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CLINICAL RESEARCH ARTICLE
Preliminary evidence for the importance of therapeutic alliance in MDMA-
assisted psychotherapy for posttraumatic stress disorder
Richard J. Zeifman
a
, Hannes Kettner
b
, Stephen Ross
a
, Brandon Weiss
b
, Michael C. Mithoefer
c
,
Ann T. Mithoefer
c
and Anne C. Wagner
d
a
Department of Psychiatry, NYU Grossman School of Medicine, NYU Langone Centre for Psychedelic Medicine, New York, NY, USA;
b
Centre
for Psychedelic Research, Department of Brain Sciences, Faculty of Medicine, Imperial College London, London, UK;
c
MAPS Public Benefit
Corporation (MPBC), San Jose, CA, USA;
d
Department of Psychology, Toronto Metropolitan University, Toronto, Canada
ABSTRACT
Background: MDMA-assisted psychotherapy (MDMA-AP) is a combined psychotherapeutic and
pharmacologic intervention that shows promise in the treatment of posttraumatic stress disorder
(PTSD). Although therapeutic alliance has been established as a key predictor across
psychotherapies and is emphasised within MDMA-AP treatment manuals, research has not yet
examined the relationship between therapeutic alliance and MDMA-AP treatment outcomes.
Objective: Examine whether therapeutic alliance predicts changes in PTSD symptoms following
MDMA-AP.
Method: Twenty-three individuals with chronic PTSD participated in a MDMA-AP clinical trial
that included a randomised (MDMA vs. placebo) and open-label phase. The present analyses
focused on participants who were administered MDMA over the course of the randomised
and open-label phases (n= 22). Therapeutic alliance was assessed using the Working Alliance
Inventory at sessions baseline (pre-session 3) and sessions 4 and 9. PTSD symptoms were
assessed using the Clinician Administered PTSD Scale and the Impact of Events Scale-Revised.
Results: Controlling for baseline clinician-assessed PTSD severity, therapeutic alliance at sessions
4 and 9 (but not baseline) significantly predicted post-MDMA-AP clinician-assessed PTSD severity.
Controlling for baseline self-reported PTSD severity, therapeutic alliance at baseline (although
this did not survive correction for multiple comparisons) and sessions 4 and 9 predicted post-
MDMA-AP self-reported PTSD severity.
Conclusions: The present results provide the first preliminary evidence for the relationship
between the therapeutic alliance and treatment outcomes within MDMA-AP for PTSD. These
findings highlight the important role of psychotherapy, and common psychotherapeutic
factors, within MDMA-AP. Replication in studies with larger and more diverse clinical samples
remain necessary.
Trial registration: ClinicalTrials.gov identifier: NCT00090064.
Evidencia preliminar de la importancia de la alianza terapéutica en la
psicoterapia asistida con MDMA para el trastorno de estrés postraumático
Antecedentes: La psicoterapia asistida por MDMA (MDMA-AP por sus siglas en inglés) es una
combinación de intervención psicoterapéutica y farmacológica que muestra ser prometedora
en el tratamiento del trastorno de estrés postraumático (TEPT). Aunque la alianza terapéutica
ha sido bien establecida como un predictor clave a través de las psicoterapias y se enfatiza en
los manuales de tratamiento MDMA-AP, la investigación aún no ha examinado la relación entre
la alianza terapéutica y los resultados del tratamiento MDMA-AP.
Objetivo: Examinar si la alianza terapéutica predice cambios en los síntomas de TEPT después
de MDMA-AP.
Método: Veintitrés individuos con TEPT crónico participaron en un ensayo clínico de MDMA-
AP que incluyó una fase aleatorizada (MDMA vs placebo) y abierta. El presente análisis se centra
en los participantes a los que se les administró MDMA en el curso de las fases aleatorias y
abiertas (n= 22). La alianza terapéutica se evaluó utilizando el Inventario de Alianza de
Trabajo en las sesiones iniciales (antes de la sesión 3) y en las sesiones 4 y 9. Los síntomas
de TEPT se evaluaron utilizando la Escala de TEPT administrada por el Clínico y la Escala
Revisada del Impacto de los Eventos.
Resultados: Al controlar según la severidad del TEPT evaluada por el clínico al inicio, la alianza
terapéutica en la sesión 4 y 9 (pero no la inicial) predijo significativamente la severidad del TEPT
post tratamiento evaluada por el clínico post MDMA-AP. Al controlar al inicio según la
ARTICLE HISTORY
Received 19 June 2023
Revised 22 November 2023
Accepted 14 December 2023
KEYWORDS
Posttraumatic stress
disorder; MDMA; MDMA-
assisted psychotherapy;
therapeutic alliance;
mechanism of change
PALABRAS CLAVE
Trastorno de estrés
postraumático; MDMA;
Psicoterapia asistida por
MDMA; alianza terapéutica;
mecanismos de cambio
HIGHLIGHTS
•Among individuals with
chronic posttraumatic
stress disorder, therapeutic
alliance predicted changes
in posttraumatic stress
disorder severity following
MDMA-assisted
psychotherapy.
•Therapeutic alliance may
play a key role in
facilitating therapeutic
improvement within
MDMA-assisted
psychotherapy.
•Further research remains
necessary to confirm these
preliminary findings and
the role of therapeutic
alliance in MDMA-assisted
psychotherapy.
© 2024 The Author(s). Published by Informa UK Limited, trading as Taylor & Francis Group
This is an Open Access article distributed under the terms of the Creative Commons Attribution-NonCommercial License (http://creativecommons.org/licenses/by-nc/4.0/), which
permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited. The terms on which this article has been
published allow the posting of the Accepted Manuscript in a repository by the author(s) or with their consent.
CONTACT Richard J. Zeifman richard.zeifman@nyulangone.org Department of Psychiatry, NYU Grossman School of Medicine, NYU Langone
Centre for Psychedelic Medicine, 1 Park Avenue, New York, NY 10016, USA
Supplemental data for this article can be accessed online at https://doi.org/10.1080/20008066.2023.2297536
EUROPEAN JOURNAL OF PSYCHOTRAUMATOLOGY
2024, VOL. 15, NO. 1, 2297536
https://doi.org/10.1080/20008066.2023.2297536
severidad del TEPT por auto-reporte, la alianza terapéutica al inicio (aunque esto no sobrevivió
a la corrección para comparaciones múltiples) y en las sesiones 4 y 9 predijeron la severidad del
TEPT auto-reportada post-MDMA-AP.
Conclusiones: Los resultados actuales proporcionan la primera evidencia preliminar de la
relación entre la alianza terapéutica y los resultados del tratamiento en MDMA-AP para
TEPT. Estos hallazgos resaltan el importante papel de la psicoterapia y los factores
psicoterapéuticos comunes, dentro de la MDMA-AP. Sigue siendo necesario la replicación en
estudios con muestras clínicas mas grandes y diversas.
Posttraumatic stress disorder (PTSD) is a chronic
and debilitating disorder, characterised by symptoms
of re-experiencing, avoidance, negative alterations in
mood and cognition, and alterations in arousal and
reactivity after experiencing a traumatic event
(American Psychiatric Association, 2013). Despite
the existence of several evidence-based psychothera-
peutic (American Psychological Association, 2017)
and pharmacological treatments for PTSD, there
remains a need for exploring additional PTSD inter-
ventions that may help to optimise outcomes and
reduce treatment dropout (Bryant, 2019;Krystal
et al., 2017). 3,4-methylenedioxymethamphetamine
(MDMA)-assisted psychotherapy (MDMA-AP) is a
promising novel intervention for PTSD, with several
randomised controlled (Mitchell et al., 2021;Mithoe-
fer et al., 2011,2018; Oehen et al., 2013;Ot’alora
et al., 2018) and uncontrolled (Jardim et al., 2021;
Monson et al., 2020; Wang et al., 2021)trials
suggesting that MDMA-AP leads to significant
reductions in PTSD and depression severity. For
instance, a recently completed Phase 3 placebo-con-
trolled trial found that, relative to placebo-assisted
therapy, MDMA-AP decreased PTSD severity func-
tional impairment, and depressive symptoms (Mitch-
ell et al., 2021). Given its therapeutic potential, it is
important to understand MDMA-AP’sunderlying
mechanisms of change.
Importantly, MDMA-AP is a combined pharmaco-
logic-psychotherapeutic intervention in which two
therapists provide psychotherapy and/or psychologi-
cal support prior to, during, and following MDMA
administration. Accordingly, the psychotherapeutic
component of MDMA-AP is assumed to play an
important role in facilitating positive therapeutic out-
comes (Mithoefer et al., 2016). However, research has
not yet formally examined the role of psychotherapeu-
tic factors in the context of MDMA-AP. A broad
swathe of research indicates that therapeutic alliance
(i.e. the collaborative relationship developed between
a patient and therapist; Bordin, 1979) is an essential
component of psychotherapeutic interventions
broadly (Flückiger et al., 2018). Therapeutic alliance
is most commonly measured using the Working Alli-
ance Inventory (Horvath & Greenberg, 1989), which
was developed based on a transtheoretical model of
therapeutic alliance (Bordin, 1979). The WAI consists
of the three components: (a) bonds (trust acceptance,
and confidence between the client and therapist[s]);
(b) goals (agreement on treatment priorities and
intended outcomes); and (c) tasks (agreement on the
means and processes through which treatment priori-
ties and outcomes are facilitated). Research suggests
that the strength of the therapeutic alliance is a key
predictor of treatment outcomes generally (Flückiger
et al., 2018), as well as within the context of PTSD
treatment (Howard et al., 2022). For instance, it is esti-
mated that therapeutic alliance accounts for 12% of
the variance in PTSD treatment outcomes (Howard
et al., 2022). Although the role of the therapeutic alli-
ance is highlighted within the MDMA-AP treatment
manual (http://maps.org/treatment-manual) and
research publications (e.g. Feduccia et al., 2019),
empirical research has not yet explored the effect of
therapeutic alliance on MDMA-AP treatment out-
comes. Therefore, using data from a previously pub-
lished clinical trial of MDMA-AP for PTSD
(Mithoefer et al., 2011), we examined therapeutic alli-
ance as a predictor of both self-reported and clinician-
assessed PTSD outcomes.
1. Methods
1.1. Participants
The clinical trial aimed to enrol a total of 21 individ-
uals with PTSD with replacement of drop-outs (clini-
caltrials.gov; NCT00090064). To be eligible for the
clinical trial, participants were required to meet the
following criteria: (a) aged ≥18; (b) chronic PTSD
(based on the DSM-IV) resulting from a crime-related
or military related traumatic experience; (c) moderate
to severe PTSD severity (based on a Clinician Admi-
nistered PTSD Scale [CAPS; Blake et al., 1990] score
of ≥50); (d) at least one unsuccessful PTSD treatment
with a selective serotonin reuptake inhibitor (SSRI) or
serotonin–norepinephrine reuptake inhibitor (SNRI)
and one course of psychotherapy or unwillingness to
engage in conventional PTSD treatment; (e) absence
of current psychiatric comorbidities including border-
line personality disorder or DSM-IV Axis I disorders
(with the exception of anxiety disorders, affective dis-
orders other than bipolar I disorder, substance abuse
or dependence disorder in remission for ≥60 days,
2R. J. ZEIFMAN ET AL.
and eating disorder without active purging); (f)
absence of major medical conditions; (g) absence of
pregnancy; (h) use of effective birth control if female
and able to have children; (i) weigh less than 50 kg;
(j) proficiency in the English language. The study
specifically aimed to recruit 20 individuals with treat-
ment-resistant (failed pharmacotherapy and psy-
chotherapy) PTSD (of ≥5 years in duration) and
one veteran with military-related PTSD (≥1 and ≤5
years in duration) with failed PTSD treatment or
unwillingness to engage in conventional PTSD
treatment.
Participants were recruited through internet adver-
tisements and by sending letters to psychotherapists.
Participants completed an initial telephone screen to
determine eligibility and then an in-person visit to
review and sign informed consent, followed by an
interview with an independent rater and physician to
further determine eligibility. Participants were obli-
gated to taper offof and abstain from using psychotro-
pic medications throughout the study. However, use
of study physician approved sedative hypnotics or
anxiolytics was permitted between experimental ses-
sions. Ethical approval for the study was received
from the Copernicus Group Independent Review
Board (IRB), Research Triangle Park, NC, USA.
MDMA was produced by David E Nichols, PhD for
the study sponsor (Multidisciplinary Association for
Psychedelic Studies [MAPS]).
1.2. Procedures
The parent study was a clinical trial (clinicaltrials.gov;
NCT00090064) that included a double-blind random-
ised controlled phase (Phase 1) followed by an open-
label phase (Phase 2). Participants were initially
randomised to two experimental sessions in which
they were administered either (a) MDMA (125 mg)
or (b) inactive placebo (lactose) (Phase 1). Following
a protocol amendment, the final 9 participants were
allowed to receive a supplement half-dose of MDMA
(62.5 mg) or placebo in all of their experimental ses-
sions (administered 2 h into the experimental session).
Four participants in the MDMA group and 4 partici-
pants in the placebo group received supplemental
doses in this manner. Individuals in both conditions
also received non-drug psychotherapy. In Phase 1,
participants received two preparatory psychotherapy
sessions (sessions 1 and 2), two experimental sessions
(sessions 3 and 8), and eight additional non-drug psy-
chotherapy sessions (sessions 4–7 and 9–12), includ-
ing one the day after each experimental session
(sessions 4 and 9). Additional sessions were permitted,
if needed, on a case-by-case basis. In Phase 2, partici-
pants in the placebo condition were eligible to receive
two open-label MDMA sessions (sessions 13 and 17)
each of which was followed by three psychotherapy
sessions (sessions 14–16 and 18–20). Following a pro-
tocol amendment, four participants initially in the pla-
cebo condition and five participants initially in the
MDMA condition received an additional (i.e. a
third) MDMA session.
Sixty percent of participants were randomised to
receive MDMA and 40% of participants were random-
ised to placebo (with replacement of dropouts). Thir-
teen individuals (including one individual with
military-related PTSD that was not required to be
treatment-resistant) were initially randomised to the
MDMA condition and 8 individuals were randomised
to placebo. Two individuals assigned to the MDMA
condition dropped out of treatment prior to their
second experimental session (due to travelling difficul-
ties for one individual and resumption of medication
for depression relapse for the other individual) and
two additional individuals were subsequently random-
ised to the MDMA condition. The two participants
who dropped out of treatment and one individual
with military-related PTSD (that was not required to
be treatment-resistant) were excluded from the pri-
mary outcomes paper (Mithoefer et al., 2011) but are
included here due to: (a) meeting criteria for PTSD;
(b) receiving psychotherapy and at least one
MDMA-assisted psychotherapy session; and (c) to
ensure that findings are not biased by treatment drop-
out (e.g. due to poor therapeutic alliance). One
individual in the placebo arm opted not to receive
open-label MDMA and is therefore excluded from
the present analysis. Due to limited sample size, all
participants (n= 22) administered MDMA (whether
in Phase 1 or 2) are included in the present analyses.
For study flow, see Figure 1. For study procedures,
see Figure 2.
The study was conducted in accordance with the
MDMA-AP treatment manual (http://maps.org/
treatment-manual), utilising a psychotherapeutic plat-
form administered by a dyad therapy team, and
inclusive of preparatory sessions, administration of
MDMA/placebo, and post-dosing integration ses-
sions. Preparatory sessions focused on orienting par-
ticipants to the therapeutic approach, the structure
of experimental sessions, and the acute effects of
MDMA. Experimental sessions occurred in a comfor-
table outpatient office, participants were offered the
option to use eyeshades while reclining in a comforta-
ble position, and listening to a pre-set music playlist.
Experimental sessions lasted 8–10 h after which par-
ticipants remained overnight with a nurse on site to
ensure safety. When needed, zolpidem or lorazepam
were prescribed for difficulty sleeping following exper-
imental sessions. Integration sessions focused on
emotional processing and reviewing the experimental
session, as well as identifying and reflecting on new
insights and perspectives related to their life and
PTSD. Additional integration sessions occurred
EUROPEAN JOURNAL OF PSYCHOTRAUMATOLOGY 3
when judged to be necessary by the study investi-
gators. The same male and female co-therapist team
were present for all treatment sessions. For further
details, see Mithoefer et al. (2011).
Subjects, investigators, nurses, and independent
raters were blinded to condition during Phase 1. Out-
come measures were repeated and the blind was broken
two months after participants’second MDMA/placebo-
assisted psychotherapy session. PTSD symptoms were
measured at baseline (prior to session 3) and 3–7
days after each MDMA/placebo session, 2 months
after the second experimental session, and (among
individuals that were initially assigned to receive pla-
cebo and then enrolled in Phase 2) 6–8weeksafter
their final MDMA session. Clinician-assessed PTSD
severity ratings were completed by a blinded indepen-
dent rater. PTSD symptoms at participants’final assess-
ment (with the majority occurring after session 12 and
as late as after session 24) are used as post-treatment
outcomes in the present analyses. Participants com-
pleted ratings of therapeutic alliance at baseline (prior
to session 3) and at sessions 4 and 9.
1.3. Measures
1.3.1. Therapeutic alliance
Therapeutic alliance was measured using the WAI
(Horvath & Greenberg, 1989). The WAI is a 36 item
self-report measure of the client’s perception of the
therapeutic alliance that includes three subscales
(Tasks [agreement on the task of therapy], Goals
[agreement on the goals of therapy], and Bonds [affec-
tive bond between the therapist and patient]) and a
Total score. Items (e.g. ‘I believe _____ is genuinely
concerned for my welfare’and ‘___ and I trust one
another’) are rated on a Likert scale from 1 (never)
to 7 (always). Fourteen items are reverse scored. The
total WAI score is the mean of all items with higher
scores representing a stronger therapeutic alliance.
The WAI shows good psychometric properties,
including strong internal consistency (Horvath &
Greenberg, 1989). In line with previous research
with co-therapists (e.g. Crowe & Grenyer, 2008; Heck-
man et al., 2017; Woody & Adessky, 2002), partici-
pants were instructed to complete the WAI once at
each timepoint with reference to both of their
co-therapists.
1.3.2. PTSD symptoms
Clinician-assessed PTSD symptoms were measured
using the Clinician Administered PTSD Scale
(CAPS; Blake et al., 1990). The CAPS assesses the
17 PTSD symptoms in the DSM-IV, including
identification of a criterion A trauma, symptoms of
re-experiencing, avoidance, and hyperarousal, symp-
tom duration, and level of distress/impairment. For
each symptom, the CAPS includes measures of fre-
quency (rated on a scale 0–4) and intensity (rated on
Figure 1. Study flow for the present analyses.
4R. J. ZEIFMAN ET AL.
Figure 2. A timeline of patient progression through study procedures.
Note: CAPS: Clinician Administered PTSD Scale; IES: Impact of Event Scale-Revised; WAI: Working Alliance Inventory. Grey dashed lines ( ) indicates
that not all patients entered Stage 2. The solid double line ( ) indicates a visit with assessments but no therapy sessions occurred. Sessions with
striped backgrounds ( ) represent those added following protocol amendments. *Supplemental half doses were available after a protocol amend-
ment, and the final nine participants enrolled were allowed this supplement. Four patients in the MDMA group and four in the placebo group received
supplemental doses. #A protocol amendment allowed four participants initially in the placebo condition and five participants initially in the MDMA con-
dition to receive an additional (i.e. a third) MDMA session and three integration sessions.
EUROPEAN JOURNAL OF PSYCHOTRAUMATOLOGY 5
a scale 0–4), which are then summed to calculate the
severity for each symptom (ranging from 0 to 8). A
total PTSD severity is then calculated by summing
each of the 17 severity scores. The CAPS was con-
sidered a gold-standard measure of PTSD at the
time the parent trial was conducted and has excellent
psychometric properties (Weathers et al., 2001).
Self-reported PTSD symptoms were measured
using the revised Impact of Event Scale-Revised
(IES-R; Weiss, 2007). The IES-R is a 22-item self-
report measure developed to assess PTSD symptoms
based on the DSM-IV. It includes three subscales
(intrusion [8 items], avoidance [8 items], and hyperar-
ousal [6 items]), and a total score. Participants identify
a stressful life event and rate event-related items (e.g. ‘I
tried not to think about it’and ‘I had waves of strong
feelings about it’) based on the amount of distress they
caused them over the previous 7 days. Items are rated
on a scale from 0 (not at all) to 4 (extremely). The IES-
R has shown good psychometric properties, including
good internal consistency and test-retest reliability
(Weiss, 2007; Weiss & Marmar, 1997).
1.4. Data analysis
Independent samples t-tests examined potential differ-
ences in therapeutic alliance based on participant sex.
Correlation coefficients were calculated for thera-
peutic alliance (baseline and sessions 4 and 9) and
self-reported and clinician-assessed PTSD severity
(baseline and post-treatment). Hierarchical regression
was used to examine the contribution of therapeutic
alliance in explaining the variance in post-treatment
PTSD severity (controlling for baseline PTSD severity
and the number of days since baseline that post-treat-
ment PTSD severity was measured at). Separate ana-
lyses were run for self-reported (IES-R) and
clinician-assessed (CAPS) PTSD treatment outcomes.
In the first stage, pre-treatment PTSD severity and
days since baseline were entered as independent vari-
ables. Post-treatment PTSD severity was entered as the
dependent variable. For the second stage, therapeutic
alliance was entered as an independent variable with
separate analyses conducted for therapeutic alliance
at baseline (Stage 2a) and sessions 4 (Stage 2b) and 9
(Stage 2c). We set the alpha level for significance as
p< .05 (two-tailed) and further examined statistical
significance following FDR correction for multiple
comparisons using the Benjamini and Hochberg
method (p-FDR < .05). Analyses were conducted
using SPSS version 28. Sensitivity analyses were con-
ducted to confirm results were consistent when
excluding the three participants excluded from the
primary outcomes paper (due to not having treat-
ment-resistant PTSD [n= 1] or only receiving single
dose of MDMA [n= 2]).
The above frequentist hierarchical regression ana-
lyses were supplemented with Bayesian generalised
linear modelling, which is known to produce less
biased results compared to maximum likelihood esti-
mation methods when sample sizes are small (McNe-
ish, 2016). The Region of Practical Equivalence
(ROPE) was defined as the range from −0.1–0.1
(Kruschke, 2015), corresponding to a negligible
effect size according to Cohen (1988) after z-standard-
ization of the outcome (CAPS and IES-R) and predic-
tor (WAI at stage 2a, 2b, and 2c) variables (to achieve
scale-invariance of the posterior coefficient estimates
in relation to the ROPE; Makowski, Ben-Shachar,
Chen, et al., 2019). Significance of an effect was
defined as <2.5% of the posterior distribution falling
into the ROPE. Bayesian analyses were conducted in
R using the rstanarm (Gabry & Goodrich, 2017) and
bayestestR packages (Makowski, Ben-Shachar, and
Lüdecke, 2019).
Following reporting guidelines recommended by
Makowski, Ben-Shachar, Chen, et al. (2019), three
indices are provided for each model: (1) existence of
effect, indicated by the probability of direction (pd;
i.e. the percentage probability that an effect of the pre-
dictor on the outcome exists in a given direction); (2)
significance of the effect, indicated by the percentage
of the full posterior distribution within the ROPE;
and (3) effect size, indicated by the standardised
median coefficient.
2. Results
2.1. Descriptive statistics and preliminary
analyses
The sample (Mean age = 57.50; SD =7.51) wasexclu-
sively Caucasian (100%) and predominantly female
(77.3%). There were no statistically significant differ-
encesbetweenmalesandfemalesintherapeuticalli-
ance at baseline (female mean = 220.94, SD = 27.99;
male mean = 224.20, SD = 19.69; t(20) = .24,
p= .812), session 4 (female mean = 226.75, SD =
24.46; male mean = 227.00, SD = 19.60; t(18) = .02,
p= .985), or session 9 (female mean = 227.59, SD =
22.19; male mean = 223.20, SD = 11.65; t(20) = −.42,
p= .679). The mean duration of participants’PTSD
was 18.2 years with a baseline clinician-assessed
PTSD severity of 82.9 (SD = 21.77). Twenty indi-
viduals (90.9%) had a crime-related index trauma
and two individuals (9.1%) had a military-related
index trauma. All individuals had at least one
unsuccessful PTSD treatment with an SSRI or
SNRI. Twenty-one individuals (95.5%) had pre-
viously received at least one course of psychother-
apy. For means, standard deviations, and
correlations for therapeutic alliance and PTSD
severity measures, see Table 1.
6R. J. ZEIFMAN ET AL.
2.2. Primary analysis
2.2.1. Therapeutic alliance and clinician-assessed
PTSD severity
In Stage 1, baseline clinician-assessed PTSD severity
and days since baseline were not significantly associ-
ated with post-treatment clinician-assessed PTSD
severity (F[2, 19] = .14, p= .869, R
2
= .12) and
accounted for 1% of the variance. At Stage 2(a), adding
therapeutic alliance at baseline to the model did not
result in a significant change in explained variance
(R
2
= .13; F
change
= 2.42, p= .137, p-FDR = .137;
r2
change = .11). At Stage 2(b), adding therapeutic alliance
at session 4 to the model resulted in a significant
increase in explained variance (R
2
= .29; F
change
=
6.77, p= .019, p-FDR = .038) and accounted for an
additional 29% of the variation in post-treatment
PTSD severity, above and beyond baseline PTSD
severity and days since baseline. At Stage 2(c),
adding therapeutic alliance at session 9 to the model
resulted in a significant increase in explained variance
(R
2
= .26; F
change
= 5.89, p= .026, p-FDR = .039) and
accounted for an additional 24% of the variation in
post-treatment PTSD severity, above and beyond
baseline PTSD severity and days since baseline. Baye-
sian analyses were consistent with frequentist analyses,
with therapeutic alliance at baseline not resulting in a
significant change in explained variance (12.3% in
ROPE), while therapeutic alliance at sessions 4 and 9
accounted for a significant amount of variance (both
0% in ROPE) above and beyond baseline clinician-
assessed PTSD severity and days since baseline. See
Supplementary Materials for further details.
2.2.2. Therapeutic alliance and self-reported
PTSD severity
At Stage 1, baseline self-reported PTSD severity was
not significantly associated with post-treatment self-
reported PTSD severity (R
2
= .03; F[1, 19] = .27,
p= .767) and accounted for 3% of the variance. At
Stage 2(a), adding therapeutic alliance at baseline to
the model resulted in a significant increase in
explained variance (R
2
= .22; F
change
= 4.54, p= .047),
although this increase did not survive correction
(p-FDR = .056), and accounted for an additional 20%
of the variation in post-treatment PTSD severity,
above and beyond baseline PTSD severity and days
since baseline. At Stage 2(b), adding therapeutic alli-
ance at session 4 to the model resulted in a significant
increase in explained variance (R
2
= .40; F
change
=
10.56, p= .005, p-FDR = .030) and accounted for an
additional 40% of the variation in post-treatment
PTSD severity, above and beyond baseline PTSD
severity and days since baseline. At Stage 2(c), adding
therapeutic alliance at session 9 to the model resulted
in a significant increase in explained variance
(R
2
= .29; F
change
= 6.70, p= .019, p-FDR = .038) and
accounted for an additional 26% of the variation in
post-treatment PTSD severity, above and beyond base-
line PTSD severity and days since baseline. Bayesian ana-
lyses were consistent with frequentist analyses, with
therapeutic alliance at baseline not resulting in a signifi-
cant change in explained variance (3.1% in ROPE), while
therapeutic alliance at sessions 4 and 9 accounted for a
significant amount of variance (0% and 0.01% in
ROPE, respectively) above and beyond baseline self-
reported PTSD severity and days since baseline. See Sup-
plementary Materials for further details.
2.3. Sensitivity analyses
Supplementary frequentist and Bayesian analyses
confirmed that the above results were consistent
when excluding the three participants who had been
excluded from the primary outcomes paper (see
Supplementary Material).
3. Discussion
In this examination of therapeutic alliance as a puta-
tive mechanism underlying MDMA-AP’s therapeutic
effect on PTSD, therapeutic alliance at baseline (pre-
session 3) and sessions 4 and 9 significantly predicted
self-reported PTSD outcomes. Notably, the relation-
ship between therapeutic alliance at baseline and
self-report PTSD outcomes did not survive correction
for multiple comparisons. Additionally, therapeutic
alliance at sessions 4 and 9 (but not baseline) signifi-
cantly predicted clinician-assessed PTSD outcomes.
The relationship between therapeutic alliance and
treatment was fairly strong with therapeutic alliance
accounting for 11–40% of the variance in PTSD treat-
ment outcomes, above and beyond baseline PTSD and
days since baseline. Therapeutic alliance at baseline
accounted for 11% of the variance in clinician-assessed
PTSD outcome, which is a medium sized effect that is
consistent with previous research on the relationship
between therapeutic alliance and PTSD treatment out-
comes (for a meta-analysis, see Howard et al., 2022).
Importantly however, this effect was not statistically
significant and should therefore be interpreted with
strong caution. All results were consistent when exam-
ined in the full sample of individuals that had received
at least one MDMA session, as well as among those
that had received at least two MDMA sessions and
had a history of both failed psychotherapeutic and
pharmacological PTSD treatment. These findings pro-
vide the first preliminary empirical support for the
importance of therapeutic alliance within MDMA-
AP or the relationship between therapeutic factors
and MDMA-AP treatment outcomes. These findings
are generally consistent with research indicating the
therapeutic alliance is predictive of treatment out-
comes across psychotherapeutic interventions
EUROPEAN JOURNAL OF PSYCHOTRAUMATOLOGY 7
(Flückiger et al., 2018), including treatments for PTSD
(Howard et al., 2022), and suggest that the importance
of therapeutic alliance may extend to MDMA-AP.
There is a growing debate regarding the importance
of psychotherapy in MDMA-AP and interventions
with related pharmacological properties (e.g. psilocy-
bin therapy; Carhart-Harris et al., 2018). The results
of the present study provide preliminary support for
the importance of the psychotherapeutic component
of MDMA-AP and against MDMA being a traditional
stand-alone pharmacological intervention. They also
provide early support for suggestions that such
pharmacologically-enhanced interventions lead to
change via common factors of psychotherapy, includ-
ing the therapeutic alliance (Gukasyan & Nayak,
2022). While further research remains necessary due
to the limited sample size and correlational nature of
present findings, several studies have similarly found
support for a relationship between the therapeutic alli-
ance and one’s bond with individuals present during
one’s acute experience and subsequent improvements
in mental health (Haijen et al., 2018; Kettner et al.,
2021; Murphy et al., 2022). For instance, a recent
study found that therapeutic alliance was predictive
of reductions in depressive symptoms following psilo-
cybin therapy for major depressive disorder (Murphy
et al., 2022).
Although further replication remains necessary to
draw strong conclusions, the present findings have sev-
eral potentially important clinical implications. First,
they suggest that it is worthwhile to pay specificatten-
tion to developing and enhancing therapeutic alliance
prior to providing MDMA sessions. It may therefore
be worthwhile for MDMA-AP training manuals and
treatment development provide specific guidance on
enhancing the therapeutic alliance (e.g. Pinto et al.,
2012), resolving ruptures in the alliance (Eubanks
et al., 2018), and to draw more explicitly from common
factor techniques (Solomonov et al., 2018). Addition-
ally, the present results suggest that if MDMA-AP is
extended to samples of individuals that exhibit complex
comorbidities or greater difficulties with establishing a
strong therapeutic alliance or where the strength of
the therapeutic alliance plays an especially important
role (e.g. individuals with borderline personality dis-
order [BPD]; Boritz et al., 2018;Zeifmanetal.,2021),
further attention may be needed to ensure that a strong
therapeutic alliance is established (Traynor et al., 2022;
Zeifman & Wagner, 2020).
The present study has several important limitations.
The sample was fairly small and non-diverse (i.e. mostly
female and exclusively Caucasian), which is a key issue
in MDMA-AP research to date (Williams et al., 2019).
Further research in larger samples with greater diversity
will be necessary to identify the generalizability of these
findings. Therapeutic alliance was only measured via
patient-rated self-report. Therefore, additional research
that includes therapist and observer-rated therapeutic
alliance (Horvath & Greenberg, 1989)willhelpto
further elucidate the role of therapeutic alliance within
MDMA-AP. The PTSD symptom measures used in the
present study were based on DSM-IV PTSD symptoms.
Therefore, it will be important for future research to
examine the relationship between therapeutic alliance
and measures of DSM-5-TR PTSD symptoms (e.g.
the CAPS-5; Weathers et al., 2018). The present
findings were only examined in the context of
MDMA-AP for PTSD. As research begins to expand
the application of MDMA-AP, including to alcohol
use disorder (Sessa et al., 2021),, distress related to
life-threatening illness (Wolfson et al., 2020), and
couples-based therapy (Wagner, 2021), it will be
necessary to examine whether the role of therapeutic
alliance within MDMA-AP extends across clinical
samples. It will also be important to examine the
relationships between therapeutic alliance and out-
comes including: (a) experiences during MDMA ses-
sions (e.g. cognitive reappraisal [Agin-Liebes et al.,
2022], insight [Davis et al., 2021], and acceptance/
avoidance [Wolffet al., 2022]); (b) trait-level changes
(e.g. insight [Peill et al., 2022] and avoidance [Zeifman,
Wagner et al., 2023]); and (c) treatment outcomes that
extend beyond PTSD severity (e.g. quality of life and
relational improvements [e.g. see Wagner et al., 2021]).
Although the therapy model used in the present
study is the most commonly researched MDMA treat-
ment model, there remains a need for examining the
role of therapeutic alliance within alternative
MDMA-AP models (e.g. MDMA-assisted cognitive
behavioural conjoint therapy or exposure therapy;
Monson et al., 2020). Additionally, a single therapist
dyad provided MDMA-AP for all participants in the
present study. Further research will therefore be
necessary to determine the generalizability of the
Table 1. Means, standard deviations and correlation coefficients.
Mean SD Range 1. 2 3. 4. 5. 6.
1. Therapeutic Alliance
-Baseline
6.16 .72 4.00–7.00 ––––––
2. Therapeutic Alliance
-Session 4
6.30 .64 4.67–7.00 .69
+
–––––
3. Therapeutic Alliance
-Session 9
6.29 .56 5.14–7.00 .68
+
.89
+
––––
4. PTSD Severity (CAPS)
-Baseline
82.86 21.77 43.00–113.00 −.01 .19 .07 –––
5. PTSD Severity (CAPS)
-Post-Treatment
25.14 19.05 .00–79.00 −.33 −.52* −.50* .04 ––
6. PTSD Severity (IES-R)
-Baseline
47.68 14.40 13.00–72.00 .09 .04 .15 .59
#
−.08 –
7. PTSD Severity (IES-R)
-Post-Treatment
16.73 14.84 .00–51.00 −.43* −.62
#
−.48* .10 .70
+
.16
Note: *p< .05.
#
p< .01.
+
p< .001.
8R. J. ZEIFMAN ET AL.
present findings across MDMA-AP providers. Finally,
the present study only assessed therapeutic alliance at
three timepoints, had a small sample (particularly
within the placebo condition), and was not designed
to establish a unique causal role of therapeutic alliance
or the effect of MDMA-AP on therapeutic alliance
itself. Given research suggesting that MDMA may
enhance feelings of closeness and alters processing of
physiological and behavioural responses to social
stimuli (Bedi et al., 2009; Bershad et al., 2019; Molla
et al., 2023; Schmid et al., 2014; Wardle & de Wit,
2014; Zeifman, Kettner et al., 2023), larger studies
that measure therapeutic alliance at each session
(including during MDMA sessions) will be important
for examining the effect of MDMA on therapeutic alli-
ance, differences with therapy that does not include
MDMA, and the potential causal role of therapeutic
alliance within MDMA-AP.
Acknowledgements
We thank MAPS for sharing these data, as well as the study
participants, coordinators, and therapists for their contri-
bution to this research.
Author contributions
MCM and ATM conducted the clinical trial. RJZ and
AW contributed the conceptualisation of the manu-
script. RJZ and HK conducted the statistical analyses.
RJZ wrote the original draft of the manuscript. All
authors reviewed and edited the manuscript.
Disclosure statement
No potential conflict of interest was reported by the author(s).
Funding
This work was supported by Canadian Institutes of Health
Research [grant number 202110MFE-472921-HTB-
272687]; MAPS Public Benefit Corporation.
Data availability statement
The data that support the findings of this study are available
from the sponsor (MAPS). However, restrictions apply to
the availability of these data, which were used under license
for the current study, and so are not publicly available. Data
are, however, available from the authors upon reasonable
request and with the permission of MAPS at http://maps.
org/datause. All requests for raw and analysed data are
promptly reviewed by the sponsor delegate and trial organ-
iser, MAPS PBC, to verify if the request is subject to any
confidentiality obligations. Patient-related data not included
in the paper were generated as part of clinical trials and may
be subject to patient confidentiality. Any data that can be
shared will be released via a data use agreement.
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