The long-awaited results of the Multidisciplinary Association for Psychedelic Studies (MAPS) Phase 3 clinical trial have arrived. This randomized placebo-controlled trial had primary outcome measures of assessing changes in PTSD severity following treatment and secondary outcome measures assessing clinician-rated functional impairment following treatment with the drug as directed (de sure estimand).
Sessions
Participants had 3 preparation sessions, 3 experimental sessions, 9 integration sessions and 4 endpoint assessments over 18 weeks, with a final termination visit.
Prior to baseline assessments, participants had to taper and discontinue their psychiatric medications for a minimum of 5 half-lives and 1 week.
Preparation sessions focused on therapeutic rapport and guidance on the upcoming experience. Baseline measures were taken on Visit 3 conducted by an independent rater.
Treatment period was approximately 12 weeks, consisting of 3 experimental sessions with either MDMA or inactive placebo spaced 3-5 weeks apart in combination with therapy.
Participants fasted for 10-h before experimental sessions and they began with a C-SSRS assessment and vital measurements before initial drug dose.
Participants received a split dose of MDMA: 80 mg in session 1, 80 or 120 mg in subsequent sessions; or placebo followed by a half-dose of MDMA: 40 mg in session 1, and 40 or 60 mg in subsequent sessions, or placebo 1-2 h later.
Experimental session was followed by 90-minute integration session of non-drug therapy to provide support.
Measures throughout the study
CAPS-5 PTSD severity measures
Sheehan Disability Scale (SDS) clinical rated assessments
Clinician-Administered PTSD Scale for DSM-5
Columbia Suicide Severity Rating Scale (C-SSRS)
Blood pressure
Body temperature
Pulse
PTSD severity was defined using the CAPS-5 total severity score: asymptomatic (0–10), mild (11–22), moderate (23–34), severe (35–46), extreme (47+). A ≥10-point reduction in CAPS-5 total severity score was considered to be clinically meaningful as agreed upon with the US Food and Drug Administration (FDA) through a Special Protocol Assessment.
The Treatment Team
One person licensed to manage and administer controlled substances
A physician to assess participant safety at Screening
One or more two-person therapy pairs, male/female preferred
One person per therapy pair licensed to provide psychotherapy according to state and local requirements
Inclusion and Exclusion
Eligible individuals:
Met DSM-5 criteria for current post-traumatic stress disorder (PTSD) for ≥6 months
Had experienced at least moderate PTSD symptoms in the month before baseline
Had a Clinician-Administered PTSD Scale for DSM-5 (CAPS-5) total severity score of ≥28.
Medical conditions such as hypertension, asymptomatic hepatitis C virus, diabetes mellitus, hyperthyroidism, and glaucoma were eligible, providing the condition was well managed and mild.
Current mild alcohol or cannabis use disorders, or with a moderate alcohol or cannabis-use disorder in early remission for ≥3 months prior to enrollment, were also eligible.
Ineligible individuals:
Unable to give informed consent
History of or current primary psychotic disorder, bipolar I disorder, dissociative identity disorder, eating disorder with active purging, major depressive disorder with psychotic features, personality disorders, severe or moderate alcohol or cannabis use disorder
Any substance use disorder other than cannabis or alcohol within 12 months prior to enrollment
Use of ecstasy (material represented as containing MDMA) more than 10 times within the last 10 years or at least once within 6 months of the first experimental session
Serious imminent suicide risk
Any medical condition that could make receiving a sympathomimetic drug harmful due to increased blood pressure and heart rate, including uncontrolled hypertension, history of arrhythmia, or marked baseline prolongation of QT and/or QTc interval
Weighed ≤48 kg
Pregnant or nursing
Engaged in electroconvulsive therapy within 12 weeks of enrollment
Engaged in ketamine-assisted therapy or had used ketamine within 12 weeks of enrollment
Results
Adverse Events and Suicidality
see supplemental table 9 on the right
Almost every participant experienced at least one treatment-emergent physiological adverse events (TEAE), frequently reported which twice the prevalence in the MDMA treatment group. These included muscle tightness, nausea, decreased appetite and increased sweating.
There were also reported cardiovascular TEAEs in some participants which included palpitations and tachycardia.
Psychiatric TEAEs were equally as common, with suicidal ideation, insomnia and anxiety reported most frequently. Two participants in the MDMA and placebo groups had suicidal ideation, one from each group engaged in self-injurious behavior.
Many participants had reported suicidal ideation at the final preparation session.
Placebo group had generally more increased suicide ideation across experimental sessions.
Participants in the MDMA group showed a greater increase in suicidality during the third integration session following experimental session 3.
Some participants (2 in the MDMA group and one in placebo) had treatment-emergent active suicidal ideation with some intent to act.
One participant in the MDMA group with no suicidal ideation at baseline had the emergence of active suicidal ideation with some intent to act.
Primary Outcomes: Decrease in PTSD Severity
MDMA-assisted therapy reduced PTSD symptomatology compared to the placebo group across 18 weeks.
The mean change of score from baseline to 18 weeks was -23.7 in the MDMA group and -14.8 in the placebo group.
As per the initial stated ≥10-point reduction in CAPS-5 total severity score was considered to be clinically meaningful, this suggest that the placebo group (aka therapy alone) was also found to be clinically meaningful.
71.2% of participants in the MDMA group no longer met DSM-5 criteria for PTSD versus 47.6% of participants in the placebo + therapy group.
46.2% in MDMA group and 21.4% in the placebo + therapy group met remission criteria.
Secondary Outcomes: Clinician Rated Functional Impairment
In the SDS measure, MDMA was found to significantly mitigate functional impairment as rated by clinicians, although the scores only differed slightly between MDMA and placebo group.
The mean change for the MDMA group was -3.3 and the placebo group was -2.1, with reports of improvement across all domains.
Exploratory Outcomes: Covariate Analyses
These outcomes aimed to explore the relationship between severity, demographics and other facts in the outcomes.
Participants had similar treatment response regardless of disease severity, risk of hazardous alcohol or substance use disorder, severe adverse childhood experiences or dissociative subtype PTSD.
A significant covariate interaction was lifetime history of SSRI use associated with improved efficacy of MDMA-AT
Covariates significantly impacting the main effect of treatment were sex assigned at birth and baseline Beck Depression Inventory (BDI)-II score.
A sex difference was highlighted in this analysis: female sex assigned at birth and baseline BDI-II score ≥23 were both associated with improved outcomes irrespective of treatment assignment (P < 0.05).
Blinding of Treatment
Researchers conducted a blinding survey at study termination to assess both placebo and MDMA groups for blinding issues.
75.0% participants in the placebo with therapy group were certain or thought they received placebo, whereas nine of 20.5% participants inaccurately thought that they received MDMA, and two of 4.5% participants could not tell.
In the MDMA group, 94.2% participants were certain or thought that they received MDMA. Only one participant inaccurately thought that they received placebo and two participants could not tell.
Thoughts & Conclusions
Overall, this phase 3 trial demonstrates some efficacy of MDMA-assisted therapy. While the results are promising, there is a few things to be considered.
Placebo therapy participants still had a high percentage of response, which was clinically meaningful.
Sample sizes were well-powered, but evaluations only extended to 2 months post-therapy and are only focusing on acute treatment course. It would be beneficial to extend the follow up period as some have reported acute improvements followed by increased depression or suicidality following.
These studies use a "manualized inner-directed therapy" developed for MDMA-assisted therapy by MAPS, which has been critiqued previously for the lack of concrete methodology or diverse methodology across sites.
While blinding was measured, the expectancy was not, which could've provided further insight to the results.
LS mean scores were reported, but individual changes across time points were not. It would be interested to see each individual on the CAPS score graphs. They did group the participants into responders and non-responders in Figure 3.
Interestingly, they report a sex effect in female participants, which is something to be further explored (hopefully!)
Suicidal ideation and psychiatric adverse events should be included in the primary research article not in supplemental. This is important information that should be discussed instead of sticking it where it cannot be easily accessed by the public.
One note: the competing interest section includes several instances of MAPS funding and positions within the MAPS board. It's important to remember that this is a sponsored study and that can influence responses and results (big name, big expectations). The competing interest section is 752 words... the primary outcome results section is only 144.