Efficacy and Safety of Oral L-Ergothioneine Supplementation in Primary Dysmenorrhea: A Randomized, Double-Blind, Placebo-Controlled Clinical Trial

Abstract Purpose To evaluate the efficacy and safety of oral L-ergothioneine (EGT) in alleviating pain and associated symptoms in women with primary dysmenorrhea (PD). Methods In this randomized, double-blind, placebo-controlled trial, 40 women with PD (aged 18–30 years) were randomized (1:1) to receive EGT capsules (120 mg/day) or a matching placebo for 3 consecutive menstrual cycles. Outcomes evaluated at baseline and post-cycle included peak pain (Visual Analog Scale, VAS), Dysmenorrhea Symptom Score, and the COX Menstrual Symptom Scale (CMSS). Results EGT significantly improved PD symptoms over 3 cycles. Mean VAS for peak pain decreased from 4.80 ± 1.12 to 2.32 ± 1.59 in the EGT group (p < 0.001), compared to a non-significant reduction (4.10 ± 1.30 to 3.45 ± 1.69) in the placebo group. The between-group difference at cycle 3 was significant (p < 0.01). A linear mixed-model confirmed a significant Time × Group interaction (p < 0.001), showing an accelerated decline in symptom severity for EGT. Furthermore, 84% of EGT-treated patients achieved ≥50% VAS reduction versus 35% in the placebo group (p = 0.003). Serum inflammatory biomarkers showed no significant between-group differences or correlation with VAS improvements, suggesting EGT’s analgesic effects likely operate via cytoprotective pathways independent of classical inflammatory cascades. No adverse events were reported. Conclusion Oral EGT supplementation (120 mg/day) effectively and progressively mitigates menstrual pain and systemic symptoms in PD, offering a well-tolerated, non-pharmacological intervention. Trial Registration ChiCTR2500112557; Retrospectively registered on 2025-11-17.