pool of blinded, independent diagnostic assessors. MDMA-assisted therapy for PTSD was granted an FDA Breakthrough Therapy designation, and the protocol and statistical analysis plan (SAP) were developed in conjunction with the FDA.

Results

Demographics

Participants were recruited from 7 November 2018 to 26 May 2020, with the last participant visit conducted on 21 August 2020. A total of 345 participants were assessed for eligibility, 131 were enrolled, 91 were confirmed for randomization (United States, n = 77; Canada, n = 9; Israel, n = 5), and 46 were randomized to MDMA and 44 to placebo (Fig. 1).

Fig. 1: Procedure timeline and study flow diagram.

a, Procedure timeline. Following the screening procedures and medication taper, participants attended a total of three preparatory sessions, three experimental sessions, nine integration sessions and four endpoint assessments (T1–4) over 18 weeks, concluding with a final study-termination visit. IR, independent rater; T, timepoint of endpoint assessment; T1, baseline; T2, after the first experimental session; T3, after the second experimental session; T4, 18 weeks after baseline. b, CONSORT diagram indicating participant numbers and disposition through the course of the trial.

Study arms were not significantly different in terms of race, ethnicity, sex, age, dissociative subtype, disability or CAPS-5 score (Table 1). The mean duration of PTSD diagnosis was 14.8 (s.d. 11.6) years and 13.2 (s.d. 11.4) years in the MDMA and placebo groups, respectively. Of note, six participants in the MDMA group and 13 participants in the placebo group had the dissociative subtype according to CAPS-5 score.

Table 1 Demographics and baseline characteristics

BMI, body mass index; CBT, cognitive behavioral therapy; EMDR, eye movement desensitization and reprocessing therapy.

^a Two participants included in the assigned female at birth MDMA group identified their gender as non-binary.

^b Medications were tapered down and washed out prior to baseline assessments and the first experimental session, in accordance with the protocol.

^c Lifetime accounts for all suicidal ideation and behavior prior to the study. Serious ideation is defined as a score of 4 or 5 in the suicidal ideation category.

Efficacy

MDMA significantly attenuated PTSD symptomology, as shown by the change in CAPS-5 total severity score from baseline to 18 weeks after baseline. Mixed model repeated measure (MMRM) analysis of the de jure estimand (that is, the effects of the drug if taken as directed) showed a significant difference in treatment arms (n = 89 (MDMA n = 46), P < 0.0001, between-group difference = 11.9, 95% confidence interval (CI) = 6.3–17.4, d.f. = 71) (Fig. 2a). MMRM sensitivity analysis of the de facto estimand (that is, the effects of the drug if taken as assigned, regardless of adherence) showed a significant difference in treatment arms (n = 90, P < 0.0001, d.f. = 72).

Fig. 2: Measures of MDMA efficacy in the MDMA-assisted therapy group and the placebo group.

a, Change in CAPS-5 total severity score from T1 to T4 (P < 0.0001, d = 0.91, n = 89 (MDMA n = 46)), as a measure of the primary outcome. Primary analysis was completed using least square means from an MMRM model. b, Change in SDS total score from T1 to T4 (P = 0.0116, d = 0.43, n = 89 (MDMA n = 46)), as a measure of the secondary outcome. Primary analysis was completed using least square means from an MMRM model. c, Change in BDI-II score from T1 to study termination (t = −3.11, P = 0.0026, n = 81 (MDMA n = 42)), as a measure of the exploratory outcome. Data are presented as mean and s.e.m.

The mean change in CAPS-5 scores from baseline to 18 weeks after baseline in the completers (per protocol set) was −24.4 (s.d. 11.6) (n = 42) in the MDMA-assisted therapy group compared with −13.9 (s.d. 11.5) (n = 37) in the placebo with therapy group.

The effect size of the MDMA-assisted therapy treatment compared with placebo with therapy was d = 0.91 (95% CI = 0.44–1.37, pooled s.d. = 11.55) in the de jure estimand and d = 0.97 (95% CI = 0.51–1.42) in the de facto estimand. When the within-group treatment effect (which included the effect of the supportive therapy that was administered in both arms) was compared between the MDMA and placebo groups, the effect size was 2.1 (95% CI = −5.6 to 1.4) in the MDMA group and 1.2 (95% CI = −4.9 to 2.5) in the placebo group.

Over the same period, MDMA significantly reduced clinician-rated functional impairment as assessed with the SDS. MMRM analysis of the de jure estimand showed a significant difference in treatment arms (n = 89 (MDMA n = 46), P = 0.0116, d.f. = 71, effect size = 0.43, 95% CI = −0.01 to 0.88, pooled s.d. = 2.53) (Fig. 2b). The mean change in SDS scores from baseline to 18 weeks after baseline in the completers was −3.1 (s.d. 2.6) (n = 42) in the MDMA-assisted therapy group and −2.0 (s.d. 2.4) (n = 37) in the placebo with therapy group.

MDMA was equally effective in participants with comorbidities that are often associated with treatment resistance. Participants with the dissociative subtype of PTSD who received MDMA-assisted therapy had significant symptom reduction on the CAPS-5 (mean MDMA Δ = −30.8 (s.d. 9.0), mean placebo Δ = −12.8 (s.d. 12.8)), and this was similar to that in their counterparts with non-dissociative PTSD (mean MDMA Δ = −23.6 (s.d. 11.7), mean placebo Δ = −14.3 (s.d. 11.2)). The benefit of MDMA therapy was not modulated by history of alcohol use disorder, history of substance use disorder, overnight stay or severe childhood trauma. Results were consistent across all 15 study sites with no effect by study site (P = 0.1003). In MMRM analysis there was no obvious impact of SSRI history on effectiveness of MDMA (Supplementary Table 2).

MDMA therapy was effective in an exploratory endpoint analysis of the reduction of depression symptoms (using the Beck Depression Inventory II (BDI-II)) from baseline to study termination of the de jure estimand (mean MDMA Δ = −19.7 (s.d. 14.0), n = 42; mean placebo Δ = −10.8 (s.d. 11.3), n = 39; t = −3.11, P = 0.0026, d.f. = 79, effect size = 0.67, 95% CI = 0.22–1.12) (Fig. 2c).

Clinically significant improvement (a decrease of ≥10 points on the CAPS-5), loss of diagnosis (specific diagnostic measure on the CAPS-5), and remission (loss of diagnosis and a total CAPS-5 score ≤ 11) were each tracked. At the primary study endpoint (18 weeks after baseline), 28 of 42 (67%) of the participants in the MDMA group no longer met the diagnostic criteria for PTSD, compared with 12 of 37 (32%) of those in the placebo group after three sessions. Additionally, 14 of 42 participants in the MDMA group (33%) and 2 of 37 participants in the placebo group (5%) met the criteria for remission after three sessions (Fig. 3).

Fig. 3: Treatment response and remission for MDMA and placebo groups as a percentage of total participants randomized to each arm (MDMA, n = 46; placebo, n = 44).

Responders (clinically significant improvement, defined as a ≥10-point decrease on CAPS-5), loss of diagnosis (specific diagnostic measure on CAPS-5), and remission (loss of diagnosis and a total CAPS-5 score of ≤11) were tracked in both groups. Non-response is defined as a <10-point decrease on CAPS-5. Withdrawal is defined as a post-randomization early termination.

Safety

Treatment-emergent adverse events (TEAEs, adverse events that occurred during the treatment period from the first experimental session to the last integration session) that were more prevalent in the MDMA study arm were typically transient, mild to moderate in severity, and included muscle tightness, decreased appetite, nausea, hyperhidrosis and feeling cold (Supplementary Table 3). Importantly, no increase in adverse events related to suicidality was observed in the MDMA group. A transient increase in vital signs (systolic and diastolic blood pressure and heart rate) was observed in the MDMA group (Supplementary Table 4). Two participants in the MDMA group had a transient increase in body temperature to 38.1 °C: one had an increase after the second MDMA session, and one had an increase after the second and third MDMA sessions.

Two participants, both randomized to the placebo group, reported three serious adverse events (SAEs) during the trial. One participant in the placebo group reported two SAEs of suicidal behavior during the trial, and another participant in the placebo group reported one SAE of suicidal ideation that led to self-hospitalization. Five participants in the placebo group and three participants in the MDMA group reported adverse events of special interest (AESIs) of suicidal ideation, suicidal behavior or self-harm in the context of suicidal ideation. One participant in the placebo group reported two cardiovascular AESIs in which underlying cardiac etiology could not be ruled out (Table 2). One participant randomized to the MDMA group chose to discontinue participation due to being triggered by the CAPS-5 assessments and to an adverse event of depressed mood following an experimental session; this participant met the criterion as a non-responder, which was defined as having a less than 10-point decrease in CAPS-5 score. MDMA sessions were not otherwise followed by a lowering of mood.

Table 2 Participants with treatment-emergent SAEs and AESIs

The number of participants experiencing one or more SAEs or AESIs relating to suicidality, cardiovascular symptoms that could indicate QT prolongation, and abuse potential following the first experimental session.

Suicidality was tracked throughout the study using the Columbia Suicide Severity Rating Scale (C-SSRS) at each study visit. More than 90% of participants reported suicidal ideation in their lifetime, and 17 of 46 participants (37%) in the MDMA group and 14 of 44 participants (32%) in the placebo group reported suicidal ideation at baseline. Although the number of participants who reported suicidal ideation varied throughout the visits, prevalence never exceeded baseline and was not exacerbated in the MDMA group. Serious suicidal ideation (a score of 4 or 5 on the C-SSRS) was minimal during the study and occurred almost entirely in the placebo arm (Fig. 4).

Fig. 4: Number of participants reporting the presence of suicidal ideation as measured with the C-SSRS at each visit and separated by treatment group.

Discussion

Here, we demonstrate that three doses of MDMA given in conjunction with manualized therapy over the course of 18 weeks results in a significant and robust attenuation of PTSD symptoms and functional impairment as assessed using the CAPS-5 and SDS, respectively. MDMA also significantly mitigated depressive symptoms as assessed using the BDI-II. Of note, MDMA did not increase the occurrence of suicidality during the study.These data illustrate the potential benefit of MDMA-assisted therapy for PTSD over the FDA-approved first-line pharmacotherapies sertraline and paroxetine, which have both exhibited smaller effect sizes in pivotal studies. Previous comparison of change in CAPS score between sertraline and placebo showed effect sizes of 0.31 and 0.37. Similarly, comparison of change in CAPS score between paroxetine and placebo showed effect sizes of 0.56, 0.45 and 0.09. By contrast, the effect size of 0.91 demonstrated in this study between MDMA-assisted therapy and placebo with therapy was larger than that for any other previously identified PTSD pharmacotherapy. To directly assess superiority, a head-to-head comparison of MDMA-assisted therapy with SSRIs for PTSD would be needed. Although the present study tested the effects of MDMA using a model in which both treatment groups received supportive therapy, participants who received MDMA and supportive therapy (d = 2.1) had greater improvement in PTSD change scores compared with those who received placebo with supportive therapy (d = 1.2), suggesting that MDMA enhanced the effects of supportive therapy. In clinical practice, both MDMA and supportive therapy will be components of this PTSD treatment.Previous research on MDMA for PTSD has suggested that those with a recent history of SSRI treatment may not respond as robustly to MDMA. Given that 65.5% of participants in the current trial have a lifetime history of SSRI use, it is difficult to separate the ramifications of long-term SSRI treatment from the effects of treatment resistance. However, there was no obvious effect of previous SSRI use on therapeutic efficacy in this trial. Similarly, although years of PTSD diagnosis or age of onset may affect treatment efficacy, no obvious relationship was seen here between duration or onset of PTSD diagnosis and treatment efficacy. Serotonin and the serotonin transporter are of particular importance in the generation, consolidation, retrieval and reconsolidation of fear memories. Reduced serotonin transporter levels (which result in greater amounts of extracellular serotonin) have been shown to predict propensity to develop PTSD, increase fear and anxiety-related behaviors, and induce greater amygdalar blood oxygenation level-dependent (BOLD) activity in response to fearful images. There is extensive serotonergic innervation of the amygdala, and amygdalar serotonin levels have been shown to increase following exposure to stressful and fear-inducing stimuli. MDMA enhances the extinction of fear memories in mice through increased expression of brain-derived neurotrophic factor in the amygdala, and human neuroimaging studies have demonstrated that MDMA is associated with attenuated amygdalar BOLD activity during presentation of negative emotional stimuli. Together these data suggest that MDMA may exert its therapeutic effects through a well-conserved mechanism of amygdalar serotonergic function that regulates fear-based behaviors and contributes to the maintenance of PTSD. Perhaps by reopening an oxytocin-dependent critical period of neuroplasticity that typically closes after adolescence, MDMA may facilitate the processing and release of particularly intractable, potentially developmental, fear-related memories. It is intriguing to speculate that the pharmacological properties of MDMA, when combined with therapy, may produce a ‘window of tolerance,’ in which participants are able to revisit and process traumatic content without becoming overwhelmed or encumbered by hyperarousal and dissociative symptoms. MDMA-assisted therapy may facilitate recall of negative or threatening memories with greater self-compassion and less PTSD-related shame and anger. Additionally, the acute prosocial and interpersonal effects of MDMA may support the quality of the therapeutic alliance, a potentially important factor relating to PTSD treatment adherence and outcome. Indeed, clinicians have suggested that “MDMA may catalyze therapeutic processing by allowing patients to stay emotionally engaged while revisiting traumatic experiences without becoming overwhelmed“. Given that PTSD is a strong predictor of disability in both veteran and community populations, it is promising to note that the robust reduction in PTSD and depressive symptoms identified here is complemented by a significant improvement in SDS score (for example, work and/or school, social and family functioning). Approximately 4.7 million US veterans report a service-related disability, costing the US government approximately $73 billion per year. Identification of a PTSD treatment that could improve social and family functioning and ameliorate impairment across a broad range of environmental contexts could provide major medical cost savings, in addition to improving the quality of life for veterans and others affected by this disorder. PTSD is a particularly persistent and incapacitating condition when expressed in conjunction with other disorders of mood and affect. In the present study, perhaps most compelling are the data indicating efficacy in participants with chronic and severe PTSD, and the associated comorbidities including childhood trauma, depression, suicidality, history of alcohol and substance use disorders, and dissociation, because these groups are all typically considered treatment resistant. Given that more than 80% of those assigned a PTSD diagnosis have at least one comorbid disorder, the identification of a therapy that is effective in those with complicated PTSD and dual diagnoses could greatly improve PTSD treatment. Additional studies should therefore be conducted to evaluate the safety and efficacy of MDMA-assisted therapy for PTSD in those with specific comorbidities.Although recent research suggests that dissociative subtype PTSD is difficult to treat, participants with the dissociative subtype who received MDMA-assisted therapy had significant symptom reduction that was at least similar to that of their counterparts with non-dissociative PTSD. Given that this covariate was significant, it warrants further study. Furthermore, given that other treatments for PTSD are not consistently effective for those with the dissociative subtype, these data, if replicated, would indicate an important novel therapeutic niche for MDMA-assisted therapy for typically hard-to-treat populations. Importantly, there were no major safety issues reported in the MDMA arm of this study. Although abuse potential, cardiovascular risk and suicidality were recorded as AESIs, MDMA was not shown to induce or potentiate any of these conditions. In addition, although there was often a transient increase in blood pressure during MDMA sessions, this was expected based on phase 2 data and previous studies in healthy volunteers. These data suggest that MDMA has an equivalent, if not better, safety profile compared with that of first-line SSRIs for the treatment of PTSD, which are known to carry a low risk of QT interval prolongation. There are several limitations to the current trial. First, due to the coronavirus disease 2019 (COVID-19) pandemic, the participant population is smaller than originally planned. However, given the power noted in this study, it is unlikely that population size was an impediment. Second, the population is relatively homogeneous and lacks racial and ethnic diversity, which should be addressed in future trials. Third, this report describes the findings of a short-term pre-specified primary outcome, 2 months after the last experimental session and 5 weeks since the final integrative therapy session; long-term follow-up data from this controlled trial will be collected to assess durability of treatment. Fourth, safety data were by necessity collected by site therapists, perhaps limiting the blinding of the data. To eliminate this effect on the primary and secondary outcome measures, all efficacy data were collected by blinded, independent raters. Last, given the subjective effects of MDMA, the blinding of participants was also challenging and possibly led to expectation effects. However, although blinding was not formally assessed during the study, when participants were contacted to be informed of their treatment assignment at the time of study unblinding it became apparent that at least 10% had inaccurately guessed their treatment arm. Although anecdotal, at least 7 of 44 participants in the placebo group (15.9%) inaccurately believed that they had received MDMA, and at least 2 of 46 participants in the MDMA group (4.3%) inaccurately believed that they had received placebo.We may soon be confronted with the potentially enormous economic and social repercussions of PTSD, exacerbated by the COVID-19 pandemic. Overwhelmingly high rates of psychological and mental health impairment could be with us for years to come and are likely to impart a considerable emotional and economic burden. Novel PTSD therapeutics are desperately needed, especially for those for whom comorbidities confer treatment resistance.In summary, MDMA-assisted therapy induces rapid onset of treatment efficacy, even in those with severe PTSD, and in those with associated comorbidities including dissociative PTSD, depression, history of alcohol and substance use disorders, and childhood trauma. Not only is MDMA-assisted therapy efficacious in individuals with severe PTSD, but it may also provide improved patient safety. Compared with current first-line pharmacological and behavioral therapies, MDMA-assisted therapy has the potential to dramatically transform treatment for PTSD and should be expeditiously evaluated for clinical use.

Methods

Study design

This was a randomized double-blind study designed to compare the efficacy of MDMA-assisted therapy with that of placebo with therapy. Fifteen study sites, consisting of 11 in the United States, two in Canada and two in Israel, included both institutional sites and private clinics. Ethics approval was obtained from Copernicus Group Independent Review Board, Western Institutional Review Board, University of British Columbia Providence Healthcare Research Ethics Board, and the Helsinki Committees of Be’er Ya’akov Ness Ziona Mental Health Center and Chaim Sheba Medical Center. This clinical study was conducted in accordance with the principles of the Declaration of Helsinki. The public study protocol is available at http://maps.org/mapp1. The therapist manual is available at http://maps.org/treatment-manual.

Participants

Participants were recruited through print and internet advertisements, referrals from treatment providers, and by word of mouth. Participants were required to initiate contact with the study sites themselves, even if recommended by a provider. After providing written informed consent, participants were screened for eligibility. The criteria for inclusion consisted of meeting the Diagnostic and Statistical Manual of Mental Disorders, fifth edition (DSM-5) criteria for current PTSD with a symptom duration of ≥6 months at screening (as assessed with the Mini International Neuropsychiatric Interview (MINI) for DSM-5), and a CAPS-5 total severity score of ≥35 at baseline. Exclusion criteria consisted of primary psychotic disorder, bipolar I disorder, dissociative identity disorder, eating disorders with active purging, major depressive disorder with psychotic features, personality disorders, current alcohol and substance use disorders, pregnancy or lactation, and any medical condition that could make receiving a sympathomimetic drug harmful due to increased blood pressure and heart rate, including uncontrolled hypertension, history of arrhythmia, or marked baseline prolongation of QT and/or QTc interval. Participants with other mild, stable, chronic medical problems (for example, type 2 diabetes mellitus or well-controlled hypertension) were eligible for enrollment if the site physician, clinical investigator and medical monitor agreed that the condition would not increase the risk associated with MDMA administration. Participants were required to comply with lifestyle modifications, including a medically supervised discontinuation of psychiatric medications for a minimum of five half-lives plus one additional week before the baseline assessments (see the study protocol for inclusion and exclusion criteria).The study protocol was amended on three occasions during study enrollment: first, to add clarity to eligibility criteria related to comorbid medical conditions; second, to add terms of suicidal ideation and behavior as AESIs, as requested by the FDA; and third, to increase the frequency of suicidality assessments following experimental sessions, as requested by the FDA, and to add an option for some telemedicine visits following the COVID-19 pandemic. Given that the study was at full enrollment (n = 105) when COVID-19 shut down in-person interactions at most of the study sites, the FDA and sponsor concluded that a reduced sample size of 90 participants, instead of the planned 100, would maintain sufficient statistical power to meet study objectives and would avoid COVID-19 delays of experimental sessions, which might confound the assessment of treatment effects.

Study drug

The study drug was manufactured in accordance with Current Good Manufacturing Practice (CGMP) standards by Onyx Scientific and compounded by Sharp Clinical Services. Assays for chemistry, manufacturing and controls were completed in accordance with the CGMP and International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH) standards, and reported to the FDA, Health Canada and the Israel Ministry of Health.

Randomization, masking and bias minimization

Participants were randomized in a blinded fashion and were allocated 1:1 to either the MDMA-assisted therapy group or the placebo with therapy group. Randomization was stratified by site and occurred following enrollment confirmation (after preparatory visits). Randomization was managed via an interactive web randomization system—ITClinical IWRS, version 11.0.1 (ITClinical, LDA)—based on a centralized randomization schedule developed by an independent third-party vendor to maintain blinding. Participants, site staff and the sponsor were blinded to participant group assignment until after the database was locked.An inactive placebo with therapy was utilized as the comparator to isolate the efficacy of the MDMA itself. Although low-dose MDMA improved blinding in phase 2 studies, it led to decreased effectiveness compared with an inactive placebo in a PTSD population, making it easier to detect a difference between the active and comparator groups. The use of inactive placebo also allows for uncontaminated comparison of safety data between groups. Therefore, an inactive placebo was determined in partnership with the FDA as a more conservative statistical comparison, and the study utilized observer-blinded efficacy assessments to minimize bias in efficacy measurements.An observer-blind and centralized independent rater pool was used to administer the primary and secondary outcome measures, that is, the CAPS-5 and the SDS for functional impairment, the latter of which was adapted to limit missing item-level data as per the FDA requirements and included use of the three-item mean as the total score and imputation of work-related impairment as the maximum score, if caused by PTSD. The independent rater measurements were conducted at baseline and following each experimental session via live video interviews. Independent raters did not repeatedly see the same participant and the independent rater pool was blinded to the complete study design, visit number, treatment assignment, and all data collected by the therapy team after baseline, with the exception of safety data related to suicidality. Participants were instructed to withhold their opinion on treatment group assignment from independent raters and to refrain from sharing details regarding the study design and their number of completed visits. To ensure that all site and sponsor staff were shielded from study outcome measures, primary and secondary outcome measures were collected from the blinded independent rater pool and stored in a dedicated database that was separate from the blinded, clinical database.

Procedures

Following an initial phone screening, participants provided written informed consent and underwent further screening assessments for eligibility. These included the PTSD Checklist for DSM-5 (PCL-5), the MINI for DSM-5, the Structured Clinical Interview for DSM-5 Screening Personality Questionnaire and Structured Clinical Interview for DSM-5 Personality Disorders (SCID-5-SPQ and -PD), the Lifetime C-SSRS, medical history, and pre-study medications. Study staff contacted outside providers, ordered medical records, and conducted a physical examination, laboratory testing (including pregnancy and drug tests), electrocardiogram, and 1-min rhythm strip. Eligible participants were enrolled in the study and began psychiatric medication taper (Table 1) if needed, and collection of adverse events. Anticipated effects of MDMA, such as euphoria, stimulation and feelings of closeness, were intentionally not solicited as adverse events to avoid biasing the collection of adverse event data. Participant medication taper was variable, lasting from 0 d (no taper needed) to 103 d. Clinical data were electronically captured using Medrio EDC versions R40–R40.7.In accordance with FDA guidance, we paid special attention to a subset of adverse events, termed AESIs, relating to cardiac function that could be indicative of QT interval prolongation or cardiac arrhythmias, abuse liability, and suicidal ideation and behavior. All adverse events that included signs or symptoms potentially associated with a cardiovascular event such as palpitations or dizziness were further evaluated for reporting as a cardiovascular adverse event. To assess signs of MDMA abuse potential, any adverse event terms such as ‘behavioral addiction’, ‘drug abuser’, ‘substance abuser’, ‘dependence’, ‘intentional product misuse’, ‘overdose’ (accidental, intentional or prescribed) or ‘drug diversion’ were collected and coded as AESIs. Suicidal ideation that was judged as serious or severe by the investigator, serious ideation defined as a C-SSRS suicidal ideation score of a 4 or 5, self-harm in the context of any suicidal ideation, and any suicide attempts were reported as AESIs.Enrolled participants underwent three 90-min preparatory sessions of therapy with a two-person therapist team in preparation for experimental sessions (Fig. 1). The preparatory sessions focused on establishing therapeutic alliance and trust, and also provided guidance on how to respond to the memories and feelings that could arise during treatment. Participants who failed to meet all eligibility criteria were withdrawn during this preparatory period. Baseline CAPS-5 assessment (to confirm PTSD diagnosis and total severity score of ≥ 35 for randomization) was performed by the independent rater pool after completion of two preparatory sessions and any necessary psychiatric medication taper to establish baseline symptom severity following removal of psychiatric medications. At the end of the preparatory period, participants were assessed for final eligibility and enrollment was confirmed prior to randomization (Fig. 1).The treatment period consisted of three 8-h experimental sessions of either MDMA-assisted therapy or therapy with inactive placebo control, spaced ~4 weeks apart. Following a 10-h fast, experimental sessions began with a qualitative urine drug screen, pregnancy screen if applicable, and C-SSRS, as well as measurement of baseline blood pressure, body temperature and heart rate immediately before the initial drug dose. Any positive findings on the urine drug screen that could not be attributed to pre-approved concomitant medications were reviewed by the medical monitor to assess compliance with ongoing eligibility criteria and for possible AESIs. Experimental sessions were conducted following a circadian rhythm-adjusted dosing schedule for a morning (~10:00 hours) initial dose.In each experimental session the participants received a single divided dose of 80–180 mg MDMA or placebo. In the first experimental session, an initial dose of 80 mg was followed by a supplemental half-dose of 40 mg 1.5–2.5 h after the first dose. In the second and third experimental sessions, an initial dose of 120 mg was followed by a supplemental half-dose of 60 mg. If tolerability issues emerged with the initial dose or if participants declined, the protocol permitted the supplemental dose and/or dose escalation to be withheld. There were no instances in which the supplemental dose was withheld due to tolerability issues. Six participants chose either not to take the supplemental dose (n = 3, 1 MDMA) or not to escalate to the 120 mg dose (n = 3, 2 MDMA) in a total of six experimental sessions (2.3% of the total sessions across the study). Blood pressure, body temperature and heart rate were measured before the supplemental dose was given. Manualized therapy was conducted in accordance with the MDMA-assisted therapy treatment manual (http://maps.org/treatment-manual). Therapy was inner-directed and designed to invite inquiry and to facilitate therapeutic effect by providing support for approaching difficult material in a manner that would not interfere with the participant’s spontaneous experience. Every therapist held a Master’s degree or above, and the protocol requirement was that one person per therapy team was licensed to provide psychotherapy in accordance with state and local requirements. Therapists were additionally required to take part in the sponsor’s five-part training process, which consisted of an online course (15 h), a training course (5 d), experiential learning (3 d), role playing (1 d), and supervision (52 h).Blood pressure, body temperature and heart rate were measured at the end of each experimental session prior to discharging the participant.Each experimental session was followed by three 90-min integration sessions that were spaced ~1 week apart to allow the participant to understand and incorporate their experience. The first integration session always occurred on the morning after the experimental session, and the remaining two integration sessions occurred over the following 3–4 weeks (Fig. 1).Independent raters conducted CAPS-5 and SDS assessments ~3 weeks after each of the first two experimental sessions. The primary outcome assessment was conducted ~8 weeks after the third experimental session (18 weeks after the baseline assessment), in which the independent raters collected the final CAPS-5 and SDS assessments. Twenty per cent of independent rater assessments were randomly selected and reviewed for fidelity. Lead independent raters evaluated the fidelity of all assessments related to enrollment failures as well as an additional 20% of remaining baseline CAPS-5 assessments. Diagnostic concordance between the raters had a Cohen’s kappa coefficient of 0.94, and reliability analysis of the CAPS-5 total severity scores showed a Spearman correlation coefficient of 0.98 (P < 0.0001), demonstrating high inter-rater reliability between the independent raters. The independent raters were all mental health professionals with graduate-level training in psychology, social work or counseling, at least 1 year of experience working with trauma-exposed populations, and had previous experience administering structured assessments.Cases of non-compliance, protocol deviations, loss to follow-up, and other reasons for participant dropout were assessed for the presence of AESIs. There were two major protocol deviations (defined as the eligibility criteria not being met by the randomized participants during the course of the study). In the first protocol deviation a participant was not compliant with drug use lifestyle modifications on study, and in the second protocol deviation a participant disclosed cannabis use at study entry but abstained for the duration of the study. There was one dosing error in which a participant in the placebo group received 80 mg placebo as an initial dose and 100 mg as a supplemental dose (n = 1). Additionally, 14 participants (10 of whom were in the MDMA arm) requested further integrative visits, as permitted by the protocol.

Objectives

The primary objective of this trial was to evaluate the efficacy and safety of MDMA-assisted therapy for PTSD compared with placebo with therapy, based on comparison of CAPS-5 total severity score at baseline with that at 18 weeks after baseline. The CAPS-5 is a semi-structured interview that assesses the index history of DSM-5-defined traumatic event exposure, including the most distressing event, to produce a diagnostic score (presence versus absence) and a PTSD total severity score. The CAPS-5 rates intrusion symptoms (intrusive thoughts or memories), avoidance, cognitive and mood symptoms, arousal and reactivity symptoms, duration and degree of distress, and dissociation. The CAPS-5 is scored on a scale from 0 to 80, with moderate PTSD defined from a rationally derived severity range of 23–34, and severe PTSD as ≥35.The secondary objective of this trial was to evaluate the efficacy of MDMA-assisted therapy for PTSD compared with placebo with therapy in clinician-rated functional impairment, as measured by the mean change in SDS total scores from baseline to 18 weeks after baseline. Exploratory outcome measures included the BDI-II, the Alcohol Use Disorders Identification Test (AUDIT), the Drug Use Disorders Identification Test (DUDIT) and the Adverse Childhood Experiences (ACE) Questionnaire.

Follow-up

Participants agreed to be recontacted for potential enrollment in a long-term follow-up study, which will include follow-up measures to assess the durability of the treatment. These data will be published at a later date.

Statistics and reproducibility

Statistical power calculations for the initial sample size were made by fitting an MMRM of CAPS-4 data (converted to the CAPS-5 scale and pooled from the phase 2 studies) to obtain variance and covariance parameter estimates. Using the estimated effect size and variance and covariance parameters, the sample size was calculated to achieve a power of 90% at an alpha of 0.049.The intent-to-treat (ITT) set consisted of 91 randomized participants, however, one participant declined dosing on the morning of the session and provided no additional data, and therefore it was not possible to complete this analysis. Participants were randomized in a blinded fashion with 1:1 allocation as described in the section on randomization, masking and bias minimization above. The modified intent-to-treat (mITT) set consisted of 90 randomized participants who had completed at least one blinded experimental session and at least one post-treatment assessment. The mITT set consisted of 46 participants randomized to the MDMA group and 44 participants randomized to the placebo group, with identical therapy. The per protocol set (completers) consisted of all participants who completed three experimental sessions and assessments (MDMA, n = 42; placebo, n = 37) (Fig. 1).The SAP was guided by the ICH E9 (R1) guidelines, which describe the use of estimands and sensitivity analyses to measure the effects of the drug if taken as directed (de jure, assessment of efficacy), and the effects of the drug if taken as assigned, regardless of adherence (de facto, assessment of effectiveness). The SAP was developed in accordance with FDA requirements and was approved by the European Medicines Agency to meet the requirements for future marketing applications. The primary and secondary efficacy analyses therefore utilized a de jure estimand of the mITT set for assessing treatment efficacy from the CAPS-5 and SDS data while on the study drug. The de jure dataset did not include outcome measurements taken after treatment discontinuation in the analysis of treatment efficacy. Missing data were not imputed.One participant in the placebo group completed only the baseline assessment, and discontinued intervention but provided CAPS data at the T4 timepoint, ~18 weeks after baseline. Given that no endpoint assessment was collected prior to treatment discontinuation, this participant is excluded from the de jure estimand (leaving n = 89) but is included in the de facto estimand sensitivity analysis (for a total of n = 90). Two additional CAPS data points at the T4 timepoint, ~18 weeks after baseline, from two participants in the placebo group who provided these data following discontinuation of treatment, were not included in the de jure estimand (Supplementary Table 1).The de facto estimand assessed the impact of these missing data points in the mITT set. That is, the CAPS measures at the T4 timepoint, ~18 weeks after baseline for the three placebo participants who discontinued treatment but provided off-treatment outcome assessments were included in a sensitivity analysis, which determined that inclusion of these measures in the model did not significantly alter the results.The primary and secondary efficacy analyses were carried out using an MMRM that included all outcome data from baseline and the first, second and third experimental sessions. The efficacy of treatment was tested by comparing the change from baseline to the third experimental session in CAPS-5 and SDS scores between treatment groups in two-sided tests. The fixed effects were treatment (MDMA or placebo), baseline CAPS score, dissociative subtype and investigational site, with random effect specified as study participant.A hierarchical testing strategy was used to control for type I error, such that the hypothesis for the key secondary endpoint (SDS) would be tested only if the statistical test for the primary efficacy comparison rejected the null hypothesis. An analysis of covariance (ANCOVA) to test the effects of study participation before versus after the COVID-19 pandemic declaration by the World Health Organization indicated a non-significant interaction and therefore was not included in the primary outcome model (Supplementary Table 2). The primary outcome analysis was replicated independently by one blinded programmer and one unblinded programmer.An independent data monitoring committee monitored adverse events for safety and conducted one administrative interim analysis, after completion of enrollment and of 60% of primary endpoints to examine the adequacy of the sample size. The data monitoring committee recommended that no additional participants should be added, based on conditional power calculations supporting 90% statistical power, but in keeping with the SAP did not provide the sponsor with any information on the conditional power or effect size. The alpha level was set to 0.05, and 2% of the alpha (0.001) was spent on the interim analysis and 98% (0.0499) was left for the final analysis.Statistics for the primary and secondary efficacy comparisons (CAPS and SDS) are reported as P values from the results of the MMRM analysis. In exploratory analyses, additional baseline covariates of age, gender, ethnicity, prior use of SSRIs, depression as measured by the BDI-II, adverse childhood experiences, and alcohol and substance use disorders were assessed in the model, with the threshold of significance set at P < 0.05 (Supplementary Table 1). BDI-II score was also assessed as an exploratory efficacy outcome measure with a paired, two-tailed t-test. Results are reported as mean (s.d.) throughout the text. Between-group effect size was calculated with Cohen’s d, and 95% CIs are reported. SAS version 9.4 (SAS Institute) was used for analyses.The safety analysis included all participants who were given at least one dose of the study drug or placebo. The primary safety analysis evaluated TEAEs as a participant-level analysis. An association with MDMA was determined based on the relative incidence of TEAEs with at least a twofold difference between the MDMA and placebo groups.

Main

Post-traumatic stress disorder (PTSD) is a widespread and severe health issue that causes significant societal and financial burden, affecting hundreds of millions of individuals annually. Various environmental and biological factors contribute to the development and persistence of PTSD. Poor treatment outcomes are often linked to co-occurring health problems, including childhood trauma, alcohol and substance use disorders, depression, suicidal thoughts, and dissociation. Therefore, it is crucial to find treatments that can benefit individuals with these conditions, which often make treatment difficult.

Common antidepressants like sertraline and paroxetine, known as selective serotonin reuptake inhibitors (SSRIs), are approved as initial treatments for PTSD. However, approximately 40-60% of individuals do not respond to these medications. Similarly, while trauma-focused therapies such as prolonged exposure and cognitive behavioral therapy are considered standard treatments for PTSD, many individuals do not improve significantly or stop treatment early. This highlights the urgent need for new, cost-effective therapies.

The substance 3,4-methylenedioxymethamphetamine (MDMA), a substituted amphetamine, promotes serotonin release primarily by interacting with serotonin transporters. In animal studies, MDMA has been shown to improve the extinction of fear memories, modify the reshaping of fear memories (possibly through a mechanism involving oxytocin), and enhance social behavior. A combined analysis of six earlier clinical trials of MDMA-assisted therapy for PTSD has indicated promising safety and effectiveness. This study examined the effectiveness and safety of MDMA-assisted therapy in individuals with severe PTSD. Participants received three doses of MDMA or a placebo in a controlled clinical setting, accompanied by a trained therapy team. Primary and secondary symptom measures were assessed by independent, blinded evaluators. MDMA-assisted therapy for PTSD received a special designation from the Food and Drug Administration (FDA), and its study plan was developed in conjunction with the FDA.

Results

Demographics

Participant recruitment occurred from November 2018 to May 2020. Out of 345 individuals assessed, 131 were enrolled, and 91 were confirmed for randomization across sites in the United States, Canada, and Israel. Ultimately, 46 participants were assigned to MDMA and 44 to placebo.

The two study groups (MDMA and placebo) were similar in terms of race, ethnicity, sex, age, dissociative subtype, disability status, and initial PTSD symptom severity. The average length of PTSD diagnosis was around 13-15 years for both groups. Notably, six participants in the MDMA group and 13 in the placebo group had the dissociative subtype of PTSD.

Efficacy

MDMA significantly reduced PTSD symptoms, as indicated by changes in the CAPS-5 total severity score from the study's start to 18 weeks later. Statistical analysis confirmed a notable difference in symptom reduction between the MDMA and placebo groups. Among those who completed the full treatment, the average CAPS-5 score reduction was greater in the MDMA-assisted therapy group compared to the placebo with therapy group. The observed treatment effect size was substantial.

Over the same period, MDMA also significantly improved daily functioning, as rated by clinicians. The average improvement in daily functioning was greater in the MDMA-assisted therapy group compared to the placebo with therapy group.

MDMA demonstrated effectiveness even in participants with other health conditions often linked to treatment difficulties. Individuals with the dissociative subtype of PTSD who received MDMA-assisted therapy experienced significant symptom reduction, similar to those with non-dissociative PTSD. The benefits of MDMA therapy were consistent across all study sites and were not affected by a history of alcohol use disorder, substance use disorder, or severe childhood trauma. Previous SSRI use did not appear to impact the effectiveness of MDMA.

Exploratory analysis also showed MDMA therapy reduced depression symptoms, as measured by the Beck Depression Inventory II (BDI-II), from the start of the study to its conclusion.

At the primary study endpoint 18 weeks after baseline, 67% of individuals in the MDMA group no longer met the diagnostic criteria for PTSD, compared to 32% in the placebo group after three sessions. Additionally, 33% of participants in the MDMA group and 5% in the placebo group met the criteria for remission (loss of diagnosis and a low CAPS-5 score) after three sessions.

Safety

Side effects that appeared during treatment and were more common in the MDMA group were typically temporary and mild to moderate. These included muscle tightness, decreased appetite, nausea, increased sweating, and feeling cold. Importantly, no increase in suicidal thoughts or behaviors was observed in the MDMA group. A temporary increase in blood pressure and heart rate was noted in the MDMA group. Two participants in the MDMA group experienced a temporary increase in body temperature.

Two participants, both in the placebo group, reported three serious adverse events during the trial, including suicidal behavior and suicidal ideation requiring hospitalization. Overall, five participants in the placebo group and three in the MDMA group reported adverse events of special interest related to suicidal ideation, suicidal behavior, or self-harm. One participant in the placebo group reported two cardiovascular events. One participant in the MDMA group discontinued participation due to being triggered by assessments and experiencing depressed mood after a session, but MDMA sessions were not generally followed by a lowering of mood.

Suicidal ideation was tracked throughout the study. More than 90% of participants reported having suicidal thoughts at some point in their lives, and a significant percentage in both groups reported suicidal ideation at the start of the study. While the number of participants reporting suicidal ideation varied, it never exceeded baseline levels and was not worsened in the MDMA group. Serious suicidal ideation was minimal during the study and occurred almost entirely in the placebo group.

Discussion

This study demonstrates that three doses of MDMA, administered with structured therapy over 18 weeks, lead to a significant and strong reduction in PTSD symptoms and functional impairment. MDMA also significantly lessened depressive symptoms and did not increase the occurrence of suicidality during the study.

These findings suggest that MDMA-assisted therapy for PTSD may offer greater benefits compared to currently approved first-line drug treatments like sertraline and paroxetine, which have shown smaller effects in previous studies. While a direct comparison with SSRIs is needed to confirm superiority, the current study observed greater improvement in PTSD symptoms in the MDMA and supportive therapy group compared to the placebo and supportive therapy group, indicating that MDMA enhanced the effects of the therapy. In clinical practice, both MDMA and supportive therapy are intended components of this PTSD treatment.

MDMA may exert its therapeutic effects by influencing serotonin function in the amygdala, a brain region involved in fear. This mechanism could help regulate fear-based behaviors that contribute to PTSD. It is also theorized that MDMA might temporarily create a "window of tolerance," allowing individuals to revisit and process traumatic experiences without becoming overwhelmed by intense emotional or dissociative symptoms. This could facilitate a more compassionate approach to negative memories and potentially strengthen the therapeutic relationship, which is vital for treatment success.

The robust reduction in PTSD and depressive symptoms, coupled with significant improvement in daily functioning, is particularly promising. PTSD is a strong predictor of disability, and an effective treatment that improves social, family, and work functioning could lead to substantial medical cost savings and enhance quality of life for those affected. Most compelling are the data showing efficacy in individuals with chronic and severe PTSD, as well as those with co-occurring conditions like childhood trauma, depression, suicidality, and substance use disorders—groups typically considered resistant to treatment. Given that most PTSD diagnoses occur with at least one other disorder, a therapy effective in these complex cases could greatly improve treatment outcomes. Future studies should further evaluate MDMA-assisted therapy in individuals with specific co-occurring conditions, including the dissociative subtype of PTSD, where current treatments are often less effective.

The study reported no major safety concerns in the MDMA group. Although potential for abuse, cardiovascular risk, and suicidality were monitored, MDMA was not found to cause or worsen any of these conditions. Temporary increases in blood pressure during MDMA sessions were expected and consistent with previous research. These findings suggest MDMA's safety profile is comparable to, if not better than, first-line SSRIs for PTSD.

The study had some limitations, including a smaller participant population than initially planned due to the COVID-19 pandemic, although statistical power was maintained. The participant population also lacked racial and ethnic diversity, which should be addressed in future trials. This report presents short-term outcomes, and long-term follow-up data will assess treatment durability. While efficacy data were collected by blinded, independent evaluators, safety data were collected by site therapists, which could potentially introduce some bias. Participant blinding was also challenging due to the subjective effects of MDMA, though some participants in both groups inaccurately guessed their treatment assignment. Despite these limitations, the potential for MDMA-assisted therapy to significantly transform PTSD treatment, especially for treatment-resistant cases, warrants rapid evaluation for clinical use, particularly given the potential for increased psychological and mental health challenges in society.

Methods

Study Design and Participant Selection

This was a randomized, double-blind study designed to compare the effectiveness of MDMA-assisted therapy with placebo and therapy. The study involved 15 sites across the United States, Canada, and Israel, including both institutional and private clinics. All procedures were conducted with ethical approval and in accordance with established guidelines. Participants were recruited through advertisements and referrals, and individuals were required to initiate contact with the study sites. After providing consent, participants were screened for eligibility. Key inclusion criteria included a current PTSD diagnosis lasting at least six months with a significant symptom severity score. Exclusion criteria involved serious psychiatric conditions such as primary psychotic disorders or bipolar I disorder, active eating disorders, current substance use disorders, pregnancy, or medical conditions that could make a sympathomimetic drug harmful. Participants taking psychiatric medications underwent a medically supervised tapering period before baseline assessments. The study protocol was amended during enrollment to clarify eligibility criteria, add suicidal ideation and behavior as special interest events, increase the frequency of suicidality assessments, and allow some remote visits due to the COVID-19 pandemic. The sample size was slightly reduced due to pandemic-related disruptions, but statistical power remained sufficient.

Study Drug and Administration

The study drug was manufactured following strict quality standards. Assays for chemistry, manufacturing, and controls were completed according to regulatory guidelines and reported to relevant health authorities.

Therapeutic Procedures

Enrolled participants completed three 90-minute preparatory therapy sessions with a two-person therapist team to establish trust and guide participants on how to respond to memories and feelings during treatment. After these sessions and any necessary medication taper, participants underwent a baseline assessment to confirm their PTSD diagnosis and severity for randomization. The treatment phase involved three 8-hour experimental sessions, spaced approximately four weeks apart, where participants received either MDMA-assisted therapy or inactive placebo with therapy. Before each experimental session, participants underwent screenings and vital sign measurements. Participants received a single divided dose of MDMA (80–180 mg) or placebo. In the first session, an initial 80 mg dose was followed by a 40 mg supplemental dose; in subsequent sessions, 120 mg was followed by 60 mg. Manualized therapy, provided by a team of therapists with advanced degrees and specialized training, was inner-directed and designed to support participants in processing difficult material without interfering with their spontaneous experience. Following each experimental session, participants engaged in three 90-minute integration sessions, spaced about one week apart, to help them understand and incorporate their experiences.

Outcome Measurement and Blinding

Participants were randomly assigned 1:1 to either the MDMA or placebo group, with randomization managed by an independent system to maintain blinding for participants, site staff, and the sponsor until after database lock. An inactive placebo was used as the comparison to clearly assess the effect of MDMA. To minimize bias in efficacy measurements, an observer-blinded and centralized pool of independent raters administered the primary and secondary outcome measures. These raters, who were mental health professionals, were blinded to the study design, visit number, and treatment assignment. Participants were instructed not to reveal their treatment assignment to the independent raters. The primary objective was to evaluate efficacy and safety based on the CAPS-5 total severity score change from baseline to 18 weeks after baseline. The CAPS-5 is a semi-structured interview assessing PTSD symptoms and severity. The secondary objective evaluated clinician-rated functional impairment using the SDS. Exploratory measures included the BDI-II for depression, and questionnaires for alcohol and drug use disorders, and adverse childhood experiences.

Safety and Statistical Analysis

Special attention was paid to a subset of adverse events, termed Adverse Events of Special Interest (AESIs), related to cardiac function, abuse potential, and suicidal ideation and behavior. These were thoroughly collected and coded. Suicidality was tracked throughout the study using a standardized scale at each visit. Statistical analyses utilized a mixed model repeated measure (MMRM) approach, including all outcome data. The primary and secondary efficacy analyses aimed to assess treatment efficacy based on the effects of the drug as directed. Sensitivity analyses were also performed. A hierarchical testing strategy was used to control for statistical errors. An independent data monitoring committee oversaw adverse events and confirmed the adequacy of the sample size. The safety analysis included all participants who received at least one dose of the study drug or placebo, evaluating side effects based on their relative incidence between groups. Long-term follow-up data will be collected to assess treatment durability.

Main

Post-traumatic stress disorder (PTSD) is a serious and widespread condition that impacts the lives of many individuals each year, leading to significant social and economic burdens. Various environmental and biological factors can contribute to its development and persistence. Poor outcomes from PTSD treatment are often linked to other co-occurring conditions, such as childhood trauma, alcohol and substance use disorders, depression, thoughts of suicide, and dissociation. Therefore, it is crucial to find treatments that work well for individuals who also have these conditions, as they typically make PTSD harder to treat.

The medications sertraline and paroxetine, both selective serotonin reuptake inhibitors (SSRIs), are approved as initial treatments for PTSD. However, a large number of patients, estimated between 40% and 60%, do not respond to these drugs. Similarly, while evidence-based psychotherapies like prolonged exposure and cognitive behavioral therapy are considered top-tier treatments, many people either do not improve significantly, continue to have symptoms, or drop out of treatment. This highlights a clear need for new, affordable, and effective treatments.

The compound 3,4-methylenedioxymethamphetamine (MDMA), a type of substituted amphetamine, primarily works by releasing serotonin. In animal studies, MDMA has been shown to improve the unlearning of fear memories, affect how fear memories are re-stored (possibly through a mechanism involving oxytocin), and enhance social behaviors. A combined analysis of six early-stage clinical trials for MDMA-assisted therapy in PTSD has already shown promising results regarding its safety and effectiveness. This study evaluates the effectiveness and safety of MDMA-assisted therapy in individuals with severe PTSD. Participants received three doses of either MDMA or a placebo in a supervised clinical setting, supported by a trained therapy team. Key measures of symptom reduction and functional improvement were assessed by independent evaluators who were unaware of the treatment assignment. The U.S. Food and Drug Administration (FDA) has given MDMA-assisted therapy for PTSD a "Breakthrough Therapy" designation, and the study's design and analysis plan were developed in cooperation with the FDA.

Results

Demographics

Participants were enrolled in the study from November 2018 to May 2020, with the final participant visit in August 2020. A total of 345 individuals were screened for eligibility, 131 were enrolled, and 91 were confirmed for randomization. Of these, 46 were assigned to receive MDMA, and 44 were assigned to receive placebo.

The two study groups did not show significant differences in terms of race, ethnicity, sex, age, dissociative subtype, disability status, or baseline PTSD symptom scores. The average length of time participants had been diagnosed with PTSD was about 14.8 years for the MDMA group and 13.2 years for the placebo group. Notably, 6 participants in the MDMA group and 13 in the placebo group had the dissociative subtype of PTSD.

Efficacy

MDMA significantly reduced PTSD symptoms, as evidenced by changes in total symptom severity scores from the start of the study to 18 weeks later. Analysis showed a significant difference between the treatment groups, indicating that MDMA-assisted therapy led to greater improvement. A similar analysis, which included all participants regardless of their adherence to the full treatment, also found a significant difference.

The average change in PTSD symptom scores from baseline to 18 weeks was a reduction of 24.4 points in the MDMA-assisted therapy group, compared to a reduction of 13.9 points in the placebo group. The treatment effect size for MDMA-assisted therapy was notably larger than those observed in previous studies of other PTSD medications. While this study provided supportive therapy to both groups, participants who received MDMA along with the therapy showed greater improvement in PTSD symptoms compared to those who received placebo with therapy, suggesting that MDMA enhanced the effects of the supportive therapy.

Over the same period, MDMA also significantly improved participants' functional impairment as rated by clinicians. The average reduction in functional impairment scores was 3.1 points in the MDMA-assisted therapy group versus 2.0 points in the placebo group.

MDMA proved equally effective in participants with co-occurring conditions often linked to treatment resistance. Individuals with the dissociative subtype of PTSD who received MDMA-assisted therapy experienced significant symptom reduction, similar to those with non-dissociative PTSD. The benefits of MDMA therapy were not influenced by a history of alcohol or substance use disorder, requiring an overnight stay, or severe childhood trauma. Results were consistent across all study sites, and there was no clear impact of prior SSRI use on the effectiveness of MDMA.

In an additional analysis, MDMA therapy was found to be effective in reducing symptoms of depression from baseline to the end of the study. The average reduction in depression scores was 19.7 points in the MDMA group compared to 10.8 points in the placebo group.

Clinical improvements were also tracked. At 18 weeks, 67% of participants in the MDMA group no longer met the diagnostic criteria for PTSD, compared to 32% in the placebo group. Furthermore, 33% of participants in the MDMA group achieved remission (no longer met diagnostic criteria and had very low symptom scores), compared to 5% in the placebo group after three sessions.

Safety

Adverse events that occurred more frequently in the MDMA group during the treatment period were generally temporary and mild to moderate in severity. These included muscle tightness, decreased appetite, nausea, increased sweating, and feeling cold. Importantly, there was no increase in adverse events related to suicidal thoughts or behaviors in the MDMA group. A temporary increase in blood pressure and heart rate was observed in the MDMA group. Two participants in the MDMA group experienced a temporary increase in body temperature to 38.1 °C.

During the trial, two participants, both from the placebo group, reported three serious adverse events. One placebo participant reported two serious events of suicidal behavior, and another reported one serious event of suicidal ideation that required hospitalization. Overall, suicidal thoughts, suicidal behavior, or self-harm in the context of suicidal ideation were reported by five participants in the placebo group and three in the MDMA group. One placebo participant also reported two heart-related adverse events where an underlying heart problem could not be ruled out. One participant in the MDMA group stopped participating due to being triggered by assessment questions and experiencing depressed mood after an experimental session, but MDMA sessions were not generally followed by a lowering of mood.

Suicidality was monitored throughout the study. Over 90% of participants reported suicidal ideation at some point in their lives before the study, and at baseline, 37% of the MDMA group and 32% of the placebo group reported suicidal ideation. While the number of participants reporting suicidal ideation varied during the study, it never exceeded baseline levels and was not made worse in the MDMA group. Serious suicidal ideation was minimal during the study and occurred almost entirely in the placebo group.

Discussion

This study demonstrates that three doses of MDMA, administered with structured therapy over 18 weeks, significantly and powerfully reduce PTSD symptoms and functional impairment. MDMA also notably lessened depressive symptoms. Importantly, MDMA did not increase the occurrence of suicidality during the study.

These findings highlight the potential benefits of MDMA-assisted therapy for PTSD, especially when compared to currently approved first-line medications like sertraline and paroxetine, which have shown smaller treatment effects in their primary studies. The effect size observed in this study for MDMA-assisted therapy was larger than any previously identified for PTSD medications. While both treatment groups in this study received supportive therapy, participants who received MDMA along with therapy experienced greater improvement in PTSD symptoms than those who received placebo with therapy, suggesting that MDMA enhanced the therapeutic process. In clinical practice, both MDMA and supportive therapy would be combined for PTSD treatment.

Previous research suggested that recent SSRI treatment might reduce MDMA's effectiveness. However, in this trial, which included many participants with a history of SSRI use, no clear impact of prior SSRI use on MDMA's therapeutic effectiveness was observed. Similarly, the duration or onset age of PTSD diagnosis did not appear to affect treatment efficacy in this study. MDMA may exert its therapeutic effects by influencing serotonin function in the amygdala, a brain region critical for fear responses. This could potentially re-open a period of brain flexibility, allowing individuals to process traumatic memories with less overwhelm or dissociation. This "window of tolerance" may enable participants to revisit and process difficult content with greater self-compassion and less shame or anger. Additionally, MDMA's effects on social connection might improve the therapeutic relationship, which is vital for treatment success.

Given that PTSD is a strong predictor of disability, the observed robust reduction in PTSD and depressive symptoms, coupled with significant improvements in daily functioning, is promising. Identifying a PTSD treatment that can improve social and family functioning and reduce impairment across various life contexts could lead to substantial healthcare cost savings and vastly improve the quality of life for those affected. The study's most compelling finding may be MDMA's effectiveness in individuals with chronic and severe PTSD, especially those with co-occurring conditions like childhood trauma, depression, suicidality, and substance use disorders, as these groups are often considered resistant to typical treatments. Since over 80% of individuals diagnosed with PTSD have at least one co-occurring disorder, a therapy effective for complicated PTSD and dual diagnoses could greatly enhance PTSD care. Further studies should explore MDMA-assisted therapy's safety and efficacy in specific co-occurring conditions.

While the dissociative subtype of PTSD is often challenging to treat, participants with this subtype who received MDMA-assisted therapy experienced significant symptom reduction, comparable to those with non-dissociative PTSD. If replicated, these findings suggest an important new therapeutic option for populations that are typically difficult to treat. Importantly, no major safety concerns were reported in the MDMA group of this study. Although potential for abuse, cardiovascular risk, and suicidality were closely monitored, MDMA was not found to cause or worsen any of these conditions. The temporary increase in blood pressure during MDMA sessions was expected and consistent with prior research. These data suggest MDMA has a safety profile comparable to, or even better than, first-line SSRIs used for PTSD, which are known to carry a low risk of certain heart rhythm issues.

This trial had several limitations. First, the participant population was smaller than originally planned due to the COVID-19 pandemic. However, the study's statistical power suggests that this reduced size did not hinder its ability to detect effects. Second, the population was relatively uniform, lacking diverse racial and ethnic representation, an aspect for future trials to address. Third, this report covers only short-term outcomes; long-term follow-up data will be collected to assess treatment durability. Fourth, while efficacy data were collected by blinded, independent raters, safety data were necessarily collected by site therapists, which might have introduced some bias. Finally, blinding participants to their treatment was challenging due to MDMA's subjective effects, potentially leading to expectation effects. However, informal checks showed that a notable percentage of participants guessed their treatment assignment incorrectly.

The potential economic and social impacts of PTSD, possibly worsened by the COVID-19 pandemic, are significant. High rates of psychological and mental health challenges could persist for years, imposing considerable emotional and financial burdens. New PTSD treatments are urgently needed, especially for those whose co-occurring conditions make them resistant to current therapies.

In summary, MDMA-assisted therapy rapidly improves symptoms, even in individuals with severe PTSD and associated conditions like dissociative PTSD, depression, a history of alcohol and substance use disorders, and childhood trauma. Not only is MDMA-assisted therapy effective in individuals with severe PTSD, but it may also offer improved patient safety. Compared to current first-line pharmacological and behavioral therapies, MDMA-assisted therapy has the potential to dramatically change PTSD treatment and warrants swift evaluation for clinical use.

Methods

Study design

This was a randomized, double-blind study designed to compare the effectiveness of MDMA-assisted therapy with therapy plus an inactive placebo. The study involved 15 sites, including institutional sites and private clinics across the United States, Canada, and Israel. Ethical approval was obtained from various review boards, ensuring the study followed ethical principles for clinical research.

Participants

Participants were recruited through advertisements, referrals, and word-of-mouth, initiating contact with study sites themselves. After providing informed consent, individuals were screened for eligibility. Key inclusion criteria included meeting diagnostic criteria for current PTSD with symptoms lasting at least six months, and a PTSD symptom severity score of 35 or higher at the start of the study. Exclusion criteria included primary psychotic disorders, bipolar I disorder, dissociative identity disorder, active eating disorders, major depressive disorder with psychotic features, certain personality disorders, current alcohol or substance use disorders, pregnancy, lactation, or any medical condition that would make taking a drug that increases blood pressure and heart rate unsafe. Participants with mild, stable, chronic medical issues were eligible if deemed safe by medical professionals. Participants were required to discontinue psychiatric medications under medical supervision before baseline assessments. During the study, eligibility criteria were clarified or adjusted, and suicidality assessments were increased in frequency. Due to the COVID-19 pandemic, the planned sample size was slightly reduced to maintain statistical power and avoid delays.

Study drug

The study drug was manufactured according to strict quality standards and tested thoroughly before use.

Randomization, masking and bias minimization

Participants were randomly assigned, with equal probability, to either the MDMA-assisted therapy group or the placebo with therapy group. This assignment was managed by an independent system to ensure that participants, site staff, and the study sponsor remained unaware of who received which treatment until after the study data were finalized. An inactive placebo was used to clearly isolate the effects of MDMA itself. While a low-dose MDMA was considered in earlier studies, an inactive placebo was chosen to allow for a clearer comparison of safety data and to maximize the ability to detect a difference between active treatment and control. To further minimize bias in evaluating treatment effects, all primary and secondary outcome measures were assessed by independent evaluators who were unaware of the participant's treatment assignment or specific study details. Participants were instructed not to reveal their treatment beliefs or study details to these evaluators.

Procedures

After an initial phone screening, participants provided consent and underwent further assessments, including psychiatric interviews, medical history, physical exams, and lab tests. Participants began a psychiatric medication taper if needed, and adverse events were monitored. Preparatory therapy sessions were conducted with a two-person therapist team to build trust and guide participants on how to engage with their experiences during treatment. Eligibility was confirmed before randomization.

The treatment period involved three experimental sessions, spaced about four weeks apart, where participants received either MDMA or inactive placebo. Each session began with a fast and checks for drug use, pregnancy, and vital signs. Dosing involved an initial dose followed by a supplemental half-dose. Blood pressure, body temperature, and heart rate were monitored before the supplemental dose. Therapy, guided by a manual, was designed to support participants in processing difficult material without overwhelming them. All therapists had advanced degrees and underwent extensive training.

Following each experimental session, three integration therapy sessions were held over the next few weeks to help participants understand and incorporate their experiences. Independent evaluators conducted PTSD and functional impairment assessments after the first two experimental sessions and the primary outcome assessment at 18 weeks. A portion of these assessments were reviewed for accuracy, showing high agreement among evaluators. Any protocol deviations or participant dropouts were reviewed, and specific adverse events related to cardiac function, abuse potential, and suicidality were closely tracked.

Objectives

The main goal of this trial was to assess how effective and safe MDMA-assisted therapy is for PTSD compared to placebo with therapy. This was primarily measured by changes in the total severity score of the CAPS-5, a structured interview that evaluates PTSD symptoms, from the start of the study to 18 weeks later. The CAPS-5 scores range from 0 to 80, with scores of 35 or higher indicating severe PTSD. The secondary goal was to evaluate the effectiveness of MDMA-assisted therapy in improving clinician-rated functional impairment, measured by changes in SDS total scores over the same period. Other exploratory measures included assessments for depression, alcohol and drug use disorders, and adverse childhood experiences.

Follow-up

Participants agreed to be contacted for a future long-term follow-up study to assess how long the treatment effects last. These data will be published at a later time.

Statistics and reproducibility

Statistical power calculations were performed to determine the initial sample size, aiming for a 90% power to detect a significant treatment effect. The primary analyses included participants who completed at least one experimental session and one post-treatment assessment. Efficacy was primarily assessed using a mixed-model repeated measures (MMRM) analysis, which included all available outcome data over time. This analysis compared changes in CAPS-5 and SDS scores between the MDMA and placebo groups. The study also conducted sensitivity analyses to ensure results were robust even with missing data.

A sequential testing strategy was used to control for statistical errors, meaning the secondary outcome was tested only if the primary outcome showed a significant result. An independent data monitoring committee regularly reviewed adverse events for safety and conducted an interim analysis to confirm the sample size was adequate. The statistical analyses were independently replicated to ensure accuracy. The safety analysis included all participants who received at least one dose of the study drug or placebo, evaluating adverse events that occurred during the treatment period. Any adverse events that appeared at least twice as often in the MDMA group compared to the placebo group were considered potentially associated with MDMA.

Main

Post-traumatic stress disorder (PTSD) is a serious and widespread condition that impacts the lives of millions annually, incurring significant social and economic costs. Several environmental and biological factors contribute to its development and persistence. People with PTSD often experience other conditions, such as childhood trauma, alcohol or substance use disorders, depression, suicidal thoughts, and dissociation, which can make treatment less effective. Therefore, it is important to find treatments that work well for individuals with these co-occurring conditions.

Current first-line treatments for PTSD include the medications sertraline and paroxetine, which are approved by the Food and Drug Administration (FDA). However, an estimated 40–60% of patients do not respond to these drugs. Similarly, while evidence-based trauma-focused psychotherapies, such as prolonged exposure and cognitive behavioral therapy, are considered the best available treatments for PTSD, many participants still experience significant symptoms or drop out of therapy. This highlights a critical need for new, cost-effective treatments.

MDMA, a type of amphetamine, affects brain chemistry by increasing the release of serotonin. In animal studies, MDMA has been shown to help reduce fear memories, change how fear memories are stored, and improve social behavior. Recent analyses of six earlier Phase 2 trials of MDMA-assisted therapy for PTSD have shown promising results regarding its safety and effectiveness.

This study evaluated the effectiveness and safety of MDMA-assisted therapy in individuals with severe PTSD. Participants received three doses of MDMA or a placebo in a controlled clinical setting, accompanied by a trained therapy team. The main and secondary results were measured by trained, independent evaluators who did not know whether a participant received MDMA or placebo. MDMA-assisted therapy for PTSD was given a special "Breakthrough Therapy" status by the FDA, and the study plan was developed with the FDA's input.

Results

Demographics

Participants were recruited between November 2018 and May 2020. Of 345 people screened for eligibility, 91 were confirmed for randomization, with 46 assigned to the MDMA group and 44 to the placebo group. The study groups were similar in terms of age, race, ethnicity, gender, and initial PTSD symptom severity. On average, participants had been diagnosed with PTSD for over 13 years. A notable number of participants, including 6 in the MDMA group and 13 in the placebo group, experienced the dissociative subtype of PTSD.

Efficacy

MDMA significantly reduced PTSD symptoms, as measured by the CAPS-5 score, from the start of the study to 18 weeks later. Analysis showed a significant difference between the MDMA and placebo groups, indicating MDMA's effectiveness. Participants receiving MDMA therapy experienced a much larger decrease in their CAPS-5 scores compared to those receiving placebo therapy. The treatment showed a strong effect size, indicating a significant benefit from MDMA compared to placebo with therapy. MDMA also significantly improved daily functioning, as reported by clinicians using the SDS scale.

MDMA was effective even in participants with other conditions often considered difficult to treat, such as the dissociative subtype of PTSD, where symptom reduction was similar to those without dissociation. The positive effects of MDMA therapy were consistent regardless of a participant's history of alcohol or substance use disorder, or severe childhood trauma. Additionally, MDMA therapy helped reduce symptoms of depression. By the end of the study, 67% of participants in the MDMA group no longer met the criteria for a PTSD diagnosis, compared to 32% in the placebo group. Furthermore, 33% in the MDMA group achieved full remission from PTSD, while only 5% in the placebo group did.

Safety

Side effects that appeared during the treatment period were generally temporary, mild to moderate, and included muscle tightness, decreased appetite, nausea, increased sweating, and feeling cold. Crucially, the MDMA group did not show an increase in suicidal thoughts or behaviors. Temporary increases in blood pressure and heart rate were seen in the MDMA group, which was expected. A temporary slight increase in body temperature was noted in two MDMA participants.

In contrast, all serious adverse events reported during the trial, including suicidal behavior and suicidal thoughts leading to hospitalization, occurred in the placebo group. One MDMA participant stopped treatment due to emotional triggers during assessments and depressed mood after a session, but MDMA sessions were not otherwise linked to a lowering of mood. While over 90% of all participants reported suicidal thoughts at some point in their lives, and about a third reported them at the study's start, these thoughts did not worsen in the MDMA group and never surpassed initial levels. Serious suicidal thoughts were rare and nearly all occurred in the placebo group.

Discussion

This study shows that three doses of MDMA combined with structured therapy over 18 weeks significantly reduced PTSD symptoms and improved daily functioning. MDMA also lessened symptoms of depression. Importantly, MDMA did not increase suicidal thoughts or behaviors during the study. These results suggest MDMA-assisted therapy may be more effective than current FDA-approved first-line medications like sertraline and paroxetine, which have shown smaller benefits in past studies. The strong effect size found in this study is greater than that seen with any other PTSD medication before. While both groups received supportive therapy, MDMA appeared to make the supportive therapy more effective. This suggests MDMA and supportive therapy together form a powerful treatment. While some past studies suggested that previous SSRI use might affect MDMA's effectiveness, this study found no clear impact of prior SSRI use on the treatment's success, nor did the duration of PTSD diagnosis.

It is thought that MDMA might help the brain become more flexible, allowing individuals to process deeply rooted, fear-related memories. The combination of MDMA and therapy might create a "window of tolerance," allowing individuals to revisit traumatic experiences without becoming overwhelmed by intense emotions or dissociation. This therapy could help people recall difficult memories with more self-compassion, and reduce shame and anger related to PTSD. The temporary effects of MDMA, such as increased connection with others, may also strengthen the bond between patient and therapist, which can improve treatment results.

Since PTSD often leads to disability in veterans and the general public, finding a PTSD treatment that improves social and family life and reduces widespread impairment could lead to major cost savings and significantly improve quality of life. Perhaps the most important finding is MDMA's effectiveness for people with long-term and severe PTSD, especially those with other conditions like childhood trauma, depression, suicidal thoughts, substance use disorders, and dissociation, as these groups are often hard to treat. Because over 80% of people with PTSD also have another disorder, finding a therapy effective for complex PTSD and dual diagnoses could greatly improve treatment outcomes. Even for the dissociative subtype of PTSD, which is often challenging to treat, MDMA-assisted therapy led to significant symptom reduction, similar to that seen in those without this subtype.

Crucially, no major safety concerns were reported in the MDMA group. While potential for abuse, heart risks, and suicidality were monitored closely, MDMA did not appear to cause or worsen any of these conditions. These findings suggest that MDMA may have a safety profile comparable to, or even better than, current first-line SSRI medications for PTSD. This study did have some limitations: the number of participants was smaller than planned due to the COVID-19 pandemic, and the participants were not very diverse in terms of race and ethnicity. This report focuses on short-term results; long-term follow-up data will be collected to see how lasting the treatment effects are. Due to the noticeable effects of MDMA, it was hard to keep participants unaware of whether they received the drug or placebo, which could have influenced expectations. However, at least 10% of participants incorrectly guessed their treatment group.

In summary, MDMA-assisted therapy quickly showed effectiveness, even in people with severe PTSD and other complex conditions. Beyond its effectiveness in severe PTSD, MDMA-assisted therapy may also offer improved safety for patients. Compared to existing treatments, MDMA-assisted therapy has the potential to significantly change how PTSD is treated and should be quickly considered for widespread use.

Methods

Study design

This was a randomized, double-blind study designed to compare the effectiveness of MDMA-assisted therapy with that of a placebo. The study took place at 15 locations across the United States, Canada, and Israel, including both institutional sites and private clinics. The study received approval from ethics review boards and was conducted according to ethical principles.

Participants

Participants were recruited through various methods, including advertisements and referrals. To be included, participants had to meet the diagnostic criteria for current PTSD for at least six months and have severe PTSD symptoms. People were excluded if they had other serious mental health conditions, active substance use disorders, were pregnant or breastfeeding, or had medical conditions that would make MDMA unsafe. Participants on psychiatric medications had to stop them under medical supervision before the study began. The study plan was updated several times during the study to clarify eligibility, increase monitoring for suicidal thoughts, and allow for some remote visits due to the COVID-19 pandemic. Due to the pandemic, the planned number of participants was reduced to 90, which was still enough to gather meaningful data. The study drug was manufactured following strict quality standards.

Randomization, masking and bias minimization

Participants were randomly assigned, without knowing which group they were in, to either the MDMA group or the placebo group. An inactive placebo was used to determine the specific effects of MDMA and to allow for a clear comparison of safety between the groups. To minimize bias, independent evaluators assessed treatment effectiveness without knowing participants' assigned groups. Participants were asked not to reveal their treatment group or study details to these evaluators.

Procedures

Before receiving the study drug, participants had three preparatory therapy sessions with a two-person therapist team. These sessions built trust and prepared participants for the emotional work involved. Baseline PTSD symptom severity was assessed after preparatory sessions and any necessary medication tapering. The main treatment involved three 8-hour sessions, about four weeks apart, where participants received either MDMA or the placebo along with therapy. During each session, participants received a dose of MDMA (or placebo), typically an initial dose followed by a smaller booster dose a few hours later. The therapy was guided by a specific manual and aimed to support participants in exploring difficult memories and feelings. All therapists were highly trained and underwent extensive training specific to this therapy. After each main session, participants had three follow-up "integration" sessions over several weeks to help them process their experiences.

Objectives

The main goal of the study was to evaluate MDMA-assisted therapy's effectiveness and safety for PTSD by comparing changes in CAPS-5 scores from baseline to 18 weeks. The CAPS-5 is a standard interview that measures PTSD symptoms like intrusive thoughts, avoidance, mood changes, and arousal, with scores ranging from 0 to 80, where higher scores indicate more severe PTSD. A secondary goal was to assess improvements in daily functioning, measured by the SDS scale. Other measures included assessments for depression (BDI-II), alcohol and drug use, and adverse childhood experiences. Participants agreed to be contacted later for a long-term study to see how long the treatment effects last. Statistical methods were used to ensure the study could detect significant effects. The main analysis included 90 participants who completed at least one session and one follow-up assessment. The study's statistical plan followed strict guidelines to accurately measure the drug's effects. An independent committee regularly reviewed adverse events for safety and conducted an interim analysis to ensure the study's design was sound.

Main

PTSD is a serious problem for many people. It can make life very hard and cause much pain. People with PTSD often have other problems too, like bad experiences from childhood, drinking too much, using drugs, feeling very sad, or feeling disconnected. These other problems can make it harder for treatments to work. Because of this, a good treatment is needed for people who have PTSD along with these other issues.

Some common medicines for PTSD are sertraline and paroxetine. Doctors have approved them as a first choice. However, these medicines do not work for 40 to 60 out of 100 people. Talking therapies, like prolonged exposure or CBT, are also good for PTSD. But many people still do not get better, or they stop going to therapy. This means new, affordable treatments are greatly needed.

MDMA is a drug that makes the brain release more of a chemical called serotonin. In studies with animals, MDMA helped reduce fear, changed how scary memories are stored, and made animals act more social. Past studies of MDMA therapy for PTSD have shown it is safe and works well.

This study looked at how well MDMA therapy works and if it is safe for people with serious PTSD. People in the study were given MDMA or a dummy pill three times. This happened in a clinic with trained therapists. Trained helpers who did not know who got which pill checked how well the treatment worked. The Food and Drug Administration (FDA) has called MDMA therapy a "Breakthrough Therapy" for PTSD. The study plan was made with the FDA's help.

Results

Demographics

People joined the study between November 2018 and May 2020. The last visit was in August 2020. Out of 345 people checked, 91 were chosen for the study. 46 people received MDMA, and 44 received a dummy pill. They came from the United States, Canada, and Israel.

The groups were similar in terms of background, age, and how bad their PTSD was at the start. On average, people had PTSD for about 13 to 15 years. A few people in both groups had a type of PTSD where they felt disconnected from themselves or the world.

Efficacy

MDMA greatly reduced PTSD symptoms. After 18 weeks, people who got MDMA had much lower PTSD scores than those who got the dummy pill. On average, MDMA patients' scores dropped by about 24 points, while dummy pill patients' scores dropped by about 14 points. MDMA also helped people with their daily lives, like work and social activities.

MDMA worked well even for people who had other problems that usually make PTSD treatment harder. This included people who felt disconnected, or had a history of alcohol or drug use, or bad childhood experiences. MDMA therapy also helped reduce feelings of sadness.

After 18 weeks, 67 out of 100 people who got MDMA no longer had PTSD. Only 32 out of 100 people who got the dummy pill no longer had it. Also, 33 out of 100 people in the MDMA group had their PTSD go away completely, compared to 5 out of 100 in the dummy pill group.

Safety

Side effects from MDMA were usually mild and did not last long. These included tight muscles, less hunger, feeling sick to the stomach, sweating a lot, and feeling cold. It is important that MDMA did not make people feel more like harming themselves. People who took MDMA had a small, short-term rise in blood pressure and heart rate. Two people who took MDMA also had a small, short-term rise in body temperature.

Two people who got the dummy pill had serious problems, like thinking about harming themselves or acting on it. More people in the dummy pill group reported thinking about harming themselves than in the MDMA group. One person in the dummy pill group also had heart-related issues. One person who got MDMA stopped the study because they felt sad after a session and found the symptom checks upsetting. But generally, MDMA sessions did not make people feel sad later.

Many people in the study had thought about harming themselves at some point in their lives, even before the study started. During the study, thinking about harming oneself did not get worse for people taking MDMA. Most serious thoughts about harming oneself happened in the dummy pill group.

Discussion

This study showed that MDMA therapy greatly reduced PTSD symptoms and problems with daily life after 18 weeks. It also helped with sadness. Importantly, MDMA did not make people feel more like harming themselves. MDMA therapy worked better than common PTSD medicines like sertraline and paroxetine. The effect of MDMA therapy was stronger than any other drug treatment for PTSD found before.

Both groups received therapy. People who got MDMA plus therapy got much better than those who got a dummy pill plus therapy. This means MDMA made the therapy work even better. Past studies thought that if someone had used certain antidepressants before, MDMA might not work as well. But in this study, past antidepressant use did not seem to stop MDMA from working.

MDMA may help the brain process scary memories better. It might help people feel safer and more open during therapy, making it easier to work through hard feelings and past events. PTSD can make it hard for people to work, go to school, or have good relationships. This treatment helped people do better in these areas. Finding a treatment that helps with daily life can save a lot of money and make life much better for many people, including veterans.

The treatment worked well for people who had serious, long-term PTSD and other problems like childhood trauma, sadness, thoughts of self-harm, and drug or alcohol use. These groups are usually very hard to treat. It was also helpful for people with the "dissociative" type of PTSD, which is usually hard to treat. Since many people with PTSD have other problems, this therapy could help a lot of people.

There were no major safety problems with MDMA. While there were some checks for abuse, heart issues, and thoughts of self-harm, MDMA did not cause or worsen these. The small, temporary rise in blood pressure was expected. Overall, MDMA seems as safe as or safer than current PTSD medicines. The study had some limits. The number of people was smaller due to the COVID-19 pandemic. Most people in the study were of similar backgrounds, so more diverse groups should be studied next. This study looked at short-term effects; long-term results will be checked later. Also, it was hard to keep people from knowing if they got MDMA or the dummy pill, but many guessed wrong, showing it wasn't a big problem.

PTSD can cause big problems for many people, especially after events like the COVID-19 pandemic. New treatments are needed, especially for those with PTSD that is hard to treat. In short, MDMA therapy quickly helped people with serious PTSD, even those with other problems. It seems safe and could greatly change how PTSD is treated. It should be considered for wider use soon.

Methods

Study design

This study was designed to compare MDMA therapy with therapy alone, using a dummy pill. The study took place at 15 locations in the United States, Canada, and Israel. Groups that protect patient rights approved the study. The study followed rules for ethical research.

Participants

People joined the study after seeing ads or being told by others. They had to contact the study sites themselves. Before joining, people agreed to take part and were checked to make sure they qualified. They had to have PTSD for at least six months and serious PTSD symptoms.

People could not join if they had other serious mental health problems, actively used alcohol or drugs, were pregnant, or had certain heart problems. People with mild, controlled health issues could join if doctors agreed it was safe. Patients also had to stop taking other mental health medicines before starting the study, under a doctor's care. The study plan changed a few times. For example, rules for other health problems became clearer, and checks for thoughts of self-harm happened more often. The study also had fewer people than planned because of the COVID-19 pandemic, but it still had enough people to show clear results.

Procedures

The study drug was made to strict rules. People were randomly put into one of two groups: one got MDMA and therapy, the other got a dummy pill and therapy. This was done so no one knew which treatment they were getting, to make the results fair. Doctors and study staff also did not know.

Before getting any medicine, people had three therapy sessions. These sessions helped build trust and prepared them for what might happen during treatment. Over about 18 weeks, people had three main treatment sessions, about 4 weeks apart. Each session lasted about 8 hours. During these sessions, people received either MDMA or a dummy pill. They got a main dose and then a smaller dose a few hours later. Trained therapists worked with people during the sessions, following a special guide for MDMA therapy.

Doctors checked blood pressure, heart rate, and body temperature during and after sessions. After each main session, people had three more therapy sessions to talk about what they felt and learned. People's PTSD symptoms and how well they were doing in daily life were checked often by independent helpers who did not know which treatment they got. The study also carefully watched for certain side effects, like heart problems, potential for abuse, and thoughts of self-harm. The study plans to follow up with people later to see if the effects last. The study used strong math methods to make sure the results were accurate and reliable.