How it works

Researchers have proposed several ways that palmitoylethanolamide acts. Almost all of the evidence comes from cells and laboratory animals. A mechanism shown in the laboratory does not show an effect in patients.

This summary follows Rankin and Fowler 2020, an independent review.

Proposed targets, by strength of evidence

• PPAR-alpha. The best supported target. Read more.
• Mast cells. Effects are shown in several models, but the mechanism is unclear. Read more.
• TRPV1. Moderate evidence. Some effects appear direct and some appear to follow from PPAR-alpha.
• GPR55. Moderate evidence from a small number of studies.
• GPR119. Weak. A related molecule, oleoylethanolamide, is the main actor at this receptor.
• The entourage effect. Proposed, but not supported by the human and dog data. Read more.

What the review says is unknown

• Whether effects come from palmitoylethanolamide or from palmitic acid, its breakdown product.
• Which targets explain the effects that do not involve PPAR-alpha.
• The review also notes that almost all of the animal studies used males only.

• PPAR-alphaThe nuclear receptor most often linked to palmitoylethanolamide, and the evidence for that link.
• Mast cellsWhat laboratory studies show about palmitoylethanolamide and mast cells, and what remains unclear.
• The entourage effectThe proposal that palmitoylethanolamide works by raising other signalling fats, and what the human and dog data show.
• Breakdown: FAAH and NAAAThe two enzymes that break palmitoylethanolamide down, and what it becomes.