Introduction

In the past decade, research on the therapeutic use of 3,4-methylenedioxymethamphetamine (MDMA) in psychotherapy has gathered pace. MDMA-assisted psychotherapy (MDMA-AP) uses a combined pharmacotherapy-psychotherapy model, with MDMA thought to ‘catalyze’ the effects of psychotherapy. In typical protocols, patients attend 3–4 initial ‘preparatory’ psychotherapy sessions, followed by 2–3 full day MDMA- (or placebo-) assisted sessions, each followed by 3–4 ‘integration’ psychotherapy sessions. Methodological questions notwithstanding [1, 2], growing evidence now suggests that MDMA-AP has therapeutic potential for posttraumatic stress disorder (PTSD) [3, 4] and possibly other psychiatric conditions [5,6,7]. Several clinical trials are planned or ongoing [8].After a recent decision by the Australian Therapeutic Goods Administration (TGA), psychiatrists who are authorized prescribers can now prescribe MDMA for PTSD [9], making Australia the first country to schedule MDMA for medicinal use. It also appears likely that MDMA-AP will be approved by the U.S. Food and Drug Administration (FDA) for PTSD in 2024 [10], with the first new drug application submitted to the FDA in late 2023. While the literature to date has largely concluded that MDMA [11] and MDMA-AP are safe and well tolerated, concerns exist about the unique potential for substances like MDMA—when combined with psychotherapy—to cause harm [12, 13], as well as inadequacies in the assessment and reporting of adverse events in existing research [14]. A comprehensive understanding of potential safety issues in MDMA-AP is needed to inform both ongoing research and translation to clinical practice.While acute adverse effects of MDMA without psychotherapy have been determined in detail in placebo-controlled studies in healthy subjects [11], previous reviews of the safety and tolerability of MDMA-AP did not include meta-analyses of safety outcomes [14,15,16,17,18,19,20,21,22], or were limited to PTSD [15, 16, 20,21,22,23], terminal illness [19], or depression [18]. Reviews which included meta-analyses of side effects did not assess the full range of safety outcomes reported [23, 24], and no prior evidence synthesis has included the most recent Phase 3 study of MDMA-AP [4]. Given regulatory changes to the status of MDMA-AP and the large pipeline of ongoing research, a comprehensive updated quantitative assessment of the safety and tolerability of MDMA-AP is timely. Here, we conducted a systematic review and meta-analysis of the side effects of MDMA-AP across psychiatric indications. We also addressed concerns about the adequacy of safety reporting in this research (e.g., [12, 14]), providing the first assessment of the quality of side effect-reporting in published trials of MDMA-AP against the CONSORT Harms 2022 guidelines [25]. Herein, ‘side effects’ is used as an umbrella term to describe the range of safety outcomes reported, which are variously described in published reports as spontaneously reported reactions, treatment emergent adverse events, adverse events, adverse effects and harms.

Methods

This systematic review and meta-analysis was pre-registered on PROSPERO (CRD42022355572) and is reported according to the PRISMA guidelines [26].

Search strategy

PubMed, EMBASE, PsycINFO, MEDLINE and Cochrane Central Register of Controlled Trials (CENTRAL) were searched from inception using the following search terms: (“MDMA” OR “3,4-methylenedioxymethamphetamine”) AND (“psychotherapy” OR “therapy”) AND (“safe” OR “side” OR “adverse”), adapted to the technical requirements of each database (Table S1). No restriction on publication date or status was applied.The primary reviewer (JC) screened titles and abstracts. Full-text articles were reviewed by two independent authors (JC and AAG), with disagreements resolved by consensus. Searches were re-run just before the final analysis on 30 October 2023. Articles were screened and full-texts stored using Covidence (Veritas Health Innovation, Melbourne, Australia).

Inclusion and exclusion criteria

Studies included were published in English-language peer-reviewed journals and involved administration of one or more MDMA doses to humans (any dose frequency and timing) combined with psychotherapy, with the aim of treating a target psychiatric condition. Exclusion criteria included: (1) studies not including psychotherapy; (2) papers not including original data e.g., reviews or commentaries; (3) conference abstracts; (4) book chapters; and (5) animal studies. These criteria meant that only Phase 2 and 3 studies were included: all Phase 1 studies assessed MDMA in the absence of psychotherapy [11].

Data extraction

We extracted information on: (1) design; (2) population; (3) demographics (age, sex, ethnicity); (4) MDMA administration (dosage, number of doses); (5) control condition(s); (6) previous MDMA/ecstasy/molly use; (7) health screening; (8) medical comorbidity; (9) concomitant medications; (10) timing of side effects assessment; (11) outcomes of interest (i.e., side effects, study withdrawal); and (12) whether structured assessments were used to assess side effects or safety.Data were extracted by the primary reviewer (JC), and subsequently checked for accuracy and completeness by a second reviewer (AAG or SM). For missing data, reviewers first contacted study authors for unreported data and/or additional details. If additional information was not available, missing data were coded as “Not Reported”.

Data synthesis

Qualitative synthesis included the following steps: (1) data were extracted; (2) quality and risk of bias was assessed; and (3) findings were summarized in a table for each outcome. Results were synthesized using a narrative approach.Where at least two studies contributed data for an outcome, we conducted pairwise meta-analyses using Review Manager 5.4 (The Cochrane Collaboration, United Kingdom), comparing MDMA-AP to the control. Various doses for the MDMA group were pooled, and control groups included both active (low-dose MDMA) and inactive placebo. As outcomes were dichotomous, odds ratios (ORs) with 95% confidence intervals (95% CI) were calculated (Mantel–Haenzsel method). Random-effects models were used to control for heterogeneity. The significance level was set to p < 0.05 (two-tailed). Publication bias was not assessed as there were ≤10 studies in each analysis [27]. Heterogeneity was estimated using the I² statistic, and subgroup analyses of PTSD studies and non-PTSD studies were completed (it was not possible to conduct more specific subgroup analyses as to particular types of PTSD patients—e.g., combat veterans – as most studies included participants with a range of different types of trauma exposure). Sensitivity analyses were performed to assess effects of method used to assess side effects and number of medication sessions on the outcomes.We synthesized outcomes from Phase 2 and 3 studies separately due to differences in data collection and reporting. We defined the following primary outcomes for Phase 2 studies: (1) any side effect—during medication sessions; (2) any side effect—7 days following medication sessions; (3) treatment emergent adverse event (TEAE); and (4) psychiatric treatment emergent adverse event. Outcomes 1 and 2 were based on ‘spontaneous reported reactions’ data from Phase 2 studies, which included a subset of events that were judged to be expected based on evidence about MDMA’s side effects from healthy control studies [11]. TEAEs and psychiatric TEAEs were defined as events not on the expected reactions list, or which continued for >7 days after medication sessions [28]. We defined the following primary outcomes for Phase 3 studies: (1) treatment emergent adverse event; and (2) adverse event of special interest. Consistent with Phase 3 study [3, 4] reporting, we defined TEAEs for Phase 3 outcomes as any adverse event occurring across the treatment period. Adverse events of special interest were prespecified events related to cardiac function, suicidality, and MDMA abuse, misuse, or diversion identified as of special interest by the FDA [3, 4]. We also defined study withdrawal as a primary outcome across all studies. Secondary outcomes broke down each primary outcome by type (e.g., anxiety, reason for withdrawal; see Supplemental Table 8 for primary and secondary outcomes).

Quality of side effect-reporting

Data on side effects from all included randomized controlled trials (RCTs) were independently assessed by two reviewers (JC and AAG) using the CONSORT Harms 2022 guideline, a 17-item checklist for reporting of harms in randomized trials [25]. Each checklist item was scored individually (1 = adequately reported; 0 = inadequately or not reported at all) (e.g., [29, 30]). Overall adherence to the CONSORT Harms guideline was calculated by dividing the sum of individual scores by the total number of items to generate a percentage. Adherence of ≥70% was defined as adequate [30].The 2007 FDA Amendments Act mandated the reporting of all clinical trial results, including adverse events, in the ClinicalTrials.gov database [31]. To assess whether the adverse events reported in published articles aligned with those recorded in ClinicalTrial.gov, we compared the total number of serious and ‘non-serious’ adverse events from each of these sources for each trial.

Quality and risk of bias assessment

The outcome being assessed for risk of bias was side effects. For the extracted RCTs, two reviewers (JC and AAG) independently assessed bias using the Cochrane Risk of Bias Tool for randomized trials (RoB 2 [32]), which evaluates bias arising from the randomization process, deviations from intended interventions, missing outcome data, outcome measurement and selection of the reported result. Cohen’s kappa was calculated for overall bias to determine agreement between reviewers. Any conflict between reviewers was resolved through discussion to reach consensus.Further, based on the approach of the Cochrane Adverse Effects Methods Group [33] consideration was given to the following issues that affect the quality of side effects-data: (1) how side effects data were collected (spontaneous reporting, use of structured scales or questionnaires); (2) how side effects were reported (systematically or ad hoc); and (3) the presence of a control group.The GRADE framework was used to assess the overall certainty of evidence for each outcome [34]. Under the GRADE approach, RCT evidence is initially graded as high but then downgraded to lower levels depending on risk of bias, inconsistency, indirectness, imprecision and publication bias. Two reviewers (JC and AAG) completed this analysis, categorizing each outcome as having very low, low, moderate or high certainty.

Results

Study selection

Thirteen studies met inclusion criteria for the systematic review, involving 333 unique participants (Fig. 1). Characteristics of eligible studies are in Table 1. Five studies were excluded from meta-analyses because there was no control group (Table S2). The remaining eight RCTs included 298 participants, and reported 138 different safety outcomes, of which 64 provided sufficient data for meta-analysis (i.e., at least two studies per outcome; Table S3). A description of which studies contributed data to each analysis is provided in Table S4.

Fig. 1: PRISMA flow diagram.

_{Flowchart describing the search strategy, including identification, screening and inclusion of studies.}

Table 1 Characteristics of included studies.

Systematic review: measurement of side effects

Of 13 studies included in the systematic review, most (n = 11) used passive monitoring of side effects [3,4,5,6, 35,36,37,38,39,40,41]. One [42] systematically assessed side effects using the UKU Scale of Secondary Effects [43], while another formally assessed long-term follow-up outcomes, including harms, using a Long-Term Follow-Up Questionnaire [44]. Use of scales to systematically assess specific side effects was mixed. Eight studies assessed suicidal ideation and behavior with the Columbia Suicide Severity Rating Scale [3,4,5,6, 35, 36, 40, 41]. In addition, one study [36] measured cognitive function using the Paced Auditory Serial Addition Task [45], Repeatable Battery for the Assessment of Neuropsychological Status [46] and Rey-Osterrieth Complex Figure [47], while another [35] assessed dissociation using the Dissociative Experience Scale-II [48]. Most studies measured vital signs at regular intervals during medication sessions [3,4,5,6, 35, 36, 38, 40,41,42]. Four also assessed subjective units of distress (SUDs) during medication sessions [5, 6, 35, 38].

Systematic review: reporting of side effects

Phase 2 and 3 studies used different methods to report side effects. Phase 2 studies [6, 36,37,38, 40, 41] typically reported ‘spontaneously reported reactions’ – a subset of adverse events that could be expected based on findings from healthy volunteer studies [11] – during and 7 days following medication sessions [28]. These were collected and reported separately to TEAEs, defined as events not on the expected reactions list, or which continued for >7 days after medication sessions [28]. In contrast, Phase 3 studies [3, 4] did not have separate data collection for spontaneously reported reactions and TEAEs, instead only reporting TEAEs across the entire treatment period. In addition, Phase 3 studies monitored and reported Adverse Events of Special Interest (AESI) relating to cardiac function, suicide risk and MDMA abuse, misuse or diversion. AESIs were prespecified based on FDA guidance [3, 4]. Only four studies reported sides effects by dose administered [38, 40,41,42], while all other studies either combined doses in their analyses, or only use one dose.

Meta-analysis

We report on primary outcome measures below, together with any secondary outcomes achieving statistical significance (p < 0.05; Fig. 2). Sub-group analyses of PTSD studies are provided in Fig. S1. Other secondary outcomes are presented in Table S3.

Fig. 2: Summary of meta-analysis results.

_{Odds ratios (OR) and 95% confidence intervals (CIs) comparing MDMA-AP with control groups on all primary outcomes and secondary outcomes that achieved statistical significance (p < 0.05). OR > 1 indicates an increased likelihood of the event when treated with MDMA-AP compared with control groups and an OR < 1 indicates a reduced likelihood. Phase 2 studies: odds of experiencing any side effects during medication sessions was higher in the MDMA-AP group compared to control groups (p = 0.01), with anxiety and jaw-clenching more likely in the MDMA-AP group compared to control groups (ps < 0.05). Odds of experiencing any side effect in the 7 days following medication sessions were also higher in the MDMA-AP group compared to control groups (p = 0.007). Phase 3 studies: odds of experiencing any treatment emergent adverse events was higher in the MDMA-AP group compared to control groups (p < 0.001), with muscle tightness, decreased appetite, nausea, excessive perspiration, feeling cold, restlessness, dilated pupils, jaw clenching/tight jaw, uncontrolled eye movements, feeling jittery, non-cardiac chest pain/discomfort, blurred vision, and chills more likely in the MDMA-AP group compared to control groups (ps < 0.05). There were no other significant associations in Phase 2 or 3 studies.}

Phase two studies

Side effects—during medication sessions

In Phase 2 studies, the odds of experiencing any side effect during medication sessions were higher in the MDMA-AP group compared with controls. In total, 45% of MDMA-AP participants versus 30% of controls reported side effects during medication sessions. Odds of experiencing anxiety and jaw clenching during medication sessions were also higher in MDMA-AP than control participants. Based on dose-dependent reports [38, 41], jaw clenching may be more likely to occur when receiving a higher dose (125 or 150 mg). All other specific side effects during medication sessions did not reach significance (Table S3). In PTSD studies only, anxiety was also more common under MDMA-AP than controls. All other results for PSTD studies did not reach significance.

Side effects—7 days following medication sessions

In Phase 2 studies, the odds of experiencing any side effect in the 7 days following medication sessions were higher in the MDMA-AP group compared with controls. In total, 46% of MDMA-AP participants versus 31% of controls reported side effects in the 7 days following medication sessions. No specific side effects in the 7 days following medication sessions reached significance (Table S3). In PTSD studies only, the odds of experiencing any side effect in the 7 days following medication sessions were higher in the MDMA-AP group compared with controls, as were the odds of experiencing anxiety during this time. No other results for PSTD studies reached significance.

Treatment emergent adverse events (TEAE)

In Phase 2 studies, there was no difference in the odds of experiencing any TEAE in the MDMA-AP group compared with controls, and all specific TEAEs were also non-significant (Table S3). In PTSD studies only, the odds of experiencing any TEAE were lower in the MDMA-AP group compared with control. All other results for PSTD studies did not reach significance.

There was no difference in the odds of experiencing any psychiatric TEAE in the MDMA-AP group compared with controls, and all specific psychiatric TEAEs were also non-significant (Table S3). The same results were observed in PSTD studies only.

Phase three studies

Treatment emergent adverse events (TEAE)

In Phase 3 studies, the odds of experiencing any TEAE in the MDMA-AP group compared with controls was higher, with 16% of MDMA-treated participants reporting TEAEs, compared with 5% of those treated with placebo. MDMA-AP was associated with increased odds of muscle tightness; decreased appetite; nausea; excessive perspiration; feeling cold; restlessness; dilated pupils; jaw clenching/tight jaw; uncontrolled eye movements; feeling jittery; non-cardiac chest pain/discomfort; blurred vision; and chills. All other specific TEAEs were non-significant (Table S3). Both Phase 3 studies focused on PSTD, so no sub-group analyses were performed.

Adverse event of special interest (AESI)

In Phase 3 studies, there was no difference in the odds of experiencing an AESI related to suicidality in the MDMA-AP group compared with controls, and all specific AESIs related to suicidality were also non-significant (Table S3). Similarly, there was no difference in the odds of experiencing an AESI related to cardiac function in the MDMA-AP group compared with controls, and all specific AESIs related to cardiac function were also non-significant (Table S3). No AESIs related to MDMA abuse, misuse or diversion were reported. As above, no sub-group analyses were performed.

Phase 2 and 3 studies

Withdrawal

Across all studies, there was no difference in the odds of withdrawing from the study for any reason in the MDMA-AP group compared with controls, and all specific reasons for withdrawal were also non-significant (Table S3). In PTSD studies only, all results were also non-significant.

Sensitivity analyses

Sensitivity analyses assessing effects of method used to assess side effects and number of medication sessions did not change outcomes.

Risk of bias

With side effects specified as the outcome of interest, the risk of bias assessment found that of eight studies included in the meta-analysis, seven were rated as having a high risk of bias [3, 4, 36, 38, 40,41,42], and one was rated as having some concerns [6] (see Fig. 3 and Fig. S2). The Cohen’s Kappa statistic for overall bias was 1.00 (i.e., excellent agreement between reviewers).

Fig. 3: Quality assessment of studies included in the meta-analyses.

_{Overall, seven of the eight studies included in the meta-analysis were rated as having a high risk of bias, with Domain 4 (bias in the measurement of the outcome) the domain most likely to be rated high risk across studies.}

Certainty of evidence

Table S5 presents results of the GRADE assessment. For Phase 2 studies, all primary outcomes were rated as having very low certainty of evidence. For Phase 3 studies, two primary outcomes were rated as having low certainty of evidence, and one rated as moderate. For all studies, withdrawal for any reason was rated as having moderate certainty of evidence.

Adherence to CONSORT Harms 2022

No included RCT had adequate adherence to the CONSORT Harms 2022 recommendations (>70%; Table 2). The median adherence rate was 50% (range 21–64%).

Table 2 Adherence of papers to CONSORT Harms 2022 checklist by study and item. 1 = adequately reported, 0 = inadequately or not reported at all.

Comparison of adverse events published versus reported on ClinicalTrial.gov

We were only able to complete this analysis for five studies for non-serious adverse events and eight for serious adverse events, because there were differences in how adverse events were reported between publications and ClinicalTrial.gov, and some studies did not have an entry or data on ClinicalTrial.gov (the two studies without ClinicalTrial.gov entries were also not registered on EudraCT). In ClinicalTrial.gov registers, we found 1487 non-serious adverse events recorded, versus 661 reported in published articles (Table S6). In ClinicalTrial.gov registers, we found 13 serious adverse events recorded, versus 9 reported in published articles (Table S7). The four serious adverse events not reported in published articles all concerned participants from MDMA-AP groups and included: (1) metastases to central nervous system; (2) clavicle fracture; (3) syncope; and (4) suicidal behavior.

Discussion

To our knowledge, this is the first comprehensive systematic review and meta-analysis of side effects of MDMA-AP across psychiatric indications. In Phase 2 studies, although participants undergoing MDMA-AP had higher odds of experiencing side effects during and 7 days after medication sessions relative to placebo-AP participants, there was no difference in TEAEs. Moreover, the observed differences between active and placebo conditions were relatively modest. For Phase 3 studies, participants undergoing MDMA-AP had higher odds of experiencing any TEAE as well as thirteen different types of TEAEs compared with placebo. These were largely transient and mild to moderate in severity. These findings should, however, be interpreted with caution; we identified marked shortcomings in published information on side effects, including heterogeneity and weaknesses in how side effects were defined, assessed, and reported. Indeed, the certainty of evidence was rated as very low or low for 6 of 8 primary outcomes, with 2 rated as moderate certainty. This indicates that much remains unknown about the safety profile of MDMA-AP.In Phase 2 studies, MDMA-AP participants had 1.7 times greater odds of experiencing any side effect during medication sessions than placebo participants, and 1.6 greater odds of side effects in the 7 days following. These results, however, were based on ‘spontaneously reported reactions’ data, defined as a subset of adverse events that could be expected based on findings in healthy volunteers [28]. It is therefore unsurprising that an effect was detected, albeit a small one [49]. Participants treated with MDMA-AP also had 4.7 greater odds of anxiety and 4.8 greater odds of jaw clenching during medication sessions relative to placebo participants. Anxiety was also prominent in PTSD patients, who had 4.1 greater odds of anxiety during medication sessions when treated with MDMA-AP, and 4.8 greater odds in the 7 days following compared to the placebo-AP group. These findings are consistent with results of previous meta-analyses [14, 23, 24] and evidence from healthy subjects [11, 50]. No differences between the MDMA-AP and control groups were observed in the odds of experiencing any TEAE, psychiatric TEAE or in withdrawal from the study, suggesting that side effects typically resolved within 7 days of MDMA-AP sessions and did not result in study withdrawal. Contrary to expectations, sub-group analyses found that people with PTSD who received MDMA-AP had 0.5 lower odds of experiencing any TEAE. Notably, only two studies were included in this meta-analysis, both of which used a low-dose MDMA active control rather than inert placebo. While active placebos improve blinding in studies evaluating MDMA-AP, this may complicate comparison of safety data between groups where treatments are not pharmacologically-distinct [1].In Phase 3 studies, MDMA-AP participants had 3.5 times greater odds of experiencing any TEAE compared with placebo participants. They also had increased odds of muscle tightness, decreased appetite, nausea, excessive perspiration, feeling cold, restlessness, dilated pupils, jaw clenching, uncontrolled eye movements, feeling jittery, non-cardiac chest pain/discomfort, blurred vision, and chills. The higher number of adverse events reaching significance in Phase 3 studies was likely due to increased statistical power, given the larger sample size (N = 194). These results are largely consistent with evidence about the acute and residual effects of MDMA in healthy subjects [50], suggesting that the side effects of MDMA-AP are primarily due to direct effects of MDMA (or that side effects arising from the combination of MDMA and psychotherapy are not well detected using the methods employed). No differences between MDMA-AP and control groups were observed in the odds of experiencing AESIs related to suicide risk or cardiac function, however, these are likely rare adverse events that were unlikely to reach significance in the meta-analysis. Nonetheless, AESIs related to suicidality were reported at rates which were similar or lower in the MDMA group compared with control. Regardless of assignment, incidences of suicidality should be an important safety consideration in MDMA-AP trials, as there may be specific risks for people randomized to placebo, given the possibility of high expectations driven by hype about psychedelics coupled with blinding failure [1, 2].While all RCTs included aimed to examine MDMA-AP’s safety, none had adequate adherence to the CONSORT Harms 2022 recommendations for reporting of safety data. Reporting rates for adverse events were also low: 56% of non-serious and 31% of serious adverse events recorded on ClinicalTrial.gov registers were not reported in published articles. The discrepancy in non-serious adverse events was primarily driven by the two Phase 3 studies, which only reported adverse events with at least a two-fold difference between the MDMA-AP and placebo-AP groups. In addition, two studies [36, 38] stated that there were ‘no drug-related serious adverse events’, but otherwise did not systematically report on adverse events. Among the four serious adverse events not reported in these papers, there was one instance of syncope and one of suicidal behavior in the MDMA-AP groups. Greater transparency is required regarding the timing of these events (i.e., did they occur during or immediately after medication sessions?) and the rationale for deeming them unrelated to condition.This review identified several limitations of existing MDMA-AP evidence. First, although most studies reported side effect information, reporting practices were largely insufficient. This finding is not limited to MDMA-AP research (e.g., see [29, 51]) and is consistent with concerns about safety reporting in trials of mental health interventions more broadly [52]. Indeed, evidence from clinical trials outside of psychiatry also suggest that compliance with the guidelines on reporting of harms is often inadequate (e.g., [53, 54]). Greater emphasis on the CONSORT Harms 2022 recommendations during review is recommended to improve reporting of side effect information. Heterogeneous reporting practices across studies also placed limitations on our ability to combine side effect data for meta-analyses. Most prominently, we had to analyze data from Phase 2 and Phase 3 studies separately due to differences in assessment and reporting of side effects. Further, we could only draw conclusions regarding acute and short-term side effects because insufficient data were available regarding longer-term risks beyond active treatment.Second, certainty of the evidence was rated as very low for Phase 2 side effect outcomes, and low to moderate for Phase 3. The improvement in certainty of the evidence in Phase 3 studies was mainly attributable to their larger more ethno-racially diverse samples. The overall evidence on MDMA-AP, however, consists of a relatively limited number of studies with highly selective samples (i.e., most people volunteering for these studies were excluded from participation). While appropriate for this early stage of research, this means we cannot yet with high confidence determine the safety profile or risk-benefit ratio of MDMA-AP. It is likely that implementation beyond controlled clinical trials – in people with more complex needs—will increase the incidence of side effects. In addition, while heterogeneity was low, in many cases estimates lacked precision. We also could not formally test for publication bias, due to the low number of studies available (<10), however possible sources of publication bias were identified, including the body of evidence largely consisting of small studies sponsored by a single advocacy group [34]. Taken together, there is a need for further independent clinical trials, with larger more representative samples to enable more definitive conclusions about the safety of MDMA-AP.Third, consistent with a previous review [14], we found that most studies relied on passive monitoring of spontaneously reported side effects. While spontaneous reporting avoids the problem of suggestive questions influencing outcomes, evidence suggests that it likely underestimates the extent of side effects compared with a more systematic approach [55]. One implication is that alongside spontaneous reporting, studies of MDMA-AP should also use systematic checklists or scales to assess expected and general side effects which appear acutely, between doses, and at long-term follow-up. This is particularly important at this early stage of research as the data build about the risk-benefit profile of MDMA-AP [55].Fourth, given differences in dosage, sample sizes, and reporting procedures between Phase 2 and 3 studies, we were unable to assess whether side effects differed as a function of trial design e.g., for instance due to nocebo effects in placebo-controlled studies. Future trials using comparative effectiveness designs could provide further information about the extent to which expectations contribute to the effects (therapeutic or adverse) of MDMA-AP versus control conditions (e.g., see [56]). Lastly, only four studies assessed the dose-dependent nature of side effects. It is critical for future studies to examine at what dose each side effect emerges to identify the ideal dosage and reduce unnecessary risks.

Conclusion

The evidence synthesized indicates that relative to placebo-AP, MDMA-AP is associated with greater likelihood of experiencing mild to moderate, but largely transient side effects. Findings, however, need to be interpreted cautiously due to limitations of the existing evidence. Our review revealed a need to improve practices for assessing side effects and adherence to reporting guidelines for harms in MDMA-AP studies. Based on results reported to date, any assessment of the risk-benefit profile of MDMA-AP remains limited due to the identified issues. Further large-scale trials which systematically assess side effects (including long-term follow up), comprehensively report all potential side-effects and follow CONSORT Harms guidelines are recommended. In Australia, and other countries soon expected to implement MDMA-AP, systematic, independent post-marketing studies of real-world side effects are also needed.

Introduction

Research into the therapeutic application of 3,4-methylenedioxymethamphetamine (MDMA) within psychotherapy has expanded significantly over the past decade. MDMA-assisted psychotherapy (MDMA-AP) employs a combined pharmacotherapy-psychotherapy approach, wherein MDMA is hypothesized to enhance psychotherapeutic effects. Clinical protocols typically involve preparatory psychotherapy, followed by MDMA-assisted sessions, and subsequent integration sessions. Growing evidence suggests MDMA-AP holds therapeutic potential for posttraumatic stress disorder (PTSD) and other psychiatric conditions, with regulatory bodies in Australia already scheduling MDMA for medicinal use in PTSD, and a similar approval anticipated from the U.S. Food and Drug Administration (FDA) in 2024. While MDMA and MDMA-AP have generally been deemed safe and well-tolerated, concerns persist regarding the potential for harm, particularly when combined with psychotherapy, and perceived inadequacies in adverse event reporting within existing research. A comprehensive understanding of potential safety issues is crucial for ongoing research and clinical translation. Previous safety reviews were often limited in scope, and no prior synthesis included the most recent Phase 3 study. This systematic review and meta-analysis aimed to quantitatively assess MDMA-AP side effects across psychiatric indications and evaluate the quality of safety reporting against CONSORT Harms 2022 guidelines.

Methods

This systematic review and meta-analysis was pre-registered and reported according to PRISMA guidelines. A comprehensive search of major academic databases was conducted for studies involving MDMA administration combined with psychotherapy for a psychiatric condition, excluding those without psychotherapy, non-original data, or animal studies. Data extraction encompassed study design, population demographics, MDMA administration details, control conditions, and safety outcomes, including side effects and study withdrawal. Qualitative synthesis summarized findings, and pairwise meta-analyses were performed using Review Manager 5.4 to compare MDMA-AP to control groups for dichotomous outcomes, employing odds ratios and random-effects models. Phase 2 and 3 study data were analyzed separately due to differing reporting methods, with primary outcomes defined for each phase including various categories of side effects and treatment emergent adverse events (TEAEs). The quality of side effect reporting was assessed using the CONSORT Harms 2022 guideline, and a comparison was made between reported adverse events in published articles and those registered on ClinicalTrials.gov. Risk of bias was evaluated using the Cochrane Risk of Bias Tool (RoB 2), and the GRADE framework was applied to assess the overall certainty of evidence for each outcome.

Results

Thirteen studies were included in the systematic review, with eight randomized controlled trials (RCTs) providing sufficient data for meta-analysis (298 participants, 64 analyzable safety outcomes). Most studies (11 of 13) relied on passive monitoring of side effects, though some used specific scales for suicidal ideation or vital signs. Phase 2 studies typically reported "spontaneously reported reactions" separately from TEAEs, whereas Phase 3 studies focused solely on TEAEs and Adverse Events of Special Interest (AESIs). In Phase 2 studies, MDMA-AP was associated with higher odds of experiencing any side effect during and up to 7 days following medication sessions (e.g., anxiety, jaw clenching), but no significant difference in TEAEs or psychiatric TEAEs was observed. Conversely, in Phase 3 studies, MDMA-AP was linked to significantly higher odds of any TEAEs, including muscle tightness, decreased appetite, nausea, and other transient physical symptoms. No significant differences were found in AESIs related to suicidality or cardiac function across phases, nor in rates of study withdrawal. The assessment of bias revealed that seven of eight studies had a high risk of bias, primarily concerning outcome measurement. The certainty of evidence was rated as very low for Phase 2 outcomes and low to moderate for Phase 3 outcomes, indicating substantial uncertainty. Adherence to CONSORT Harms 2022 guidelines for reporting safety data was inadequate across all included RCTs, with a median adherence rate of 50%. Furthermore, a significant discrepancy was identified between adverse events reported in published articles and those recorded on ClinicalTrials.gov, particularly for non-serious events, suggesting underreporting in publications.

Discussion

This systematic review and meta-analysis indicates that MDMA-AP is associated with a greater likelihood of experiencing mild-to-moderate, largely transient side effects compared to placebo-AP. However, these findings must be interpreted with considerable caution due to identified limitations in the existing evidence. Significant shortcomings were observed in the definition, assessment, and reporting of side effects across studies, contributing to the low certainty of evidence for most primary outcomes. While Phase 2 studies showed modest increases in acute side effects but no difference in overall TEAEs, Phase 3 studies, with their larger sample sizes, revealed a more pronounced increase in TEAEs, aligning with known acute effects of MDMA. The lack of significant differences in serious adverse events like suicidality or cardiac issues likely reflects their rarity, yet the discrepancies between published and registry data raise concerns about reporting transparency. The heavy reliance on passive monitoring of spontaneously reported side effects, as opposed to systematic assessment, may lead to underestimation of actual side effect incidence. The highly selective nature of study samples further limits the generalizability of these safety findings to broader patient populations with more complex needs.

Conclusion

The available evidence suggests that MDMA-AP is associated with an increased likelihood of mild to moderate, predominantly transient side effects compared to placebo-AP. Nevertheless, a comprehensive understanding of MDMA-AP's safety profile and risk-benefit ratio remains limited by notable deficiencies in existing research. Critical areas for improvement include standardizing side effect assessment practices, ensuring rigorous adherence to established reporting guidelines such as CONSORT Harms 2022, and enhancing transparency in reporting all adverse events, including those registered on clinical trial databases. Future large-scale, independent clinical trials with more representative samples and systematic, long-term follow-up for safety outcomes are essential to generate more definitive conclusions. Furthermore, as MDMA-AP becomes clinically available in certain regions, systematic post-marketing surveillance of real-world side effects is imperative to complement existing research data.

Introduction

Research into using 3,4-methylenedioxymethamphetamine (MDMA) as part of psychotherapy has increased significantly in the last ten years. This approach, known as MDMA-assisted psychotherapy (MDMA-AP), combines medication with therapy. MDMA is thought to enhance the effects of the psychotherapy sessions. Typically, patients first attend three to four "preparatory" therapy sessions. This is followed by two to three full-day sessions where MDMA (or a placebo) is given. Each of these sessions is then followed by three to four "integration" therapy sessions.

Despite some questions about the research methods, growing evidence suggests that MDMA-AP could be a useful treatment for post-traumatic stress disorder (PTSD) and possibly other mental health conditions. Several clinical trials are currently being planned or are underway. Recently, the Australian Therapeutic Goods Administration (TGA) decided to allow psychiatrists who are authorized prescribers to prescribe MDMA for PTSD. This makes Australia the first country to permit MDMA for medical use. The U.S. Food and Drug Administration (FDA) is also likely to approve MDMA-AP for PTSD in 2024, with the first application submitted in late 2023.

While existing literature largely concludes that MDMA and MDMA-AP are safe and well-tolerated, some concerns remain. There is a unique potential for substances like MDMA, when combined with psychotherapy, to cause harm. There are also reported shortcomings in how adverse events are assessed and reported in current research. A full understanding of potential safety issues in MDMA-AP is necessary to guide both ongoing research and its future use in clinical practice. This study conducted a thorough review and meta-analysis of the side effects of MDMA-AP across various psychiatric conditions. It also examined the quality of side effect reporting in published trials of MDMA-AP, comparing it against established guidelines. "Side effects" in this context refers to all reported safety outcomes, including spontaneously reported reactions and treatment-emergent adverse events.

Methods

This comprehensive review and meta-analysis was registered beforehand and followed specific reporting guidelines.

Search strategy

Researchers searched several major medical and psychological databases from their beginning, using terms such as "MDMA," "psychotherapy," "safe," and "adverse." No limits were placed on the publication date or status. Titles and abstracts were reviewed by one researcher, and full-text articles were reviewed by two independent researchers, with any disagreements resolved by discussion. Searches were re-run just before the final analysis in October 2023.

Inclusion and exclusion criteria

Studies were included if they were published in English-language, peer-reviewed journals and involved giving one or more MDMA doses to humans alongside psychotherapy, specifically to treat a mental health condition. Studies were excluded if they did not include psychotherapy, were not original research (e.g., reviews or commentaries), were conference abstracts, book chapters, or animal studies. This meant that only Phase 2 and Phase 3 studies were included, as Phase 1 studies assessed MDMA without psychotherapy.

Data extraction

Information was collected on study design, participant characteristics (population, age, sex, ethnicity), MDMA administration (dosage, number of doses), control conditions, prior MDMA use, health screening, co-existing medical conditions, other medications, timing of side effect assessments, specific outcomes (side effects, study withdrawal), and whether structured assessments were used for safety. Data were initially extracted by one researcher and then checked for accuracy by a second. If data were missing, study authors were contacted; if information was unavailable, it was noted as "Not Reported."

Data synthesis

For qualitative synthesis, data were extracted, quality and risk of bias were assessed, and findings were summarized. When at least two studies provided data for an outcome, statistical meta-analyses were performed. The MDMA treatment group, which included various doses, was compared to control groups, which included both low-dose MDMA and inactive placebo. Odds ratios were calculated, and random-effects models were used to account for differences between studies.

Phase 2 and Phase 3 study outcomes were analyzed separately due to differences in data collection and reporting. For Phase 2 studies, primary outcomes included any side effect during medication sessions or within 7 days afterward, and any treatment-emergent adverse event (TEAE), including psychiatric TEAEs. TEAEs were defined as events not expected or lasting more than 7 days. For Phase 3 studies, primary outcomes were any TEAEs across the treatment period and adverse events of special interest, which were predefined events related to heart function, suicide, and MDMA abuse. Study withdrawal was a primary outcome for all studies. Secondary outcomes broke down each primary outcome by type (e.g., anxiety, reason for withdrawal).

Quality of side effect-reporting

Data on side effects from all included randomized controlled trials (RCTs) were assessed by two independent reviewers using a 17-item checklist for reporting harms in clinical trials. Each item was scored based on whether it was adequately reported. Overall adherence was calculated as a percentage, with 70% or more considered adequate reporting. Additionally, the adverse events reported in published articles were compared with those listed in the ClinicalTrials.gov database to see if they matched.

Quality and risk of bias assessment

The risk of bias was assessed by two independent reviewers for the extracted RCTs, focusing on side effects as the outcome. They used a specific tool that evaluates bias from randomization, deviations from planned treatments, missing data, outcome measurement, and reporting of results. Reviewers also considered how side effect data were collected (e.g., spontaneous reporting vs. structured scales), how they were reported, and the presence of a control group. The overall certainty of evidence for each outcome was assessed, categorizing it as very low, low, moderate, or high certainty.

Results

Study selection

Thirteen studies met the criteria for the systematic review, involving 333 unique participants. Five studies were excluded from meta-analyses because they lacked a control group. The remaining eight RCTs included 298 participants and reported 138 different safety outcomes, 64 of which had enough data for meta-analysis.

Systematic review: measurement of side effects

Of the 13 studies in the systematic review, most (11) used passive monitoring, meaning participants reported side effects on their own. One study systematically assessed side effects using a specific scale, and another formally assessed long-term follow-up outcomes. While some studies assessed specific side effects using scales (e.g., suicidal thoughts), most measured vital signs regularly during medication sessions. Some also measured subjective units of distress.

Systematic review: reporting of side effects

Phase 2 and Phase 3 studies used different methods for reporting side effects. Phase 2 studies typically reported "spontaneously reported reactions" – expected adverse events – during and up to 7 days after medication sessions. These were reported separately from treatment-emergent adverse events (TEAEs), which were unexpected or longer-lasting events. In contrast, Phase 3 studies did not separate these, reporting only TEAEs across the entire treatment period. Phase 3 studies also monitored and reported "Adverse Events of Special Interest" (AESI) related to heart function, suicide risk, and MDMA abuse, as specified by the FDA. Only four studies reported side effects based on the dose administered, while others combined doses or used a single dose.

Meta-analysis

The following summarizes the main findings for primary outcomes and any statistically significant secondary outcomes.

Phase two studies

Participants receiving MDMA-AP in Phase 2 studies had a higher chance of experiencing side effects during medication sessions compared to control groups (45% vs. 30%). Anxiety and jaw clenching were also more likely in the MDMA-AP group. Jaw clenching appeared more common with higher doses. All other specific side effects during these sessions were not statistically significant. In PTSD-specific studies, anxiety was also more common with MDMA-AP.

For side effects occurring within 7 days after medication sessions, MDMA-AP participants in Phase 2 studies again had a higher chance of experiencing them (46% vs. 31% in controls). No specific side effects in this period reached statistical significance for all Phase 2 studies. However, in PTSD-specific studies, both any side effect and anxiety within 7 days were more likely with MDMA-AP.

There was no statistically significant difference in the chance of experiencing any TEAE or any psychiatric TEAE between the MDMA-AP group and control groups in Phase 2 studies. This suggests that side effects generally resolved within 7 days and did not lead to study withdrawal. Surprisingly, PTSD patients receiving MDMA-AP in subgroup analyses had a lower chance of experiencing any TEAE, though this finding was based on only two studies that used a low-dose MDMA as an active control.

Phase three studies

In Phase 3 studies, MDMA-AP participants had a higher chance of experiencing any TEAE compared to placebo participants (16% vs. 5%). MDMA-AP was linked to an increased likelihood of muscle tightness, decreased appetite, nausea, excessive perspiration, feeling cold, restlessness, dilated pupils, jaw clenching/tight jaw, uncontrolled eye movements, feeling jittery, non-cardiac chest pain/discomfort, blurred vision, and chills. Other specific TEAEs were not statistically significant.

Regarding adverse events of special interest (AESI) in Phase 3 studies, there was no difference in the chance of experiencing AESIs related to suicidality or heart function between MDMA-AP and control groups. No AESIs related to MDMA abuse, misuse, or diversion were reported.

Phase 2 and 3 studies

Across all studies, there was no statistically significant difference in the likelihood of participants withdrawing from the study for any reason between the MDMA-AP group and control groups. Specific reasons for withdrawal also showed no significant differences.

Sensitivity analyses

Additional analyses examining the effects of side effect assessment methods and the number of medication sessions did not change these outcomes.

Risk of bias

When assessing the risk of bias specifically for side effects, seven of the eight studies included in the meta-analysis were rated as having a high risk of bias, and one had some concerns. Bias in how outcomes were measured was the most common issue across studies.

Certainty of evidence

For Phase 2 studies, the certainty of evidence for all primary outcomes was rated as very low. For Phase 3 studies, two primary outcomes had low certainty of evidence, and one had moderate certainty. Across all studies, the certainty of evidence for withdrawal for any reason was rated as moderate. This indicates that much about MDMA-AP's safety profile remains uncertain.

Adherence to CONSORT Harms 2022

None of the included randomized controlled trials adequately followed the CONSORT Harms 2022 recommendations for reporting safety data (meaning less than 70% adherence). The average adherence rate was 50%.

Comparison of adverse events published versus reported on ClinicalTrial.gov

Researchers could only complete this analysis for some studies due to differences in reporting methods between published articles and ClinicalTrials.gov. In ClinicalTrials.gov, 1487 non-serious adverse events were recorded, compared to 661 reported in published articles. For serious adverse events, 13 were recorded in ClinicalTrials.gov, while 9 were reported in publications. The four serious adverse events not reported in published articles all occurred in MDMA-AP groups and included metastasis to the central nervous system, clavicle fracture, syncope, and suicidal behavior.

Discussion

This is the first comprehensive review and meta-analysis of MDMA-AP side effects across different psychiatric conditions. In Phase 2 studies, although MDMA-AP participants had a higher chance of experiencing side effects during and 7 days after medication sessions compared to placebo-AP participants, there was no difference in the overall number of treatment-emergent adverse events (TEAEs). The differences observed between active and placebo conditions were relatively small. For Phase 3 studies, MDMA-AP participants had a higher chance of experiencing any TEAE, as well as thirteen specific types of TEAEs, compared to placebo. These side effects were mostly temporary and mild to moderate in severity. However, these findings should be interpreted with caution. Researchers found significant limitations in published information on side effects, including inconsistencies and weaknesses in how side effects were defined, assessed, and reported. In fact, the certainty of evidence was rated as very low or low for six out of eight primary outcomes, with only two rated as moderate certainty. This indicates a significant lack of complete information regarding MDMA-AP's safety profile.

In Phase 2 studies, MDMA-AP participants were 1.7 times more likely to experience any side effect during medication sessions and 1.6 times more likely in the 7 days following sessions than placebo participants. These results were based on "spontaneously reported reactions," which are expected adverse events. It is therefore not surprising that an effect was detected, though it was small. Participants receiving MDMA-AP were also 4.7 times more likely to experience anxiety and 4.8 times more likely to experience jaw clenching during medication sessions compared to placebo participants. Anxiety was also prominent in PTSD patients receiving MDMA-AP. These findings align with previous meta-analyses and data from healthy individuals. Crucially, no differences were found between MDMA-AP and control groups in the likelihood of experiencing any TEAE, psychiatric TEAE, or withdrawing from the study. This suggests that side effects typically resolved within 7 days and did not lead to study withdrawal. Unexpectedly, a subgroup analysis found that individuals with PTSD who received MDMA-AP had a lower chance of experiencing any TEAE. However, this finding involved only two studies that used a low-dose MDMA as an active control, which might complicate direct comparisons.

In Phase 3 studies, MDMA-AP participants were 3.5 times more likely to experience any TEAE compared to placebo participants. They also had increased odds of muscle tightness, decreased appetite, nausea, excessive perspiration, feeling cold, restlessness, dilated pupils, jaw clenching, uncontrolled eye movements, feeling jittery, non-cardiac chest pain/discomfort, blurred vision, and chills. The larger number of statistically significant adverse events in Phase 3 studies was likely due to their larger sample size, which provides greater statistical power. These results are largely consistent with what is known about the immediate and lingering effects of MDMA in healthy individuals. This suggests that the side effects of MDMA-AP are primarily due to the direct effects of MDMA, or that side effects from the combination of MDMA and psychotherapy are not well detected by current methods. No differences were observed between MDMA-AP and control groups in the odds of experiencing adverse events of special interest related to suicide risk or heart function. However, these are rare adverse events and were unlikely to reach statistical significance in the meta-analysis. Nonetheless, reports of suicidality were similar or lower in the MDMA group compared to the control group. Regardless of treatment assignment, instances of suicidality are an important safety consideration in MDMA-AP trials, as there may be specific risks for individuals randomized to placebo, possibly due to high expectations or a failure of blinding.

While all included randomized controlled trials aimed to examine MDMA-AP's safety, none fully adhered to the recommendations for reporting safety data. Adverse event reporting rates were also low. For instance, 56% of non-serious and 31% of serious adverse events recorded on ClinicalTrials.gov were not reported in published articles. The discrepancy in non-serious adverse events was mainly driven by two Phase 3 studies that only reported adverse events with at least a two-fold difference between the MDMA-AP and placebo-AP groups. Furthermore, two studies stated that there were "no drug-related serious adverse events" but did not systematically report other adverse events. Among the four serious adverse events not reported in these papers, one instance of syncope and one of suicidal behavior occurred in the MDMA-AP groups. Greater transparency is needed regarding the timing of these events and the rationale for deeming them unrelated to the treatment.

This review identified several limitations in the existing MDMA-AP evidence. First, although most studies reported some side effect information, reporting practices were largely insufficient. This issue is not unique to MDMA-AP research and is consistent with broader concerns about safety reporting in mental health interventions. Greater emphasis on adhering to reporting guidelines during peer review is recommended to improve the reporting of side effect information. Inconsistent reporting practices across studies also made it difficult to combine side effect data for meta-analyses. Researchers had to analyze data from Phase 2 and Phase 3 studies separately due to different assessment and reporting methods. Furthermore, conclusions could only be drawn regarding acute and short-term side effects because insufficient data were available on longer-term risks beyond the active treatment period.

Second, the certainty of the evidence was rated as very low for Phase 2 side effect outcomes, and low to moderate for Phase 3. The improved certainty in Phase 3 studies was mainly due to their larger and more diverse samples. However, the overall evidence on MDMA-AP consists of a relatively limited number of studies with highly selected participants (meaning most people volunteering for these studies were excluded from participation). While this is appropriate for early-stage research, it means researchers cannot yet confidently determine the full safety profile or risk-benefit ratio of MDMA-AP. It is likely that implementing MDMA-AP beyond controlled clinical trials, especially in individuals with more complex needs, will increase the incidence of side effects. Additionally, while variability between studies was low, estimates often lacked precision. Researchers also could not formally test for publication bias due to the small number of available studies. However, potential sources of publication bias were identified, including the fact that much of the evidence comes from small studies sponsored by a single advocacy group. Taken together, more independent clinical trials with larger, more representative samples are needed to draw more definitive conclusions about the safety of MDMA-AP.

Third, consistent with a previous review, most studies relied on passive monitoring of spontaneously reported side effects. While spontaneous reporting avoids leading questions, evidence suggests it likely underestimates the true extent of side effects compared to more systematic approaches. This implies that along with spontaneous reporting, MDMA-AP studies should also use systematic checklists or scales to assess both expected and general side effects that appear acutely, between doses, and during long-term follow-up. This is particularly important at this early stage of research as data are being gathered on MDMA-AP's risk-benefit profile. Fourth, given the differences in dosage, sample sizes, and reporting procedures between Phase 2 and 3 studies, researchers could not assess whether side effects varied based on trial design, for example, due to "nocebo effects" in placebo-controlled studies. Future trials using comparative effectiveness designs could provide more information about how much patient expectations contribute to the effects (both therapeutic and adverse) of MDMA-AP compared to control conditions. Lastly, only four studies assessed whether side effects were dose-dependent. It is crucial for future studies to examine at what dose each side effect emerges to identify the ideal dosage and reduce unnecessary risks.

Conclusion

The synthesized evidence suggests that, compared to placebo-assisted psychotherapy, MDMA-AP is associated with a greater likelihood of experiencing mild to moderate, mostly temporary side effects. However, these findings must be interpreted carefully due to limitations in the existing evidence. The review revealed a need to improve how side effects are assessed and how reporting guidelines for harms are followed in MDMA-AP studies. Based on the results reported to date, any assessment of the risk-benefit profile of MDMA-AP remains limited due to the identified issues. Further large-scale trials that systematically assess side effects (including long-term follow-up), comprehensively report all potential side effects, and follow established reporting guidelines are recommended. In Australia, and other countries expected to implement MDMA-AP soon, systematic, independent post-marketing studies of real-world side effects are also needed.

Introduction

Over the last ten years, there has been a significant increase in research on using 3,4-methylenedioxymethamphetamine (MDMA) as a treatment alongside psychotherapy. This approach, known as MDMA-assisted psychotherapy (MDMA-AP), combines medicine and therapy, with MDMA believed to enhance the effects of psychotherapy. Typically, patients have several therapy sessions to prepare, followed by two to three full-day sessions with MDMA (or a placebo), and then several follow-up therapy sessions to help them process their experiences. Despite some ongoing questions about research methods, there is growing evidence that MDMA-AP may help individuals with post-traumatic stress disorder (PTSD) and possibly other mental health conditions. Many clinical trials are currently planned or underway.

Recently, Australia's Therapeutic Goods Administration (TGA) decided that psychiatrists authorized to prescribe medications can now prescribe MDMA for PTSD. This makes Australia the first country to approve MDMA for medical use. The U.S. Food and Drug Administration (FDA) is also expected to approve MDMA-AP for PTSD in 2024, with the first application submitted in late 2023. While most research so far has concluded that MDMA and MDMA-AP are safe and generally well-tolerated, some concerns exist. There is a unique possibility for substances like MDMA, when combined with psychotherapy, to cause harm. Additionally, there have been concerns about how adverse events are assessed and reported in current research. A full understanding of potential safety issues in MDMA-AP is necessary to guide future research and its use in clinics.

While the immediate side effects of MDMA without psychotherapy have been thoroughly studied in trials with healthy individuals, previous reviews of MDMA-AP's safety did not include a complete statistical analysis of all safety outcomes. Some reviews focused only on PTSD, severe illness, or depression. Those that did include statistical analysis of side effects did not look at the full range of reported safety outcomes. No previous summary of evidence has included the most recent large-scale study of MDMA-AP. Given the recent changes in how MDMA-AP is regulated and the large amount of ongoing research, a complete and up-to-date assessment of its safety and how well it is tolerated is important. This study therefore reviewed and statistically analyzed the side effects of MDMA-AP across various mental health conditions. It also looked at concerns about how thoroughly safety is reported in this research, making it the first to evaluate the quality of side effect reporting in published MDMA-AP trials against standard guidelines. The term "side effects" here covers all reported safety outcomes, which are sometimes called other names like "adverse events" or "harms."

Methods

This study was a systematic review and meta-analysis, planned in advance and reported following standard research guidelines. Researchers searched several major medical databases from their beginning up to October 2023. They used specific search terms related to MDMA, psychotherapy, and safety. There were no limits on when the studies were published or their status.

The lead researcher screened titles and summaries of articles. Two independent researchers then reviewed the full text of articles, resolving any disagreements by discussion. Studies were included if they were published in English, peer-reviewed journals, and involved giving MDMA doses to people along with psychotherapy to treat a mental health condition. Excluded studies included those without psychotherapy, those that were not original research (like other reviews), conference summaries, book chapters, or animal studies. This meant only studies from Phase 2 and 3 of clinical trials were included.

Information was gathered on the study design, participant groups (age, sex, background), MDMA dosage and number of doses, control groups, past MDMA use, health screenings, other medical conditions, other medications taken, when side effects were assessed, and the types of side effects or reasons for leaving the study. One researcher extracted this data, and a second researcher checked it for accuracy. If data was missing, authors of the original studies were contacted.

The collected information was first summarized qualitatively. When at least two studies provided data for a specific outcome, statistical analysis (meta-analysis) was performed to compare MDMA-AP groups with control groups. This analysis looked at the odds of experiencing various side effects. Control groups included both those given a low dose of MDMA and those given an inactive placebo. Different doses for the MDMA group were combined. Due to differences in data collection, results from Phase 2 and Phase 3 studies were analyzed separately. Key outcomes for Phase 2 studies included any side effect during sessions or within 7 days after, and specific treatment-related adverse events. For Phase 3 studies, key outcomes included any treatment-related adverse events and specific adverse events of special interest, such as those related to heart function, suicide risk, or MDMA abuse. Study withdrawal was also a primary outcome across all studies.

The quality of side effect reporting in all included randomized controlled trials was independently assessed by two researchers using a 17-item checklist designed for reporting harms in clinical trials. Each item was scored based on whether it was adequately reported. Overall adherence to the guidelines was calculated as a percentage. Adherence of 70% or more was considered adequate. To see if the side effects reported in published articles matched what was recorded in the ClinicalTrials.gov database, researchers compared the total number of serious and non-serious adverse events from both sources for each trial. Finally, two researchers independently assessed the risk of bias in the included studies, looking at how the studies were designed and conducted, and how outcomes were measured and reported. The overall certainty of the evidence for each outcome was also evaluated, categorizing it as very low, low, moderate, or high certainty.

Results

Thirteen studies, involving 333 unique participants, met the criteria for the systematic review. Five studies were excluded from the statistical analysis because they did not have a control group. The remaining eight controlled trials included 298 participants and reported 138 different safety outcomes, of which 64 had enough data for statistical analysis (meaning at least two studies contributed data).

Of the 13 studies in the systematic review, most (11) relied on participants spontaneously reporting side effects. One study systematically assessed side effects using a specific scale, and another formally assessed long-term follow-up outcomes, including harms, with a questionnaire. While many studies checked vital signs regularly during MDMA sessions, specific scales to assess side effects were used inconsistently. For example, eight studies used a specific scale to assess suicidal thoughts and behavior.

Phase 2 and 3 studies reported side effects differently. Phase 2 studies typically reported "spontaneously reported reactions"—a type of adverse event expected based on studies with healthy volunteers—during and up to 7 days after MDMA sessions. These were collected separately from "treatment emergent adverse events" (TEAEs), which were unexpected events or those lasting longer than 7 days. In contrast, Phase 3 studies did not separate these, instead reporting only TEAEs over the entire treatment period. Phase 3 studies also tracked "Adverse Events of Special Interest" (AESIs) related to heart function, suicide risk, and MDMA abuse, which were specified by the FDA. Only four studies reported side effects based on the dose given; others combined doses or used only one dose.

Phase two studies

In Phase 2 studies, the odds of experiencing any side effect during MDMA sessions were higher in the MDMA-AP group compared to control groups. Overall, 45% of MDMA-AP participants reported side effects during sessions versus 30% of controls. Participants receiving MDMA-AP also had higher odds of experiencing anxiety and jaw clenching during sessions. Jaw clenching appeared more likely with higher doses. Within studies specifically on PTSD, anxiety was also more common with MDMA-AP. No other specific side effects during sessions were statistically significant.

Regarding side effects within 7 days after MDMA sessions in Phase 2 studies, the odds were again higher in the MDMA-AP group compared to controls. In total, 46% of MDMA-AP participants reported side effects in the 7 days following sessions versus 31% of controls. However, no specific side effects during this period reached statistical significance across all studies. In PTSD-focused studies, the odds of experiencing any side effect, as well as anxiety, in the 7 days after sessions were higher in the MDMA-AP group.

For Phase 2 studies, there was no statistical difference in the odds of experiencing any treatment emergent adverse event (TEAE) or any psychiatric TEAE in the MDMA-AP group compared to controls. This was also true for PTSD-focused studies. This suggests that side effects generally cleared up within 7 days and did not lead to participants dropping out of the study.

Phase three studies

In Phase 3 studies, the odds of experiencing any treatment emergent adverse event (TEAE) were higher in the MDMA-AP group compared to controls. Specifically, 16% of MDMA-treated participants reported TEAEs, compared to 5% of those treated with placebo. MDMA-AP was linked to increased odds of muscle tightness, decreased appetite, nausea, excessive perspiration, feeling cold, restlessness, dilated pupils, jaw clenching/tight jaw, uncontrolled eye movements, feeling jittery, non-cardiac chest pain/discomfort, blurred vision, and chills. These studies focused on PTSD, so specific subgroup analyses were not performed.

Regarding Adverse Events of Special Interest (AESI) in Phase 3 studies, there was no statistical difference in the odds of experiencing an AESI related to suicidality or cardiac function in the MDMA-AP group compared to controls. No AESIs related to MDMA abuse, misuse, or diversion were reported.

All studies

Across all studies (Phase 2 and 3), there was no statistical difference in the odds of participants withdrawing from the study for any reason in the MDMA-AP group compared to controls. This finding remained consistent in PTSD-focused studies.

When researchers performed sensitivity analyses to check if the method of assessing side effects or the number of MDMA sessions affected the outcomes, the main results did not change.

Concerning potential bias, the assessment found that seven of the eight studies included in the statistical analysis had a high risk of bias, meaning their results might not be entirely accurate due to how the study was designed or carried out. One study had "some concerns" about bias. Specifically, bias in how outcomes were measured was the most common issue. The overall certainty of the evidence was rated as very low for most Phase 2 study outcomes, and low to moderate for Phase 3 study outcomes. This indicates that there is still much uncertainty about the safety profile of MDMA-AP.

None of the included controlled trials adequately followed the CONSORT Harms 2022 recommendations for reporting safety data, with adherence rates ranging from 21% to 64% (median 50%). When comparing adverse events reported in published articles versus those registered on ClinicalTrials.gov, a significant discrepancy was found. Out of 1487 non-serious adverse events recorded on ClinicalTrials.gov, only 661 were reported in published articles. For serious adverse events, 13 were recorded on ClinicalTrials.gov, but only 9 were reported in published articles. The four serious adverse events not reported in publications all occurred in MDMA-AP groups and included conditions like a clavicle fracture, fainting, and suicidal behavior.

Discussion

This review is the first comprehensive study to statistically analyze the side effects of MDMA-AP across various mental health conditions. In Phase 2 studies, participants receiving MDMA-AP had a higher chance of experiencing side effects during and up to 7 days after their sessions compared to those receiving placebo with psychotherapy. However, there was no difference in the overall occurrence of treatment emergent adverse events (TEAEs). The differences observed between the active drug and placebo groups were relatively small. For Phase 3 studies, MDMA-AP participants had a higher chance of experiencing any TEAE, as well as thirteen specific types of TEAEs, compared to the placebo group. These side effects were mostly temporary and mild to moderate in severity.

However, these findings should be considered with caution because this review identified notable weaknesses in how side effects were defined, assessed, and reported in the published studies. In fact, the certainty of the evidence for 6 out of 8 main outcomes was rated as "very low" or "low," with only 2 rated as "moderate." This suggests that much remains unknown about MDMA-AP's full safety profile. The increased odds of anxiety and jaw clenching during MDMA sessions, observed in Phase 2 studies, are consistent with previous research on MDMA's effects in healthy individuals. The lack of difference in TEAEs or study withdrawal rates between groups suggests that side effects generally resolved within 7 days and did not lead to participants dropping out.

In Phase 3 studies, MDMA-AP participants were 3.5 times more likely to experience any TEAE compared to placebo participants. They also had increased odds of various physical and sensory side effects, like muscle tightness, nausea, and blurred vision. The higher number of significant adverse events in Phase 3 studies was likely due to their larger participant numbers, which provide more statistical power. These results align with known acute and lingering effects of MDMA in healthy individuals, suggesting that MDMA-AP side effects are primarily due to the direct effects of MDMA itself. While there was no statistical difference in serious adverse events related to suicide risk or heart function, these are rare events and might not show up as statistically significant in current analyses. Nonetheless, instances of suicidal thoughts or behaviors should be a serious safety concern in MDMA-AP trials, especially given potential risks for those assigned to placebo due to high expectations and possible unblinding of the study.

All included randomized controlled trials aimed to examine MDMA-AP's safety, yet none fully met the recommendations for reporting safety data. The reporting of adverse events was also incomplete: more than half of non-serious and nearly a third of serious adverse events recorded in public databases were not reported in the published articles. This discrepancy for non-serious events was mainly due to two Phase 3 studies that only reported adverse events if they occurred at least twice as often in the MDMA-AP group compared to the placebo group. Also, some studies stated there were "no drug-related serious adverse events" without providing systematic details. More transparency is needed regarding the timing of these events and why they were deemed unrelated to the treatment.

This review identified several limitations in the existing MDMA-AP research. Firstly, even though most studies reported side effect information, the reporting was largely insufficient and inconsistent across studies. This made it difficult to combine side effect data for statistical analysis. Additionally, conclusions could only be drawn about immediate and short-term side effects because there was not enough data on long-term risks beyond the active treatment period. Secondly, the certainty of the evidence was generally low, particularly for Phase 2 studies. While Phase 3 studies offered slightly more certainty due to larger and more diverse groups, the overall evidence on MDMA-AP comes from a limited number of studies with highly selected participants. This means a high level of confidence about MDMA-AP's safety or its risk-benefit balance is not yet possible. It is likely that when MDMA-AP is used more widely outside of controlled trials, especially with people who have more complex needs, the occurrence of side effects may increase. Also, while there was little variation between studies, many estimates lacked precision.

Thirdly, most studies relied on participants spontaneously reporting side effects. While this approach avoids leading questions, evidence suggests it likely underestimates the true extent of side effects compared to more systematic methods. Therefore, future MDMA-AP studies should use systematic checklists or scales in addition to spontaneous reporting to assess expected and general side effects both during and after sessions, and in long-term follow-up. Fourthly, only four studies looked at whether side effects changed with different doses. It is crucial for future research to determine the ideal dosage that reduces unnecessary risks. Finally, given differences in dosage, sample sizes, and reporting methods between Phase 2 and 3 studies, it was not possible to assess how these factors influenced side effects. Future trials using different study designs could provide more information on how expectations might contribute to the effects (both positive and negative) of MDMA-AP.

Conclusion

The evidence suggests that MDMA-assisted psychotherapy (MDMA-AP), when compared to placebo with psychotherapy, is linked to a greater chance of experiencing mild to moderate, mostly temporary side effects. However, these findings must be interpreted with caution due to the limitations of the existing research. This review showed a need for better practices in assessing side effects and stricter adherence to reporting guidelines for harms in MDMA-AP studies. Based on the results reported so far, any assessment of the risk-benefit balance of MDMA-AP remains limited because of the identified issues. Therefore, further large-scale clinical trials are recommended. These trials should systematically assess side effects, including long-term follow-up, comprehensively report all potential side effects, and follow standard reporting guidelines. In countries like Australia, and others that may soon implement MDMA-AP, systematic and independent studies of real-world side effects after the drug is approved for market use are also necessary.

Introduction

In recent years, doctors have been studying a treatment that uses a drug called MDMA with talk therapy. This treatment is called MDMA-assisted psychotherapy, or MDMA-AP. It is thought that MDMA helps the talk therapy work better. People usually have a few talk therapy sessions first, then a few full-day sessions with MDMA (or a dummy pill). After that, they have more talk therapy sessions.

More and more proof shows that MDMA-AP could help people with post-traumatic stress disorder (PTSD) and possibly other mental health problems. Australia has already approved MDMA for medical use with PTSD, and the United States may do so in 2024. While earlier studies mostly found MDMA and MDMA-AP to be safe, some worries exist. It is not always clear how well side effects were checked and reported in these studies. A full understanding of possible safety issues with MDMA-AP is needed for future research and for its use in clinics.

Earlier studies on MDMA-AP did not always look at all types of side effects. Some focused only on certain conditions like PTSD, or did not gather all safety information together. This new study looked at all past research on MDMA-AP's side effects for many mental health conditions. It also checked how well side effects were reported in those studies, using a special set of rules. Here, "side effects" means all reported health problems or unwanted reactions.

Methods

This study was planned beforehand and followed clear rules for gathering information. Researchers looked through major medical databases for studies on MDMA and talk therapy combined. They used search words like "MDMA," "psychotherapy," and "safety" to find all relevant papers.

The studies included needed to be published in English and involve giving MDMA with talk therapy to people for a mental health problem. They did not include studies without talk therapy, or those that were not original research, like reviews. This meant only studies in later stages of research (Phase 2 and 3) were part of this review.

Researchers took important information from each study. This included details about the study plan, the people involved, the MDMA dose, and what control group was used. They also noted how and when side effects were checked and reported. Two researchers checked this information to make sure it was correct.

The information was put together to get an overall picture. If at least two studies had data for a side effect, researchers used special methods to compare the MDMA-AP group to the control group. This helped them see if MDMA-AP made certain side effects more likely. They looked at different types of side effects and how they were reported in Phase 2 versus Phase 3 studies.

Researchers also checked how well side effects were reported in each study, using a set of guidelines called CONSORT Harms 2022. They compared the side effects listed in the published papers to those in a public database called ClinicalTrials.gov. Finally, they checked for possible flaws in how the studies were done, which could affect the results. This was done to see how trustworthy the side effect data was.

Results

This review looked at 13 studies in total, with 8 of them having enough data to be part of the main comparisons. These 8 studies included 298 people. Most of the studies (11 out of 13) just recorded side effects that people mentioned on their own, rather than using a standard checklist to ask about them. Also, the way side effects were reported changed between earlier (Phase 2) and later (Phase 3) studies.

In the earlier Phase 2 studies, people receiving MDMA-AP were more likely to have side effects during and for 7 days after their treatment sessions. For example, 45% of those on MDMA-AP had side effects during sessions compared to 30% on the dummy pill. Common side effects included anxiety and jaw clenching. However, there was no major difference in more serious or lasting unwanted events between the MDMA-AP group and the control group in these studies.

In the later Phase 3 studies, people in the MDMA-AP group were more likely to have any unwanted events (called "treatment emergent adverse events" or TEAEs). Sixteen percent of MDMA-AP participants reported these events, compared to 5% in the control group. These included muscle tightness, less hunger, nausea, sweating, feeling cold, restlessness, large pupils, jaw clenching, unusual eye movements, feeling shaky, chest pain (not heart related), blurry vision, and chills. These studies found no difference in serious safety issues related to heart problems or suicide risk between the groups. Across all studies, there was no difference in how many people stopped the study early, for any reason.

When checking the quality of the studies, most of the eight studies included in the main comparisons were found to have a high chance of bias, meaning their results might not be fully accurate. This was often because of how side effects were measured. The overall certainty of the findings was low to very low for most results, meaning there is still much to learn about MDMA-AP's safety.

A closer look at how side effects were reported showed that none of the studies fully followed the recommended guidelines for sharing safety information. On average, studies met only half of the reporting rules. Also, many side effects that were recorded in public study databases (like ClinicalTrials.gov) were not fully included in the studies that were published. For example, 56% of less serious unwanted events and 31% of serious unwanted events found in the databases were not in the published articles. This means important safety details might be missing from what is publicly shared.

Discussion

This study is the first to gather all available information on the side effects of MDMA-AP for different mental health issues. It found that people getting MDMA-AP were more likely to have mild to moderate side effects that did not last long. However, these findings should be considered carefully. The way side effects were checked and reported in past studies had many weaknesses. This means that we still do not fully know the complete safety details of MDMA-AP.

In earlier studies (Phase 2), MDMA-AP users had more short-term side effects like anxiety and jaw clenching during and right after sessions. But they did not have more serious unwanted events. In later studies (Phase 3), MDMA-AP users had more unwanted events overall, such as muscle tightness, nausea, and changes in body temperature. These side effects seem to come mostly from the MDMA itself. It is important to note that MDMA-AP did not lead to more cases of heart problems or thoughts of suicide compared to control groups.

A big problem found in this review is that none of the studies fully followed the rules for reporting safety information. On average, only half of the recommended details about harm were shared. Also, many side effects that were recorded in a public database were not fully included in the studies that were published. This lack of clear and full reporting makes it hard to get a true picture of MDMA-AP's safety.

Current research on MDMA-AP also has other limits. The studies often involved a small number of people who were carefully chosen, meaning the results might not apply to everyone. There is also not enough information about long-term risks. Most studies just waited for people to report side effects, instead of using regular checklists to ask about all possible issues. This method can miss many side effects. Future studies should use better ways to collect and share safety information.

Finally, very few studies looked at how the dose of MDMA affected side effects. It is important to know if certain side effects only appear with higher doses, so that doctors can find the best and safest amount to use. More independent, large studies are needed to clearly understand the safety of MDMA-AP, especially as its use becomes more widespread.

Conclusion

The studies reviewed show that MDMA-AP usually leads to more mild to moderate, but short-lived, side effects compared to a dummy pill. However, these findings should be viewed with care because of the limits in the current research. This review found a clear need for better ways to check for and report side effects in MDMA-AP studies.

Based on the information available today, it is hard to fully understand the risks and benefits of MDMA-AP. More large studies are needed that carefully check for all side effects, including those that last a long time. These studies also need to follow clear rules for reporting all possible side effects. As MDMA-AP starts to be used more in places like Australia, it will be important to keep studying its real-world side effects.