MDMA-Assisted Psychotherapy for Borderline Personality Disorder

Evidence is growing for the use of MDMA-AP as a promising treatment for various psychiatric conditions such as PTSD (33, 34) and co-occurring eating disorder symptoms (35), alcohol use disorder (36), anxiety associated with life-threatening illness (37), and social anxiety in autism spectrum disorder (38). In North America, MDMA is currently moving through the U.S. Food and Drug Administration’s (FDA) drug development process for the treatment of PTSD. On the basis of the outcomes observed in phase 2 clinical trials (33), MDMA has obtained the FDA’s breakthrough therapy designation. MDMA and other controlled substances are also available for use in severe and life-threatening conditions through Health Canada’s Special Access Program. A recently completed phase 3 trial strongly suggests that MDMA-AP is a safe and efficacious treatment for chronic and severe PTSD, with a 67% rate of remission observed among participants treated with MDMA (vs. 32% in the placebo group) by the primary study endpoint (34). Overall, across phase 2 and phase 3 trials for PTSD, most participants noted sustained benefits lasting at least 12 months posttreatment (33, 34, 39); however, a minority of participants (N=7, 8.4%) in the phase 2 trials reported harms (none reported as severe), with two participants reporting lingering harms lasting up to the present time point of the long-term follow-up study (33). It is important to note that in contrast to traditional pharmacological treatments in psychiatry, which often entail taking a psychotropic medication daily for an indeterminant amount of time, MDMA, when used as an adjunct to psychotherapy, has been shown to be clinically efficacious when administered two to three times during a treatment course (40).

MDMA is a phenethylamine compound that is structurally similar to methamphetamine and mescaline and produces psychostimulant effects. It was first synthesized in 1912 by the German chemist Anton Köllisch as part of a search for new hemostatic agents (41). In the late 1970s, the American chemist Alexander Shulgin resynthesized the compound and shared it with a close colleague and psychotherapist Leo Zeff. It was then disseminated to a growing number of clinicians who observed its therapeutic potential in individual, couples, and group psychotherapy settings (42); however, in 1985, the U.S. Drug Enforcement Administration declared it a schedule I substance, making its use illegal. For a review of the pharmacological mechanisms of MDMA, we refer readers to available resources (40, 43). MDMA is most often classified as an “entactogen” (44), referring to the effects of increased self-awareness and introspection that the drug stimulates. MDMA is also sometimes referred to as an “empathogen” because of its properties of increasing empathy and emotional connection with others (45), whereas others combine the two terms and refer to it as an “entactogen-empathogen” (40).

Approximately 20 years ago, controversy erupted about the dangers of recreational MDMA use (often referred to as “ecstasy” or “molly” in recreational settings), with sensational claims made about overdose deaths, irreversible neurologic damage, and addiction (46). It is important to contrast uncontrolled recreational use of MDMA with controlled use in clinical research settings. In the recreational setting, although medical toxicity (i.e., malignant hyperthermia, seizures) and deaths associated with MDMA use have been reported, rates of morbidity and mortality are very low, especially after controlling for polydrug use (47). In contrast, more than 1,600 doses of MDMA have been administered in clinical research settings throughout the world, including in phase 2 and phase 3 clinical trials of MDMA-AP for PTSD, with only one report of an MDMA-related serious adverse medical event and no deaths (34, 48–50). The most common adverse events related to MDMA administration in research settings include elevated heart rate and blood pressure, muscle tightness, bruxism, decreased appetite, nausea, hyperhidrosis, and feeling cold (48, 50).

Regarding MDMA’s neurotoxic potential, animal and human data suggest that high dose and prolonged use of MDMA may be associated with neurotoxicity (i.e., cognitive impairment in humans) (51); however, data from recent clinical trials with MDMA-AP suggest that in limited dosing regimens (i.e., two to three doses), MDMA is not associated with acute or chronic neurotoxicity (34, 48). Regarding addictive liability, recreational MDMA use is substantially less likely to produce dependence syndromes, especially compared with other dopaminergic stimulants (i.e., methamphetamine, cocaine), with MDMA addiction being rare (46). In the last 17 years of clinical research with MDMA, illicit use of recreational MDMA has also been rarely observed (39). Given its safety profile, the risk-benefit ratio is favorable for the use of MDMA in the treatment of chronic and severe psychiatric disorders that are often associated with a substantially increased risk of death (e.g., PTSD).

To date, the most substantial evidence for MDMA-AP pertains to the treatment of PTSD (34), a disorder that is highly comorbid with borderline personality disorder (e.g., 30%–80% comorbidity in clinical settings) (52–54). Compared with each individual disorder alone, comorbid borderline personality disorder and PTSD is also associated with higher comorbidity of additional psychiatric disorders (54), greater symptom severity (55), more self-harm and suicidal behaviors (55, 56), and higher utilization of mental health and emergency services (57). Given their overlap, a brief review of shared phenomenological features and neurobiological substrates of borderline personality disorder and PTSD is presented to contextualize a discussion of treatment targets for MDMA-AP for borderline personality disorder.

Borderline personality disorder is a stress-related disorder often associated with a history of adverse and traumatic experiences going back to childhood (58, 59). It is not well understood how chronic stress or traumatic exposures might lead to the manifestation and severity of borderline personality disorder or PTSD (or their co-occurrence); indeed, their nosology has been the subject of long-running debate among clinicians and researchers in the fields of personality and traumatology (60). For example, Martin Bohus has put forth the view that borderline personality disorder is linked to past traumatic experiences and perhaps would be better classified as a trauma- and stress-related disorder (60). However, even when conceptualizing borderline personality disorder as a distinct nosological entity, most seminal theories emphasize a strong association between traumatic or disturbed early attachment experiences and subsequent borderline personality disorder symptoms appearing more conspicuously during adolescence (61, 62).

Indeed, Marsha Linehan suggested that those who go on to develop borderline personality disorder likely grew up in a “traumatic invalidating environment” (63). Bender and Skodol (64) further posited that early experiences of trauma and invalidation are the fundamental causes of self-interpersonal disturbances in borderline personality disorder. Diagnostically, this matter is compounded by the official introduction of a separate diagnosis of complex PTSD by the World Health Organization in the ICD-11 (65). Some proponents of this diagnosis argue that complex PTSD is an amalgam of borderline personality disorder and PTSD (66), whereas others propose that borderline personality disorder alone should be rebranded to complex PTSD (67, 68). Still, others advise that borderline personality disorder should remain a separate diagnostic entity from complex PTSD (69).

Relatedly, although it is less clear how neurobiological underpinnings translate to symptomatology (e.g., whether they represent etiological causes or sequalae of a particular disorder), dysfunctions in the hypothalamic-pituitary-adrenal (HPA), oxytocinergic, serotonergic, and endogenous opioid systems have been observed in both borderline personality disorder and PTSD (70–72). Amad et al. (73), in their quantitative meta-analysis of functional neuroimaging studies exploring similarities in brain region activation between borderline personality disorder and PTSD diagnostic groups, noted that borderline personality disorder and PTSD share the FKBP5 variant as a genetic vulnerability. This gene is an important regular of the glucocorticoid receptor complex (74, 75), and this receptor complex plays a role in the dysregulation of the HPA axis observed in both disorders (76, 77). The authors also noted that both disorders share functional abnormalities in frontolimbic networks, particularly in reduced activation of executive-related frontal brain regions, a hyperactivation of the emotion-related limbic regions (73, 78, 79), and an increased activation in the superior and inferior frontal gyri (areas involved in attention, working memory, and response inhibition). Additionally, reduced hippocampal and amygdala volumes (compared with healthy control groups) have been observed among patients with either disorder (80).

Although an in-depth critical examination of these diagnostic constructs is beyond the scope of this review, it is important to appreciate the significant degree to which research findings support the hypothesis that trauma plays a role in the development and manifestation of borderline personality disorder. Several studies have demonstrated that trauma is a strong predictor of the disorder (81–83) and its associated social cognitive impairments (84). The conceptual and phenomenological similarities between borderline personality disorder and PTSD are also substantial; they include impairments in social cognition and self-concept, interpersonal difficulties, affect dysregulation, and dysregulated stress responses such as dissociation (66, 72, 85). Moreover, research that contributed to the recently developed Hierarchical Taxonomy of Psychopathology (HiTOP), a dimensional classification model, provides empirical support for shared traits across borderline personality disorder and PTSD within the domain of internalizing distress (e.g., dysphoria, suicidality, irritability, avoidance, hyperarousal, numbing, and dissociation) (86).

Given the many similarities between the two disorders, it is plausible that adaptations to early traumatic invalidation (i.e., “extreme or repetitive invalidation of individuals’ significant private experiences, characteristics identified as important aspects of themselves, or reactions to themselves or to the world”) (87) and trauma may differ more in their severity along a traumatic adaptation continuum, rather than being distinct phenomena. Following this logic, it is perhaps unsurprising that compared with gold-standard treatments for borderline personality disorder or PTSD alone, trauma-focused psychotherapies for comorbid borderline personality disorder and PTSD, such as Melanie Harned’s DBT-prolonged exposure and Martin Bohus’s DBT-PTSD, show greater efficacy for improving several functional and borderline personality disorder–relevant outcomes (88, 89).

Altogether, given the growing body of research supporting the efficacy of MDMA-AP for PTSD, the conceptual and observed similarities between borderline personality disorder and PTSD, and the significant comorbidity and subsequent degree of suffering and public health burden of borderline personality disorder and PTSD, the consideration of researching MDMA-AP as a treatment option for borderline personality disorder (with or without comorbid PTSD) is fully warranted. In the following section, we outline potential treatment targets of MDMA-AP for borderline personality disorder.

Zeifman and Wagner (90) have proposed various borderline personality disorder treatment targets that psychedelic and related substances, including MDMA, may affect, such as behavioral and emotional dysregulation, self-identity disturbances, and social functioning. Here, we emphasize MDMA-AP’s potential as a fruitful therapeutic medium to target the interpersonal, affective, and identity features of borderline personality disorder. Given the theoretical associations between early attachment disruptions and borderline personality disorder symptoms (61–63), we suggest that targeting interpersonal and affective symptoms may be realized in MDMA-AP for borderline personality disorder by focusing on processing traumatic invalidation or trauma.

Although borderline personality disorder has historically been an exclusion criterion in MDMA-AP clinical trials (34, 38, 50), long-term follow-up findings from phase 2 MDMA-AP for PTSD trials have shown substantial improvements in areas relevant to borderline personality disorder. Interpersonally, 66% of phase 2 participants endorsed long-term improvements in their general relationships, with 61% reporting improvements in close relationships (33). Relatedly, about 62% of participants reported long-term increases in empathy (33). Affectively, around 74% of participants reported increases in their ability to feel emotions (33). Furthermore, the most commonly endorsed long-term benefit was increased awareness and understanding of self; 89% of phase 2 participants endorsed improvements in self-awareness (33). These findings are also consistent with a smaller trial of MDMA-assisted cognitive-behavioral conjoint therapy for PTSD, which found improvements in emotion regulation and relationship functioning (91, 92). Notably, these long-term improvements also converge with dimensional models of personality psychopathology that propose that disturbances in self (i.e., identity and self-direction) and interpersonal functioning (i.e., empathy and intimacy) are central to personality disorders (including borderline personality disorder) (93, 94). Thus, it is reasonable to speculate that similar functional improvements may be observed in MDMA-AP for borderline personality disorder, although this hypothesis requires empirical study.

Moreover, researchers have also found MDMA-AP–related changes in personality structure by way of decreased neuroticism and increased openness (95), which are two personality traits shown to have significant genetic correlations with borderline personality disorder in a recent study (96). Plausibly, decreased neuroticism and increased openness could help to loosen the rigid self-other beliefs and schemas (e.g., views of self or others as “all good” or “all bad”) that are common in borderline personality disorder (97) and trauma (98). It is also worth noting that suicidality was monitored in four out of six phase 2 clinical trials of MDMA-AP for PTSD; at baseline, most (∼87%) participants reported a lifetime history of suicidal ideation, 37% of which was categorized as “severe,” and about 43% reported a lifetime history of suicidal behavior. Long-term improvements in suicidal ideation were substantial, with an approximately 36% decrease in the number of participants endorsing suicidal ideation from baseline to follow-up, and with no increases in suicidal behavior (33).

We hypothesize that mechanisms of change in MDMA-AP for borderline personality disorder may include reduced avoidance of emotions that are activated by thinking or talking about difficult experiences related to traumatic invalidation and trauma as well as increased willingness to disclose covert experiences to therapists (e.g., memories, emotions, affects, thoughts, beliefs, and somatic feelings), leading to deeper processing. It is plausible to speculate that these mechanisms would be catalyzed by the acute effects of MDMA, which are predominantly attributed to its activation of the serotonergic system, and include improved mood, reduced fear-related amygdala reactivity (46), and reduced aggression and impulsivity (99). Beyond the serotonergic system, it is likely that a combination of MDMA’s complex biochemical activity may result in additionally observed effects to support these hypothesized mechanisms, including increased introspection (100), social engagement (101), feelings of connectedness (45), empathy (102), disclosure of emotional content in conversation (103), access to and tolerability of emotionally intense memories (104), and ability to forgive others and oneself (43). Moreover, a recent animal study showed that a single dose of MDMA was able to reopen an oxytocin-mediated critical period of social reward learning (105).

Mithoefer et al. (49) posited that mechanisms of change at work in MDMA-AP for PTSD may parallel those in Edna Foa’s prolonged exposure therapy (106). In particular, the sense of calmness, openness, and increased clarity promoted by MDMA may support an optimal level of emotional arousal within one’s window of tolerance (49), allowing for sufficient immersion into emotional processing with reduced avoidance. In prolonged exposure therapy for PTSD, Foa has emphasized the necessity of deep emotional immersion to effectively activate one’s trauma-related “fear network” and reconsolidate traumatic memories (106); these principals may also be applied to MDMA-AP for borderline personality disorder.

Indeed, in MBT for borderline personality disorder, Bateman and Fonagy emphasized the need for therapists to help their patients maintain an optimal level of arousal, which they described as an attachment relationship between therapist and patient that is “not too intense and yet not too detached” (107). Because psychedelics are thought to reduce one’s usual roster of psychological defense mechanisms (108), we hypothesize that the acute effects of MDMA may induce a temporary reorganization of the attachment structures and defense mechanisms that maintain borderline personality disorder symptoms; this alteration may help to facilitate an optimal level of arousal and immersion into memories of traumatic invalidation and trauma (e.g., salient past experiences of rejection or punishment and introspection on present-day behaviors that are conceptually tied to them, such as frantic attempts to avoid abandonment, idealizing and devaluing others, or suicidal ideas preceded by interpersonal conflict). Especially if conceptualizing traumatic invalidation and trauma on a dimensional continuum, it is plausible that immersion into such processing in MDMA-AP for borderline personality disorder may support the activation of a “traumatic invalidation” or “traumatic attachment” network of memories, thoughts, emotions, and somatic experiences.

Although the activation of such networks may normally provoke strong emotional reactivity or maladaptive avoidance and defenses that can interfere with therapy, these reactions may be held at bay under the acute effects of MDMA. This consequence may be especially helpful to reduce emotional oscillations and interpersonal reactivity that are observed in borderline personality disorder and that can be associated with highly treatment-interfering behaviors (e.g., anger outbursts or refusing to speak about salient issues in therapy sessions). In fact, in addition to life-threatening behaviors, Linehan has emphasized the need to prioritize targeting “therapy-interfering behaviors” in DBT for borderline personality disorder before being able to effectively address other problems related to quality of life (5). In combination with a reduction in emotional hyperreactivity, MDMA’s ability to increase feelings of trust and connectedness may also lead to a stronger therapeutic rapport, which is a mechanism of change posited to increase patient investment across evidence-based therapies for borderline personality disorder (109).

Initial evidence to suggest that these mechanisms may improve borderline personality disorder outcomes can be derived from Barnicot et al. (110), who conducted a mixed-methods study of 73 patients with borderline personality disorder who were receiving either DBT or MBT; they found that patient accounts of learning to tolerate painful introspection and exposure to negative emotions and memories that may have previously been avoided were associated with significantly less baseline-adjusted self-harm at 12 months posttreatment. This finding is also consistent with a recent meta-analysis showing associations of experiential avoidance with self-harm and suicidal ideation (111). Moreover, oxytocin, a neurohormone released by MDMA, was administered in two large, placebo-controlled studies of borderline personality disorder (112, 113). Lischke et al. (112) found an attenuating effect of oxytocin on limbic system hyperactivation among individuals with borderline personality disorder. Similarly, in their double-blind, placebo-controlled study, Domes et al. (113) found that a single administration of intranasal oxytocin led to improvements in affective empathy and approach behavior among women with borderline personality disorder. These findings mirror two other studies showing an attenuating effect of oxytocin on amygdala responses to angry faces (114) and dysphoric mood among individuals with borderline personality disorder (115). Although, another research group found reduced trust and cooperation following oxytocin administration among patients with borderline personality disorder (116). Thus, although oxytocin is a potential mechanism that could subserve MDMA-AP–related improvements, its effects on individuals with borderline personality disorder are not clear and require further study.

With the therapy targets and hypothesized mechanisms described earlier in mind, this review concludes with several initial clinical research considerations pertaining to the design of MDMA-AP clinical trials to test the safety, feasibility, and initial clinical effects of MDMA-AP for borderline personality disorder.

For a review of MDMA-AP, we refer readers to several available resources (34, 46, 117). Briefly, MDMA-AP involves at least one preparatory session in which therapists work with patients to plan for the dosing session, including discussions around safety, expectations, intentions, and coping with anticipated difficulties or psychological tendencies that may arise during the dosing session (e.g., addressing maladaptive avoidance of specific emotions, coping with feelings of anxiety or panic). An MDMA dosing session lasts around 8 hours and involves two therapists who support and guide a patient through the MDMA experience, typically in a nondirective fashion while the patient is laying down, wearing eye shades, and listening to music to promote immersion into the experience (118). One or more psychotherapy sessions follow the dosing session (often referred to as integration sessions) and focus on helping the patient to gradually reflect on and process (i.e., integrate) their experience.

Although MDMA-AP has typically been practiced using a nondirectional approach, we suggest that MDMA sessions may loosely focus on processing salient experiences of traumatic invalidation or trauma or on the patient’s primary problems that are theoretically related to traumatic invalidation or early attachment disruptions (e.g., frantic efforts to avoid abandonment, self-harm or suicide attempts in response to relational distress, or maladaptive emotional avoidance). To aid in this focus, psychoeducation may be provided before MDMA dosing sessions so that patients can identify and tie together salient past experiences and current problem behaviors (e.g., by sharing a case formulation with a patient or discussing theories of borderline personality disorder development that emphasize how trauma may have shaped a patient’s presenting problems). Although two to three doses (80–180 mg) of MDMA are typically given throughout a course of MDMA-AP, case studies and pilot trials would be helpful to explore optimal MDMA dosage, dosing frequency, and dosing intervals for patients with borderline personality disorder.

Relatedly, studies are needed to explore the cost-effectiveness of MDMA-AP for borderline personality disorder, relative to first-line specialist treatments (e.g., DBT), which are likely cost-effective in the short term (119). Research to date on MDMA-AP for PTSD suggests that it is cost-saving in cases of severe and chronic PTSD, relative to the standard of care (120, 121). The estimated cost of a course of MDMA-AP (which includes three preparatory sessions, three MDMA-assisted experimental sessions, and nine post-MDMA integration sessions with two study therapists) is approximately $11,000 (range $8,076–$14,998) (121). Comparatively, a recent estimate of the annual cost of illness on society for an average treatment-seeking patient with borderline personality disorder was €31,130 (or $33,370) (122).

Despite the potential of MDMA-AP for treating borderline personality disorder, some unique risks warrant careful consideration. First, although no deaths by suicide have been reported across phase 2 or 3 MDMA-AP for PTSD clinical trials (34, 48), chronic suicidal behavior is a symptom of borderline personality disorder (3); thus, suicide risk management is of paramount importance. Relatedly, because impulsivity and anger dysregulation are also symptoms of borderline personality disorder, the development of a safety plan, especially for patients with a history of impulsive aggression, is prudent.

In particular, individuals with borderline personality disorder are highly sensitive and reactive to negative affect (5), which can be heightened during the MDMA experience and as the acute effects of the drug wear off. Given associations of negative affect with both suicidal behavior (26, 27) and impulsivity among patients with borderline personality disorder (28), several risk management strategies may be considered. For example, given the particular effectiveness of DBT and MBT for treating self-harm and suicidal behavior among patients with borderline personality disorder, a phase-based treatment approach to MDMA-AP could be used to reduce, eliminate, or place contingencies around self-harm and suicidal behavior using relevant treatment strategies. Following risk assessment and planning, MDMA preparation, dosing, and integration sessions may be incorporated at strategic windows throughout the treatment course, with the dosing session facilitated in a controlled environment (90). Behavioral strategies, such as contingency management, reinforcement and shaping, and creating a safety plan to cope with self-harm and suicidal urges, may also provide beneficial structure in which MDMA-AP may be effectively practiced with patients with borderline personality disorder.

Additionally, similar to the structure of interventions for comorbid borderline personality disorder and PTSD (in which patients are taught skills to support adequate experiential immersion into exposures) (89), skills to cope with avoidance behaviors, impulsive urges, suicidal ideation, and dissociation (e.g., mindfulness, distress tolerance, and anti-dissociation skills) may be taught before MDMA dosing sessions to support immersion into the experience and to cope with distress that may arise. Alternatively, given the length of specialist treatments for borderline personality disorder, a more generalist approach could also be used in conjunction with MDMA-AP; for example, good psychiatric management is an approach that has been found to be as efficacious as DBT for borderline personality disorder in a previous clinical trial (15). Finally, as in standard DBT, patients may have access to on-call phone coaching for help using skills to cope with difficult experiences (including suicidal ideation) and negative affect that may arise after the experience and before their integration session, which is typically scheduled for the day following the MDMA session.

Moreover, because the acute effects of MDMA can promote strong feelings of connectedness and increased disclosure of difficult experiences, patients are more vulnerable and may become very attached to therapists or experience stronger transferences. As such, boundary considerations are an important aspect of treatment planning. In the context of borderline personality disorder symptomatology, it is possible that strong feelings of idealizing and abandonment sensitivity may arise. To anticipate this possibility, we suggest that discussions about relationship boundaries should occur during MDMA preparation. For example, boundaries around physical touch (e.g., whether patients can ask for supportive hand-holding during difficult or emotional moments of the MDMA experience) and when the dosing session and treatment course will end should be discussed upfront to manage patient expectations about levels of intimacy and contact within the parameters of the study.

Importantly, Williams et al. (123) have also proposed several considerations for designing MDMA-AP research that is racially inclusive. Among other steps, the authors discussed the importance of assessing for racial trauma, thoughtful research advertising and selection of dosing session music, fair compensation of participants for their time and travel, and ensuring that the research team includes therapists of color. MDMA-AP is a novel, experimental intervention, and it is crucial to examine whether it is efficacious for people of color, who are grossly underrepresented in clinical research studies. Additionally, given the strong potential for placebo effects to be heightened in the context of a highly novel, biological intervention, after the initial safety and feasibility of MDMA-AP for borderline personality disorder are examined, researchers should ideally use randomized, double-blind, placebo-controlled trials (124–126).

Lastly, because the majority of treatment-seeking individuals with borderline personality disorder are women (127), the generalizability of research findings to other genders has been limited; thus, more targeted recruitment of gender-diverse samples in future work is crucial. For example, recent research has suggested that compared with women, men with borderline personality disorder have poorer top-down control of aggression (128), suggesting that treatment targets for men with borderline personality disorder may differ from those of women.

In summary, MDMA may have potential to improve treatment outcomes for individuals with borderline personality disorder. In particular, we hypothesize that the acute effects of MDMA may promote reduced emotional avoidance and support the development of a strong therapeutic rapport associated with disclosure of important therapeutic material, catalyzing more fulsome processing of traumatic invalidation or trauma. These hypothesized mechanisms may support shifts in the attachment-related structures that play a role in persistent areas of dysregulation and dysfunction among patients with borderline personality disorder, such as interpersonal and affective symptoms and related suicidal tendencies. With recent findings supporting the efficacy of MDMA-AP for PTSD, exploring the use of MDMA among individuals with borderline personality disorder appears fully warranted.