Main

Post-traumatic stress disorder (PTSD) is a serious neuropsychiatric condition affecting approximately 5% of the US population each year. Managing PTSD is particularly complicated in individuals experiencing the dissociative subtype of PTSD, recurrent exposure to trauma and comorbidities, such as mood disorders and alcohol and substance use disorders. Together, these factors are associated with symptom exacerbation, treatment resistance and treatment discontinuation. Trauma-focused psychotherapies are the gold standard treatment for PTSD. However, many individuals have persisting symptomology, and dropout rates are high. Although the selective serotonin reuptake inhibitors (SSRIs) sertraline and paroxetine are FDA approved for treating PTSD, 35–47% of individuals do not respond to treatment. More effective, therapeutic interventions are needed to address the immense individual, societal and economic burdens of PTSD.

Mounting evidence supports substituted phenethylamine 3,4-methylenedioxymethamphetamine-assisted therapy (MDMA-AT) as a treatment for PTSD. MDMA, an entactogen that promotes monoamine reuptake inhibition and release (primarily by inducing conformational change of pre-synaptic transporters), effectively modulates fear memory reconsolidation, enhances fear extinction and promotes openness and prosocial behavior. Several phase 2 trials indicated that MDMA-AT has an acceptable risk–benefit profile in individuals with PTSD. A pivotal phase 3 study (MAPP1) showed that MDMA-AT was generally well tolerated and met the trial’s primary and secondary endpoints of reduced PTSD symptom severity and decreased functional impairment.

Due to disparities in trauma exposure, gender-diverse and transgender individuals, ethnoracial minorities, first responders, military personnel, veterans and victims of chronic sexual abuse have a disproportionately higher risk of developing PTSD. However, these diverse populations are historically underrepresented in clinical trials. Here we report the results of MAPP2, the second, confirmatory phase 3 study that extends the findings of MAPP1 in an ethnoracially diverse population with moderate to severe PTSD (Supplementary Table 1).

Results

Demographics and baseline characteristics

Participants were recruited from 21 August 2020 to 18 May 2022 (last participant visit on 2 November 2022). Overall, 324 individuals were screened, and 121 were enrolled. Of these, 17 individuals did not meet enrollment confirmation after initiation of preparation therapy, and 104 were confirmed for randomization: 53 were assigned to MDMA-AT and 51 to placebo with therapy (Fig. 1). Ninety-four participants completed the study, and nine discontinued (n = 1 MDMA-AT; n = 8 placebo with therapy) (Fig. 1 and Supplementary Table 3).

Baseline characteristics were generally similar between groups (Table 1). In total, 74 of 104 (71.2%) participants were assigned female sex at birth, with a higher proportion in the placebo with therapy group (42/51, 82.4%) than the MDMA-AT group (32/53, 60.4%). Participants were ethnically and racially diverse: 35 of 104 (33.7%) participants identified their race as other than White, and 28 of 104 (26.9%) identified their ethnicity as Hispanic/Latino. The mean (s.d.) duration of PTSD was 16.2 (13.3) years. The mean (s.d.) Clinician-Administered PTSD Scale for DSM-5 (CAPS-5) score at baseline was 39.0 (6.6) and was similar between groups. Overall, 28 of 104 (26.9%) and 76 of 104 (73.1%) participants had moderate and severe PTSD, respectively; the dissociative subtype was present in 24 of 104 (23.1%) participants.

Figure 1. CONSORT diagram. CONSORT diagram, indicating participant numbers and disposition throughout the course of the trial. Endpoint assessments (T1, T2, T3 and T4) of CAPS-5 and SDS were conducted after each experimental session. ^a The number of individuals after an initial phone screening who gave informed consent. ^b Other reasons for exclusion could include withdrawal of consent, adverse event or death, discontinuation of treatment by investigator, lack of therapeutic rapport and illness or lost to follow-up. ^c One participant in the placebo with therapy group completed the study but had missing item-level data on the final CAPS-5 assessment, and the final assessment was not included in the analysis of the de jure estimand. AE, adverse event; ITT, intention to treat; mITT, modified intention to treat; T, time of endpoint assessment; T1, baseline; T2, after experimental session 1; T3, after experimental session 2; T4, 6–8 weeks after experimental session 3 (18 weeks after baseline).

Table 1 Demographics and clinical characteristics of participants at baseline

^a Medications were tapered and washed out before baseline assessments and the first experimental session, in accordance with the protocol. ACE, adverse childhood experience; BMI, body mass index.

Primary outcomes

MDMA-AT significantly attenuated PTSD symptomology versus placebo with therapy, as measured by a reduction in CAPS-5 total severity score from baseline to 18 weeks. Mixed models for repeated measures (MMRM) analysis of the de jure estimand showed a least squares (LS) mean (95% confidence interval (CI)) change of −23.7 (−26.94, −20.44) for MDMA-AT versus −14.8 (−18.28, −11.28) for placebo with therapy (treatment difference: −8.9 (−13.70, −4.12), P < 0.001; Fig. 2a). The Cohen’s d effect size of MDMA-AT versus placebo with therapy was d = 0.7; the within-group effect sizes were d = 1.95 for MDMA-AT and d = 1.25 for placebo with therapy. MMRM analysis of the de facto estimand revealed an LS mean change (95% CI) in CAPS-5 scores of −23.7 (−26.97, −20.47) for the MDMA-AT group versus −14.8 (−18.24, −11.33) for the placebo with therapy group (P < 0.001).

Figure 2. Measures of efficacy in the MDMA-AT and placebo with therapy groups. a, LS mean change (±s.e.m.) in CAPS-5 total severity score from baseline to after session 3 (primary outcome) for placebo with therapy (n = 50) versus MDMA-AT (n = 53, P < 0.001, Cohen’s d = 0.7). b, LS mean change (±s.e.m.) in SDS total score from baseline to after session 3 (key secondary outcome) for placebo with therapy (n = 50) versus MDMA-AT (n = 53, P = 0.03, Cohen’s d = 0.4).

Secondary outcomes

MDMA-AT significantly mitigated clinician-rated functional impairment, as measured by a reduction in the Sheehan Disability Scale (SDS) from baseline. MMRM analysis of the de jure estimand revealed that the LS mean change (95% CI) in SDS total scores was −3.3 (−4.03, −2.60) with MDMA-AT versus −2.1 (−2.89, −1.33) with placebo with therapy (treatment difference: −1.20 (−2.26, −0.14); P = 0.03, d = 0.4; Fig. 2b). Improvements were observed across all domains, including family life, social life and work life (Supplementary Table 4).

Exploratory outcomes

In the MDMA-AT group, 45 of 52 (86.5%) participants were responders with a clinically meaningful improvement at 18 weeks after baseline, defined as a ≥10-point reduction in CAPS-5 total severity score, versus 29 of 42 (69.0%) in the placebo with therapy group (Fig. 3). By study end, 37 of 52 (71.2%) participants in the MDMA-AT group no longer met DSM-5 criteria for PTSD versus 20 of 42 (47.6%) participants in the placebo with therapy group. Furthermore, 24 of 52 (46.2%) participants in the MDMA-AT group and nine of 42 (21.4%) participants in the placebo with therapy group met remission criteria (Fig. 3). The net number of participants needed to treat for each responder analysis group was as follows: responder, six; non-responder, six; loss of diagnosis, four; remission, four.

Covariate analyses demonstrated similar responses to treatment regardless of disease severity, risk of hazardous alcohol or substance use disorder, severe adverse childhood experiences or dissociative subtype PTSD. The only measured exploratory covariate with a significant interaction with treatment was lifetime history of SSRI use, which was associated with improved efficacy of MDMA-AT (P = 0.02; Supplementary Table 5). Covariates significantly impacting the main effect were sex assigned at birth and baseline Beck Depression Inventory (BDI)-II score; female sex assigned at birth and baseline BDI-II score ≥23 were both associated with improved outcomes irrespective of treatment assignment (P < 0.05).

A blinding survey conducted at study termination showed that 33 of 44 (75.0%) participants in the placebo with therapy group were certain or thought they received placebo, whereas nine of 44 (20.5%) participants inaccurately thought that they received MDMA, and two of 44 (4.5%) participants could not tell. In the MDMA-AT group, 49 of 52 (94.2%) participants were certain or thought that they received MDMA; one of 52 (1.9%) participants inaccurately thought that they received placebo; and two of 52 (3.8%) participants could not tell (Supplementary Table 6). When asked for the reason for their belief in treatment assignment, most participants in the MDMA-AT group reported attributing their response on the blinding survey to experiencing positive mental or emotional effect (45/52 (86.5%)) and positive physical effect (29/52 (55.8%)), whereas most of the participants in the placebo with therapy group reported experiencing no effect (28/44 (63.6%)).

Figure 3. Treatment response and remission in the MDMA-AT (n = 53) and placebo with therapy (n = 50) groups.A ≥10-point reduction in CAPS-5 total severity score was considered to be clinically meaningful. Responders (≥10-point reduction from baseline), loss of diagnosis (≥10-point reduction from baseline and no longer meeting PTSD diagnostic criteria) and remission (loss of diagnosis and CAPS-5 total severity score of 11 or less) were tracked in both groups as a percentage of participants. Non-responders were defined as any CAPS-5 total severity score change <10-point reduction from baseline.

Safety

Most participants (102/104, 98.1%) experienced at least one treatment-emergent adverse event (TEAE) during the study (Table 2); seven experienced a severe TEAE (MDMA-AT, n = 5 (9.4%); placebo with therapy, n = 2 (3.9%)). None had a serious TEAE. Two participants (3.9%) in the placebo with therapy group discontinued treatment due to TEAEs. Frequently reported TEAEs (occurring with incidence >10% and at least twice the prevalence in the MDMA-AT group versus the placebo with therapy group) included muscle tightness, nausea, decreased appetite and hyperhidrosis (Table 2). These were mostly transient and of mild or moderate severity. At least one treatment-emergent adverse event of special interest (TEAESI) occurred in six of 53 (11.3%) participants in the MDMA-AT group and three of 51 (5.9%) participants in the placebo with therapy group (Table 2). No TEAESIs of MDMA abuse, misuse, physical dependence or diversion were reported.

Eight participants (MDMA-AT, n = 7; placebo with therapy, n = 1) experienced cardiac TEAEs, which included palpitations (MDMA-AT, n = 5 (9.4%); placebo with therapy, n = 1 (2.0%)) and tachycardia (MDMA-AT, n = 2 (3.8%)); all were mild. Nine participants (MDMA-AT, n = 7; placebo with therapy, n = 2) experienced vascular TEAEs; all were mild, except for one participant in the MDMA-AT group who had a history of hypertension, who was not taking anti-hypertensive medications and who experienced a TEAE of moderate hypertension (Supplementary Table 7). Five participants had cardiac TEAESIs: four participants in the MDMA-AT group and one participant in the placebo with therapy group reported palpitations (Supplementary Table 7). Participants in the MDMA-AT group experienced temporary dose-dependent increases in mean blood pressure (BP) and pulse during experimental sessions compared to the placebo with therapy group (Supplementary Table 8).

Transient increases in heart rate and BP were expected and were observed during experimental sessions in a dose-dependent manner. Greater fluctuations in BP were seen during experimental sessions 2 and 3 in the participants treated with MDMA, most likely due to the higher doses of MDMA administered. These transient elevations did not require clinical intervention, including among the subset of participants with well-controlled hypertension. Because the current dosing regimen involves administering a single, split drug dose under observation, for a limited number of times, each after a lengthy washout, cardiovascular risk is likely to have been sufficiently mitigated by the study procedures and screening measures.

Psychiatric TEAEs occurred at a similarly high frequency in both groups (MDMA-AT, n = 44 (83.0%); placebo with therapy, n = 37 (72.5%)), with suicidal ideation, insomnia and anxiety reported most frequently. Psychiatric TEAEs were mostly mild to moderate; three severe events occurred in the MDMA-AT group (5.7%; n = 1 each: dissociation, flashback and grief reaction) and two in the placebo with therapy group (3.9%; n = 1 each: agitation and anxiety). No severe TEAEs of suicidal ideation or behavior were reported. Two participants in the MDMA-AT group had suicidality TEAESIs of suicidal ideation, one of whom engaged in non-suicidal self-injurious behavior. Two participants in the placebo with therapy group had suicidality TEAESIs; one engaged in non-suicidal self-injurious behavior, and one had suicidal ideation and trichotillomania (Supplementary Table 9).

More than 80% (87/104) of participants had a lifetime history of suicidal ideation; 13 of 53 (24.5%) in the MDMA-AT group and 12 of 51 (23.5%) in the placebo with therapy group reported suicidal ideation during the final preparation session (V4). The number of participants reporting positive suicidal ideation varied throughout the study but collectively never exceeded baseline values in either group (Supplementary Fig. 2). Three participants (two MDMA-AT and one placebo with therapy) had treatment-emergent active suicidal ideation with at least some intent to act (Columbia-Suicide Severity Rating Scale (C-SSRS) score of 4 or 5), which was observed on five occasions (MDMA-AT, three events; placebo with therapy, two events) (Supplementary Fig. 2). Of these, one participant in the MDMA-AT group with no suicidal ideation at baseline had the emergence of active suicidal ideation with at least some intent to act.

Table 2 Adverse events occurring during treatment

^a The most common TEAEs occurring with incidence >10% and at least twice the prevalence in the MDMA-AT group versus the placebo with therapy group.

Discussion

In this confirmatory phase 3 study of participants with moderate to severe PTSD, MDMA-AT significantly improved PTSD symptoms and functional impairment, as assessed by CAPS-5 and SDS, respectively, compared to placebo with therapy over 18 weeks. Notably, 45 of 52 (86.5%) participants treated with MDMA-AT achieved a clinically meaningful benefit, and 37 of 52 (71.2%) participants no longer met criteria for PTSD by study end. In a historic first, to our knowledge, for psychedelic treatment studies, participants who identified as ethnically or racially diverse encompassed approximately half of the study sample. These findings confirm and extend the results observed in MAPP1 (ref. ¹²), with general consistency across endpoints.

Given the diverse population and degree of participant complexity, the replication of efficacy is particularly notable. In our study, 26.9% (28/104) of participants expressed moderate PTSD, whereas, in MAPP1, all participants expressed severe PTSD¹². A substantial proportion of participants displayed comorbid features associated with high treatment resistance⁵, such as major depression, multiple sources of trauma (including childhood and combat trauma) and dissociative subtype PTSD. In keeping with MAPP1, treatment was not significantly affected by disease severity, risk of hazardous alcohol or substance use disorder, severe adverse childhood experiences or dissociative subtype. Furthermore, there was no observed site-to-site variability and no differential effect if participants stayed overnight after the experimental session. However, lifetime history of SSRIs, female sex assigned at birth and BDI-II score ≥23 at baseline were associated with positive impacts on outcomes and may warrant further study based on the exploratory nature of these analyses.

MDMA simultaneously induces prosocial feelings and softens responses to emotionally challenging and fearful stimuli¹⁹, potentially enhancing the ability of individuals with PTSD to benefit from psychotherapy by reducing sensations of fear, threat and negative emotionality^18,19. The low dropout rate for MDMA-AT has been replicated across seven studies, suggesting that MDMA induces a true shift in participant engagement^12,13. In contrast, a recent study comparing psychotherapies in veterans with PTSD reported dropout rates of 55.8% and 46.6% for prolonged exposure and cognitive processing therapy, respectively³¹. The MAPP2 dropout rate was 1.9% (1/53) in the MDMA-AT group and 15.7% (8/51) in the placebo with therapy group. The higher proportion of dropouts in the placebo with therapy group relative to MDMA-AT could be attributed to participants receiving less effective treatment and to disappointment from ineffective therapeutic blinding, although blinding survey data showed that not all participants correctly identified the treatment that they received.

Consistent with MAPP1, no new major safety issues were reported. Common TEAEs were similar to previous studies and consistent with expected effects of MDMA^12,32. Rates of cardiac TEAEs were low, and increases in BP and pulse were mild, transient and consistent with MDMA’s sympathomimetic effects^18,33,34. Consistent with PTSD, suicidal ideation was observed in both groups. MDMA did not appear to increase this risk, and no suicidal behavior was observed. C-SSRS scores varied throughout the study but never exceeded baseline values for either group. Notably, there were five total events of treatment-emergent C-SSRS scores of 4 or 5: three in the MDMA-AT group and two in the placebo with therapy group. MAPP2 enrolled participants with a history of suicidality but excluded those with a current, serious imminent suicide risk; thus, special attention to this vulnerable population is warranted in future studies. In alignment with MAPP1 (ref. ¹²), there were no reports of problematic MDMA abuse or dependence, including in participants with histories of, or current, alcohol and substance use disorders. However, it is important to note that participants with any substance use disorder other than cannabis or alcohol in the 12 months before enrollment were excluded from MAPP2, as were participants with severe or moderate (in early remission) alcohol or cannabis use disorder. However, exploratory findings from the MAPP1 phase 3 trial indicated that MDMA-AT was actually associated with a significantly greater reduction in mean Alcohol Use Disorder Identification Test change scores compared to placebo with therapy, suggesting that the effects of MDMA-AT on hazardous alcohol use secondary to PTSD should be further studied³⁵. Long-term data are also needed to assess the risk of MDMA abuse or misuse after study participation.

Although the sample sizes of the MAPP1 and MAPP2 phase 3 studies had 90% statistical power and were developed with guidance from the FDA to ensure adequate, rigorous testing of outcomes, these evaluations did not extend further than 2 months after therapy and were intended to support an acute treatment course. To support these studies, data from the ongoing follow-up of participants from phase 2 and 3 studies (ClinicalTrials.gov Identifier: NCT05066282) will be important for further assessment of the long-term effectiveness of MDMA-AT in participants with PTSD. It is of interest to note that pooled phase 2 analyses of participants with at least 12 months of follow-up after their final MDMA-AT session have shown that LS mean CAPS-IV scores continue to improve between the final session and follow-up³².

Several limitations may impact the integration of MDMA-AT into clinical care, including the exclusion of participants with high suicide risk, comorbid personality disorders and underlying cardiovascular disease. Observed effect sizes for MDMA-AT (between-group, d = 0.7; within-subject, d = 1.95) were similar to MAPP1 (ref. ¹²) (between-group, d = 0.91; within-subject, d = 2.1), and, although higher than those observed in SSRI studies (ranging from 0.09 to 0.56 versus placebo for sertraline and paroxetine³⁶), the superiority of MDMA-AT over SSRIs cannot be assumed without a direct comparison. The complex relationship between SSRI use/history and MDMA-AT treatment efficacy was beyond the scope of the current statistical analysis plan and sample size but will be important to consider in future studies. In addition, further study of MDMA with other forms of psychotherapy for PTSD should be explored.

The notable effect seen in the placebo with therapy arm could suggest the standalone value of the manualized inner-directed therapy that was developed for use with MDMA. Additional head-to-head studies will need to be conducted to evaluate whether this form of manualized therapy provides greater value in the treatment of PTSD than the current first-line cognitive behavioral therapy and prolonged exposure therapy treatments³⁷.

Although treatment expectancy, per se, was not measured in this study, prospective treatment expectancy would likely have been high in both study arms, with random assignment expected to distribute this equally between groups. Although expectancy effects are a well-known issue in psychiatric clinical trials and are intertwined with the observation of treatment benefit during a trial³⁸, several observations support expectancy mitigation in the current study: (1) the groups did not separate after the first experimental session; (2) placebo with therapy dropouts did not uniformly occur after the first experimental session; and (3) blinding survey data (Supplementary Table 6) showed that not all participants correctly identified the treatment that they received.

The therapists who participated in this study were required to complete the sponsor’s training program (see Supplementary Methods for further details). To ensure consistent clinical practice and to mitigate harm, it may be of benefit for prescribers to complete additional training and continuing education if MDMA-AT is approved for use by a regulatory agency.

This confirmatory phase 3 trial showed consistent benefits of MDMA-AT in an ethnoracially diverse group of individuals with longstanding moderate to severe PTSD and numerous comorbidities. The dropout rate was low, and treatment was generally well tolerated. These findings represent the culmination of over two decades of research³⁹, and, together with MAPP1, indicate that further consideration of this treatment in individuals with moderate to severe PTSD is warranted.

Methods

Study design and oversight

This multi-site, randomized, double-blind, placebo-controlled study assessed the efficacy and safety of MDMA-AT versus placebo with therapy in participants diagnosed with moderate or severe PTSD (NCT04077437). Thirteen study sites (11 in the United States and two in Israel, both institutional and private) participated. The trial was conducted in accordance with the Good Clinical Practice guidelines of the International Council for Harmonization and with the ethical principles of the Declaration of Helsinki. An independent data monitoring committee ensured that the study was conducted safely and had sufficient sample size. The review boards and institutions that approved the study protocol are listed in the Supplementary Methods.

Participants

After written informed consent, participants were screened for eligibility. Adults (≥18 years of age) meeting the full DSM-5 criteria for current PTSD per CAPS-5 assessment and a CAPS-5 total severity score ≥28 (moderate or higher severity) with symptom duration of ≥6 months were eligible for enrollment confirmation. During the Preparation Period that preceded the Treatment Period, participants were tapered off all psychiatric medications before baseline to avoid potential drug interactions and confounding efficacy (Supplementary Fig. 1). Full inclusion and exclusion criteria are outlined in the Supplementary Methods.

Randomization and masking

Participants were randomized in a 1:1 allocation and in a blinded fashion to the MDMA-AT and placebo with therapy groups, stratified by clinical site. Randomization was managed via an interactive web randomization system (IWRS) (IT Clinical version 11.0.1) based on a centralized randomization schedule developed by an independent third-party vendor to maintain blinding.

A central pool of blinded independent assessors was used to mitigate the risk of functional unblinding⁴². Assessors were trained and supervised by independent consultants with expertise in PTSD diagnostics and the CAPS-5 to ensure inter-rater reliability and validity of assessments. Supervision involved reviewing each assessor’s first two assessments as well as 20% of all assessments (chosen at random) throughout the study, with each review resulting in detailed feedback for the assessor. The independent assessors were blinded to the general study design, study visit, treatment assignment, number of treatments received and any safety data for the participant. Participants were instructed to withhold their opinion on treatment group assignment and the number of completed visits from the independent assessors. Each assessor conducted no more than one CAPS-5 assessment with each participant to reduce potential bias and expectancy effect from having conducted repeat CAPS-5s with a participant. Assessors were also vetted before their onboarding to ensure that there were no conflicts of interest (such as other involvement within the Multidisciplinary Association for Psychedelic Studies (MAPS) organization or a bias toward MDMA-AT), and assessors were instructed to not expose themselves to scholarly presentations and papers related to MDMA-AT for PTSD to maintain their blinding to study design.

Procedures

Trial procedures were consistent with MAPP1 (ref. ¹²). Enrolled participants underwent three 90-min preparation sessions with a two-person therapy team, including at least one licensed therapist, and were then randomized 1:1 to receive MDMA-AT or placebo with therapy for approximately 3 months. The treatment period consisted of three 8-h dosing sessions, in conjunction with therapy, spaced approximately 1 month apart. Therapy was conducted by trained personnel in accordance with the MAPS MDMA-AT treatment manual (https://maps.org/treatment-manual) and trial protocol. During experimental sessions, and in keeping with the dosing in MAPP1, participants received a split dose of 120–180 mg of MDMA or placebo. For the first experimental session, the initial dose of 80 mg was followed by a supplemental half-dose of 40 mg. In the second and third experimental sessions, the initial dose of 120 mg was followed by a supplemental half-dose of 60 mg. The supplemental half dose was administered 1.5–2 h after the initial dose. Participants in both treatment groups received identical therapy. The 120-mg (80 mg + 40 mg) split dose was selected for the first experimental session in phase 3 trials to allow patients to acclimate to the treatment regimen using a clinical titration approach based on clinician recommendations from a phase 2 trial in veterans and first responders¹³. During the second and third experimental sessions, doses were escalated to 180 mg (120 mg + 60 mg), as this was the most frequently studied efficacious dose in phase 2 trials. This dosing regimen also provides clinicians with the option of dose adjustments if needed.

Within the MDMA-AT group, three participants did not undergo dose escalation in experimental sessions 2 and 3, and two participants experienced dose administration timing errors (Supplementary Table 2). Each experimental session was followed by three 90-min integration sessions to support participants in processing and understanding their experience (Supplementary Fig. 1). Full procedures, including details on therapy teams and training, are outlined in the Supplementary Methods.

Outcomes

Independent assessors conducted CAPS-5 and SDS outcome assessments at baseline, after experimental sessions 1 and 2 and 6–8 weeks after experimental session 3 (18 weeks after baseline) via video interviews. Primary and secondary objectives were mean change in CAPS-5 total severity and SDS scores, respectively, for MDMA-AT versus placebo with therapy from baseline to 18 weeks after baseline.

Exploratory outcome measurements included characterization of the treatment response and differences between the treatment groups by demographics and characteristics. Responder analyses were based on categorical diagnostic assessment data and the CAPS-5 total severity score assessment. PTSD severity was defined using the CAPS-5 total severity score as follows: asymptomatic (0–10), mild (11–22), moderate (23–34), severe (35–46) and extreme (47+) (ref. ⁴¹). A ≥10-point reduction in CAPS-5 total severity score was considered to be clinically meaningful as agreed upon with the FDA through a Special Protocol Assessment. Four responder categories were derived and compared at each post-experimental session visit using CAPS-5 scores. These categories were: non-responder (<10-point reduction from baseline), responder (≥10-point reduction from baseline), loss of diagnosis (≥10-point reduction from baseline and no longer meeting PTSD diagnostic criteria) and remission (CAPS-5 total severity score of 11 or less and no longer meeting PTSD diagnostic criteria).

Safety objectives included assessment of differences between groups in severity, incidence and frequency of TEAEs, serious TEAEs, TEAESIs, suicidal ideation and behavior and vital signs. TEAEs were defined as any adverse event that occurred during the treatment period from the first experimental session to the last integration session. The severity of TEAEs was determined by the site physician as mild (no limitation in normal daily activity), moderate (some limitation in normal daily activity) or severe (unable to perform normal daily activity). A serious TEAE was defined as any unforeseen medical event at any dose of the drug that resulted in death; was life-threatening; required inpatient hospitalization; caused significant disability or incapacity; resulted in a congenital anomaly or birth defect; or required intervention to prevent permanent impairment or damage. Serious TEAEs also included any event, based on medical judgement, that jeopardized the participant or may have required intervention to prevent one of the events listed previously. With the exception of serious adverse event reporting, relatedness to study drug was not assessed by investigators, to preserve blinding. In an effort to identify common adverse events that may be most related to MDMA, TEAEs occurring with incidence >10% and at least twice the prevalence in the MDMA-AT group versus the placebo with therapy group are reported. Suicidality was tracked at each study visit using the C-SSRS (see the Supplementary Methods for more information).

Statistical analysis

SAS version 9.4 (SAS Institute) was used for analyses. Sample size was calculated to achieve a power of 90% at an alpha of 0.0499.

Efficacy was tested using an MMRM analysis comparing the change from baseline to 18 weeks after baseline in CAPS-5 and SDS scores between treatment groups in two-sided tests with alpha set at 0.0499. The alpha was adjusted to account for an administrative interim analysis for sample size re-estimation conducted after all participants were enrolled and 60% of primary endpoint data had been collected. Fixed effects were treatment, visit, treatment group by visit interaction and dissociative subtype; baseline CAPS-5 score was a covariate. Primary and secondary efficacy analyses used a de jure (related to initially randomized treatment) estimand and a supportive de facto (treatment policy) estimand of the modified intention-to-treat population, which required exposure to MDMA or placebo and at least one follow-up CAPS-5 assessment, as in MAPP1. The de jure dataset included all available data, except for 12 (one MDMA-AT and 11 placebo with therapy) outcome measurements taken after treatment discontinuation in analysis of treatment efficacy (Supplementary Table 3). Missed observations were considered missing at random (MAR), and choice of this assumption was tested with a tipping point analysis (Supplementary Methods).In additional exploratory analyses, 13 covariates were assessed in the model, with alpha set at 0.0499: age, sex (self-reported), prior use of selective SSRIs, work disability, disease severity, PTSD duration, dissociative subtype, overnight site stay, site ID, moderate depression (as measured by the BDI-II), severe adverse childhood experiences and moderate alcohol and substance use disorder risk (as measured by the Drug Use Disorders Identification Test and the Alcohol Use Disorders Identification Test). Analyses of primary or secondary outcomes by gender were not planned a priori; some exploratory analyses included sex as a covariate (Supplementary Methods).

Safety analysis evaluated TEAEs at the participant level, including all participants who received MDMA or placebo. Causal association with MDMA was determined based on relative incidence of TEAEs with at least a two-fold difference between groups.

Adverse events of special interest

In accordance with FDA guidance, special attention was paid to a subset of adverse events, TEAESIs, relating to cardiac function, suicide risk and MDMA abuse, misuse or diversion. TEAESIs involving cardiac function that could be indicative of QT prolongation or cardiac arrhythmias were collected, including torsade de pointes, sudden death, ventricular extrasystoles, ventricular tachycardia, ventricular fibrillation and flutter, non-postural syncope and seizures. TEAESIs involving suicide risk included suicide, suicide attempts, self-harm associated with suicidal ideation, suicide ideation assessed as a score of 4 or 5 on the C-SSRS and suicidal ideation judged by the investigator to be serious/severe. TEAESIs involving terms of MDMA abuse, misuse, drug diversion, dependence or overdose were also collected.

Understanding Post-Traumatic Stress Disorder and New Treatments

Post-traumatic stress disorder (PTSD) is a significant mental health condition, affecting approximately 5% of the U.S. population each year. Managing PTSD becomes particularly complex when individuals also experience the dissociative subtype of the disorder, repeated exposure to trauma, or other co-occurring conditions such as mood disorders and substance use disorders. These combined factors often lead to more severe symptoms, resistance to treatment, and individuals discontinuing therapy. While trauma-focused psychotherapies are considered the standard treatment for PTSD, many individuals still have persistent symptoms, and dropout rates are high. Medications like sertraline and paroxetine are approved for PTSD, but 35–47% of individuals do not respond to these treatments. More effective therapies are needed to address the substantial personal, societal, and economic impact of PTSD.

Growing evidence supports the use of MDMA-assisted therapy (MDMA-AT) as a potential treatment for PTSD. MDMA, a substance that influences brain chemistry, appears to help individuals process traumatic memories by altering fear responses, improving the ability to reduce fear, and fostering feelings of openness and connection with others. Several earlier studies (Phase 2 trials) indicated that MDMA-AT has an acceptable balance of benefits and risks for individuals with PTSD. A key Phase 3 study (MAPP1) demonstrated that MDMA-AT was generally well-tolerated and met its main goals of reducing PTSD symptom severity and decreasing problems with daily functioning. Certain populations, including gender-diverse and transgender individuals, ethnoracial minorities, first responders, military personnel, veterans, and survivors of chronic sexual abuse, face a higher risk of developing PTSD due to greater exposure to trauma. However, these diverse groups have historically been underrepresented in clinical trials. This report presents the findings of MAPP2, the second confirmatory Phase 3 study, which expanded on the results of MAPP1 by including an ethnically and racially diverse group of participants with moderate to severe PTSD.

Results

Demographics and baseline characteristics

Participant recruitment for the study took place from August 2020 to May 2022. Of the 324 individuals screened, 121 were initially enrolled. After starting preparation therapy, 17 individuals did not meet the final enrollment criteria, leaving 104 participants confirmed for randomization. Fifty-three participants were assigned to the MDMA-AT group, and 51 were assigned to the placebo with therapy group. Ninety-four participants completed the study, while nine discontinued (one from the MDMA-AT group and eight from the placebo with therapy group).

The characteristics of participants at the start of the study were generally similar between the two groups. Among the 104 participants, 74 (71.2%) were assigned female sex at birth, with a higher proportion in the placebo with therapy group (82.4%) compared to the MDMA-AT group (60.4%). The participant group was diverse in terms of ethnicity and race; 33.7% identified their race as other than White, and 26.9% identified as Hispanic/Latino. The average duration of PTSD among participants was 16.2 years. The average baseline score on the Clinician-Administered PTSD Scale for DSM-5 (CAPS-5), which measures PTSD severity, was 39.0 and was similar in both groups. Overall, 26.9% of participants had moderate PTSD, and 73.1% had severe PTSD. The dissociative subtype of PTSD was present in 23.1% of participants.

Primary outcomes

MDMA-AT significantly reduced PTSD symptoms compared to placebo with therapy, as measured by a decrease in CAPS-5 total severity scores from the beginning of the study to 18 weeks later. Statistical analysis showed an average reduction of -23.7 points for the MDMA-AT group, compared to -14.8 points for the placebo with therapy group. This difference of -8.9 points was statistically significant (P < 0.001), indicating a strong effect. The treatment effect size for MDMA-AT versus placebo with therapy was moderate (d = 0.7). Within the MDMA-AT group, the effect size was large (d = 1.95), and for the placebo with therapy group, it was also substantial (d = 1.25). Similar results were found when using another statistical approach.

Secondary outcomes

MDMA-AT also significantly improved daily functioning, as measured by a reduction in scores on the Sheehan Disability Scale (SDS) from baseline. Statistical analysis revealed that the average reduction in SDS scores was -3.3 for the MDMA-AT group, compared to -2.1 for the placebo with therapy group. This difference of -1.20 was statistically significant (P = 0.03) and represented a small to moderate effect size (d = 0.4). Improvements were observed across all areas of daily life, including family, social, and work life.

Exploratory outcomes

In the MDMA-AT group, 86.5% of participants (45 out of 52) showed a clinically meaningful improvement in their PTSD symptoms by 18 weeks, defined as at least a 10-point reduction in their CAPS-5 score. This compares to 69.0% of participants (29 out of 42) in the placebo with therapy group. By the end of the study, 71.2% of MDMA-AT participants (37 out of 52) no longer met the criteria for a PTSD diagnosis, compared to 47.6% of placebo with therapy participants (20 out of 42). Furthermore, 46.2% of MDMA-AT participants (24 out of 52) achieved remission from PTSD, while 21.4% of placebo with therapy participants (9 out of 42) reached this stage.

Analyses of other factors showed that treatment responses were similar regardless of the initial severity of PTSD, risk of alcohol or substance use disorder, history of severe adverse childhood experiences, or the presence of dissociative subtype PTSD. The only factor that significantly interacted with treatment was a history of SSRI use, which was linked to improved effectiveness of MDMA-AT. Factors significantly influencing the overall outcome, regardless of treatment, included sex assigned at birth and baseline depression scores; being assigned female sex at birth and having higher baseline depression scores were both associated with better outcomes.

A survey conducted at the end of the study assessed whether participants believed they received MDMA or placebo. In the placebo with therapy group, 75.0% of participants were certain or thought they received placebo, while 20.5% incorrectly thought they received MDMA, and 4.5% were unsure. In the MDMA-AT group, 94.2% of participants were certain or thought they received MDMA; 1.9% incorrectly thought they received placebo; and 3.8% were unsure. Most participants in the MDMA-AT group attributed their belief to experiencing positive mental, emotional, or physical effects. In contrast, most participants in the placebo with therapy group reported experiencing no effect.

Safety

Most participants (98.1%) experienced at least one adverse event during the study period; seven individuals experienced a severe adverse event (five in MDMA-AT group, two in placebo group). No serious adverse events occurred. Two participants in the placebo with therapy group discontinued treatment due to adverse events. Common adverse events reported more than twice as often in the MDMA-AT group compared to the placebo with therapy group included muscle tightness, nausea, decreased appetite, and excessive sweating. These events were mostly temporary and mild or moderate in severity.

Specific adverse events of particular interest occurred in 11.3% of MDMA-AT participants and 5.9% of placebo with therapy participants. No specific adverse events related to MDMA abuse, misuse, physical dependence, or drug diversion were reported. Eight participants (seven in MDMA-AT, one in placebo with therapy) experienced cardiac adverse events, such as palpitations and rapid heart rate; all were mild. Nine participants (seven in MDMA-AT, two in placebo with therapy) experienced vascular adverse events, mostly mild, with one moderate case of high blood pressure in the MDMA-AT group. Temporary, dose-dependent increases in blood pressure and pulse were observed during MDMA-AT sessions compared to the placebo group. These expected changes did not require clinical intervention, even for participants with well-controlled high blood pressure. Because of the controlled study procedures and screening, the risk of cardiovascular issues was likely reduced.

Psychiatric adverse events were common in both groups (83.0% in MDMA-AT, 72.5% in placebo with therapy), with suicidal thoughts, insomnia, and anxiety being the most frequently reported. Most were mild to moderate; three severe psychiatric events occurred in the MDMA-AT group (dissociation, flashback, grief reaction), and two in the placebo with therapy group (agitation, anxiety). No severe suicidal ideation or behavior was reported. Two participants in the MDMA-AT group and two in the placebo with therapy group had specific adverse events related to suicidality, including suicidal ideation or self-injurious behavior.

Over 80% of participants had a history of suicidal thoughts. The number of participants reporting suicidal thoughts varied throughout the study but never exceeded baseline levels in either group. Three participants (two in MDMA-AT, one in placebo with therapy) experienced active suicidal ideation with some intent to act at various points during the study. Of these, one participant in the MDMA-AT group who had no suicidal thoughts at baseline developed active suicidal ideation with intent to act.

Discussion

This confirmatory Phase 3 study, involving participants with moderate to severe PTSD, demonstrated that MDMA-AT significantly improved PTSD symptoms and functional impairment, as measured by CAPS-5 and SDS scores, respectively, over 18 weeks, compared to placebo with therapy. Notably, 86.5% of participants treated with MDMA-AT achieved a clinically meaningful benefit, and 71.2% no longer met the criteria for a PTSD diagnosis by the end of the study. This study is considered a landmark for psychedelic treatment research because approximately half of the study participants identified as ethnically or racially diverse. These findings confirm and expand upon the results observed in the previous MAPP1 study, with consistent outcomes across various measures.

The replication of treatment effectiveness is particularly important given the diverse population and the complexity of participant conditions in this study. In the current study, 26.9% of participants had moderate PTSD, while all participants in MAPP1 had severe PTSD. A significant portion of participants presented with conditions often associated with high treatment resistance, such as major depression, various types of trauma (including childhood and combat trauma), and dissociative subtype PTSD. Consistent with MAPP1, the treatment's effectiveness was not significantly affected by disease severity, risk of hazardous alcohol or substance use, severe adverse childhood experiences, or dissociative subtype PTSD. Furthermore, there was no observed difference in outcomes between sites, nor any difference if participants stayed overnight after the experimental session. However, a history of SSRI use, being assigned female sex at birth, and higher baseline depression scores were associated with better outcomes, suggesting areas for future research. MDMA is believed to induce prosocial feelings and reduce strong reactions to emotionally challenging and fearful stimuli, which may help individuals with PTSD benefit more from psychotherapy by decreasing feelings of fear, threat, and negative emotions. The consistently low dropout rate for MDMA-AT across multiple studies suggests that MDMA genuinely enhances participant engagement. In contrast, a recent study comparing psychotherapies for veterans with PTSD reported much higher dropout rates. The MAPP2 study had very low dropout rates in the MDMA-AT group (1.9%) compared to the placebo with therapy group (15.7%). The higher dropout rate in the placebo group might be due to individuals receiving less effective treatment and disappointment from ineffective blinding, though not all participants correctly identified their treatment.

Consistent with MAPP1, no new major safety concerns were identified. Common adverse events were similar to those in previous studies and aligned with the expected effects of MDMA. Cardiac adverse events were infrequent, and temporary increases in blood pressure and pulse were mild and consistent with MDMA's effects on the nervous system. Suicidal ideation was observed in both groups, as is common with PTSD, but MDMA did not appear to increase this risk, and no suicidal behavior was observed. Suicidality scores varied throughout the study but never exceeded baseline values for either group. There were a total of five instances of active suicidal ideation with some intent to act, with three occurring in the MDMA-AT group and two in the placebo with therapy group. MAPP2 included participants with a history of suicidality but excluded those with an immediate serious suicide risk; thus, continued careful monitoring of this vulnerable population is important in future studies. In line with MAPP1, there were no reports of problematic MDMA abuse or dependence, even in participants with histories of, or current, alcohol and substance use disorders. However, it is important to note that participants with substance use disorders other than cannabis or alcohol within the 12 months before enrollment were excluded from MAPP2, as were those with severe or moderate alcohol or cannabis use disorder (in early remission). Exploratory findings from the MAPP1 study, however, suggested that MDMA-AT was linked to a greater reduction in hazardous alcohol use, suggesting that the effects of MDMA-AT on alcohol use secondary to PTSD warrant further investigation. Long-term data are also needed to assess the risk of MDMA abuse or misuse after study participation. Although the Phase 3 studies (MAPP1 and MAPP2) were designed with sufficient statistical power and FDA guidance for rigorous testing, these evaluations did not extend beyond two months after therapy, focusing on acute treatment. Ongoing follow-up studies will provide important data on the long-term effectiveness of MDMA-AT in individuals with PTSD. Interestingly, combined analyses of Phase 2 studies with at least 12 months of follow-up have shown that PTSD symptom scores continued to improve between the final MDMA-AT session and follow-up.

Several limitations may affect the widespread adoption of MDMA-AT into clinical practice, including the exclusion of participants with high suicide risk, certain personality disorders, and underlying cardiovascular disease. The observed effect sizes for MDMA-AT were similar to MAPP1 and higher than those seen in SSRI studies, but a direct comparison is needed to confirm superiority over SSRIs. The complex relationship between past SSRI use and MDMA-AT effectiveness requires further study. Additionally, the use of MDMA with other types of psychotherapy for PTSD should be explored. The notable effectiveness seen in the placebo with therapy group suggests the value of the specific therapy used with MDMA. Further comparative studies are needed to determine if this manualized therapy offers greater benefits for PTSD treatment than current first-line therapies like cognitive behavioral therapy and prolonged exposure therapy. While treatment expectation was not directly measured, it was likely high in both study arms, and random assignment should have distributed it evenly. Several factors suggest that expectation effects were mitigated in the current study: the groups did not show significant differences after the first experimental session, placebo group dropouts did not occur uniformly after the first session, and blinding survey data showed that not all participants correctly identified their treatment. Therapists in this study completed a specific training program. To ensure consistent and safe clinical practice, prescribers may benefit from additional training and continuing education if MDMA-AT is approved for clinical use. This confirmatory Phase 3 trial demonstrated consistent benefits of MDMA-AT in an ethnically and racially diverse group of individuals with long-standing moderate to severe PTSD and multiple co-occurring conditions. The dropout rate was low, and treatment was generally well-tolerated. These findings represent the culmination of over two decades of research and, along with MAPP1, suggest that this treatment warrants further consideration for individuals with moderate to severe PTSD.

Methods

Study design and oversight

This study was a multi-site, randomized, double-blind, placebo-controlled trial evaluating the effectiveness and safety of MDMA-AT versus placebo with therapy in participants diagnosed with moderate or severe PTSD. Thirteen study sites, located in the United States and Israel, participated. The trial followed international guidelines for good clinical practice and ethical principles. An independent committee monitored the data to ensure the study's safety and adequate participant numbers.

Participants

After providing written informed consent, participants were screened to determine their eligibility. Adults aged 18 years or older who met the full diagnostic criteria for current PTSD according to the DSM-5 and had a CAPS-5 total severity score of 28 or higher (indicating moderate or greater severity), with symptoms lasting at least six months, were eligible for enrollment. During a "Preparation Period" before the actual treatment, participants gradually stopped all psychiatric medications to prevent potential drug interactions and to ensure that the study results accurately reflected the treatment's effects.

Randomization and masking

Participants were randomly assigned, in a 1:1 ratio, to either the MDMA-AT or placebo with therapy group. This assignment was done in a way that kept participants and researchers unaware of who received which treatment (blinding), and it was balanced by clinical site. A computer system managed the randomization process to maintain blinding. A central group of independent assessors, who were also unaware of treatment assignments, conducted outcome measurements to reduce potential bias. These assessors were specifically trained and supervised to ensure consistency and accuracy in their PTSD assessments. They were blinded to the study design, visit type, treatment assignment, number of treatments received, and any safety data for the participants. Participants were asked not to share their opinions about their treatment or the number of completed visits with these assessors. Each assessor conducted only one PTSD assessment with each participant to minimize bias. Additionally, assessors were vetted to avoid conflicts of interest and were instructed to avoid exposure to research related to MDMA-AT for PTSD to maintain their blinding. To further protect the study's integrity, the independent assessors collected and stored outcome measures in a separate database from the clinical information. A survey at the end of the study assessed whether participants thought they received MDMA or placebo.

Procedures

The study procedures were consistent with those of the MAPP1 study. Enrolled participants first underwent three 90-minute preparation sessions with a two-person therapy team. Then, they were randomly assigned to either receive MDMA-AT or placebo with therapy for approximately three months. The treatment period involved three 8-hour dosing sessions, conducted with therapy, spaced about one month apart. Therapy was provided by trained personnel following a specific treatment manual. During the experimental sessions, participants received either a split dose of 120–180 mg of MDMA or placebo. For the first session, an initial dose of 80 mg was followed by a half-dose of 40 mg. In the second and third sessions, the initial dose was 120 mg, followed by a half-dose of 60 mg. The half-dose was administered 1.5–2 hours after the initial dose. The 120 mg split dose for the first session was chosen to help participants acclimate to the treatment, based on recommendations from previous studies. Doses were increased to 180 mg for later sessions, as this was the most common and effective dose in earlier trials, also allowing for dose adjustments if needed. In the MDMA-AT group, a few participants did not have dose escalation, or experienced minor timing errors in dose administration. Each experimental session was followed by three 90-minute integration sessions to help participants process and understand their experiences. Both treatment groups received identical therapy.

Outcomes

Independent assessors conducted evaluations of PTSD symptoms (CAPS-5) and functional impairment (SDS) at the start of the study, after the first and second experimental sessions, and 6–8 weeks after the third experimental session (18 weeks after the study began) through video interviews. The main goals were to measure the average change in CAPS-5 and SDS scores for MDMA-AT compared to placebo with therapy from baseline to 18 weeks.

Other exploratory measurements included characterizing the treatment response and examining differences between treatment groups based on demographics and participant characteristics. Response to treatment was assessed using categorical diagnostic data and CAPS-5 scores. PTSD severity was categorized from asymptomatic to extreme based on CAPS-5 scores. A reduction of 10 points or more in the CAPS-5 total severity score was considered a clinically meaningful improvement. Four categories of response were defined: non-responder (less than a 10-point reduction), responder (10-point or more reduction), loss of diagnosis (10-point or more reduction and no longer meeting PTSD criteria), and remission (CAPS-5 score of 11 or less and no longer meeting PTSD criteria). Safety goals included assessing the severity, occurrence, and frequency of adverse events, serious adverse events, specific adverse events of interest, suicidal ideation and behavior, and changes in vital signs. Adverse events were defined as any medical event occurring during the treatment period. Site physicians determined the severity of adverse events (mild, moderate, or severe). Serious adverse events were defined as severe medical events that could be life-threatening or require hospitalization, among other criteria. To preserve blinding, investigators did not assess whether adverse events were related to the study drug, except for serious adverse events. Adverse events occurring more than 10% of the time and at least twice as often in the MDMA-AT group compared to the placebo with therapy group were specifically reported to highlight those most likely related to MDMA. Suicidality was tracked at each study visit using a standardized scale (C-SSRS).

Statistical analysis

Statistical analyses were performed using SAS software. The study's sample size was calculated to provide a 90% chance of detecting a significant difference. The effectiveness of the treatment was assessed using a statistical method called mixed models for repeated measures (MMRM). This method compared the change in CAPS-5 and SDS scores from baseline to 18 weeks between the treatment groups. The analysis considered factors such as treatment, visit, and the interaction between treatment and visit, as well as the dissociative subtype. The baseline CAPS-5 score was also included as a factor. Two main types of analysis were performed: one focused on the effect of the treatment as initially assigned (de jure estimand), and another that considered the actual treatment received (de facto estimand). These analyses included all available data, excluding some measurements taken after participants stopped treatment. Missing observations were assumed to be random, and this assumption was tested. Additional exploratory analyses examined 13 other factors to see their influence on the results, including age, self-reported sex, prior SSRI use, work disability, disease severity, PTSD duration, dissociative subtype, overnight site stay, study site, moderate depression, severe adverse childhood experiences, and risk of moderate alcohol and substance use disorder. Analyses of primary or secondary outcomes specifically by gender were not planned beforehand, though some exploratory analyses included sex as a factor. Safety analyses evaluated adverse events for all participants who received MDMA or placebo. A causal link to MDMA was considered if an adverse event occurred at least twice as often in the MDMA-AT group compared to the placebo with therapy group.

Adverse events of special interest

Following specific guidelines, particular attention was given to certain adverse events related to heart function, suicide risk, and the potential for MDMA abuse, misuse, or diversion. Adverse events related to heart function included issues that could indicate abnormal heart rhythms or other cardiac problems. Adverse events related to suicide risk included suicide, suicide attempts, self-harm linked to suicidal thoughts, and high scores on the C-SSRS for suicidal ideation, or suicidal ideation deemed serious by the investigator. Adverse events involving terms like MDMA abuse, misuse, drug diversion, dependence, or overdose were also specifically collected and monitored.

Post-Traumatic Stress Disorder (PTSD) and New Treatment Options

Post-traumatic stress disorder (PTSD) is a serious condition affecting many individuals each year. Managing PTSD can be challenging, especially for those who experience the dissociative subtype, have faced multiple traumas, or also have other mental health issues like mood disorders or substance use problems. These factors can make symptoms worse, make treatment less effective, or lead to people stopping treatment.

Standard treatments for PTSD include trauma-focused psychotherapies and certain antidepressant medications, such as sertraline and paroxetine. However, many individuals still experience symptoms, and some stop treatment. A significant portion of individuals also do not respond well to these approved medications. There is a clear need for more effective therapies to lessen the personal, social, and economic impact of PTSD.

MDMA-assisted therapy (MDMA-AT) is emerging as a potential new treatment. MDMA, a substance that affects brain chemistry, appears to help reduce fear memories, improve emotional processing, and encourage openness and social connection. Earlier studies, including phase 2 trials and a first phase 3 study (MAPP1), showed that MDMA-AT was generally safe and effective in reducing PTSD symptoms and improving daily functioning.

Certain groups, such as gender-diverse and transgender individuals, racial and ethnic minorities, first responders, military personnel, veterans, and survivors of chronic sexual abuse, are at a higher risk of developing PTSD due to varied trauma exposure. Historically, these groups have been underrepresented in clinical trials. This report presents the findings of MAPP2, a second phase 3 study designed to confirm the results of MAPP1 within a diverse population experiencing moderate to severe PTSD.

Results

Demographics and Baseline Characteristics

The study enrolled 121 individuals between August 2020 and May 2022, with 104 confirmed for randomization into either the MDMA-AT group (53 participants) or the placebo with therapy group (51 participants). The majority (94 participants) completed the study, with significantly more discontinuations in the placebo group (8 participants) compared to the MDMA-AT group (1 participant). Participant groups were generally similar at baseline. Most participants (71.2%) were assigned female sex at birth, with a slightly higher proportion in the placebo group. The study population was notably diverse racially and ethnically. Participants had experienced PTSD for an average of 16.2 years, and at baseline, the majority had severe PTSD (73.1%) or moderate PTSD (26.9%). The dissociative subtype of PTSD was present in 23.1% of participants.

Primary Outcomes

MDMA-AT led to a significant decrease in PTSD symptoms compared to placebo with therapy, as measured by the CAPS-5 scale. The MDMA-AT group showed an average symptom reduction of 23.7 points, while the placebo group experienced a reduction of 14.8 points. This difference was statistically significant, indicating a strong treatment effect.

Secondary Outcomes

MDMA-AT also significantly reduced limitations in daily functioning, as measured by the Sheehan Disability Scale (SDS). The average reduction in SDS scores was 3.3 points for the MDMA-AT group, compared to 2.1 points for the placebo with therapy group. This improvement extended across various aspects of life, including family, social, and work activities.

Exploratory Outcomes

A clinically meaningful improvement (at least a 10-point reduction in CAPS-5) was achieved by 86.5% of MDMA-AT participants, versus 69.0% in the placebo group. By study end, 71.2% of MDMA-AT participants no longer met PTSD diagnostic criteria, compared to 47.6% of placebo participants. Additionally, 46.2% of MDMA-AT participants achieved remission, meaning very low symptoms and no longer meeting diagnostic criteria, compared to 21.4% in the placebo group. Treatment responses were similar regardless of initial PTSD severity or history of substance use. A lifetime history of SSRI use was associated with improved MDMA-AT efficacy, and being assigned female sex at birth or having a higher baseline depression score correlated with better outcomes overall. A survey revealed that most MDMA-AT participants correctly identified their treatment due to positive mental/emotional effects, while most placebo participants reported no effect.

Safety

Most participants experienced at least one temporary side effect during the study, but no serious adverse events occurred. Common temporary side effects more prevalent in the MDMA-AT group included muscle tightness, nausea, decreased appetite, and increased sweating. Cardiac effects like temporary increases in heart rate and blood pressure were observed during MDMA dosing, which were expected and did not require intervention. Psychiatric side effects, such as suicidal ideation, insomnia, and anxiety, occurred frequently in both groups. However, suicidal ideation did not increase above baseline levels in either group, and no severe suicidal behavior was reported. Importantly, no issues related to MDMA abuse, misuse, physical dependence, or diversion were observed.

Discussion

In this phase 3 study, it was confirmed that MDMA-assisted therapy significantly improved PTSD symptoms and reduced daily functional impairment in participants with moderate to severe PTSD. A substantial majority (86.5%) of those treated with MDMA-AT experienced a clinically meaningful benefit, and over 71% no longer met PTSD diagnostic criteria by the study's end. Notably, this study successfully included a racially and ethnically diverse participant group, which is a significant achievement for psychedelic treatment research. These results align well with findings from the previous MAPP1 study.

The replication of positive outcomes is particularly important given the diversity and complexity of the study population, which included individuals with moderate PTSD (unlike MAPP1, which focused only on severe cases) and those with other challenging conditions such as major depression, multiple trauma exposures, and dissociative PTSD. The effectiveness of the treatment was consistent across various factors, including disease severity and history of certain substance use risks. It is thought that MDMA helps individuals with PTSD engage in therapy more effectively by fostering prosocial feelings and reducing overwhelming fear and negative emotions. The low dropout rate observed in the MDMA-AT group (1.9%) further supports this, suggesting a higher level of participant engagement compared to both the placebo group and other standard psychotherapies for PTSD.

No new major safety concerns emerged in this study, consistent with previous research. Common temporary side effects were those expected from MDMA. While temporary increases in heart rate and blood pressure occurred, these were generally mild and transient. Suicidal ideation was present in many participants at baseline, as is common with PTSD, but MDMA-AT did not appear to increase this risk. The study carefully excluded participants with a current, serious risk of suicide. No reports of problematic MDMA abuse or dependence were found. However, longer-term data are still needed to fully assess the sustained effects and potential risks of MDMA-AT over time, with ongoing follow-up studies planned to address this.

Limitations of the study include the exclusion of individuals with very high suicide risk, certain personality disorders, or significant heart conditions. While MDMA-AT showed strong effects, direct comparisons to currently approved SSRIs for PTSD were not conducted, so its superiority cannot be definitively claimed without such studies. The therapy component delivered in both groups also showed a notable positive effect, suggesting the standalone value of this specific manualized therapy. While participant expectations can influence clinical trial outcomes, several factors in this study, including participant blinding results, suggest that these effects were minimized. The importance of specialized training for therapists administering MDMA-AT is also highlighted for future clinical practice.

In conclusion, this confirmatory phase 3 trial consistently demonstrated the benefits of MDMA-assisted therapy for a diverse group of individuals with long-standing moderate to severe PTSD and various co-occurring conditions. The treatment was well-tolerated and had a low dropout rate. Together with the MAPP1 study, these findings provide strong evidence that MDMA-AT warrants further consideration as a therapeutic option for individuals suffering from moderate to severe PTSD.

Methods

Study Design and Oversight

This multi-site, randomized, double-blind, placebo-controlled study assessed the effectiveness and safety of MDMA-assisted therapy versus placebo with therapy for moderate to severe PTSD. The study, involving 13 sites, adhered to strict ethical guidelines, with an independent committee overseeing safety and conduct. Eligible participants were adults aged 18 or older with at least six months of PTSD symptoms, confirmed by standard diagnostic assessments. Before treatment, all psychiatric medications were gradually discontinued.

Randomization and Blinding

Participants were randomly assigned equally to either MDMA-AT or placebo with therapy through a centralized system, ensuring both participants and therapy teams remained unaware of the assignment. Independent assessors, separate from the therapy teams and rigorously trained, conducted all outcome measurements to prevent bias, only assessing each participant once and storing data in a separate, blinded database.

Procedures

The treatment protocol involved three 90-minute preparation sessions, followed by three 8-hour dosing sessions spaced approximately one month apart. During dosing, participants received either MDMA or placebo in a split dose, with higher doses in later sessions. Both groups received identical psychotherapy guided by a specific treatment manual. Each dosing session was followed by three 90-minute integration sessions to help participants process their experiences.

Outcomes

Primary outcomes measured PTSD symptom severity (CAPS-5), and secondary outcomes assessed functional impairment (SDS). Exploratory analyses examined treatment response rates, including clinically meaningful improvement, loss of diagnosis, and remission. Safety was continuously monitored through the reporting of adverse events, including general side effects, serious events, and specific events of interest related to cardiac function, suicide risk, and any potential for MDMA abuse or misuse.

Statistical Analysis

Statistical analysis compared symptom changes and safety profiles between groups, factoring in various demographic and clinical characteristics. This rigorous approach aimed to confirm the treatment's effects while maintaining scientific integrity.

Adverse Events of Special Interest

In line with regulatory guidance, particular attention was given to specific types of adverse events that could pose a higher risk. These included events related to heart function, indicators of suicide risk (including ideation and self-harm), and any signs of MDMA abuse, misuse, or illegal diversion of the drug. These categories were closely monitored throughout the study.

Post-traumatic Stress Disorder (PTSD) Treatment Study

Post-traumatic stress disorder (PTSD) is a serious mental health condition that affects many people each year. It can be especially difficult to manage for individuals who also experience dissociation, repeated exposure to trauma, or other conditions like mood disorders or substance use issues. These factors can worsen symptoms, make treatment less effective, and lead people to stop treatment.

Standard treatments for PTSD include trauma-focused therapies. However, many individuals still have symptoms, and many also stop therapy early. While some medications, like sertraline and paroxetine (types of SSRIs), are approved for PTSD, a significant number of people do not respond to them. Therefore, more effective treatments are needed to reduce the personal, social, and economic burdens of PTSD.

A new treatment called MDMA-assisted therapy (MDMA-AT) shows promise for PTSD. MDMA is a substance that affects brain chemicals and can help modulate fear memories, improve how people cope with fear, and encourage openness and positive social behavior. Earlier studies (Phase 2 trials) found that MDMA-AT was generally safe and beneficial for people with PTSD. A key Phase 3 study (MAPP1) also showed that MDMA-AT was well-tolerated and significantly reduced PTSD symptoms and improved daily functioning. Many groups, including gender-diverse and transgender individuals, racial and ethnic minorities, first responders, military personnel, veterans, and victims of chronic sexual abuse, are at a higher risk of developing PTSD. However, these diverse groups have historically not been well-represented in clinical trials. This report shares the results of MAPP2, the second major Phase 3 study, which further tested MDMA-AT in a diverse group of people with moderate to severe PTSD.

Results

Demographics and baseline characteristics

Participants were recruited between August 2020 and May 2022. Overall, 324 individuals were considered, and 121 were enrolled. After some initial preparation, 104 individuals were ready for the study, with 53 assigned to receive MDMA-AT and 51 to receive placebo with therapy. Most participants (94 out of 104) completed the study, with only nine stopping early.

The characteristics of participants were generally similar between both groups at the start of the study. A majority (71.2%) of participants were assigned female sex at birth, with more in the placebo group. The study included a diverse group of participants: about one-third identified their race as something other than White, and over a quarter identified as Hispanic/Latino. On average, participants had been living with PTSD for about 16 years. At the start of the study, the average PTSD symptom score (measured by CAPS-5) was similar in both groups. About a quarter of participants had moderate PTSD, and three-quarters had severe PTSD. Roughly a quarter of participants experienced the dissociative subtype of PTSD.

Primary outcomes

MDMA-AT significantly reduced PTSD symptoms compared to placebo with therapy. Symptoms were measured using the CAPS-5 total severity score, from the start of the study up to 18 weeks later. The MDMA-AT group showed a much greater improvement in symptoms compared to the group that received placebo with therapy. This difference was statistically significant.

Secondary outcomes

MDMA-AT also significantly improved how well participants could function in their daily lives, as measured by the Sheehan Disability Scale (SDS). Improvements were seen in various areas, including family life, social life, and work life.

Exploratory outcomes

In the MDMA-AT group, a large majority (86.5%) showed a meaningful improvement in their symptoms after 18 weeks. This was higher than the placebo group, where 69% showed such improvement. By the end of the study, most participants in the MDMA-AT group (71.2%) no longer met the criteria for a PTSD diagnosis, compared to 47.6% in the placebo group. Furthermore, nearly half (46.2%) of the MDMA-AT group achieved remission from PTSD, while only 21.4% in the placebo group did.

The treatment was effective regardless of how severe a person's PTSD was at the start, if they were at risk for substance use disorders, if they had experienced severe childhood trauma, or if they had dissociative PTSD. The only factor that seemed to significantly affect the treatment's success was a history of using SSRI medications, which was linked to better results with MDMA-AT. Additionally, participants assigned female sex at birth and those with higher depression scores at the start of the study generally had better outcomes, regardless of the treatment they received.

A survey at the end of the study showed that most participants correctly guessed whether they received MDMA or placebo. In the MDMA-AT group, 94.2% thought they received MDMA, largely because they experienced positive mental or emotional effects. In the placebo group, 75% thought they received placebo, mainly because they felt no particular effect.

Safety

Most participants (98.1%) experienced at least one side effect during the study. However, only a few experienced severe side effects, and none had a serious medical event that required hospitalization or was life-threatening. Only two participants in the placebo group stopped treatment due to side effects. Common side effects reported more often in the MDMA-AT group included muscle tightness, nausea, reduced appetite, and excessive sweating. These effects were usually temporary and mild or moderate in severity. There were no reports of MDMA abuse, misuse, physical dependence, or drug diversion.

Eight participants had heart-related side effects, mostly palpitations (a feeling of a fast or irregular heartbeat) or a rapid heart rate, all of which were mild. Temporary increases in blood pressure and pulse were expected during MDMA sessions, and these were mild and did not require medical intervention. The study procedures, including specific dosing and screening, helped manage any potential cardiovascular risks.

Psychiatric side effects were common in both groups, including suicidal thoughts, insomnia, and anxiety. Most of these were mild to moderate. A few severe psychiatric events occurred in both groups, such as dissociation, flashbacks, or agitation. No severe suicidal thoughts or behaviors were reported. While some participants had suicidal thoughts at various points, the numbers never exceeded the levels reported at the beginning of the study in either group. Very few participants (three in total across both groups) had active suicidal thoughts with some intent to act. The study excluded individuals with current, serious, and immediate suicide risk.

Discussion

This second Phase 3 study confirmed that MDMA-AT significantly improved PTSD symptoms and daily functioning in individuals with moderate to severe PTSD. A large percentage (86.5%) of participants treated with MDMA-AT showed meaningful clinical improvement, and most (71.2%) no longer met the criteria for a PTSD diagnosis by the end of the study. This trial included a diverse group of participants, marking a significant step for psychedelic treatment studies. These findings support and expand upon the positive results seen in the earlier MAPP1 study.

The consistent effectiveness of MDMA-AT is particularly notable because the study included a diverse population with complex conditions, including moderate PTSD, major depression, multiple trauma experiences, and dissociative PTSD. The treatment remained effective regardless of these factors. The dropout rate for MDMA-AT was very low (1.9%), which is significantly less than the high dropout rates often seen in other PTSD psychotherapies. The higher dropout rate in the placebo group might be due to participants receiving less effective treatment or their disappointment if they suspected they were not receiving the active drug.

Consistent with the MAPP1 study, no new major safety concerns were identified. The common side effects were similar to what was expected with MDMA and were generally temporary and manageable. Heart-related effects, such as temporary increases in blood pressure and pulse, were mild and handled well. While suicidal thoughts were observed in both groups, as is common with PTSD, MDMA-AT did not appear to increase this risk, and no suicidal behavior was seen. There were also no reports of problematic MDMA abuse or dependence.

More long-term data are needed to assess the effectiveness of MDMA-AT over time and any potential risks of abuse or misuse after the study. Data from ongoing follow-up studies will be important for understanding the long-term benefits. Some limitations of the study include the exclusion of participants with very high suicide risk, certain personality disorders, or underlying heart conditions. While MDMA-AT showed a stronger effect than some other PTSD medications, a direct comparison between MDMA-AT and SSRIs has not been done. The fact that the placebo group also showed some improvement suggests that the specific type of therapy used alongside MDMA may itself be valuable, and further studies are needed to compare it with other standard therapies. The study also highlights the importance of proper training for therapists who deliver MDMA-AT.

In conclusion, this confirmatory Phase 3 trial consistently showed that MDMA-AT offers significant benefits for a diverse group of individuals with long-standing moderate to severe PTSD and other co-occurring conditions. The treatment was generally well-tolerated, and participants had a low dropout rate. These findings, along with previous research, suggest that MDMA-AT should be further considered as a treatment option for individuals with moderate to severe PTSD.

Methods

Study design and oversight

This study was a multi-site, randomized, double-blind, placebo-controlled trial. This means it took place at several locations, participants were assigned to groups by chance, and neither the participants nor the researchers knew who received which treatment. The study aimed to evaluate how effective and safe MDMA-AT was compared to a placebo (an inactive substance) combined with therapy for adults diagnosed with moderate or severe PTSD. The trial was conducted following strict ethical guidelines, with independent committees overseeing its safety and ensuring the study had enough participants to produce reliable results.

Participants

To be included in the study, participants had to be adults (18 years or older) with a current diagnosis of moderate or severe PTSD (as determined by a specific assessment tool called CAPS-5) and have had symptoms for at least six months. Before the study treatments began, participants gradually stopped taking any other psychiatric medications to avoid potential interactions or confusion in results.

Randomization and masking

Participants were randomly assigned to either the MDMA-AT group or the placebo with therapy group, with an equal chance of being in either group. This assignment was done using a computer system to ensure that neither participants nor most study staff knew which treatment was given. To prevent any bias, independent assessors, who were unaware of the participant's treatment group or even the overall study design, conducted the main assessments of PTSD symptoms and functioning. These assessors were trained and supervised to ensure consistency and accuracy, and they only assessed each participant once. A survey was also conducted at the end of the study to see if participants thought they knew which treatment they had received.

Procedures

The study procedures were similar to those used in the previous MAPP1 trial. All enrolled participants first had three 90-minute preparation sessions with a team of two therapists. After this, they were randomly assigned to either receive MDMA-AT or placebo with therapy for approximately three months.

The treatment phase involved three 8-hour dosing sessions, each combined with therapy, spaced about one month apart. During these sessions, participants received either MDMA or a placebo, given as an initial dose followed by a smaller supplemental dose a few hours later. The doses of MDMA were carefully chosen based on previous research. Following each dosing session, participants had three 90-minute integration sessions, which helped them process and understand their experiences during the experimental session. Both groups, MDMA-AT and placebo with therapy, received the exact same type of therapy.

Outcomes

Independent assessors measured the main results using two tools: the CAPS-5 to track PTSD symptom severity and the SDS to track daily functioning. These assessments were done at the beginning of the study, after each experimental session, and 6–8 weeks after the final session. The primary goal was to see the average change in PTSD symptoms, and the secondary goal was to see the average change in functional impairment.

The study also explored other results, such as how many participants showed a significant improvement in symptoms, no longer met the diagnosis for PTSD, or achieved remission. A meaningful improvement was defined as a drop of at least 10 points on the CAPS-5 score. For safety, researchers tracked all side effects, noting their severity and frequency, as well as any serious events. They also specifically monitored for suicidal thoughts or behaviors and changes in vital signs like blood pressure and heart rate.

Statistical analysis

Computer software was used to analyze the study data, ensuring the results were reliable and meaningful. Statistical methods were used to compare the changes in PTSD symptoms and functional impairment between the MDMA-AT and placebo groups over time. Researchers also looked at how different factors like age, sex, prior medication use, or other health conditions might have influenced the treatment outcomes. All safety data, including side effects, were carefully analyzed to understand any potential risks.

Adverse events of special interest

Due to specific health concerns, researchers paid special attention to certain types of side effects. These "adverse events of special interest" included heart-related issues, such as irregular heartbeats. They also closely monitored any signs of suicide risk, including suicidal thoughts or self-harming behaviors. Lastly, they watched for any signs of MDMA abuse, misuse, or dependence.

Understanding PTSD and New Treatments

Post-traumatic stress disorder, called PTSD, is a serious mental health condition affecting many adults each year. It can be very hard to manage, especially for people who have experienced trauma many times, or who also have other issues like mood problems or drug and alcohol use. These extra challenges can make PTSD symptoms worse, make treatments not work as well, or cause people to stop treatment altogether. Doctors often use therapy focused on trauma to help with PTSD. However, many people still have symptoms, and many stop therapy early. Some medicines, like sertraline and paroxetine, are approved for PTSD, but they do not work for everyone. There is a need for better ways to help people with PTSD, as it causes a lot of trouble for individuals, society, and the economy.

A newer treatment being studied is called MDMA-assisted therapy (MDMA-AT). MDMA, a drug that helps change how the brain deals with fear, can make it easier to face hard memories, reduce fear, and help people feel more open and friendly. Past studies have shown that MDMA-AT is generally safe for people with PTSD. A main study, called MAPP1, found that MDMA-AT was well tolerated and greatly reduced PTSD symptoms and improved daily life. Because some groups of people are more likely to get PTSD due to past trauma—like gender-diverse and transgender people, different ethnic and racial groups, first responders, military members, veterans, and victims of ongoing abuse—they were often not included enough in past studies. This new study, MAPP2, was the second large study, looking at MDMA-AT in a diverse group of people with moderate to severe PTSD to confirm the earlier findings.

Results of the Study

This study included 121 people who were screened from August 2020 to May 2022. In the end, 104 people were ready to be part of the main study. Fifty-three people received MDMA-AT, and 51 received a placebo (a dummy pill) with therapy. Ninety-four people finished the study, with only a few dropping out, mostly from the placebo group. The groups were largely similar at the start. Most people were women (71.2%), and about a third were from different racial groups (33.7%), with about a quarter being Hispanic/Latino (26.9%). On average, people had lived with PTSD for a long time, about 16 years. Most had severe PTSD (73.1%).

The main finding was that MDMA-AT significantly reduced PTSD symptoms. People in the MDMA-AT group saw a much bigger drop in their PTSD symptoms compared to those who received the placebo with therapy. This means MDMA-AT helped people feel much better. The study also looked at how well people could do everyday tasks. MDMA-AT helped people get better at handling family life, social life, and work life, more so than the placebo with therapy. This shows MDMA-AT improved how people function in their daily lives.

More people in the MDMA-AT group showed meaningful improvement. About 86.5% of people in the MDMA-AT group felt much better, compared to 69% in the placebo group. By the end of the study, 71.2% of people in the MDMA-AT group no longer met the signs for PTSD, compared to 47.6% in the placebo group. Also, 46.2% of people in the MDMA-AT group showed full remission, meaning their symptoms were very low, compared to 21.4% in the placebo group. These good results for MDMA-AT were seen no matter how severe a person's PTSD was, whether they had issues with alcohol or drugs, had bad childhood experiences, or had a certain type of PTSD that includes feeling detached. The study also found that having used certain antidepressant medicines (SSRIs) in the past, being a woman, or having higher depression scores at the start were linked to better outcomes for all participants, no matter what treatment they received. When asked, most people in the MDMA-AT group correctly guessed they received the real medicine, often because they felt positive mental or physical changes. Most in the placebo group guessed they got the placebo because they felt no change.

Almost all people in the study had at least one side effect. However, only a few had severe side effects, and none had very serious ones that caused major harm. The most common side effects in the MDMA-AT group included muscle tightness, feeling sick to the stomach, not wanting to eat, and sweating a lot. These side effects were mostly mild or medium in strength and did not last long. Some people had heart-related side effects, like a racing heart, but these were also mild and temporary. Blood pressure and heart rate went up during MDMA sessions, as expected, but these changes did not require medical help. Problems related to mental health, like suicidal thoughts, trouble sleeping, and anxiety, happened in both groups. Importantly, MDMA did not seem to increase the risk of suicidal thoughts or actions. The study found no signs that people misused MDMA or became dependent on it.

Discussion of Findings

This study confirms that MDMA-AT greatly helps with PTSD symptoms and daily functioning. A large number of people who received MDMA-AT felt much better, and many no longer met the definition of PTSD. This study is important because about half of the participants were from diverse ethnic and racial backgrounds, which is a new step for studies on psychedelic treatments. The good results matched those from the MAPP1 study. The treatment worked well even though many people had long-term PTSD and other tough issues like depression or different kinds of trauma. The number of people who dropped out of the study was very low for MDMA-AT (1.9%) compared to the placebo group (15.7%), suggesting that MDMA helps people stay engaged in therapy.

No new major safety concerns came up in this study. The common side effects were expected and generally mild. Heart rate and blood pressure changes were temporary and manageable. While suicidal thoughts were reported by some in both groups, MDMA did not seem to make this risk worse, and no one attempted suicide. The study did not find any issues with MDMA abuse or dependence, even in people who had past problems with alcohol or drugs. However, this study only looked at results for up to two months after treatment. More long-term studies are needed to see how well MDMA-AT works over time and if there are any long-term risks of misuse. This study also didn't directly compare MDMA-AT to standard antidepressant medicines, so we cannot say one is better than the other yet. The therapy used in the study, even with the placebo, showed some good results, suggesting the therapy itself is helpful. It is important that therapists using MDMA-AT get special training to ensure safe and proper care. Overall, this study, along with earlier research, strongly suggests that MDMA-AT is a promising treatment for adults with moderate to severe PTSD.

Methods of the Study

This study was designed to be a strong test of MDMA-AT. It was a multi-site study, meaning it happened in many places (11 in the U.S. and two in Israel). It was set up so that neither the participants nor the study staff knew who was getting the real MDMA or the placebo; this is called "double-blind." This helps make sure the results are fair. The study followed strict rules to protect participants and ensure good research practices.

Adults aged 18 or older who had moderate to severe PTSD for at least six months could join the study. Before starting treatment, participants stopped taking any other psychiatric medicines under a doctor's care. To keep the study fair, participants were randomly placed into one of two groups: MDMA-AT or placebo with therapy. This was done like drawing names from a hat. Special assessors, who did not know which treatment a person received, spoke with participants to measure their PTSD symptoms and daily function. These assessors were trained to ask questions the same way each time to make sure their measurements were reliable. They also did not meet with the same person more than once to prevent their personal feelings from affecting the results.

The treatment process involved three main parts. First, participants had three preparation sessions with a team of two therapists. Then, during the treatment period, they had three main "dosing sessions" about one month apart. In these 8-hour sessions, participants received either MDMA or a placebo, along with therapy. The amount of MDMA given was carefully planned, starting with a lower dose and possibly increasing it in later sessions. After each dosing session, participants had three more "integration sessions" with their therapists to help them understand and work through their experiences.

The main things the study measured were changes in PTSD symptoms and how well people could do daily activities. They also looked at other things, like how many people got better, lost their PTSD diagnosis, or went into remission (meaning their symptoms were very low). For safety, the study tracked all side effects, how severe they were, and if they were related to heart issues, suicidal thoughts, or signs of drug misuse. Experts carefully looked at all the data to see if the two groups were different and to understand how MDMA-AT affected people. They paid special attention to certain side effects that could be concerning, like serious heart problems or an increase in suicidal thoughts.