Table 3.

Overview of clinical studies of MDMA for the treatment of PTSD.

Study First Author, Year References	Sample Size	Method	Measures	Study Type	Effect	Statistical Outcome
Mitchell et al., 2021 [40]	n = 90	MDMA-assisted therapy for severe PTSD: A randomized, double-blind, placebo-controlled trial (PAP)	Screening Measures: 1. PCL-5 2. MINI 3. SCID-5-SPQ 4. SCID-5-PD 5. C-SSRS Primary Outcome Measure: • CAPS Secondary Outcome Measure: • SDS Exploratory Measures: • BDI-II • AUDIT • DUDIT • ACE	Phase III	Three doses of MDMA, combined with psychotherapy over 18 weeks, significantly reduced PTSD symptoms, functional impairment, and depressive symptoms. MDMA did not induce adverse events of abuse potential, suicidality, or QT prolongation.	CAPS-5 score: MDMA group vs. placebo: P < 0.0001, d = 0.91 SDS score MDMA group vs. placebo: P = 0.0116, d = 0.43
Monson et al., 2020 [399]	n = 12 (6 dyads w/one person w/PTSD diag., one no PTSD)	Uncontrolled trial. Initial test of the safety, tolerability, and efficacy of MDMA-facilitated cognitive behavioral conjoint therapy. (PAP)	Screening Measures: • SCID-5 Primary Outcome Measures: • CAPS-5 • PCL-5 patient and partner versions • CSI Secondary Outcome Measures: • BDI-II • Pittsburgh Sleep Quality Questionnaire • ERQ • TABS	Phase I	Significant improvements in clinician-assessed, patient-rated, and partner-rated PTSD symptoms as well as patient depression, sleep, emotion regulation, and trauma-related beliefs	Pre- to post-treatment/follow-up effect sizes ranged from d = 1.85-3.59
Mithoefer et al., 2018 [323]	n = 26	Randomized, double-blind, dose-response study to assess efficacy of MDMA-AT for PTSD in military veterans, firefighters, and police officers. Compared dosages of 30, 75, and 125 mg. (PAP)	Primary Outcome Measure: • CAPS IV Secondary Outcome Measures: • BDI-II • PSQI • PTGI • NEO-PI-R • DES-II • GAF • C-SSRS	Phase II	The 75 mg and 125 mg groups had significantly greater decreases in PTSD symptom severity than the 30 mg group. PTSD symptoms were significantly reduced at the 12-month follow-up compared with baseline after all groups had full-dose MDMA.	Compared with the 30 mg group, Cohen's d effect sizes were large: 2·8 (95% CI 1·19-4·39) for the 75 mg group and 1·1 (0·04-2·08) for the 125 mg group.
Ot’alora et al., 2018 [873]	n = 28	Randomized double-blind dose-response study comparing two active doses (100 and 125 mg) with a low dose (40 mg) of MDMA during psychotherapy sessions (PAP)	Screening Measures: • SCID • CAPS IV Primary Outcome Measure • CAPS IV Secondary Outcome Measures • BDI-II • DES-II • PSQI • C-SSRS	Phase II	In the intent-to-treat set, the active groups had the largest reduction in CAPS total scores at the primary endpoint.	In the intent-to-treat set, the active group’s mean CAPS score changes were -26.3 (29.5) for 125 mg, -24.4 (24.2) for 100 mg, and -11.5 (21.2) for 40 mg, though statistical significance was reached only in the per protocol set (p = 0.03). 76% (n = 25) did not meet PTSD criteria at follow-up.
Mithoefer et al., 2013 [275]	n = 19	Long-term follow-up (LTFU) on the durability of improvement in PTSD symptoms and absence of harmful effects or drug dependency after MDMA-AT (PAP)	• Long-term follow-up questionnaire (original measure for this study) • CAPS • IES-R	LTFU	On average, subjects maintained statistically and clinically significant gains in symptom relief between Study Exit and LTFU.	CAPS results showed no statistical differences between mean CAPS score at LTFU (3.5 years after initial study) (mean = 23.7; SD = 22.8) and the mean CAPS score previously obtained at Study Exit.
Oehen et al., 2013 [874]	n = 12	A randomized, controlled pilot study of MDMA-assisted therapy for treatment-resistant chronic PTSD (PAP)	• CAPS • PDS • SCID-I Substance Abuse Module • In-session SUDS	Pilot	MDMA-AP can be safely administered in a clinical setting. Subjects with treatment-resistant chronic PTSD showed, on average, a substantial improvement in self-reported PTSD symptoms over the course of MDMA-AP.	Clinically and statistically significant self-reported (PDS) improvement (p = 0.014) documented. CAPS scores improved further at the 1-year follow-up. In addition, 3 MDMA sessions were more effective than 2 (p = 0.016).
Mithoefer et al., 2011 [366]	n = 20	Randomized, double-blind placebo-controlled study evaluating the safety and efficacy of MDMA-assisted therapy in subjects with chronic, treatment-resistant PTSD (PAP)	Screening Measures: • SCID-I • SCID-II • CAPS Primary Outcome Measure: • CAPS Secondary Outcome Measures: • IES-R • SCL-90-R Neurocognitive Measures: • RBANS • PASAT • RCFT	Pilot	Decreased CAPS scores from baseline for the group that received MDMA compared with placebo. No drug-related serious adverse events, adverse neurocognitive effects, or clinically significant blood pressure increases.	Clinical response rate was 10/12 (83%) in the active treatment group vs. 2/8 (25%) in the placebo group.

Abbreviations: ACE: Adverse Childhood Experiences Questionnaire, AUDIT: Alcohol Use Disorders Identification Test, BDI-II: Beck Depression Inventory 2 or Beck Depression Inventory II, CAPS: Clinician-Administered PTSD Scale, CAPS-IV: Clinician Administered PTSD Scale for DSM-IV, CAPS-5: Clinician-Administered PTSD Scale for DSM-5, CSI: Couples Satisfaction Index, C-SSRS: Columbia Suicide Severity Rating Scale, DES-II: Dissociative Experiences Scale II, DUDIT: Drug Use Disorders Identification Test, ERQ: Emotion Regulation Questionnaire, GAF: Global Assessment of Functioning, IES-R: Impact of Events Scale-Revised, LTFU: Long-term follow-up, MDMA: 3,4-methylenedioxy-methamphetamine, MDMA-AT: MDMA-assisted therapy, MINI: Mini International Neuropsychological Interview, NEO-PI-R: Neuroticism-Extroversion-Openness-Personality Inventory Revised, PAP: Psychedelic-Assisted Psychotherapy, PASAT: The Paced Auditory Serial Addition Task, PCL-5: PTSD Checklist for DSM-5, PDS: Posttraumatic Diagnostic Scale, PSQI: Pittsburgh Sleep Quality Index, PTGI: Post-Traumatic Growth Inventory, PTSD: Post-traumatic stress disorder, QT prolongation: A measure of delayed ventricular repolarization, RBANS: The Repeatable Battery for the Assessment of Neuropsychological Status, RCFT: Rey-Osterrieth Complex Figure Test, SCID-I: Structured Clinical Interview for DSM-IV Axis I Disorders, SCID-II: Structured Clinical Interview for DSM-IV Axis II Personality Disorders, SCID-5: Structured Clinical Interview for DSM-5, SCID-5-PD: Structured Clinical Interview for DSM-5 Personality Disorders, SCID-5-SPQ: Structured Clinical Interview for DSM-5 Screening Personality Questionnaire, SDS: Sheehan Disability Scale, SCL-90-R: Symptom Checklist-90-Revised, SUDS: Subjective Units of Distress Scale, TABS: Traumatic and Attachment Beliefs Scale.