Palmitoylethanolamide

Anti-inflammatory: PEA reduces inflammation by modulating mediators and inhibiting mast cell activation, as seen in animal models of colitis where effects were measured 3 days post-induction (source).
Analgesic: It provides pain relief, with clinical studies showing reductions in pain intensity within 10 to 14 days to 4 weeks (source).
Neuroprotective: PEA protects nerve cells, potentially beneficial in neurodegenerative conditions, with mechanisms involving PPAR-α and GPR55 receptors (source).
Immunomodulatory: It modulates immune responses, aiding in conditions like allergies and autoimmune disorders (source).
Antimicrobial: Limited evidence suggests antimicrobial properties, though less studied compared to other actions (source).
These actions are mediated through targets like PPAR-α (EC50 3 μM), GPR55 (EC50 4 nM), and entourage effects on CB1, CB2, and TRPV1, as noted in pharmacological reviews (source).

Pain Relief: Clinical trials indicate significant pain reduction can occur within 10 to 14 days in some studies, with others showing effects after 4 weeks, reflecting the chronic nature of conditions treated (source).
Anti-inflammatory Effects: In a murine colitis model, anti-inflammatory effects were assessed 3 days after induction, suggesting rapid action in acute inflammation (source).
Plasma Concentration: Pharmacokinetic studies show plasma levels peak at approximately 2 hours after oral administration in humans, with a study on 300 mg micronized PEA showing a twofold increase at this time, returning to baseline by 4-6 hours (source).

This variability suggests that while plasma levels rise quickly, clinical effects, especially for chronic conditions, may require days to weeks.
Half-Life
The half-life of PEA is relatively short, with data primarily from animal studies:

In Rats: Plasma elimination half-time is approximately 12 minutes, calculated from a study using a one-compartment model with first-order kinetics (source).
In Vitro: Rat liver homogenates show a half-life of about 25 minutes at 50 nM concentration (source).
In Humans: Not explicitly stated, but plasma levels return to baseline within 4-6 hours after peaking at 2 hours, suggesting a half-life likely in the range of 1-2 hours, based on the observed pharmacokinetics (source).

In Humans: Not explicitly stated, but plasma levels return to baseline within 4-6 hours after peaking at 2 hours, suggesting a half-life likely in the range of 1-2 hours, based on the observed pharmacokinetic.
Bioavailability
PEA's bioavailability, particularly via the oral route, is a critical factor due to its lipophilic nature:

General Oral Bioavailability: Initially low due to poor water solubility, with estimates suggesting limited absorption in standard forms (source).
Improved Formulations: Micronized and ultra-micronized forms enhance bioavailability. A study on PEAΩ and PEA DynoΩ showed absorption rates of 82-63% at 3 hours, compared to 30-60% for micronized, ultra-micronized PEA, and commercial products, with optimal doses at 300-600 mg (source).
Human Studies: A study with 300 mg micronized PEA showed a twofold increase in plasma levels at 2 hours, indicating improved bioavailability with advanced formulations (source).

Dosage
Dosage recommendations vary by population and condition, based on clinical and experimental data:

Adults: Typical oral doses range from 300 to 1200 mg per day, used for conditions like chronic pain, diabetic neuropathy, and ALS, with durations from 2 to 12 weeks (source).
Children: Recommended at 600 mg per day for up to 3 months, primarily for conditions like migraine (source).
Animal Studies: Doses like 10 mg/kg subcutaneously in mice and 100 mg/kg orally in rats have been used, providing context for experimental efficacy (source).

Safety, LD50, and Risk Thresholds
PEA is generally considered safe, with extensive data supporting its tolerability:

Safe Range: Clinical trials suggest doses up to 1200 mg per day are safe, with no serious adverse effects reported for treatment durations up to 49 days at an incidence of 1/200 or greater (source).
Minimum Effective Dose: Evidence suggests 300 mg per day can be effective, as seen in studies on pain and inflammation (source).
Maximum Safe Dose: Given the high LD50 and lack of toxicity at therapeutic doses, up to 1200 mg per day appears safe, with reports of 1.8 g/day showing excellent tolerability (source).
LD50: In rats, LD50 is >2000 mg/kg body weight, indicating low acute toxicity (source).
When It Starts to Become Dangerous: Given the high LD50 and safety profile, significant risks are likely only at doses far exceeding typical use, potentially above 2000 mg/kg, but specific human thresholds are not well-defined due to limited high-dose studies.