MDMA-assisted therapy significantly reduces eating disorder symptoms in a randomized placebo-controlled trial of adults with severe PTSD

This trial (n=90) used the Eating Attitudes Test (EAT-26) to assess the impact MDMA-assisted therapy has on symptoms of eating disorders (ED) in participants with PTSD. There was a significant reduction in total EAT-26 scores in the total group of PTSD participants following MDMA-AT versus placebo (p = .03). Overall, MDMA-AT significantly reduced ED symptoms compared to therapy with placebo among participants with severe PTSD.

Abstract

“Introduction: Eating disorders (EDs) and posttraumatic stress disorder (PTSD) are highly comorbid, yet there are no proven integrative treatment modalities for ED-PTSD. In clinical trials, MDMA-assisted therapy (MDMA-AT) has shown marked success in the treatment of PTSD and may be promising for ED-PTSD.

Methods: Ninety individuals with severe PTSD received treatment in a double-blind, placebo-controlled pivotal 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.“

Authors: Timothy D. Brewerton, Julie B. Wang, Adele Lafrance, Chelsea Pamplin, Michael Mithoefer, Berra Yazar-Klosinski, Amy Emerson & Rick Doblin

Summary

Ninety individuals with severe PTSD received treatment with MDMA-assisted therapy. The Eating Attitudes Test 26 was administered for exploratory purposes at baseline and at study termination. The results showed that individuals with PTSD have an increased risk of ED psychopathology even in the absence of active purging or low weight. MDMA-AT reduced ED symptoms compared to therapy with placebo among participants with severe PTSD.

The clinical trial was sponsored by the Multidisciplinary Association for Psychedelic Studies (MAPS) and was fully funded from private and foundation donations. TB, AL, JW, CP, AE, MM, RD, TB conceived and designed the study, MM carried out supervision and training, AE carried out oversight of data collection, JW carried out statistical analysis and interpretation of data. The authors would like to thank all the participants, therapists, physicians, nurse practitioners, nurses, independent raters, and study coordinators for their contributions, as well as MAPS staff and donors for fundraising and financial support.

A clinical development program was conducted to evaluate the safety and efficacy of MDMA. A number of people contributed to the development of the program, including Jerome, C. Hennigan, Z. Goldberg, L. Heimler, S. Kleiman, K. Parker-Guilbert, S. Hamilton, G. Moore, A. Lilienstein, A. de Boer, and R. Matthews.

In a double-blind, placebo-controlled pivotal trial of MDMA-assisted therapy for severe PTSD, ED psychopathology was significantly reduced compared to therapy with placebo among participants with severe PTSD. MDMA-AT for ED-PTSD appears promising and requires further study.

Eating disorders and posttraumatic stress disorder are interrelated psychiatric disorders that commonly occur in the general population. Higher rates of EDs and PTSD symptoms have been associated with each other, and vice versa. EDs and PTSD share several risk factors, 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. Individuals with both disorders have higher comorbidity and mortality. MDMA-assisted therapy has emerged as a highly efficacious integrated intervention for patients with treatment resistant PTSD, but the use of this powerful modality in EDs has been relatively unexplored. The Eating Attitudes Test 26 was assessed in a randomized placebo-controlled trial of MDMA-AT for PTSD. MDMA-AT significantly reduced EAT-26 scores in comparison to placebo-assisted therapy in women with PTSD.

In this study, exploratory data were analyzed on ED psychopathology that were collected as part of a Phase 3 trial. The trial recruited participants across fifteen study sites in the United States, Canada, and Israel. Participants were recruited through advertisements, referrals from treatment providers, and by word of mouth. They were required to provide written informed consent, meet DSM-5 criteria for current PTSD, and agree to comply with lifestyle modifications including a discontinuation of psychiatric medications.

Participants underwent three 8-hour experimental sessions of either MDMA-AT (80 – 180 mg MDMA followed by a supplemental half-dose of 40-60mg MDMA) or inactive placebo with therapy (PLAC-AT). Therapy sessions aimed to help participants work through memories of traumatic events, arrive at emotional resolution, and find new perspectives on the meaning of those events.

EAT-26 was used to assess participants’ attitudes about eating and food in addition to the presence of previously undetected EDs. Participants with a total cut-off score of 20 or greater were considered likely candidates for having an ED diagnosis. The EAT-26 has high reliability coefficients and concurrent validity, and has demonstrated good test-retest reliability over 18 to 24 months. However, the extended test-retest reliability of the measure remains uncertain. In the Phase 3 trial, participants completed the Clinician-Administered PTSD Scale for DSM-5 (CAPS-5) to measure change in PTSD symptoms. The score was combined to produce a PTSD total severity score ranging from 0 to 80.

The CAPS-5 was administered by blinded, independent raters, and scores ranging from 23 to 34 were indicative of moderate PTSD, and scores of 35 or over were indicative of severe PTSD. Statistical analyses were performed on demographic, baseline, and outcome variables. T-tests and ANCOVA models were used to compare between-group EAT-26 change scores for MDMA and Placebo groups, and Pearson correlation coefficients were calculated to measure the linear relationship between change in EAT-26 scores and change in CAPS-5 scores.

The Reliable Change Index (RCI) was calculated to examine reliable change from baseline to follow-up. A clinically meaningful change was considered if the mean follow-up EAT-26 score was at least two standard deviations above the mean baseline EAT-26 score. A total of 90 participants were randomized and received treatment, 82 completed both baseline and follow-up assessments, and 15 had a current eating disorder, 13 had a previous eating disorder, and the mean age was 41.0 (12.00) years. At baseline, 56.2% of participants were in the normal BMI range, 28.1% were overweight, and 15.7% were obese. There were no treatment group differences in demographic variables, or baseline assessments. Baseline EAT-26 scores were similar between placebo and MDMA groups, with 13.4% having clinical scores >20 and 28.3% having at risk scores >11.

After adjusting for baseline EAT-26 scores, the MDMA group had a statistically significant reduction in EAT-26 scores from baseline to follow-up.

The reduction in EAT-26 scores in the MDMA group was statistically significant compared to the placebo group, but the change was not clinically meaningful. Additionally, participants with greater baseline EAT-26 scores had significantly greater improvement at follow-up. The MDMA group had a statistically significant within-subject mean (SD) reduction in EAT-26 scores compared to the placebo group, and the MDMA group had a significantly greater reduction in reliable and clinically meaningful change.

The difference in change scores among those with baseline EAT-26 11 was statistically significant between MDMA vs. placebo, but neither group showed a clinically meaningful reduction in EAT-26 score. The change in EAT-26 score for women with baseline EAT-26 20 from baseline to follow-up was indicative of reliable change. Figure 2 shows that in the placebo group, the proportion of participants with EAT-26 -20 did not change from baseline to follow-up.

Two participants identified as non-binary, and the gender analysis and group comparisons were limited by this. There were no significant differences in p-values between females in either the total sample or the baseline EAT-26 11 subset sample, or between change in EAT-26 scores and change in CAPS-5 PTSD total severity scores. This exploratory analysis found that individuals with severe PTSD had a significant proportion of ED symptoms, both in the clinical range and in the at-risk range, even in the absence of active purging and/or low weight according to BMI parameters. The results demonstrated that individuals with severe PTSD experienced significantly reduced symptoms of ED psychopathology following MDMA-AT versus PLAC-AT. There was an apparent gender effect, with MDMA-AT producing a greater decrease in symptoms in women than PLAC-AT. MDMA-AT showed positive effects in patients with full syndromal EDs, and these results support testing this hypothesis in controlled trials.

The specific factors that account for the improvement in ED symptoms following MDMA-AT are unknown, although its anxiolytic and prosocial effects and facilitation of socio-emotional processing may contribute to its effects. This study has several strengths, including a double-blind controlled 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. However, the generalizability of its findings to the treatment of EDs is limited.

In this trial of individuals with severe PTSD, MDMA-AT significantly reduced ED symptoms compared to PLAC-AT. MDMA-AT shows potential for treatment of ED-PTSD with no active purging.

Trauma exposure, DSM-5 Posttraumatic Stress Disorder, and Binge Eating Symptoms are associated with greater eating disorder and comorbid symptom severity in residential eating disorder treatment centers. Difficulties in emotion regulation across the spectrum of eating disorders may contribute to these difficulties.

Budden, A., Curran, H.V., Robjant, K., 2020. The social and economic cost of eating disorders in the United States of America: A report for the Strategic Training Initiative for the Prevention of Eating Disorders and the Academy for Eating Disorders. Children who have experienced abuse or a dysfunctional household are at higher risk of developing eating disorders and posttraumatic stress disorder.

A systematic review of the prevalence of eating disorders over the 2000-2018 period was conducted by Galmiche, Dechelotte, Lambert, G., Tavolacci, M.P., and Garfinkel, P.E., Newman, A. Posttraumatic stress disorder, comorbidity, and mortality following diagnoses of severe stress and adjustment disorders: a nationwide cohort study. Harrison, A., Tchanturia, K., Naumann, U., Treasure, J., Himmerich, H., Hotopf, M., Shetty, H., Schmidt, U., Treasure, J., Chang, C.K.

Methods for reporting variability and evaluating clinical significance in behavior therapy research, a longitudinal pooled analysis of six phase 2 trials, a study on the prosocial effects of 3,4-methylenedioxymethamphetamine (MDMA), and a study on the prevalence, severity, and comorbidity of 12-month DSM-IV disorders.

Post-traumatic stress disorder and eating disorders: maintaining mechanisms and treatment targets. Orbitello, B., Ciano, R., Corsaro, M., Rocco, P.L., Taboga, C., Tonutti, L., Armellini, M., Balestrieri, M., 2016, MDMA-assisted psychotherapy for treatment of post-traumatic stress disorder in service personnel.

The Columbia-Suicide Severity Rating Scale, the Columbia Classification Algorithm of Suicide Assessment, and the Preti, A., Rocchi, M.B., Sisti, D., Camboni, M.V., Miotto, P., 2011 scales have been used to evaluate the risk of suicide in eating disorders. A representative national sample of women was interviewed about civilian trauma and posttraumatic stress disorder. The Mini-International Neuropsychiatric Interview (M.I.N.I.) was developed and validated for the DSM-IV and ICD-10 diagnostic manuals.

26 There are many studies on the topic of eating disorders, and they include: incidence, prevalence and mortality rates, positive effects of psychedelics on depression and wellbeing scores in individuals reporting an eating disorder, and a three-phase model of the social emotional functioning in eating disorders. Trottier, K., MacDonald, D.E., 2017. Psychological Trauma, Other Severe Adverse Experiences, and Eating Disorders: State of the Research and Future Research Directions.

27 Trottier, K., Wonderlich, S.A., Monson, C.M., Crosby, R.D., Olmsted, M.P., 2018. Investigating posttraumatic stress disorder as a psychological maintaining factor of eating disorders. Wardle, M.C., de Wit, H., Weathers, F.W., Blake, D.D., Schnurr, P.P., Kaloupek, D.G., Marx, B.P., Keane, T.M., 2018, The Clinician-Administered PTSD Scale for DSM-5 (CAPS-5), and Wood, A., 1994.

TB, AL, MM, AE, CP, JW, BYK, and RD have received payments from the MAPS Public Benefit Corporation.

Contributors: TB, AL, JW had full access to all the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis.