Study of 3,4-Methylenedioxymethamphetamine-assisted Psychotherapy in People With Posttraumatic Stress Disorder: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Study of 3,4-Methylenedioxymethamphetamine-assisted Psychotherapy in People With Posttraumatic Stress Disorder (NCT00353938), a randomized phase 2 study. The primary outcome is Change From Baseline to Primary Endpoint in Clinician Administered PTSD Scale for DSM-IV (CAPS-IV).

2. Clinical Question

3. Trial Design

This was a phase 2 pilot randomized trial with a parallel-group design. The registry identifies masking as triple, but does not specify which participant, clinician, assessor, or other roles were masked. It also does not report the procedures used to maintain masking or whether masking was assessed during the trial.

The registry lists an enrollment of 14. Participants were randomly assigned to full-dose MDMA-assisted therapy or active-placebo MDMA-assisted therapy. Both groups received psychotherapy and took part in three experimental sessions. The contrast therefore concerns assignment to two MDMA dose regimens within psychotherapy, not psychotherapy versus no psychotherapy. The study description gives the full dose as 125 mg and the active-placebo dose as 25 mg, with supplemental doses of 62.5 mg and 12.5 mg, respectively.

The primary endpoint was change in CAPS-IV severity from baseline to 3 weeks after the third experimental session. The posted primary-outcome summaries include 8 participants in the full-dose arm and 4 in the active-placebo arm. The registry record does not explain how these outcome counts relate to the enrollment figure, whether any randomized participants were excluded from the primary analysis, or how missing outcome measurements were handled.

The study is marked completed. Its pilot designation and enrollment describe a small study, but the registry record does not report the protocol’s sample-size justification or design assumptions. It also does not report a detailed statistical analysis plan. Those omissions limit what can be inferred about the intended precision, analysis population, and prespecified comparisons.

4. Participant Flow and Accounting

The registry reports how participants moved through each stage of the study. All counts below are exactly as posted; missing counts are not inferred from other stages.

Before assignment: Only active control participants from Stage 1 entered into open-label Stage 2 and only participants who received full dose in Stage1 or Stage 2 and did not respond with significant improvement were offered the opportunity to partake in open-label Stage 3.

Overall Study

5. Baseline Characteristics

The table reproduces the baseline characteristics posted in the registry, which describe the participants analysed at baseline and help show whether the randomized groups were comparable.

6. Primary Endpoint

The registry lists the primary outcome as Change From Baseline to Primary Endpoint in Clinician Administered PTSD Scale for DSM-IV (CAPS-IV), measured over Less than 4 weeks before first experimental session (Baseline) to 3 weeks post 3rd experimental session (Primary Endpoint).

The primary endpoint was change from baseline to the primary endpoint in the Clinician Administered PTSD Scale for DSM-IV, or CAPS-IV. The baseline assessment took place less than 4 weeks before the first experimental session; the endpoint assessment was 3 weeks after the third experimental session. The CAPS-IV is a structured clinical interview assessing PTSD symptom frequency and intensity, effects on social and occupational functioning, overall symptom severity, global improvement since baseline, and rating validity.

The registry states that total severity scores range from 0 to 136, with higher scores indicating greater PTSD symptom severity. A change score describes how the recorded score shifted between the two assessment times. The posted arm summaries report mean changes and standard deviations. A mean is useful for describing the average change among participants included in an arm’s outcome summary, while the standard deviation describes variation among their individual changes.

Change in a structured symptom-severity measure is relevant to the study’s stated question because it captures symptom ratings over the treatment period. It does not, by itself, establish why scores changed, whether the treatment caused the change, or how participants experienced other aspects of care. The registry record does not report further details about endpoint assessment procedures or the handling of incomplete assessments.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

Randomization assigns participants to study groups using a chance-based process. Its purpose is to reduce systematic differences between groups at assignment, so that a properly conducted comparison can support a causal interpretation. Randomization does not guarantee that groups will have similar characteristics in a small study, and it cannot correct problems arising from missing data, deviations from assigned treatment, or outcome measurement. The registry identifies this trial as randomized but does not report the sequence-generation method, allocation concealment procedures, or details of the analysis based on assignment.

What the arm summaries describe

The primary outcome is continuous: it is a score whose values can vary across a range. The registry reports the mean change and standard deviation for each arm. The mean describes the central average of the recorded changes for participants included in that arm’s summary. The standard deviation describes how dispersed those changes were around the arm mean. It is not a confidence interval and does not directly quantify uncertainty in a comparison between arms.

A negative change on this scale represents a lower follow-up score than baseline, while a positive change represents a higher follow-up score. Since higher CAPS-IV scores indicate greater PTSD severity, the direction of a change can be interpreted in relation to the scale’s scoring. That direction alone does not demonstrate a treatment effect. The comparison of interest is between the assigned groups, and the record does not report an estimable comparison for this endpoint.

Comparisons and uncertainty

A between-group estimate would quantify the difference in mean change between the assigned regimens. A confidence interval gives a range of values compatible with the data and the assumptions of the analysis; its width conveys precision. A p-value, when reported, addresses how compatible the observed data are with a specified null hypothesis under the analysis assumptions. Neither measure establishes clinical importance on its own. No comparative confidence interval or p-value is reported for this primary outcome, so the magnitude and precision of a group contrast cannot be assessed from the registry record.

In general, a comparison can be adjusted for baseline characteristics or other prespecified factors, or it can be unadjusted. Adjustment can account for selected differences and may affect precision, but it depends on a specified model and adequate data. The registry record does not report an adjusted analysis or identify covariates. The posted group means and standard deviations are descriptive summaries; a recalculated comparative result is not reported.

Small samples and variability

Small outcome groups yield limited information about the range of plausible effects. A few unusually large or small changes can influence a mean, and a standard deviation estimated from few observations can be unstable. Unequal group sizes also mean that the summaries have different amounts of information. These are general statistical considerations, not evidence that any particular observation was influential in this trial. Individual participant data and the distribution of scores are not reported in the registry record.

Over-dispersion is a general concern when observed variability exceeds what a model assumes. If a model understates variability, calculated uncertainty may be too narrow. The registry reports standard deviations for the endpoint but does not report a fitted model, an over-dispersion assessment, or an analysis that addresses it. With a continuous endpoint, the relevance of such a concern depends on the chosen analysis and its assumptions; no specific model can be attributed to this trial from the registry record.

Planning illustrations

Sample-size planning estimates describe how many participants might be needed under stated assumptions to detect a chosen effect with a specified significance level and power. They are planning illustrations, not observed power and not evidence that the trial had a particular probability of detecting an effect. The accompanying planning approach is described as using the observed effect, equal allocation, a two-sided significance level of 0.05, and a normal approximation, with the target effect defined as a fraction of the observed effect. The registry record does not report a trial-specific sample-size justification, and no planning totals are reported in the registry record for this record.

Planning based on an observed effect from a small study can be especially sensitive to random variation in that estimate. Such calculations cannot resolve uncertainty in the trial’s outcome comparison, and they do not substitute for a prespecified design rationale. The record’s planning assumptions should therefore be interpreted as illustrative rather than as proof that the trial was adequately sized for a particular question.

Multiplicity and analytic choices

Multiplicity arises when several outcomes or comparisons are tested. In general, conducting multiple tests without an appropriate plan can increase the chance of at least one apparently noteworthy result arising by chance. The registry lists a primary CAPS-IV outcome and one secondary PDS outcome, but does not report a multiplicity strategy or analysis plan. The record also does not specify whether any additional outcomes or comparisons were analyzed.

The registry lists no analyses. This means that analysis details and comparative inferential results are not available in the record; it does not establish what analyses may have been performed outside the registry. Choices such as the analysis population, treatment of missing values, model specification, and handling of protocol deviations are not reported in the registry record.

10. Confidence Intervals for Each Arm

No two-arm comparison is shown for this trial, but each arm's mean can be given with a t-based 95% confidence interval computed from the posted mean, spread and number of participants.

R code and output

arm <- c("Full Dose MDMA-assisted Therapy (125 mg)", "Active Placebo MDMA-assisted Therapy (25 mg)")
n   <- c(8, 4)
m   <- c(-15.6, 3.3)
sp  <- c(18.1, 15.3)
sd  <- sp      # posted standard deviations
for (i in seq_along(n)) {
  se <- sd[i] / sqrt(n[i]); h <- qt(0.975, n[i] - 1) * se
  cat(sprintf("CARM|%s|%d|%.3f|%.3f|%.3f|%.3f\n", arm[i], n[i], m[i], sd[i], m[i] - h, m[i] + h))
}

CARM  Full Dose MDMA-assisted Therapy (125 mg)  8  -15.600  18.100  -30.732  -0.468
CARM  Active Placebo MDMA-assisted Therapy (25 mg)  4  3.300  15.300  -21.046  27.646

11. Multiplicity, Missing Data and Analysis Populations

The registry identifies change in CAPS-IV score as the primary outcome and lists change in Posttraumatic Stress Diagnostic Scale score as a secondary outcome. It reports two outcome measures and lists no analyses. A multiplicity strategy for interpreting multiple outcomes or comparisons is not reported in the registry record. Consequently, the record does not establish whether the outcomes were assessed under a prespecified hierarchy, whether any adjustment was planned, or how results across outcomes were to be interpreted together.

Missing-data methods are not reported in the registry record. The primary outcome summaries include 8 participants in the full-dose arm and 4 in the active-placebo arm, while enrollment is listed as 14. The record does not explain the difference between enrollment and the outcome-summary counts, identify whether assessments were unavailable, or state whether participants were excluded for other reasons. It also does not report imputation, sensitivity analyses, or assumptions about missing outcomes.

The analysis population is not reported in the registry record. It is therefore unclear whether the summaries follow randomized assignment, treatment received, or another selection rule. The record does not state how participants who did not complete sessions, changed treatment, or had incomplete follow-up were handled. These details matter because analysis choices can affect the estimate and the population to which it applies.

Without information on prespecification, analysis population, missingness, and multiplicity, the posted arm summaries cannot be placed within a complete inferential analysis plan. The absence of those details is uncertainty about reporting, not evidence that a particular method was or was not used.

12. Safety Results

The registry reports serious adverse events as affected participants divided by participants at risk.

Deaths

Other (non-serious) adverse events

Participants with at least one non-serious event at or above the registry's 5% reporting threshold.

Most frequent serious adverse event terms

Most frequent non-serious adverse event terms

Serious events with the highest arm-level rate: metasteses to central nervous system (11.1%), suicidal behavior (11.1%).

The registry reports serious adverse events for several dose-stage groups. In the full-dose MDMA-assisted therapy Stage 1 group, 2 of 9 participants at risk were reported as affected by a serious adverse event. In the active-placebo Stage 1 group, 0 of 5 were affected. In the full-dose Stage 2 group, 0 of 4 were affected, and in the Full or Larger Dose Stage 3 group, 0 of 3 were affected. No deaths are reported in any of these listed groups.

The registry also lists the serious-event terms “Metasteses to central nervous system” and “Suicidal behavior,” each at 11.1%. The record does not connect these terms to a particular group in the listed details, so they should not be assigned to a dose arm based on the information available. Nor do the group summaries establish whether participants experienced more than one event.

Other adverse events are reported separately: 8 of 9 at risk in full-dose Stage 1, 3 of 5 in active-placebo Stage 1, 2 of 4 in full-dose Stage 2, and 1 of 3 in Full or Larger Dose Stage 3 were affected. These counts are not the same as serious adverse event counts. The registry does not report event definitions, severity grades for these other events, relatedness assessments, or a comparative safety analysis. The staged group labels and differing group sizes should be kept in view; the record does not explain how the groups relate to one another.

13. What the Result Does, and Does Not, Mean

The registry results describe mean change in CAPS-IV severity among participants included in each arm’s outcome summary. The full-dose arm’s mean change was -15.6, and the active-placebo arm’s mean change was 3.3. The respective standard deviations were 18.1 and 15.3. These values summarize observed scores over the stated assessment period; they are not a reported estimate of the difference between randomized groups.

The record does not report an estimable two-arm comparison, comparative confidence interval, or p-value for the primary endpoint. It therefore does not quantify the uncertainty of the difference between the regimens. Separate arm summaries do not by themselves show whether a difference is statistically distinguishable from chance or whether any contrast is clinically important. No conclusion about a treatment’s efficacy or lack of efficacy follows from these summaries alone.

This was a randomized phase 2 pilot study with enrollment of 14. The outcome summaries include 8 participants in one arm and 4 in the other. The record does not explain the relationship between those figures, nor does it describe missing data or the analysis population. Those omissions affect how confidently the arm-level outcomes can be generalized to all enrolled or randomized participants.

The study compared full-dose MDMA-assisted therapy with a low-dose active-placebo regimen, with psychotherapy in both groups. Thus, even a fully reported comparison would address the assigned regimens in this study context rather than isolate the contribution of psychotherapy from the contribution of MDMA. The registry’s reported endpoint also focuses on clinician-rated symptom severity at a particular follow-up time, not every possible benefit, harm, or longer-term outcome.

The appropriate reading is limited: the record provides descriptive endpoint and adverse-event summaries, while leaving key comparative and analytic details unreported. These data can inform understanding of what the registry recorded, but they do not establish a definitive treatment effect.

14. Why This Trial Matters Statistically

This trial raises statistical questions that are important in small randomized studies. The registry reports a pilot design, an enrollment of 14, and a primary continuous symptom-score outcome. The primary outcome summaries have different arm sizes, and the record does not give an estimable comparison. This makes the distinction between descriptive results and comparative inference especially important.

Reporting arm means and standard deviations can help readers understand the direction and variability of observed changes. Yet the scientific question concerns the comparison between groups. A comparative estimate with uncertainty would show how much the observed difference could plausibly vary under the analysis assumptions. Without it, readers cannot assess precision in the treatment contrast from the registry record. The arm summaries should not be mistaken for a direct estimate of that contrast.

The endpoint is a structured clinician-administered severity measure, and the study uses an active-placebo dose alongside psychotherapy in both groups. This design makes interpretation dependent on the details of assignment, masking, outcome assessment, adherence, and analysis. The registry identifies randomization and triple masking but does not report the operational details needed to assess those processes.

The registry also lists a secondary symptom measure and safety summaries across dose-stage groups. Taken together, the record illustrates why transparent reporting of outcome definitions, analysis populations, missing-data handling, multiplicity, and adverse-event methods matters. These details help distinguish what was planned from what was observed and how the estimates were obtained. Their absence does not establish a flaw in the conduct of the trial, but it limits independent statistical interpretation.

The trial is statistically informative as a case in which a small pilot’s arm-level observations are available but a comparative analysis is not. It shows why sample-size planning illustrations, descriptive change scores, and inferential treatment comparisons answer different questions. None can replace the others.

15. Limitations

• The posted summary statistics are the only data these results rest on; patient-level data, full protocols and statistical analysis plans are not available.
• Recalculated results are simple, unadjusted calculations from posted summaries. They do not replace the sponsor's prespecified analysis.

The registry record gives limited information for evaluating the primary outcome. Although it reports mean change and standard deviation by arm, it does not report an estimable two-arm comparison, a comparative confidence interval, or a p-value. The uncertainty around the group contrast therefore cannot be assessed from the posted outcome summaries.

The outcome-summary group sizes are 8 and 4, while enrollment is listed as 14. Reasons for this difference are not reported in the registry record. The record does not describe participant flow, incomplete assessments, exclusions, analysis populations, or missing-data methods. These omissions prevent assessment of whether the summaries represent all randomized participants or a selected subset.

Details of randomization and masking are also limited. The registry identifies randomized allocation and triple masking, but does not report allocation concealment, which roles were masked, or whether masking remained intact. A detailed statistical analysis plan, model specification, covariate adjustment, and multiplicity approach are not reported in the registry record.

The primary assessment is defined as occurring 3 weeks after the third experimental session. The registry does not report longer-term primary-outcome follow-up or further outcomes beyond the listed measures. Safety results are separated into dose-stage groups, but the relationship among those groups and the event-attribution procedures are not explained in the record. The listed serious-event terms are not linked to a specific group in the registry entries.

These reporting limits constrain what can be concluded from registry results. They do not establish that unreported procedures were absent, and they do not identify the direction of any bias. They mark areas where the registry record does not provide enough detail for independent evaluation.

16. Related Tutorials

17. Related Statistical Calculators

18. Sources

• ClinicalTrials.gov: Study of 3,4-Methylenedioxymethamphetamine-assisted Psychotherapy in People With Posttraumatic Stress Disorder — NCT00353938.
• Registry record last updated 2024-07-15; status last verified 2024-07.
• Results first posted 2021-09-16.
• Data retrieved from ClinicalTrials.gov on 2026-11-09.
• Group sizes, means, event counts and sponsor-reported p-values are reproduced as posted. Effect estimates, confidence intervals and p-values not attributed to the sponsor are independently calculated from the posted summary statistics.

19. Record Summary

NCT00353938 is a completed phase 2 randomized, triple-masked, parallel-group pilot study of MDMA-assisted psychotherapy in people with PTSD. Enrollment is listed as 14. The comparison was full-dose MDMA-assisted therapy, using 125 mg with a supplemental dose of 62.5 mg, versus active-placebo MDMA-assisted therapy, using 25 mg with a supplemental dose of 12.5 mg. Both regimens involved three 8-hour sessions.

The primary outcome was change in CAPS-IV total severity score from baseline to 3 weeks after the third experimental session. The registry reports mean changes of -15.6 for 8 participants in the full-dose arm and 3.3 for 4 participants in the active-placebo arm, with standard deviations of 18.1 and 15.3. An estimable two-arm comparison is not reported. One secondary outcome is listed, and the registry lists no analyses.

Serious adverse events and other adverse events are reported for dose-stage groups, with no deaths listed. The registry record does not report a detailed analysis plan, missing-data methods, or the relationship between enrollment and primary-outcome group sizes.