Concomitant medications associated with ischemic, hypertensive, and arrhythmic events in MDMA users in FDA adverse event reporting system

MDMA (3,4-methylenedioxymethamphetamine; also known as Ecstasy) is under active investigation as an adjunct to psychotherapy, most notably in Phase III trials for PTSD. Its principal pharmacology includes increased release and inhibited reuptake of serotonin, norepinephrine and, to a lesser extent, dopamine, and it also raises oxytocin levels. While these effects may facilitate fear-extinction learning and enhance therapeutic engagement, modulation of monoamine signalling produces sympathomimetic physiological effects that have been associated with transient increases in heart rate and blood pressure and, more rarely, arrhythmic, hypertensive or ischemic adverse events (AEs) in the literature and in clinical trials. Makunts and colleagues set out to examine reports of arrhythmic, ischemic and hypertensive AEs in MDMA users recorded in the FDA Adverse Event Reporting System (FAERS). The study aimed to determine whether MDMA was reported as the primary suspect in such events and to evaluate the contribution of concomitant prescription drugs and illicit substances to these cardiovascular AEs, recognising that many psychiatric populations exhibit polypharmacy that was excluded from controlled trials.

The investigators used the FAERS/AERS public repository, which contained 18,274,795 reports from January 2004 to September 2022 at the time of analysis. Quarterly FAERS/AERS data sets (demographics, drug, indication, outcome, reaction, report source) were downloaded in text format and standardised into a unified table structure using Unix shell scripts for restructuring and filtering. The authors note that partially missing demographic fields (age, weight, sex) in MDMA reports were comparable to the rest of the database. Cases were selected if a reported drug field contained terms for MDMA (methylenedioxymethamphetamine, midomaphetamine, MDMA, ecstasy, and variants). This initial query yielded 1,475 reports. To increase clinical relevance and limit reporting bias, only reports submitted by healthcare professionals were retained. The resulting cohort was searched for adverse events using Standardized MedDRA Queries (SMQs) targeting cardiovascular outcomes: Torsade de pointes/QT prolongation (level 1), various arrhythmia-related SMQs at multiple levels including supraventricular and ventricular tachyarrhythmias, and Hypertension (level 1), among others. The authors selected cases containing either at least one narrow-scope Preferred Term (PT) or two or more broad-scope PTs; a comprehensive PT list was referenced in a Supplementary Table. Individual case narratives were reviewed to remove duplicate submissions, yielding 17 unique reports included in the study. No additional inclusion or exclusion criteria were applied. Analysis consisted of descriptive review of the identified cases, focusing on concomitant medications/substances, their known cardiac associations, and whether MDMA was listed as a primary suspect.

Seventeen unique FAERS reports matching the cardiovascular SMQ criteria for MDMA-containing cases were identified and reviewed. In none of these reports was MDMA the sole reported substance, and in none was MDMA listed as the primary suspect for the adverse event. All cases involved at least one concomitant medication or illicit substance previously associated with cardiac dysfunction; all concomitant agents except acetaminophen had known cardiac-related effects and were marked as primary suspects in the reports. Specific query results included four cases matching the Torsade de pointes/QT prolongation SMQ. One of the reports that met ventricular tachyarrhythmia criteria described ventricular fibrillation. The Supraventricular tachyarrhythmia SMQ returned three reports, one overlapping with the Torsade de pointes/QT prolongation set. Two reports matched the nonspecific cardiac arrhythmia SMQ and contained concomitant use of cocaine, opioids, benzodiazepines, gamma-hydroxybutyrate and cannabis. Two reports were identified under the Arrhythmia-related investigations, signs and symptoms query, one overlapping with supraventricular tachyarrhythmia. Search for myocardial infarction–related terms produced one report of increased troponin where MDMA was taken with clozapine. The Tachyarrhythmia terms nonspecific query produced no reports. The Other ischaemic heart disease query identified two unique reports. The Hypertension SMQ yielded seven reports, two of which overlapped with Torsade de pointes/QT prolongation and supraventricular tachyarrhythmia SMQs. Overall, 76% of the reports involved two or more drugs or illicit substances known to be associated with arrhythmic, ischemic or hypertensive AEs. Two cases described acetaminophen overdose with MDMA listed only as a concomitant substance. The extracted text indicates that the detailed summary of concomitant medications by class appears in a Table and in Supplementary material.

The authors interpret these findings to indicate that reports of arrhythmic, hypertensive and ischemic AEs in FAERS involving MDMA are uncommon and, in this set of 17 clinician-submitted reports over approximately 18 years, were always associated with concomitant substances that have established cardiac risk profiles. They note that MDMA was not the primary suspect in any case and was never the sole reported drug. Makunts and colleagues highlight that multiple reports contained several co-ingested substances, supporting prior observations of comorbidity between psychiatric disorders and illicit substance use. While acknowledging that MDMA has sympathomimetic properties that could plausibly contribute to cardiovascular AEs, the investigators state that their data do not support MDMA as the sole cause in these reports; they also raise the possibility of pharmacokinetic interactions (for example, CYP2D6-mediated) but do not provide direct evidence of such mechanisms in the reviewed reports. The authors remark on the low number of FAERS reports relative to an estimated global MDMA/ecstasy user base of about 20 million, suggesting that transient blood pressure increases seen in clinical trials may not commonly translate into reported serious hypertension events in post-market surveillance. Key limitations are emphasised: FAERS is a voluntary reporting system (except for sponsor/manufacturer reports) and therefore captures only a subset of events and cannot be used to infer population incidence. The unregulated nature of illicit MDMA manufacture means the substance reported may not have been pure MDMA; dose information and methods for confirming MDMA presence were not available because case narratives are confidential. Detailed medical and psychiatric histories of individuals were also not accessible. The authors point out that all included reports were submitted by healthcare professionals (Form 3500), which they suggest provides some level of clinical adjudication despite the other limitations.