Abstract
Background and Aims
Post-Traumatic Stress Disorder (PTSD) is a debilitating condition that affects a sizable proportion of U.S. civilians, military personnel, and veterans. 3,4-Methylenedioxymethamphetamine-Assisted Therapy (MDMA-AT) is a novel treatment approach for PTSD that has both stirred media enthusiasm and drawn criticism. This critical review analyzes individual randomized, controlled trials of MDMA-AT and provides a narrative synthesis.
Methods
A library search and analysis of extant literature reviews was conducted to identify publications containing original research findings with inter-group statistical comparisons from randomized, controlled trials of MDMA-AT. Seven articles were identified. One pilot study was excluded due to a lack of inter-group comparison.
Results
To date, six (four Phase II and two Phase III) randomized, controlled trials of MDMA-AT have been published which met criteria for inclusion in this review. Study design, sponsor, recruitment methods, and participant demographics are similar across trials.
Conclusions
Five out of six reviewed studies provide evidence for the apparent safety and efficacy of MDMA-AT. However, the lack of suitable comparison condition, poor blinding, and rigid study design across trials make interpretation of results difficult. In addition, the high costs of MDMA-AT and lack of head-to-head comparisons with validated PTSD therapies cast doubt on its potential promise as a treatment. The role of the sponsoring organization behind all trials may further introduce bias into findings. Though research to date is encouraging, there is not yet sufficient evidence to suggest that MDMA-AT should see widespread adoption over current, validated forms PTSD treatment.
Introduction
Post-traumatic stress disorder (PTSD) is often a debilitating condition that can develop after an individual experiences or witnesses a single or series of traumatic events, affecting approximately 5% of U.S. adults per year (U.S. Department of Veterans Affairs, n.d.). PTSD is associated with symptom clusters of reexperiencing, avoidance, hyperarousal, dissociation, and disordered sleep (Thakur, Choudhary, Kumar, & Chaudhary, 2022). Despite large-scale investments by the National Institutes of Mental Health and the Department of Defense on research into treatments for PTSD (Davis et al., 2022), the disorder continues to impose an economic burden of an estimated $232.2 billion per year in the U.S. (DeAngelis, 2023). Chronic PTSD is connected to a higher incidence of comorbid medical and psychiatric diagnoses, decreased occupational and social function, and increased risk of suicide (Merz, Schwarzer, & Gerger, 2019). Adverse outcomes of social, occupational, medical, and behavioral dysfunction are more common among certain groups with high risk of exposure to trauma (e.g., military veterans; Ramchand, Rudavsky, Grant, Tanielian, & Jaycox, 2015).
Effectively treating PTSD has proven to be challenging (Bisson, Roberts, Andrew, Cooper, & Lewis, 2013). Lack of efficacy and early drop-out from treatment plague many first-line, “gold standard,” or commonly used psychotherapies such as Cognitive Behavioral Therapy (CBT), Cognitive Processing Therapy (CPT), and Prolonged Exposure (PE), with rates of drop-out and non-response exceeding 50% in some studies (Schottenbauer, Glass, Arnkoff, Tendick, & Gray, 2008). Pharmacologic management of PTSD is also common, with nearly 9 out of 10 military veterans with PTSD receiving a drug prescription for the alleviation of symptoms (Alexander, 2012). The selective serotonin reuptake inhibitors (SSRIs) sertraline and paroxetine HCI have been approved by the U.S. Food and Drug Administration (FDA) for the treatment of PTSD (Alexander, 2012). Randomized, controlled trials (RCTs) studying the efficacy of these two treatments evince similar non-response rates to psychotherapeutic interventions, with estimates ranging from 35 to 47% (Alexander, 2012; Mitchell et al., 2023). For both psychotherapeutic and pharmacologic interventions, cases of full remission usually make up a minority of outcomes (Alexander, 2012; Schottenbauer et al., 2008).
The treatment modality of 3,4-Methylenedioxymethamphetamine-Assisted Therapy (MDMA-AT) for PTSD has recently made international headlines as a promising, novel approach to symptom reduction (Barber & Aaronson, 2022). Results from Phase II studies prompted the FDA to designate MDMA-AT a “breakthrough therapy” in 2017 to facilitate its movement to Phase III trials (Madero & Alvarez, 2023), which have since been conducted with close collaboration from the agency (Mitchell et al., 2023). Much of the fanfare surrounding MDMA-AT occurs in the context of a psychedelic “renaissance” (p. 584) in the field of psychiatry, as compounds such as MDMA, psilocybin, lysergic acid diethylamide (LSD), ayahuasca, ketamine, and others have begun to achieve prominence as possible psychotherapy facilitators (Barber & Aaronson, 2022). Policy consequences of the movement are already evident, with a July 2023 reclassification of MDMA by the Australian Therapeutic Goods Administration for use by psychiatrists in the treatment of depression (Nogrady, 2023). Other countries' regulatory bodies show signs of intending to follow suit in rescheduling MDMA and other compounds, including the UK and, most likely, the U.S. FDA (Meara, 2024; Murugesu, 2023; Nogrady, 2023).
Enthusiasm for MDMA-AT for PTSD has been criticized as premature, however, with many investigators arguing that current evidence is incomplete (Barber & Aaronson, 2022; Halvorsen, Naudet, & Cristea, 2021; Morgan, 2020). Indeed, the American Psychiatric Association (APA) released a 2022 position statement stressing the lack of sufficient evidence for the treatment's efficacy and urging caution (Knopf, 2022). The study design and recruitment protocols for RCTs of MDMA-AT have drawn criticism (Halvorsen et al., 2021), as has the exaggeration of positive results in media statements (Morgan, 2020). Though reviews and meta-analyses of the literature on MDMA-AT for PTSD are available (Bahji, Forsyth, Groll, & Hawken, 2020; Illingworth et al., 2021; Sessa, Higbed, & Nutt, 2019; Smith, Sicignano, Hernandez, & White, 2022; Womperski, 2023; Žuljević, Vidak, Vukojević, Hren, & Poklepovic Pericic, 2022), there has not yet been a critical review that combines an exploration of the structure and origins of the therapeutic modality, a qualitative synthesis of available evidence for MDMA-AT for PTSD, an analysis of the role of the organization orchestrating all extant RCTs, and a summary of clinical implications and current gaps in the literature. This critical review seeks to fill this gap and provide a summary of unanswered questions about this novel therapy.
Background
Structure of MDMA-AT for PTSD
To explore the evidence for MDMA-AT for PTSD, it is important first to understand each component of treatment and the overall schedule of activities. As the name implies, MDMA-AT combines the entactogen/empathogen MDMA with a form of psychotherapy (Barber & Aaronson, 2022; Mithoefer et al., 2017).
MDMA
Commonly known by its street names “Molly,” or, when pressed into a pill or tablet (often in combination with other stimulants), “Ecstasy,” (NIDA, 2022), MDMA is a synthetic amphetamine first derived in 1912 by Merck Pharmaceuticals (Madero & Alvarez, 2023) that has a broad range of physiological and psychological effects (Parekh, Adams, Barkell, & Lysle, 2022). Research into the therapeutic effects of MDMA was abruptly halted with its designation as a schedule 1 drug in 1985 (Barber & Aaronson, 2022). Neuropsychologically, MDMA modulates the release and reuptake of dopamine, norepinephrine, and serotonin (Feduccia, Jerome, Mithoefer, & Holland, 2021; Parekh et al., 2022). MDMA is also hypothesized to modulate memory function including reconsolidation, destabilization following recall, extinction, and generalization (Raut et al., 2022). It has been shown to reduce stress-induced neuroinflammation, thereby attenuating fear learning (Parekh et al., 2022).
Subjectively, participants in MDMA-AT trials have reported that the drug promotes tolerance for conflict, enhanced emotional processing, euphoria, interpersonal function, and a sense of connection to self and others (Godes, Lucas, & Vermetten, 2023). The drug's effects include a release of oxytocin, which, when combined with therapy, may strengthen therapeutic alliance and bolster approach toward feared memories (Mithoefer, Jerome, et al., 2011; Raut et al., 2022). MDMA's safety profile and toxicity compare favorably to other recreational drugs, and adverse events associated with drug administration are rare in clinical trials (Barber & Aaronson, 2022).
Therapeutic approach
The non-directive therapy utilized in MDMA-AT is atypical and warrants detailed description. The psychotherapeutic component of the treatment centers on participants' phenomenological experience while under the influence of the empathogen compound (Godes et al., 2023; Mithoefer et al., 2017). The approach of MDMA-AT is largely inherited from methods described by Greer and Tolbert (1998), a husband-and-wife team of psychiatric professionals who treated consenting patients with MDMA, often in the living room of their own home. Their approach was to “serve only as ‘sitters’ or assistants to clients… rather than to become involved in a traditional psychoanalytic relationship” (p. 373). Following the example of Greer and Tolbert, sessions of MDMA-AT are conducted by a male and female co-therapist team, occur in a living room-style environment, involve extensive therapist self-disclosure, and proceed with minimal direction from the therapists (Mithoefer et al., 2017).
The MDMA-AT for PTSD treatment manual stipulates that the psychotherapeutic element of treatment is broad and open-ended (Mithoefer et al., 2017). The manual notes that a diverse array of treatment approaches may be applied ad hoc during sessions of MDMA-AT, and that the use of these methods “will be determined by the therapist's preexisting skill sets” (p. 14) to be employed with “creative latitude” (p. 7). The manual notes that therapists are to utilize “empathic presence and listening” (p. 8) and allow participants' “inner healing intelligence” (p. 11) to guide recovery with the aid of the study drug. The treatment modality additionally includes the use of music, physical touch, art supplies, and incorporation of significant others into therapy.
In summary, the non-directive psychotherapeutic component of MDMA-AT contextually applies methods of many validated treatments for PTSD, including Rogerian Client-Centered Therapy (Blanchard et al., 2003), mindfulness meditation (Hopwood & Schutte, 2017), breathing exercises (Kim, Schneider, Kravitz, Mermier, & Burge, 2013), music therapy (Landis-Shack, Heinz, & Bonn-Miller, 2017), art therapy (Schouten, de Niet, Knipscheer, Kleber, & Hutschemaekers, 2015), and physical touch (McGreevy & Boland, 2022), to name a few. Though the manual describes a method for independent reviewers to ensure therapist adherence to the treatment protocol, it also notes that “… high adherence for its own sake may interfere with effectiveness” (Mithoefer et al., 2017, p. 11). Ratings of adherence are principally determined by “a qualitative evaluation of the sense of flow or allowance” of the session (p. 11), making it unclear which specific treatment ingredients are required. Pinpointing mechanisms of action is therefore difficult. Though described as a manualized treatment (Mitchell et al., 2021, 2023; Mithoefer et al., 2018), as noted by Bedi, Cotton, Guerin, and Jackson (2023), its standardization and replicability are questionable despite the publication of an adherence rating manual (see MAPS, 2021).
Schedule of activities of MDMA-AT
Following screening, participants in MDMA-AT undergo two to three 90-min preparatory sessions oriented toward familiarizing participants with the course of treatment, building rapport, and establishing expectations for drug sessions (Mithoefer et al., 2017). Then, participants undergo an MDMA drug session, which lasts approximately eight hours. Commonly, meals, overnight accommodations, and a trained attendant are provided for participants following drug sessions. After each MDMA-AT drug session, participants undergo three to four 90-min integration sessions, the first of which usually occurs the morning following the drug session. Recent instantiations of MDMA-AT for PTSD treatment last approximately 12–18 weeks altogether (Mitchell et al., 2023).
Individual studies
A library search was conducted by the primary author and recent systematic reviews were assessed to identify relevant literature for a critical synthesis. To date, there have been seven RCTs testing the safety and efficacy of MDMA-AT for PTSD. The first pilot trial was terminated prematurely and presents only limited descriptive data for six participants with no inter-group statistical comparison (Buoso et al., 2008); it is therefore excluded from this review. The design, methods, results, and conclusions of all other extant trials are described below in order of publication. Table 1 presents a summary of relevant data from each trial.
Summary of study design and relevant findings from each trial
| Study | Participants | Design | Comparator | Dosage | Significant Findings | Blinding Evaluation |
| Mithoefer, Jerome, et al. (2011) | 20 (12 MDMA-AT, 8 placebo) | Two-arm RCT with open-label crossover | Inactive placebo | 125 mg + 62.5 mg optional supplemental | Large between-group effect size in CAPS and IES-R score reductions in the MDMA group | 95% correctly guessed group assignment |
| Oehen et al. (2013) | 12 (8 MDMA-AT, 4 active placebo) | Two-arm RCT with open-label crossover | Low dose MDMA (25 + 12.5 mg) | 125 mg + 62.5 mg optional supplemental | Mixed results, significant difference in PDS scores, no significant difference in CAPS scores | 59% correctly guessed group assignment |
| Ot'alora et al. (2018) | 28 (9 low-dose, 9 medium-dose, 10 high-dose) | Three-arm ascending dose RCT with open-label crossover | Low dose MDMA (40 + 20 mg) | 40 + 20 mg, 100 + 50 mg, or 125 + 62.5 mg | Significant reduction in CAPS scores in the 125 mg group compared to the 40 mg group | Total not provided, approximately 73–86% correctly guessed assignment between therapists and participants. |
| Mithoefer et al. (2018) | 26 (7 low-dose, 7 medium-dose, 12 high-dose) | Three-arm ascending dose RCT with open-label crossover | Low dose MDMA (30 + 15 mg) | 30 + 15 mg, 75 + 47.5 mg, 125 + 62.5 mg | Significant differences in CAPS, DES-II, PTGI, GAF, and PSQI scores between high-dose and low-dose groups | Not specified |
| Mitchell et al. (2021) | 90 (46 MDMA-AT, 44 placebo) | Two-arm RCT, Phase III | Inactive placebo | 80–180 mg (varying by session) | Significant reductions on CAPS, SDS, and BDI scores | Not formally assessed, approximately 80–90% correctly guessed assignment |
| Mitchell et al. (2023) | 104 (53 MDMA-AT, 51 placebo) | Two-arm RCT, Phase III | Inactive placebo | 80–180 mg (varying by session) | Significant attenuations to CAPS and SDS scores | 95% of MDMA group guessed correctly, 75% of the placebo group guessed correctly |
Note: BDI = Beck Depression Inventory; CAPS = clinician-administered posttraumatic stress disorder scale; DES-II = dissociative experiences scale-II; GAF = global assessment of functioning; IES-R = impact of events scale-revised; MDMA = 3,4-Methylenedioxymethamphetamine; MDMA-AT = MDMA-assisted therapy; PSQI = Pittsburgh sleep quality index; PDS = posttraumatic diagnostic scale; RCT = randomized, controlled trial; SDS = Sheehan disability scale.
Mithoefer, Jerome, et al. (2011)
The first completed randomized, placebo-controlled pilot trial of MDMA-AT was conducted in the U.S. by Mithoefer, Jerome, et al. (2011). Participants (n = 20) with treatment-refractory PTSD were randomized to one of two groups: One group received a two-drug-sessions-version of MDMA-AT (n = 12), and the other received the same therapy with inactive placebo (n = 8). After study completion, an open-label crossover of MDMA-AT with two drug sessions was offered to those in the placebo condition, of which seven elected to take part. Following a protocol amendment, a subgroup of participants in both conditions (n = 9; 4 placebo group, 5 treatment group) participated in a third drug session and three additional integration sessions. Participants, therapists, and independent outcome raters were blinded to study group in the initial phase, and participants and investigators guessed randomization group after treatment sessions.
The course of MDMA-AT differed slightly from the prematurely terminated Buoso et al. trial (2008; Mithoefer, Jerome et al. 2011). Two preparatory sessions were conducted before and four integration sessions after drug administration sessions (all 90 min), drug sessions lasted 8–10 h, overnight accommodations were provided to participants after drug sessions, and therapists made daily phone contact for one week following drug sessions. The MDMA dosages included an initial dose of 125 mg and an optional supplemental dose of 62.5 mg administered 2–2.5 h after the first. The investigators note that supplemental doses among the treatment group were accepted in 22 out of the 23 cases in which they were offered but did not specify the number of supplemental doses offered to and accepted by the control group. In all other respects, the therapeutic methodology mirrored that which is described in the treatment manual.
Recruitment occurred via online advertisements and letters to therapists (Mithoefer, Wagner, et al., 2011). The vast majority of interested subjects were excluded during eligibility screening (n = 112). An additional two subjects dropped out of the treatment condition after the first MDMA-AT drug session, and another was determined to have failed screening following randomization. Included participants obtained a baseline Clinician-Administered PTSD Scale (CAPS; Weathers, Keane, & Davidson, 2001) score of ≥50, met Structured Clinical Interview for Axis I Diagnosis (SCID; First, Spitzer, Gibbon, & Williams, 1994) criteria for war- or crime-related PTSD, had no major medical comorbidities, and had a history of nonresponse to PTSD treatments. The study's primary outcome measure was the CAPS. Secondary instruments included the Impact of Events Scale-Revised (IES-R; Weiss, 1997) and the Symptom Checklist 90-Revised (SCL-90-R; Derogatis, 1994), neurocognitive measures, and physiological measures. Non-physiological measures were administered at baseline, four days after drug sessions, and two months after the final drug session.
Notable results of Mithoefer and colleagues' study included participant demographics, treatment side effects, efficacy findings, and blinding evaluation (2011). The rate of prior experience with MDMA among subjects was nearly six times that of the national average (SAMSA, 2021), the sample was entirely White (100%) and predominantly female (85%), most participants (80%) had comorbid major depression, all but one (95%) had crime-related, chronic PTSD. No serious adverse events were recorded, and side effects were mild and transient. Significant score reductions were observed on the CAPS and IES-R in both groups, though participants in the MDMA group saw significantly greater score reductions with a large between-group effect size. Control group subjects who proceeded to the open-label MDMA-AT treatment saw further significant reductions in CAPS scores. No significant differences on neurocognitive measures were detected between groups pre- or post-treatment. Rates of clinical response (>30% CAPS score reduction) for those in the treatment group was 83.3%, compared to 25% in the control group. During the open-label crossover, clinical response was observed in 100% of placebo participants. Additional sessions for those in the treatment group did not significantly alter outcomes. Blinding was poor with 95% of therapists and participants correctly guessing group assignment.
Mithoefer and colleagues conclude that the results of the trial are promising, but that future studies should investigate methods for improving blinding and attempt to discern essential elements of the therapeutic approach (2011).
Oehen, Traber, Widmer, and Schnyder (2013)
The randomized, placebo-controlled MDMA-AT pilot trial conducted by Oehen and colleagues in Switzerland mirrors the approach in the previous study (Mithoefer, Wagner, et al., 2011). Participants were first randomized to two groups, then control group subjects were offered the opportunity to take part in an open-label crossover. The same two-step MDMA dose was utilized as in Mithoefer, Jerome, et al. (2011) for the treatment group. However, participants in the control group were administered an “active placebo” (p. 40) of a low dose of MDMA (25 mg initial dose, 12.5 mg supplemental dose) to enhance blinding. In the initial phase, (n = 12; 8 MDMA-AT and 4 control) preparatory, drug, and integration sessions followed a 2:3:3 ratio. The 1:3 placebo to MDMA group allocation design was intended to “enhance recruitment efforts” (p. 42).
As the methods utilized by Oehen et al. (2013) closely resemble that of the previous trial, description will focus on points of departure. Notably, due to lack of clinical response in several full-dose participants, a protocol amendment was sought to offer two additional treatment and six integration sessions to three non-responders in the treatment group. These treatment sessions used higher MDMA doses (150 mg followed by 75 mg). All participants in the control group participated in the open-label crossover, which utilized one preparatory session. Participants were mostly female (83%), European (100%), had diverse index traumas, and typically had comorbid depression (88%). Measures included the CAPS and the Posttraumatic Diagnostic Scale (PDS; Foa, Cashman, Jaycox, & Perry, 1997) and were administered at baseline, multiple times over the course of treatment, and again at 12-month follow up. Two treatment group participants dropped out after a single drug session; both were ethnic minorities.
Results from Oehen and colleagues' trial were mixed (2013). Though the placebo and treatment group differed significantly on PDS scores, no significant difference was observed in average CAPS scores despite a score increase in the placebo group. Insomnia and loss of appetite were common adverse outcomes across study groups. Initial non-responders in the treatment group who consented to additional higher-dose sessions of MDMA-AT did not experience meaningful improvement. While the control group participants responded to treatment in the open-label crossover, statistical significance is not reported. The blinding evaluation revealed that slightly over half of subjects and therapists correctly predicted group assignment. The authors conclude by noting that while there was no significant difference between groups on the primary outcome measure, the administration of MDMA was safe. They suggest that future trials use three rather than two preparatory sessions to facilitate rapport-building.
Ot'alora et al. (2018)
The randomized, controlled, Phase II trial of MDMA-AT for PTSD conducted by Ot'alora et al. in the U.S. (2018) allocated participants (n = 28) to one of three groups: a low-dose comparator (n = 6; 40 and 20 mg supplemental), or one of two full-dose arms (n = 9 received 100 and 50 mg supplemental; n = 13 received 125 mg then 62.5 mg). The ratio of preparation, drug, and integration sessions was 3:2:6 in the initial treatment phase. An open-label crossover was again offered to those in the low-dose group which included three treatment sessions (n = 5 participated). An additional treatment and three integration sessions were offered to those in the two full-dose groups (9/9 of the 100 mg group and 12/13 of the 125 mg group participated). Participation was discontinued by one subject in the low-dose arm after one drug session, one subject in the 125 mg arm after initial treatment, and three additional subjects in the 125 mg arm were found to have exclusionary comorbid disorders following the initial study phase.
Methodologically, Ot'alora et al. (2018) made few changes from the basic format seen across prior trials (Mithoefer, Wagner, et al., 2011; Oehen et al., 2013). Participants were recruited by online advertisements and were mostly White (93%), female (68%), and had moderate to severe treatment-resistant, chronic (average duration nearly 30 years) PTSD. Notably, subjects with prior and current suicidal ideation (SI; 96%), and prior suicidal behavior (29%) were included. Measures included the CAPS (Weathers et al., 2001), the Beck Depression Inventory (BDI; Beck & Steer, 1984), the Dissociative Experiences Scale-II (DES-II; Carlson & Putnam, 1993), and the Pittsburgh Sleep Quality Index (PSQI; Buysse, Reynolds, Monk, Berman, & Kupfer, 1989). Blinded raters administered measures at baseline, one month after the second blinded session, one month after the second open-label session (low-dose group), two months after the third open-label session, and at 12 months after the final treatment session. Physiological measures and the Columbia Suicide Severity Rating Scale (CSSRS; Posner et al., 2011) were used to ensure participant safety.
Primary and secondary outcomes reported by Ot'alora et al. (2018) among participants who received all sessions included a significant reduction in CAPS scores in the 125 mg group compared to the 40 mg group, no significant comparative effect for the 100 mg group, roughly equivalent decreases in BDI scores across all three groups, and insignificant score differences across the PSQI and DES-II. During the open-label phase, significant score reductions were observed on the CAPS and DES-II for those in the 100 and 125 mg groups. Low-dose subjects in the crossover phase saw significant score reductions after two treatment sessions on the CAPS, BDI, and DES-II, though effects were not augmented by a third session. At the 12-month follow-up, lower scores across measures were observed and 76% of participants no longer met diagnostic criteria for PTSD. Treatment was generally safe and well-tolerated, with no serious adverse events associated with MDMA-AT. The blinding evaluation revealed that most therapists and subjects correctly guessed group assignment. In their conclusion, the authors highlighted the discrepancy between the low-dose and full-dose groups on outcomes following a third treatment session of MDMA-AT and note that future research should aim to clarify the number of sessions required for maximum efficacy.
Mithoefer et al. (2018)
Conducted with military veterans and first responders in the U.S. (n = 26), the randomized, controlled, Phase II trial of MDMA-AT for PTSD reported by Mithoefer et al. (2018) also utilized an active, low-dose control group (n = 7; 30 mg) and two ascending-dose treatment groups (n = 7 at 75 mg and n = 12 at 125 mg). All groups were offered a supplemental dose of half the initial dose 2–2.5 h after initial dosing. Consistent with the design described by Ot'alora et al. (2018), the ratio of preparation, drug, and integration sessions was 3:2:6 in the initial phase, with a control group open-label crossover and additional treatment sessions offered to the full-dose groups (1 additional session for the 125 mg group, 3 additional sessions at 100–125 mg for the 75 mg group). Two participants withdrew after one treatment session (n = 1 at 30 mg, n = 1 at 75 mg).
Participants were again recruited via internet advertisement, referral, and word-of-mouth (Mithoefer et al., 2018). Similarly, outcome measures followed the model of previous trials Sampled subjects were mostly White (85%), male (73%), military veterans (85%) with moderate to severe chronic, treatment-refractory PTSD. Major depression (77%) and lifetime incidence of SI (85%) were common comorbidities. Independent raters administered the CAPS (primary outcome) the BDI, PSQI, Post-Traumatic Growth Inventory (PTGI; Tedeschi & Calhoun, 1996), DES-II, Global Assessment of Functioning (APA, 1994), and a personality measure (secondary outcomes). Safety was again monitored via physical measures, phone screening, and the CSSRS.
At the conclusion of the randomized phase of the study, the active-dose groups typically outperformed the low-dose group across outcome measures (Mitheofer et al., 2018). Significant differences in CAPS, DES-II, PTGI, GAF, and PSQI scores were observed in both the 75 and 125 mg groups compared to the 30 mg group. Scores on the BDI differed significantly between the 125 mg group and 30 mg group while the 75 mg group scores fell approximately equidistant between the other two. However, subjects in the 75 mg group showed the greatest decreases on CAPS scores. The six low-dose participants who participated in the open-label crossover saw significant reductions on CAPS scores from their crossover baseline, though participants in the 75 mg group did not show significant score reductions after additional sessions. At the 12-month follow-up, CAPS scores were lower among all subjects, though two participants experienced symptom recurrence. Across secondary measures, participants who completed the final assessment demonstrated significant improvements from baseline. Despite a high incidence of adverse events (85 among 20 participants), most were mild and only one severe adverse event was deemed to be plausibly related to MDMA-AT (ventricle fibrillation).
The authors conclude by emphasizing the promising safety and efficacy findings for MDMA-AT, though they note that low doses of MDMA, consistent with findings from Oehen et al. (2013), appear to have a counter-therapeutic effect (Mithoefer et al., 2018). Perhaps unexpectedly, the therapeutic approach combined with inactive placebo has a salutary effect, despite its comparatively poor blinding (Mithoefer, Wagner, et al., 2011). The authors concede that 12-month outcome data cannot distinguish group effects due to the crossover design.
Mitchell et al. (2021)
The first randomized, controlled, Phase III trial of MDMA-AT for PTSD was conducted at participating sites in the U.S., Canada, and Israel and reported by Mitchell et al. (2021). Participants (n = 90) were randomized 1:1 to two groups, each receiving manualized psychotherapy (Mithoefer et al., 2017), with one receiving an 80–180 mg dose of MDMA (session 1: 80 mg + 40 mg, sessions 2–3: 120 mg + 60 mg), and the other receiving inactive placebo. The ratio of preparatory, drug, and integration sessions was 3:3:9, with one optional additional integration session. Due in large part to COVID-19, seven participants withdrew before completion of all treatment visits. Overall dropout was slightly greater in the placebo arm, with 37/44 (84.1%) completing all outcome measures compared to 42/46 (91.3%) in the treatment arm.
Methods were typical of other trials (Mitchell et al., 2021). Participants were primarily recruited via advertisement and referral, with standard inclusion and exclusion criteria regarding PTSD severity, chronicity, treatment resistance, and comorbidity. Included subjects were mostly White (77%), females (66%), with chronic, treatment-resistant PTSD from childhood trauma (84%) with comorbid major depression (91%). The primary outcome measure was the CAPS, the secondary measure was the Sheehan Disability Scale (SDS; Coles, Coon, DeMuro, McLeod, & Gnanasakthy, 2014), and exploratory measures included the BDI, measures of substance use, and the Adverse Childhood Experiences Questionnaire (ACE; Gette, Gissandaner, Littlefield, Simmons, & Schmidt, 2022). Blinded raters administered measures at baseline, three weeks after the first two drug sessions, and eight weeks after the final drug session. Physical measures and the CSSRS were used for safety monitoring. Attention was paid to a subset of adverse events of special interest to the FDA related to abuse liability, cardiac issues, and suicidality.
Outcomes for the MDMA arm were superior across the board at study conclusion (Mitchell et al., 2021). Significant reductions were observed with moderate to large effect sizes on CAPS (d = 0.91), SDS (d = 0.41), and BDI (d = 0.67) scores. MDMA-AT demonstrated equivalent efficacy across study sites, and across participants of various morbidity and comorbidity profiles. Treatment-emergent adverse events associated with cardiac function and suicidality were equal across study arms. Though blinding results are not formally reported, the authors note that a relatively small proportion of participants (10–16%) were incorrect in their guesses about group assignment. The authors conclude by noting the safety and efficacy of MDMA-AT in attenuating PTSD symptoms among participants with chronic, severe symptomatology and high comorbidity.
Mitchell et al. (2023)
The most recent randomized, controlled, multisite (U.S. and Israel) Phase III trial of MDMA-AT for PTSD replicates the findings of the previous trial with an ethno-racially diverse sample (Mitchell et al., 2023). To this end, its design is nearly identical to the previous study (Mitchell et al., 2021). The only noteworthy design change was the provision for a formal evaluation of blinding. Dropout was again greater among the placebo (43/51 [84.3%] completed study) than the MDMA group (52/53 [98.1%] completed), with five placebo subjects withdrawing after the first treatment session and three more withdrawing after the second.
Apart from the more demographically representative sample (34% non-White, 27% identified as Hispanic/Latino), study methods in the Mitchell et al. (2023) trial were otherwise identical to Mitchell et al. (2021) in terms of recruitment, primary/secondary measures, timing of assessments, use of independent raters, provisions for safety, and adverse events of special interest. Participants were mostly women (71%), most had moderate to severe chronic, treatment-resistant PTSD associated with developmental trauma (88%) and endorsed comorbid major depression (96%) and lifetime history of SI (88%). Prior MDMA use was reported and participants with a history of use were again oversampled at a rate of nearly 6 times that of the national average (46%; SAMHSA, 2021).
Participants assigned to the active treatment condition outperformed those in the control arm on primary and secondary outcome measures at study closure (Mitchell et al., 2023). Significant differences on CAPS and SDS scores were observed between treatment and placebo groups, with effect sizes of d = 0.7 and d = 0.4, respectively. Few outcome-associated covariates demonstrated significance, with female sex, lifetime SSRI use, and baseline BDI scores of ≥23 predicting improved outcomes across groups. Side effects among this sample were overwhelmingly common. Over 98% of participants reported at least one treatment-emergent adverse event, with more subjects in the MDMA group than the placebo group reporting transient cardiac, vascular, and blood-pressure-related adverse events. The authors note that no adverse events included heightened risk for addiction or abuse of MDMA. Blinding was poor overall, with over 94% of MDMA subjects, and 75% of the placebo subjects correctly identifying their group assignment.
The authors conclude by underscoring the positive efficacy findings of the trial and the tolerability of treatment (Mitchell et al., 2023). They suggest that MDMA-AT be compared directly to existing treatments and that other forms of psychotherapy be trialed in combination with MDMA.
Discussion
Though important caveats should be noted, randomized clinical trials of MDMA-AT for PTSD to date broadly demonstrate the apparent efficacy and safety of the approach. Participants in full-dose MDMA treatment arms have shown statistically greater improvements on the primary outcome measure (CAPS) in 5/6 studies (83.3%). In recent Phase III trials, observed between-group effect sizes are moderate to large and treatment effects are durable to a year post-intervention (Mitchell et al., 2021, 2023). MDMA administration has been associated with few serious adverse events across all studies. It appears well-tolerated among healthy, young to middle-aged volunteers without medical comorbidities, though potentially risky among those with a prior history of poor cardiovascular health (Mitchell et al., 2023).
Critical synthesis
However, many features of these RCTs cloud the interpretation of results. Importantly, the comparator used across trials of MDMA-AT is the same therapy with either an inactive placebo or a low dose of MDMA. Given the novelty of the complex psychotherapeutic approach and the lack of data on its individual efficacy in treating PTSD, it constitutes an unknown comparison. It is not possible to draw definitive conclusions about the efficacy of MDMA-AT as heretofore it has only been tested against versions of itself. The efficacy of MDMA-AT in comparison to standard cognitive-behavioral therapy is, as yet, unanswered. Trials comparing MDMA-AT to existing, validated therapies are needed (Halvorsen et al., 2021). Despite media claims to the contrary (Morgan, 2020), the fact remains that MDMA-AT treatment effect sizes, response rates, and rates of loss of diagnosis are similar to existing therapies (Halvorsen et al., 2021). In addition, MDMA-AT is exceptionally broad and inclusive of diverse therapy techniques (Mithoefer et al., 2017). Interpretation of results must incorporate the approach's inconsistency across and within individual studies.
Importantly, blinding across trials of MDMA-AT demonstrates that participants and therapists alike can correctly guess group assignment well above chance. Though comparison of MDMA-AT to a placebo version of the same therapy is circular, such a design could have been enhanced by using midazolam (Grunebaum et al., 2018) or niacin (Ross et al., 2016), which have been used to enhance blinding in other studies of psychedelic compounds. Low doses of MDMA moderately improved blinding but had a counter-therapeutic effect (Mithoefer et al., 2018), possibly inflating the efficacy results of Phase II trials. The insufficient blinding raises the possibility of allegiance bias and expectancy effects.
The free-form therapeutic approach and rigid design of MDMA-AT trials make discerning mechanisms of action difficult. No trial to date has included a comparator arm with MDMA alone, the non-directive therapy alone, or MDMA with a sham version of the therapy, muddying the interpretation of their independent effects. Given the ad hoc application of therapeutic techniques in MDMA-AT (Mithoefer et al., 2017), it is unclear which therapeutic components are critical. The overall design of MDMA-AT is further based on borrowed techniques that were developed non-scientifically (Greer & Tolbert, 1998). With no comparative data on the value of a male and female co-therapist team, a comfortable, living-room style environment, preparatory and integration sessions, and overnight stays, evaluation of the approach's merits is difficult.
Assessing which MDMA-AT components are essential is critical given the high resource and time demands of the approach. In the version of MDMA-AT trailed in Phase III studies (Mitchell et al., 2021, 2023), total face-to-face treatment time was approximately 42 h, more than double that required for a usual course of psychotherapy (Halvorsen et al., 2021). The use of a two-therapist team suggests that the approach would vastly exceed costs of existing psychotherapeutic modalities, which are already prohibitively expensive for approximately 40% of individuals (Conroy, Lin, & Ghaness, 2020). Notably, this does not account for drug costs, overnight accommodations with a trained attendant, or daily therapist phone contact for a week after treatment sessions. Conservative estimates of total treatment costs for MDMA-AT range from between $11–12,000 (Marseille, Mitchell, & Kahn, 2022), whereas clients will typically spend under $5,000 for a course of PE with a doctoral-level clinician (Le, Doctor, Zoellner, & Feeny, 2014). Treatment costs suggest that, if approved, MDMA-AT may represent a boutique therapy that is largely unaffordable to most PTSD sufferers.
Role of sponsoring organization
The Multidisciplinary Association for Psychedelic Studies (MAPS) is a nonprofit organization chiefly responsible for the funding, study design, treatment manual, and participant recruitment for every RCT of MDMA-AT for PTSD to date (Bedi et al., 2023; Mitchell et al., 2021; Mithoefer et al., 2017). MAPS has used philanthropy and direct donations to fund trials studying a variety of substances, including LSD, ayahuasca, cannabis, and MDMA (Bedi et al., 2023; Sessa, 2012). Per the MAPS website, the organization seeks both to conduct research trials to test the efficacy of psychedelic therapies, and to promote policy initiatives for the legalization and wider availability of psychedelic compounds (Multidisciplinary Association for Psychedelic Studies MAPS). The obstacles associated with orchestrating lengthy, multisite trials of MDMA-AT, which involve use of a Schedule 1 compound, a complex treatment regimen, and a vulnerable patient population, are difficult to overstate (Sessa et al., 2019). MAPS is so far the only organization that has proved equal to the challenge (Morgan, 2020). Still, the organization's monopoly on this field of inquiry has raised questions about the validity and interpretability of MDMA-AT studies (Bedi et al., 2023; Halvorsen et al., 2021).
MAPS’ commitment to advocacy has caused some reviewers to question if a priori assumptions have underpinned presuppositions about treatment efficacy and fueled policy proposals before a full investigation of MDMA-AT has occurred (Bedi et al., 2023). This was exemplified in a MAPS-sponsored 2018 contribution to a session of the United Nations' Committee on Economic, Cultural, and Social Rights (Ginsberg & Ali, 2018). The statement claimed that MDMA-AT “dramatically outperforms current methods of PTSD treatment” (p. 2) despite the absence of any head-to-head trials with current PTSD treatments that would facilitate such a comparison (Ginsberg & Ali, 2018; Halvorsen et al., 2021). This and similar proposals prompted a statement from the APA urging that treatments be determined not by “ballot initiatives and popular opinion,” but by evidentiary support (APA, 2022, p. 2; Knopf, 2022). MDMA-AT research, however, has been used strategically by MAPS to turn popular opinion toward favoring the wider availability of psychedelic compounds; a strategy that was explicitly elucidated by MAPS founder Rick Doblin (Doblin, 2002).
MAPS’ funding and participant recruitment for most extant RCTs of MDMA-AT has also drawn criticism. Without doubt, philanthropic funding sources are a vital lifeline for psychedelic research given the paucity of available federal grants (Barnett, Parker, & Weleff, 2022). However, some authors have argued that MAPS’ dependency on donors has encouraged inflated efficacy claims to secure funding (Bedi et al., 2023). Relatedly, the role of MAPS in the sampling of participants may also limit the generalizability of findings, as subjects who volunteer for MDMA-AT trials may be unduly influenced by inflated claims of the treatment's efficacy, allegiance to the organization's policy goals, and self-selection bias (Bedi et al., 2023). For example, some participants have later admitted to withholding negative effects and overreporting positive changes under a self-imposed obligation to help MDMA be approved by the FDA (Dickinson & Mugianis, 2021). Though perhaps not true to all participants' experiences, this vividly illustrates how potential selection bias, demand characteristics, response desirability effects, and commitment to the policy aims of MAPS among research subjects may skew results of RCTs of MDMA-AT.
Conclusion
Though many trials demonstrate promising efficacy and safety results for MDMA-AT for PTSD, the literature to date is dominated by poorly blinded, circularly designed studies orchestrated by a single organization with apparent conflicting interests. MDMA-AT trials have perhaps further suffered from their own media success and the concurrent psychedelic renaissance in psychiatry, both of which may contribute to dramatically altered participant responses. Future studies should be undertaken by independent researchers to lessen the influence of allegiance bias and expectancy effects. Deconstruction studies and head-to-head trials are critical to understand which components of the intervention are central to efficacy and to compare MDMA-AT's efficacy to current, evidence-based treatments. Given the high costs of MDMA-AT, the simplification and streamlining of the treatment may promote greater treatment accessibility and enhance the feasibility of its widespread adoption.
Clinical implications are unclear, given the many unanswered questions pertaining to MDMA-AT's mechanisms of action, the diversity of training competencies that are relevant to deliver the non-directive therapy, and the absence of any studies that directly compare MDMA-AT to current therapies (Halvorsen et al., 2021). Without doubt, however, there is little evidence to support the substitution of MDMA-AT for current, validated PTSD treatments. Widespread adoption is unwise until there is empirical support for its comparability to the available evidence-based treatments.
Funding sources
The authors received no specific financial support for the research, preparation, or publication of this article.
Authors' contribution
Hood, Alex: conceptualization, writing – original draft preparation, writing – review and editing.
Corlett, Chris: writing – review and editing, project administration.
Alldredge, Cameron: writing – review and editing, visualization.
Elkins, Gary: writing – conceptualization, review and editing, project administration, supervision.
Conflict of interest
The authors have no conflicts of interest to disclose.
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