A Review of MDMA-Assisted Therapy for Posttraumatic Stress Disorder

Posttraumatic stress disorder (PTSD) is a common and often disabling condition with prevalence in the tens of millions of people in the United States alone (1). It is classified as a “trauma- and stressor-related disorder” in the DSM-5, with diagnostic criteria across four symptom clusters: reexperiencing (e.g., recurrent intrusive memories, traumatic nightmares, or flashbacks), avoidance (e.g., avoiding trauma-related thoughts and feelings or avoiding objects, people, and places associated with the traumatic event), negative alterations in cognition or mood (e.g., distorted beliefs about oneself or the world, persistent guilt or shame, emotional numbing, feelings of alienation, or inability to recall key details of the traumatic event), and alterations in arousal and reactivity (e.g., irritability, hypervigilance, reckless behavior, sleep disturbance, or concentration difficulties) (2). To qualify for a diagnosis of PTSD, symptoms must be present for longer than 1 month; result in significant distress or functional impairment; and not be caused by medications, substance use, or a separate medical condition. These symptom clusters were revised from three clusters in the DSM-IV to four clusters in the DSM-5 through splitting avoidance and numbing into distinct clusters of avoidance and negative alteration in mood and cognition. Given the heterogeneity in the application of PTSD diagnoses, familiarity with DSM criteria is important in valid diagnosis as well as in tracking treatment response.

PTSD has been associated with a wide range of traumatic events, with variable risk of PTSD symptoms depending on trauma type (3). PTSD develops after exposure to a potentially traumatic event that involves exposure to actual or threatened death, serious injury, or sexual violence. Exposure is defined as either directly experiencing or witnessing the traumatic event or learning that the trauma has occurred to a close family member or friend (2).

Although most people experience traumatic events that result in a transient stress response throughout the course of a lifetime, the majority do not go on to develop PTSD. Approximately 10%–20% of individuals who have been exposed to a traumatic event go on to develop PTSD symptoms that persist with associated impairment (4). The lifetime prevalence of PTSD is estimated at 8.3% (5). In military service members and veterans, the reported incidence rate of PTSD ranges from 5.4 to 16.8 (6, 7).

Risk factors for the development of PTSD include genetic factors, preexisting neuroendocrine and inflammatory pathway alterations, and psychological factors. The heritability of PTSD is estimated to be 30% (8). The most studied genetic risk factors have involved polymorphisms in the hypothalamic-pituitary-adrenal (HPA) axis and catecholamine pathways such as COMT and FKBP5; however, a more recent genomewide association study identified other genes, including PARK2, that were implicated in dopamine regulation (9). There have been epigenetic studies investigating how stress exposure can affect offspring gene expression, conferring risk of PTSD development (10–12). Traumatic exposures activate the HPA axis and stress-response pathways, resulting in downstream inflammatory changes and immune suppression. There is some evidence that preexisting alterations to inflammatory mediators may confer risk for the development of PTSD after exposure to a traumatic event (13). A dose-response relationship has been identified between exposure to traumatic events and subsequent PTSD diagnosis, with higher rates of diagnosis associated with increased number of traumatic exposures (5). Specifics related to the kind of trauma also appear to confer variable risk of subsequently developing PTSD, with higher rates associated with military combat and sexual assault (14). Several other factors have also been linked to higher risk of developing PTSD after exposure to a traumatic event, including a history of such exposure before the index event, economic and educational disadvantage, and female gender (15, 16).

There are several evidence-based treatments for PTSD—both psychotherapeutic and pharmacologic—that we briefly review here on the basis of the current guidelines from the American Psychological Association (17), published in 2017, and from the Veterans Health Administration and Department of Defense (VA–DoD). Psychological interventions recommended by these organizations are generally divided along “trauma-focused” interventions and “nontrauma-focused” interventions (18). Trauma-focused interventions include prolonged exposure (PE) therapy and cognitive processing therapy. Nontrauma-focused interventions include relaxation exercises, stress-inoculation training, and interpersonal therapy. A large body of evidence supports trauma-focused exposure therapies, particularly PE, including several meta-analyses that support the superiority of PE over nontrauma-focused therapies (19–22). Rates of successful treatment with PE—defined as loss of PTSD diagnosis—is in the range of 41%–95% (23). However, trauma-focused therapies suffer from high rates of treatment discontinuation and dropout: Rates of dropout for exposure-based therapies are approximately 36% (24). Exposure to a traumatic event and subsequent PTSD can problematize the ability to form the stable, trusting interpersonal relationships required for a sustained working alliance between patient and therapist that is thought to be critical for therapeutic change (25–27). Trauma-focused therapies also often involve aversive reexperiencing related to the traumatic event that can overwhelm a patient’s capacities. As such, remission of symptoms with these therapies accounting for rates of dropout is only around 44% (28). Even after a course of cognitive processing or PE therapy, up to two-thirds of patients will retain their diagnosis after treatment (29) Furthermore, there is a limited evidence base, to date, to suggest that current evidence-based trauma-specific psychotherapies are superior to other non–evidence-based interventions (30).

Evidence-based pharmacological treatments for PTSD center around selective serotonin reuptake inhibitors (SSRIs). Of note, the VA–DoD and National Institute for Health and Care Excellence treatment guidelines have both unequivocally designated exposure-based psychotherapy as the first-line treatment for PTSD, meaning that psychopharmacological treatments—which have smaller effect sizes—are recommended as second-line (31, 32). Sertraline, paroxetine, fluvoxamine, and citalopram have received U.S. Food and Drug Administration (FDA) support for the treatment of PTSD symptoms (33–39). Treatment response to these agents is estimated at 15%–30%, with small effect sizes (40). There is also a tendency for patients to relapse on discontinuation of the medication (38, 39). There are several other agents used in the treatment of PTSD symptoms, including prazosin, a noradrenaline alpha-blocker agent that has shown efficacy in PTSD-related sleep disruption and nightmares. Although early studies that investigated prazosin (41, 42) were encouraging, subsequent randomized controlled trials (RCTs) have failed to show a significant effect (43, 44). Polypharmacy is common among patients with PTSD, involving frequent use of second-generation antipsychotics (despite minimal evidence supporting efficacy) as well as benzodiazepines, which demonstrably worsen outcomes related to PTSD (45, 46).

In sum, the evidence base for current standard-of-care pharmacological and psychotherapeutic interventions for PTSD suggests significant limitations. As such, there is a significant need for new strategies for treating this condition. MDMA-assisted therapy for PTSD has emerged as a promising intervention that combines a pharmacological approach with an embedded psychotherapeutic protocol.

3,4-methylenedioxymethamphetamine (MDMA) is a ring-substituted amphetamine with structural similarities to mescaline (47, 48). Although it can produce consciousness-altering effects similar to those of classic psychedelics (understood as agonists at the serotonin 5-HT_2A-receptor) MDMA is often referred to as an “entactogen,” given its prosocial effects and the relative absence of perceptual alterations compared with classic psychedelics (49). MDMA was first synthesized by Merck in 1912 as an intermediate substance in the synthesis of a hemostatic drug (50). It was largely shelved until the 1950s and emerged briefly as a chemical of interest during the mind-control experiments of the CIA project MK-ULTRA. There was limited recreational use of MDMA during the 1960s; however, after the rescheduling of LSD and psilocybin in the late 1960s, there was a renewed interest in the therapeutic use of MDMA. MDMA was used frequently through the 1970s until 1985 (when MDMA was rescheduled by the Drug Enforcement Administration to Schedule I) in conjunction with psychotherapy, in particular with couples therapy, given its empathogenic qualities (51). The first Phase I trial with MDMA was completed in 1995 by Charles Grob and involved the administration of two doses of MDMA and one dose of placebo to six normal volunteers to track physiological and safety variables (52). The first controlled study of MDMA-assisted psychotherapy for PTSD was published in 2010 (53). This study included 20 patients with treatment-refractory PTSD symptoms and demonstrated an 80% remission rate sustained at 3 years after two or three sessions. The Multidisciplinary Association for Psychedelic Studies (MAPS) has supported research into MDMA-assisted psychotherapy, including six FDA Phase II trials and ongoing FDA Phase III trials (with one published study to date, which we discuss later). In response to promising results from initial trials, on August 15, 2017, the FDA designated MDMA-assisted psychotherapy as a “breakthrough therapy designation” for the treatment of PTSD on the basis of criteria for treatment of a life-threatening illness and greater safety and initial efficacy than that seen with existing approved medications (i.e., sertraline, paroxetine). This intervention involves the use of a medication in conjunction with a psychotherapeutic process, which is a novel model that challenges the standard model of FDA approval (which historically has only applied to medications alone) as well as standard models of mental health care delivery and reimbursement.

Therapeutic mechanisms of MDMA can be explored at several different levels of explanation. From a neurobiological standpoint, MDMA interacts with several neurotransmitter systems but predominantly exerts its pharmacological action by means of the monoaminergic system, with the strongest affinity at the serotonin transporter, followed by norepinephrine and dopamine transporters (54). MDMA also binds directly at the alpha-2 adrenergic, serotonin, H1 histamine, beta-1 adrenergic, and D₁ and D₂ dopaminergic receptors (55). Acute effects of MDMA involve elevation in extracellular serotonin, both through increased release into the synapse through reuptake inhibition. There are concomitant increases in extracellular dopamine and norepinephrine. MDMA is absorbed by the gastrointestinal tract, has an onset of action typically at approximately 30–45 minutes, and reaches peak brain levels at 60–180 minutes. It is metabolized primarily by CYP450 2D6 and 2C19 pathways with an elimination half-life of 8–9 hours (56, 57).

MDMA also causes an increase in oxytocin release (58). This neuropeptide has been implicated in social bonding, trust, and prosocial behaviors (59). MDMA increases levels of oxytocin through action on the serotonin transporter and 5-HT₄ receptors on oxytocin neurons (60, 61), which has been shown in animal studies to mediate the prosocial effects of MDMA (62). Changes in oxytocin signaling and prosocial feelings have also been correlated in healthy volunteer humans (63), and there is evidence that intranasal oxytocin administration can normalize deficits in social reward processing in terms of neural sensitivity to social reward in patients with PTSD (64). However, at least one study in humans failed to show a significant correlation between plasma levels of oxytocin and the prosocial effects of MDMA (65), although the authors noted that plasma concentration may not be representative of the central availability of oxytocin. The relationship between the prosocial and empathogenic effects of MDMA and oxytocin is incompletely characterized with demonstrated divergent effects when administered individually in subjects (58): As such, it appears that the effects of MDMA on social reward processing are not likely to be due solely to alterations in oxytocin.

From a psychological standpoint, one rationale behind MDMA-assisted psychotherapy is the idea that MDMA acts as a catalyst of sorts for psychotherapy by reducing the fear response, enhancing interpersonal trust and openness, and allowing for the exploration of content and past traumatic experiences that are otherwise difficult to engage with (66) and that have historically problematized adherence to exposure-based therapies alone. MDMA has been shown to increase emotional empathy (67), prosocial behaviors (68), and interpersonal trust (60, 69). There is preliminary evidence that the direct effects of MDMA on the personality trait of openness moderate the effects of MDMA-assisted psychotherapy on the reduction of PTSD symptomatology (70). These changes are hypothesized to facilitate therapeutic engagement, rapport building, and exploration of difficult psychological terrain. There is evidence to suggest that enhanced sociability with MDMA may be related to diminished response to threatening stimuli through attenuation of the amygdala response as well as enhanced responses to social reward signals related to enhanced ventral striatum response (71). The ventral striatum plays a central role in reward processing, and enhanced ventral striatum response is associated with social approach behavior (72). It has been hypothesized that MDMA may reduce PTSD symptoms through the two distinct processes of memory reconsolidation and fear extinction (73). Other research on memory reconsolidation during psychotherapy suggests that feelings of safety and trust are critical elements to reconsolidating emotional memories in the treatment of trauma (74)—MDMA may facilitate this process.

A more recent—albeit preliminary—explanatory model for the therapeutic effects of MDMA (as well as of classic psychedelics) examines the effects of MDMA on neuroplasticity and the opening of a “critical period,” or “critical window,” for new learning. Although this model is still early in development and based on animal models, it provides a bridge between psychological and neurobiological levels of explanation and supports the importance of embedding MDMA administration within a thoughtful psychotherapeutic framework for therapeutic effect. A critical period is a period of heightened neuroplasticity when the brain is increasingly receptive to environmental stimuli, flexible in laying down new neurocircuitry pathways, and more open to engaging with learning. These periods occur naturally developmentally, and they can explain the often significant longitudinal effects that early life trauma can have over the course of a lifetime. It is hypothesized that, in disease states, the closure or constraints on synaptic plasticity afforded by critical periods limit adaptation and therapeutic change, even in the context of optimizing environmental conditions (1). Although there are many different forms of critical periods (i.e., critical periods for language development), the social reward learning critical period informs durable changes in social cognition, emotion regulation, and attachment—all domains heavily implicated in the pathogenesis and symptomatology of PTSD. Animal model studies have demonstrated that MDMA opens a critical period for social reward learning that appears to be mediated by changes in oxytocin-dependent synaptic plasticity in the nucleus accumbens (75). It is interesting that this effect was only present for mice in social contexts (76). MDMA has been shown to increase neuroplasticity by stimulating the expression of immediate-early gene transcription factor c-Fos, which is a marker for neuroplastic populations in the brain. Additionally, there is evidence that MDMA results in an increase of brain-derived neurotrophic factor (BDNF) in areas related to fear extinction and that this increase is dependent on 5-HT_2A receptors (77).

MDMA downregulates amygdala activity (78) and has direct effects on fear extinction pathways (79). This is, in part, due to effects on neurotrophic factors implicated in neuroplasticity. Effects of MDMA administration on the enhancement of fear extinction pathways appear to be dependent on increases in BDNF expression in the amygdala (80). MDMA has also been shown to raise BDNF levels in cortical regions of rodents, which is reflected in increased spine density and heightened neurogenesis of cortical neurons. Genetic polymorphisms associated with reduced BDNF expression have been shown to predict reduced response to exposure-based therapies for PTSD (81).

MDMA-assisted therapy for PTSD—as instantiated in recent Phase II and Phase III trials—involves a robust psychotherapeutic protocol that involves approximately 40 hours of therapist time (with two therapists present; typically, a male-female dyad) for the complete course of treatment. This has involved a manualized protocol that is supportive in nature, is nondirective, and uses the following core principles: safety, support, inner healing intelligence, inner-directed process, beginner’s mind, trusting the process, somatic manifestation, therapeutic alliance, and trust (73). The therapeutic approach emphasizes the interaction of the medication and the therapeutic setting and relationship with the therapy team. Although unique insofar as involving a catalyzed form of psychotherapy, many aspects of the therapeutic approach are similar to those of other models of psychotherapy for PTSD and may include elements of exposure therapy, stress-inoculation training, anxiety management, and cognitive restructuring. However, the emphasis of the therapeutic approach is nondirective, and these therapeutic elements are not incorporated in an explicit fashion. MAPS has developed a five-part therapy training program that comprises in-person trainings, role-plays, video-recorded MDMA sessions, e-learning modules, and readings.

The therapy protocol involves three preparatory sessions before any MDMA sessions to establish trust with the therapist team, provide psychoeducation as to the expected MDMA effects, and begin to explore material related to the exposure to trauma, again with a predominantly nondirective approach. There is a significant emphasis on the importance of these nondrug preparatory sessions to establish safety and maximize the therapeutic potential of the subsequent MDMA sessions. The MDMA sessions (2, 3) are 8 hours in duration, again with two therapists present for the session. Typically, this has involved a male therapist and a female therapist present for the sessions; however, it has been recognized that this may not be the most appropriate default in increasing the access, safety, and acceptability of this treatment to transgender and gender-diverse individuals (82). These sessions use a music playlist and eyeshades to encourage an internal experience. Although there may be intermittent interaction to process the psychological material that may arise, these MDMA sessions are largely nondirective, with the encouragement that patients “go inward.” Music is emphasized as a critical component of the therapy that assists patients as they move into difficult emotional terrain. Dosing has typically involved an initial dose of 75–125 mg MDMA followed by the possibility of a “booster” dose of half of the initial dose at 1.5–2 hours. After each MDMA session, three integration sessions all take place within a comfortable, living room–style clinical setting with an emphasis on “set and setting.” “Set” refers to the patient’s intentions, mindset, and psychological approach to the treatment; “setting” refers to the environment of the session. These integration sessions again follow a nondirective therapeutic model and focus on processing and incorporating emotional and psychological content that arose in the MDMA sessions within the broader framework of the individual’s illness symptoms, functioning, and life.