Therapeutic effect of increased openness: investigating mechanism of action in MDMA-assisted psychotherapy

This follow-up study (n=20) finds that Openness (but not Neuroticism) plays a moderating role in the relationship between PTSD reduction following MDMA-assisted psychotherapy treatment as measured using the NEO Personality Inventory.


“A growing body of research suggests that traumatic events lead to persisting personality change characterized by increased neuroticism. Relevantly, enduring improvements in Post-Traumatic Stress Disorder (PTSD) symptoms have been found in response to 3,4-methylenedioxymethamphetamine (MDMA)-assisted psychotherapy. There is evidence that lasting changes in the personality feature of “openness” occur in response to hallucinogens, and that this may potentially act as a therapeutic mechanism of change. The present study investigated whether heightened Openness and decreased Neuroticism served as a mechanism of change within a randomized trial of MDMA-assisted psychotherapy for chronic, treatment-resistant PTSD. The Clinician-Administered PTSD Scale (CAPS) Global Scores and NEO PI-R Personality Inventory (NEO) Openness and Neuroticism Scales served as outcome measures. Results indicated that changes in Openness but not Neuroticism played a moderating role in the relationship between reduced PTSD symptoms and MDMA treatment. Following MDMA-assisted psychotherapy, increased Openness and decreased Neuroticism when comparing baseline personality traits with long-term follow-up traits also were found. These preliminary findings suggest that the effect of MDMA-assisted psychotherapy extends beyond specific PTSD symptomatology and fundamentally alters personality structure, resulting in long-term persisting personality change. Results are discussed in terms of possible mechanisms of psychotherapeutic change.”

Authors: Mark T. Wagner, Michael C. Mithoefer, Ann T. Mithoefer, Rebecca K. MacAulay, Lisa Jerome, Berra Yazar-Klosinski & Rick Doblin


This study is a follow-up analysis of data from Mithoefer and colleagues (2011) which describes the MDMA-assisted psychotherapy for PTSD study.

The original study was sponsored by MAPS.



The Diagnostic and Statistical Manual of Mental Disorders (DSM-III) provided a unified criteria for posttraumatic stress disorder (PTSD) that was largely unchallenged despite controversies. The concept of complex PTSD was introduced to capture the profound alterations in personality reported by a subset of individuals exposed to the most severe trauma.

World Health Organization (WHO) has classified enduring personality change following a catastrophic experience as “enduring personality change following a precipitating extreme stressor” (DSM-III PTSD). This diagnosis notes changes in personality including hostility, mistrust, withdrawal, feelings of emptiness, hopelessness, and estrangement.

A randomized trial of 3,4-methylenedioxymethamphetamine (MDMA)-assisted psychotherapy for chronic, treatment-resistant PTSD found that increased Openness and decreased Neuroticism served as a mechanism of change. This suggests that MDMA-assisted psychotherapy alters personality structure, resulting in long-term persisting personality change.

To our knowledge, no study has investigated change in personality associated with PTSD treatment response. However, there is evidence that certain personality features are linked to trauma experience, and higher Neuroticism scores are associated with a history of childhood sexual, physical, and emotional abuse.

In modern research, psilocybin can cause lasting beneficial change in personality with possible therapeutic implications. Subjects rated the experience positively as causing substantial insight about personal meaning and spiritual growth. The NEO PI-R was used to study the effect of psilocybin on five broad domains of personality, and the authors speculated that psilocybin could have a clinical application in treating anxiety and depression in cancer patients.

MDMA, a psychedelic compound, has been used in clinical trials as an adjunct, or enhancing agent, for therapeutic change in combination with psychotherapy for PTSD. The pharmacological mechanism of action is not well understood, but it may temporarily reduce avoidance, allowing patients to tolerate feelings associated with revisiting the trauma memory.

Psychological research suggests that MDMA increases prosocial feelings and behaviors and reduces negative mood when subjects are asked to think of a difficult memory. The present study theorized that MDMA treatment may reduce PTSD symptoms by broadening characteristics of the way an individual feels, thinks and interacts. The present study investigated whether personality changes were associated with PTSD symptom reduction. It also examined whether the personality changes would persist after the psychotherapy.


The current study analyzed changes in Openness and Neuroticism variables from the NEO PI-R to investigate the mechanism of action of MDMA-assisted psychotherapy. Twenty subjects were screened for PTSD, with a mean age of 40.4 years. All had a diagnosis of crime or war-related chronic PTSD and had a CAPS score of at least 50 following at least 3 months of prior SSRI or SNRI treatment.


The NEO PI-R is a 240-item, well-validated inventory of personality traits that was created through pooling hundreds of trait measures from self-report questionnaires, peer ratings, and other psychological indices.

The present study investigated the factors of Neuroticism and Openness, and found that individuals with high scores on the neuroticism facet are more prone to experience anxiety, anger, guilt, envy, or dysphoria.

NEO PI-R Openness is measured by subset scales that measure aspects of fantasy, aesthetics, feelings, actions, ideas, and values. Those who score high in Openness are liberal in political beliefs, imaginative, and sensitive.


All subjects were randomized to either the placebo or experimental condition, and 16 of the 20 subjects who initially received placebo participated in an open-label crossover condition. The results showed an enduring and clinically meaningful benefit from MDMA-assisted psychotherapy.

A male and female co-therapist team performed a therapeutic intervention with MDMA on 12 subjects. The intervention consisted of two introductory sessions, two experimental sessions, and up to four integration sessions after each experimental session.


All analyses were conducted using IBM SPSS Statistics Version 21.0. There were no significant differences between the control and experimental group for CAPS scores or trauma type at baseline.

Mixed-design repeated measure ANOVAs were used to examine the relationship between MDMA-assisted psychotherapy and PTSD symptoms. Next, between-group differences in personality change were examined using NEO PI-R Openness and Neuroticism scores.

Analyses 1: Group differences at baseline and 2-month follow-up

At baseline, 24 months, and LTFU visits, subjects did not differ in PTSD symptoms, but showed an enduring and clinically meaningful benefit from MDMA-assisted psychotherapy as measured by their significantly lowered CAPS scores.

When Openness and Neuroticism were included as covariates, there was a significant between-group effect of MDMA-assisted psychotherapy improvements in CAPS scores, but this effect was attenuated when Neuroticism was adjusted for in the model.

A mixed-design repeated measure test did not find a significant difference in Openness or Neuroticism between the MDMA group and the therapy only group at baseline or 2-month follow-up. However, a correlational analysis indicated that as Openness increased, Neuroticism decreased.

Analyses 2: Personality changes following crossover condition across groups at LTFU

MDMA-assisted psychotherapy results in long-term change in personality traits. There are significant differences in both Openness and Neuroticism when comparing baseline personality traits with long-term follow-up traits.


The present study extends previous findings on the effect of MDMA-assisted psychotherapy on PTSD symptoms by finding that MDMA treatment alters personality structure, resulting in long-term persisting personality change.

The present study indicates that increased openness may be a psychological mechanism by which MDMA exerts its therapeutic effects. Decreases in Neuroticism were also associated with PTSD symptom reduction.

In the literature, there have been mixed results regarding the study of personality change in the laboratory. Kipper et al. (2009) found that the psychopharmacological treatment of panic disorder did not change personality patterns, while Piedmont (2001) showed personality change after drug rehabilitation.

Several authors have argued that personality traits are biologically defined and reflect genetic vulnerability for depression. Lastly, Tang et al. (2009) tested whether patients taking an SSRI reported greater changes in neuroticism.

The overall trend for all subjects to have lower scores on neuroticism and higher scores on openness post-treatment was consistent with a therapeutic change in behaviors and cognitions associated with an epiphany-type experience.

To our knowledge, this is the first published report of the therapeutic use of MDMA associating with persisting personality change. Research suggests that epigenetic factors may be involved in personality change, and that early childhood adversity is associated with DNA methylation at the BDNF promotor region.

Although this study was intended to be a double-blind trial, many participants and therapists were able to correctly guess treatment conditions, which may have influenced expectancies about therapy. Nevertheless, significant group effects were found, and the treatment effect was maintained at 45.4 month follow-up.

MDMA-assisted psychotherapy can result in abrupt and lasting personality change, with subjects reporting a profound cathartic experience. This experience may be a catalyst for increased openness, reducing PTSD-related symptoms and associated negative neuroticism, and may prove to be a frontline treatment for those with “complex” PTSD.

Study details

Compounds studied

Topics studied

Study characteristics
Placebo-Controlled Double-Blind Randomized Follow-up

20 Humans


Authors associated with this publication with profiles on Blossom

Rick Doblin
Rick Doblin Ph.D. is the founder of MAPS. His persistent work since 1986 has been one of the main drivers behind why psychedelics (including MDMA) are now coming back to therapy.

Michael Mithoefer
Michael Mithoefer is a psychiatrist and a Clinical Investigator and acting Medical Director of MAPS Public Benefit Corporation.


Institutes associated with this publication

MAPS stands for Multidisciplinary Association for Psychedelic Studies, it's the front runner in making psychedelics a legal way to use (and improve) in therapy.

Compound Details

The psychedelics given at which dose and how many times

MDMA 125 mg | 2x

Linked Research Papers

Notable research papers that build on or are influenced by this paper

The safety and efficacy of ±3,4-methylenedioxymethamphetamine-assisted psychotherapy in subjects with chronic, treatment-resistant posttraumatic stress disorder: the first randomized controlled pilot study
This is the first placebo-controlled study (n=20) to shown the effectiveness of MDMA-assisted psychotherapy (MDMA-AT) in alleviating the symptoms of PTSD. Following two MDMA-AT sessions, 83% of participants in the active treatment group didn't qualify for PTSD anymore (CAPS score).

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