3,4-methylenedioxymethamphetamine also known as MDMA or its street name Ecstasy, is currently a schedule I controlled substance in the United States and the European Union, and a Class A substance in the United Kingdom. There is growing interest in MDMA’s utilization in psychiatry based on promising efficacy and safety findings from multiple controlled clinical trials including a Phase 3 study for MDMA assisted therapy for post-traumatic stress disorder (PTSD) (1–5).

MDMA’s psychoactive effects are due to its complex pharmacology, including modulation of release and reuptake of serotonin, norepinephrine, and dopamine (6–9), and an increase in oxytocin levels (10). The efficacy of MDMA in PTSD treatment is attributed to supporting fear-extinction learning an increased ability to confront adverse memories, and improved social and interpersonal interactions (5, 11–13).

However, due to the monoamine neurotransmission modulation, cardiovascular physiology may be affected as well (14–16). Arrhythmia-related adverse events (AEs), in addition to hypertensive and ischemia-related AEs have been reported in literature (17–20). In controlled clinical trials in both healthy volunteers and patients with PTSD, AEs of transient increases in blood pressure and heart rate were observed along with muscle tightness, decreased appetite, nausea, hyperhidrosis, and feeling cold (4, 21).

Considering the polypharmacy often present in PTSD populations due to other comorbid conditions such as substance use (22, 23), anxiety (24), depression (25), sleep (26) and pain disorders (27), and the respective treatment drugs, further MDMA AE evaluation is warranted using the FAERS database. This is particularly important since the clinical trials excluded many of these medications, and there is potential for drug–drug interactions (28).

In this study, we evaluated arrhythmic, ischemic, and hypertensive AE reports in MDMA users from the FDA Adverse Event Reporting System (FAERS). These AEs were reviewed in submissions where MDMA was reported to be used alone or with additional therapeutics or illicit substances. The contribution of concomitant drugs and substances to the risk of cardiovascular AEs was evaluated.

A total of 17 unique cases were reviewed in this study. There were no reports where MDMA was taken as a single agent and ischemic, hypertensive, or arrhythmic AEs were reported. All cases included concomitant medications with known associated cardiac function abnormalities. There were a total of four cases matching the Torsade de pointes/QT prolongation SMQ search criteria (Supplementary Table S1). In all of the cases, MDMA was taken with concomitant medications (SSRIs, antihistamines/anticholinergics, amphetamines) with known effects on cardiac function (Table 1). These cases included one report of ventricular fibrillation which matched the Ventricular tachyarrhythmias SMQ search query (Table 2). The Supraventricular tachyarrhythmia SMQ query produced three reports with one report overlapping with Torsade de pointes/QT prolongation SMQ terms (Table 3). The Cardiac arrhythmia terms nonspecific SMQ search produced two reports with concomitant reported cocaine, opioid, benzodiazepine, gamma hydroxybutyrate, and cannabis use (Table 4). There were two reports in the Arrhythmia related investigations, signs and symptoms query, both based on three broad scope AE PTs (Supplementary Table S1), one of which (case #6) overlapped with the Supraventricular tachyarrhythmia query (Table 5). The Myocardial infarction SMQ based search produced one report of an AE of troponin increased, where MDMA was taken with clozapine (Table 6). The Tachyarrhythmia terms nonspecific SMQ search produced no reports. The Other ischaemic heart disease query found two unique reports and the ‘Hypertension’ query produced seven reports with two overlaps with Torsade de pointes/QT prolongation and Supraventricular tachyarrhythmias SMQs (Table 7). There were seven Hypertension SMQ cases with two reports overlapping with Torsade de pointes/QT prolongation and Supraventricular tachyarrhythmias SMQs (Table 8).

The summary of all of the cases, with the concomitant medications organized by class, is provided in Table 9.

In this study, we evaluated AEs related to arrhythmias, hypertension, and ischemia in MDMA reports from the FDA adverse Event Reporting System (See Supplementary Table S1). There were no reports of those AEs in cases where MDMA was the sole reported drug. A limited number of 17 cases associated with MDMA use, reported in the last ~18 years, were evaluated. Interestingly, in every single case, MDMA was not reported as the primary suspect of those AEs. Furthermore, in all the cases, all listed concomitant drugs except one, acetaminophen, had known cardiac function related effects and were marked as primary suspects. There were two unique acetaminophen overdose cases that reported MDMA as a concomitant drug. Additionally, 76% of the reports included two or more drugs or illicit substances associated with arrhythmic, ischemic, or hypertensive AEs. It is interesting to note that in majority of the cases, illicit substances were taken in combination with psychoactive prescription medications supporting previous observations that substance use and abuse are often comorbid with psychiatric disorders. While individuals with mental health are more susceptible to misuse/abuse of illicit substances, this correlation is more complex and multidimensional as misuse/abuse may themselves lead to psychiatric disorders (35, 36).

There is still the possibility that MDMA contributed to the cardiovascular AE due to its sympathomimetic mechanism of action or CYP2D6-mediated drug–drug interaction(s) (37, 38). However, it was neither a sole culprit nor a primary suspect in any of the reported cases. The United Nations Office of Drugs and Crime estimated the number of people who report MDMA/ecstasy use to be nearly 20 million people (39). Surprisingly, considering this number, the number of reported MDMA cases with cardiovascular AE in FAERS/AERS was surprisingly low. Despite the fact that MDMA, as a known sympathomimetic, transiently increases blood pressure which is also observed in clinical trials, the number of FAERS reports on hypertension is relatively low, supporting the transient nature of this observation.

Study limitations. Due to the voluntary nature of FAERS/AERS reporting, with the exception of spontaneous reports from sponsors/manufacturers, the data presented only represents a subset of actual cases and should not be confused with actual population frequencies. Additionally, since the manufacturing and distribution of MDMA is not regulated, it is not clear whether the reported compound was pure MDMA or if it was laced with another compound not caught by the conventional drug tests. Information on the ingested MDMA dose and how the presence of MDMA was evaluated is missing from the reports, since case narratives are kept confidential by the FDA due to privacy concerns. Detailed medical and psychiatric history of the individuals in the reports were also not available. However, all of the 17 cases presented in the study were submitted by healthcare professionals (Form-3,500), thus some level of clinical adjudication prior to reporting is expected.

The datasets presented in this study can be found in online repositories. The names of the repository/repositories and accession number(s) can be found below: https://fis.fda.gov/extensions/FPD-QDE-FAERS/FPD-QDE-FAERS.html.

Ethical approval was not provided for this study on human participants because Ethical review and approval was not required for the study on human participants in accordance with the local legislation and institutional requirements. Written informed consent from the participants’ legal guardian/next of kin was not required to participate in this study in accordance with the national legislation and the institutional requirements. Study utilized de-identified postmarketing data available online to the public. Written informed consent for participation was not required for this study in accordance with the national legislation and the institutional requirements.

TM performed the research. TM, DD, LJ, AB, and RA designed the study, drafted the manuscript, and reviewed the final version. RA processed the data sets. All authors contributed to the article and approved the submitted version.

The study was funded by MAPS Public Benefit Corporation and in part by Skaggs School of Pharmacy and Pharmaceutical Sciences, UC San Diego Health.

TM, DD, and LJ were employed by MAPS Public Benefit Corporation. AB was employed by Tulip Medical Consulting LLC.

The remaining author declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.