Journal of Psychiatric Research 149 (2022) 128–135

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Journal of Psychiatric Research

journal homepage: www.elsevier.com/locate/jpsychires

MDMA-assisted therapy significantly reduces eating disorder symptoms in a

randomized placebo-controlled trial of adults with severe PTSD
Timothy D. Brewerton a, *, Julie B. Wang b, Adele Lafrance c, Chelsea Pamplin b,
Michael Mithoefer a, b, Berra Yazar-Klosinki d, Amy Emerson b, Rick Doblin d
a
Department of Psychiatry and Behavioral Sciences, Medical University of South Carolina, Charleston, SC, 29425-0742, USA
b
MAPS Public Benefit Corporations, 3141 Stevens Creek Blvd #40547, San Jose, CA, 95117, USA
c
Department of Psychology, Laurentian University, 935 Ramsey Lake Road, Sudbury, ON, P3E 2C6, Canada
d
Multidisciplinary Association for Psychedelic Studies, 3141 Stevens Creek Blvd #40563, San Jose, CA, 95117, USA

A R T I C L E I N F O A B S T R A C T

Keywords: Introduction: Eating disorders (EDs) and posttraumatic stress disorder (PTSD) are highly comorbid, yet there are
PTSD no proven integrative treatment modalities for ED-PTSD. In clinical trials, MDMA-assisted therapy (MDMA-AT)
Eating disorders has shown marked success in the treatment of PTSD and may be promising for ED-PTSD.
MDMA-Assisted therapy
Methods: Ninety individuals with severe PTSD received treatment in a double-blind, placebo-controlled pivotal
EAT-26
Treatment
trial of MDMA-AT. In addition to the primary (Clinician-Administered PTSD Scale) and secondary (Sheehan
Disability Scale) outcome measures, the Eating Attitudes Test 26 (EAT-26) was administered for pre-specified
exploratory purposes at baseline and at study termination.
Results: The study sample consisted of 58 females (placebo = 31, MDMA = 27) and 31 males (placebo = 12,
MDMA = 19) (n = 89). Seven participants discontinued prior to study termination. At baseline, 13 (15%) of the
89 individuals with PTSD had total EAT-26 scores in the clinical range (≥20), and 28 (31.5%) had total EAT-26
scores in the high-risk range (≥11) despite the absence of active purging or low weight. In completers (n = 82),
there was a significant reduction in total EAT-26 scores in the total group of PTSD participants following MDMA-
AT versus placebo (p = .03). There were also significant reductions in total EAT-26 scores in women with high
EAT-26 scores ≥11 and ≥ 20 following MDMA-AT versus placebo (p = .0012 and p = .0478, respectively).
Conclusions: ED psychopathology is common in individuals with PTSD even in the absence of EDs with active
purging and low weight. MDMA-AT significantly reduced ED symptoms compared to therapy with placebo
among participants with severe PTSD. MDMA-AT for ED-PTSD appears promising and requires further study.

1. Introduction
Eating disorders (EDs) and posttraumatic stress disorder (PTSD) are
interrelated psychiatric disorders that are challenging in their own right
to individuals, families, and society at large (Deloitte Access Economics,
2020; Kaye and Bulik, 2021; Kessler, 2000; Streatfeild et al., 2021;
Walker et al., 2003; Watson, 2019). Both EDs and PTSD commonly occur
in the general population. The lifetime prevalence of EDs is reported as
8.4% for women and 2.2% for men, with higher rates being reported in
North and South America, while broad categories of EDs worldwide are
estimated to be 19.4% for women and 13.8% for men (Galmiche et al.,
2019). Lifetime PTSD rates in national samples of North America range
between 6.1% and 9.2%, with rates substantially higher in women
(10%–12%) than men (5%–6%), while one-year prevalence rates range
between 3.5% and 4.7% (Goldstein et al., 2016; Kessler et al., 2005; Olff,
2017; Resnick et al., 1993).
Significantly higher rates of PTSD or PTSD symptoms have been
associated with EDs and ED symptoms and vice versa (Dansky et al.,
1997; Ferrell et al., 2020; Hudson et al., 2007; Mitchell et al., 2012). EDs
and PTSD share several common risk factors that may contribute to their
co-occurrence, including female gender, history of personal and/or
family psychiatric disorder, history of child maltreatment or other prior
traumas, higher trauma dose and severity, personality factors, and lack
of social supports (Brewerton, 2018). Both EDs and PTSD have high
degrees of morbidity and mortality, including suicide and self-harm
(Arcelus et al., 2011; Fichter and Quadflieg, 2016; Gradus et al., 2010,

* Corresponding author.
E-mail address: drtimothybrewerton@gmail.com (T.D. Brewerton).

https://doi.org/10.1016/j.jpsychires.2022.03.008
Received 14 August 2021; Received in revised form 24 February 2022; Accepted 4 March 2022
Available online 5 March 2022
0022-3956/© 2022 The Authors. Published by Elsevier Ltd. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-
nc-nd/4.0/).
T.D. Brewerton et al.
2015; Himmerich et al., 2019; Lee et al., 2014; Mandelli et al., 2018;
Papadopoulos et al., 2009; Preti et al., 2011; Roberts et al., 2020; Smink
et al., 2012; Stein et al., 2010). Individuals with both disorders
(ED-PTSD) have significantly greater psychiatric and medical comor­
bidity, higher symptom severity, higher treatment dropout rates, worse
prognosis, and poorer quality of life (Brewerton, 2018; Brewerton et al.,
2020; Trottier, 2020). Novel integrated trauma-informed treatment
approaches are needed to address individuals with these overlapping
and challenging conditions (Brewerton, 2018; Brewerton et al., 2020;
Mitchell, K.S. et al., 2021; Trottier and MacDonald, 2017; Trottier et al.,
2016).
3,4-methylenedioxymethamphetamine (MDMA)-assisted therapy
has emerged as a highly efficacious integrated intervention for patients
with treatment resistant PTSD (Jerome et al., 2020; Mitchell, J.M. et al.,
2021; Mithoefer et al., 2019; Mithoefer et al., 2018; Sessa et al., 2019;
Wang et al., 2021). However, the use of this powerful modality has been
relatively unexplored in EDs, although it has been hypothesized to be a
promising intervention for ED-PTSD (Brewerton et al., 2021). The
rationale for this proposal, as well as its potential benefits and risks, span
neurobiological, psychological, and social perspectives, and have been
discussed in detail elsewhere (Brewerton et al., 2021).
The Eating Attitudes Test 26 (EAT-26) was assessed in a randomized
placebo-controlled trial of MDMA-AT for PTSD (Garner et al., 1982). We
hypothesized that 1) a substantial subset of research participants with
PTSD would demonstrate high scores on the EAT-26 indicative of sig­
nificant ED symptoms, despite not being currently underweight or
actively purging, and 2) MDMA-AT would significantly reduce EAT-26
scores in comparison to placebo-assisted therapy (PLAC-AT) in the
total group of participants with PTSD, especially in women. The primary
purpose of this study was to examine changes in EAT-26 scores in in­
dividuals with severe PTSD receiving MDMA-AT vs. PLAC-AT.
2. Methods
2.1. Study design
In the present study, exploratory data on ED psychopathology were
analyzed that were collected as part of a Phase 3 trial (trial ID:
NCT03537014), which was a double-blind randomized controlled study
that compared efficacy and safety of MDMA-AT between placebo and
MDMA groups for treatment of PTSD. The trial recruited participants
across fifteen study sites, which included both institutional sites and
private clinics, across the United States (n = 11), Canada (n = 2), and
Israel (n = 2). Ethics approval was obtained from the Copernicus Group
Independent Review Board, Western Institutional Review Board, Uni­
versity of British Columbia Providence Healthcare Research Ethics
Board, and the Helsinki Committees of Be’er Ya’akov Ness Ziona Mental
Health Center and Chaim Sheba Medical Center. Primary outcome re­
sults and detailed study methods of the Phase 3 trial are published
elsewhere (Mitchell, J.M. et al., 2021).
2.2. Participant recruitment
Study participants were recruited through advertisements, referrals
from treatment providers, and by word of mouth. After providing
written informed consent, participants were screened for eligibility such
that participants were ≥18 years old, met DSM-5 criteria for current
PTSD (with a symptom duration of 6 months or longer), were not
diagnosed with an ED with active purging using the Mini International
Neuropsychiatric Interview (M.I.N.I.) version 7.0.2 for DSM-5 (Sheehan
et al., 1998), and agreed to comply with lifestyle modifications including
a discontinuation of psychiatric medications. Participants with active
purging were excluded as a safety precaution to minimize cardiac ar­
rhythmias. The washout phase was defined as 5 half-lives plus one
additional week (Mitchell, J.M. et al., 2021). Concomitant medications
were assessed throughout the trial via urine drug screens. Any positive
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Journal of Psychiatric Research 149 (2022) 128–135
findings that could not be attributed to pre-approved concomitant
medications were reviewed by the medical monitor to assess compliance
with ongoing eligibility criteria and for possible adverse events. A
comprehensive list of study inclusion/exclusion criteria is published
elsewhere (Mitchell, J.M. et al., 2021). Can be found in the study pro­
tocol (http://maps.org/mapp1).
2.3. MDMA-AT vs. placebo intervention groups
Participants underwent three 8-h experimental sessions, which were
spaced approximately 4 weeks apart, of either MDMA-AT (80–180 mg
MDMA followed by a supplemental half-dose of 40–60 mg MDMA) or
inactive placebo with therapy (PLAC-AT). Experimental sessions were
preceded by a 10-h fast (to minimize nausea and/or vomiting), drug and
pregnancy screening, assessment of suicidality using the Adapted
Columbia-Suicide Severity Rating Scale (C-SSRS) (Posner et al., 2011),
and measurement of participants’ vital signs. In experimental sessions,
trained therapists supported participants’ intentions and therapeutic
goals by helping participants work through memories of traumatic
events, arrive at emotional resolution, and find new perspectives on the
meaning of those events. Participants were encouraged to welcome and
explore difficult emotions, and therapists guided participants to fully
explore, express, and understand their PTSD symptoms and how those
symptoms might have impacted their lives. Each experimental session
was followed by three 90-min follow-up session, spaced around 1 week
apart, which started the morning after the experimental session and
spanned the following 3–4 weeks. Follow-up sessions aimed to address
any difficult situations and help participants integrate lessons learned in
their therapy sessions into their daily lives. The therapist manual is
available at http://maps.org/treatment-manual.
2.4. Measures
EAT-26 was included as a pre-specified exploratory measure to assess
participants’ attitudes about eating and food in addition to the presence
of previously undetected EDs. EAT-26 assessments were collected at
baseline (visit 4) and study termination (visit 20) (Garfinkel and New­
man, 2001; Garner et al., 1982). This self-reported questionnaire con­
sists of 25 components, each rated on a six-point scale of 0 (Never) to 3
(Always), plus an additional component rated from 0 (Always) to 3
(Never). The 27th item addresses occurrence and frequency of specific
eating behaviors, such as binge eating. Scores were combined to produce
a total EAT-26 score, ranging from 0 to 78, with lower values indicating
fewer symptoms. Participants meeting a total cut-off score of 20 or
greater are considered likely candidates for having an ED diagnosis and
warrant referral to a qualified professional. Items on the EAT-26 have
high reliability coefficients (Cronbach’s α = 0.83–0.90) and have con­
current validity (Koslowsky et al., 1992). The EAT-26 has demonstrated
good test-retest reliability over 18–24 months (Dolan et al., 1992; Wood
et al., 1994). However, the extended test-retest reliability of the measure
remains uncertain in that scores are vulnerable to fluctuation over
longer testing periods of around 4 years (Nunes et al., 2005), possibly
due to natural changes in eating behavior over time. Lowering the
cut-off score to 11 has been shown to improve sensitivity rates in a wider
range of EDs such as binge eating disorder (BED) and eating disorder not
otherwise specified (EDNOS) (Orbitello et al., 2006).
In the Phase 3 trial, the primary outcome measure was the Clinician-
Administered PTSD Scale for DSM-5 (CAPS-5) to measure change in
PTSD symptoms. CAPS-5 is a 30-item semi-structured interview utilizing
DSM-5 symptomatology (Weathers et al., 2013) and was administered at
baseline (visit 3), during treatment (visits 8 and 13), and study termi­
nation (visit 19). Items 21 and 22 assess the onset and duration of the
disturbance and are rated 0 (no) or 1 (yes). Item 28 examines the global
improvement of the participant since the previous rating on a scale of
0 (participant now asymptomatic) to 5 (insufficient information pro­
vided). The remaining 27 items are rated on a scale of 0–4. Scores were
T.D. Brewerton et al.
combined to produce a PTSD total severity score ranging from 0 to 80,
with lower values indicating a better outcome. Severity scores ranging
from 23 to 34 are indicative of moderate PTSD, and scores of 35 or over
are indicative of severe PTSD. The CAPS-5 has demonstrated strong
test-retest reliability and internal consistency (Weathers et al., 2018). To
eliminate potential for unblinding of the data, the CAPS-5 assessment
was administered by blinded, independent raters. Further details on the
training and diagnostic concordance of the independent raters are
published elsewhere (Mitchell, J.M. et al., 2021).
Demographic variables included age, sex, gender, ethnicity/race,
education, body mass index (BMI), trauma history, and pre-study
treatment. Other baseline characteristics included the Adverse Child­
hood Experiences (ACE) (Felitti et al., 1998), Beck Depression Inventory
II (BDI-II) (Beck et al., 1996), and the Columbia-Suicide Severity Rating
Scale (C-SSRS) (Posner, 2007).
2.5. Statistical methods
Descriptive analyses were performed on demographic, baseline, and
outcome variables. Group means (SD) were compared using t-tests or
analyses of covariance (ANCOVA) and proportions were compared using
chi-square tests. Non-parametric tests were performed on samples with
non-normal distributions. T-tests were conducted to test within-subject
comparison of baseline and follow-up EAT-26 scores. ANCOVA
models, adjusting for baseline EAT-26 scores, compared between-group
EAT-26 change scores for MDMA and Placebo groups. Tests were
repeated in a series of subset analyses stratified by gender (women, men,
and non-binary), sex (female and male), and baseline EAT-26 cutoff
scores of ≥11 and ≥ 20. Subset analyses were performed to specifically
examine the effects of MDMA-AT on EAT-26 scores in those who were
the most symptomatic (total scores ≥20) and the most at ED risk (total
scores ≥11, women and women plus non-binary). Pearson correlation
coefficients were calculated to measure the linear relationship between
change in EAT-26 vs. change in CAPS-5 scores. Cohen’s d (for equal
samples) and Hedge’s g (for unequal samples) effect sizes were calcu­
lated for main findings with statistically significant between treatment
group differences. All analyses were conducted using SAS Version 9.4
(SAS Institute, Cary, North Carolina). To examine reliable change from
baseline to follow-up, Reliable Change Index (RCI) values were calcu­
lated for our analyses (Jacobson et al., 1984; Jacobson and Truax,
1991). To calculate the RCI, an internal consistency of α = .83
(Koslowsky et al., 1992) was used as the reliability of the EAT-26. RCI
values less than − 1.96 or greater than 1.96 are indicative of negative
and positive reliable change, respectively.
The Jacobson-Truax method was used to examine clinically mean­
ingful change. Given that normative data were not available for the EAT-
26 measure, criterion A was utilized such that a change was considered
clinically meaningful if the mean follow-up EAT-26 score was at least
two standard deviations above the mean baseline EAT-26 score
(Jacobson et al., 1984; Jacobson and Truax, 1991).
3. Results
3.1. Sample characteristics
Among a total of 90 participants who were randomized and received
treatment, 89 participants completed the EAT-26 assessment at baseline,
and seven participants withdrew from the study and were missing
follow-up data (3 MDMA, 4 placebo). A total of 82 of 90 participants
(91.1%) completed both baseline and follow-up EAT-26 assessments and
were included in the final analysis. This preliminary analysis of an
exploratory measure included only completers of both EAT-26 scores at
baseline and follow-up assessments to avoid imputation of data that
would attenuate the accuracy of results. Of the 89 initial participants, 15
(15.7%) met criteria for a current ED (binge eating disorder (BED): n =
5; other specified feeding and eating disorder (OSFED): n = 9), and 13
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Journal of Psychiatric Research 149 (2022) 128–135
others (14.6%) had a previous history of an ED (anorexia nervosa –
binge-purge type (AN-BP); bulimia nervosa (BN): n = 6; OSFED: n = 6).
The baseline sample consisted of participants who were majority female
(65.2%), identified as women (62.9%), non-Hispanic White or Latino
(89.9%), college graduates (70.8%), and the mean (SD) age was 41.0
(12.00) years. In total, 17 participants had been prescribed sertraline, of
which 8 and 9 were assigned to the MDMA and placebo treatment
groups, respectively. Furthermore, 6 participants had been prescribed
paroxetine, which were equally distributed between MDMA and placebo
treatment groups (3 and 3, respectively). At baseline, BMI (kg/m2)
scores were in the ‘normal’ range (BMI 18.5–24.9) in 56.2%, ‘over­
weight’ (BMI 25.0–29.9) in 28.1%, and ‘obese’ (BMI ≥30) in 15.7% of
participants. There were no treatment group differences in demographic
variables or baseline ACE, BDI-II, CAPS-5, or lifetime C-SSRS assess­
ments. Sample demographics and baseline characteristics are summa­
rized in Table 1. Mean BMI (SD) was 26.0 (4.8) kg/m2 in the MDMA-AT
group and 24.8 (4.2) kg/m2 in the PLAC-AT group (t = 1.3, p = .2).
3.2. Baseline EAT-26 scores
At baseline, 13 (15%) of the 89 participants starting the study had
EAT-26 scores ≥20, which is defined as within the “clinical” range
(Garfinkel and Newman, 2001; Garner et al., 1982), and 28 (31.5%) had
total EAT-26 scores ≥11, which has been defined as an “at risk” range
(Orbitello et al., 2006). Among the study completers (n = 82), 11
(13.4%) had baseline EAT-26 scores in the “clinical” range (≥20) and 24
(29.3%) had EAT-26 scores in the “at risk” range (≥11). Otherwise,
there were no significant differences in baseline EAT-26 scores between
the placebo and MDMA groups in study completers (see Table 2).
3.3. Change in EAT-26 scores
In the total sample, there was a significant treatment group differ­
ence in EAT-26 change scores between placebo and MDMA groups after
adjusting for baseline EAT-26 scores [F (2,79) = 4.68, p = .0335; Hed­
ge’s g = 0.33] (Table 2 & Fig. 1). The MDMA group had a statistically
significant within-subject mean (SD) reduction (improvement) in EAT-
26 scores of − 3.04 (6.24) from baseline to follow-up (p = .02), and
this reduction in EAT-26 scores was significantly greater compared to a
reduction of -.68 (8.04) in the placebo group. However, analysis of
reliable and clinically meaningful change in the total sample yielded RCI
values for placebo and MDMA groups that were not indicative of reliable
change (RCI = − 0.15 and − 0.84, respectively), nor were these changes
determined to be clinically meaningful.
A stratified analysis by gender indicated women in the MDMA group
(n = 22) had a statistically significant within-subject mean (SD) reduc­
tion in EAT-26 scores of − 4.50 (7.67) from baseline to follow-up (p =
.02). However, this change was determined to be not clinically mean­
ingful and yielded an RCI value of − 1.01 which was not indicative of
reliable change. In women, there were no statistically significant within-
subject differences in EAT-26 changes scores in the placebo group or
between treatment groups following treatment. In men, there were no
within-subject or between treatment group differences in EAT-26
change scores from baseline to follow-up.
Additional subset analyses indicated participants with greater base­
line EAT-26 scores generally had significantly greater improvement at
follow-up. Approximately 12 (30.0%) placebo and 12 (28.6%) MDMA
participants indicated having a baseline EAT-26 score ≥11; and 6
(15.0%) placebo and 5 (11.9%) MDMA participants had baseline EAT-
26 score ≥20. In the baseline EAT-26 ≥ 11 subset sample, the MDMA
group (women = 7, men = 4, non-binary = 1) had a statistically sig­
nificant within-subject mean (SD) reduction in EAT-26 scores of − 9.58
(7.59) (p = .0007), and this was significantly greater compared to a
reduction of − 3.58 (14.29) in the placebo group (women = 9, men = 3)
[F (2,21) = 9.45; p = .0058; Cohen’s d = 0.52]. Analysis of reliable and
clinically meaningful change in the EAT-26 ≥ 11 subset sample showed
T.D. Brewerton et al. Journal of Psychiatric Research 149 (2022) 128–135

Table 1 Table 1 (continued )

Demographics and baseline characteristics. Treatment Group
Treatment Group
Total Placebo MDMA
Total Placebo MDMA Sample
Sample
(N = 89) (N = 43) (N = 46) p-
(N = 89) (N = 43) (N = 46) p- value1,2
value1,2
Serious Suicidal 12.40 12.33 12.48 .8984
Age (years), mean (SD) 41.00 38.26 43.55 .0673 Ideation, mean (SD) (5.59) (5.893) (5.41)
(12.00) (10.47) (12.86) Suicidal Behavior 28 12 16 .4852
Sex, n (%) (yes), n (%) (31.46%) (27.91%) (34.78%)
Male 31 12 19
1Mean (SD) were compared using t-tests.
(34.83%) (27.91%) (41.30%)
Female 58 31 27 2Proportions (%) were compared using overall chi-square tests.
(65.17%) (72.09%) (58.70%) 3Abbreviations: ACE = Adverse Childhood Experiences; BDI-II = Beck Depres­
Gender sion Inventory II; CAPS-5 = Clinician Administered PTSD Scale for DSM-5; C-
Man 31 12 19 .1270 SSRS = Columbia-Suicide Severity Rating Scale.
(34.83%) (27.91%) (41.30%)
Woman 56 31 25
(62.92%) (72.09%) (54.35%)
that only the MDMA group yielded an RCI score indicative of reliable
Non-binary 2 (2.25%) 0 2 (4.35%) change (RCI = -2.16), compared to an RCI score of − 0.43 for the placebo
Ethnicity, n (%) group. However, neither group showed a clinically meaningful reduc­
Hispanic or Latino 8 (8.99%) 3 (6.98%) 5 (10.87%) .4842 tion in EAT-26 score. In women, the difference in change scores among
Not Hispanic or Latino 80 39 41
those with baseline EAT-26 ≥ 11 was statistically significant between
(89.89%) (90.70%) (89.13%)
Not reported 1 (1.12%) 1 (2.33%) 0 MDMA vs. placebo [F (2, 14) = 17.68; p = .0009; Hedge’s g = 0.63).
Race, n (%) Analysis of reliable and clinically meaningful change in women with
American Indian or 3 (3.35%) 0 3 (6.52%) .0667 EAT-26 ≥ 11 showed that the MDMA group produced an RCI score
Alaska Native
indicative of reliable change (RCI = -2.90), which was not seen in the
Asian 7 (8.05%) 5 2 (4.35%)
(12.20%)
placebo group (− 0.50). However, neither change was determined to be
Black or African 2 (2.30%) 2 (4.88%) 0 clinically meaningful.
American In the baseline EAT-26 ≥ 20 subset sample, there was a statistically
White 68 29 39 significant within-subject mean (SD) reduction in EAT-26 scores in both
(78.16%) (70.73%) (84.78%)
the placebo group (women = 6) (− 13.50, SD = 12.35; p = .01) and
More than one 7 (8.05%) 5 2 (4.35%)
(12.20%) MDMA group (women = 5, men = 1) (− 14.08, SD = 8.96; p = .0047);
Education, n (%) however, the treatment group difference was not statistically significant.
< High School 3 (3.37%) 0 3 (6.52%) .3163 Analysis of reliable and clinically meaningful change in the EAT-26 ≥ 20
High School Graduate 3 (3.37%) 1 (2.33%) 2 (4.35%) subset sample showed that only the MDMA group yielded an RCI score
Some College 20 11 9 (19.57%)
(22.47%) (25.58%)
indicative of reliable change (RCI = -2.83), compared to an RCI score of
College Graduate 30 17 13 − 1.85 for the placebo group. The reduction in EAT-26 score was
(33.71%) (39.53%) (28.26%) determined to be clinically meaningful for both MDMA and placebo
> College 33 14 19 groups. In women, the difference in change scores among those with
(37.08%) (32.56%) (41.30%)
baseline EAT-26 ≥ 20 was statistically significant between MDMA vs.
BMI (kg/m2), n (%)
Normal range 50 24 26 .4763 placebo [F (1, 7) = 5.75; p = .0478; Hedge’s g = 0.60). The change in
(18.5–24.9) (56.18%) (55.81%) (56.52%) EAT-26 score for women with baseline EAT-26 ≥ 20 from baseline to
Overweight (25.0–29.9) 25 14 11 follow-up was indicative of reliable change (RCI = -18.80) and was
(28.09%) (32.56%) (23.91%) determined to be clinically meaningful. Fig. 2 shows a significant dif­
Obese (≥30.0) 14 5 9 (19.57%)
(15.73%) (11.63%)
ference between those with EAT-26 ≥ 20 at baseline and follow-up
Trauma History, n (%) among placebo and MDMA groups. Specifically, in the placebo group,
Veteran status 16 6 10 .3392 the proportion of those with EAT-26 ≥ 20 did not change from baseline
(17.98%) (13.95%) (21.74%) to follow-up (n = 6, 15.0%); whereas in the MDMA group, the propor­
Served in combat area 11 6 5 (11.63%) .8393
tion of participants was reduced from 5 (11.90%) to 1 (2.38%).
(12.36%) (13.04%)
Developmental trauma 75 35 40 .4715 Two participants identified as non-binary which limited the gender
(84.27%) (81.40%) (86.96%) analysis and group comparisons. Both participants indicated their sex at
Multiple trauma (yes) 78 37 41 .6587 birth as female and were in the MDMA group. Additional analyses
(87.64%) (86.05%) (89.13%) stratified by sex (female = 53 and male = 29) found no marked differ­
Pre-study treatment, n (%)
Medications (Sertraline 20 10 10 .8640
ences in p-values, compared to the gender analysis, among females in
or Paroxetine) (22.47%) (23.26%) (21.874%) either the total sample (p = .0767) or the baseline EAT-26 ≥ 11 subset
Continuing therapy 52 26 26 .7060 sample (p = .0010). The redistribution of the two non-binary partici­
(58.43%) (60.47%) (56.52%) pants into the female category did not change the sample size in the
3
Baseline Measures
baseline EAT-26 ≥ 20 subset group.
ACE, mean (SD) 5.00 5.00 5.00 (2.71) 1.00
(2.79) (2.90) Change in EAT-26 scores were independent of change in CAPS-5
BDI-II, mean (SD) 32.53 34.70 30.50 .1282 PTSD total severity scores. There were no significant correlations be­
(12.98) (12.64) (13.11) tween change in CAPS-5 scores and change in EAT-26 scores in the
CAPS-5, mean (SD) 44.16 44.35 43.98 .7748 overall sample (r = 0.13, p = .26) or placebo (r = 0.06, p = .72), MDMA
(5.97) (6.17) (6.01)
C-SSRS, Lifetime
(r = 0.07, p = .67), baseline EAT-26 ≥ 11 (r = 0.31, p = .14), baseline
Suicidal Ideation, 3.00 3.00 3.00 (1.76) 1.00 EAT-26 ≥ 20 (r = 0.06, p = .86), women (r = 0.18, p = .21), men (r =
mean (SD) (1.64) (1.51) − 0.001, p = 1.00), and non-binary subsets (r = 1.00, p = n/a).

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T.D. Brewerton et al. Journal of Psychiatric Research 149 (2022) 128–135

Table 2
Mean (SD) EAT-26 scores for total sample of completers by gender and baseline EAT-26 cutoff scores by treatment group.
Placebo MDMAMDMA Between-group
Change

N Baseline Follow-up Change p- N Baseline Follow-up Change p- Effect p-

value1 value1 Size2 value3

Total Sample 40 9.28 (9.94) 8.60 (8.16) − 0.68 (8.04) .74 42 8.86 (7.06) 5.81 (4.80) − 3.04 (6.24) .0232 .33 .0335
Gender
Women 29 10.34 9.34 (9.00) − 1.00 (9.39) .71 22 10.77 6.27 (4.40) − 4.50 (7.67) .02194 .40 .07824
(11.21) (7.70)
Men 11 6.45 (4.68) 6.64 (5.14) 0.18 (2.09) .93 18 6.61 (5.41) 5.17 (5.09) − 1.44 (3.90) .4153 .48 .2063
Non-binary – – – – – 2 8.00 6.50 (9.19) − 1.50 (2.12) – – –
(11.31)
Baseline EAT-26
≥ 11 12 21.67 (9.80) 18.08 − 3.58 (14.29) .35 12 18.33 8.75 (6.18) − 9.58 (7.59) .0007 .52 .0058
(8.40) (5.71)
Women 9 24.78 (9.34) 20.00 − 4.78 (16.54) .2805 7 20.29 7.43 (4.96) − 12.86 .00135 .63 .00095
(8.80) (6.45) (7.60)
Men 3 12.33 (2.31) 12.33 0 (1.73) 1.00 4 15.50 10.00 − 5.50 (5.80) .2991 1.19 .0765
(3.51) (3.87) (8.87)
Non- – – – – – 1 16.00 13.00 − 3.00 – – –
binary – – –
≥ 20 6 30.17 (5.67) 16.67 − 13.50 .01 5 23.80 9.00 (7.65) − 14.80 .0047 .12 .0741
(8.48) (12.53) (2.77) (8.96)
Women 6 30.17 (5.67) 16.67 − 13.50 .0088 4 24.75 6.00 (4.24) − 18.75 .0005 .53 .0478
(8.48) (12.53) (3.59) (1.71)
Men – – – – – 1 20.00 21.00 1.00 – – –
– – –
Non- – – – – – – – – – – – –
binary

1Within-subjects t-tests comparing baseline and follow-up EAT-26 scores.

2Effect size: Cohen’s d = equal sample sizes/Hedge’s g = unequal sample sizes.
3Between-group ANCOVA comparing placebo vs. MDMA EAT-26 change scores adjusting for baseline EAT-26 scores.
4Two participants identified as non-binary indicated female sex at birth and were in the MDMA group. Analysis stratified by sex in the total sample: in females, change
in EAT-26 scores in the MDMA group (n = 24, p = .0257) and between-group (n = 53, p = .0767).
5Two participants identified as non-binary indicated female sex at birth and were in the MDMA group. Analysis stratified by sex in the baseline EAT-26 ≥ 11 subset: in
females, change in EAT-26 scores in the MDMA group (n = 9, p = .0010) and between-group (n = 17, p = .0009).

Fig. 1. Change in EAT-26 scores by treatment group.

3.4. Change in BMI 4. Discussion

In the subset of subjects with post-treatment BMI’s (n = 69), there
was no treatment group difference in BMI change scores at follow-up
(MDMA-AT: n = 39, 0.036 (1.59) kg/m2; PLAC-AT: n = 30, 0.305
(1.2) kg/m2, t = − 1.50, p = .4).
This exploratory analysis was the first to examine the effects of
MDMA-AT on ED symptomatology in individuals with severe PTSD
using data from a randomized placebo-controlled trial. Despite having
excluded participants who were underweight according to BMI param­
eters and who had current histories of an ED with active purging, 15.7%
met criteria for a current ED and another 16% had past histories of an
ED. We also found that a significant proportion of individuals endorsed

132
T.D. Brewerton et al.
Fig. 2. EAT-26 Scores 26 Scores by Treatment Groupores in the MDMA group.
ED symptoms using the EAT-26 in the “clinical” range (15%) as well as
in the “at-risk” range (31.5%). These results confirm previous reports
that EDs and ED symptoms are indeed associated with PTSD even in the
absence of active purging and/or low weight according to BMI param­
eters (Braun et al., 2019; Litwack et al., 2014; Mitchell et al., 2016;
Mitchell and Wolf, 2016).
Most importantly, our results demonstrated significantly reduced
symptoms of ED psychopathology following MDMA-AT versus PLAC-AT
in individuals with severe PTSD. There was an apparent gender effect in
that the reduction was primarily seen in women, who not only consisted
of 63% of the sample but are known to have higher rates of EDs and their
symptoms (Udo and Grilo, 2018). Although there was a significant
decrease in total EAT-26 scores in women following MDMA-AT and not
PLAC-AT the between-group change was only at a trend level. This may
have been due to reduced power associated with the low sample size in
the women only group. In addition, we found significantly reduced total
EAT-26 scores following MDMA-AT compared to PLAC-AT in the
“at-risk” group who had total EAT-26 scores ≥11 as well as a trend for
such an effect in the much smaller “clinical” group with total EAT-26
scores ≥20. Analysis of clinically meaningful and reliable change
showed that while both MDMA-AT and PLAC-AT produced clinically
meaningful change in participants with total EAT-26 scores ≥20, only
MDMA-AT was able to demonstrate reliable change in both the “at-risk”
(total EAT-26 score ≥11) and “clinical” (total EAT-26 score ≥20)
groups. Whether these positive effects of MDMA-AT would translate to
therapeutic effects in individuals with full syndromal EDs is unknown,
but these results support testing this hypothesis in controlled trials of ED
patients with and without PTSD. Our results also add to previous reports
that indicate the potential therapeutic benefits of other psychedelic
agents in individuals with EDs (Renelli et al., 2020; Spriggs et al., 2020).
The specific factors that account for the improvement in ED symp­
toms following MDMA-AT are unknown, although proposed mecha­
nisms have been reviewed in detail elsewhere (Brewerton et al., 2021).
These include the unique psychopharmacologic effects of MDMA-AT,
including its anxiolytic and prosocial effects, as well as facilitation of
socio-emotional processing (Kamilar-Britt and Bedi, 2015; Wardle and
de Wit, 2014), which is known to be disturbed in both EDs (Brockmeyer
et al., 2014, 2016; Harrison et al., 2012; Treasure et al., 2012) and PTSD
(Budden, 2009; Etkin and Wager, 2007; Stevens and Jovanovic, 2019).
MDMA-AT may exert its effects on ED symptoms by reducing PTSD
symptoms, although there were no significant correlations between re­
ductions in CAPS-5 scores and EAT-26 scores.
4.1. Strengths and limitations
Our study has several strengths, including its double-blind controlled
133
Journal of Psychiatric Research 149 (2022) 128–135
design, the use of validated, structured instruments for the diagnosis of
PTSD, and the use of a pre-specified reliable self-report measure of ED
psychopathology. A major limitation of this study was that full syn­
dromal EDs were not exclusively studied, so the generalizability of our
findings to the treatment of EDs is limited. The present study analyzed
only participants who completed baseline and follow-up EAT-26 as­
sessments to avoid imputation of missing data in a ITT sample but might
have also created other sample biases. Additionally, in the subset ana­
lyses, sample sizes were small and may have been inadequate to detect a
significant effect in men and non-binary individuals; the number of
women in the clinical range was also small. However, due to the small
sample size, additional analyses were performed to further examine
reliable and clinically meaningful change in EAT-26 scores. Another
limitation was that BMI was not obtained in all subjects post-treatment,
although there was no significant change in those that were measured.
However, MDMA was not expected to cause significant weight change
(Curran and Robjant, 2006). Overall, these results are promising and
studies of MDMA-AT in individuals with a primary aim of treating
DSM-5 EDs are warranted.
4.2. Conclusions
EDs and ED symptoms were common in individuals with PTSD even
in the absence of active purging and underweight status, which were
initially ruled out in this group of research subjects. MDMA-AT signifi­
cantly reduced ED symptoms compared to PLAC-AT in individuals with
severe PTSD. MDMA-AT for individuals with ED-PTSD comorbidity and
perhaps for those with EDs without PTSD shows potential and requires
study in future controlled trials. This trial provides preliminary evidence
to support efficacy and safety of MDMA-AT for treatment of ED-PTSD
with no active purging. A fully funded study (“A Multi-Site Study of
MDMA-Assisted Psychotherapy for Eating Disorders”) that will examine
the effects of MDMA in EDs is planned (NCT04454684).
Role of funding sources
The clinical trial was sponsored by the Multidisciplinary Association
for Psychedelic Studies (MAPS), a 501(c) (3) nonprofit organization.
MAPS provided the MDMA and fully funded this study from private and
foundation donations. MAPS Public Benefit Corporation (MAPS PBC), a
wholly owned subsidiary of MAPS, was the trial organizer.
Contributors
TB, AL, JW had full access to all the data in the study and take re­
sponsibility for the integrity of the data and for the accuracy of the data
analysis. BYK, AE, MM, RD, TB conceived and designed the study. MM
carried out supervision and training. AE carried out oversight of data
collection on behalf of the sponsor. TB, AL, JW, CP drafted the paper. JW
carried out statistical analysis and interpretation of data. RD obtained
funding for the study. All authors contributed to the critical review and
final version of the manuscript.
Declaration of competing interest
TB has been paid as a consultant for training by the MAPS Public
Benefit Corporation (MAPS PBC). AL and MM are paid as contractors by
MAPS PBC. AE, CP, and JW received salary support for full-time
employment with MAPS PBC. BYK and RD received salary support for
full-time employment with MAPS. MM is on the Clinical Advisory Board
of Awakn Life Sciences.
Acknowledgements
The authors would like to thank the candidates who were willing to
be screened for eligibility; the participants in the trial who contributed
T.D. Brewerton et al.
their data; the therapists, physicians, nurse practitioners, nurses, inde­
pendent raters, and study coordinators who generated these data; the
therapy trainers, clinical supervisors and adherence raters who helped
standardize the therapy, and MAPS staff and donors for fundraising and
financial support. The authors would also like to thank: J. Holland who
supported this trial as a Medical Monitor and Advisor; L. Jerome for her
numerous and varied contributions to this Clinical Development Pro­
gram since prior to its inception with global systematic literature re­
views and medical coding; C. Hennigan and Z. Goldberg for supporting
data management; L. Heimler for coordinating independent raters and
diagnostic assessments; S. Kleiman and K. Parker-Guilbert for training
and supervision of independent raters; S. Hamilton for leading statistical
design and analyses; G. Moore for statistical programming; A. Lilien­
stein, S. Garcia-Velazquez, and A. de Boer for medical oversight of the
trial; R. Matthews, C. Harrison, M. Brown, A. Nary, E. Shainer, P. Perl, E.
Gworek, A. McNamara, A. Schwind, M. Leighton, D. Iszak, H. Gilmore,
K.Miller, K. Brown, J. Lykke, and A. Long for clinical operations and
support; B. Ventimiglia for medical coding; A. Coker for regulatory af­
fairs support; J. Lindgren for ethics submission support and registration
of the trial; H. Clouting, K. Cohn, and B. Melton for ensuring manufac­
ture and supply chain of MDMA for the trial; J. Densmore and C. Friel for
randomization support; S. Carlin, S. Scheld, W. Hale, A. Garcia, B.
Crowell, J. Lin, L. Smith, G. Barrera, and G. Noble for designing, coor­
dinating, and supporting therapy training, supervision, and adherence
ratings, J. Poncini, C. Shelley, C. White, J. Alinovi, and M. Tromba for
designing, coordinating, and supporting video recording, and M. Boeger,
S. Pihl, and R. Alcocer for supporting SOPs and quality assurance.
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