Palmitoylethanolamide (PEA) is an endogenous fatty acid amide that has garnered interest for its anti-inflammatory and analgesic properties. Scientific interest in PEA for headache relief, including general headache and migraine, is based on its modulation of the endocannabinoid system and reduction of neuroinflammation. Several small-scale clinical trials and case reports have suggested a potential benefit of PEA for migraine and other headache disorders. For example, a randomized, double-blind, placebo-controlled trial published in 2017 (Cephalalgia) found that PEA supplementation reduced the frequency and intensity of migraine attacks compared to placebo. Other observational studies and open-label trials have reported improvements in headache-associated pain and quality of life with PEA supplementation. Preclinical studies further support its role in attenuating neuroinflammation and mast cell activation, which are implicated in headache pathophysiology.

However, the overall quality of clinical evidence remains low due to small sample sizes, lack of large-scale randomized trials, and heterogeneity in study design. There is also a paucity of data specifically addressing non-migraine general headaches. As such, while PEA shows promise and there is an emerging scientific rationale, current evidence supporting its use for general headache is limited and preliminary. More rigorous, large-scale clinical trials are needed to conclusively establish efficacy and safety for this indication.