Palmitoylethanolamide (PEA)

PEA

Written by Whittney Wacker, RN, BSN, MS-MCT

03/09/2023         

 Palmitoylethanolamide (PEA) is a naturally occurring fatty acid with many uses. Cannabis clinicians, along with other healthcare providers of today, are touting it as an entourage effect influencing molecule, available over the counter and found in many foods. According to Cannakeys (n.d.) PEA was identified in 1957 (Cannakeys, n.d.). Di Marzo (2018) reports in his paper New approaches and challenges to targeting the endocannabinoid system, PEA impacts homeostasis through the modulation of TRPv1, GPR55, GPR119 and PPAR alpha receptors, this is further confirmed in the Clayton, et al (2021) paper. Much like other related endogenous fatty acid derivatives, like OEA and SEA, PEA does not directly interact with the CB1 or CB2 receptors. In the presence of PEA mammalian physiologic functions like inflammation, immune functions, pain, GI/GU distress, behaviors associated with autism, sleep, oxidative stress, amongst others, improves (Cannakeys n.d.). PEA associates itself with other endocannabinoids, like AEA, at the specific sites of CB1, CB2, Trpv1, GPR55 and GRP118, influencing (not binding) and enhancing activity towards equilibrium, thus furthering the argument for PEA adding to the “entourage effect” (Foster, 2021). PEA is “synthesized on demand in the lipid bilayer (Clayton, 2021).” Petrosino and Di Marzo (2017) report PEA is degraded by fatty acid amide hydrolase (FAAH) into palmitic acid and ethanolamine (Petrosino and Di Marzo, 2017). In the absence of blood tests that directly measure PEA’s activity, it could be detected through AEA activity via enzyme-linked immunosorbent assay (ELISA) tests (Sahinovic, et al 2022). If an AEA deficiency is detected through ELISA test, PEA could be ingested either by micronized (smaller particle size for improved absorbing action) capsules on the market today or through dietary means by eating peanuts, corn, soy, egg yolks and certain milks (Cannakeys, n.d.). Over the counter PEA is well-tolerated and devoid of side effects as Clayton et al (2021) report.

Resources:

Cannakeys. (n.d.), retrieved from https://cannakeys.com/palmitoylethanolamide-pea-cannabinoid-research/

Clayton, P., Hill, M., Bogoda, N., Subah, S., & Venkatesh, R. (2021, May 18). Palmitoylethanolamide: A natural compound for health management. International journal of molecular sciences. Retrieved from https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8157570/

Di Marzo, V. (2018, September 17). New approaches and challenges to targeting the endocannabinoid system. Nature reviews. Drug discovery. Retrieved from https://pubmed.ncbi.nlm.nih.gov/30116049/

Foster, D. A. (2021). Chapter 2: The Human Endocannabinoid System (ECS): Physiology. In C.S. Clark (Ed.), Cannabis: A handbook for nurses (pp. 44–114). Wolters Kluwer.

Petrosino, S., & Di Marzo, V. (2017, June). The pharmacology of Palmitoylethanolamide and first data on the therapeutic efficacy of some of its new formulations. British journal of pharmacology. Retrieved from https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5429331/ 

Sahinovic, I., Mandic, S., Mihic, D., Duvnjak, M., Loinjak, D., Sabadi, D., Majic, Z., Peric, L., & Seric, V. (2022, June 1). Endocannabinoids, anandamide and 2-arachidonoylglycerol, as prognostic markers of sepsis outcomes and compliations. LibertPub. Retrieved from https://www.liebertpub.com/doi/10.1089/can.2022.0046

Journal Articles on PEA listed below:

• 2024
• The Effect of Palmitoylethanolamide (PEA) on Skeletal Muscle Hypertrophy, Strength and Power in Response to Resistance Training in Healthy Active Adults: A Double-Blind Randomized Control Trial. https://sportsmedicine-open.springeropen.com/articles/10.1186/s40798-024-00732-6 
• PEALut in the Dietary management of Patients with Acute Ischemis Stroke: A Prospective randomized controlled clinical trial. https://pubmed.ncbi.nlm.nih.gov/38256644/ 
• 2023
• The effect of Levagen+ (Palmitoylethanolamide) supplementation on symptoms of allergic rhinitis, a double blind placebo controlled trial. https://pubmed.ncbi.nlm.nih.gov/38068797/ 
• Therapeutic use of Palmitoylethanolamide as an anti-inflammatory and immunomodulator. https://www.preprints.org/manuscript/202310.0675/v1 
• PEA the anti-inflammatory superstar. https://projectcbd.org/science/pea-antiinflammatory/ 
• (2021)
• Palmitoylethanolamide: a natural compound for health management. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8157570/ 
• PubChem compound classification: https://pubchem.ncbi.nlm.nih.gov/compound/Palmitoylethanolamide 
• (2020)
• Rankin, L., & Fowler, C. J. (2020). The Basal Pharmacology of Palmitoylethanolamide. International journal of molecular sciences, 21(21), 7942. https://doi.org/10.3390/ijms21217942
• Chronic Oral Palmitoylethanolamide administration rescues cognitive deficit and reduces neuro-inflammation, oxidative stress and Glutamate levels  in a transgenic murine model of Alzheimer's Disease. https://alzped.nia.nih.gov/chronic-oral 
• (2018)
• New approaches and challenges to targeting the endocannabinoid system. https://pubmed.ncbi.nlm.nih.gov/30116049/ 

• Ghazizadeh-Hashemi, M., Ghajar, A., Shalbafan, M. R., Ghazizadeh-Hashemi, F., Afarideh, M., Malekpour, F., Ghaleiha, A., Ardebili, M. E., & Akhondzadeh, S. (2018). Palmitoylethanolamide as adjunctive therapy in major depressive disorder: A double-blind, randomized and placebo-controlled trial. Journal of affective disorders, 232, 127–133. https://doi.org/10.1016/j.jad.2018.02.057

• (2017)
• The Pharmacology of Palmitoylethanolamide and first data on the therapeutic efficacy of some of its new formulations. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5429331/  
• Efficacy of Palmitoylethanolamide for Pain: A meta-analysis. https://pubmed.ncbi.nlm.nih.gov/28727699/ 
• (2016)
• Gabrielsson, L., Mattsson, S., & Fowler, C. J. (2016). Palmitoylethanolamide for the treatment of pain: pharmacokinetics, safety and efficacy. British journal of clinical pharmacology, 82(4), 932–942. https://doi.org/10.1111/bcp.13020
• (2015)

• Borrelli, F., Romano, B., Petrosino, S., Pagano, E., Capasso, R., Coppola, D., Battista, G., Orlando, P., Di Marzo, V., & Izzo, A. A. (2015). Palmitoylethanolamide, a naturally occurring lipid, is an orally effective intestinal anti-inflammatory agent. British journal of pharmacology, 172(1), 142–158. https://doi.org/10.1111/bph.12907 

• (2013)

• Citraro, R., Russo, E., Scicchitano, F., van Rijn, C. M., Cosco, D., Avagliano, C., Russo, R., D'Agostino, G., Petrosino, S., Guida, F., Gatta, L., van Luijtelaar, G., Maione, S., Di Marzo, V., Calignano, A., & De Sarro, G. (2013). Antiepileptic action of N-palmitoylethanolamine through CB1 and PPAR-α receptor activation in a genetic model of absence epilepsy. Neuropharmacology, 69, 115–126. https://doi.org/10.1016/j.neuropharm.2012.11.017

• Esposito, E., & Cuzzocrea, S. (2013). Palmitoylethanolamide in homeostatic and traumatic central nervous system injuries. CNS & neurological disorders drug targets, 12(1), 55–61. https://doi.org/10.2174/1871527311312010010

• Keppel Hesselink, J. M., de Boer, T., & Witkamp, R. F. (2013). Palmitoylethanolamide: A Natural Body-Own Anti-Inflammatory Agent, Effective and Safe against Influenza and Common Cold. International journal of inflammation, 2013, 151028. https://doi.org/10.1155/2013/151028

• Keppel Hesselink, J. M. (2013). Professor Rita Levi-Montalcini on nerve growth factor, mast cells and palmitoylethanolamide, an endogenous antiinflammatory and analgesic compound. J Pain Relief, 2(1), 1000114. https://www.allesoverpea.nl/wp-content/uploads/2016/03/professor-rita-levi-montalcini-on-nerve-growth-factor-mast-cells-and-palmitoylethanolamide-an-endogenous-anti-inflammatory-and-analgesic-compound-2167-0846.10001141.pdf