Immune Health with Palmitoylethanolamide

The immune system is key to whole-body health, and when out of balance it not only fails to protect the body, but can even attack it, mistaking “self” cells for invading pathogens. This imbalanced immune response can cause autoimmune issues.

In addition, years of chronic low-level inflammation, another indicator of an out-of-balance immune system, can prevent us from achieving optimal health. The stresses of normal life—travel, personal problems, strenuous exercise and change in diet—can all cause imbalances in the immune system and affect overall health.

While getting adequate sleep, managing stress, staying hydrated, exercising regularly and practicing proper hygiene are effective ways to help maintain a healthy immune system, science has shown that nutrients gained through a healthy diet or supplementation are critical in maintaining balance.

Inflammation is the first biological immune response to physical injury as a normal part of life, and the duration depends on the time required to eliminate the harmful causes and repair the damage. Although treatment with synthetic anti-inflammatory drugs may be useful, routine use poses the danger of addiction and worsening the general condition of the body. In this regard, endogenous and naturally occurring food/dietary supplements may be a good alternative, as well as potentially preventing the situation from becoming chronic in the first place by boosting the body’s overall immunity.*

Since the 1970s, palmitoylethanolamide (PEA) has been studied for its potential role in optimizing immune health against viral infections and inflammatory issues.* It is an endogenous fatty acid amide, that via modulation of mast cells and spinal glial cells demonstrated to be effective against various inflammatory mechanisms that develop during chronic pain states.1* Based on the foundation of its anti-inflammatory effects, more than 350 scientific papers have documented PEA’s wide range of therapeutic effects, such as anti-allergic, analgesic, neuroprotective, anti-influenza, and modulation of immune response in both animal and human studies.2*

The multifaceted immune response of PEA is due to its unique mechanism of actions that targets multiple pathways at different sites, working synergistically to produce its therapeutic effects.3* The most relevant mechanisms of action related to immunopathology are PEA’s affinity toward the orphan cannabinoid receptor (GPR55 and GPR11), the vanilloid receptor TRPV1 and the nuclear peroxisome proliferator-activated receptor (PPAR)-alpha.2*

Masek et al. conducted a randomized trial with 444 subjects who registered symptoms such as temperature of 99.5 degrees Fahrenheit or higher, headache, sore throat, myalgia, and nasal stuffiness or discharge.2 The episodes of fever and pain (45.5% reduction compared to placebo) and total number of sick days were significantly reduced in the group receiving PEA.*

In a second prophylactic trial, the same researchers had 899 volunteers ages 18-20 from an army unit complete a trial period where medical personnel registered wellness complaints during a period of eight weeks. The incidence of discomfort was shown to be 40% and 32% lower at weeks 6 and 8 respectively in the PEA group versus placebo.*

To validate these conclusions, three more trials in soldiers were conducted.In all three trials, the soldiers in the PEA group had significantly less symptoms and were less often diagnosed as patients.*

Plesnik et al., studied the effect of PEA in the prevention of respiratory irritation in 457 school children (ages 11 to 15) in a double-blind trial.5* Placebo or PEA doses in the range 46-74 mg/kg body weight were administered for 10 days, with a two-day weekend break in the middle. Results indicated the treatment group had a lower occurrence (by 15.7%) of respiratory tract complaints.*

Over the years, research on the gut microbiome, probiotics and immunity has grown. Due to the presence of PEA in most tissues of the body and its anti-inflammatory properties, PEA may be able to help provide symptomatic relief for a number of concerns linked to occasional inflammation in the gastrointestinal (GI) tract.2*

Certain disorders cause prolonged inflammation in the GI tract, which can alter the gut microbiota.6 This could lead to increased gut permeability, making way for further inflammation and additional changes to the gut microbiota. Changes to the normal gut flora may result in infections, further increasing inflammation. Exogenous administration of PEA can serve to relieve inflammatory symptoms of such disorders through its action on PPAR-alpha in the colon, which helps prevent alterations of the gut microbiota.*

Gut microbiota are also indispensable in the development of the innate immune system and are essential in shaping adaptive immunity. Therefore, PEA may potentially be able to contribute to the correction of dysbiosis and shape the immune system.7* PEA is becoming an increasingly popular area of research in probiotic studies.

Given the multifaceted effects of PEA via multiple targets and the fact that PEA is a naturally occurring compound makes it a perfect candidate as an important regulator of inflammatory processes and mediator of interactions between the nervous system and immune system to boost overall immunity.2* However, the onset of the inflammatory state causes a decrease in the production of PEA. Thus, the supplementation of exogenous PEA can replenish endogenous levels and restore its anti-inflammatory and immunomodulatory potential.*

PEA serves as the body’s first response anti-inflammatory and pain-control mechanism.8* It is currently being researched in an allergic rhinitis study to see if water-dispersible PEA reduces nasal congestion, sneezing and runny nose. There is also a cold and flu study underway to gauge the effectiveness of bioavailability-enhanced PEA (the same type found in Mirica Advanced) in reducing upper respiratory tract infection (URTI) symptoms during the winter months.*

Keeping the complex immune system in balance is crucial for maintaining health. On top of leading a healthy lifestyle through diet and exercise, nutritional supplementation can play an important role.





1 Hesselink JM, Hekker TA. “Therapeutic utility of palmitoylethanolamide in the treatment of neuropathic pain associated with various pathological conditions: a case series.” J Pain Res. 2012;5:437-442.

2 Keppel Hesselink JM, de Boer T, Witkamp RF. “Palmitoylethanolamide: A Natural Body-Own Anti-Inflammatory Agent, Effective and Safe against Influenza and Common Cold.” Int J Inflam. 2013;2013:151028.

3 Petrosino S et al. “The anti-inflammatory mediator palmitoylethanolamide enhances the levels of 2-arachidonoyl-glycerol and potentiates its actions at TRPV1 cation channels.” Br J Pharmacol. 2016;173(7):1154-1162.

4 Kahlich R et al. “Studies on prophylactic efficacy of N-2-hydroxyethyl palmitamide (Impulsin) in acute respiratory infections. Serologically controlled field trials.” J Hyg Epidemiol Microbiol Immunol. 1979;23(1):11-24.

5 Plesník V et al. “Impulsin in the prevention of acute respiratory diseases in school children.” Cesk Pediatr. 1977;32(6):365-369.

6 Russo R et al. "Gut-brain axis: Role of lipids in the regulation of inflammation, pain and CNS diseases.” Curr Med Chem. 2018;25(32):3930-3952.

7 Couch DG et al. "Palmitoylethanolamide and cannabidiol prevent inflammation-induced hyperpermeability of the human gut in vitro and in vivo—a randomized, placebo-controlled, double-blind controlled trial." Inflamm Bowel Dis. 2019;25(6):1006-1018.

8 Artukoglu BB et al. "Efficacy of Palmitoylethanolamide for Pain: A Meta-Analysis." Pain Physician. 2017;20(5):353-362.

9 Briskey D, Mallard AR, Rao A. "Increased Absorption of Palmitoylethanolamide Using a Novel Dispersion Technology System (LipiSperse®)." J Nutraceuticals Food Sci 2020;5(2):3.


Article originally written by Maggie McNamara from Gencor, reprinted with permission by Young Nutraceuticals.