Randomized, Double-blind, Controlled of MDMA-assisted Psychotherapy in 12 Subjects With PTSD: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Randomized, Double-blind, Controlled of MDMA-assisted Psychotherapy in 12 Subjects With PTSD (NCT01958593), a randomized phase 2 study. The primary outcome is Change in Clinician-Administered PTSD Scale (CAPS-IV) Score From Baseline to Primary Endpoint.

2. Clinical Question

This is a clinical question about a treatment package and a measured symptom score. The intervention includes psychotherapy as well as MDMA, and the comparator includes psychotherapy as well as placebo. Consequently, the endpoint summaries alone cannot separate the contribution of the drug from the contribution of psychotherapy or other features of the treatment program. The study also described safety assessment between groups, but safety counts need to be read in light of the very small enrollment and the registry’s separate safety group listings.

3. Trial Design

The registry describes a randomized, triple-masked, parallel-group Phase 2 pilot study. It was designed to compare MDMA-assisted psychotherapy with placebo plus psychotherapy among people with treatment-resistant PTSD. The listed enrollment is 6. The trial title refers to 12 subjects, while the registry reports enrollment of 6; no explanation for this difference is reported in the registry record.

In the placebo-with-therapy group, participants were to receive placebo during each of two experimental sessions. In the MDMA-assisted-therapy group, participants were to receive MDMA during each of two experimental sessions, with an initial dose of 125 mg of MDMA HCl followed by a supplemental dose of 62.5 mg. The description also includes non-drug preparatory therapy and integration sessions. The sessions were described as spaced three to five weeks apart. The registry record does not provide further detail about how psychotherapy was standardized or delivered.

The primary endpoint was change in CAPS-IV score from baseline to the primary endpoint. The timeframe is described as approximately 18 weeks after baseline and 1 month after the second experimental session. Secondary outcomes listed in the registry include measures of PTSD symptoms, depression, functioning, sleep, dissociation, and posttraumatic growth. The record lists six secondary outcomes, but no analyses are listed.

The recorded status is terminated. The start date is 2014-10-14, and the primary completion date is 2015-09-10. The registry record does not report why the trial was terminated, whether the planned recruitment target changed, or the detailed procedures for allocation concealment and masking. Although the record labels the study triple-masked, it does not specify which roles were masked. It also does not report the protocol’s sample-size justification or any interim-analysis plan.

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.

Stage 1

Stage 2 Open-label Crossover

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 in Clinician-Administered PTSD Scale (CAPS-IV) Score From Baseline to Primary Endpoint, measured over Baseline to Primary Endpoint (Primary Endpoint was approximately 18 weeks after Baseline and 1 month after the 2nd experimental session).

The primary endpoint is change in the Clinician-Administered PTSD Scale for DSM-IV (CAPS-IV) score from baseline to the primary endpoint. CAPS-IV is a clinician-administered structured interview assessing PTSD symptoms. Its total severity score sums symptom frequency and intensity scores across re-experiencing, avoidance, and hypervigilance subscales. The scale ranges from 0 to 136, with higher scores indicating greater PTSD symptom severity.

A change score expresses how a participant’s measured score at follow-up differs from that participant’s baseline score. In general, a negative change on a scale where higher values mean greater severity represents a lower score at follow-up than at baseline. The reported endpoint is a score, not a direct measure of every aspect of PTSD or of a participant’s overall experience.

Using a structured clinician-administered measure can provide a consistent way to assess symptoms across participants and time points. The registry description also notes that CAPS-IV includes a diagnostic score and subscale scores, but the primary endpoint is the total severity score change. The endpoint timeframe is described as approximately 18 weeks after baseline and 1 month after the second experimental session. That timing anchors the outcome to a specific period after treatment; it does not describe longer-term symptom change.

The registry record reports mean change and standard deviation for each group. It does not provide confidence intervals or a statistical test for the between-group contrast. The score summaries therefore describe the recorded changes within each group, but do not by themselves establish how precisely the groups differ.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

Statistical methods help distinguish the pattern of observations from the uncertainty around a treatment comparison. The registry record provides group sizes, mean change, and standard deviation for the primary continuous outcome. It lists no analyses. As a result, interpretation can describe the reported group summaries and explain what additional statistical quantities would ordinarily contribute, but it cannot attribute an unreported model, test, or adjustment to this trial.

What does the mean change describe?

For each group, the mean change is the average of participants’ changes in CAPS-IV score from baseline to the primary endpoint. The placebo-with-therapy group has a reported mean change of -21.5, and the MDMA-assisted-therapy group has a reported mean change of -17.3. These are separate within-group averages. They are not a direct estimate of the between-group treatment contrast, and the difference between them should not be treated as a reported analysis.

In general, a mean is a measure of the center of a set of observations. It can be informative when the distribution and sample size are appropriate, but a mean alone does not show whether individual observations were similar or widely spread. Here, the reported standard deviations are 12.02 in the placebo-with-therapy group and 13.05 in the MDMA-assisted-therapy group. A standard deviation describes how observations are dispersed around their group mean. It is not a measure of uncertainty in the mean itself, and it does not substitute for an interval estimate of a between-group effect.

Why is a between-group estimate important?

In general, a randomized trial’s comparative question is addressed by estimating how outcomes differ between assigned groups, with uncertainty quantified using an appropriate method. A confidence interval gives a range of values compatible with the data and the model’s assumptions; it communicates precision as well as the estimated direction and magnitude. A p-value, when reported, measures how unusual the data would be under a specified null hypothesis and statistical model. Neither a confidence interval nor a p-value can replace assessment of the study design, measurement, and completeness of follow-up.

No confidence interval, p-value, or other inferential estimate for the primary between-group comparison is reported in the registry record. The appropriate conclusion is therefore not that a statistically significant difference was found or not found, but that the registry reports descriptive group summaries without a posted comparative analysis. The record lists 0 analyses.

What does the small sample imply?

In general, estimates based on small samples tend to be unstable: individual observations can materially affect the mean and the estimate of variability. Randomization supports fair comparison in principle, but it cannot ensure that small groups are balanced on every characteristic. The registry reports 2 participants in the placebo-with-therapy group and 4 in the MDMA-assisted-therapy group. These group sizes make it especially important not to read the means as precise estimates of what would be expected in a larger population.

Over-dispersion is a general concern when observed variation is greater than assumed by a statistical model. If a model underestimates variation, its uncertainty estimates can be too narrow. This is a general statistical issue, not a reported finding about this trial. With a very small sample, there is limited information for judging the shape of outcome distributions or whether model assumptions are reasonable. The registry record does not report the model used for an analysis, so no model assumptions can be assessed from the record.

What can a planning illustration say?

In general, a sample-size calculation estimates how many participants a future study might need under specified assumptions about the target effect, variability, significance level, allocation, and analysis. Such a calculation is a planning exercise, not an estimate of the probability that a completed study has demonstrated an effect. The planning approach associated with this record is described as using the observed effect, a two-sided significance level of 0.05, equal allocation, and a normal approximation, with the target effect expressed as a fraction of the observed effect.

However, the record notes that values are missing or not estimable for a two-arm comparison of this continuous endpoint. No usable planning results are reported for this comparison. Any planning illustration based on an observed effect would also be especially sensitive to the instability of an estimate from the recorded group sizes. It should not be interpreted as observed power, nor as evidence that the original trial was designed around these assumptions. The protocol’s own sample-size justification is not reported in the registry record.

What does missing inferential detail leave unresolved?

The record does not report an analysis population, a method for handling missing measurements, or a model adjusting for baseline score. It also does not report whether the primary endpoint analysis followed an intention-to-treat principle or another approach. These choices can affect both the estimate and its uncertainty. In general, transparent reporting of the analysis population and missing-data methods helps readers understand which participants contribute to each result and what assumptions support the estimate. Because those details are not reported, the posted means cannot be used to reconstruct a full analysis plan or determine how incomplete measurements were handled.

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("Placebo With Therapy", "MDMA-assisted Therapy")
n   <- c(2, 4)
m   <- c(-21.5, -17.3)
sp  <- c(12.02, 13.05)
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  Placebo With Therapy  2  -21.500  12.020  -129.495  86.495
CARM  MDMA-assisted Therapy  4  -17.300  13.050  -38.065  3.465

11. Multiplicity, Missing Data and Analysis Populations

The registry lists the CAPS-IV change as the primary outcome and lists six secondary outcomes: PTSD Diagnostic Scale total severity, Beck Depression Inventory score, Global Assessment of Functioning score, Pittsburgh Sleep Quality Index score, Dissociation Experiences Scale II total score, and Posttraumatic Growth Inventory total score. The record lists 0 analyses. It therefore does not report inferential results for the primary endpoint or the secondary outcomes.

Multiplicity is a general statistical issue that arises when several outcomes or comparisons are tested. The more tests considered, the greater the chance that at least one result may appear notable by chance if no adjustment or prespecified hierarchy is used. The registry record does not report a multiplicity strategy, outcome hierarchy beyond identifying the primary outcome, or an analysis plan for the listed secondary measures. No claims about adjustment or selective reporting can be made from the available record.

Missing-data handling and the analysis populations are also not reported in the registry record. The recorded enrollment is 6, and the primary outcome summaries include 2 participants in one group and 4 in the other. The record does not explain whether all enrolled participants had endpoint measurements, whether any measurements were excluded, or how missing values would have been treated. In general, missing-data assumptions can influence estimates, especially in small studies, so the absence of those details limits assessment of the results.

The record does not report interim analyses, stopping criteria, or whether the termination affected outcome collection. The study status is terminated, but the reason and timing of the decision are not reported in the registry record. Without those details, it is not possible to determine how termination relates to the planned analysis or whether the listed outcomes were collected as intended.

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 non-serious adverse event terms

The registry lists serious adverse event counts separately for several group labels. For Placebo With Therapy (Stage 1), 0 of 2 participants are recorded as affected by serious adverse events; for MDMA-assisted Therapy (Stage 1), the figure is 0 of 4. The listed Stage 2 placebo group also records 0 of 2, and the SRR listings record 0 of 2 for placebo with therapy and 0 of 4 for MDMA-assisted therapy. No deaths are recorded in these listings.

These are counts within the registry’s safety categories, not estimates of a treatment’s overall safety. The separate labels include Stage 1, Stage 2, and SRR groups; the record does not explain how these categories relate to one another or whether they represent distinct participants or reporting periods. Their counts should not be added together as if they were necessarily independent sets of people.

The record reports other adverse events affecting 2 of 2 participants in the Stage 1 placebo group, 4 of 4 in the Stage 1 MDMA-assisted group, 2 of 2 in the Stage 2 placebo group, and all participants in the two SRR listings. The record does not provide event terms in the serious-event list, and the top serious-event terms are empty. Counts alone do not describe the type, timing, severity, duration, or relationship of non-serious events to treatment. With an enrollment of 6, the safety summaries are descriptive and limited; they do not rule out uncommon or unrecorded events.

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

The posted primary outcome summaries describe mean CAPS-IV change within each randomized group. Both reported group means are negative, and the scale description indicates that higher scores correspond to greater PTSD symptom severity. The summaries therefore show lower follow-up scores on average than baseline scores in both groups. They do not establish why those scores changed or whether one treatment program produced a different change from the other.

The primary question is comparative, but the registry record does not report a between-group estimate, confidence interval, or p-value. A comparison cannot be judged for magnitude or precision using the two group means alone. In general, the evidence for a treatment contrast depends on both the estimated difference and its uncertainty, as well as on the design, measurement, and completeness of the data. No treatment conclusion should be drawn from the descriptive values alone.

The result also needs to be understood in the context of a very small enrolled sample and a terminated study. The registry reports 2 participants in the placebo-with-therapy group and 4 in the MDMA-assisted-therapy group. The reason for termination is not reported in the registry record. The title refers to 12 subjects, while recorded enrollment is 6; the record does not explain the discrepancy. These registry entries constrain how confidently the observed summaries can be generalized beyond the participants whose results are reported.

The intervention and comparator both include psychotherapy, so the study addresses MDMA-assisted psychotherapy relative to placebo with psychotherapy. It is not a comparison of medication alone against no treatment. The record lists secondary outcomes, but no analyses are listed, and it does not report missing-data methods or analysis populations. The appropriate reading is therefore narrow: the registry contains descriptive primary outcome summaries and safety counts, but does not provide the inferential evidence needed to resolve the comparative clinical question.

14. Why This Trial Matters Statistically

This trial is statistically instructive because it illustrates the difference between reporting outcome summaries and reporting a comparative analysis. Means and standard deviations convey information about the observed changes within each group. A randomized comparison, however, asks whether outcomes differ between groups and how uncertain that estimate is. Without an inferential contrast or interval estimate, the posted group summaries do not answer the comparative question with quantified precision.

The very small enrollment makes that distinction especially important. When only 2 participants are represented in one group and 4 in the other, individual observations can strongly affect group averages and variability estimates. In general, randomization does not eliminate the possibility of chance imbalance in small studies. A striking-looking within-group change may coexist with substantial uncertainty about the relative effect, and the registry record does not report a confidence interval or statistical test that would quantify it.

The record also emphasizes why trial status and recruitment context belong in statistical interpretation. The trial is marked terminated, enrollment is 6, and the title refers to 12 subjects. The reason for termination and explanation for the difference are not reported. These details do not establish that the results are biased, but they leave important questions about the planned and completed study unanswered.

Finally, the treatment contrast is a package comparison: MDMA-assisted therapy versus placebo with therapy. The endpoint is a structured symptom score measured at a specified follow-up period, not a complete account of every clinical outcome. The registry lists multiple secondary outcomes but no analyses. Together, these features show why transparent reporting of analysis methods, uncertainty, missing data, and study completion is essential for interpreting small pilot trials.

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 main limitation for interpretation is the small recorded enrollment: 6 participants, with 2 in the placebo-with-therapy group and 4 in the MDMA-assisted-therapy group. Such small groups provide limited information about variability and make averages sensitive to individual observations. The registry record does not report confidence intervals or an inferential between-group analysis for the primary endpoint.

The study is marked terminated, while its title refers to 12 subjects and the recorded enrollment is 6. The reason for termination and the explanation for this difference are not reported in the registry record. Without those details, it is not possible to assess whether the trial ended as planned or how termination affected the intended follow-up and analysis.

The registry record does not report the analysis population, missing-data methods, or whether all enrolled participants contributed to the endpoint summaries. It also does not describe the statistical model or provide an analysis plan, interim-analysis information, or a protocol-based sample-size justification. The record lists six secondary outcomes but no analyses, limiting assessment of results beyond the primary descriptive summaries.

The primary endpoint is a clinician-rated symptom score at a specified follow-up, and the registry’s outcome description defines its scale and direction. The record does not provide longer-term results or enough information to evaluate how the treatment programs were implemented beyond the summarized session descriptions. Because both groups received psychotherapy, the comparison concerns MDMA-assisted therapy against placebo with therapy, not MDMA in isolation. These constraints limit both causal interpretation and generalization.

16. Related Tutorials

17. Related Statistical Calculators

18. Sources

• ClinicalTrials.gov: Randomized, Double-blind, Controlled of MDMA-assisted Psychotherapy in 12 Subjects With PTSD — NCT01958593.
• Registry record last updated 2025-06-05; status last verified 2025-05.
• Results first posted 2021-08-02.
• 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

This randomized, triple-masked, parallel-group Phase 2 pilot studied MDMA-assisted psychotherapy compared with placebo plus psychotherapy for treatment-resistant PTSD. The registry records enrollment of 6 and a terminated status. The trial title refers to 12 subjects; the reason for the difference is not reported in the registry record.

The primary outcome was change in CAPS-IV total severity score from baseline to the primary endpoint, described as approximately 18 weeks after baseline and 1 month after the second experimental session. The registry reports mean changes of -21.5 (standard deviation 12.02; 2 participants) for placebo with therapy and -17.3 (standard deviation 13.05; 4 participants) for MDMA-assisted therapy. No inferential comparison is listed.

Six secondary outcomes are listed, but the record reports 0 analyses. Safety listings record 0 serious adverse events and 0 deaths in the listed groups. The reason for termination, missing-data handling, analysis populations, and protocol-based sample-size justification are not reported in the registry record.