Breakthrough therapy designation (BTD) is one of the Food and Drug Administration’s (FDA) expedited drug development pathways. To be eligible for BTD, a sponsor must demonstrate that the investigational product is intended to treat a serious and life-threatening condition, with preliminary evidence supporting a substantial advantage at a clinically significant endpoint over existing drugs (1). On August 16, 2017, the FDA granted breakthrough therapy designation for MDMA-assisted psychotherapy for the treatment of posttraumatic stress disorder (PTSD). This application was among the 45% of applications granted BTD status in 2017 (2). The aim of this review is to summarize the data and rationale presented in the application that led FDA to grant this designation.

PTSD is considered a serious and life-threatening disorder and is associated with increased mortality, cardio-metabolic morbidity, and suicide risk. PTSD negatively impacts a person’s daily life, often resulting in fractured relationships, depression, decreased daily functioning, diminished cognitive and psychosocial functioning, substance abuse, and high-cost healthcare utilization ($34.9 billion in inflation-adjusted charges for hospitalizations (2002–2011) (3). Approximately 7% of the U.S. population, and 11.2–17.1% of veterans (4), will have PTSD sometime in their life (5).

Only two drugs, the selective serotonin reuptake inhibitors (SSRIs) sertraline hydrochloride (Zoloft) and paroxetine hydrochloride (Paxil), are approved oral medications for PTSD (6–8). These medications and trauma-focused psychotherapies (e.g., eye movement desensitization, cognitive processing therapy, prolonged exposure) are recommended as first-line treatments for PTSD (9–12). In a meta-analysis evaluating psychotherapy versus pharmacotherapy, trauma-focused psychotherapies resulted in greater and longer lasting improvements than medications (12). Meta-analyses and network meta-analyses found paroxetine, but not sertraline, performed better than placebo (13, 14). Hoskins and colleagues reported that SSRIs had a small effect size with respect to PTSD symptom reduction. When compared to a control group, SSRIs either had insignificant effects or small/moderate effects, while trauma-focused therapies varied from small to large effects (12). The average dropout rate for the 55 studies included in the meta-analysis was 29% (0–79%) demonstrating that many individuals fail to tolerate or respond to available treatments (12), including trauma-focused psychotherapies, where the dropout can range from 28 to 68% (15, 16). A network meta-analysis reported that dropout rate for paroxetine and sertraline was greater than placebo (14).

The Multidisciplinary Association for Psychedelic Studies (MAPS) holds an Investigational New Drug Application (IND) for MDMA as an adjunct to psychotherapy for treatment of PTSD. MAPS has sponsored six phase 2 trials of MDMA-assisted psychotherapy for PTSD that lasted from April 2004 to March 2017. The safety and efficacy results from these trials were submitted to the FDA, along with a summary of the sertraline and paroxetine data that supported the New Drug Application (NDA) for approval of these drugs for the indication of PTSD. Sertraline and paroxetine summary data was extracted from documents found in the FDA drug database, including the Review and Evaluation of Clinical Data and the drug labels (17–20).

Here, we present the evidence included within the breakthrough therapy application showing that MDMA-assisted psychotherapy was superior in phase 2 trials in terms of safety and efficacy compared to the two approved SSRIs for treatment of PTSD. The control groups in the MDMA trials also received intensive psychotherapy (approximately 30 h), while SSRIs pivotal trials used a placebo without any type of therapy for comparison. Since the FDA does not regulate psychotherapy, the BT application did not compare MDMA-assisted psychotherapy to trauma-focused therapies. However, since trauma-focused therapies have evidence for the greatest effectiveness in reducing PTSD symptoms, we have included an additional section in this review comparing MDMA-assisted-psychotherapy with first-line psychological therapies.

The dropout rate in active (75–125 mg blinded) MDMA-treated subjects in MAPS-sponsored Phase 2 trials was 6.8% (5 of 74, with 2 excluded for missing outcome data and 3 excluded for early termination, with outcome data), considerably less than SSRI trials where dropout rates were 11.7% in paroxetine-treated and 28% in sertraline-treated subjects, indicating that MDMA is better tolerated by a PTSD population than the two SSRIs. Reduced drop-out rates in MAPS’ Phase 2 studies may result from a strong therapeutic alliance, and commitment to the course of psychotherapy, as well as the therapeutic effects of MDMA. On the other hand, dropout rates (3 of 31, 9.7%) were also low for the control group which could reflect some benefit from the psychotherapy alone, or increased motivation to remain in the study to receive active MDMA during the open-label crossover segment.

In paroxetine trials, the most common adverse events (5% or greater and at least 2× that of placebo) in the PTSD population were: asthenia, sweating, nausea, dry mouth, diarrhea, decreased appetite, somnolence, libido decreased, abnormal ejaculation, female genital disorders, and impotence. Reported by 19% of subjects, nausea was the most frequently experienced treatment-emergent adverse event. For sertraline, the most common effects were nausea, headache, insomnia, diarrhea, dry mouth, ejaculation failure, somnolence, dizziness, and fatigue.

Administering MDMA in single doses spaced a month apart in a controlled setting has several inherent benefits over chronic daily dosing of paroxetine or sertraline. Firstly, compliance is not an issue in studies of MDMA, because all dosing occurs in a clinic under supervision, whereas SSRIs rely on patients self-administering daily doses which can be a challenge due to cognitive and behavioral impairments that can accompany PTSD (52).

Secondly, fewer side effects are reported after MDMA due to the limited number of administrations. Phase 2 safety data showed that reactions were reported most frequently on the day of MDMA administration and typically diminished in the few days following. The most commonly reported reactions on the day of the experimental session were anxiety, tight jaw/jaw clenching, lack of appetite, headache, and fatigue (48). On the day of blinded experimental sessions, reactions reported by the active MDMA group by at least 2x of the frequency of the control group were diarrhea, difficulty concentrating, dizziness, heavy legs, impaired gait/balance, jaw clenching/tight jaw, lack of appetite, nausea, nystagmus, paresthesia, perspiration, sensitivity to cold, thirst, and weakness. These findings are in line with clinical trials in healthy controls (53, 54). On the other hand, patients taking paroxetine and sertraline experience more prolonged adverse reactions due to steady state drug plasma levels across the 12-week treatment period.

Discontinuation of paroxetine and sertraline may be accompanied by adverse effects (55), likely caused by neuroadaptations of decreased levels of serotonin transporters in neuronal membranes after use of SSRIs (56). For discontinuation of sertraline and paroxetine gradual tapering is recommended, and patients should be monitored for discontinuation emergent symptoms, which can be very troubling. Adverse events during discontinuation (incidence of 2% or greater for paroxetine and at least 2x that of placebo) were abnormal dreams, paresthesia, and dizziness, and for sertraline, they were nausea, insomnia, and diarrhea (18, 20). Post-marketing surveillance identified a number of additional discontinuation emergent negative effects, including sensory disturbances, agitation, anxiety, nausea, and sweating; however causal relationship to drug hasn’t been confirmed.

Single doses of MDMA have not produced discontinuation symptoms. Some adverse reactions are reported during the 7 days following an MDMA dose, including anxiety, dizziness, depressed mood, fatigue, headache, jaw clenching or tightness, lack of appetite, nausea, and panic attack (48). By Day 5, the only reactions reported in over 20% of active dose participants were fatigue and anxiety. Both were reported by nearly equal numbers of active and control dose participants. Symptoms were mild to moderate in severity, and nearly all resolved within 7 days of dosing. Eight participants in the active dose group and three in the control group, reported a reaction on the seventh day of follow-up (not seven consecutive days of experiencing the reaction) that was therefore recorded as an adverse event (AE). Reactions fitting AE criteria and reported by more than two participants were anxiety and low mood, occurring in both active and control groups. Both are prominent symptoms of PTSD. Only three participants had the same reaction on day of experimental session and 7 days following the session, which included anxiety, low mood, and muscle tension.

Estimating risk of long-term deleterious effects of discrete doses of MDMA in a controlled setting compared to retrospective studies in people reporting ecstasy use is inappropriate for several reasons. Ecstasy can contain an unknown quantity of MDMA and adulterants, or no MDMA at all, and most people ingesting MDMA are polydrug users. Most studies are retrospective, with only a single prospective study reported detecting signs of a specific impairment in verbal memory in a sample of people reporting nonmedical use, without detecting any functional or structural changes in the brain (57, 58). Systematic reviews of the literature found that most research enrolls people whose lifetime use far exceeds the average (59–61). In contrast, cognitive function in three trials of MDMA-assisted psychotherapy failed to find impairment after any dose of MDMA (48). When asked about ‘ecstasy’ use at 12-month follow-up after participation in a Phase 2 trial, eight participants, six of whom had taken ecstasy prior to enrollment, reported having used it one to three times. This indicates that MDMA given in the context of psychotherapy does not have high abuse liability (41, 43, 44, 47, 62).

An additional risk of SSRIs is that they are contraindicated with MAOIs and some other drugs due to inhibition of P450 enzymes. Since these drugs are take-home medications, patients are at risk of accidentally consuming a contraindicated medication that could have serious adverse effects, including death. Accidental and intentional overdoses have been reported with both SSRIs (63). Since clinicians collect concomitant medication information at each session before administering MDMA, the risk for accidental use of a contraindicated medication is far reduced, and risk of overdose is eliminated by dispensing only the recommended dosage by a prescribing physician. Both SSRI drug labels state that alcohol is not recommended, but given that a significant number of people with PTSD also have comorbid alcohol use disorders, refraining from alcohol may be particularly problematic for this population and lead to negative effects (64, 65).

MDMA-assisted psychotherapy received BTD based on its use in treating PTSD, a serious and life-threatening condition, and on the basis of phase 2 clinical data that MDMA produced substantial clinical improvement and greater compliance than the two approved drugs for PTSD, paroxetine and sertraline. Data from Phase 2 provides evidence that PTSD, independent of cause, is treatable with 2 to 3 sessions of MDMA-assisted psychotherapy, and offers a larger treatment effect, increased compliance and lower risk of dropout, reduced possibility of drug interactions compared to paroxetine and sertraline. There have been no deaths related to MDMA in controlled Phase 1 and 2 studies, and if it is approved for clinical use, MDMA will be administered directly to patients, and only in licensed MDMA clinics under controlled conditions similar to those in clinical research. The single-dose regimen of MDMA produces fewer, self-limiting, transient side effects and greater compliance compared to daily dosing of paroxetine and sertraline.

In meta-analyses comparing efficacy of PTSD treatments investigated in randomized controlled trials, trauma-focused psychotherapies generally result in greater and more sustained response than pharmacotherapies and other psychological therapies (12, 66). Lee et al. report comparative effect sizes from meta-analyses of randomized trials that included a control condition, with controls for psychotherapy trials including supportive psychotherapy, biofeedback, and relaxation training, and excluding those with waitlist and treatment-as-usual controls. Compared to control, after 14–27 weeks of trauma-focused therapies the effect size was −0.96. For all medications, which included SSRIs, SNRIs, antiepileptics, antipsychotics, the effect size was −0.44. The magnitude of effect (0.9) of MDMA-assisted psychotherapy is in the range of first-line trauma-focused therapies. MDMA was compared to psychotherapy alone, or low dose MDMA plus psychotherapy, as the control condition and Phase 2 studies enrolled only participants who had previously tried and failed to respond to or tolerate available treatments.

Beyond the quantifiable change of PTSD symptoms, the degree to which MDMA supports the unfolding of a healing experience through neurochemical changes should be considered. Biochemically inducing a mental state more receptive to engaging in deep therapeutic processing could help to speed up symptom improvement or improve treatment outcomes for those resistant to other therapies. There is some evidence from nonclinical experiments that MDMA may increase neuroplasticity through BDNF-dependent mechanism (67), and otherwise alter brain activity in key networks for emotional-memory processing (30). Psychologically, MDMA may ease the challenge of recalling traumatic memories and feeling deeply into the associated emotions. Posttraumatic growth measured by the Posttraumatic Growth Inventory (PTGI), and personality shifts measured by the NEO Personality Profile have been observed after MDMA-assisted psychotherapy (43, 68). In addition, the importance of patient choice regarding therapy for PTSD has been pointed out, and MDMA-assisted psychotherapy may offer advantages in this area if it makes processing trauma less arduous (69).

Another recent meta-analysis paper, found no significant differences in benefits of pharmacological, psychotherapeutic, or the combination at the end of treatment, except at the last available endpoint during long-term follow-up, at which point psychotherapeutic treatments were significantly better than medications. In this analysis, the combined treatments, which included one MDMA-assisted psychotherapy trial, were slightly but not significantly more beneficial than psychotherapeutic treatments alone (66). Data from the other five phase 2 MDMA trials were not included, and the outcome from the MDMA trial was analyzed along with other medication-therapy combinations (e.g., SSRIs and CBT). Until MDMA-assisted psychotherapy is compared to trauma-focused therapies in a randomized trial, it is uncertain whether either approach is superior in terms of efficacy or tolerance. Though it may potentially have greater risks and increased likelihood of mild to moderate adverse events compared with non-drug therapies, MDMA has thus far demonstrated a favorable safety profile with limited administrations in clinical settings. Patient experience of each therapy, time to respond, and durability of response should be evaluated. Future research could also explore whether MDMA combined with existing manualized trauma-focused therapies potentiates PTSD symptom reduction.

BTD is intended to expedite the development and approval of promising treatments by allowing for more frequent interactions with the FDA, rolling review of documents, and the possibility for priority review (6 months rather than the normal 10-month review period) (1). BTD also receives an organizational commitment from the FDA with more guidance and involvement of FDA senior managers for efficient drug development.

After receiving BTD for this program, MAPS and the FDA also reached agreement under the Special Protocol Assessment (SPA) process for the design of two multi-site Phase 3 trials (MAPP1 and MAPP2) of MDMA-assisted psychotherapy for patients with at least severe PTSD. These two pivotal Phase 3 trials will enroll approximately 200-300 participants at sites in the USA, Canada, and Israel.

The pivotal Phase 3 trial started in November 2018. If Phase 3 trials produce significant confirmatory results and satisfactory safety profile, an application for marketing approval of MDMA-assisted psychotherapy for PTSD will be filed with the FDA. Filing of a New Drug Application is projected for 2021, with anticipated approval in 2022.

It is anticipated that MDMA, with its unique pharmacological mechanisms combined with psychotherapy, has advantages over existing medications used as first-line PTSD treatments in terms of safety and side effect profiles, efficacy, and length of remission. PTSD is a chronic condition that afflicts a substantial number of individuals who do not adequately respond to available therapies and are at increased risk of suicide, other mental health conditions, cardiovascular disease, and cognitive impairment. Findings from both nonclinical and clinical studies support a novel mechanism by which MDMA amplifies the therapeutic effects of psychotherapy by a dynamic interaction of brain regions, and affiliated neurochemicals therein, known to be involved in fear extinction learning, memory reconsolidation, emotional processing, and cognition (30, 32, 39, 48, 70). With many apparent advantages over existing medications, including efficacy, tolerability, and duration of therapeutic effects, MDMA-assisted psychotherapy has the potential to favorably impact the lives of thousands who suffer from PTSD world-wide.

Concept and review design: LJ, AF, AE, BY-K, RD, and MM. Acquisition, analysis, or interpretation of data: LJ, AF, AE, BY-K, RD, and MM. Drafting of the manuscript: LJ, AF, AE, BY-K, RD, and MM. Critical revision of the manuscript for important intellectual content: LJ, AF, AE, BY-K, RD, and MM. Obtained funding: RD.

AF received salary support for full time employment with MAPS PBC. LJ received salary support for full time employment with MAPS PBC. BY-K received salary support for full time employment with MAPS. AE received salary support for full time employment with MAPS PBC. MM received salary support from MAPS PBC as a clinical investigator and clinical trial medical monitor as well as for training and supervision of research psychotherapists. RD received salary support for full time employment with MAPS.

The Multidisciplinary Association for Psychedelic Studies (MAPS), a 501(c)(3) nonprofit organization, provided the MDMA and fully funded this study. MAPS Public Benefit Corporation (MAPS PBC), a wholly owned subsidiary of MAPS, was the trial organizer. MAPS and MAPS PBC assisted with study design; monitoring of study data; analysis, management, and interpretation of data; preparation, review, and approval of manuscript; and decision to submit the manuscript for publication. The funder had no role in the collection of data or conduct of the study.