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MDMA-Assisted Psychotherapy for Borderline
Personality Disorder
Jenna M. Traynor, Ph.D., Daniel E. Roberts, M.D., M.S.W., Stephen Ross, M.D., Richard Zeifman, M.A.,
Lois Choi-Kain, M.D., M.Ed.
Borderline personality disorder is a complex psychiatric
disorder with limited treatment options that are associated
with large heterogeneity in treatment response and high
rates of dropout. New or complementary treatments for
borderline personality disorder are needed that may be
able to bolster treatment outcomes. In this review, the
authors comment on the plausibility for research on
3,4-methylenedioxymethamphetamine (MDMA) used in
conjunction with psychotherapy for borderline personality
disorder (i.e., MDMA-assisted psychotherapy [MDMA-AP]).
On the basis of the promise of MDMA-AP in treating
disorders overlapping with borderline personality disorder
(e.g., posttraumatic stress disorder), the authors speculate on
initial treatment targets and hypothesized mechanisms of
change that are grounded in prior literature and theory. Initial
considerations for designing MDMA-AP clinical trials to
investigate the safety, feasibility, and preliminary effects of
MDMA-AP for borderline personality disorder are also presented.
Focus 2022; 20:358–367; doi: 10.1176/appi.focus.20220056
Borderline personality disorder is a serious psychiatric dis-
order with an especially high risk of suicide (1). Individuals
with borderline personality disorder experience a substan-
tial degree of impairment in psychosocial functioning (2),
and symptoms of the disorder cut across behavioral, affec-
tive, interpersonal, and cognitive domains (3). Clinical
pharmacological findings suggest that no effective medication
options exist to treat global borderline personality disorder
symptoms (4); moreover, clinical guidelines advise that inpa-
tient hospitalization for suicidality can increase rather than
reduce the long-term risk of suicide among some patients with
borderline personality disorder (5). Thus, clinical management
poses unique challenges for health care providers, who, when
surveyed, have reported that the chronic suicidality and in-
terpersonal dynamics are the most challenging features of the
disorder to manage (6, 7). At present, many patients are re-
ferred to specialist treatments in which some wait times are
years long because of a dearth of clinicians who are trained in
specialist interventions, which typically range in length from
1 to several years. This backlog results in a revolving door of
waitlisted patients who often present to the emergency de-
partment in suicidal crisis (8). Taken together, these facts de-
pict the limitation of clinical resources available to mental
health practitioners for stabilizing the prevalent and disabling
presentation of those with borderline personality disorder.
Although several evidence-based psychotherapies are
effective for treating borderline personality disorder, there is
large heterogeneity in individual treatment response and
high rates of attrition (9); a recent systematic review has
shown that almost half of patients prematurely drop out of
treatment (10). The largest bodies of evidence support the
efficacy of mentalization-based therapy (MBT) and dialectical
behavior therapy (DBT) for reducing self-harm and suicidal
behavior among patients with borderline personality disorder
(11–13). Significant reductions in self-harm are often observed
at 4–6 months into a treatment course (14–16) and sometimes
earlier in a proportion of patients (17). Although suicidal be-
havior is relatively slower to remit, a gradual decline has been
observed extending into 1 year of specialist treatment (11). In
contrast, suicidal ideation often persists, even when suicidal
behavior has remitted (11, 18). Regarding other borderline
personality disorder symptoms (e.g., interpersonal, affective,
and identity disturbances), meta-analyses have shown large
variation in treatment effects across randomized controlled
trials (9, 12, 13), with a relatively small amount of available
follow-up data suggesting that improvements are not sus-
tained among a proportion of patients (9). The most recent
Cochrane review of psychotherapies for borderline person-
ality disorder also found that improvements in areas such as
interpersonal functioning and fears of abandonment are small
and no better than those observed in treatment as usual (13).
In tandem, naturalistic studies on the longitudinal course
of borderline personality disorder symptoms have shown that
relative to behavioral symptoms, the interpersonal and af-
fective features of the disorder persist into later courses ofthe
illness (19–21); this stage is also when death by suicide is more
likely to occur among persons with borderline personality
disorder (1, 22). Dependency-related interpersonal symptoms
such as intolerance of aloneness and fears of abandonment
appear especially persistent, even in samples in which the
358 focus.psychiatryonline.org Focus Vol. 20, No. 4, Fall 2022
REVIEW
majority of participants have received individual therapy (19,
23). This finding suggests that a substantial degree of im-
pairment inattachment functioningthroughout one’slifetime
is not adequately treated by existent interventions. In this
regard, although a couple of longitudinal studies have sug-
gested that symptom remission is common over the course of
one’s lifetime, sustained recovery from borderline personality
disorder, as defined by adequate psychosocial functioning, is
not (20, 24).
It is important to note that the enduring nature of inter-
personal and affective symptoms in borderline personality
disorder, along with the persistence of suicidal ideation,
even alongside reduced suicidal behavior (11), infers an on-
going suicide risk that is not adequately addressed by avail-
able treatments and may increase in the context of
subsequent stressors. Specifically, interpersonal stressors are
more likely to precipitate suicide attempts among persons
with borderline personality disorder versus other disorders,
with experiences of rejection and abandonment as highly
potent antecedents (25, 26). Negative affectivity also appears
to exert a strong moderating role on the association between
interpersonal distress and suicidal behavior in borderline
personality disorder (26, 27). Negative affectivity has been
associated with the medical seriousness of suicide attempts
(28) and other suicide-related processes in borderline per-
sonality disorder, such as reduced inhibitory control (28) and
greater neurobiological reactivity to social exclusion (29).
These findings reflect the convergence across borderline
personality disorder theories in their emphasis on the inter-
personal (30, 31), the affective (5),and, most recently, both the
interpersonal and affective components of the disorder (32).
Taken together, borderline personality disorder is a
complex disorder with limited treatments that do not appear
to fully target the mechanisms by which interpersonal and
affective features (and by extension, suicidality and poor
functioning) are maintained. Thus, new or complementary
treatments are needed that can address these gaps in treat-
ment efficacy. In this review, we comment on the plausibil-
ity for research on 3,4-methylenedioxymethamphetamine
(MDMA) used in conjunction with psychotherapy for bor-
derline personality disorder (i.e., MDMA-assisted psycho-
therapy [MDMA-AP]) to target these mechanisms and
improve treatment outcomes. On the basis of the promise of
MDMA-AP for treating disorders that overlap with bor-
derline personality disorder (e.g., posttraumatic stress dis-
order [PTSD]), we speculate on initial treatment targets and
hypothesized mechanisms of change that are grounded in
prior literature and theory. Finally, initial considerations for
designing MDMA-AP clinical trials to investigate the safety,
feasibility, and preliminary effects of MDMA-AP for bor-
derline personality disorder are presented.
MDMA-AP
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 spec-
trum 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 sub-
stances 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 (N57, 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 treat-
ments 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 structur-
ally similar to methamphetamine and mescaline and pro-
duces 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 psy-
chotherapist 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 Admin-
istration 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), re-
ferring to the effects of increased self-awareness and intro-
spection 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 sensa-
tional claims made about overdose deaths, irreversible
neurologic damage, and addiction (46). It is important to
contrast uncontrolled recreational use of MDMA with
Focus Vol. 20, No. 4, Fall 2022 focus.psychiatryonline.org 359
TRAYNOR ET AL.
controlled use in clinical research settings. In the recrea-
tional setting, although medical toxicity (i.e., malignant hy-
perthermia, 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 ad-
ministered 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 pres-
sure, 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 ad-
dictive liability, recreational MDMA use is substantially less
likely to produce dependence syndromes, especially com-
pared with other dopaminergic stimulants (i.e., metham-
phetamine, 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 sub-
stantially increased risk of death (e.g., PTSD).
CONCEPTUALIZING BORDERLINE PERSONALITY
DISORDER THROUGH A TRAUMA-FOCUSED LENS
To date, the most substantial evidence for MDMA-AP per-
tains 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). Com-
pared with each individual disorder alone, comorbid bor-
derline 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 sub-
strates of borderline personality disorder and PTSD is pre-
sented to contextualize a discussion of treatment targets for
MDMA-AP for borderline personality disorder.
Borderline personality disorder is a stress-related disor-
der 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); in-
deed, 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 bor-
derline personality disorder as a distinct nosological entity,
most seminal theories emphasize a strong association be-
tween 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 disor-
der. 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 pro-
ponents 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 re-
main 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 endoge-
nous 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 be-
tween 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 dysre-
gulation 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 hyper-
activation 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 diag-
nostic constructs is beyond the scope of this review, it is
important to appreciate the significant degree to which re-
search findings support the hypothesis that trauma plays a
role in the development and manifestation of borderline
personality disorder. Several studies have demonstrated that
360 focus.psychiatryonline.org Focus Vol. 20, No. 4, Fall 2022
MDMA-ASSISTED PSYCHOTHERAPY FOR BORDERLINE PERSONALITY DISORDER
trauma is a strong predictor of the disorder (81–83) and its
associated social cognitive impairments (84). The concep-
tual 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 dysre-
gulated stress responses such as dissociation (66, 72, 85).
Moreover, research that contributed to the recently devel-
oped Hierarchical Taxonomy of Psychopathology (HiTOP),
a dimensional classification model, provides empirical sup-
port 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’sig-
nificant 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 ef-
ficacy for improving several functional and borderline per-
sonality disorder–relevant outcomes (88, 89).
Altogether, given the growing body of research support-
ing the efficacy of MDMA-AP for PTSD, the conceptual and
observed similarities between borderline personality disorder
and PTSD, and the significant comorbidity and subsequent de-
gree of suffering and public health burden of borderline per-
sonality 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.
POTENTIAL TREATMENT TARGETS IN 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 dis-
turbances, 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 asso-
ciations between early attachment disruptions and border-
line personality disorder symptoms (61–63), we suggest that
targeting interpersonal and affective symptoms may be re-
alized 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 im-
provements in areas relevant to borderline personality dis-
order. 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 in-
creases in empathy (33). Affectively, around 74% of partici-
pants 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 con-
joint 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 rea-
sonable 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 correla-
tions with borderline personality disorder in a recent study
(96). Plausibly, decreased neuroticism and increased open-
ness 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 improve-
ments in suicidal ideation were substantial, with an ap-
proximately 36% decrease in the number of participants
endorsing suicidal ideation from baseline to follow-up, and
with no increases in suicidal behavior (33).
HYPOTHESIZED MECHANISMS OF MDMA-AP FOR
BORDERLINE PERSONALITY DISORDER
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 in-
validation and trauma as well as increased willingness to
disclose covert experiences to therapists (e.g., memories,
Focus Vol. 20, No. 4, Fall 2022 focus.psychiatryonline.org 361
TRAYNOR ET AL.
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 ef-
fects 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 tol-
erability 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 re-
open 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
immersionintoemotionalprocessing with reduced avoidance.
In prolonged exposure therapy for PTSD, Foa has emphasized
the necessity of deep emotional immersion to effectively acti-
vate 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 border-
line 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 introspec-
tion on present-day behaviors that are conceptually tied to
them, such as frantic attempts to avoid abandonment, ide-
alizing and devaluing others, or suicidal ideas preceded by
interpersonal conflict). Especially if conceptualizing trau-
matic 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 per-
sonality 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 intro-
spection 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 avoid-
ance with self-harm and suicidal ideation (111). Moreover,
oxytocin, a neurohormone released by MDMA, was ad-
ministered in two large, placebo-controlled studies of bor-
derline personality disorder (112, 113). Lischke et al. (112)
found an attenuating effect of oxytocin on limbic system
hyperactivation among individuals with borderline person-
ality 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 disor-
der (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 de-
sign of MDMA-AP clinical trials to test the safety, feasibility,
and initial clinical effects of MDMA-AP for borderline per-
sonality disorder.
362 focus.psychiatryonline.org Focus Vol. 20, No. 4, Fall 2022
MDMA-ASSISTED PSYCHOTHERAPY FOR BORDERLINE PERSONALITY DISORDER
DESIGNING CLINICAL TRIALS 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 dis-
cussions around safety, expectations, intentions, and coping
with anticipated difficulties or psychological tendencies that
may arise during the dosing session (e.g., addressing mal-
adaptive 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 nondi-
rective 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 invali-
dation or early attachment disruptions (e.g., frantic efforts to
avoid abandonment, self-harm or suicide attempts in re-
sponse 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 dis-
order 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 dis-
order, relative to first-line specialist treatments (e.g., DBT),
which are likely cost-effective in the short term (119). Re-
search 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). Com-
paratively, a recent estimate of the annual cost of illness on
society for an average treatment-seeking patient with bor-
derline personality disorder was €31,130 (or $33,370) (122).
Despite the potential of MDMA-AP for treating border-
line 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 man-
agement 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 ag-
gression, 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 associ-
ations 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 be-
havior 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 incor-
porated 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 per-
sonality disorder.
Additionally, similar to the structure of interventions for
comorbid borderline personality disorder and PTSD (in
which patients are taught skills to support adequate expe-
riential 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, pa-
tients 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 pro-
mote strong feelings of connectedness and increased dis-
closure of difficult experiences, patients are more vulnerable
and may become very attached to therapists or experience
Focus Vol. 20, No. 4, Fall 2022 focus.psychiatryonline.org 363
TRAYNOR ET AL.
stronger transferences. As such, boundary considerations
are an important aspect of treatment planning. In the con-
text of borderline personality disorder symptomatology, it is
possible that strong feelings of idealizing and abandonment
sensitivity may arise. To anticipate this possibility, we sug-
gest 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 mo-
ments of the MDMA experience) and when the dosing ses-
sion and treatment course will end should be discussed
upfront to manage patient expectations about levels of inti-
macy 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 in-
cludes therapists of color. MDMA-AP is a novel, experi-
mental intervention, and it is crucial to examine whether it is
efficacious for people of color, who are grossly underrepre-
sented 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 ide-
ally use randomized, double-blind, placebo-controlled trials
(124–126).
Lastly, because the majority of treatment-seeking indi-
viduals with borderline personality disorder are women
(127), the generalizability of research findings to other gen-
ders has been limited; thus, more targeted recruitment of
gender-diverse samples in future work is crucial. For ex-
ample, 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 dis-
order may differ from those of women.
CONCLUSIONS
In summary, MDMA may have potential to improve treat-
ment 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 mate-
rial, catalyzing more fulsome processing of traumatic in-
validation 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.
AUTHOR AND ARTICLE INFORMATION
Gunderson Personality Disorders Research Institute, McLean Hospital,
Belmont, Massachusetts (Traynor, Choi-Kain); Faculty of Medicine,
Harvard Medical School, Boston (Traynor, Choi-Kain); Langone Center
for Psychedelic Medicine, Department of Psychiatry, New York Univer-
sity Grossman School of Medicine, New York (Roberts, Ross); Depart-
ment of Psychology, Ryerson University, Toronto (Zeifman); Centre for
Psychedelic Research, Imperial College London, London (Zeifman).
Send correspondence to Dr. Traynor (jtraynor1@partners.org).
Dr. Traynor is a coinvestigator on a Multidisciplinary Association for
Psychedelic Studies (MAPS)-funded clinical trial of 3,4-methylenedioxy-
methamphetamine (MDMA)-assisted psychotherapy; she has also re-
ceived compensation as an independent contractor for the role of study
therapist on a MAPS-funded clinical trial of MDMA-assisted psycho-
therapy. Dr. Roberts has received compensation as an independent
contractor for his role as an assistant trainer from Fluence. Dr. Ross is a
coinvestigator on the MAPS MDMA-assisted psychotherapy for post-
traumatic stress disorder phase 3 trials; he also reports research support
from Usona and Reset Pharmaceuticals related to psilocybin research,
two patents with Reset, and funding from the National Institute on Drug
Abuse. Mr. Zeifman has received compensation as an independent
contractor for the role of study therapist on a MAPS-funded clinical trial
of MDMA-assisted psychotherapy. Dr. Choi-Kain receives book royalties
from Springer Publishing and the American Psychiatric Association.
None of the aforementioned organizations were involved in the design,
execution, interpretation, or communication of findings of this
publication.
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