Cardiac Arrhythmia Associated with Psychoactive Drugs: An analysis of the FDA Adverse Event Reporting System

Background: Several Schedule I substances have demonstrated potential benefits for refractory psychiatric conditions and addiction. Some have been legalized at the state level, while others like kratom (mitragynine) are available over-the-counter in some states and illegal in others. A recent presidential executive order directs certain federal agencies to accelerate development and facilitate access to psychedelic drugs through increased funding and expedited FDA review. Studies investigating the therapeutic potential of these drugs are limited and focused disproportionately on efficacy over safety. Rigorous evaluation of cardiovascular safety, including potential arrhythmia liability, is essential. Methods: We analyzed reports from the FDA Adverse Event Reporting System from 2000-2024. involving Schedule 1 and other unscheduled drugs with purported therapeutic potential including 3,4-methylenedioxy-methamphetamine (MDMA), mitragynine, ibogaine, lysergic acid diethylamide (LSD), mescaline, psilocybin, tetrahydrocannabinol (THC), and dimethyltryptamine (DMT). We used FDA-approved drugs (e.g., dofetilide, naltrexone) as quasi-experimental positive and negative controls respectively, then calculated proportional reporting ratios (PRR) for the composite of ventricular arrhythmia and cardiac arrest, ventricular arrhythmia only, and QTc-prolongation. Results: Among 18,499,626 unique cases, 61,961 (0.3%) mentioned at least one psychoactive drug of interest. The psychedelic drugs ibogaine, MDA, MDMA, and LSD and the non-psychedelic mitragynine exhibited a significant PRR for ventricular arrhythmia/cardiac arrest; the strongest signals were observed for mitragynine (PRR 8.8; 84/1171 reports), and ibogaine (PRR 38.8; 7/25 reports). When restricting analysis to ventricular arrhythmia alone (excluding potential non-arrhythmic cardiac arrest), the signal remained significant for mitragynine (PRR 4.4, 8/1171 reports) and was markedly higher for ibogaine (PRR 142.0, 5/25 reports), approximately 6-fold higher than dofetilide (PRR 24.0; 533/11,950 reports). This corresponded with QTc-prolongation signals for ibogaine (PRR 121.0; 6/25 reports) and mitragynine (PRR 15.9; 38/1171 reports), which were comparable to dofetilide (PRR 30.9; 771/11,950 reports) and methadone (PRR 12.4; 1428/55,895 reports). MDA, MDA, and LSD did not show ventricular arrhythmia signal, and although MDMA was associated with disproportionate reporting of QTc-prolongation (PRR 9.9; 10/474 reports). Conclusions: Ibogaine and mitragynine demonstrated disproportionate reporting of ventricular arrhythmia similar to or exceeding established proarrhythmic drugs. These data suggest that robust cardiac safety evaluations will be a regulatory priority given accelerated development of psychedelic drugs.