MDMA-Assisted Therapy for Severe PTSD: a Randomized, Double-Blind, Placebo-Controlled Phase 3 Study

Design

Randomized, double-blind, placebo-controlled, multi-center phase 3 clinical trial

N= 90

Objective

To test the efficacy and safety of 3,4-methylenedioxymethamphetamine (MDMA)-assisted therapy for the treatment of patients with severe post-traumatic stress disorder (PTSD), including those with common comorbidities such as dissociation, depression, a history of alcohol and substance use disorders, and childhood trauma

Study Groups

MDMA-assisted (n= 46)

Placebo (n= 44)

Inclusion Criteria

Current PTSD (as determined by Diagnostic and Statistical Manual of Mental Disorders, fifth edition [DSM-5] criteria), symptom duration of ≥ 6 months at screening, Clinician-Administered PTSD Scale for DSM-5 (CAPS-5) total severity score of ≥ 35 at baseline

Exclusion Criteria

Primary psychotic disorder, bipolar I disorder, dissociative identity disorder, eating disorders with active purging, major depressive disorder with psychotic features, personality disorders, current alcohol, and substance use disorders, pregnancy or lactation, any medical condition that could make receiving a sympathomimetic drug harmful due to increased blood pressure and heart rate

Methods

Patients were randomized (1:1) to MDMA-assisted group or placebo with therapy group. The treatment period consisted of three, eight-hour experimental sessions for each group, spaced about four weeks apart. Each experimental session was followed by three 90-min integration sessions that were spaced approximately one week apart to allow the participant to understand and incorporate their experience

In each experimental session, patients were given a single divided dose of 80-180 mg MDMA or placebo. In the first session, an initial dose of 80 mg was given followed 1.5 to 2.5 hours later by a supplemental half dose of 40 mg. In the second and third sessions, the initial dose of 120 mg was given followed by a supplemental half dose of 60 mg. Blood pressure, body temperature, and heart rate were measured before administering the supplemental dose. Anticipated effects of MDMA, such as euphoria, stimulation, and feelings of closeness, were intentionally not solicited as adverse events.

Manualized therapy utilized during sessions was an inner-directed and facilitated inquiry and support for approaching difficult material without interfering with the patient's spontaneous experience.

Duration

Recruitment: November 7, 2018, to May 26, 2020

Intervention: 18 weeks

Follow-up: two months

Outcome Measures

Primary: PTSD symptoms (measured with CAPS-5) at 18 weeks from baseline

Secondary: functional impairment (measured with Sheehan Disability Scale [SDS]) at 18 weeks from baseline

Baseline Characteristics

MDMA-assisted (n= 46)

Placebo (n= 44)

Age, years

Female

Race

White

Asian

Black

39 (84.8%)

2 (4.3%)

0

30 (68.2%)

5 (11.4%)

2 (4.5%) 

Mean duration of PTSD, years

Dissociative subtype of PTSD

Comorbid major depression

Trauma history

Developmental trauma

Combat exposure

Multiple trauma

40 (87%)

6 (13%)

41 (89.1%)

36 (81.8%)

5 (11.4%)

38 (86.4%)

Pre-study PTSD medications

Sertraline

Paroxetine

8 (17.4%)

3 (6.5%)

9 (20.5%)

3 (6.8%)

Pre-study therapy

Cognitive behavioral therapy

Eye movement desensitization and reprocessing therapy

Group therapy

Prolonged exposure therapy

Psychodynamic

Other

None

12 (26.1%)

17 (37.0%)

19 (41.3%)

1 (2.2%)

11 (23.9%)

41 (89.1%)

1 (2.2%)

22 (50.0%)

13 (29.5%)

14 (31.8%)

0

10 (22.7%)

38 (86.4%)

1 (2.3%)

Baseline CAPS-5 total score

Baseline SDS modified score

Results

Endpoint

MDMA-assisted (n= 42)

Placebo (n= 37)

p-Value

Mean change in CAPS-5

Mean change in SDS

MDMA was found to induce significant and robust attenuation in CAPS-5 score compared with placebo (p< 0.0001, d = 0.91) and to significantly decrease the SDS total score (p= 0.0116, d= 0.43).

At 18 weeks, 28 of 42 (67%) of the participants in the MDMA group no longer met the diagnostic criteria for PTSD, compared with 12 of 37 (32%) of those in the placebo group.

Adverse Events

Common Adverse Events: N/A

Serious Adverse Events: suicide attempt (0% MDMA vs. 2.3% placebo), suicidal ideation resulting in self-hospitalization (0% MDMA vs. 2.3% placebo)

Adverse Events of Special Interest: suicidality (overall: 6.5% MDMA vs. 11.4% placebo; includes suicidal ideation [4.3% MDMA vs. 6.8% placebo]; intentional self-harm in context of suicidal ideation [2.2% MDMA vs. 0% placebo]; suicidal behavior and self-harm [0% MDMA vs. 2.3% placebo]; suicidal behavior, self-harm, and suicidal ideation [0% MDMA vs. 2.3% placebo]); irregular heartbeats and palpitations (0% MDMA vs. 2.3% placebo)

Study Author Conclusions

MDMA-assisted therapy induces rapid onset of treatment efficacy, even in those with severe PTSD, and in those with associated comorbidities including dissociative PTSD, depression, history of alcohol and substance use disorders, and childhood trauma. Not only is MDMA-assisted therapy efficacious in individuals with severe PTSD, but it may also provide improved patient safety. Compared with current first-line pharmacological and behavioral therapies, MDMA-assisted therapy has the potential to dramatically transform treatment for PTSD and should be expeditiously evaluated for clinical use.

InpharmD Researcher Critique

The results presented in this study have relatively short-term benefits as assessed at a period of two months following the final experimental session and five weeks after the final integration session. Long-term follow-up data collection is ongoing.