PPIG and major depressive disorder: In conclusion, whilst a satisfactory explanation for the lacking anti-depressant activity of DHA remains obscure, there is a body of indirect evidence that EPA improves depression at least partially by acting as a pro-drug through competition with AA for integration and release from membranes, by its abundant CYP-mediated metabolome, and by the high CB2 receptor affinities of its endocannabinoid EPEA and its epoxy-metabolite 17,18-EEQ-EA.