Research Summary

Single-Dose Palmitoylethanolamide Reduces Menstrual Pain in Double-Blind Trial

Miranda Manier, BA

Key Highlights:

  • Palmitoylethanolamide (PEA) significantly reduced acute menstrual pain compared with placebo at multiple early time points post-dose.
  • A single dose of PEA (300 mg) provided approximately 25% greater pain relief than placebo within 2.5 hours.
  • No significant differences were found in adverse events or rescue medication use, confirming PEA’s favorable safety profile.
  • PEA may serve as an effective alternative to nonsteroidal anti-inflammatory drugs for primary dysmenorrhea.

Palmitoylethanolamide (PEA) supplementation significantly reduced acute menstrual pain in a randomized, double-blind, placebo-controlled crossover study conducted in Australia. Participants who received a single 300 mg dose of a highly bioavailable PEA formulation experienced statistically significant reductions in pain at 1.0 (P = .045), 1.5 (P = .009), 2.0 (P = .015), and 2.5 (P = .039) hours post-dose, compared with placebo. The intervention provided pain relief for approximately 25% more participants by 2.5 hours, without an increase in adverse events or rescue medication usage.

Dysmenorrhea is the most common gynecologic condition among women of reproductive age, characterized by painful uterine cramping often severe enough to impact daily activities. Despite its high prevalence, effective and well-tolerated treatments remain limited. Nonsteroidal anti-inflammatory drugs, while commonly prescribed, are associated with gastrointestinal and systemic side effects and may be ineffective or intolerable for a subset of patients. PEA, an endocannabinoid-like compound with anti-inflammatory and analgesic properties, has shown promise in treating various pain conditions. However, its role in treating menstrual pain—particularly with acute, single-dose administration—remains underexplored.

To address this gap, researchers enrolled 80 healthy, menstruating women aged 18 years or older with a history of primary dysmenorrhea in a 16-week crossover trial. Participants received either 300 mg of PEA or a placebo (microcrystalline cellulose) at the onset of menstrual pain (NRS ≥5), followed by pain score assessments every 30 minutes for up to four hours. A second dose was allowed at the 2-hour mark if pain persisted. Data from 217 pain episodes (103 PEA, 114 placebo) without rescue medication use were analyzed. Pain scores were evaluated using repeated measures ANOVA.

Participants receiving PEA showed a significantly greater reduction in pain than those receiving placebo at several early time points. Specifically, significant between-group differences in pain scores were observed at 1.0, 1.5, 2.0, and 2.5 hours post-dose. Although both groups reported similar levels of pain relief by 4 hours, the earlier and greater effect observed with PEA may offer a clinically meaningful advantage. The study found no significant differences between groups in rescue medication use, treatment satisfaction, or adverse event rates. Eight mild adverse events were recorded across both groups, none of which were definitively attributed to the study products.

A limitation of this study is the inclusion of participants using hormonal contraceptives, which can independently affect pain severity and menstrual cycle characteristics. While their distribution was balanced by the crossover design, these factors could introduce variability.

“This study demonstrates PEA supplementation is a safe and effective option for reducing menstrual pain compared to a placebo, with significant pain reduction observed at multiple time points post-dosage,” the study authors concluded.

Reference:
Rao A, Erickson J, Briskey D. Palmitoylethanolamide (Levagen+) for acute menstrual pain: a randomized, crossover, double-blind, placebo-controlled trial. Women Health. 2025;65(3):237-245. doi:0.1080/03630242.2025.2458243