Reported Cases of Serotonin Syndrome in MDMA Users in FAERS Database

Corkery and colleagues situate their work in the context of expanding clinical interest in 3,4-methylenedioxymethamphetamine (MDMA) as an investigational treatment for PTSD and other anxiety-related disorders. They note that MDMA produces psychoactive effects via multiple actions on monoamine neurotransmission, including release and reuptake inhibition of serotonin, dopamine and norepinephrine, and that proposed therapeutic mechanisms include facilitation of emotional processing and interpersonal connectedness. Adverse events reported in controlled trials have been generally transient (for example, hypertension, muscle tension and nausea), but because MDMA affects serotonergic signalling there is a theoretical risk of serotonin syndrome (SS), a potentially life-threatening condition characterised by neuromuscular, autonomic and cognitive symptoms when serotonergic activity is excessive. The study sets out to examine whether cases of SS attributed to MDMA have been reported in the FDA Adverse Event Reporting System (FAERS). Specifically, the investigators sought to identify FAERS reports listing MDMA together with SS, to determine whether any SS cases listed MDMA as the sole compound, and to characterise concomitant substances—particularly other serotonergic agents—that might have contributed to SS risk. This work aims to place the safety profile observed in controlled clinical trials in the broader context of spontaneous surveillance data from real-world use.

The researchers used FAERS, the FDA’s repository of adverse event (AE) reports submitted via MedWatch, as their primary data source; FAERS accepts voluntary reports from consumers, healthcare professionals and manufacturers and may include unapproved or scheduled substances. Quarterly FAERS/AERS datasets were downloaded from the FDA public repository and saved in a dollar-sign separated text format. Each quarterly dataset contains subsets corresponding to variables such as demographics, drug exposures, indications, outcomes and reactions; these subsets were recompiled using the common case number to reconstruct individual AE reports. The analysis covered FAERS reports submitted from September 2004 through June 2021, yielding a total of 16,014,341 AE reports after standardisation. Because reporting fields were inconsistently populated across quarters, the team standardised the data structure (inserting blank tables where values were missing) and used Unix/Linux code for data restructuring and manipulation. Within this assembled dataset the investigators identified reports that included MDMA and screened those for a reported reaction of serotonin syndrome. For identified SS cases they examined the list of co-reported drugs and classified concomitant compounds by pharmacologic class, with particular attention to agents that have serotonergic properties. To assess whether identified FAERS cases had been reported previously in the medical literature, the authors queried PubMed using multiple search terms for MDMA and for serotonin syndrome. The extracted text does not provide further detail on the exact search dates, search strategy syntax, or whether any formal case validation (for example, review of narratives or toxicology reports) was conducted beyond the coding and classification described above.

From the FAERS dataset covering September 2004 to June 2021, 1,143 adverse event reports included MDMA. Of these, 20 reports listed serotonin syndrome as an adverse reaction. No FAERS reports were identified in which serotonin syndrome was attributed to MDMA as the sole reported compound; the only FAERS report in which MDMA (reported as ecstasy) was listed as the sole responsible compound concerned cardiomyopathy rather than SS. Reporter type and case adjudication were described: 19 of the 20 SS reports were submitted by healthcare professionals and one by a consumer. The remaining 1,142 MDMA-related AE reports all included MDMA together with at least one additional concomitant drug. In the 20 SS reports, concomitant psychoactive substances were common and frequently multiple: amphetamines were reported in 12 cases, opioids in 10, benzodiazepines and sedative-hypnotics in 8, cannabis/THC in 8, selective serotonin reuptake inhibitors (SSRIs) in 6, monoamine oxidase inhibitors (MAOIs) in 4, second-generation antipsychotics in 3, cocaine in 2, alcohol in 2, ergot alkaloids in 1, serotonin–norepinephrine reuptake inhibitors (SNRIs) in 1, and ketamine in 1. Seventeen of the 20 SS cases included two or more concomitant psychoactive substances. The authors report that none of the SS reports designated MDMA as the "primary suspect" for the adverse event. A PubMed search returned no published reports corresponding to the FAERS cases; the authors suggest this may reflect that MDMA was not listed as the primary suspect in the events. The results section also notes that the number of MDMA-related FAERS reports was small relative to international estimates of recreational ecstasy use (cited as nearly twenty million people), but no formal incidence calculation is presented.

Corkery and colleagues interpret their findings as supporting the absence of spontaneous FAERS evidence that MDMA alone precipitates serotonin syndrome. They emphasise that across roughly 17 years of FAERS data they identified only 20 reports of SS in people exposed to MDMA, and in every one of those reports additional serotonergic or psychoactive substances were co-reported. The pattern observed in FAERS is said to be concordant with controlled clinical trials of MDMA-assisted therapy, in which SS has not been reported and participants are generally tapered off serotonergic medications before MDMA administration. The authors highlight that most SS reports involved polypharmacy: 85% of the FAERS SS reports included at least two other drugs with serotonergic properties. They also note that none of the reports adjudicated MDMA as the primary suspect and raise the possibility that pharmacokinetic interactions (for example, via CYP2D6-mediated mechanisms) could have contributed to adverse effects in some cases. In considering the broader safety signal, the investigators find the absolute number of MDMA-related FAERS reports unexpectedly low given the global extent of ecstasy use. The study team acknowledges several important limitations of using FAERS data. Reporting is largely voluntary, so case counts cannot be interpreted as incidence or prevalence. Most FAERS reports are not clinically adjudicated for causality and full case narratives or confirmatory toxicology data are often unavailable in the public files; the extracted text notes that while hospitalised cases typically prompt drug testing, FAERS does not provide a consistent means of reporting test confirmation. The authors further observe uncertainty about the identity and purity of illicitly manufactured MDMA in reported cases, since adulteration or mislabelling is possible. Finally, the extracted text contains an incomplete sentence regarding SSRIs' effects, and the remainder of that discussion is not available in the provided extraction.

The authors conclude that FAERS contains no reports of serotonin syndrome attributed to MDMA when MDMA was the sole administered drug; SS in FAERS occurred only in the context of MDMA combined with other substances, including stimulants, opioids and antidepressants. They note that this pattern aligns with clinical-trial safety data for MDMA-assisted therapy, in which participants are typically tapered off serotonergic medications and SS has not been reported.