Evaluation of longer-term outcomes, though infrequently reported in the psychiatric literature, may contribute significantly to the understanding and treatment of chronic mental illnesses like PTSD and their associated morbidity and disability. For example, long-term follow-up (LTFU) studies could help to formulate treatment guidelines, permit evaluation of the rates of sustained symptom reduction or remission, predict the need for maintenance treatment, permit the assessment of long-term tolerability and help rule out a placebo response ( Price et al., 2008 ).

Prior to its placement into the most restrictive category of drug regulation in the US and internationally, uncontrolled published reports suggested that the substituted phenethylamine 3,4-methylenedioxymethamphetamine (MDMA), when administered in conjunction with psychotherapy, could yield substantial benefits for those afflicted with a variety of disorders ( Greer and Tolbert, 1986 ). When we published the first randomized controlled trial of MDMA-assisted psychotherapy, our results demonstrated that there were positive effects on PTSD symptom severity by the end of the treatment program ( Mithoefer et al., 2011 ).

Because of our protocol amendment permitting an additional MDMA-assisted session, 8 subjects received three MDMA sessions and 11 subjects received two MDMA sessions prior to LTFU participation. Analysis of this small, internal pilot comparing the effects of two versus three MDMA-assisted sessions demonstrated that there was no statistical evidence of a difference in the participant’s LTFU outcomes (CAPS: t independent = 0.2; df =14, p =0.83 and IES-R: t independent = 0.7; df = 14, p = 0.48). Based on this analysis, LTFU scores were compared to the CAPS and IES-R scores obtained two months from the second MDMA-assisted session (2-month scores). These 2-month scores were the final short-term outcome time-point reported in our initial study ( Mithoefer, 2011 ).

Study subjects were mailed the LTFU questionnaire and an IES-R, to complete and mail back. Also, they were contacted to schedule administration of the CAPS in person or via phone, administered by the same independent rater who had administered the CAPS to all subjects in the original study. Our participants also completed the NEO-PI-R personality inventory ( Costa and Macrae, 1992 ), but this NEO data will be presented in a separate publication, currently in preparation.

In conjunction with the questionnaire, subjects were informed in writing that the investigators had obtained a certificate of confidentiality, a document issued by the US Department of Health and Human Services in line with the National Institutes of Health Service Act, that protects research subjects from the legal consequences of providing investigators with sensitive information, such as information on past illegal drug use during the course of research ( Health and Human Services, 2011 ). The participants were not specifically instructed nor requested to abstain from the use of ecstasy or any other drugs after completing the original study.

We created the LTFU questionnaire for use in LTFU evaluations of MDMA-assisted psychotherapy. This questionnaire is designed to specifically capture the perceived benefit or harm of MDMA-assisted psychotherapy and changes in any areas not addressed by standard outcome measures, such as changes in relationships or creativity. The questionnaire measured the degree (with an ordinal scale of 1-Slight to 5-Large) and persistence (scale of 1-Small to 5-All) of the perceived benefits and/or harms of MDMA-assisted psychotherapy for PTSD. Additionally, the questionnaire included items addressing participant beliefs concerning the potential benefit of receiving an additional MDMA-assisted psychotherapy session, any psychiatric treatment after the study (whether psychotherapy or psychiatric medications), and their use of “ecstasy” (material represented as containing MDMA) and/or any other illicit psychoactive substances after study participation, plus any perceived changes in cognition after study participation. The participants were invited to write comments relating to their participation in the study. The full questionnaire is available online ( MAPS, 2009 ) as supplemental material.

The CAPS, as in the original trial, remained the primary outcome measure. The CAPS yields a global symptom severity score, as well as a categorical ranking as to whether or not a subject meets DSM-IV-R criteria ( American Psychiatric Association, 2000 ) for PTSD diagnosis ( Weathers et al., 2001 ). The IES-R ( Weiss and Marmar, 1996 ) is a global measure of psychological response to stress that we used as a secondary outcome measure.

There were three subjects who did not complete the measures: one moved and so was lost to follow-up after answering the LTFU questionnaire, but before completing the IES-R or scheduling administration of the CAPS; while the other two declined to repeat these two measures. Of the latter, one subject, who had previously shown the smallest reduction in CAPS score at the 2-month follow-up, was concerned that testing might trigger more symptoms and the other subject, who had responded well during the original study, declined to complete the measures again, citing stressful family matters as the reason for not devoting time nor attention to our current study.

All 20 subjects completed our LTFU questionnaire, and 17 (14 women/3 men, mean age at enrollment = 42.3 yrs) completed the Clinician-Administered PTSD Scale (CAPS) and Impact of Events Scale-Revised (IES-R) as well ( Figure 1 ). Because the purpose of our LTFU was to see if benefits from MDMA-assisted psychotherapy persisted over time, the data from the one subject who never received MDMA was excluded from the data analysis, but is reported below. Results focused on the 19 subjects (16 women/3 men, mean age at enrollment = 41.01) who received MDMA-assisted treatment, 16 of whom had also completed CAPS and IES-R measures.

At the end of this controlled study, the participants who had received the psychotherapy-only treatment were offered open-label MDMA-assisted psychotherapy, using the same schedule of sessions as were used in the controlled study protocol. Of the eight therapy-only subjects, seven accepted and completed the crossover arm of the study, which resulted in 19 of the 20 study subjects receiving the MDMA-assisted psychotherapy treatment. The one therapy-only subject had recovered from PTSD symptoms with psychotherapy alone, and did not participate in the crossover. As allowed by a protocol amendment, the last eight subjects recruited (five in the double-blind stage and three in the crossover stage) also received a third MDMA-assisted psychotherapy session. This protocol change was sought because of tentative clinical impressions by the investigators that a third session would likely enhance the processing of trauma and the integration process that were essential to the treatment.

In the initial study ( Mithoefer et al., 2011 ), 20 subjects with treatment-resistant PTSD (in most cases from sexual abuse or assault) were randomly assigned to psychotherapy with the active drug ( n = 12) or with an inactive placebo (psychotherapy-only; n = 8), each administered during two 8-hour sessions scheduled 3–5 weeks apart, accompanied by weekly non-drug sessions. The MDMA-assisted sessions were conducted in a comfor setting, in which participants were encouraged to spend considerable time focused inward without talking, alternated with time spent talking to the therapists. The therapists took a non-directive approach to supporting their subjects in processing trauma-related material. More information concerning the nature of the psychotherapy is found in the Mithoefer et al. (2011) study, as well as in the author’s treatment manual (MAPS, 2011).

The subject who had a good CAPS response to psychotherapy with placebo and did not choose to receive MDMA-assisted psychotherapy reported a 4 out of 5 benefit level and a 4 out of 5 persistence of benefit on the LTFU Questionnaire. This subject, in psychotherapy at both study entry and at LTFU, was on one psychiatric medication at entry and on three psychiatric medications at LTFU.

Of the 19 subjects who received MDMA-assisted psychotherapy, 15 wrote comments in the space provided on the questionnaire. Participants described the experimental treatment as being helpful, sometimes dramatically so (“The therapy made it possible for me to live”), but also as being difficult at times (“one of the toughest things I have ever done”). Several participants described it as a step in an “ongoing process” rather than simply a completed cure. Some comments shed light on the participants’ understanding of the way MDMA affected the therapeutic process (“It increased my ability to stay with and handle getting through emotions.” “The MDMA provided a dialogue with myself I am not often able to have, and there is the long-term effect of an increased sense of well-being.” “I was always too frightened to look below the sadness. The MDMA and the support allowed me to pull off the controls, and I … knew how and what and how fast or slow I needed to see my pain”). The full text of all comments is provided online, as supplementary material.

In the original study, by using pre/post neuropsychological measures, we empirically demonstrated that there is no cognitive morbidity associated with the use of MDMA ( Mithoefer et al., 2011 ). In this LTFU study, the participants subjectively reported either no change, or some improvement in their cognitive function, memory and concentration. None of the participants indicated that their “cognition (thinking), memory, or concentration” had worsened or decreased after study participation. Out of 19 participants, seven reported no change, while 13 reported improvements in these areas.

Cannabis was the most frequently mentioned drug ( n = 8), with reported frequency of use ranging from “once” to “occasionally” in the intervening months leading to LTFU. One participant reported having used psilocybin-containing mushrooms, but did not report the frequency. All subjects who were reporting use of these substances during the LTFU period had informed the investigators that they had also used them prior to enrollment in the original study, so these reports of use were not for new onset of use during the period leading up to LTFU. Only one participant, who had received two MDMA-assisted psychotherapy sessions, reported the subsequent use of “ecstasy” in a quasi-therapeutic setting, on a single occasion before the LTFU. Attempting a therapeutic setting similar to the study by asking a friend to be present during the session, the subject found the arrangement unsatisfactory and so reported no interest in repeating it outside a legal therapeutic context.

Study subjects had been treated with psychotherapy as a pre-condition to study participation. At the time of enrollment, 16 of 19 (84%) subjects were in active psychotherapy. At LTFU, only 8 of 19 (42%) were in psychotherapy. Two continued with the same psychotherapy they had been in at the start of the study, while five were receiving a different type of psychotherapy or psychotherapy from a different therapist. Only one participant not in psychotherapy just prior to the study was attending psychotherapy at LTFU. Cognitive behavioral psychotherapy ( n = 3) and Eye Movement Desensitization and Reprocessing (EMDR) ( n = 4) were the most common types of psychotherapy reported at LTFU. Other psychotherapies included psychodynamic ( n = 1) and Holotropic Breathwork ( Brewerton et al., 2011 ) ( n = 2).

The 16 LTFU CAPS completers reported a degree of benefit (median = 5 (maximum score possible); range = 3), similar to the degree of benefit reported by the three LTFU non-completers (median = 4; range = 3; independent Mann-Whitney U test, p = 0.58). Additionally, the 16 LTFU CAPS completers reported the same degree of persistence of benefit (median = 5; range = 3) as the three non-completers (median = 5, range = 3; independent Mann-Whitney U test, p = 0.18). These findings suggest that there were no significant differences between CAPS completers and non-completers in terms of the degree of and persistence of their benefits from the MDMA-assisted psychotherapy, reported at LTFU.

At LTFU, two subjects had CAPS scores above 50 (13%), which indicates relapse with moderate-to-severe PTSD symptoms, which is above the cut-off for original study entry. Using an intent-to-treat analysis, the three subjects who did not complete the CAPS were treated as negative outcomes, as were the two who relapsed. Thus, the intent-to-treat analysis produced 5 out of 19 (26%) PTSD subjects with negative outcomes, as compared to 2 out of 16 (13%) CAPS completers with negative outcomes.

Discussion

The evidence we report in this LTFU study, conducted on the average of nearly 3 ½ years after the prior study’s exit date, indicates that there was an enduring, clinically meaningful benefit from MDMA-assisted psychotherapy to PTSD patients.

The fact that 3 of the 19 subjects did not complete the CAPS and IES-R must be taken into consideration in interpreting these data. These three “CAPS non-completers” did complete the LTFU Questionnaire, where they reported nearly the degree of benefit and the same degree of persistence of benefit as those who had completed the CAPS. Therefore, it may be the case that up to 89% (17/19) of those who received MDMA had long-term improvement in their PTSD symptoms. However, these three “CAPS non-completers” should be assumed to have had higher CAPS scores than the others. An intent-to-treat analysis, that made the assumption that each of these three individuals had relapsed, concluded that 74% (14/19) of these previously treatment-resistant subjects demonstrated meaningful, sustained reductions in their CAPS scores at LTFU.

At LTFU, two of the subjects who completed the CAPS had relapsed, with CAPS scores above the cutoff (≥50) that was the original study entry criterion. In other long-term follow-up investigations of PTSD treatment (listed in the introduction), relapse rates range from 0.05–41%, so this rate is comparable (from a minimum of 11% of the CAPS completers to a maximum of 26%, in the intent-to-treat analysis).

The LTFU questionnaire we developed to assess the participants, while not a validated instrument, did shed light on several important points: the apparent lack of risk of substance abuse and of neurocognitive decline, coupled with symptom improvement and other perceived benefits.

Risk of substance abuse The data we obtained about illicit drug use from the LTFU Questionnaire supports the hypothesis 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. This is consistent with the comments from many study subjects, who expressed the strong opinion that the therapeutic setting and close follow-up were essential elements of the treatment, and they did not think MDMA should be used without this level of clinical monitoring and therapeutic support. Furthermore, no subject developed a substance abuse problem with any illicit drug after their MDMA-assisted psychotherapy. PTSD is associated with a high incidence of co-morbid substance abuse (Brown and Wolfe, 1994; Ford et al., 2007) and MDMA, as ecstasy (which is a material that may contain other substances in addition to or instead of MDMA), has a history of being a drug of abuse, so our findings were reassuring, though not unexpected: As it is the emotional distress of PTSD that often contributes to the use of intoxicants as an escape or an attempt at self-medication (Brady et al., 2000b), when that emotional distress is reduced, as it was with this experimental treatment, it follows that the subject’s motivation for drug abuse would be reduced, as well.

Symptom improvement and other benefits reported on our LTFU Questionnaire It is notable that no subjects reported any harm from study participation and all of them reported some degree of benefit. Consistent with the investigators‘ clinical observations in the original study, the responses we obtained on the questionnaire indicated that participants often experienced benefits beyond decreased PTSD symptoms. This is not a radical idea; many forms of psychotherapy produce benefits in terms of psychological growth and development that are not limited to improvements in a specific disorder that may have been the original target of therapy (Tedeschi and Calhoun, 2006; Zoellner and Maercker, 2006). Such benefits may prove to be a particularly prominent and valuable feature of MDMA-assisted psychotherapy. Some of the areas of benefit that were endorsed on the LTFU Questionnaire, such as an increased self-awareness, improved relationships, an enhanced spiritual life, and more involvement in the community or world, represent effects that are not fully measured by the PTSD symptom scales. A sustained improvement in PTSD symptoms documented on the CAPS, plus other benefits reported on the LTFU Questionnaire, have implications regarding one of the limitations of the previous study: the fact that the blinding turned out to be transparent to the investigators and to most of the participants (though not to the independent rater). This problem is inherent in all drug studies, but is particularly challenging to overcome in studies of MDMA-assisted psychotherapy, because of the prominent psychoactive effects MDMA has, as well as its effects on blood pressure and pulse rate. Observation of these effects may have contributed to the investigators’ ability to correctly distinguish MDMA-assisted sessions from therapy-only sessions (Bjorkedal and Flaten, 2011). In addition, any studies of drug-assisted psychotherapy (rather than of drug effect alone) present particular challenges in distinguishing the drug effects from the effects of psychotherapy with placebo. Nevertheless, if the placebo response is tied to receiving an apparent therapy, the favorable LTFU results we obtained a year or more later in this cohort of previously treatment-resistant subjects would suggest that the strength and duration of symptomatic improvement that we observed is not easily attributable to a placebo response or a spontaneous remission (Price et al., 2008; Benedetti and Amanzio, 2011), though further studies will be needed to establish this conclusively. Additional evidence of the positive MDMA treatment effects is apparent in the types of benefits endorsed by the subjects on the LTFU Questionnaire and its Comments section. While not a substitute for the validated primary outcome measures, this descriptive material provides us with an important context in which the outcome data can be evaluated and understood. The benefits endorsed and described extend beyond the realm of symptom reduction. Many subjects reported deeply meaningful therapeutic experiences and ensuing improvements in their lives. A majority of participants endorsed benefits such as, “increased self-awareness and understanding” and “enhanced spiritual life.” These responses and many of the individual comments on the Questionnaire point to a subjectively authentic process of psychological and spiritual exploration and growth that could logically be expected to facilitate trauma processing and symptom reduction, and to promote healthy psychological development. Improvements of this kind could reasonably be expected to persist for a year or more, as was endorsed by 80% of the subjects, and even to “last and continue to grow,” as endorsed by 40% of subjects. In addition, several participants wrote comments describing an incomplete but ongoing process of improvement, referring to an “ongoing journey” or having “gained tools” while “still struggling in many areas.” Since these comments were usually accompanied by persistently low CAPS scores, we believe that they represent additional evidence for a meaningful, ongoing, therapeutic process that was originally catalyzed by MDMA-assisted psychotherapy and is likely leading to important benefits in addition to PTSD symptom reduction. On the other hand, these comments could be taken to indicate a weakness in the treatment, as evidenced by continued psychological challenges; however, they more likely convey a strength of the treatment, in that it can enhance participants‘ capacity to engage more effectively in their own continued healing and growth.