Peatonide, marketed by San Marino-based supplement company Pharmaluce “may be a promising adjunctive approach for migraine management,” wrote the researchers from the University of Naples and the Interuniversity Consortium of Biostructures and Biosystems in Rome.
They noted that existing non-specific migraine medications, such as antiepileptic drugs, antidepressants and beta-blockers may have numerous side effects, making it challenging for patients to continue treatment.
More specific drug treatments approved in recent years may have fewer side effects, but doctors may only prescribe them to patients with debilitating regular attacks, suggesting a need for natural therapies for individuals with low-frequency episodic migraine.
Potential mechanisms
Peatonide combines palmitoylethanolamide (PEA) and melatonin.
PEA, studied for its anti-inflammatory, analgesic and immunoregulatory effects, is synthesized in the brain and is usually upregulated in diseased states. Its neuroprotective properties are related to increases in peroxisome proliferator-activated receptor (PPAR) alpha. Additionally, it reduces NF-kB activation and inhibits mast cell degranulation, which can decrease the inflammation associated with migraine.
Headache disorders have a multifactorial and complex relationship with circadian rhythms and sleep disturbance. The current study noted that melatonin may decrease vasodilation and regulate several pathways involved in triggering migraines, “including GABA, opioid, serotonergic, adrenergic, cholinergic and melatonergic receptors.”
In addition, melatonin, like PEA, is involved in mast cell degranulation.
“Therefore, the combination of the two molecules could increase the potential anti-migraine activity through a synergistic effect,” the researchers wrote.
Study details
The randomized, double-blind, placebo-controlled trial recruited 60 men and women who had been diagnosed with episodic migraines with or without aura for at least a year before recruitment and experienced at least two migraine attacks for a minimum of three months prior to the study.
The researchers assigned participants to consume either a Peatonide supplement (1,200 mg of hydrodispersible PEA and 0.2 mg of melatonin) or placebo at bedtime for three months. They were also permitted to take acetaminophen and NSAIDs as needed for acute phase migraine attacks.
Symptoms were evaluated using a self-reported daily headache diary.
Results revealed that 27% of those treated with Peatonide had an at least 50% reduction in monthly migraine days (MMDs), and 25% had at least a 50% reduction in analgesic use and the duration of attacks after three months. No significant variation in MMDs or medication was observed in the placebo group.
The study noted that the supplement significantly reduced the frequency, duration, intensity, disability and incidence of associated symptoms. Additionally, no adverse effects were observed.
While the researchers consider the results promising, they noted the small sample size and called for further large-scale and multi-center trials to confirm the supplement’s clinical applicability in broader populations.
Source: Frontiers in Nutrition. doi: 10.3389/fnut.2025.1560654. “Fixed combination of palmitoylethanolamide and melatonin in preventive therapy of migraine: results from a randomized clinical trial”. Authors: V. Piccolo et al.