Durability of improvement in post-traumatic stress disorder symptoms and absence of harmful effects or drug dependency after 3,4-methylenedioxymethamphetamine-assisted psychotherapy: a prospective long-term follow-up study

This study presents follow-up data (17-74 months; n=19) on a trial using MDMA-assisted psychotherapy to treat PTSD and found that most participants had maintained their therapeutic benefit over time (similar CAPS scores).


“We report follow-up data evaluating the long-term outcomes for the first completed trial of 3,4-methylenedioxymethamphetamine (MDMA)-assisted psychotherapy for chronic, treatment-resistant post-traumatic stress disorder (PTSD) (Mithoefer et al., 2011). All of the 19 subjects who received MDMA-assisted treatment in the original trial participated in the long-term follow-up (LTFU), with 16 out of 19 completing all of the long-term outcome measures, which were administered from 17 to 74 months after the original study’s final MDMA session (mean = 45.4; SD = 17.3). Our primary outcome measure used was the Clinician-Administered PTSD Scale (CAPS). Secondary outcome measures were the Impact of Events Scale-Revised (IES-R) and the Neuroticism Extroversion Openness Personality Inventory-Revised (NEO PI-R) Personality Inventory. We also collected a long-term follow-up questionnaire. Results for the 16 CAPS completers showed there were no statistical differences between mean CAPS score at LTFU (mean = 23.7; SD = 22.8) (tmatched = 0.1; df = 15, p = 0.91) and the mean CAPS score previously obtained at Study Exit (mean = 24.6, SD = 18.6). On average, subjects maintained statistically and clinically-significant gains in symptom relief, although two of these subjects did relapse. It was promising that we found the majority of these subjects with previously severe PTSD who were unresponsive to existing treatments had symptomatic relief provided by MDMA-assisted psychotherapy that persisted over time, with no subjects reporting harm from participation in the study.”

Authors: Michael C. Mithoefer, Mark T. Wagner, Ann T. Mithoefer, Lisa Jerome, Scott F. Martin, Berra Yazar-Klosinski, Yvonne Michel, Timothy D. Brewerton & Rick Doblin


This is a follow-up to Mithoefer and colleagues (2011) which describes the original study.



Post-traumatic Stress Disorder (PTSD) is a chronic, severely disabling condition causing sustained loss of functionality. Existing pharmacological and psychotherapeutic treatments for PTSD are effective for many, but not all sufferers.

Prior to its placement into the most restrictive category of drug regulation, uncontrolled published reports suggested that MDMA could yield substantial benefits for those afflicted with a variety of disorders.

We report follow-up data for the first completed trial of 3,4-methylenedioxymethamphetamine (MDMA)-assisted psychotherapy for chronic, treatment-resistant post-traumatic stress disorder (PTSD). The majority of subjects with previously severe PTSD who were unresponsive to existing treatments had symptomatic relief provided by MDMA-assisted psychotherapy that persisted over time.

MDMA is hypothesized to support and enhance psychotherapy by increasing the subject’s access to emotionally-upsetting material, modulating the associated level of arousal and strengthening the therapeutic alliance. It does this through a complex combination of pharmacological effects. Brain imaging studies show that MDMA administration reduces amygdala activity and changes the response to angry and happy facial expressions. These effects may combine to increase the effectiveness of psychotherapy for PTSD by increasing self-acceptance and promoting interpersonal trust with therapists.

Long-term follow-up studies may help to formulate treatment guidelines for chronic mental illnesses, predict the need for maintenance treatment, and assess long-term tolerability.

Studies of treatment effects for PTSD have ended within several months, but open-label studies have shown that treatment effects can be maintained for up to four years. This suggests that pharmacological agents can augment psychotherapy in the treatment of PTSD.


20 subjects with treatment-resistant PTSD were randomly assigned to receive MDMA-assisted psychotherapy for two 8-hour sessions, accompanied by weekly non-drug sessions. The therapists took a non-directive approach to supporting their subjects in processing trauma-related material.

At the end of the controlled study, all subjects who had received psychotherapy-only treatment were offered open-label MDMA-assisted psychotherapy. Seven of the eight therapy-only subjects accepted and completed the crossover arm of the study, and 19 of the 20 study subjects received the MDMA-assisted psychotherapy treatment.

All 20 subjects completed the LTFU questionnaire, and 17 completed the CAPS and IES-R measures. The data from the one subject who never received MDMA was excluded from the analysis.

Three subjects did not complete the measures: one moved, one was lost to follow-up, and two declined to repeat the measures.

We administered the CAPS and IES-R to participants 17–74 months after the final MDMA session, and completed a questionnaire 10–74 months after completion.

Outcome measures

The CAPS remained the primary outcome measure, and the IES-R was used as a secondary outcome measure.

We created the LTFU questionnaire to measure the perceived benefit and harm of MDMA-assisted psychotherapy for PTSD. It includes items addressing the potential benefit of receiving an additional MDMA-assisted psychotherapy session, any psychiatric treatment after the study, and cognition after study participation.

The investigators obtained a certificate of confidentiality from the US Department of Health and Human Services, and the subjects were not specifically instructed to abstain from ecstasy use after completing the original study.

Study design

The 2-month follow-up outcome scores were compared to the LTFU outcome scores to test the hypothesis that PTSD symptom improvement was sustained.

Participants were mailed a questionnaire and an IES-R, and were contacted to schedule administration of the CAPS. They also completed the NEO-PI-R personality inventory.

Analysis of the small, internal pilot study comparing two versus three MDMA-assisted sessions prior to LTFU participation demonstrated that there was no statistical evidence of a difference in the participant’s LTFU outcomes.


At LTFU, two subjects had CAPS scores above 50 (13%), which indicates relapse with moderate-to-severe PTSD symptoms. Using an intent-to-treat analysis, 5 out of 19 PTSD subjects had negative outcomes.

LTFU questionnaire results for 19 PTSD subjects

All participants reported some benefit from participation in the study, and all reported that the benefit persisted. There were no significant differences between CAPS completers and noncompleters in terms of the degree of and persistence of their benefits.

16 of 19 study subjects were in active psychotherapy at the time of enrollment, and 8 of 19 were in psychotherapy at LTFU. Two continued with the same psychotherapy, and five were receiving a different type of psychotherapy.

Cannabis was the most frequently mentioned drug, and one participant reported having used psilocybin-containing mushrooms, but did not report the frequency of use. All participants had used these substances prior to enrollment in the original study.

In the original study, participants reported no cognitive morbidity associated with the use of MDMA. In this study, participants subjectively reported either no change, or some improvement in their cognitive function, memory and concentration.

The comments of 15 participants who received MDMA-assisted psychotherapy are provided online as supplementary material. They describe the experimental treatment as being helpful, sometimes dramatically so, but also as being difficult at times.

One subject who did not receive MDMA reported a good CAPS response to psychotherapy with placebo and a 4 out of 5 persistence of benefit on the LTFU Questionnaire.


In this long-term follow-up study, 9 out of 19 patients who received MDMA had improvement in their PTSD symptoms. The three subjects who did not complete the CAPS and IES-R had similar improvement in their symptoms as those who did complete the LTFU Questionnaire.

Two out of 10 subjects who completed the CAPS had relapsed, which is comparable to other long-term follow-up investigations of PTSD treatment.

Risk of substance abuse

We found that MDMA can be administered in a clinical setting with minimal risk that the subjects will subsequently seek out and self-administer “street ecstasy” or become dependent on the drug. Furthermore, no subject developed a substance abuse problem with any illicit drug after their MDMA-assisted psychotherapy.

Risk of neurocognitive decline

The long-term self-reported evidence from the original study is consistent with findings from formal measures of cognitive function that were taken before and after psychotherapy with MDMA versus placebo, and with the most well-controlled studies of recreational ecstasy use and neurocognitive performance, which report largely negative findings.

Symptom improvement and other benefits reported on our LTFU Questionnaire

No subjects reported any harm from study participation, and all of them reported some degree of benefit. Participants often experienced benefits beyond decreased PTSD symptoms, which may be a particularly prominent and valuable feature of MDMA-assisted psychotherapy.

The sustained improvement in PTSD symptoms documented on the CAPS, plus other benefits reported on the LTFU Questionnaire, suggest that the improvement is not easily attributable to a placebo response or a spontaneous remission.

The subjects’ responses to the LTFU Questionnaire and Comments section provide additional evidence of the positive MDMA treatment effects.

Many subjects reported profoundly meaningful therapeutic experiences and ensuing improvements in their lives, which extended beyond the realm of symptom reduction. These improvements were accompanied by persistently low CAPS scores, which indicates that the treatment is likely to continue to promote healthy psychological development.


The study design had several limitations, including the fact that only 16 out of 19 subjects completed the LTFU CAPS or IES-R, and that there was no meaningful control group for the LTFU because all but one subject ultimately received active treatment in the initial study.

The long follow-up period allowed us to identify relapses that would not have been identified within a shorter follow-up period. However, the longer the time elapsed between the experimental intervention and follow-up, the more likely it is that life events will have intervened.

Although the use of psychotherapy and psychiatric drugs decreased at LTFU, it is impossible to know how much these treatments may have influenced the durability of benefits measured at LTFU. However, it is noteworthy that only participants with PTSD who had already proven resistant to prior therapy and medication were included.

There are several possible explanations for the substantial rates of continued psychotherapy and psychiatric medications at LTFU in subjects with persistently low CAPS scores, including the CAPS failing to capture some PTSD symptoms, the CAPS targeting another psychopathology, and medications being prescribed without an active Axis I disorder.

The authors are currently conducting a study with military veterans with PTSD to address the limitations of the blind and to capture more information about other possible beneficial effects.

Investigators have recently obtained approval for a new proof-of-principle study to determine if one additional open-label MDMA-assisted psychotherapy session can restore prior therapeutic gains in people who had responded well to MDMA-assisted psychotherapy initially, but had relapsed a year or more later.


We conceived this study over a decade ago to develop and test a novel therapy for PTSD. The results indicate that MDMA-assisted psychotherapy may become an important treatment option for this challenging clinical and public health problem.


Authors associated with this publication with profiles on Blossom

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

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.


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

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).

Linked Clinical Trial

A Test of MDMA-Assisted Psychotherapy in People With Posttraumatic Stress Disorder
This randomized, double-blind, placebo-controlled trial (n=23) assessed the safety and effectiveness of MDMA-assisted therapy among people with chronic, treatment-resistant PTSD, including veterans.

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