Abstract
Background:
3,4-Methylenedioxymethamphetamine (MDMA)-assisted psychotherapy (MDMA-AP) has demonstrated considerable efficacy in treating post-traumatic stress disorder (PTSD). PTSD and complex PTSD (CPTSD) frequently co-occur with borderline personality disorder (BPD), a complex disorder marked by emotional dysregulation, interpersonal difficulties and abandonment fears – often accompanied by suicidal and non-suicidal self-injury. While MDMA-AP is beneficial for PTSD and hypothesised to be effective for BPD, its application to CPTSD and BPD has not been systematically reviewed.
Objectives:
To systematically evaluate primary evidence on the use of MDMA-AP in treating PTSD, CPTSD, and BPD.
Design:
Descriptive systematic review.
Data sources and methods:
A systematic search of four databases (Ovid Medline, Embase, APA PsycINFO and CENTRAL) identified 24 eligible peer-reviewed studies published before 17 February 2025. Risk of bias and data extraction were conducted independently using standardised methods.
Results:
Of the 24 studies involving 335 participants, 15 reported outcomes from seven clinical trials, four were case reports, and five were non-randomised interventions. Four studies included participants with multiple forms of trauma, and three included those with dissociative PTSD. Most reported reduced PTSD symptoms post-intervention; some noted decreased dissociative symptoms at higher MDMA doses. Six studies did not exclude participants with BPD. Although none directly assessed MDMA-AP for CPTSD or BPD, improvements in emotional regulation, interpersonal functioning, identity coherence and abandonment concerns were reported. Adverse drug reactions were mild to moderate, although specific safety concerns remain.
Conclusion:
Findings from this review suggest that MDMA-AP may have applicability beyond PTSD, with potential benefits for CPTSD and BPD, offering preliminary insights to inform future research and clinical considerations.
Protocol registration:
PROSPERO ID: CRD42025594896.
Keywords
Introduction
3,4-Methylenedioxymethamphetamine (MDMA), also known as ‘ecstasy’, is an entactogen-empathogen in a separate classification from psychedelics such as psilocybin and lysergic acid diethylamide (LSD). 1 MDMA blocks the reuptake of neurotransmitters by acting on serotonin, dopamine and norepinephrine transporters. 2 This is accompanied by reduced activity in the amygdala and neurohormonal effects such as increased release of oxytocin and prolactin.1,3 These drug actions lead to increased trust, extinction and reconsolidation of fear memories, relaxation and increased receptivity or openness. 4 This contrasts markedly with the hallucinogenic effects and perceptual distortions associated with the use of classic psychedelics. 1
Post-traumatic stress disorder (PTSD) is a psychiatric condition that can arise following a psychologically traumatic event, characterised by re-experiencing symptoms (e.g. flashbacks and recurring dreams of the event), anxiety, low mood, poor sleep quality, irritability, hypervigilance and avoidant behaviours that persist longer than a month after exposure to the event. 5 In some cases, symptoms persist despite prolonged evidence-based treatment, indicating treatment-resistant PTSD (TR-PTSD), which often necessitates more intensive or alternative approaches. 6 Additionally, some people with PTSD may present with prominent symptoms of depersonalisation and derealisation, which can complicate diagnosis and treatment due to overlapping features with other dissociative disorders. 7 According to DSM-5, this presentation is classified as the dissociative subtype of PTSD (PTSD-DT), with some arguing that PTSD-DT cannot be distinguished from complex PTSD (CPTSD). 7
It is important to note, however, that the formulation of CPTSD, a PTSD subtype recognised in the International Classification of Diseases, version 11 (ICD-11),7–9 differs somewhat from PTSD and TR-PTSD. CPTSD is usually associated with a history of sustained, repeated or multiple forms of trauma, including exposure to childhood or developmental trauma.8–10 In addition to symptoms of PTSD, CPTSD includes ‘disturbances in self-organisation’ (DSO), which also differentiates it meaningfully from PTSD-DT. 7 DSO symptoms include (a) affect dysregulation, (b) negative self-concept and (c) relationship disturbances8,9 – symptoms that are also observed in people with borderline personality disorder (BPD), albeit with distinctive patterns of manifestation. BPD is a severe and complex mental health disorder with symptoms including unstable and intense relationships, overwhelming fears of abandonment, unstable self-image, impulsivity, emotional dysregulation, suicidal and/or self-injurious behaviours, derealisation or depersonalisation and chronic feelings of emptiness. 5 In contrast to BPD, people with CPTSD present with a persistently negative affect, as opposed to the shifting mood states often observed in people with BPD. 8 While self-injurious behaviours are common in people with BPD, their frequency and intensity are lower among people with CPTSD. People with BPD desire relationships despite struggling to maintain them, whereas people with CPTSD tend to avoid or end relationships when distressed. 8 Thus, while PTSD and CPTSD overlap considerably, as do CPTSD and BPD, all differ with respect to symptom expression.
Trauma disorders, such as (complex) PTSD, co-occur in 25%–74% of people diagnosed with BPD and vice versa. 11 Among people whose lives end in death by suicide, close to 10% have a primary diagnosis of BPD. 12 People with BPD are estimated to have a reduction in life expectancy of around 20 years, more than for any other serious mental health disorder. 13 For people who have co-occurring BPD and PTSD/CPTSD, there are few cost-effective treatments available. These involve stage-based treatment, which is usually intensive and long-term. 14 Although short-term interventions for BPD-PTSD demonstrate some symptom improvement, further rigorous research is needed to clarify the durability of reported improvements.15,16
Evidence suggests that integrating MDMA treatment into psychotherapy for PTSD may enhance recovery outcomes and shorten treatment duration, even for people who are treatment resistant, by enhancing therapeutic trust and facilitating trauma processing.3,4,17–21 An earlier literature review outlined similarities in the neurobiology of PTSD and BPD, building a case for the investigation of MDMA-assisted psychotherapy (MDMA-AP) for the treatment of BPD. 22 Diminished activity in the prefrontal cortex and hyperactivity in the amygdala feature in people living with trauma-related disorders such as PTSD/CPTSD and BPD.23–25 MDMA may attenuate these abnormalities, enabling effective processing of traumatic content during therapy sessions.1,3,26 People with a history of trauma are thought to have a narrow window between over- and under-arousal, known as the ‘window of tolerance’, making them vulnerable to extremes of overwhelming anxiety or emotional numbing when they recall their past. This can be a barrier when the therapist is assisting the person to process their trauma, particularly when dissociation and/or overwhelming emotions interfere with the person’s capacity to engage in the treatment. Use of MDMA as an adjunct to therapy is believed to widen this window, helping the person stay in an ‘optimal arousal zone’ with diminished feelings of fear. 26 Additionally, entactogen-empathogens such as MDMA can foster feelings of unity, an emotional connection with others, and empathy.1,3 Collectively, these drug effects may promote engagement and compliance with treatment, enhance therapeutic alliance, and evoke compassion for oneself and others.
Alongside MDMA’s benefits, there are likely to be adverse drug reactions (ADRs). MDMA mimics the effects of endogenous chemical transmitters in the sympathetic nervous system, causing symptoms such as increased body temperature, blood pressure and heart rate, headache, nausea, muscle fatigue, anxiety, jaw tightness, coldness and jitters.1,26 Substantial evidence supports the benefits of MDMA-AP for the treatment of PTSD in association with mild-to-moderate ADRs,3,4,17–21 but little is known about the feasibility of MDMA-AP for other trauma-related disorders such as CPTSD and BPD. Limited evidence concerning the use of MDMA-AP for CPTSD is unsurprising, given its relatively recent inclusion in ICD-11 and emerging treatment evidence. 8 However, the similarities between PTSD and CPTSD suggest that the evidence for the effectiveness of MDMA-AP for PTSD may extend to the treatment of CPTSD. In terms of evidence for the treatment of BPD, however, previously published MDMA-AP trials have generally excluded people diagnosed with BPD, perhaps due to concerns around suicide risk, complexity and a lack of researchers’ expertise working with people diagnosed with BPD.22,27–29 As a result, previous systematic reviews have not specifically scoped for evidence of the potential benefits of MDMA-AP for people with BPD, likely due to the absence of direct evidence.
While extant meta-analyses of randomised controlled trials (RCTs) provide robust evidence for the efficacy of MDMA-AP in treating PTSD, they are limited in scope with respect to treatment population as well as the breadth of evidence previously reported.3,4,17–21 Given a substantial overlap in the neurobiology and symptomatology of BPD, PTSD and CPTSD, and the pressing need for improved treatment options – particularly for CPTSD and BPD – the aim of this review was to evaluate the evidence and feasibility of using MDMA as a therapeutic adjunct for these disorders. We hypothesised that some studies evaluating MDMA-AP for PTSD may have included participants with CPTSD or BPD diagnoses or traits, even if they were not explicitly identified. To our knowledge, no prior systematic review has synthesised all available evidence relevant to CPTSD and BPD and included relevant secondary outcome measures (e.g. suicidal risk, fear of abandonment). 29 Green et al. 2023 published a pre-print meta-analysis, reporting select secondary outcome measures of six RCTs; however, the present review is more recent and comprehensive.
Most research on MDMA-AP for PTSD has been conducted in private practice settings, leaving its feasibility and scalability within public mental health services largely unexplored. 30 The findings of this review are intended to inform a subsequent pilot study assessing the feasibility and acceptability of MDMA-AP for BPD-PTSD and/or BPD-CPTSD within a specialist public health service in Victoria, Australia. This is particularly important given the costs to the consumer when accessing MDMA-AP as a prescribed treatment in private health settings. 31 Accordingly, this review addresses an underexplored outcome: premature treatment discontinuation. Aside from Colcott et al., previous systematic reviews have not examined this outcome in the context of MDMA-AP.3,4,17–21 While Colcott et al. 20 provided valuable quantitative comparisons, their analysis lacked nuance regarding specific factors driving discontinuation. Given the long waitlists and high demand in publicly funded systems, insights into intervention-specific reasons for treatment discontinuation can guide sustainability and implementation strategies. 32
The following research questions were addressed:
What beneficial health outcomes are associated with the use of MDMA-AP for the treatment of PTSD or CPTSD and/or BPD?
What harms, including ADRs and factors leading to treatment discontinuation, are associated with the use of MDMA-AP for the treatment of PTSD or CPTSD and/or BPD?
Methods
The protocol for this systematic review was pre-registered on PROSPERO (CRD42025594896). The Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA) guidelines were adhered to in reporting our findings. 33
Eligibility criteria
Studies for inclusion examined the use of MDMA-AP for the treatment of people living with PTSD or CPTSD and/or BPD, which assessed benefits and/or ADRs of MDMA-AP for PTSD or CPTSD and/or BPD. Studies that had a specific comparator group (either standard psychotherapy, other psychedelic drug-assisted psychotherapies, or low-dose MDMA-AP) or lacked a comparator group were also included. The review was restricted to English-language studies. No restrictions were placed on study design or participant demographics.
We excluded studies that focused on other psychoactive drugs or psychedelics other than MDMA as the intervention of interest, and studies of MDMA that focused on participants with mental health conditions other than PTSD or CPTSD and/or BPD (or where these data could not be meaningfully separated). Studies conducted in naturalistic settings were excluded due to uncontrolled variability and lack of scientific rigour. Protocol papers, abstracts, previous reviews or meta-analyses, books, chapters, news articles, and non-peer-reviewed articles were excluded. Studies reporting pooled analyses were also excluded in preference for primary research, as they provide more detailed information regarding the effectiveness of each intervention.
Search strategy
Following consultation with a health sciences librarian at the Royal Melbourne Hospital, a search strategy was developed (refer to Additional File 1) using a PICO (Population, Intervention, Comparator and Outcome) framework. The following databases were searched for peer-reviewed publications exploring the efficacy and/or feasibility of MDMA-AP for people diagnosed with PTSD or CPTSD and/or BPD: Ovid Medline, Embase, APA PsycINFO and CENTRAL. We included studies, irrespective of their study design and publication date. The final literature search for this review was conducted on 25 September 2024. Auto-alerts were set up for new publications that matched the search strategy after this date. These were regularly imported to Covidence for screening until 17 February 2025, when data extraction commenced. Additionally, three reviewers searched for additional studies using reference lists from included studies, clinical trial registrations, relevant reviews and/or meta-analyses.
Study selection
Studies identified through the search strategy were imported into the Covidence systematic review software, which identified duplicates. Following a calibration meeting, four reviewers independently screened studies by titles and abstracts against the eligibility criteria. Regular meetings took place for conflict resolution. A similar approach was used to screen full-text articles. Discrepancies arising at this later stage were resolved with the assistance of a field expert. The average interrater reliability for title and abstract screening and full text screening was calculated.
Data items and extraction
A data extraction form was created in Covidence with guidance from the Cochrane Handbook of Systematic Reviews. 34 Two reviewers extracted data from all included studies based on study characteristics: surname of the first author, year of publication, the title of the study, study setting & country, aim(s) or research question(s), study design including methods used for randomisation and masking, potential biases noted, funding source for the study, declared conflicts of interests, steps taken to prevent and control confounding factors, biases, and missing data, sample characteristics (including whether diagnoses were verified, eligibility criteria, age, sex, co-occurring diagnoses, severity of the trauma-related disorder), intervention details (dosage, route of drug administration, dosing interval, timing, frequency, duration and number of sessions for both intervention and/or control arms, qualifications of staff delivering the intervention including any study-related training received, integrity of the intervention, definition of comparator groups (if applicable), and method(s) of data collection including sampling procedures, enrolment year(s), duration of participant follow up, and specific study outcomes. Details about the number of participants included in the analysis, the number of participants who withdrew, and the number of participants who were lost to follow-up or excluded from the analyses (with reasons) were also extracted.
Data relevant to the following outcomes were extracted.
Effectiveness of MDMA-AP
This outcome was selected as it was anticipated that MDMA-AP would reduce symptom severity for people experiencing PTSD or CPTSD and/or BPD, and improve quality of life, informed by prior research on MDMA-AP for PTSD.3,17 A frequently used scale for measuring symptom severity of PTSD across the included studies was the Clinician-Administered PTSD scale (CAPS), which is a validated and reliable tool for assessing symptom severity for PTSD and potentially the non-DSO symptoms of CPTSD.35,36 Therefore, the reviewers selected CAPS as the primary outcome measure to maintain consistency. Secondary or exploratory outcomes (e.g. Beck’s Depression Inventory 2, BDI-2 for depressive symptoms; Pittsburgh’s Sleep Quality Index, PSQI for sleep quality) reported by the study authors are also summarised due to their relevance for trauma-related disorders, including BPD. For studies that did not use CAPS, symptom severity for PTSD is reported using an appropriate alternative measure (e.g. Severity of Symptoms Scale for PTSD, SSS-PTSD) identified by respective study authors. A similar approach was employed for studies that reported benefits other than a reduction in CAPS scores. In cases of qualitative data, outcomes are summarised descriptively. Evidence for the effectiveness of MDMA-AP was extracted at baseline, post-intervention, and follow-up (where applicable) for pre–post study designs, and at a single post-intervention time point for cross-sectional studies.
Adverse drug reactions
Another outcome of interest for this review was the ‘adverse drug reactions’ or ADRs, as distinct from adverse drug effects. 37 Adverse drug effects are changes occurring at a molecular level through the action of a drug, whereas ADRs are sequelae of these molecular changes. Consequently, adverse drug effects are recognised through clinical investigation or laboratory tests (e.g. elevated blood pressure post-MDMA administration), whereas ADRs are identified from symptoms or signs reported by participants (e.g. headache arising from elevated blood pressure). 37 The reviewers evaluated this outcome by assessing whether a study reported ADRs systematically (e.g. based on CONSORT Harms 2022) or if it reported them non-systematically (informal and/or voluntary reporting of ADRs by participants). ADRs measured by the study investigators or reported by participants (during and/or after the MDMA intervention session) were documented. This included noting the elapsed time between the last MDMA intervention session and ADR reporting (e.g. within 7 days after an MDMA session). ADRs reported across all included studies are presented as frequencies.
Treatment discontinuation due to ADRs
This outcome is defined as withdrawal of participants from the study due to a health problem likely caused or exacerbated by the MDMA-AP treatment for PTSD or CPTSD and/or BPD, for example, ‘relapse of depression’. The reviewers have documented this outcome descriptively for a single time point when the discontinuation occurred.
Methods of assessing risk of bias
Risk of bias was assessed for the included studies using validated and reliable tools, including the Revised Cochrane tool for Risk of Bias (RoB 2) for randomised clinical trials, 38 Risk of Bias in Non-randomised Studies of Interventions (ROBINS-I), 39 Critical Appraisal Skills Program (CASP) Qualitative Research Checklist for qualitative studies, 40 Mixed Methods Appraisal Tool (MMAT) for mixed methods studies, 41 and the Joanna Briggs Institute tool for Case Reports. 42 Two reviewers independently appraised the risk of bias for two of the 24 included studies and met to discuss conflicts. This was followed by an independent risk appraisal of the remaining studies, interspersed with scheduled calibration meetings. Conflicts were resolved by involving a field expert.
All appraisal tools classified the risk of bias as ‘low’, ‘moderate’ or ‘high’ for each domain except ROBINS-I, which used classifications of ‘low’, ‘moderate’, ‘serious’ and ‘critical’. Studies were not excluded from the analysis based on the outcome of this assessment. It was possible to assess an overall risk of bias using ROB 2 and ROBINS-I; however, domain-specific risks are reported for checklists lacking a standardised method for appraising the overall risk.
To assess the risk of bias due to missing results in RCTs and non-randomised studies of intervention (NRSIs), the integrity of the study intervention was examined using published protocols (if available). The timestamps of the finalised version of the protocol and/or the statistical analysis plan (SAP) were cross-checked with study recruitment dates to assess whether study investigators had access to unblinded study results before the protocol or the SAP was finalised. Protocols were also compared with the published findings for inconsistencies in analysis or measures using domains five and seven of the ROB 2 and ROBINS-I tool, respectively.
The reviewers judged published studies of RCTs or NRSIs as having a high risk of bias if they used a per-protocol (PP) analysis (participants withdrawing from the intervention due to ADRs being excluded from the final analysis). The concern is that PP analyses often overestimate the intervention effect in favour of the experimental condition and do not reflect real-world settings where consumers’ adherence to the intervention can vary. 43 Studies that did not use a systematic method to measure ADRs were also assessed as having a high risk of bias for the respective domain due to potential selective reporting of harms. 20
Data synthesis and effect measures
For RCTs, change scores from baseline to the end of the study and effect sizes of correlations comparing MDMA versus placebo are reported. p-values (<0.05) of comparisons assessing MDMA-AP and its effectiveness for trauma-related disorders at the study end and/or respective follow-ups are reported. For NRSIs, within-group change scores and effect sizes are reported. Mean scores and standard deviations for outcome variables at baseline, end of study and/or follow-up are documented. Means and standard deviations were calculated for studies that supplied raw data.44,45 Similarly, mean differences were calculated to compare the change from baseline for pre- to post-test study designs.27,44–50 Findings from the qualitative study 51 that aligned with the outcomes of interest (effectiveness of MDMA-AP and ADRs) are summarised. ADRs from all included studies are summarised as frequencies, with ADRs that led to treatment discontinuation reported descriptively.
Results
Study selection
Out of 8220 total records, 5557 were screened by title and abstract, after which 154 full texts were assessed for eligibility. Interrater reliability was k = 0.43 for title and abstract screening and k = 0.56 for full-text screening, indicating moderate agreement among reviewers and supporting reasonable confidence in the screening process. 46
The PRISMA flowchart (Figure 1) documents the number of studies identified at each stage and reasons for exclusion. Twenty-four eligible studies were identified, including one identified through clinical trial registration 46 and another through citation searching. 52
PRISMA flowchart.
Study characteristics
Descriptive data concerning study characteristics are presented in Table 1. Studies are grouped according to author name/year of publication, study design, study condition(s), method of recruitment, eligibility criteria, sample size, participant demographics and study aim(s).
Characteristics of included studies (n = 24).
Number of randomised participants.
Participants under the care of an external therapist (referrer) were included if they consented to an initial assessment, a few introductory sessions, and at least one integration session following each experimental session. All therapists involved in the treatment shared information about these participants with the participant’s consent. Four individuals with CPTSD had co-occurring borderline personality traits and were thoroughly assessed for risk before enrolment. It remains unclear whether the case described in Oehen & Gasser 2022 had co-occurring borderline personality traits.
ADHD, Attention Deficit Hyperactivity Disorder; AUD, Alcohol Use Disorder; CBCT, Cognitive Behavioural Conjoint Therapy; C-SSRS, Columbia Suicide Severity Rating Scale; DSM, Diagnostic and Statistical Manual; EAT-26, Eating and Attitudes Test 26; ECG, Electrocardiogram; EDs, eating disorders; GAD, Generalised Anxiety Disorder; IQR, Interquartile Range; LTFU, long-term follow-up; M, Mean; MDD, Major Depressive Disorder; PCL-5, PTSD Check List for DSM-5; SD, Standard Deviation; SNRI, Selective Norepinephrine Reuptake Inhibitor; SSRI, Selective Serotonin Reuptake Inhibitor; SUD, Substance Use Disorder.
The studies were conducted between 2000 and 2022 and published between 2008 and 2024. Across 24 studies involving 335 participants, 23 reported outcomes on the effectiveness of MDMA-AP, and the remaining study reported the utility of therapeutic alliance as a facilitator for achieving beneficial outcomes using MDMA-AP for moderate to severe PTSD. 53 Ten studies (three NRSIs and seven RCTs) reported primary outcome data. Eight additional studies reported secondary or exploratory outcomes from seven RCTs and two NRSIs. Two studies reported long-term follow-up data from two previously conducted RCTs,25,27 with one presenting qualitative data. 51 Of the four included case studies, one selected its case from a previously conducted RCT 54 and two from previously conducted NRSIs.55,56 The remaining one was an independent case study. 57
Five RCTs were conducted at a single site,21,25,27,44,46 and two at multiple sites.24,28 Single-site trials were conducted in the United States (n = 3),25,27,46 Spain (n = 1) 44 and Switzerland (n = 1). 21 Multi-site trials were conducted in the United States, Israel and/or Canada.24,28 One study reported results for two separate single-site RCTs (MP-16 in the United States and MP-17 in Canada) with respective trial registrations and published protocols. 52 This study was included because the CAPS-5 scores for the two studies could be distinguished and reported separately. Pooled results of efficacy reported in the paper were excluded from the present review.
Of the included studies, 23 recruited participants diagnosed with PTSD, 13 of which specifically focused on treatment-resistant cases. Only one study reported a case involving CPTSD, and none explicitly evaluated participants with BPD. Most studies (n = 23) were conducted in outpatient private practices; one was conducted in a public hospital setting and was prematurely discontinued for political reasons. 44 Eleven studies reported ADRs, with seven reporting ADRs that led to treatment discontinuation. While some studies reported suicidality using the validated Columbia Suicide Severity Rating Scale (C-SSRS), most studies (except one study, which used the validated UKU side effects scale) 44 used non-systematic methods to report ADRs.
Twenty-one studies followed the Multidisciplinary Association of Psychedelic Studies (MAPS) treatment manual for MDMA assisted treatment, presumably utilising generalist care principles. One NRSI utilised the CBCT for PTSD in couples where one partner had a diagnosis of PTSD.47,56,58 Most studies (n = 23) were sponsored by MAPS, including five NRSIs (four reported outcomes of two different NRSIs), three case studies (one received funding for publication through the Swiss Medical Society for Psycholytic therapy), and one qualitative study. Nineteen studies declared conflicts of interest, both financial and non-financial (Additional File 2).
Risk of bias results
Barone et al. 51 was assessed as having a low risk of bias in eight domains, high in one domain and moderate in one domain. Risk of bias for the remaining studies is visually represented using the robvis tool in Figures 2 and 3 and summarised in Table 4. Detailed comments are provided in Additional File 3.
Assessment of risk of bias domains in RCTs.
Assessment of risk of bias domains in NRSIs.
The reviewers identified concerns around selective reporting in ten studies. Eight studies had finalised their protocol or planned statistical analysis after unblinded outcome data may have been available to the study investigators. The remaining two studies partly reported what was initially planned (Additional File 3).
MDMA-AP outcomes for CPTSD and PTSD
While only one case study explicitly included a participant with CPTSD, four studies (two RCTs and two NRSIs) on MDMA-AP for PTSD involved people with a history of multiple forms of trauma.24,28,47,52 Out of 237 participants across the four studies, 199 (84%) had a history of multiple forms of trauma, 202 (85%) had childhood/developmental trauma, and 116 (49%) received MDMA-AP. Findings from these studies reported significant improvements in participants’ symptoms post-MDMA as compared to people who received the placebo intervention.24,28,47,52 Additionally, three studies included participants with the dissociative subtype of PTSD,24,28,52 with one reporting significant improvements post-intervention with MDMA compared to placebo. 28 A summary of outcomes for participants with PTSD, a history of multiple forms of trauma and the dissociative subtype of PTSD is summarised in Tables 2–4, with supplemental information provided in Additional File 2.
RCTs involving MDMA-assisted psychotherapy for PTSD (characteristics and outcomes).
Both PP and mITT results are presented due to the paucity of results reported for the mITT set
Only mITT results are presented
ITT for change in CAPS was conducted, but not reported by the authors
Themes and quotes extracted from the study are summarised in Additional File 2– Data extraction. The risk of bias for this qualitative study was assessed using the CASP checklist for qualitative studies
Only ITT results are presented
Studies that did not exclude participants with BPD
AUDIT, Alcohol Use Disorders Identification Test; CI, Confidence Interval; DES, Dissociative Experiences Scale; DUDIT, Drug Use Disorders Identification Test; EAT-26, Eating Attitudes Test-26; Fchange, change in F statistic; GAF, Global Assessment of Function; HAM-D, Hamilton Depression Rating Scale; Haq, Helping Alliance questionnaire; HRS, Hallucinogen Rating Scale; IASC, Inventory of Altered Self Capacities; IES-R, Impact of Events Scale - Revised; ITT, Intent To Treat; LS, Least Squares; MD, Mean difference; mITT, modified Intent To Treat; MS, Maladjustment Scale; MSF, Modified Fear Scale; n, number of participants; NEO-PI-R, Revised NEO Personality Inventory; PASAT, Paced Auditory Serial Addition Task; PDS, Post-traumatic diagnostic scale; PTGI, Post-traumatic Growth Inventory; r, correlation coefficient; R2, coefficient of determination; R2change, change in R2; RBANS, Repeatable Battery for the Assessment of Neuropsychological Status; RCFT, Rey-Osterrieth Complex Figure Test; SCS, Self Compassion Scale; SD, Standard Deviation; SDS, Sheehan’s Disability Scale; SE/R, Rosenberg Self-Esteem scale; SMD, Standardised Mean Difference (effect size); STAI/S, State Anxiety Scale; TA, Therapeutic Alliance; TAS-20, Toronto Alexithymia Scale; WAI, Therapeutic Alliance Inventory
Non-randomised studies of intervention involving MDMA- assisted psychotherapy for PTSD (characteristics and outcomes).
Number of participants analysed in MP-16 and MP-17 respectively
Studies that did not exclude participants with BPD
ACE, Adverse Childhood Experience; CPGS, Chronic Pain Grade Scale; CSI, Couples’ Satisfaction Index; ERQ, Emotion Regulation Questionnaire; IPF, Inventory of Psychosocial Functioning; IRI, Interpersonal Reactivity Index; MSIS, Miller Social Intimacy Scale; PTGI, Post-traumatic Growth Inventory; QRI, Quality of Relationships Inventory; SORTS, Significant Others' Responses to Trauma Scale; TABS, Trauma and Attachment Belief Scale
Case studies involving MDMA-assisted psychotherapy for trauma-related disorders (studies’ characteristics and outcomes).
Themes extracted by the study authors from the participant narratives were as follows: (a) Psychological mechanisms of symptom change → improved trauma reprocessing, positive cognitive changes, greater emotional awareness and regulation (b) Reduced PTSD symptoms → reduced intrusions, reduced avoidance, improved cognitions and mood, reduced vigilance and arousal (c) Additional effects → reduced suicidality, reduced substance use, pursuing priorities. Case selected from MP-16 (Wang et al. 2021) sample
Risk of bias assessed using MMAT
Studies that did not exclude participants with BPD
The one case study that specifically reported outcomes for a participant with CPTSD reported fewer benefits from MDMA-AP (Table 4). 57 Despite not all dysfunctional behaviours associated with CPTSD resolving with MDMA-AP, the participant (Anne) benefitted from reduced trauma avoidance and reluctance, and improved self-esteem, motivation to change, interpersonal relationships and therapeutic trust. 57 Additionally, a range of benefits post- MDMA for PTSD symptoms are relevant for people with CPTSD, including:
reduction in PTSD symptom severity (n = 11)21,24,25,27,28,44–47,52,57;
increased openness (n = 2),25,48 including openness to future therapies 51 ;
increased self-compassion (n = 2)55,59 and self-awareness (n = 2)55,59;
decreased neuroticism (n = 2),25,48 pain intensity, disability and severity (n = 1), 50 depressive symptoms (n = 7),25,28,44–47,55 co-occurring eating disorder symptoms (n = 2),54,60 co-occurring substance use issues (n = 2),55,61 abandonment concerns (n = 1), 59 alexithymia (n = 1), 59 idealisation disillusionment (n = 1), 59 identity impairment (n = 1), 59 identity diffusion (n = 1), 59 susceptibility to influence (n = 1), 59 affect dysregulation (n = 3),47,55,59 affect instability (n = 1), 59 affect skill deficit (n = 1) 59 and tendency to react adversely to emotional pain/distress (n = 1) 59 ;
improved sleep quality (n = 4),25,45–47 relationship satisfaction (n = 1), 47 quality of life (n = 1) 58 and relationship happiness (n = 1) 47 ;
One study identified therapeutic alliance as a significant predictor of PTSD symptom reduction in participants who received MDMA-AP. 53 A majority of participants (>60%) who received MDMA-AP no longer met diagnostic criteria for PTSD post-treatment, compared to <50% of participants who received an inactive placebo with psychotherapy.24,27,28 Similar remission rates were observed 1 year after treatment by Oehen et al. 21 (41.6%) and Ot’alora et al. 46 (76%). This concurs with participant self-reporting in Mithoefer et al., 49 in which 58% of participants who received MDMA-AP perceived a large benefit, with 42% reporting that the benefits had continued to grow years after the intervention had ended. Improvements in post-traumatic growth, openness, relationship quality, sleep quality, self-awareness, empathic concern, intimacy with one’s partner, individual trauma-related beliefs, psychosocial functioning and reductions in depressive symptoms, neuroticism, medication and substance misuse, emotion dysregulation and interpersonal difficulties were also sustained for some participants followed up post-intervention at different time points,25,44,46–48,51,58 with one participant attributing their change to therapeutic features of MDMA-AP which made them feel safe and well-equipped with ‘tools and weapons to be able to tackle the obstacles that [they] never had before’. 51
Another participant reflected that change was enabled by his ‘new understanding of the traumatic experiences and acceptance’, 56 facilitated by the entactogenic and empathogenic effects of MDMA observed in participants who received the active drug. 62 As a result, participants felt more able to connect with their sense of self and empathise with themselves and others. Notably, these changes correlated with reduced PTSD symptom severity post-treatment. 62
MDMA-AP outcomes for BPD
While none of the studies specifically included participants with a diagnosis of BPD, six out of the 24 included studies did not exclude people with BPD (Tables 2–4, Additional File 2).25,44,47,51,56,58 Out of the six studies, two were RCTs,25,44 and one was an NRSI.25,47 One was a follow-up study of the RCT, 51 and the other two derived their data from the NRSI.56,58 The RCTs, Mithoefer et al. (n = 26) and Bouso et al. (n = 6), found that participants who received MDMA-AP had a persistent decrease in neuroticism, an increase in agreeableness and openness, improvement in sleep quality, psychological function, dissociative symptoms, and depression at the end of the study and long-term follow-up.25,44,51 Notably, Bouso et al. 2008 solely included participants who had no other psychiatric disorder except for PTSD and comorbid symptoms. They did not specifically exclude participants with personality disorders, making it likely that the participants had undiagnosed BPD or BPD-related symptoms or traits. At 12-month follow-up, participants of the Mithoefer et al. study reported improvements in self-awareness (n = 19, 73%), relationship and social skills (n = 12, 46%), a reduction in substance abuse (n = 13, 50%), and felt more open about continuing therapy (n = 14, 53%). 51 Findings from the NRSI showed similar improvements, with participants (n = 6 patients) reporting additional improvements in sleep quality, empathy, psychosocial functioning, trauma-related beliefs, relationship quality, post-traumatic growth, and emotion regulation.47,56,58
Additionally, an exploratory outcome study of an RCT that excluded participants with BPD measured and reported outcomes applicable to people with BPD. 59 This study highlighted significant improvements in most measures for participants who received MDMA-AP (n = 42) compared to those who received the placebo with therapy (n = 40). 59 These included a reduction in interpersonal conflicts, abandonment concerns, alexithymia, idealisation disillusionment, identity impairment, susceptibility to influence, affect dysregulation, affect instability, affect skill deficit and tendency to react adversely to emotional pain/distress and improvements in self-awareness and self-compassion. 59 Other exploratory outcomes, particularly relevant to people with BPD – such as co-occurring chronic pain and eating disorder symptoms – also markedly improved in participants with PTSD across several studies.50,54,60
Adverse drug reactions
Of the 24 included studies, 11 reported ADRs (see Additional File 1). Of the four studies that included participants with a history of multiple forms of trauma, three reported ADRs.24,28,52 Commonly reported ADRs across these three studies included insomnia, muscle tension, lack of appetite, nausea, perspiration, blurred vision, nystagmus and suicidal ideation.24,28,52 Among the six studies that did not specifically exclude participants with BPD, three reported ADRs, with fatigue or low energy being the most common.25,44,56 This was followed by muscle tension, headache, anxiety, perspiration, restlessness, sleepiness, and difficulties with concentration.25,44,56
All included studies either reported ADRs on the day of drug administration or within 7 days following drug administration. One study reported ADRs during preparatory sessions, experimental sessions, 7 days after each experimental session and during integrative sessions. 45 Another study also reported ADRs 2 months and 12 months after the last MDMA session. 46 Two months after treatment, 15% of all study participants reported treatment-emergent adverse events (TEAE), including anxiety (3.8%), obsessive rumination (3.8%) and suicidal ideation (7.7%). Psychiatric disorders were reported by 12% of all participants at 12-month follow-up. 46
Six studies (four RCTs and two NRSIs) reported suicidality-related outcomes for their participants using C-SSRS (Table 5).24,25,28,45,46,52 Five showed reductions in suicidal ideation and intent for low/high dose MDMA-AP.24,25,28,46,52 Although in one study, similar reductions were seen in positive ideation for participants in the inactive placebo arm, 24 participants in another study who received an inactive placebo reported an increase in serious ideation at study termination compared to baseline. 28 In dose-response studies, no suicidal ideation or intent was reported by participants after crossing over from the low-dose MDMA arm to the high-dose MDMA arm.25,46 Compared to baseline, there was an 83% decrease in positive ideation and a 100% decrease in serious ideation at the 12-month follow-up. 46
Proportion of participants (n) reporting positive ideation, serious ideation, or suicidal behaviour on the C-SSRS across studies reporting the outcome.
The results at the end of stage 1 (following the last blinded session) are presented for studies with a crossover stage.
None of the participants who initially received the 40 mg MDMA reported PI, SI or PB at 12-month follow-up; however, 11% (n = 1/9) of participants from the 100 mg and 18% (n = 2/11) of participants from the 125 mg MDMA-AP group reported PI at 12-month follow-up.
Data from six participants of the 30 mg MDMA-AP group and six participants of the 75 mg MDMA-AP group who received 100–125 mg MDMA-AP post-crossover.
MP-16 and MP-17 results are combined.
Baseline values reported in Jardim et al. 2021 are not interpretable. The authors have reported final values for SI, intensity of ideation (II) and suicidal behaviour (SB), which have been converted to PI, SI and PB for consistency. PI is > 0 score on C-SSRS ideation subscale and SI is scores ⩾ 4 or 5. One participant had ideation of moderate intensity (II: 9) and one had moderate to severe intensity (II: 11) at the end of the study.
After the third experimental session, 11 participants in the MDMA arm and 16 participants in the placebo arm required extra visits owing to positive SI requiring resolution. Of the 11, two participants from the MDMA arm indicated active SI with at least some intent to act.
II, intensity of ideation; MDMA-AP, 3,4-Methylenedioxymethamphetamine-assisted psychotherapy; n, number of participants in each sub-set; N, total number of participants; PB, positive behaviour; PI, positive ideation; SB, suicidal behavior; SI, suicidal ideation.
Treatment discontinuation due to adverse drug reactions
Reasons for treatment discontinuation due to ADRs following an MDMA-AP session included re-experiencing trauma with intense negative emotions (one participant, 25 mg arm), 21 relapse of depression (one participant, 125 mg arm), 27 increased nightmares (one participant, 80–187.5 mg), 52 and distress due to CAPS assessments and depressed mood (one participant, 80–120 mg). 28 Additionally, one participant from the 30-mg MDMA arm in Mithoefer et al., one from the 125-mg MDMA arm in Oehen et al., and one from the 125-mg MDMA arm in Ot’alora et al. discontinued treatment following their respective MDMA-AP sessions due to an ADR; however, the type of ADRs that led to the withdrawal of these participants was not reported.21,25,46
Reasons for treatment discontinuation in the inactive placebo arm included suicidal ideation (two participants, one discontinued treatment and restarted medication),24,28 insomnia (one participant) 28 and abdominal pain (one participant). 24
Some studies24,28,50,52 listed reasons for participant withdrawal as either ‘participant chose to discontinue treatment’ or ‘withdrawal by subject’. In one study, this occurred for six participants in the placebo arm (one of whom withdrew because they believed they were receiving a placebo) and one in the MDMA arm. 24 In another study, all five participants who withdrew received MDMA-AP (owing to the study design), making it possible that the withdrawals occurred due to a perceived ineffectiveness of the intervention.50,52
Discussion
The evidence presented in this review supports MDMA-AP as an emerging treatment that can be beneficial for people with PTSD, including people with a history of multiple forms of trauma (e.g. CPTSD), and potentially for people with BPD. MDMA’s prolonged effects enable the person to be less defensive or avoidant, more open-minded, while retaining cognitive control over their emotions. When facilitated by a good therapeutic alliance, which is also enhanced by the effects of the active drug, MDMA-AP may assist people with a history of trauma to access and process difficult memories without fear and with self-compassion.
Along with reduced PTSD symptom severity and improved therapeutic alliance, benefits include increased self-awareness, compassion for self and others, improved relationships and social skills, and a more stable mood. MDMA-AP may also provide respite from symptoms of co-occurring disorders such as binge eating and substance misuse. ADRs associated with MDMA-AP were mild to moderate and commonly occurred within seven days of drug administration. No deaths or prolonged hospitalisations were reported. Few studies provided reasons for treatment discontinuation among participants receiving either MDMA-AP or placebo with therapy, resulting in limited insight into attrition-related factors. Where this was reported, re-experiencing of traumatic memories, nightmares and relapse of depressive symptoms were identified as potential contributors to treatment disengagement for some participants receiving the active drug.21,27,52
Relevance of MDMA-AP for CPTSD and BPD
One of the key predictors for the development of PTSD and CPTSD is the nature of trauma exposure: while people with PTSD can have a history of multiple traumatic events, these are typically repeated exposure as an adult to the same form of trauma.5,10,63 In contrast, there is an increased likelihood of developing CPTSD following exposure to multiple forms of trauma, especially developmental or childhood trauma.10,63,64 Notably, four studies in this review reported that participants with multiple forms of trauma – most commonly developmental or childhood trauma – experienced therapeutic benefits from MDMA-AP comparable to those observed in people with a history of a single form of trauma.24,28,47,52 Although there is a paucity of research directly investigating the benefit of MDMA-AP for improving symptoms of CPTSD, it should be noted that when recruiting people with PTSD, some studies inadvertently captured people with multiple forms of trauma and DSO symptoms who may have qualified for a diagnosis of CPTSD. CPTSD was included as a diagnosis in the ICD-11 in 2021, which explains the lack of representation of the diagnosis in the studies included in this review, which were completed between 2000 and 2022. Therefore, it is possible that participants in the PTSD studies met criteria for CPTSD but hadn’t received a diagnosis at the time of investigation. Findings from the single case study evaluating a participant with CPTSD (published in 2022) have limited generalisability given its specificity and individualised nature. However, it offers valuable preliminary insights, alongside evidence from studies investigating MDMA-AP in people with multiple forms of trauma and DSO symptoms.
Studies included in this review not only demonstrated beneficial outcomes of MDMA-AP on participants’ (both with single and multiple forms of trauma) overall psychological function, but also for DSO symptoms that are specific to CPTSD, 8 including affect dysregulation,47,55,59 self-compassion,55,59 and relationship skills.47,58,59 The case study raises the possibility that participants with CPTSD may have an increased need for therapeutic support before and after the experimental session to achieve these outcomes. 57 Anne underwent eight MDMA sessions with an MDMA dose of up to 125 mg, requiring an ‘extensive’ psychoeducational preparatory phase, which suggests greater presentation complexity. 57
Another feature of CPTSD is the prevalence of dissociative symptoms. 65 Although CPTSD and PTSD-DT are distinct diagnoses, both share core trauma-related and dissociative symptoms, making differential diagnosis challenging. 7 Consequently, therapeutic benefits observed in PTSD-DT may also be relevant for people with CPTSD presenting with dissociative features. Findings from this review suggest that participants with a dissociative subtype of PTSD who received MDMA-AP experienced a greater reduction in PTSD symptoms post-intervention than those who received an inactive placebo alongside psychotherapy.24,28 Furthermore, there was a larger decrease in dissociative symptom severity among participants receiving a higher dose of MDMA-AP (>75 mg MDMA-AP)25,46,55; however, these symptoms increased for participants in the low-dose group, 25 suggesting that MDMA doses higher than 75 mg may be required for participants with a trauma-related disorder accompanied by dissociative symptoms.
It is proposed that improved attachment security and reduced attachment fearfulness ameliorate CPTSD symptoms. 66 Studies analysed in this review suggest that MDMA-AP has a positive impact on interpersonal difficulties, including trust, openness, and avoidance. Other benefits include an improved therapeutic alliance, increased self-compassion, and a greater ability to connect with others.47,53,56,58,59,62 Similar to trauma-focused cognitive behavioural therapy (TF-CBT), which has shown promising results for people with CPTSD,67,68 MDMA-AP helps the person create a trauma narrative during post-session integration and alter maladaptive cognitions. Other evidence-based interventions, such as prolonged exposure (PE) and cognitive processing therapy (CPT), have also demonstrated considerable effectiveness for people with CPTSD. 69 However, each targets a specific subset of CPTSD symptoms (e.g. PE addresses trauma avoidance and negative cognition, whereas TF-CBT improves emotion regulation and interpersonal difficulties). 68 Available evidence recommends combining multiple interventions to maximise benefit. 70 Following this line of logic, due consideration should be given to offering MDMA-AP as a holistic, feasible and effective intervention that targets a range of symptoms for people with CPTSD. A lack of studies specifying CPTSD in their inclusion criteria warrants further rigorous research among participants with the disorder.
Six studies included in this review did not exclude participants with BPD. These studies reported therapeutic outcomes following MDMA-AP that were comparable to those observed in studies excluding participants with BPD.25,44,47,51,56,58 The reported outcomes included improvements in domains particularly relevant to remission and recovery in BPD, 71 such as emotion regulation, post-traumatic growth, substance use, dissociative symptoms, self-awareness, interpersonal functioning, and overall psychological well-being. As was observed in one study sample, 57 some participants with PTSD or CPTSD likely had co-occurring borderline personality traits, given the prevalence of its co-occurrence. 22 Notably, one study 25 employed the NEO-PI-R to assess changes in the five broad dimensions of personality, 72 demonstrating significant improvements. Although none of the studies specifically evaluated the feasibility of MDMA-AP for BPD, the observed benefits in PTSD populations may be cautiously extrapolated to BPD, particularly given the overlap in symptomatology and the lack of specificity in exclusion criteria across these six studies. 22
According to the DSM-5 and extant evidence, the following traits are characteristic of BPD: fear of abandonment; intense and unstable interpersonal relationships characterised by idealisation and devaluation; identity disturbance; impulsivity that may be self-damaging; recurrent suicidal or self-harming behaviours; affective instability; chronic feelings of emptiness; intense anger or difficulty controlling anger; and dissociative symptoms.5,73–80 The studies included in this review report that MDMA-AP demonstrates therapeutic efficacy across many of these domains, including reduction in abandonment concerns, interpersonal conflict, and idealisation-disillusionment cycles; improvement in identity impairment and relationship dynamics; decreased impulsivity-driven tension-reduction behaviours; reduced suicidal ideation and self-harm; enhanced emotional regulation and affective stability; improved self-concept (potentially alleviating chronic emptiness) and attenuation of dissociative symptoms and emotional dysregulation (often expressed and/or perceived as anger). Improvements in neuroticism, openness, alexithymia, and sleep quality – other symptoms commonly observed in people with BPD81–83 – were also reported. Improvements in openness, facilitated by an MDMA-AP-enhanced therapeutic alliance, can be critical for achieving better treatment outcomes in trauma-related disorders. Evidence-based treatments for BPD underscore the crucial role of such a therapeutic alliance in improving patient outcomes, particularly when mediated by mutual trust.84–87 This alliance facilitates key processes, including the emergence of psychological change, the validation of emotional experiences, and the integration of split object representations (i.e. idealisation-devaluation), all of which are central to remission and recovery in BPD.84–87
Non-suicidal self-injury and suicidality are frequently employed as maladaptive self-regulation strategies among people with BPD. 88 Across multiple studies, MDMA-AP has demonstrated reductions in tension-reduction behaviours, such as impulsive self-harm59,73 and significant decreases in suicidal ideation24,25,28,46,52 (including one study that did not exclude people with BPD). These outcomes, alongside improvements in a wide range of BPD-related symptoms, suggest that MDMA-AP may enhance self-regulatory capacity and reduce the likelihood of future self-injurious and suicidal behaviours.
One surprising finding of this review is the marked self-reported improvements in self-capacities (psychological functioning) among participants who received MDMA-AP. 59 People with trauma-related disorders often have reduced self-capacities, which inhibit their post-traumatic growth. 59 This includes decreased capacity for dialectical thinking, which is prominent in people with BPD, leading to idealisation and devaluation of situations or persons. 89 MDMA-AP can reduce feelings of fear, increase self-awareness, and improve emotional regulation as a result of decreased activity in the amygdala, enabling the person to uncouple themselves from their ‘emotional mind’ 89 and access their external and internal states. MDMA-AP’s beneficial effects for post-traumatic growth and alexithymia offer further evidence of this phenomenon. 59 With these benefits, the person can better activate their ‘wise mind’ 89 and obtain a more grounded perspective, with less likelihood of experiencing idealisation and disillusionment, abandonment concerns and identity impairment.
Standard treatment approaches for BPD, such as DBT and MBT, have proven effectiveness for BPD. However, very few treatments specifically target the fear of abandonment, which is a persistent and chronic symptom of the disorder.79,90,91 Use of a structured approach to target the fear of abandonment in BPD is proposed to reduce suicidality and help remit from symptoms. 90 MDMA can serve as a facilitator in this structured approach by reducing negative evaluations and emotions, assisting the person to disengage from trauma-related distress, increasing openness, and improving self-awareness. As identified in this review, MDMA has the potential to accelerate the therapeutic process, better enabling the symptomatic person to achieve remission. Another core feature of BPD, chronic feelings of emptiness, is slow to remit and often recurs. 91 These feelings may arise due to feelings of disconnection from self and others, impaired identity, and difficulties with personal values and goals.91,92 Reducing identity disturbances and improving relationship and social functioning skills are thought to reduce feelings of emptiness in people living with BPD. 92 In this way, MDMA-AP may also be indirectly beneficial for reducing chronic feelings of emptiness; however, further rigorous research that specifically measures this symptom is needed.
Other potential benefits of MDMA-AP for people living with BPD include decreased pain intensity, disability and severity, contributing to improved affect.50,93 Improved affect may also lead to a decrease in pain disability.50,52 This would be a significant advantage, as people living with BPD often suffer from chronic pain and vice versa. 94 Along with improvements in interpersonal and affective symptoms, the broader benefits reported for MDMA-AP for PTSD, substance use disorder, eating disorder, and depressive symptoms may also improve the chances of recovery from BPD, given the extent of their co-morbidity. 95 Notably, many of these benefits align with consumer-identified treatment goals, underscoring their relevance and potential value in supporting recovery for people living with BPD. 71 Compared to existing treatments for BPD-PTSD or BPD-CPTSD, MDMA-AP has the potential to offer rapid (18 weeks of MDMA-AP vs 12–18 months of standard psychotherapy) and enduring benefits for both personality and trauma symptoms.
Nonetheless, there are also concerns specific to BPD and CPTSD that need to be considered when considering treatment with MDMA-AP. One of the hallmark symptoms of BPD is a ‘fear of abandonment’. 5 Although evidence from this review suggests that there were significant reductions in abandonment concerns and emotional dysregulation post-MDMA-AP treatment (in 91% of all participants, n = 42/46), some participants in van der Kolk et al. 2024 experienced abandonment issues at the end of treatment. 59 Fineberg and colleagues define this as a ‘termination reaction,’ wherein participants experience acute distress and suicidal ideation before discharge despite initial improvements. 96 Given the increase in trust and emotional connection (therapeutic alliance) that accompanies MDMA-AP, it is worth considering ways to mitigate the possibility of increased emotional reactivity among participants with BPD in the context of discharge. MDMA-AP interventions for people with BPD likely require greater emphasis on participant preparedness, implementation of safeguards against participant-therapist boundary violations through formal informed consent processes for giving and receiving therapeutic touch, ensuring robust supervision for therapists delivering the intervention, and adoption of a tapered approach to discharge planning. BPD is associated with a heightened risk of suicidality, which may be exacerbated during MDMA-AP. This underscores the need for rigorous pre-treatment screening and stabilisation, as well as more frequent and enhanced monitoring throughout the intervention. Nonetheless, evidence suggests that trauma-focused treatment provides containment for people presenting with BPD-PTSD, as the person’s urges to self-harm or attempt suicide tend to decrease when their underlying trauma is addressed. 11 We also speculate that the decrease in negative emotions and participation in the integration sessions following administration of MDMA may further reduce this risk. Other treatment-emergent adverse events (TEAEs) that might be expected for people with BPD include anxiety, insomnia/increased nightmares and relapse of depression, which were noted as ADRs in multiple studies (Table S6, Additional File 1), with relapse of depression leading to treatment discontinuation in one study. 27 Given the prevalence of these symptoms in people with BPD, their exacerbation during MDMA-AP is likely. Conversely, people with CPTSD may be at increased risk of over- or under-arousal – re-experiencing trauma memories leading to nightmares, increased flashbacks, shutdown and dissociative symptoms – relative to people with PTSD. While discontinuation of treatment may be necessary for anyone receiving MDMA-AP for a trauma disorder, use of rescue medications, adequate psychoeducation during preparatory sessions, and provision of psychological support during integration sessions may help mitigate these TEAEs and support the continuation of the treatment.
Strengths and limitations
To our knowledge, this is the first systematic review to aggregate all primary evidence, including secondary outcome data, for the use of MDMA-AP for the most significant trauma-related disorders. In so doing, this review offers the first complete distillation of published research describing the use of MDMA-AP for treating PTSD or CPTSD and/or BPD. A key strength of this review lies in its transparent and replicable methodology. It systematically examined evidence concerning the broad application of MDMA-AP for trauma-related disorders while also considering the underexplored area of MDMA-AP for the treatment of BPD. The review process incorporated systematic study identification, independent risk-of-bias assessment using standardised appraisal tools, and dual-reviewer data extraction, thereby enhancing rigour and reliability.
A notable limitation, however, is that none of the included studies directly evaluated MDMA-AP in people with BPD. While this restricts the ability to draw disorder-specific conclusions, the review nonetheless confirms a critical gap in the literature.97,98 Although this review includes evidence from studies that did not explicitly exclude participants with CPTSD or BPD, the inferential process through which these cases were identified, as well as the absence of targeted inclusion criteria for BPD, limit the specificity and precision of the findings, rendering the evidence suggestive rather than conclusive. This lack of direct evidence reinforces the need for targeted research. However, a strength of the review is the identification of transdiagnostic outcomes – many of which overlap with core features of BPD – which provide insights into the potential utility of MDMA-AP for this population.97,98 Future studies should employ appropriate psychometric assessment tools for BPD-PTSD and/or BPD-CPTSD and give due consideration to the unique clinical concerns relevant to these cohorts.
The reviewers judged most studies included in this review as having a high risk of bias. Of the 24 studies, only 10 used an inactive placebo as a control, demonstrating a greater number of ADRs reported for participants who received MDMA-AP relative to the inactive placebo. This bias is compounded by the non-systematic methods the included studies used for reporting ADRs, 20 which may have contributed to an increased reporting of ADRs for one intervention over another. Standardised tools for measuring ADRs should be incorporated into future studies to systematically assess the safety of MDMA-AP for people with trauma-related disorders. Nine studies included in this review used PP or complete-case analyses (Tables 2 and 3), which may overestimate the effect of the intervention. Consequently, the findings presented should be interpreted within the context of the methodological limitations of each study.
MDMA-AP has demonstrated a reduction in suicidal ideation and intent among participants with a trauma-related disorder; however, some studies excluded people who presented with a high risk of suicide at baseline.21,45,52,55 Additionally, out of 24 studies, only six used a standardised tool for measuring suicide risk (Table 5). Therefore, results on suicidal risk/behaviours may not be generalisable to at-risk populations (e.g. people with BPD whose presentation includes suicidality and self-harm) and should be interpreted with caution.
Studies including participants with a history of multiple forms of trauma utilised CAPS to assess their PTSD symptom severity. Although CAPS-5 may potentially capture some changes in symptoms for CPTSD, 36 direct assessment of DSO symptoms is essential for a comprehensive evaluation of the disorder. Future studies should incorporate appropriate psychometric tools that are validated for use in people with CPTSD, such as the self-reported International Trauma Questionnaire (ITQ) or the clinician-administered International Trauma Interview (ITI). 36
The one study that was conducted in a public mental health setting, 44 which could have offered additional understanding of the feasibility of conducting MDMA-AP in a public setting, was discontinued prematurely, limiting insights into attrition factors. Although the study showed improvements in participants’ (n = 6) PTSD and depressive symptoms, 44 it did not collect data concerning the acceptability of the intervention, which could guide future interventions in a public mental health setting. Therefore, future studies conducted in these settings should consider collecting detailed data from participants on treatment acceptability and reasons for treatment disengagement.
Lastly, the authors of included studies were not contacted for clarification regarding reported data owing to resource limitations and time constraints, which may have impacted the overall quality of the review. 99 Despite these limitations, this review offers valuable preliminary evidence on the benefits of MDMA-AP for populations diagnosed with trauma-related disorders (i.e. PTSD, CPTSD, BPD) and identifies important areas for future study.
Conclusion
The aim of this review was to synthesise evidence concerning the effectiveness and safety of MDMA-AP for people with PTSD or CPTSD and/or BPD. MDMA-AP is an evidence-based intervention that has demonstrated considerable efficacy in treating PTSD. This review extends earlier findings by highlighting the potential benefits of MDMA-AP for people with a history of multiple forms of trauma and dissociative symptoms indicative of CPTSD, as well as relational and identity disturbances characteristic of BPD. Through the attenuation of trauma avoidance and negative emotions, MDMA facilitates processing of salient traumatic experiences with self-compassion and without fear – an emotional state considered vital in the treatment of both CPTSD and BPD. When integrated with clinician support, this process fosters insight and the restructuring of entrenched beliefs and behaviours, underscoring the relevance of MDMA-AP to both of these complex clinical presentations. ADRs reported by studies that likely included participants with CPTSD and BPD were generally mild to moderate. Nevertheless, safety concerns remain, especially given the limited evidence specifically addressing the use of MDMA-AP in CPTSD and BPD. As the first review to systematically explore MDMA-AP’s applicability to CPTSD and BPD, this work offers novel preliminary insights to inform future research and clinical practice.
Supplemental Material
sj-docx-1-tpp-10.1177_20451253251408626 – Supplemental material for Making a case for using MDMA-assisted psychotherapy for borderline personality disorder and complex PTSD: a descriptive systematic review of the literature
Supplemental material, sj-docx-1-tpp-10.1177_20451253251408626 for Making a case for using MDMA-assisted psychotherapy for borderline personality disorder and complex PTSD: a descriptive systematic review of the literature by Karthika Kasiviswanathan, Dinuli Nilaweera, Melissa Morando, Sathya Rao, Jessica Lee, Joseph Fettling and Jillian H. Broadbear in Therapeutic Advances in Psychopharmacology
Supplemental Material
sj-xlsx-1-tpp-10.1177_20451253251408626 – Supplemental material for Making a case for using MDMA-assisted psychotherapy for borderline personality disorder and complex PTSD: a descriptive systematic review of the literature
Supplemental material, sj-xlsx-1-tpp-10.1177_20451253251408626 for Making a case for using MDMA-assisted psychotherapy for borderline personality disorder and complex PTSD: a descriptive systematic review of the literature by Karthika Kasiviswanathan, Dinuli Nilaweera, Melissa Morando, Sathya Rao, Jessica Lee, Joseph Fettling and Jillian H. Broadbear in Therapeutic Advances in Psychopharmacology
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sj-xlsx-2-tpp-10.1177_20451253251408626 – Supplemental material for Making a case for using MDMA-assisted psychotherapy for borderline personality disorder and complex PTSD: a descriptive systematic review of the literature
Supplemental material, sj-xlsx-2-tpp-10.1177_20451253251408626 for Making a case for using MDMA-assisted psychotherapy for borderline personality disorder and complex PTSD: a descriptive systematic review of the literature by Karthika Kasiviswanathan, Dinuli Nilaweera, Melissa Morando, Sathya Rao, Jessica Lee, Joseph Fettling and Jillian H. Broadbear in Therapeutic Advances in Psychopharmacology
Footnotes
Acknowledgements
The authors wish to acknowledge Geoff Hill, Clinical Librarian at the Health Sciences Library, Royal Melbourne Hospital, for providing expert guidance in the development of the literature search strategy for this review.
Declarations
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References
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