Introduction

There has been a resurgence of interest in the therapeutic potential of psychedelic substances such as tryptamines (e.g., psilocybin), ketamine, and phenethylamines (e.g., 3,4-methylenedioxymethamphetamine (MDMA)) [1, 2]. Based on its positive performance with significant and sustained reductions in PTSD symptoms and acceptable safety profiles, the FDA has designated MDMA-assisted therapy as a breakthrough therapy for PTSD. A pooled analysis of six Phase 2 trials showed that 54% of patients assigned to the MDMA-assisted therapy group no longer met criteria for PTSD after 2 experimental sessions [3]. Results of the first Phase 3 multisite study of MDMA-assisted therapy were published which confirmed the safety and efficacy of MDMA-assisted therapy in individuals with severe PTSD [4]. Compared to Therapy with placebo, MDMA-assisted therapy was found to induce significant attenuation in PTSD symptom severity scores (p < 0.0001, d = 0.91), suggesting a greater therapeutic effect of MDMA-assisted therapy over Therapy with placebo. The protocol for MDMA-assisted therapy consists of a 3-month long treatment with 3 dosing sessions, as well as 3 preparation and 9 integration therapy visits. All study participants received an equal, substantial dose of manualized therapy in addition to receiving either the MDMA or placebo. This provided us with an opportunity to explore the differential effects of therapy within MDMA-assisted therapy to gain a deeper understanding of the psychological change processes induced by this therapy.

Trauma-focused psychotherapy is considered a first line treatment for PTSD [5, 6]. However, the overall success rate with psychotherapeutic treatments for PTSD has been relatively disappointing. At least one-quarter of patients drop out of trauma-focused psychotherapy, and up to one-half are left with significant lingering symptoms [7–9]. Even patients who are considered responders often remain challenged by difficulties in emotion regulation, impulse control and interpersonal functioning [10–12], all of which seem to continue relatively independent from PTSD symptomatology [13, 14].

Many trauma survivors, particularly those with histories of child abuse (developmental trauma) have been shown to experience significant defects in a variety of transdiagnostic mental processes, including loss of a sense of safety, trust and self-worth, being unable to notice internal states (alexithymia), lack of a coherent sense of self, inability to modulate or tolerate distress, difficulties negotiating interpersonal conflicts and negative self-appraisals, such as shame, self-blame and low self-compassion [15, 16]. All of these have been shown to correlate with poor treatment outcome [17, 18].

Multiple studies have shown that reduced self-capacities interfere with successful completion of psychotherapy for PTSD [19, 20]. Difficulty with emotion regulation interfere with being able to disengage from trauma-related stimuli, which increases the probability of drop out due to an inability to manage distress arising during treatment [21]. Alexithymia, deficits in being able to identify and describe emotions, is associated with posttraumatic pathology [22–24], and with a lack of habituation to emotionally distressing stimuli [25]. Persons with high alexithymia scores have been shown to display low autonomic activity in response to any task performance, regardless of the level of emotional demand, including processing traumatic material [26].

Finally, self-compassion is a core component of overall mental health and well-being [27], often lacking in trauma survivors with PTSD who frequently experience self-loathing and self-blame [28, 29]. Low self-compassion scores are associated with anxiety, depression, narcissism, self-criticism, and with poor treatment responses [30].

MDMA’s effects on emotion regulation have been studied in healthy volunteers [31, 32]. These studies, have demonstrated a positive effect of MDMA on self-regulatory capacities and self-compassion. Higher levels of emotion-regulation and self-compassion have been shown to improve treatment results for a variety of psychological interventions [33, 34], which invites an exploration of the potential for MDMA in the treatment of PTSD. MDMA may differentially alter emotion recognition, depending on the emotional valence of the stimuli [35].

In the present study, we report results of three transdiagnostic outcome measures from a MDMA-assisted therapy Phase 3 trial that was designed to test treatment effects on PTSD symptoms and associated functional impairment. Specifically, we compared treatment effects on (1) alexithymia, (2) self-compassion, and (3) an inventory of altered self-capacities. Collectively, these measures characterized participants’ self-experience levels which is known to impact treatment outcomes. The primary aim of this analysis was to examine treatment effects on self-experience measures and whether improvements occurred independently of PTSD symptoms improvements. Further, we examined whether baseline self-experience levels were associated with change in PTSD symptoms and whether there were differences between treatment groups.

Methods

Study design

This paper assesses exploratory data from a randomized, double-blind, placebo-controlled study comparing safety and efficacy of MDMA-assisted therapy to Therapy with placebo in participants with severe PTSD [36]. Details such as recruitment and locations of the 15 sites are described in the primary outcome paper [4]. All participants, site staff, independent raters, and the sponsor were blind to participants group assignments until after database lock. All participants provided written informed consent at eligibility screening after ethics approval from local Institutional Review Boards.

Participants

All participants met DSM-5 criteria for current PTSD with a symptom duration of six months or greater and a Clinician-Administered PTSD Scale for DSM-5 (CAPS-5) total severity score of 35 or greater at baseline. Exclusion criteria included primary psychotic, bipolar I, dissociative identity, personality disorders, current alcohol and substance use disorders, and any medical condition for which an acute, transient increase in blood pressure or heart rate would pose a medical concern. Full eligibility criteria are described in the study protocol (https://clinicaltrials.gov/study/NCT03537014).

Intervention

Randomization was managed via an interactive web randomization system—ITClinical IWRS, version 11.0.1 (ITClinical, LDA)—based on a centralized randomization schedule developed by an independent third-party vendor to maintain blinding. All participants underwent three 90-minute preparation therapy sessions with a co-therapist dyad to establish therapeutic alliance and prepare for experimental sessions. The treatment period consisted of three 8-hour experimental sessions of either MDMA-assisted therapy or Therapy with placebo, with sessions spaced approximately four weeks apart [4].

In each experimental session, participants were given a split-dose of MDMA or placebo, with an initial dose followed by a half-dose 1.5 to 2.5 hours later. In the first experimental session the dose was 80 mg + 40 mg MDMA HCl, and in second and third experimental sessions, the dose was escalated to 120 mg + 60 mg MDMA HCl. Manualized therapy was conducted in accordance with MAPS MDMA-assisted therapy treatment manual (https://maps.org/2014/01/27/a-manual-for-mdma-assisted-therapy-in-the-treatment-of-ptsd/). Following each experimental session, participants underwent three 90-minute integration sessions, scheduled one week apart, to provide them with the opportunity to process their experiences.

Demographic and baseline variables

Age, gender, ethnicity, race, and education were compared between treatment groups. Other variables relevant to the transdiagnostic outcomes explored here, but not reported in this publication, included employment status, detailed trauma history, pre-study treatment, and baseline outcomes measures for the Adverse Childhood Experience Questionnaire (ACE) [37], Beck Depression Inventory II (BDI-II) [38], CAPS-5 total severity score [36], and lifetime suicidality assessment from the Columbia Suicide Severity Rating Scale (C-SSRS) [39].

Self-experience measures

The Inventory of Altered Self Capacities (IASC), is a standardized self-reported measure of an individual’s psychological functioning and has been frequently utilized in treatment outcome studies of PTSD [15, 40, 41]. It consists of 63 items to measure difficulties with relationships, identity, and emotion regulation, rated on a 5-point Likert scale ranging from 1 (“Never”) to 5 (“Very Often”). The IASC consists of 11 factors and sub-factors: Items for sub-factors are summed to calculate factor raw scores that range from 9 to 45 [42].

The Toronto Alexithymia Scale (TAS-20), is a well-validated 20-item measure of self-reported difficulties with recognizing and verbalizing emotions [43]. Responses are reported on a 5-point Likert scale ranging from 1 (“Strongly disagree”) to 5 (“Strongly agree”). The scale is comprised of three subscales: Difficulty Describing Feelings, Difficulty Identifying Feelings, and Externally-Oriented Thinking. Total scores diagnostically indicate no alexithymia (≥50), border-line alexithymia (51–60), and alexithymia (≥61) [22].

The Self-Compassion Scale (SCS) is a valid and theoretically coherent self-reported measure of self-compassion [44]. The SCS consists of 26 items to measure how respondents perceive their own failures, suffering, or inadequacies with kindness and compassion as a part of the common human experience. Respondents indicate how they often feel for each item on a 5-point Likert scale ranging from 1 (“Almost never”) to 5 (“Almost always”). The SCS consists of six subscales: Self-Kindness, Self-Judgement, Common Humanity, Isolation, Mindfulness, and Over-Identified, in which the sum of each subscale scores serves as the total score. A total score of 1–2.4 indicates “low,” 2.5–3.4 “moderate,” and 3.5–5.0 “high” SCS [45].

Independent raters conducted the PTSD primary outcome assessment, CAPS-5, prior to the first experimental session and at the primary endpoint Visit 19, approximately eight weeks after the final experimental session (18 weeks post-baseline). TAS-20, SCS, and IASC were self-reported at baseline, during the final preparation session (Visit 4), and again approximately 18 weeks later at study termination (Visit 20).

Statistical methods

Descriptive analyses were performed on demographic, baseline, and outcome variables. Group means (SD) were compared using t-tests or ANOVA/ ANCOVA and proportions were compared using chi-square tests. Shapiro Wilk W tests were performed to determine normality and non-parametric tests were performed on samples with non-normal distributions. Pearson’s correlations were conducted to examine linear relationships across variables. General Linear Models (GLM) were performed which allows to build a linear relationship between the response and predictors even when the underlying relationship is non-linear and therefore can be used to analyze non-normal data [46].

In the primary analysis, separate two-way ANCOVA models, adjusting for their respective baseline scores and CAPS-5 dissociative subtype (Yes = 1 and No = 0), compared treatment group differences in change scores for TAS-20, SCS, each IASC factor, and CAPS-5 (MDMA-assisted therapy vs. Therapy with placebo). Additional analyses were performed to also adjust for CAPS-5 change scores to assess potential independent effects of each self-experience measure on PTSD.

Separate analyses examined within-subjects differences at baseline and follow-up scores for MDMA-assisted therapy and Therapy with placebo groups. Sub-set analyses evaluated change scores stratified by baseline cutoff scores; specifically: (i) TAS-20 baseline measure of having no alexithymia (≤50) and alexithymia (>51) [47]; (ii) SCS baseline measure of low (1–2.4) and moderate (2.5–3.4) or high (3.5–5.0) self-compassion [48]; (iii) and for each IASC factor baseline scores for each factor above and below the sample median. For IASC factors, the sample median (vs. the mean) was used to account for any non-normal sample distributions and since the IASC lacks a validated composite score to define a clinical cutoff. Models tested interaction terms between treatment group (MDMA-assisted therapy vs. Therapy with placebo) and baseline categories (low vs. high TAS-20, SCS, or IASC factor) and where appropriate the main effects. All models adjusted for baseline scores and CAPS-5 dissociative subtype (Yes = 1 and No = 0). Tukey’s HSD test corrected for multiple comparisons and tables reported Least Square Means (LSMEANS) which adjusted for unequal sample sizes across group comparisons. All analyses were performed using SAS Version 9.4 (SAS Institute, Cary, North Carolina).

Results

Sample characteristics

The study sample consisted of 90 participants who were randomized and completed at least one experimental dosing session (MDMA-assisted therapy = 46, Therapy with placebo = 44; S1 Fig). Follow-up data for TAS-20, SCS, and IASC were missing for eight participants due to early study termination (discontinued due to COVID-19 = 3; declined further treatment = 4; restarted pre-study treatment = 1). All available data were used in the analysis (n = 82). In the present analysis, participants were majority women (53 of 82; 64.6%), White (65 of 81; 80.3%), non-Hispanic or Latino (76 of 82; 92.7%), college graduates (57 of 82; 69.5%) and, among 82 participants, the mean (SD) age was 41.42 (12.22) years. Sixty-nine of 82 participants (84.2%) had histories of developmental trauma (e.g., childhood physical/sexual abuse), and 74 of 82 participants (90.2%) had suffered multiple traumas. Only 4 out of 90 subjects in this study had an Adverse Childhood Experience (ACE) score of 0. Among the 8 participants with missing outcome data, no remarkable differences were observed with respect to treatment group (4 were in MDMA-assisted therapy and 4 Therapy with placebo) or sociodemographic characteristics although baseline CAPS-5 total severity scores were higher (n = 8; 46.75, SD = 6.63) compared to the modified Intent-to-treat (mITT) analysis set (n = 90; 44.1, SD = 6.04). There were no statistically significant group differences between MDMA-assisted therapy and Therapy with placebo groups across demographic and baseline variables. Detailed sample characteristics of the mITT analysis set of n = 90 participants have been described in the primary outcome paper [4].

Baseline means (SD) for the overall study sample were as follows: TAS-20, 54.33 (12.24); SCS, 2.28 (0.77); IASC interpersonal conflicts, 2.55 (0.96); idealization disillusionment, 2.13 (1.04); abandonment concerns, 2.49 (1.08); self-awareness, 3.09 (1.16); identity diffusion, 2.15 (1.13); susceptibility to influence, 1.97 (0.89); affect instability, 2.69 (1.17); affect skill deficit, 2.97 (1.20); and tension reduction activities, 1.87 (0.64). For each outcome measure, t-tests were performed and there were no baseline differences between treatment groups.

Treatment effects on self-experience measures

The MDMA-assisted therapy group, compared to the Therapy with placebo group, had statistically significant greater improvements for all self-experience measures except for IASC factor identity diffusion (Tables 1 and 2 and Figs 1–3). MDMA-assisted therapy, vs. Therapy with placebo, had greater improvements on alexithymia (Fig 1), self-compassion (Fig 2), and most IASC factors (Fig 3). These results suggest that MDMA had a strong effect on these measures of emotion regulation and self-experience, even after adjusting for potential covariates and correcting for multiple comparisons. Only results for SCS change scores were stable and statistically significant after also adjusting for CAPS-5 change score (unadjusted for CAPS-5 change, p < .0001; adjusted for CAPS-5 change, p = 0.0076) (Table 1).

Fig 1. Alexithymia change scores in MDMA-assisted therapy.

_{Least square means (SE) change in Toronto Alexithymia Scale (TAS-20) scores from baseline to follow up by treatment group: MDMA-assisted therapy = -12.06 (1.75) vs Therapy with placebo = -3.39 (1.57), p < .0001.}

Fig 2. Self-compassion change scores in MDMA-assisted therapy.

_{Least square means (SE) change in Self-compassion Scale (SCS) from baseline to follow-up by treatment group: MDMA-assisted therapy = 1.08 (0.13) vs. Therapy with placebo = 0.24 (0.12), p < .0001.}

Fig 3. Inventory of Altered Self-capacities (IASC) change scores

_{Least square means (SE) change from baseline to follow-up by MDMA-assisted therapy vs. Therapy with placebo: (i) “interpersonal conflicts” -0.69 (0.12) vs. -0.25 (0.11), p = .0027; (ii) “idealization disillusionment” -0.70 (0.12) vs. -0.31 (0.11), p = .0095; (iii) “abandonment concerns” -0.62 (0.14) vs. -0.23 (0.13), p = .0293; (iv) “identity impairment” -1.57 (0.25) vs. -0.66 (0.23), p = .0036; (v) “self-awareness” -0.96 (0.16) vs. -0.29 (0.14), p = .0010; (vi) “identity diffusion” -0.61 (0.12) vs. -0.36 (0.10), p = .0757; (vii) “susceptibility to influence” -0.55 (0.10) vs. -0.14 (0.09), p = .0012; (viii) “affect dysregulation” -1.75 (0.30) vs. -0.96 (0.27), p = .0349; (ix) “affect instability” -0.76 (0.15) vs. -0.40 (0.13), p = .0454; (x) “affect skill deficit” -0.98 (0.17) vs. -0.56 (0.15), p = .0424; (xi) “tension reduction activities” -0.42 (0.08) vs. -0.19 (0.07), p = .0206.}

Table 1. Change in self-experience scores by treatment group–interaction terms and main effects.

Table 2. Alexithymia, self-compassion, and altered self-capacities scores by treatment group and baseline self-experience levels.

Baseline self-experience measures & treatment effects on PTSD symptoms

Overall, MDMA-assisted therapy, compared to Therapy with placebo, had statistically significant greater improvement in all self-experience measures (Tables 3 and 4). Results showed a significant interaction between treatment x baseline TAS-20 subgroup levels to warrant further examination of CAPS-5 change scores by baseline levels. There was a greater reduction in CAPS-5 scores in the MDMA-assisted therapy group for those who had begun the trial with greater baseline alexithymia (-16.16; 95% CI: -28.80, -7.52) (Fig 4), and there were statistically significant differences between baseline subgroups in CAPS-5 change scores for (i) MDMA-assisted therapy/ low TAS-20 vs. Therapy with placebo/ high TAS-20 (p = 0.02) and (ii) MDMA-assisted therapy/ high TAS-20 vs. Therapy with placebo/ high TAS-20 (p < .0001) (all data not shown). Table 4 reports CAPS-5 change scores for all self-experience outcomes by baseline subgroup levels.

Fig 4. Significant differences in CAPS-5 total severity change scores between treatment groups by baseline self-experience levels.

_{Interaction between treatment and baseline alexithymia subgroup levels was statistically significant to warrant further stratification (p = 0.04); and stratified results also presented for self-compassion and IASC scores. At baseline, being (i) worse-off, having borderline alexithymia/ alexithymia or low self-compassion or (ii) better-off, lower idealization disillusionment, identity impairment, identity diffusion, or susceptibility to influence were associated with statistically significant greater CAPS-5 changes scores in the MDMA-assisted therapy group compared to Therapy with placebo, at alpha p ≤ .05 (*). For all other IASC factors, there were no differences in CAPS-5 change scores by baseline subgroup levels.}

Table 3. Change in CAPS-5 total severity change scores by treatment group–interaction terms and main effects.

Table 4. CAPS-5 PTSD total severity scores by treatment group and baseline self-experience levels.

Discussion

In this study, the MDMA-assisted therapy group compared to Therapy with placebo had greater improvements in all self-experience measures, except IASC factor identity diffusion, and higher baseline alexithymia was associated with greater improvements in PTSD. Only improvements in self-compassion occurred independently of PTSD change scores. The evidence suggests alexithymia and most IASC factors likely mediated the effects of MDMA-assisted therapy treatment on PTSD symptoms (Table 1). Additional analysis showed baseline alexithymia moderated treatment effects on PTSD symptoms, which warranted examination of CAPS-5 changes scores stratified by baseline TAS-20 subgroup levels (Table 3); and those with higher alexithymia scores (those worse off) at baseline had greater PTSD symptoms improvement (Table 4). Results of this exploratory analysis show both the potential influence of baseline self-experience and MDMA-assisted therapy on self-experience to impact PTSD symptoms, which can be used to guide clinical practice. Further, results found MDMA-assisted therapy improved self-compassion independent of PTSD treatment which warrants further investigation into potential new applications.

In non-PTSD studies MDMA has been shown to promote a general sense of interpersonal “connectedness” [49] “openness” [50, 51], and to enhance positive appraisal of favorable memories, while reducing negative evaluations of painful memories [51]. It also has been shown to enhance extinction of fearful memories, modulate memory reconsolidation (possibly through an oxytocin-dependent mechanism), and to promote social behavior [52]. Moreover, MDMA inhibits habitual fear responses to emotional threats [53]. These qualities are thought to facilitate being able to put the emotional sequelae of painful past experiences into a realistic perspective.

In this study, we examined the effects of MDMA on a group of individuals with major clinical deficits in domains that are associated with treatment resistance. Our findings suggest that the therapeutic benefits of MDMA may be most pertinent for persons with clinically significant impairment in emotion regulation and self-capacities.

The vast majority (84%) of traumatized individuals in this study reported having suffered chronic early childhood trauma, i.e. physical or sexual abuse by their caregivers. Only 4 out of 90 subjects in this study had an Adverse Childhood Experience (ACE) score of 0. Histories of child maltreatment are associated with poorer responses to psychotherapy in individuals diagnosed with PTSD [50, 54]. Abuse at the hands of one’s early caregivers has been shown to put individuals at risk for deficits in emotional coping skills /altered self-capacities, major obstacles to successful completion of currently available evidence-based treatments [50, 55].

Being able to emotionally process traumatic experiences is an important element of successful treatment [56, 57]. Identifying feelings, describing them and recognizing their triggers are thought to allow an individual to reflect on the situation and to respond appropriately to the context, rather than acting solely on their emotional arousal [58]. An inability to do so, as expressed in alexithymia, avoidance of distressing wishes, feelings or experiences, and trouble recalling distressing experiences, are associated with impaired affect regulation [23–25].

Alexithymia has frequently been observed in the context of invalidating or abusive early environments where children learn that communicating emotional experiences is inappropriate, ineffective, or potentially dangerous [59, 60]. Unable to escape physically from chronic abuse, alexithymic individuals are thought to have learned to disengage from both their external reality as well as their internal experiences [61].

Even though the MDMA-assisted therapy experimental sessions often occurred in relative silence as participants focus largely on their inner experience, MDMA-assisted therapy, but not Therapy with placebo, was associated with a significant improvement in emotional self-awareness and loss of alexithymia. This suggests that MDMA-assisted therapy can facilitate accessing painful memories and experiences that under ordinary conditions are too overwhelming and terrifying to confront, even in the presence of trained therapists.

Problems with emotion regulation (ER) influence both the development and the maintenance of PTSD symptoms after exposure to potentially traumatizing experiences [8, 62, 63], and predict both functional impairment and symptom complexity [50]. Adaptive emotion regulation is essential for effective treatment of PTSD: trauma-focused treatments for PTSD require both activation and modification of fearful memories. This activation depends on two processes: physiological reactivity to trauma-related stimuli and being able to tolerate the subjective distress generated by these traumatic memories [64]. Being able to tolerate physiological arousal to trauma-related stimuli predicts improvement in exposure treatment, supporting a gradual diminution in the distress experienced in response to trauma recall (habituation) within- and between-sessions [65].

Emotion regulation deficits are major contributors to the development of a large variety of psychopathological conditions [66], including interference with being able to resolve the impact of traumatizing experience(s) [67–70]. Whereas healthy, flexible ER capacities are key factors underlying well-being, ER difficulties comprise a transdiagnostic risk factor for mental health problems in general, including the development and/or maintenance of symptoms of PTSD [71], by interfering with being able to disengage from trauma-related stimuli and inhibiting maladaptive emotion regulation strategies [72].

Self-compassion is another core component of overall mental health and well-being. Individuals suffering from traumatic stress often suffer from shame, self-blame and self-loathing [28, 29]. Appraisals of mental defeat and permanent change have a profound and debilitating effect on an individual’s identity and sense of self [73]. Low self compassion scores have consistently been associated with symptoms such as anxiety, depression, narcissism, self criticism and avoidance [27, 30, 65]. Self-compassion has been shown to boost the efficacy of cognitive reappraisals [74]: Being caring and kind to oneself, rather than critical, even under stress, can mitigate the negative effects of trauma exposure by increasing resilience and by decreasing avoidance-oriented coping [75, 76]. Notably, in this study, improvement in self-compassion occurred independently of improvements in PTSD symptoms, which confirms previous studies that have demonstrated a powerful effect of MDMA-assisted therapy on self-compassion per se [77].

The finding that participants in the placebo condition, who received a total of 36 hours of therapy during the course of the study, had significantly less improvement in the dimensions of alexithymia and self compassion is interesting and deserves further research. After all, an important focus in psychotherapy is to help individuals to become more self aware and self-accepting. The therapists in this study were experienced clinicians with previous trainings in various trauma focused therapies, including the MAPS method. Yet, participants in the MDMA condition, who, in the presence of these supportive and validating therapists, spent three experimental sessions with an internal focus on deep emotional encounters with the residues of their traumatic past, developed significantly more self compassion and self-awareness than those who only received Therapy with placebo.

Recently, questions have been raised about the optimal way to ensure safety and support for vulnerable people engaged in a psychedelic induced encounter with past trauma [78]. The role and specifics of psychotherapeutic assistance during the administration of MDMA are important research questions that should be approached with great caution since visiting devastating traumatic experiences of one’s past can be very distressing and require a delicate therapeutic approach focused on careful attention to set and setting; over fifty years of clinical experience suggest that set and setting are critical in achieving positive outcomes in psychedelic therapies [79].

Summary

MDMA may be particularly effective for enhancing treatment efficacy by improving a range of problems with self-experience that are associated with treatment resistance. Assessment of self-capacities may be as relevant for treatment planning and outcome research as measuring PTSD severity, because, as this study suggests, therapy alone may not sufficiently compensate for the debilitating effects of deficient self-experience on being able to deal with traumatic material and thus, on treatment outcome.

Limitations

This study had a strict protocol of psychological intervention supplemented with history taking, debriefing and integration sessions. Several study participants expressed a desire for further MDMA-assisted therapy sessions beyond the study protocol, particularly individuals with chronic interpersonal trauma who experienced considerable distress around issues of abandonment and separation at study termination. Many subjects in this study had experienced trauma at the hands of their early caregivers, which raised major issues during the therapy sessions around trust and security of attachment relationships. This study did not measure the effect of MDMA-assisted therapy on trust and intimacy in interpersonal relationships. Many study participants experienced considerable somatic distress while accessing traumatic material during the MDMA sessions, which was not assessed, nor investigated further, but potential shifts in somatic self-experience are hypothesized to be of considerable interest for future MDMA-assisted therapy research.

This study was a secondary analysis of exploratory outcome measures and did not control for age and nature of trauma exposure and may not reflect an epidemiologically representative PTSD population. Some of this disparity can be attributed to a lower percentage of non-White participants seeking treatment [80], which warrants systematic changes to reduce cultural barriers to increase engagement in clinical research [81]. A total of 8 participants were missing follow-up data for TAS-20, SCS, and IASC. As stated in the results section, all available data were used; no imputations were carried out. We used sample medians to set cutoff scores for baseline IASC factors since there were no referenced categories from the published literature; and this binary threshold could have missed to capture any statistically significant results. More studies are needed to examine the capacity of MDMA to ameliorate post-traumatic symptomatology in a variety of trauma populations, including whether MDMA-assisted therapy is capable of permanently altering a host of psychological processes associated with having been traumatized, including shame, self-blame, the capacity for emotional intimacy, executive functioning and affect regulation.

Introduction

Increased attention has been given to the therapeutic potential of psychedelic substances, including psilocybin, ketamine, and MDMA (3,4-methylenedioxymethamphetamine). Due to its positive results in significantly and consistently reducing PTSD symptoms with an acceptable safety profile, MDMA-assisted therapy has been granted "breakthrough therapy" designation for PTSD by the Food and Drug Administration. Pooled analysis of six Phase 2 trials indicated that 54% of patients receiving MDMA-assisted therapy no longer met PTSD criteria after two experimental sessions. The initial Phase 3 multisite study further confirmed the safety and effectiveness of MDMA-assisted therapy for individuals with severe PTSD. Compared to therapy with placebo, MDMA-assisted therapy led to a significant decrease in PTSD symptom severity, indicating a greater therapeutic effect. The treatment protocol involves a three-month period with three dosing sessions, alongside three preparation and nine integration therapy visits. All participants received a consistent and substantial amount of structured therapy, allowing for an exploration of the unique effects of MDMA-assisted therapy on psychological change processes.

While trauma-focused psychotherapy is considered a primary treatment for PTSD, its overall success has often been modest. At least one-quarter of patients discontinue trauma-focused psychotherapy, and up to half still experience significant lingering symptoms. Even those who respond to treatment often struggle with emotion regulation, impulse control, and interpersonal functioning, issues that may persist independently of PTSD symptoms.

Many trauma survivors, particularly those with a history of childhood abuse, exhibit significant deficits in various mental processes relevant across different conditions. These include a diminished sense of safety, trust, and self-worth, difficulty recognizing internal states (alexithymia), a fragmented sense of self, inability to manage or tolerate distress, challenges in navigating interpersonal conflicts, and negative self-perceptions such as shame, self-blame, and low self-compassion. These difficulties have been correlated with less favorable treatment outcomes. Reduced self-capacities often hinder the successful completion of psychotherapy for PTSD. For example, difficulties with emotion regulation can prevent individuals from disengaging from trauma-related stimuli, increasing the likelihood of dropout due to an inability to manage distress during treatment. Alexithymia, characterized by difficulty identifying and describing emotions, is associated with posttraumatic pathology and a lack of habituation to emotionally distressing stimuli.

This study examined the effects of MDMA-assisted therapy on three broad outcome measures from a Phase 3 trial designed to assess treatment effects on PTSD symptoms and associated functional impairment. Specifically, the analysis compared treatment effects on (1) alexithymia, (2) self-compassion, and (3) an inventory of altered self-capacities. Collectively, these measures characterize participants’ self-experience levels, which are known to influence treatment outcomes. The primary aim was to investigate treatment effects on these self-experience measures and determine if improvements occurred independently of PTSD symptom improvements. Furthermore, the study explored whether baseline self-experience levels were associated with changes in PTSD symptoms and if there were differences between treatment groups.

Methods

Study design

This paper presents an analysis of exploratory data from a randomized, double-blind, placebo-controlled study that compared the safety and effectiveness of MDMA-assisted therapy to therapy with placebo in participants diagnosed with severe PTSD. Details regarding recruitment and the 15 study sites have been described in the primary outcome publication. All participants, site staff, independent raters, and the sponsor remained unaware of group assignments until after the study database was locked. All participants provided written informed consent after receiving ethics approval from local Institutional Review Boards.

Participants

All participants met the DSM-5 criteria for current PTSD with symptoms lasting six months or longer, and had a Clinician-Administered PTSD Scale for DSM-5 (CAPS-5) total severity score of 35 or greater at baseline. Exclusion criteria included primary psychotic, bipolar I, dissociative identity, or personality disorders, current alcohol and substance use disorders, and any medical condition where an acute, transient increase in blood pressure or heart rate would pose a health concern. Comprehensive eligibility criteria are outlined in the study protocol.

Intervention

Randomization was managed through an interactive web system, ITClinical IWRS, version 11.0.1 (ITClinical, LDA). This system was based on a centralized randomization schedule developed by an independent third-party vendor to maintain blinding. All participants underwent three 90-minute preparation therapy sessions with a pair of co-therapists to build a therapeutic relationship and prepare for experimental sessions. The treatment period involved three 8-hour experimental sessions, spaced approximately four weeks apart, administering either MDMA-assisted therapy or therapy with placebo.

In each experimental session, participants received a split dose of MDMA or placebo: an initial dose followed by a half-dose 1.5 to 2.5 hours later. For the first session, the dose was 80 mg + 40 mg MDMA HCl, and for the second and third sessions, it was escalated to 120 mg + 60 mg MDMA HCl. Manualized therapy was conducted according to the MAPS MDMA-assisted therapy treatment manual. Following each experimental session, participants attended three 90-minute integration sessions, scheduled one week apart, to process their experiences.

Demographic and baseline variables

Age, gender, ethnicity, race, and education were compared between treatment groups. Other variables relevant to the transdiagnostic outcomes explored, but not reported in this publication, included employment status, detailed trauma history, pre-study treatment, and baseline outcome measures for the Adverse Childhood Experience Questionnaire (ACE), Beck Depression Inventory II (BDI-II), CAPS-5 total severity score, and lifetime suicidality assessment from the Columbia Suicide Severity Rating Scale (C-SSRS).

Self-experience measures

The Inventory of Altered Self Capacities (IASC) is a standardized self-reported measure of an individual’s psychological functioning, frequently used in PTSD treatment outcome studies. It comprises 63 items assessing difficulties with relationships, identity, and emotion regulation, rated on a 5-point Likert scale. The IASC includes 11 factors and sub-factors, with raw scores for factors ranging from 9 to 45.

The Toronto Alexithymia Scale (TAS-20) is a well-validated 20-item self-report measure of difficulties recognizing and verbalizing emotions. Responses are on a 5-point Likert scale. The scale has three subscales: Difficulty Describing Feelings, Difficulty Identifying Feelings, and Externally-Oriented Thinking. Total scores indicate no alexithymia (≤50), borderline alexithymia (51–60), and alexithymia (≥61).

The Self-Compassion Scale (SCS) is a valid and theoretically consistent self-reported measure of self-compassion. The SCS has 26 items that assess how respondents view their own failures, suffering, or inadequacies with kindness and compassion as part of the common human experience. Respondents indicate how often they feel each item on a 5-point Likert scale. The SCS consists of six subscales, with their sum forming the total score. A total score of 1–2.4 indicates “low,” 2.5–3.4 “moderate,” and 3.5–5.0 “high” SCS.

Independent raters conducted the CAPS-5, the primary PTSD outcome assessment, before the first experimental session and at the primary endpoint (approximately eight weeks after the final experimental session, 18 weeks post-baseline). TAS-20, SCS, and IASC were self-reported at baseline, during the final preparation session, and again approximately 18 weeks later at study termination.

Statistical methods

Descriptive analyses were performed on demographic, baseline, and outcome variables. Group means and standard deviations were compared using t-tests or ANOVA/ANCOVA, and proportions were compared using chi-square tests. Shapiro Wilk W tests assessed normality, with non-parametric tests applied to non-normal distributions. Pearson’s correlations examined linear relationships. General Linear Models (GLM) were used to analyze data, including non-normal data, by building linear relationships between responses and predictors even if the underlying relationship was non-linear.

In the primary analysis, separate two-way ANCOVA models, adjusted for baseline scores and CAPS-5 dissociative subtype, compared treatment group differences in change scores for TAS-20, SCS, each IASC factor, and CAPS-5 (MDMA-assisted therapy vs. therapy with placebo). Additional analyses were performed, also adjusting for CAPS-5 change scores, to assess potential independent effects of each self-experience measure on PTSD.

Separate analyses examined within-subject differences at baseline and follow-up scores for both MDMA-assisted therapy and therapy with placebo groups. Sub-set analyses evaluated change scores stratified by baseline cutoff scores: (i) TAS-20 baseline measures of no alexithymia (≤50) and alexithymia (>51); (ii) SCS baseline measures of low (1–2.4) and moderate (2.5–3.4) or high (3.5–5.0) self-compassion; and (iii) for each IASC factor, baseline scores above and below the sample median. For IASC factors, the sample median was used due to potential non-normal sample distributions and the lack of a validated clinical cutoff for a composite score. Models tested interaction terms between treatment group and baseline categories, and, where appropriate, main effects. All models adjusted for baseline scores and CAPS-5 dissociative subtype. Tukey’s HSD test corrected for multiple comparisons, and tables reported Least Square Means (LSMEANS), adjusted for unequal sample sizes across group comparisons. All analyses were conducted using SAS Version 9.4.

Results

Sample characteristics

The study sample included 90 participants who were randomized and completed at least one experimental dosing session (46 in MDMA-assisted therapy, 44 in therapy with placebo). Follow-up data for TAS-20, SCS, and IASC were unavailable for eight participants due to early study termination. All available data (n = 82) were used in the analysis. Of these, participants were predominantly women (64.6%), White (80.3%), non-Hispanic or Latino (92.7%), and college graduates (69.5%), with a mean age of 41.42 years. A large majority (84.2%) had a history of developmental trauma (e.g., childhood physical/sexual abuse), and 90.2% had experienced multiple traumas. Only 4 out of 90 subjects had an Adverse Childhood Experience (ACE) score of 0. No significant differences were observed between treatment groups regarding demographic and baseline variables. The baseline means for the overall sample were: TAS-20, 54.33 (SD = 12.24); SCS, 2.28 (SD = 0.77); and various IASC factors. No baseline differences between treatment groups were found for any outcome measure.

Treatment effects on self-experience measures

The MDMA-assisted therapy group demonstrated statistically significant greater improvements across nearly all self-experience measures compared to the therapy with placebo group, with the exception of the IASC factor identity diffusion. MDMA-assisted therapy showed greater improvements in alexithymia, self-compassion, and most IASC factors. These findings suggest a strong effect of MDMA on emotion regulation and self-experience, even after adjusting for covariates and correcting for multiple comparisons. Only the improvements in SCS change scores remained statistically significant after also adjusting for CAPS-5 change scores.

Baseline self-experience measures & treatment effects on PTSD symptoms

Overall, MDMA-assisted therapy led to statistically significant greater improvements in all self-experience measures compared to therapy with placebo. Results indicated a significant interaction between treatment and baseline TAS-20 subgroup levels, warranting further examination of CAPS-5 change scores by baseline levels. A greater reduction in CAPS-5 scores was observed in the MDMA-assisted therapy group for those who began the trial with greater baseline alexithymia. Statistically significant differences in CAPS-5 change scores were also found between specific baseline subgroups.

Discussion

In this study, the MDMA-assisted therapy group showed greater improvements across almost all self-experience measures compared to therapy with placebo. Importantly, higher baseline alexithymia was associated with greater improvements in PTSD symptoms within the MDMA-assisted therapy group. While improvements in self-compassion occurred independently of PTSD symptom changes, the evidence suggests that alexithymia and most IASC factors likely mediated the effects of MDMA-assisted therapy on PTSD symptoms. Further analysis indicated that baseline alexithymia moderated treatment effects on PTSD symptoms, with those having higher alexithymia scores at baseline showing greater PTSD symptom improvement. These exploratory findings highlight the potential influence of both baseline self-experience and MDMA-assisted therapy on self-experience to impact PTSD symptoms, offering guidance for clinical practice. The independent improvement in self-compassion with MDMA-assisted therapy also suggests potential for new applications and warrants further investigation.

These findings align with previous studies showing MDMA's ability to promote interpersonal "connectedness," "openness," and to enhance positive appraisal of favorable memories while reducing negative evaluations of painful ones. MDMA has also been shown to facilitate the extinction of fearful memories, modulate memory reconsolidation, and inhibit habitual fear responses. These qualities are believed to help individuals contextualize the emotional aftermath of painful past experiences. The study's examination of MDMA's effects on individuals with significant clinical deficits, often associated with treatment resistance, suggests that MDMA’s therapeutic benefits may be most relevant for those with substantial impairment in emotion regulation and self-capacities. A large majority of the traumatized individuals in this study (84%) reported chronic early childhood trauma, such as physical or sexual abuse by caregivers, with very few having no adverse childhood experiences. Histories of child maltreatment are known to be associated with poorer responses to psychotherapy in individuals with PTSD, and such abuse can lead to deficits in emotional coping skills and altered self-capacities, which are major obstacles to successful completion of currently available evidence-based treatments.

Being able to emotionally process traumatic experiences is crucial for successful treatment. Identifying and describing feelings and recognizing their triggers can enable individuals to reflect on situations and respond appropriately, rather than solely reacting to emotional arousal. An inability to do so, as seen in alexithymia and avoidance of distressing experiences, is associated with impaired affect regulation. Even though the MDMA-assisted therapy experimental sessions often involved participants focusing on their inner experience in relative silence, MDMA-assisted therapy, unlike therapy with placebo, led to significant improvement in emotional self-awareness and a reduction in alexithymia. This indicates that MDMA-assisted therapy can facilitate access to painful memories and experiences that would otherwise be too overwhelming to confront, even with trained therapists. Furthermore, self-compassion is a vital component of overall mental health and well-being, often lacking in trauma survivors with PTSD who frequently experience shame, self-blame, and self-loathing. Low self-compassion scores are consistently linked to anxiety, depression, narcissism, self-criticism, and poor treatment responses. Notably, in this study, improvement in self-compassion occurred independently of improvements in PTSD symptoms, confirming prior studies that have shown a powerful effect of MDMA-assisted therapy on self-compassion itself. The observation that participants in the placebo condition, who received substantial therapy, had significantly less improvement in alexithymia and self-compassion warrants further research, particularly given that psychotherapy typically aims to foster self-awareness and self-acceptance.

Questions have been raised about the optimal way to ensure safety and support for vulnerable individuals undergoing a psychedelic-induced encounter with past trauma. The specific role and details of psychotherapeutic assistance during MDMA administration are important research questions that require caution, as confronting devastating traumatic experiences can be highly distressing and necessitates a delicate therapeutic approach centered on careful attention to "set and setting." Decades of clinical experience suggest that these elements are critical for achieving positive outcomes in psychedelic therapies.

Summary

MDMA may be particularly effective in enhancing treatment efficacy by ameliorating a range of self-experience problems linked to treatment resistance. Assessing self-capacities may be as important for treatment planning and outcome research as measuring PTSD severity. This study suggests that therapy alone might not sufficiently compensate for the debilitating effects of deficient self-experience on processing traumatic material and, consequently, on treatment outcomes.

Limitations

This study operated under a strict protocol for psychological intervention, complemented by history taking, debriefing, and integration sessions. Some participants expressed a desire for additional MDMA-assisted therapy sessions beyond the study protocol, especially individuals with chronic interpersonal trauma who experienced considerable distress related to abandonment and separation at study termination. Many subjects in this study had experienced trauma from early caregivers, which raised significant issues during therapy sessions concerning trust and attachment security. This study did not measure the effect of MDMA-assisted therapy on trust and intimacy in interpersonal relationships. Many participants experienced significant physical distress while accessing traumatic material during MDMA sessions; this was not assessed or further investigated, although potential shifts in somatic self-experience are hypothesized to be of considerable interest for future MDMA-assisted therapy research.

This study was a secondary analysis of exploratory outcome measures and did not control for age and nature of trauma exposure, and thus may not represent an epidemiologically typical PTSD population. Some of this disparity can be attributed to a lower percentage of non-White participants seeking treatment, highlighting the need for systematic changes to reduce cultural barriers and increase engagement in clinical research. Follow-up data for TAS-20, SCS, and IASC were missing for eight participants. All available data were used, and no imputations were carried out. Sample medians were used to set cutoff scores for baseline IASC factors due to the absence of referenced categories in published literature, and this binary threshold may not have captured all statistically significant results. More studies are needed to examine MDMA's capacity to alleviate post-traumatic symptomatology across diverse trauma populations, including whether MDMA-assisted therapy can permanently alter various psychological processes associated with having experienced trauma, such as shame, self-blame, the capacity for emotional intimacy, executive functioning, and affect regulation.

Introduction

Recent years have shown a renewed interest in the therapeutic potential of psychedelic substances, including compounds like psilocybin, ketamine, and MDMA. The U.S. Food and Drug Administration (FDA) has recognized MDMA-assisted therapy as a breakthrough treatment for Post-Traumatic Stress Disorder (PTSD) due to its promising results in significantly reducing PTSD symptoms and its acceptable safety profile. Analysis of several early-phase trials indicated that many participants undergoing MDMA-assisted therapy no longer met the criteria for PTSD after just two treatment sessions. The first large-scale study further confirmed the safety and effectiveness of MDMA-assisted therapy for individuals with severe PTSD, showing a notable reduction in symptom severity compared to therapy with a placebo.

The standard protocol for MDMA-assisted therapy involves a three-month treatment period, featuring three dosing sessions alongside three preparation and nine integration therapy visits. All study participants received a substantial and equal amount of structured therapy, whether they received MDMA or a placebo. This design allowed researchers to investigate the distinct effects of therapy within the MDMA-assisted framework and better understand the psychological changes it induces.

Traditional trauma-focused psychotherapy is a primary treatment for PTSD, but its overall success rates have been somewhat limited. A significant portion of patients discontinue treatment, and many others continue to experience substantial symptoms. Even those who respond to therapy often struggle with challenges in emotion regulation, impulse control, and interpersonal relationships, which can persist independently of their PTSD symptoms.

Many individuals who have experienced trauma, especially childhood abuse, often show difficulties in several key mental processes. These include a diminished sense of safety, trust, and self-worth, an inability to recognize internal states (alexithymia), a fragmented sense of self, difficulty managing distress, challenges in interpersonal conflict, and negative self-perceptions like shame and self-blame. These issues have been linked to poorer treatment outcomes. Difficulties with emotion regulation can prevent individuals from disengaging from trauma-related thoughts, potentially leading to treatment dropout due to overwhelming distress. Alexithymia, or difficulty identifying and describing emotions, is also linked to post-traumatic pathology and a reduced ability to habituate to distressing emotional stimuli.

Self-compassion is a vital element of mental health and well-being, yet it is often lacking in trauma survivors with PTSD, who frequently experience self-loathing and self-blame. Low self-compassion is associated with anxiety, depression, self-criticism, and poor responses to treatment. Studies have shown MDMA can positively affect self-regulatory abilities and self-compassion in healthy individuals. Given that improved emotion regulation and self-compassion enhance the effectiveness of various psychological interventions, there is a strong rationale for exploring MDMA’s potential in PTSD treatment. MDMA may specifically alter how individuals recognize emotions, depending on whether those emotions are positive or negative.

The current study reports findings from three key "transdiagnostic" outcome measures collected during a Phase 3 trial of MDMA-assisted therapy for PTSD. These measures assessed alexithymia, self-compassion, and an inventory of altered self-capacities. These measures collectively describe a participant’s "self-experience," which is known to influence treatment outcomes. The primary goal of this analysis was to determine how MDMA-assisted therapy affected these self-experience measures and whether improvements occurred independently of changes in PTSD symptoms. Researchers also explored whether initial self-experience levels at the start of the study were related to changes in PTSD symptoms and if there were differences between the treatment groups.

Methods

Study design

This paper presents an analysis of exploratory data from a randomized, double-blind, placebo-controlled study. The study compared the safety and effectiveness of MDMA-assisted therapy to therapy with a placebo in individuals diagnosed with severe PTSD. Recruitment and site locations were consistent with the primary study. All participants, site staff, independent evaluators, and the study sponsor were unaware of the participants' group assignments until after data collection was complete. All participants provided informed consent after receiving approval from local ethics committees.

Participants

All participants met the diagnostic criteria for current PTSD with symptoms lasting at least six months and a certain level of severity on a standardized PTSD scale at the start of the study. Exclusion criteria included other severe mental health conditions like psychotic disorders, bipolar I disorder, dissociative identity disorder, certain personality disorders, current alcohol and substance use disorders, and any medical condition where a temporary increase in blood pressure or heart rate would pose a health risk.

Intervention

Participant randomization was managed by an independent system to maintain blinding. All participants first completed three 90-minute preparation therapy sessions with two co-therapists. These sessions aimed to build a trusting relationship and prepare for the experimental sessions. The treatment period included three 8-hour experimental sessions, where participants received either MDMA-assisted therapy or therapy with a placebo. These sessions were spaced about four weeks apart.

During each experimental session, participants received a split dose of MDMA or placebo. An initial dose was followed by a half-dose approximately 1.5 to 2.5 hours later. The first session used a lower dose of MDMA, which was increased for the second and third sessions. Therapy was administered according to a specific manual for MDMA-assisted therapy. After each experimental session, participants attended three 90-minute integration sessions, held one week apart, to process their experiences.

Demographic and baseline variables

Age, gender, ethnicity, race, and education levels were compared between the treatment groups. Other relevant variables examined, though not detailed in this publication, included employment status, a comprehensive trauma history, previous treatments, and baseline scores on standard measures for adverse childhood experiences, depression, PTSD severity, and lifetime suicidality.

Self-experience measures

The Inventory of Altered Self Capacities (IASC) is a self-report measure used to assess an individual’s psychological functioning and has often been included in PTSD treatment outcome studies. It contains items that measure difficulties in relationships, identity, and emotion regulation, with responses rated on a scale from "Never" to "Very Often." The IASC is structured into multiple factors and sub-factors.

The Toronto Alexithymia Scale (TAS-20) is a widely recognized 20-item self-report measure of difficulties in recognizing and articulating emotions. Responses range from "Strongly disagree" to "Strongly agree." The scale includes subscales for difficulty describing feelings, difficulty identifying feelings, and externally-oriented thinking. Total scores can indicate no alexithymia, borderline alexithymia, or full alexithymia.

The Self-Compassion Scale (SCS) is a valid and theoretically sound self-report measure of self-compassion. It consists of 26 items that gauge how individuals respond to their own failures, suffering, or inadequacies with kindness and compassion, viewing these experiences as part of the common human experience. Respondents indicate how often they feel each item on a scale from "Almost never" to "Almost always." The SCS has six subscales, whose sum forms the total score, indicating low, moderate, or high self-compassion.

Independent evaluators administered the primary PTSD outcome assessment, the CAPS-5, before the first experimental session and again at a later follow-up, approximately eight weeks after the final experimental session. The TAS-20, SCS, and IASC were self-reported at the start of the study, during the final preparation session, and again approximately 18 weeks later at the study’s conclusion.

Statistical methods

Researchers performed descriptive analyses of demographic, baseline, and outcome variables. Group averages were compared using statistical tests, and proportions were compared using chi-square tests. Tests for normality were conducted, and non-parametric tests were used for data that did not follow a normal distribution. Correlations were calculated to examine linear relationships between variables. General Linear Models (GLM) were used to analyze relationships between responses and predictors, even for non-normal data.

In the primary analysis, separate statistical models were used to compare treatment group differences in changes for TAS-20, SCS, each IASC factor, and CAPS-5. These models adjusted for baseline scores and the presence of a dissociative PTSD subtype. Additional analyses also adjusted for changes in CAPS-5 scores to assess whether improvements in each self-experience measure occurred independently of PTSD symptom improvements.

Further analyses examined differences within groups between baseline and follow-up scores for both the MDMA-assisted therapy and placebo groups. Subset analyses evaluated changes in scores based on baseline categories for alexithymia, self-compassion, and each IASC factor (using sample medians as cutoff scores for IASC factors). Models tested for interactions between treatment group and baseline categories. All models adjusted for baseline scores and dissociative PTSD subtype. Corrections were applied for multiple comparisons to ensure robust findings.

Results

Sample characteristics

The study included 90 participants who were randomly assigned and completed at least one experimental dosing session. Follow-up data for the self-experience measures were unavailable for a small number of participants due to early study termination for various reasons. All available data were utilized in the analysis. The majority of participants were women, White, non-Hispanic or Latino, and college graduates. The average age was approximately 41 years. Most participants had histories of developmental trauma, such as childhood physical or sexual abuse, and had experienced multiple traumas. Only a very small number of participants had no adverse childhood experiences. There were no significant differences in demographic characteristics or baseline measures between the MDMA-assisted therapy and placebo groups.

Baseline average scores for the overall study sample showed levels consistent with the targeted population, including a borderline average score for alexithymia and a low average for self-compassion. No significant baseline differences were observed between treatment groups for any outcome measure.

Treatment effects on self-experience measures

Compared to the placebo group, the MDMA-assisted therapy group showed significantly greater improvements across almost all self-experience measures, including alexithymia, self-compassion, and most factors of the Inventory of Altered Self-Capacities (IASC). These results suggest that MDMA had a strong positive effect on these aspects of emotion regulation and self-experience, even after accounting for other factors. Only improvements in self-compassion remained statistically significant after also adjusting for changes in PTSD symptom scores.

Baseline self-experience measures & treatment effects on PTSD symptoms

Overall, MDMA-assisted therapy led to greater improvements in all self-experience measures compared to therapy with placebo. Results indicated a significant interaction between treatment and baseline alexithymia levels, suggesting that initial alexithymia scores influenced the reduction in PTSD symptoms. Specifically, participants in the MDMA-assisted therapy group who started the trial with higher levels of alexithymia experienced a greater reduction in PTSD symptoms. These findings highlight that both baseline self-experience levels and the effects of MDMA-assisted therapy on self-experience can influence PTSD symptoms, offering insights for clinical practice. Furthermore, the study found that MDMA-assisted therapy improved self-compassion independently of PTSD treatment, suggesting potential new applications for the therapy.

Discussion

In this study, the MDMA-assisted therapy group showed greater improvements in nearly all self-experience measures compared to the placebo group. Notably, higher baseline alexithymia was associated with greater improvements in PTSD symptoms. Only improvements in self-compassion occurred independently of changes in PTSD symptoms. This suggests that alexithymia and most other self-capacity issues likely played a role in how MDMA-assisted therapy affected PTSD symptoms. Additional analysis indicated that baseline alexithymia influenced the treatment's effect on PTSD symptoms, with individuals experiencing more severe alexithymia at the outset showing greater PTSD symptom improvement. These exploratory findings suggest that both an individual's initial self-experience and MDMA-assisted therapy itself can impact PTSD symptoms, which can inform clinical approaches. The independent improvement in self-compassion warrants further investigation into new applications for this therapy.

Studies not focused on PTSD have shown that MDMA can foster a general sense of interpersonal connection and openness. It has also been demonstrated to enhance positive appraisals of favorable memories while reducing negative evaluations of painful ones. Additionally, MDMA appears to aid in the extinction of fearful memories, modulate memory reconsolidation (possibly through an oxytocin-related mechanism), promote social behavior, and inhibit automatic fear responses to emotional threats. These qualities are believed to help individuals contextualize the emotional aftermath of past painful experiences more realistically.

This study examined MDMA's effects on individuals with significant clinical deficits in areas linked to treatment resistance. The findings suggest that MDMA's therapeutic benefits may be most relevant for people with substantial impairments in emotion regulation and self-capacities. The vast majority of traumatized individuals in this study reported having endured chronic childhood trauma, such as physical or sexual abuse by caregivers. Histories of child maltreatment are known to be associated with poorer responses to psychotherapy in individuals with PTSD. Abuse by early caregivers can lead to deficits in emotional coping skills and altered self-capacities, which pose major obstacles to the successful completion of currently available evidence-based treatments.

The ability to emotionally process traumatic experiences is crucial for successful treatment. Identifying feelings, describing them, and recognizing their triggers are thought to allow individuals to reflect on situations and respond appropriately, rather than reacting solely to emotional arousal. An inability to do so, often seen in alexithymia, avoidance of distressing thoughts, and difficulty recalling distressing experiences, is associated with impaired emotion regulation. Alexithymia has frequently been linked to invalidating or abusive early environments where children learn that expressing emotions is inappropriate or dangerous. It is believed that individuals with alexithymia, unable to physically escape chronic abuse, may have learned to disengage from both their external reality and their internal experiences.

Even though experimental sessions often occurred in relative silence as participants focused on their inner experience, MDMA-assisted therapy, unlike therapy with placebo, was linked to significant improvements in emotional self-awareness and a reduction in alexithymia. This suggests that MDMA-assisted therapy can facilitate access to painful memories and experiences that would otherwise be too overwhelming to confront, even with trained therapists present.

Problems with emotion regulation (ER) contribute to both the development and maintenance of PTSD symptoms after traumatic experiences, and they predict both functional impairment and symptom complexity. Adaptive emotion regulation is essential for effective PTSD treatment; trauma-focused therapies require both activation and modification of fearful memories. This activation depends on physiological reactions to trauma-related stimuli and the ability to tolerate the distress generated by these memories. The capacity to tolerate physiological arousal to trauma-related stimuli predicts improvement in exposure therapy, supporting a gradual decrease in distress during trauma recall within and between sessions.

Emotion regulation deficits are major contributors to a wide variety of mental health conditions, including interfering with the ability to resolve the impact of traumatizing experiences. While healthy, flexible emotion regulation skills are key factors in well-being, difficulties with emotion regulation represent a broad risk factor for mental health problems in general, including the development and/or persistence of PTSD symptoms. These difficulties can prevent individuals from disengaging from trauma-related stimuli and inhibit effective emotion regulation strategies.

Self-compassion is another core component of overall mental health and well-being. Individuals suffering from traumatic stress often experience shame, self-blame, and self-loathing. Feelings of mental defeat and permanent change can profoundly disrupt an individual’s identity and sense of self. Low self-compassion scores have consistently been associated with symptoms such as anxiety, depression, self-criticism, and avoidance. Self-compassion has been shown to enhance the effectiveness of cognitive reappraisals: being caring and kind to oneself, rather than critical, even under stress, can lessen the negative effects of trauma exposure by increasing resilience and decreasing avoidance-oriented coping. Notably, in this study, improvement in self-compassion occurred independently of improvements in PTSD symptoms, which aligns with previous studies demonstrating a powerful effect of MDMA-assisted therapy on self-compassion itself.

The finding that participants in the placebo condition, who received a substantial amount of therapy, showed significantly less improvement in alexithymia and self-compassion is noteworthy and warrants further investigation. After all, a primary focus in psychotherapy is to help individuals become more self-aware and self-accepting. The therapists in this study were experienced clinicians trained in various trauma-focused therapies. Yet, participants in the MDMA condition, who, with the support of these therapists, spent three experimental sessions focused on deep emotional encounters with their traumatic past, developed significantly more self-compassion and self-awareness than those who only received therapy with a placebo.

Questions have recently been raised about the best ways to ensure safety and support for vulnerable individuals during psychedelic-induced encounters with past trauma. The specific role and details of psychotherapeutic assistance during MDMA administration are important research questions that require careful consideration. Confronting devastating traumatic experiences can be highly distressing and demands a sensitive therapeutic approach that pays close attention to the "set and setting" (the mindset of the participant and the environment). Decades of clinical experience suggest that set and setting are critical for achieving positive outcomes in psychedelic therapies.

Summary

MDMA may be particularly effective at enhancing treatment efficacy by addressing various self-experience issues often associated with treatment resistance. Assessing self-capacities may be as important for treatment planning and outcome research as measuring PTSD severity. This study suggests that therapy alone may not sufficiently overcome the debilitating effects of deficient self-experience on an individual’s ability to process traumatic material, which in turn impacts treatment outcome.

Limitations

This study followed a strict protocol of psychological intervention, including history taking, debriefing, and integration sessions. Several participants expressed a desire for more MDMA-assisted therapy sessions beyond the study protocol, especially those with chronic interpersonal trauma who experienced significant distress related to abandonment and separation at the study's conclusion. Many participants had experienced trauma from early caregivers, which brought up major issues regarding trust and attachment during therapy sessions. This study did not measure the effect of MDMA-assisted therapy on trust and intimacy in interpersonal relationships. Many participants experienced considerable physical distress while accessing traumatic material during the MDMA sessions, which was not formally assessed or further investigated, although potential shifts in physical self-experience are hypothesized to be of significant interest for future MDMA-assisted therapy research.

This study involved a secondary analysis of exploratory outcome measures. It did not control for the age or specific nature of trauma exposure and may not represent an epidemiologically typical PTSD population. Some of this disparity might be due to a lower percentage of non-White participants seeking treatment, which indicates a need for systematic changes to reduce cultural barriers and increase participation in clinical research. A small number of participants were missing follow-up data for certain self-experience measures. All available data were used without imputation. Researchers used sample medians to set cutoff scores for baseline IASC factors because there were no established clinical categories in published literature, and this binary threshold may not have captured all statistically significant results. More studies are needed to examine MDMA’s capacity to alleviate post-traumatic symptoms across various trauma populations and to determine if MDMA-assisted therapy can permanently alter psychological processes related to trauma, such as shame, self-blame, emotional intimacy, executive functioning, and emotion regulation.

Introduction

Interest has grown in the therapeutic potential of substances like psilocybin, ketamine, and MDMA. The U.S. Food and Drug Administration (FDA) has recognized MDMA-assisted therapy as a "breakthrough therapy" for Post-Traumatic Stress Disorder (PTSD) due to its promising results in reducing symptoms and its acceptable safety record. Studies have shown that a significant number of patients (54%) no longer met the criteria for PTSD after two sessions of MDMA-assisted therapy. The first large-scale study confirmed that this therapy is both safe and effective for individuals with severe PTSD, leading to notable improvements in symptom severity. The treatment plan typically involves three months of therapy, including three sessions where MDMA is given, along with preparation and integration therapy visits.

Standard psychotherapy for PTSD often falls short. Many patients (at least one-quarter) stop treatment early, and up to half still have significant symptoms even after therapy. Those who do respond to treatment may still struggle with managing their emotions, controlling impulses, and maintaining relationships, issues that seem to persist regardless of their PTSD symptoms.

Many individuals who have experienced trauma, especially childhood abuse, often face deep-seated psychological challenges. These can include a loss of feeling safe, difficulty trusting others, low self-worth, an inability to recognize their own internal feelings (known as alexithymia), a fragmented sense of self, and problems managing strong emotions. They may also struggle with conflicts in relationships and have negative views of themselves, such as shame, self-blame, and a lack of self-compassion. These issues are often linked to poor outcomes in treatment.

Difficulties with emotion regulation and alexithymia can make it hard for individuals to complete therapy for PTSD. For example, a person's inability to manage distress during treatment can lead them to drop out. Alexithymia, which is the inability to identify and describe emotions, is common in those with post-traumatic stress and can hinder their ability to get used to emotionally distressing situations.

Self-compassion is a vital part of mental health, but it is often missing in trauma survivors who may experience self-loathing and self-blame. Low self-compassion is connected to anxiety, depression, self-criticism, and poor responses to therapy. Research suggests that MDMA can positively affect emotion regulation and self-compassion, which could improve psychological treatments.

This study examined the effects of MDMA-assisted therapy on three key measures: the ability to recognize and describe emotions (alexithymia), self-compassion, and other changes in self-perception, all known to influence treatment success. The main goal was to see if MDMA-assisted therapy improved these areas and if these improvements happened independently of changes in PTSD symptoms. The study also looked at whether initial levels of these self-experience measures were connected to how much PTSD symptoms improved.

Study Methods

This paper reports on data from a study that compared the safety and effectiveness of MDMA-assisted therapy to therapy with a placebo in individuals with severe PTSD. The study was designed so that participants, staff, and researchers did not know who received MDMA and who received the placebo until after the study was complete. All participants provided informed consent.

Individuals were included if they met the diagnostic criteria for current PTSD with symptoms lasting six months or longer and had a certain level of symptom severity. Those with severe mental health conditions like psychosis or bipolar disorder, substance use disorders, or medical conditions that could be worsened by changes in blood pressure or heart rate were not included.

Participants were assigned to either the MDMA or placebo group randomly. Each participant had three 90-minute preparation therapy sessions with two therapists to build trust and prepare for the drug sessions. The treatment period involved three 8-hour sessions where participants received either MDMA or a placebo, with about four weeks between sessions. During these sessions, participants received a split dose, with a second, smaller dose given a couple of hours after the first. All therapy followed a specific manual. After each drug session, participants had three 90-minute integration sessions, one week apart, to help them process their experiences.

Demographic information like age, gender, and education was collected. Measures related to trauma history, mental health, and suicidal thoughts were also assessed.

Measurements and Analysis

Several questionnaires were used to measure participants' self-experience. The Inventory of Altered Self Capacities (IASC) is a self-report questionnaire with 63 items that measures difficulties in relationships, identity, and emotion regulation. The Toronto Alexithymia Scale (TAS-20) is a 20-item questionnaire that assesses difficulties in recognizing and verbalizing emotions. The Self-Compassion Scale (SCS) has 26 items to measure how individuals perceive their own failures or suffering with kindness and understanding.

PTSD symptoms were assessed by independent raters using the Clinician-Administered PTSD Scale for DSM-5 (CAPS-5) at the beginning of the study and near the end. The self-experience measures (TAS-20, SCS, and IASC) were self-reported at the start, during the final preparation session, and again at the end of the study.

Data analysis involved comparing group averages and proportions to see if there were significant differences. Statistical models were used to examine how treatment groups differed in their changes on these measures, accounting for initial scores and other factors. Additional analyses looked at whether improvements on self-experience measures occurred independently of PTSD symptom improvements. Researchers also investigated whether a participant's initial self-experience levels influenced their PTSD symptom changes and if there were differences between the treatment groups based on these initial levels.

Study Findings

The study included 90 participants who completed at least one drug session. Most participants were women (64.6%), White (80.3%), and college graduates (69.5%), with an average age of 41. Nearly all participants (84.2%) had a history of childhood trauma, and most (90.2%) had experienced multiple traumas. There were no significant differences in demographics or initial symptom levels between the MDMA-assisted therapy and placebo groups.

Compared to the placebo group, the MDMA-assisted therapy group showed significantly greater improvements in nearly all self-experience measures, including alexithymia and self-compassion, as well as most aspects of altered self-capacities. The only exception was the "identity diffusion" factor of the IASC. These results suggest that MDMA had a strong positive effect on emotion regulation and self-experience. Notably, improvements in self-compassion remained significant even after accounting for changes in PTSD symptoms, indicating that self-compassion improved independently.

Overall, MDMA-assisted therapy led to much greater improvements in all self-experience measures compared to the placebo group. The study also found that participants who started with higher levels of alexithymia experienced a greater reduction in their PTSD symptoms when treated with MDMA-assisted therapy. This suggests that the initial level of difficulty in recognizing emotions might influence how well MDMA-assisted therapy works for PTSD symptoms.

Discussion

This study found that individuals receiving MDMA-assisted therapy experienced greater improvements in self-experience measures compared to those receiving therapy with a placebo. Specifically, participants with higher initial levels of alexithymia showed greater reductions in PTSD symptoms. Only improvements in self-compassion seemed to occur independently of changes in PTSD symptoms. These findings suggest that MDMA-assisted therapy might help individuals overcome challenges with self-experience that often make treatment difficult.

MDMA is known to promote feelings of connection, openness, and to help individuals process painful memories in a more positive way. It can also reduce fear responses and promote social behavior. These qualities are believed to help individuals put past traumatic experiences into perspective. This study's findings suggest that MDMA's benefits may be most relevant for those with significant difficulties in emotion regulation and self-capacities.

A large majority of participants in this study had experienced chronic childhood trauma, such as physical or sexual abuse, which is often linked to poorer responses to psychotherapy for PTSD. Childhood abuse can lead to deficits in emotional coping skills and altered self-capacities, which are major barriers to successful treatment.

Being able to process emotions related to trauma is crucial for successful treatment. Identifying and describing feelings helps individuals understand situations and respond appropriately, rather than reacting solely based on emotional arousal. The inability to do so, as seen in alexithymia, can lead to impaired emotion regulation. Despite the experimental sessions often involving quiet internal focus, MDMA-assisted therapy significantly improved emotional self-awareness and reduced alexithymia, unlike the placebo. This suggests that MDMA-assisted therapy can help individuals access and confront painful memories that would otherwise be too overwhelming, even with therapist support.

Emotion regulation problems contribute to the development and persistence of PTSD symptoms and predict how severe and complex symptoms will be. Effective emotion regulation is essential for PTSD treatment, as it requires both activating and managing fear-related memories. The ability to tolerate the physical discomfort linked to trauma-related stimuli can predict improvement in exposure therapy.

Self-compassion is fundamental to mental health, but it is often lacking in trauma survivors who may experience shame and self-blame. Low self-compassion is consistently linked to anxiety, depression, self-criticism, and poorer treatment outcomes. Being kind and caring towards oneself, even under stress, can lessen the negative effects of trauma by increasing resilience and reducing avoidance. It is noteworthy that in this study, improvements in self-compassion happened independently of improvements in PTSD symptoms, confirming MDMA-assisted therapy's strong effect on self-compassion itself.

It is interesting that participants in the placebo group, who received many hours of therapy, showed significantly less improvement in alexithymia and self-compassion compared to the MDMA group. While therapists aim to help individuals become more self-aware and accepting, it appears that MDMA, combined with therapeutic support, may have uniquely facilitated deeper emotional processing and a greater sense of self-compassion and self-awareness.

Questions have been raised about how best to ensure safety and support for individuals engaging in psychedelic experiences related to past trauma. The role of therapy during MDMA administration is important, as confronting traumatic experiences can be highly distressing and requires a sensitive therapeutic approach focused on creating a safe and supportive environment.

Summary

MDMA may be particularly effective in improving treatment outcomes by addressing a range of self-experience issues linked to treatment resistance. Assessing self-capacities might be as important for treatment planning and research as measuring PTSD severity. This study suggests that therapy alone may not fully compensate for the challenges posed by poor self-experience when dealing with trauma, which in turn affects treatment success.

Limitations

This study followed a strict therapy protocol, including history-taking, debriefing, and integration sessions. Some participants wanted more MDMA-assisted therapy sessions, especially those with chronic relationship trauma who experienced distress related to abandonment at the end of the study. Many participants had experienced trauma from early caregivers, leading to issues with trust and attachment during therapy. This study did not measure the effect of MDMA-assisted therapy on trust and intimacy in relationships. Many experienced physical distress while accessing traumatic material during MDMA sessions, which was not assessed but is hypothesized to be important for future research.

This study was a secondary analysis and did not fully account for participant age or the specific nature of their trauma exposure. The participant group may not fully represent the general PTSD population, partly due to a lower percentage of non-White participants seeking treatment. Further systematic changes are needed to reduce cultural barriers in clinical research. A small number of participants had missing follow-up data for some measures, and these data were used as available, without filling in missing values. The study used sample medians to define categories for some measures since no standard clinical cutoffs were available, which might have affected the detection of some results. More research is needed to examine MDMA's ability to reduce PTSD symptoms across different trauma populations and to see if MDMA-assisted therapy can permanently change psychological processes related to trauma, such as shame, self-blame, emotional intimacy, executive functioning, and emotion regulation.

Introduction

There has been new interest in using certain substances like MDMA to help with mental health. The Food and Drug Administration (FDA) has recognized MDMA-assisted therapy as a major step forward for treating Post-Traumatic Stress Disorder (PTSD). This is because it has shown good results in reducing PTSD symptoms and is generally safe.

Past studies showed that over half of people who received MDMA-assisted therapy no longer had PTSD after two treatment sessions. A larger study later confirmed that MDMA-assisted therapy is safe and works well for people with severe PTSD. This therapy greatly reduced the severity of PTSD symptoms compared to a therapy that used a placebo.

The MDMA-assisted therapy plan involves a three-month treatment. This includes three sessions where the substance is given, plus three sessions before and nine sessions after for therapy and support. In the studies, all participants received the same amount of therapy, whether they got MDMA or a placebo. This allowed researchers to see how the therapy changed people psychologically when MDMA was involved.

Standard talk therapy is usually the first choice for treating PTSD. However, this type of therapy often doesn't work well enough for everyone. About one-fourth of patients stop talk therapy, and up to half still have significant symptoms. Even those who get better often struggle with managing their emotions, controlling their actions, and getting along with others. These issues seem to remain even if their PTSD symptoms improve.

Many people who have experienced trauma, especially child abuse, often struggle with several key areas. They may lose their sense of safety, trust, and self-worth. They might not be able to notice their inner feelings (a condition called alexithymia). They may also lack a clear sense of who they are, have trouble handling upsetting feelings, find it hard to deal with conflicts with others, and think negatively about themselves, feeling shame, blame, or lacking self-compassion. All these issues have been linked to poor treatment outcomes.

Studies show that having these difficulties with self-capacities makes it harder to finish PTSD therapy successfully. For example, if someone struggles with controlling their emotions, it's hard for them to separate from thoughts or feelings related to their trauma. This can make them stop therapy because they can't handle the strong feelings that come up during treatment. Alexithymia, or difficulty finding and describing emotions, is connected to trauma problems and makes it harder to get used to upsetting feelings. People with high alexithymia scores may show less body response to any task, even when thinking about traumatic events.

Also, self-compassion is very important for mental health. But it is often missing in trauma survivors with PTSD, who frequently dislike or blame themselves. Low self-compassion is linked to anxiety, sadness, self-criticism, and poor results from treatment.

MDMA's effects on emotion regulation have been studied in healthy people. These studies showed that MDMA can improve a person's ability to manage their emotions and feel self-compassion. Better emotion management and self-compassion can lead to better results in different types of therapy. This suggests that MDMA could be helpful for treating PTSD. MDMA might also change how people recognize emotions, depending on whether the emotion is positive or negative.

In the current study, researchers looked at three specific measures from an MDMA-assisted therapy study for PTSD. They compared how treatment affected (1) alexithymia, (2) self-compassion, and (3) a measure of altered self-capacities. These measures describe how people experience themselves, which is known to affect how well treatment works. The main goal of this analysis was to see how MDMA-assisted therapy affected these self-experience measures and if improvements happened even when PTSD symptoms did not change. Researchers also looked at whether starting levels of self-experience were linked to changes in PTSD symptoms and if there were differences between the treatment groups.

Methods

Study design

This paper looks at extra information from a study that compared MDMA-assisted therapy to therapy with a placebo for people with severe PTSD. It was a study where people were randomly put into groups, and neither the participants nor the staff knew who was getting MDMA and who was getting the placebo. This was done to keep the results fair. Participants gave their written permission to be part of the study.

Participants

All participants had PTSD for at least six months and had a high score on a scale that measures PTSD symptoms. People were not allowed to join if they had other serious mental health conditions like psychosis, bipolar disorder, or if they had substance use issues. They also could not join if they had medical conditions where a quick rise in blood pressure or heart rate would be risky.

Intervention

Participants were put into either the MDMA group or the placebo group by chance, using a computer system. All participants had three therapy sessions, each 90 minutes long, with two therapists. These sessions helped them get ready for the main treatment sessions and build trust with their therapists. The treatment period included three eight-hour sessions where participants received either MDMA or a placebo. These sessions were about four weeks apart.

In each of these sessions, participants took a dose of MDMA or placebo, then took half of that dose about one and a half to two and a half hours later. The first session used smaller doses, and the second and third sessions used slightly higher doses. Therapy was given according to a special guide. After each treatment session, participants had three more 90-minute therapy sessions, one week apart. These sessions helped them process their experiences.

Demographic and baseline variables

Researchers compared the age, gender, race, and education levels of people in both treatment groups. They also looked at other information important for understanding the results, such as job status, detailed history of trauma, past treatments, and scores from other tests related to childhood experiences, sadness, PTSD symptoms, and thoughts of self-harm. There were no meaningful differences between the MDMA group and the placebo group in terms of these background details.

Self-experience measures

The study used several tools to measure how people felt about themselves:

The Inventory of Altered Self Capacities (IASC) is a survey that people fill out themselves. It helps measure how well a person is doing mentally and is often used in PTSD studies. It has 63 questions about problems with relationships, identity, and managing emotions. People rate how often they experience these issues on a scale from "Never" to "Very Often." The IASC has 11 parts that measure different areas.

The Toronto Alexithymia Scale (TAS-20) is a well-known survey with 20 questions. It measures how much people struggle to recognize and talk about their feelings. People answer on a scale from "Strongly disagree" to "Strongly agree." It has three parts: difficulty describing feelings, difficulty identifying feelings, and thinking in a very practical way. Scores help show if someone has no alexithymia, some alexithymia, or clear alexithymia.

The Self-Compassion Scale (SCS) is a valid survey that measures how much self-compassion someone has. It has 26 questions that ask how people react to their own failures, suffering, or weaknesses with kindness, seeing these as normal human experiences. People answer on a scale from "Almost never" to "Almost always." The SCS has six parts, and combining their scores gives a total score. Total scores show if someone has "low," "moderate," or "high" self-compassion.

A special assessor rated PTSD symptoms using a specific scale before the first treatment session and again about eight weeks after the last session. The other self-experience measures (TAS-20, SCS, and IASC) were filled out by the participants themselves at the start, during the last preparation session, and again about 18 weeks later when the study ended.

Statistical methods

Researchers looked at information about the groups, like age and gender, and the scores from the tests. They used different math tests to compare the average scores and proportions between the groups. They also checked if the data followed a normal pattern and used special tests if it did not. They used Pearson's correlations to see if there were simple relationships between different factors. They used General Linear Models, which are a type of math model that can find relationships between things even if the connections are not simple straight lines.

For the main part of the study, they used a special math model to compare changes in TAS-20, SCS, each IASC part, and PTSD scores between the MDMA group and the placebo group. They made sure to account for the starting scores and whether a person had a certain type of PTSD. They also did more analyses to see if improvements in self-experience measures happened separately from changes in PTSD symptoms.

They also looked at how scores changed within each group from the start to the end. They did more specific analyses by dividing people into smaller groups based on their starting scores for alexithymia, self-compassion, and IASC factors (like high versus low scores). They looked at whether the treatment groups acted differently based on these starting levels. All models took into account starting scores and PTSD type. They used a special test to correct for comparing many things at once. All analyses were done using a specific computer program.

Results

Sample characteristics

The study included 90 participants who were randomly assigned to a group and completed at least one treatment session (46 in the MDMA group, 44 in the placebo group). Data for the self-experience measures were missing for eight participants who left the study early. The researchers used all the available data, which was from 82 participants. Most participants were women (64.6%), White (80.3%), not Hispanic or Latino (92.7%), and college graduates (69.5%). The average age was about 41 years.

Most participants (84.2%) had a history of trauma from childhood, such as physical or sexual abuse, and most (90.2%) had experienced multiple traumas. Only 4 out of 90 participants in the study had no history of adverse childhood experiences. For the 8 participants whose data was missing, there were no big differences in group assignment or background. However, their starting PTSD scores were a bit higher than those of the full group. Overall, there were no important differences between the MDMA group and the placebo group when the study started, looking at background information or initial test scores.

Treatment effects on self-experience measures

The group that received MDMA-assisted therapy showed much greater improvement in all self-experience measures compared to the placebo group. The only exception was one part of the IASC called "identity diffusion." This suggests that MDMA had a strong positive effect on these measures of emotion management and self-experience. This was true even after accounting for other factors and making sure the results were not due to chance. Only the improvements in self-compassion were clear and strong even after considering changes in PTSD symptoms.

The MDMA-assisted therapy group showed greater improvements in how they manage emotions (alexithymia), how kind they are to themselves (self-compassion), and most areas related to altered self-capacities.

Baseline self-experience measures & treatment effects on PTSD symptoms

Overall, the MDMA-assisted therapy group had much greater improvement in all self-experience measures compared to the placebo group. The results showed that how much alexithymia someone had at the start of the study affected how well the treatment worked for their PTSD symptoms. Specifically, people in the MDMA-assisted therapy group who started with higher levels of alexithymia (meaning they struggled more with feelings) had a greater reduction in their PTSD symptoms. This means that for those who were struggling the most with alexithymia at the beginning, MDMA-assisted therapy helped them more with their PTSD symptoms.

The study also found that if people started with "worse-off" scores (like having alexithymia or low self-compassion) or some "better-off" scores (like less idealization or identity issues), this was linked to much greater improvements in PTSD symptoms in the MDMA-assisted therapy group compared to the placebo group. For other parts of the IASC, there were no differences in PTSD symptom changes based on starting levels.

Discussion

In this study, the group that received MDMA-assisted therapy improved more across all measures of self-experience, except for one part of the IASC that deals with identity. Also, people who started the study with more alexithymia had greater improvements in their PTSD. Only the improvements in self-compassion happened regardless of changes in PTSD symptoms. This suggests that alexithymia and most other self-experience issues likely played a role in how MDMA-assisted therapy helped with PTSD symptoms. Further analysis showed that starting levels of alexithymia affected how well treatment worked for PTSD symptoms. Those with higher alexithymia scores (meaning they were struggling more) at the start saw greater improvement in their PTSD symptoms. These findings show that how a person experiences themselves at the start, and how MDMA-assisted therapy changes that, can affect PTSD symptoms. This can help guide how treatment is done. Also, the study found that MDMA-assisted therapy improved self-compassion independently of PTSD treatment, which means it could have other uses.

Other studies not focused on PTSD have shown that MDMA can make people feel more connected to others, more open, and can help them think about good memories more positively while reducing negative thoughts about painful memories. It has also been shown to help reduce fearful memories, change how memories are stored (perhaps through a certain hormone), and encourage social behavior. Also, MDMA stops normal fear responses to threats. These qualities are thought to help people see the emotional effects of past painful experiences in a more realistic way.

In this study, researchers looked at how MDMA affected a group of people with major problems in areas that make treatment difficult. The findings suggest that MDMA's benefits might be most helpful for people who have significant struggles with managing emotions and with their sense of self.

Most of the people in this study (84%) had experienced ongoing childhood trauma, such as physical or sexual abuse from their caregivers. Only a few participants (4 out of 90) had no adverse childhood experiences. A history of child abuse is linked to less positive responses to psychotherapy for PTSD. Abuse from early caregivers can make people struggle with emotional coping skills and their sense of self, which are major challenges for current evidence-based treatments.

Being able to emotionally process traumatic experiences is a key part of successful treatment. Identifying feelings, describing them, and knowing what triggers them can help a person think about a situation and react in a suitable way, rather than just acting based on strong emotions. Not being able to do this, as seen in alexithymia, avoiding upsetting thoughts or feelings, and having trouble remembering upsetting experiences, are all linked to poor emotion regulation.

Alexithymia is often seen in people who grew up in environments where their feelings were not accepted or where expressing emotions was seen as inappropriate or dangerous. It is believed that people with alexithymia, unable to escape physically from long-term abuse, learned to disconnect from both their outside world and their inner feelings.

Even though the MDMA-assisted therapy sessions often happened quietly, with participants focusing on their inner feelings, MDMA-assisted therapy (but not the placebo therapy) led to a big improvement in emotional self-awareness and a decrease in alexithymia. This suggests that MDMA-assisted therapy can help people access painful memories and experiences that would normally be too overwhelming or scary to face, even with trained therapists present.

Problems with emotion regulation affect both the development and continuation of PTSD symptoms after a traumatic event. They also predict how much a person's daily life is impacted and how complex their symptoms are. Being able to manage emotions well is vital for effective PTSD treatment. Trauma-focused treatments for PTSD require both bringing up fearful memories and changing them. This process depends on two things: how the body reacts to trauma-related cues and being able to handle the distress caused by these traumatic memories. Being able to tolerate body reactions to trauma-related cues predicts improvement in exposure therapy, helping to slowly reduce the distress felt when recalling trauma.

Difficulties with emotion regulation are a major reason for many mental health problems. They can stop someone from dealing with the impact of traumatic experiences. While healthy emotion management is key to well-being, problems with emotion regulation are a risk factor for mental health issues in general, including the development or ongoing presence of PTSD symptoms. This is because they make it hard to pull away from trauma-related feelings and stop using unhealthy ways to cope with emotions.

Self-compassion is another main part of overall mental health. People dealing with trauma often feel shame, self-blame, and self-dislike. Feeling defeated mentally and thinking that things have changed forever can deeply harm a person's identity and sense of self. Low self-compassion scores have consistently been linked to problems like anxiety, sadness, self-criticism, and poor treatment results. Self-compassion has been shown to make it easier to rethink negative thoughts. Being kind and caring to oneself, instead of critical, even when stressed, can lessen the bad effects of trauma by making a person stronger and less likely to avoid problems. Importantly, in this study, improvements in self-compassion happened without improvements in PTSD symptoms, which confirms earlier studies showing that MDMA-assisted therapy has a strong effect on self-compassion itself.

The finding that participants in the placebo group, who still received a lot of therapy during the study, had much less improvement in alexithymia and self-compassion is interesting and needs more study. After all, a key goal in therapy is to help people become more self-aware and accepting. The therapists in this study were experienced and trained in various trauma therapies. Yet, participants in the MDMA group, who spent three treatment sessions deeply exploring their inner feelings about past trauma with supportive therapists, developed much more self-compassion and self-awareness than those who only received placebo therapy.

Recently, questions have been asked about the best way to keep vulnerable people safe and supported during a psychedelic experience with past trauma. The role and specific ways therapists help during MDMA use are important research questions that should be handled with great care. This is because facing upsetting traumatic past experiences can be very hard and needs a gentle therapy approach that pays close attention to the setting and mindset; over 50 years of clinical experience suggest that setting and mindset are crucial for good results in psychedelic therapies.

Summary

MDMA may be especially good at making treatment more effective by improving a range of self-experience problems that make it hard for people to get better. Measuring these self-capacities may be as important for planning treatment and researching results as measuring how severe PTSD is. This study suggests that therapy alone may not be enough to make up for how much struggling with self-experience can affect dealing with trauma and, therefore, how well treatment works. Also, this study found that MDMA-assisted therapy improved self-compassion even when PTSD symptoms did not get better. This means it could have new uses.

Limitations

This study had strict rules for the therapy, including taking patient histories, debriefing, and follow-up sessions. Some participants wanted more MDMA-assisted therapy sessions after the study ended, especially those with long-term trauma from relationships who felt a lot of distress about being left alone or separated at the end of the study. Many participants had experienced trauma from their early caregivers. This brought up major issues during therapy sessions about trust and feeling secure in relationships. This study did not measure how MDMA-assisted therapy affected trust and closeness in relationships. Many participants felt significant body discomfort when dealing with traumatic material during the MDMA sessions, which was not measured or looked at further. But possible changes in how people feel in their bodies are thought to be very interesting for future MDMA-assisted therapy research.

This study looked at additional information that was not the main focus, and it did not account for participants' ages or the type of trauma they experienced. Therefore, the results may not represent all people with PTSD. Some of this difference might be because fewer people of color seek treatment, which means changes are needed to reduce cultural barriers and encourage more people to join clinical research. Data was missing for 8 participants for the self-experience measures. All available data were used, and no guesses were made for the missing data. Researchers used median scores to set cutoff points for certain self-experience measures because there were no standard categories from other studies. This method of dividing groups might have missed some important results. More studies are needed to see how MDMA can help with trauma symptoms in different groups of people who have experienced trauma. Future research should also explore if MDMA-assisted therapy can permanently change many psychological processes related to trauma, such as shame, self-blame, the ability to feel close to others, thinking skills, and emotion regulation.