Metoprolol Toxicity Associated With Curcuminoid and Piperine Supplementation: A Suspected CYP2D6-Mediated Drug–Supplement Interaction

Background

Herbal and dietary supplements are widely used and may produce clinically significant drug–supplement interactions through effects on drug absorption and metabolism. Metoprolol is predominantly metabolized by hepatic cytochrome P450 2D6 (CYP2D6), and inhibition of this pathway can increase metoprolol exposure and lead to excessive β-adrenergic blockade. Curcuminoids and piperine, commonly combined in commercially available turmeric supplements, have demonstrated inhibitory effects on multiple cytochrome P450 enzymes, including CYP2D6.

Case Presentation

An 83-year-old man with paroxysmal atrial fibrillation and hypertension presented after a ground-level fall preceded by dizziness and transient loss of consciousness. He was taking metoprolol tartrate twice daily for atrial fibrillation and was subsequently found to have profound bradycardia with a heart rate of 31 beats/min. Electrocardiography demonstrated atrial fibrillation with a slow ventricular response and right bundle branch block. Intravenous atropine produced no significant improvement, and the patient required isoproterenol infusion and intensive care monitoring. Trauma evaluation revealed an acute nondisplaced C4 teardrop fracture, as well as facial trauma. Cardiac biomarkers were negative, renal function was preserved, and transthoracic echocardiography demonstrated a left ventricular ejection fraction of 60%. Detailed medication reconciliation identified concurrent use of a commercially obtained turmeric supplement containing curcuminoids and piperine. Given the known inhibitory effects of curcuminoids and piperine on drug-metabolizing CYP enzymes, particularly CYP2D6, a drug-supplement interaction was considered a potential contributor to excessive metoprolol effect. Metoprolol was withheld, with subsequent resolution of the severe bradycardia. It was later restarted at 12.5 mg twice daily without recurrence of profound bradycardia during hospitalization.

Findings

The patient experienced profound symptomatic bradycardia with a heart rate of 31 beats/min, dizziness, transient loss of consciousness, and traumatic injury. Atropine produced no significant improvement, necessitating isoproterenol infusion and intensive care monitoring. Following discontinuation of metoprolol, the severe bradycardia resolved. Metoprolol was subsequently restarted at 12.5 mg twice daily without recurrence of profound bradycardia during hospitalization.

Discussion & Conclusion

This case highlights a potentially clinically significant interaction between curcuminoid/piperine supplementation and metoprolol associated with severe symptomatic bradycardia, syncope, and traumatic injury. Although direct metoprolol serum concentrations and CYP2D6 activity were not measured, the clinical course and existing pharmacologic evidence support a plausible drug supplement interaction. Clinicians should routinely inquire about herbal and dietary supplement use when evaluating unexplained bradycardia or suspected medication toxicity, particularly in older adults receiving medications predominantly metabolized through CYP2D6.