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Palmitoylethanolamide (PEA): A Key Mediator in Lifestyle and Cellular Health

By Julia Haimovich, Accredited Practicing Dietitian.

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Palmitoylethanolamide (PEA) serves as a crucial mediator linking lifestyle factors
to cellular responses, acting as a vital bridge between environmental influences
and physiological outcomes. 

In the context of harmful lifestyle changes—such as exposure to pollutants, disrupted
circadian rhythms, sedentary behaviour, and dietary imbalances—PEA plays a key role in
maintaining homeostasis and countering pathological processes. During disease states,
PEA synthesis increases to mitigate chronic inflammation, dysnutrition, dysbiosis, and
immunosenescence triggered by poor lifestyle choices. These perturbations exacerbate
conditions like metabolic disorders, cardiovascular diseases, cancers,
neurodegenerative diseases, chronic pain, joint ailments, asthma, gastrointestinal
disorders, and mood disorders. 1.

PEA offers a promising therapeutic intervention for lifestyle-related maladies. It interacts
with molecular targets like the nuclear receptor PPAR-α, novel cannabinoid receptors
(GPR55, GPR119), and TRPV1, triggering anti-inflammatory, analgesic, and
neuroprotective responses. Additionally, PEA modulates the endocannabinoid system,
inhibits mast cell activation, and promotes muscle recovery, cognitive function, mood
stability, and sleep quality. 2

PEA’s anti-inflammatory properties make it valuable in addressing allergic reactions,
promoting exercise recovery, and enhancing brain health. Its prophylactic use can
potentially prevent the onset of various chronic diseases, making it a versatile
component in lifestyle management. Additionally, PEA offers anti-aging benefits and
immuno-enhancement, further supporting its role in maintaining overall health and
wellness. 3

PEA’s antinociceptive (pain-relieving) and anti-inflammatory effects are beneficial for
managing pain, joint health, sleep disorders, and brain health. These properties make it
a useful agent for individuals suffering from chronic pain and joint ailments.4
Furthermore, PEA has been noted for its anxiolytic and nootropic (cognitive-enhancing)
effects, contributing to improved brain health and sleep quality. 5          
PEA’s ability to modulate the gut microbiome highlights its role in enhancing immunity
and brain health. This modulation can have far-reaching effects on various aspects of
health, demonstrating PEA’s potential as a comprehensive lifestyle management
solution. 6

However, chronic allostatic load from poor lifestyle patterns often depletes endogenous
PEA levels necessitate exogenous supplementation to restore physiological balance.
Several PEA-containing products are approved for use as nutraceuticals, food
supplements, or medical foods in various countries, with a commonly recommended
dose of 1200 mg/day. A new form of PEA utilizing LipiSperse® technology aims to
enhance bioavailability, potentially allowing for lower dosages. 7,8

This comprehensive understanding of PEA’s role underscores the importance of
addressing lifestyle factors in health management strategies. It highlights the potential
for targeted interventions to restore balance and promote well-being in individuals facing
the challenges of modern living. Through further exploration and application of PEA-
based therapies, the potential exists to mitigate the impact of lifestyle-related diseases
and improve overall health outcomes for individuals worldwide.


  1. Clayton P, Hill M, Bogoda N, Subah S, Venkatesh R. Palmitoylethanolamide: A
    Natural Compound for Health Management. Int J Mol Sci. 2021 May
    18;22(10):5305. doi: 10.3390/ijms22105305. PMID: 34069940; PMCID:
  2. Nau R., Ribes S., Djukic M., Eiffert H. Strategies to increase the activity of
    microglia as efficient protectors of the brain against infections. Front. Cell
    Neurosci. 2014;22:138. doi: 10.3389/fncel.2014.00138.
  3. Palmitoylethanolamide: A Natural Body-Own Anti-Inflammatory Agent, Effective
    and Safe against Influenza and Common Cold. Int. J. Inflam. 2013;2013:151028.
    doi: 10.1155/2013/151028.
  4. Steels E., Venkatesh R., Steels E., Vitetta G., Vitetta L.A. Double-blind
    randomized placebo controlled study assessing safety, tolerability and efficacy of palmitoylethanolamide for symptoms of knee
  5. osteoarthritis. Inflammopharmacology. 2019;27:475–485. doi: 10.1007/s10787-
  6. 019-00582-9.
  7. Esposito E., Cuzzocre S. Palmitoylethanolamide in homeostatic and traumatic
    central nervous system injuries. CNS Neurol. Disord. Drug
    Targets. 2013;12:55–61. doi: 10.2174/1871527311312010010
  8. Guida F., Boccella S., Belardo C., Iannotta M., Piscitelli F., De Filippis F., Paino
    S., Ricciardi F., Siniscalco D., Marabese I., et al. Altered gut microbiota and
    endocannabinoid system tone in vitamin D deficiency-mediated chronic
    pain. Brain Behav. Immun. 2020;85:128–141. doi: 10.1016/j.bbi.2019.04.006
  9. Gugliandolo E., Peritore A.F., Piras C., Cuzzocrea S., Crupi R.
    Palmitoylethanolamide and Related ALIAmides: Prohomeostatic Lipid
    Compounds for Animal Health and Wellbeing. Vet. Sci. 2020;7:78.
    doi: 10.3390/vetsci7020078.
  10. Skaper S.D., Facci L., Giusti P. Mast cells, glia and neuroinflammation: Partners
    in crime? Immunology. 2014;141:314–327. doi: 10.1111/imm.12170.
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