Reported Cases of Serotonin Syndrome in MDMA Users in FAERS Database

This study (2022) assessed the occurrence of serotonin syndrome (SS) associated with MDMA use and reported it to the FDA Adverse Event Reporting System (FAERS) through MedWatch. In each of the 20 reported cases of SS, people had also taken one or more substances with serotonergic properties in addition to MDMA, including amphetamines, stimulants and opioids. There were no reports of sole MDMA use leading to SS.

Abstract

“3,4-Methylenedioxymethamphetamine (MDMA), is investigated as a treatment for post-traumatic stress disorder and other anxiety-related conditions in multiple placebo-controlled and open-label studies. MDMA-assisted therapy is projected for approval by the United States Food and Drug Administration (FDA) and other regulatory agencies worldwide within the next few years. MDMA is a monoamine releaser and uptake inhibitor affecting serotonin, potentially increasing the risk of serotonin syndrome (SS). No instances of SS have occurred in clinical trials. The relatively small number of patients in controlled trials warranted a survey of FDA Adverse Event Reporting System data for the occurrence of SS in a larger database. We found 20 SS cases in people exposed to MDMA, all of which had also taken one or more substances with serotonergic properties in addition to MDMA, including amphetamines, stimulants, and opioids. There were no cases of SS associated with MDMA where MDMA was the solely reported compound taken.”

Authors: Tigran Makunts, Lisa Jerome, Ruben Abagyan & Alberdina de Boer

Notes

Serotonin syndrome (SS) is the result of serotonergic overactivity at the synapse and is a potentially life-threatening condition. SS is usually associated with serotonergic medications such as SSRIs and MDMA. Symptoms range in severity from physical restlessness (akathisia) and tremors to more severe symptoms including hyperthermia and muscle rigidity. As the therapeutic potential of MDMA is becoming more well-known thanks to rigorous clinical research, it is important that we understand how MDMA relates to SS.

The present paper explores the risk of MDMA induced SS. Given there have been no reported cases of SS in clinical studies with MDMA, the researchers analysed reported cases of SS in the FDA Adverse Event Reporting System (FAERS). FAERS is a database that contains adverse event reports, medication error reports and product quality complaints resulting in adverse events that are submitted to FDA.

The main findings:

• 20 out of 1,143 adverse events which included MDMA and were reported to FAERS were reports of SS.
• There were no reports of SS where MDMA was the sole responsible compound.
• In each of the 20 reported cases of SS, people had taken one or more substances with serotonergic properties alongside MDMA inlcuing amphetamines, stimulants and opioids.

Overall, the present paper confirms the observation in clinical trials that there have been no reported cases of SS when MDMA is the only substance being administered. The authors do acknowledge limitations including that reporting to FAERS is mostly voluntary and therefore the dataset represents a subset of actual cases. Nonetheless, these findings are positive for MDMA-assisted therapies.

Summary

MDMA, a monoamine releaser and uptake inhibitor affecting serotonin, is investigated as a treatment for post-traumatic stress disorder and other anxiety-related conditions. 20 cases of serotonin syndrome have been reported in people exposed to MDMA, all of whom had also taken one or more substances with serotonergic properties.

INTRODUCTION

MDMA is a schedule I controlled substance in the European Union and the United States and has been shown to increase ability to confront upsetting memories, support fear-extinction learning and increase interpersonal closeness.

MDMA use beyond research settings has been associated with Serotonin Syndrome (SS), a potentially life-threatening condition resulting from serotonergic over-activity at synapses of the central and peripheral nervous systems usually involving serotonergic medications.

We evaluated individual cases of MDMA use associated with SS, and found that additional substances may increase the risk of SS.

FDA Adverse Event Reporting System

FAERS is an important source of safety data for drugs pending approval and schedule I controlled substances, as it provides meaningful safety signals that may help in diagnosing and mitigating illicit drug toxicity cases.

Combining and Normalizing Data Sets

Quarterly FAERS/AERS data sets were downloaded from the FDA’s public repository and recompiled using the case numbers common in each of the subsets. Blank tables replaced missing values and Unix/Linux code was used in data restructuring and manipulation.

RESULTS

MDMA was included in 1,143 AE reports, 20 of which were reports of SS. MDMA was not identified as the sole responsible compound in any of the reports, and most reports included MDMA and at least one or more concomitant drugs.

Seventeen out of 20 cases included two or more concomitant psychoactive substances. The Pubmed library was queried, but no published reports were found.

DISCUSSION

In this study, we evaluated reports of serotonin syndrome (SS) associated with MDMA use reported to the FDA using the FAERS system. We found no reports of SS in cases where MDMA was the sole reported drug, which confirmed the observed lack of SS in clinical trials.

Study Limitations

Nineteen out of 20 presented case reports were submitted by healthcare professionals, and all of the reports listed additional substances as well. Although SSRIs were present in six of the presented case reports, this relationship was challenging to quantify.

CONCLUSION

In summary, reported use of MDMA as the sole administered drug produced no reports of SS in the FAERS system; however, when MDMA was combined with an additional substance, SS was reported.

ETHICS STATEMENT

In accordance with local legislation, no ethical review or approval was required for this study.