Palmitoylethanolamide

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Palmitoylethanolamide
Drug class	ALIAmide; fatty acid amide; cannabimimetic; nutraceutical
Daily dose	Typically 600–1200 mg per day in divided doses
Onset of action	Analgesic effect may begin within 2–6 weeks of regular use
Half life	Not well defined in humans; short plasma half-life suggested in animal models
Indication	Adjunctive treatment for chronic pain conditions including neuropathic and nociplastic pain
Side effects	Generally well tolerated; rare reports of gastrointestinal discomfort and fatigue
DrugBank ID	DB14043

Palmitoylethanolamide (PEA) is an endogenous fatty acid amide belonging to the N-acylethanolamine family studied in neuropathic pain and nociplastic pain, available as a supplement. It is a potential candidate for inclusion in a multimodal analgesic strategy as an add on agent (e.g. combined with gabapentinoids and/or TCAs)

Structure and Sources

Palmitoylethanolamide (PEA), chemically N-(2-hydroxyethyl)-palmitamide, is an endogenous fatty acid amide first isolated and described in 1957. It is naturally present in various common food sources, including soybean lecithin, egg yolk, peanuts, and certain meat products. Beyond dietary intake, PEA is synthesized endogenously within mammalian tissues, often produced locally "on demand" in response to cellular stress, injury, or inflammation.

This endogenous production characteristic suggests a potential physiological role for PEA as a homeostatic regulator, involved in the body's natural processes to resolve inflammation and pain signaling.

Mechanism

It is considered an "autocoid local injury antagonist" (ALIAmide), produced on demand in response to tissue injury or inflammation. PEA exerts its biological effects through multiple pathways. PEA stands out due to its apparent pleiotropic mechanism of action, influencing multiple pathways involved in pain and inflammation, including PPAR-α activation, endocannabinoid signaling enhancement, and potential modulation of glial/mast cell stabilisation activity.

PPAR-α Agonism

This is likely its primary mechanism. It is a ligand for the nuclear receptor peroxisome proliferator-activated receptor alpha (PPAR-α), activation of which leads to anti-inflammatory effects.

Indirect Endocannabinoid System Modulation (probably limited action)

PEA is is often classified within the "extended endocannabinoid system" or termed a "cannabimimetic" compound due to its structural similarity to endocannabinoids like anandamide (AEA).

PEA indirectly modulates the endocannabinoid system by inhibiting the enzyme fatty acid amide hydrolase (FAAH), which breaks down anandamide. This leads to increased levels of anandamide, enhancing signaling through cannabinoid receptors (CB1 and CB2).

However, it is crucial to note that PEA exhibits minimal direct binding affinity for the classical cannabinoid receptors, CB1 and CB2. Early hypotheses suggesting direct CB2 agonism have been largely superseded by evidence indicating that PEA exerts its biological effects primarily through other pathways. Furthermore medicinal cannabis has been proven to be ineffective for chronic pain.

Neuroinflammation

PEA reduces the recruitment, activation, and degranulation of mast cells at sites of nerve injury and inflammation. Since mast cells release numerous pro-inflammatory and pro-nociceptive mediators (e.g., histamine, serotonin, NGF, cytokines), their stabilization by PEA contributes significantly to analgesia. PEA also modulates the activity of glial cells (microglia and astrocytes), which are key players in the development and maintenance of central sensitization and chronic pain states. Furthermore, it suppresses pro-inflammatory signaling pathways and inhibits the release of inflammatory mediators, potentially reducing the activity of enzymes like cyclooxygenase (COX) and inducible nitric oxide synthase (iNOS).

Other

Additionally, PEA may interact with other receptors like the orphan G protein-coupled receptor GPR55 and the transient receptor potential vanilloid type 1 (TRPV1) channel.

Evidence

The human experimental data suggesting effects on both temporal summation (reduction) and conditioned pain modulation (enhancement) are particularly intriguing, as this implies an ability to modulate both ascending facilitatory and descending inhibitory processes relevant to CS.

There have been multiple clinical trials supporting the efficacy over placebo or other control conditions. A 2025 meta analysis (Del Giorno et al) of 18 studies (1196 patients) showed it was effective for all types of pain (nociceptive, nociplastic, neuropathic), at multiple time points up to 24-26 weeks. A 2023 systematic review (Lang-Illievich et al) of 11 double blind RCTs (774 patients) was also positive, finding a large effect size with a SMD of 1.68 for pain reduction with PEA versus comparators.

One randomised placebo controlled trial reported very interesting physiological findings. The active group took 3 x 400mg per day of PEA and showed improvements in both temporal summation and conditioned pain modulation. They described significantly decreased repetitive heat pain, significantly prolonged cold pain tolerance, improved pressure pain tolerance and conditioned pain modulation. The wind-up ratio and average distance of allodynia were also significantly decreased.

The magnitude of the reported pain reduction appears clinically relevant. A WMD of approximately 2 points on a 10-point VAS/NRS scale, as found by Artukoglu et al., is generally considered a meaningful improvement for patients. Similarly, analyses focusing on micronized PEA have shown cumulative reductions potentially exceeding 3 points over 60 days.

Beyond direct pain reduction, several studies and reviews indicate that PEA supplementation confers additional benefits on patient well-being. Significant improvements in quality of life (QoL) and functional status have been reported alongside analgesia. The meta-analysis by Del Giorno et al. found a significant pooled effect size for QoL improvement (SMD, -0.61; 95% CI, -0.93 to -0.30). Improvements in functioning, neuropathic symptoms, and reduction in the need for rescue medications have also been noted.

Dosing

Dose and Frequency

The studied doses typically fall between 600 to 1200 mg total daily dosage. Specific protocols mentioned include 600 mg twice daily and 400 mg three times daily, while some case reports describe intermittent use up to 1200 mg daily.

Clinical studies have generally studied divided dosing - twice or three times daily. Theoretically, given PEA's high lipophilicity and potential for relatively rapid metabolism (preclinical data suggests a short plasma half-life in rats, though human pharmacokinetics and the influence of formulation require further clarification), divided dosing might provide more sustained plasma concentrations and continuous engagement with target pathways compared to once-daily administration.

One clinical experience report noted that it is usually possible to eventually reduce patients down from 600mg twice daily to 300mg twice daily for long term maintenance.

Impact of Micronization

Micronized or ultra-micronized PEA formulations are generally preferred over standard preparations for faster dissolution, better absorption kinetics, and superior efficacy compared to native, larger-particle PEA. But no head-to-head RCTs directly comparing the efficacy of unmicronized versus micronized PEA could be found.

The physicochemical properties of PEA present challenges for oral administration. As a highly lipophilic compound, it is practically insoluble in water, which can limit its dissolution rate and subsequent absorption from the gastrointestinal tract, potentially leading to variable or low bioavailability. Pharmaceutical formulation strategies, specifically micronization (reducing particle size to the micrometer range) and ultra-micronization (further reduction, often to sub-micron levels), aim to overcome this limitation by increasing the surface area available for dissolution.

The lack of standardization of PEA formulation complicates direct comparisons between studies.

Trial of Treatment Duration

An adequate therapeutic trial of PEA should last for at least 60 days to properly assess efficacy. The onset of PEA's analgesic effect appears to occur within weeks of initiating treatment. Del Giorno et al. reported significant benefits emerging between 4 and 6 weeks. Research specifically evaluating micronized PEA formulations suggests a potentially time-dependent effect, with significant pain reduction observed within the first 30 days (mean NRS/VAS decrease of 2.08 points), followed by a further statistically and clinically significant reduction between 30 and 60 days (additional mean decrease of 1.36 points). This finding implies a cumulative benefit over at least two months, particularly for micronized forms, and underscores the importance of an adequate trial duration.

Adverse Effects

PEA is generally considered to have a favorable safety profile with few reported adverse effects at typical dosages (ranging from 300 mg to 1200 mg per day, often given as 300 mg or 600 mg twice daily). Its status as a supplement, however, raises potential issues regarding product quality, purity, and standardization across different formulations (e.g., micronized, ultramicronized). Potential drug interactions are not well characterized.

Resources

PEA for sciatica - Guida2010.pdf - 275 KB (f)

PEA narrative review - Mateos 2023.pdf - 3.94 MB (f)