Palmitoylethanolamide (PEA) is a naturally occurring fatty acid amide that has garnered scientific interest for its potential role in treating migraine. The rationale for its use is primarily based on its anti-inflammatory and analgesic properties, which are mediated through modulation of mast cells, glial cells, and the endocannabinoid system. Several small clinical studies and case reports have explored PEA’s efficacy in chronic pain and neuropathic pain syndromes, including migraine.

A few open-label and pilot studies have specifically investigated PEA in migraine patients. For instance, a small open-label study found that oral PEA supplementation reduced migraine frequency and intensity in some patients. Another pilot trial reported positive results in reducing pain severity. However, these studies are limited by small sample sizes, lack of blinding, and short duration. Systematic reviews note that while the mechanistic rationale is plausible—due to PEA’s effects on neuroinflammation—robust, randomized, placebo-controlled trials are lacking.

In summary, there is preliminary scientific rationale and some early clinical data supporting PEA’s use in migraine, but the evidence base remains weak (rated 2/5). Larger, well-controlled trials are needed to confirm efficacy and establish guidelines for use in migraine management.