Ginkgo BilobavsPEA (Palmitoylethanolamide)

Ginkgo biloba extract (EGb 761) contains flavonoids (quercetin, kaempferol, isorhamnetin) and terpenoids (ginkgolides A, B, C, J and bilobalide). The flavonoids are potent antioxidants that scavenge superoxide, hydroxyl radicals, and peroxynitrite, and protect neurons from oxidative damage; they may also chelate iron. The terpenoids (ginkgolides and bilobalide) improve blood flow by antagonizing platelet-activating factor (PAF) at the PAF receptor, which reduces platelet aggregation, blood viscosity, and improves microcirculation in the brain. Bilobalide protects mitochondria and reduces apoptosis. Ginkgo modulates nitric oxide (NO) availability via endothelial nitric oxide synthase (eNOS) for vasodilation. It inhibits monoamine oxidase A and B (MAO-A, MAO-B), mildly elevating dopamine and serotonin. It may enhance cholinergic transmission and reduce amyloid aggregation.

PEA activates PPAR-alpha (peroxisome proliferator-activated receptor alpha), a nuclear receptor that heterodimerizes with RXR and downregulates pro-inflammatory gene expression (NF-kB target genes, COX-2, iNOS, TNF-alpha). It has an 'entourage effect' on the endocannabinoid system — it inhibits the degradation of anandamide by fatty acid amide hydrolase (FAAH) through allosteric modulation or substrate competition, and upregulates CB2 receptor expression on immune cells. This provides anti-inflammatory and analgesic effects without directly activating CB1/CB2. PEA also activates GPR55 and GPR119. It inhibits mast cell degranulation (reducing histamine, tryptase, and cytokine release) and reduces microglial activation in the brain (inhibiting Iba1 expression and pro-inflammatory cytokine production). PEA may also modulate TRPV1.