Palmitoylethanolamide (PEA) vs Phosphatidylserine

Mechanism

Endocannabinoid-like lipid that activates PPAR-alpha and indirectly enhances endocannabinoid tone. Potent anti-inflammatory and analgesic without acting directly on CB1/CB2. Reduces mast cell activation, neuroinflammation, and chronic pain.

Contraindications

• None established at standard doses

Mechanism

Major phospholipid component of neuronal cell membranes (15-20% of total phospholipid pool) that maintains membrane fluidity and supports signal transduction. Serves as a cofactor for protein kinase C (PKC), Na+/K+-ATPase, and other membrane-bound enzymes critical for neurotransmitter release. Blunts HPA axis hyperactivation by modulating corticotrophin-releasing factor (CRF) receptor interactions, attenuating cortisol release during physical and psychological stress. Facilitates acetylcholine, dopamine, and norepinephrine release, and enhances glucose metabolism in the brain.

Standard Dosing

100-300mg daily

Timing

With meals (fat-containing preferred for absorption). Can be taken morning or evening. Cortisol-blunting effects are relevant for evening/pre-bed dosing in stressed individuals.

Cycle Duration

Ongoing; no cycling required. Clinical benefits observed from 6-12 weeks.

Side Effects

• Mild GI upset at high doses
• Insomnia (if taken too late in some individuals)
• Rare: nausea
• GI distress (uncommon)
• Insomnia (at higher doses)
• Headache (rare)

Contraindications

• Soy allergy (if soy-derived — use sunflower-derived instead)
• Known soy allergy (soy-derived PS)
• Antiphospholipid syndrome (theoretical concern)

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