Hindawi Publishing Corporation

International Journal of Inflammation

Volume 2013, Article ID 151028, 8 pages
http://dx.doi.org/10.1155/2013/151028

Review Article
Palmitoylethanolamide: A Natural Body-Own
Anti-Inflammatory Agent, Effective and Safe against
Influenza and Common Cold

J. M. Keppel Hesselink,1 Tineke de Boer,2 and Renger F. Witkamp3

1
Faculty of Medicine, University Witten/Herdecke, Alfred-Herrhausen-Straße 50, 58448 Witten, Germany
2
Department of Research and Development, Institute for Neuropathic Pain, Spoorlaan 2a, 3735 MV Bosch en Duin, The Netherlands
3
Division of Human Nutrition (Bode 62), Wageningen University, P.O. Box 8129, 6700 EV Wageningen, The Netherlands

Correspondence should be addressed to J. M. Keppel Hesselink; info@iocob.nl

Received 3 April 2013; Revised 9 June 2013; Accepted 10 June 2013

Academic Editor: Juan Carlos Kaski

Copyright © 2013 J. M. Keppel Hesselink et al. This is an open access article distributed under the Creative Commons Attribution
License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly
cited.

Palmitoylethanolamide (PEA) is a food component known since 1957. PEA is synthesized and metabolized in animal cells via a
number of enzymes and exerts a multitude of physiological functions related to metabolic homeostasis. Research on PEA has been
conducted for more than 50 years, and over 350 papers are referenced in PubMed describing the physiological properties of this
endogenous modulator and its pharmacological and therapeutical profile. The major focus of PEA research, since the work of the
Nobel laureate Levi-Montalcini in 1993, has been neuropathic pain states and mast cell related disorders. However, it is less known
that 6 clinical trials in a total of nearly 4000 people were performed and published last century, specifically studying PEA as a therapy
for influenza and the common cold. This was done before Levi-Montalcini’s clarification of PEA’s mechanism of action, analyzing
the role of PEA as an anti-inflammatory agent. We will review in depth these studies, as the results support the effectiveness and
safety of PEA in flu and respiratory infections.

1. Introduction PEA is under evaluation as a nutraceutical for inflammatory

bowel syndrome (proposed brand name Recoclix, CM&D
Palmitoylethanolamide (PEA) is a food component known Pharma Ltd.; Nestlé).
for more than 50 years. PEA is synthesized and metabolized Research on PEA has been conducted since its discovery
by different animal cell types and also present in plants. and over 350 papers are referenced in PubMed describing its
It exerts a multitude of physiological functions related to physiological properties and role as endogenous modulator
metabolic and cellular homeostasis. PEA was already iden- as well as its pharmacological and therapeutic effects. PEA is
tified in the 50s of the last century as a therapeutic substance an interesting anti-inflammatory therapeutic substance and
with potent anti-inflammatory properties. Since 1970, the might also hold great promise for the treatment of a number
anti-inflammatory and other immune-modulating properties of (auto)immune disorders, including inflammatory bowel
of PEA have been shown in a number of placebo-controlled disease and inflammatory diseases of the CNS. In this paper,
double-blind clinical trials on influenza and common cold. we will review the role of PEA as an anti-inflammatory agent
Positive results coincided with the clinical use of PEA in and as potential treatment for influenza and the common
former Czechoslovakia under the brand name Impulsin. cold. The main purpose is to highlight and discuss these
Since 2008, PEA has been marketed as a food for special earliest findings, including the 6 double blind studies in these
medical purposes in Italy and Spain, under the brand name indications published in the last century using Impulsin.
Normast (Epitech Srl). Recently, a food-supplement named Although nearly forgotten, these findings could offer new
PeaPure was introduced (JP Russell Science Ltd.). In the USA, insights or perhaps even alternative options in the light of
2 International Journal of Inflammation

the intense debate around the efficacy and safety of the nature of the acid group appeared to them to be of no
oseltamivir and zanamivir In the present paper, we will importance because in addition to ethanolamine itself, N-(2-
discuss the evolution of knowledge on the anti-inflammatory hydroxyethyl)-lauramide, S-(2-hydroxyethyl)-salicylamide,
activity of PEA and its effects in the treatment of respiratory and N-(2-hydroxyethyl)-acetamide all had potent anti-
infections. inflammatory properties. These pharmacological properties
of the ethanolamine-derivatives appeared to be quite specific
2. The Early Years: Anti-Inflammatory Activity since other homologs did not show a biological response in
of Egg-Yolk Based on a Lipid-Fraction the assay.

The protective and anti-inflammatory effects of PEA can

be traced back in the literature to 1939 [1]. The American
3. The Protective Effects of ‘‘Proto-PEA’’ in
bacteriologists Coburn and Moore demonstrated in that year Streptococcal Infections
that feeding dried egg yolk to underprivileged children living Coburn was dedicated to find the cause and prevention of
in poor parts of New York City prevented the recurrence rheumatic fever [7]. He presented his hypothesis that eggs
of rheumatic fever, in spite of repeated attacks of hemolytic contained an important protective factor against infection,
streptococcal infection. especially in rheumatic fever, in 1960 in the Lancet [2]. He
After 1939, Coburn et al. studied 30 children at a con- argued that
valescent rheumatic home and prescribed four egg yolks
daily. No other change in diet was made and no antibacterial (a) inadequate nutrition is part of a poor environment;
drugs were given. Twenty-two of these children contracted
24 serologically positive group-A streptococcal infections, (b) rheumatic-fever children usually lack sufficient eggs
but none showed clinical evidence of rheumatic recurrences. in their diets;
This was in sharp contrast to previous experience in the (c) the escape from poverty is followed by an increase
convalescent home where rheumatic recurrences had been in the consumption of eggs and a decrease in the
frequently seen each year [2]. incidence of rheumatic fever;
Subsequently in 1954, Coburn and colleagues were also
the first to report a phospholipid fraction prepared from egg (d) supplementation of children’s diets with egg yolk or
yolk that showed antiallergic activity in an assay in the guinea certain fractions thereof is followed by decreased
pig [3]. rheumatic susceptibility; and
The antiallergic factor of egg yolk was then purified by (e) there is a fraction of egg yolk, which in extremely
Long and Martin in 1956 in such a way that it was clear small amounts has been found to have high antialler-
that this factor showed a biological and chemical similarity gic activity in laboratory animals.
to a preparation obtained earlier in 1950 from peanut and
what appeared to be a closely related substance described as Coburn described his field studies in great detail [2].
“vegetable lecithin” [4, 5]. Some of these findings are summarized below.
The birth year of PEA was 1957. Kuehl Jr. and cowork- In Field study number 1, 𝑛 = 89, rheumatic boys and girls
ers reported to have succeeded in isolating a crystalline living at home in New York City all received egg-enriched
anti-inflammatory factor from soybean lecithin and they food; no prophylactic drugs were given. Sixty children had
identified it as N-(2-hydroxyethyl)-palmitamide [6]. They extra eggs during winter and spring months, and 29 served
isolated the compound also from a phospholipid fraction as “controls.” Results were as follows: of the 29 children on
of egg yolk and from hexane-extracted peanut meal. The their normal diet (with many nutritional deficiencies) 11 had
product obtained was tested positively in a local passive a recurrence. Of the 35 children whose normal diet was
joint anaphylaxis assay in the guinea pig. When applying enriched with two eggs daily, a quart of milk, meat, butter,
their isolation procedure to soybean lecithin, they obtained and halibut-liver oil, 3 had a recurrence. Of the 25 children
a partially purified fraction from which the homogeneous whose normal diet was reinforced only with powdered egg
factor was obtained by crystallization from cyclohexane. The yolk (equivalent to six eggs daily), only 1 had a recurrence.
crystalline material had a melting point of 98-99∘ C and was Field study number 2, 𝑛 = 56, was a two-year study
described as neutral, optically inactive, and possessing the into the effect of giving egg-yolk powder (equivalent of four
chemical formula C18H37O2N. egg yolks daily) to rheumatic children for three to four
Hydrolysis of the factor resulted in palmitic acid and weeks after they developed hemolytic (group A) streptococcal
ethanolamine and thus the compound was identified as N- pharyngitis. No other treatment was given during this period.
(2-hydroxyethyl)-palmitamide. In order to close the circle of Results were as follows: of 28 receiving the supplement,
isolation and identification, Kuehl et al. were able to synthe- only 1 showed fresh rheumatic activity, whereas among 28
size the compound by reflux in ethanolamine with palmitic “controls,” receiving no supplement, 10 children had fresh
acid according to a well-known procedure described in the rheumatic activity.
chemical literature of that time. Kuehl et al. further analyzed Field study number 3, 𝑛 = 40, was a one-year study
the anti-inflammatory activity of a series of derivatives of in which about 40 rheumatic children (with many dietary
PEA and could prove that the basic moiety of the molecule deficiencies) received a daily supplement of only the protein
was responsible for its anti-inflammatory activity. The fraction from four egg yolks. Results were as follows: study
International Journal of Inflammation 3

was discontinued because of too many rheumatic recur- However, between 1958 and 1969 the interest in this
rences. compound had apparently decreased, as the same authors
Field study number 4, 𝑛 = 45, was a four-year study stated that “Recently the interest on biological properties of
(Chicago, period 1952–1956) in which a normal (nutritionally PEA has been revived because of its capacity to increase
deficient) diet of rheumatic children was reinforced with egg- nonspecific tolerance to several bacterial toxins.”
yolk alcohol-soluble material (A.S.M. from Wilson Laborato-
ries). No other changes in their inadequate diets were made; 5. PEA: Anti-Influenza and Anticommon Cold
no sulphonamides, antibiotics, or other significant drugs
were administered. Forty-five highly susceptible rheumatic New interest arose by the end of the 60s, due to the fact
children received this supplement throughout the school year that SPOFA United Pharmaceutical Works brought PEA
from September to July. The equivalent of 3 egg yolks was on the market in 300 mg tablets under the brand name
consumed, in the form of an elixir taken twice daily. All but Impulsin to treat influenza and common cold. Different
one of these rheumatic children was under fifteen years of clinical trials supported the effectiveness and safety of PEA
age. Results were as follows: a minimum of 17 attacks was for this indication. Most probably the PEA in Impulsin was
expected among them after streptococcal infections, but only not specifically formulated but details are not available.
5 occurred. In the period of 1969–1979, the results of a total of 5 trials
Coburn concluded that “The data obtained under these in adults and one trial in children were published. All of these
various conditions, both in New York and a decade later in were double-blinded and placebo-controlled.
Chicago, were found to be statistically significant.” However, In the 1974 paper by Masek et al., the first two double-
he himself acknowledged that all studies had methodological blind controlled trials were described with a total of 1344
weaknesses [2]. healthy subjects randomized (see Table 1: Masek 1972a and
Coburn discussed various experimental findings around Masek 1972b). There were in total 40 dropouts during the
that time supporting the idea that there is at least one anti- studies, meaning that 1304 subjects completed the trials. The
inflammatory substance present in egg-yolk alcohol-soluble goal of these two trials was to evaluate the prophylactic
material, which was not present in the protein or acetone- and treatment efficacy of Impulsin in upper respiratory tract
soluble material [5, 8]. The anti-inflammatory activity was infections. Both trials ended in February 1973 [13].
confirmed by different groups, for instance, by measuring The first trial (Masek 1972a) was a treatment trial; 468
joint and skin lesions in either the Arthus or tuberculin employees of the Skoda car factory were randomized in this
reaction. Various models were used and all results were trial; of these 444 were completers, available for analysis. The
supportive of Coburn’s observations. The anti-inflammatory employees had to register the following symptoms: tempera-
compound clearly was part of the lipid fraction of the egg and ture of 37.5∘ C or higher, headache, sore throat, myalgia, nasal
not the protein-water fraction. stuffiness or discharge, productive or dry cough, malaise, and
fatigue and had to make a clear impression of being sick.
4. Acceptance of PEA’s Dosing was 600 mg Impulsin three times daily during 12 days
Anti-Inflammatory Effects (total daily dose 1800 mg PEA).
The second trial was a prophylactic trial; 918 volunteers
Already in 1965 the anti-inflammatory activity of PEA between 18 and 20 years of age from an army unit were
seemed to be quite well known in the scientific community. included, and 899 completed the trial period. In this trial,
Amongst others, Bachur, from the Laboratory of Clinical Bio- medical personnel registered the complaints during a period
chemistry and Experimental Therapeutics Branch, National of 8 weeks. The treatment schedule was 600 mg PEA three
Heart Institute, National Institutes of Health, Bethesda, MD, times daily for the first 3 weeks, after which a continuation
USA, and colleagues referred extensively to the findings of phase started based on a single dose of 600 mg once daily for
Kuehl et al. (1957): “Kuehl et al. have previously reported the 6 weeks.
isolation of PEA, as a naturally occurring anti-inflammatory The results from the first trial showed that patients
agent, from egg yolks. PEA was known to occur in nature and receiving PEA had a lower number of episodes of fever,
to have pharmacological activity” [9]. headache, and sore throat, compared with placebo patients
The group of Bachur analyzed the content of PEA and (18 versus 33). PEA had less effect on symptoms such as nasal
found it to be present in several tissues of the rat and guinea stuffiness, discharge, and cough. The episodes of fever and
pig. The amounts found in liver were quite variable, but pain were significantly reduced by 45.5% in the PEA group
PEA was consistently found in brain, liver, and muscle tissue compared with the placebo group (𝑃 < 0.05). The beneficial
and was not detected in other tissues examined. Around effect of PEA was apparent from the second week of the
that time, the anti-inflammatory action of PEA could also trial. The total number of sickness days was also significantly
be demonstrated in a classical anti-inflammatory model, the reduced in the PEA group. In the prophylactic trial, Masek
carrageen-induced edema model [10]. 1972b, the incidence of disease in the PEA group was 40%
In the beginning of the 70s, the modifying effects of PEA lower at week 6, and 32% lower at week 8 compared to placebo
on immunological reactions were well established [11]. Perlik (𝑃 < 0.0005).
et al. summarized [12] that “It has been shown that N-(2- In order to verify the conclusions, 3 more trials in soldiers
hydroxyethyl)-palmitamide (PEA) can decrease the intensity were conducted. Soldiers were selected as they were housed
of several inflammatory and immunological processes.” close together. In the period of 1973–1975, these new trials
4 International Journal of Inflammation

Table 1: Incidence of endpoints between both the PEA and the placebo groups.

Study (year) PEA (𝑛) Placebo (𝑛) % Protection Significance (𝑃)

Masek (1972a) [14] 223 221 45% <0.05
Masek (1972b) [14] 436 463 32% <0.0005
Kahlich (1973) [14] 436 465 34% <0.0002
Kahlich (1974) [14] 411 199 52% <0.002
Kahlich (1975) [14] 235 118 59% <0.004
Plesnik (1977) [15] 196 224 16% NS

were initiated (Kahlich 1973, 1974, and 1975 in Table 1) and communities.” Kahlich et al. also pointed out that the effects
the results were reported in 1979 by Kahlich et al. [14]. Due to of PEA had a clear advantage over vaccines and antiviral
the positive effects, it was felt to be unethical to randomize 1 : 1 compounds such as amantadine, due to the optimal balance
and in the last two trials a different randomization schedule of efficacy and side effects of PEA. They also stated that the
was selected, in order to dose the majority of volunteers ease of application of PEA offers the possibility to have a quick
with Impulsin (2 : 1). The authors compared the incidence of therapeutic answer ready in case of a flu epidemic, especially
clinical endpoints and the titers of influenza viruses between in cases of a mismatch between circulating strains and the
both the PEA and placebo groups. In all three trials, the recommendations from WHO.
soldiers in the PEA group had significantly less symptoms and A last placebo-controlled study with PEA in children aged
were less often diagnosed as flu patients (see Table 1). 11 to 15, examining the incidence of acute respiratory tract
The evaluation of results according to morbidity, regard- infections, was performed in January 1976 [15]. 457 children
less of etiology, showed a significant reduction in acute were included and divided into 2 groups; 64 children dropped
respiratory diseases (ARD) after administration of PEA. In out. In the PEA group, 169 children completed the study who
the 1973 trial (901 volunteers), 22.7% of ARD cases were received 300 mg PEA 2 times daily with an interval of 6 hours.
found in the PEA group compared to 34.4% in the placebo The placebo group included 224 children receiving 2 placebo
group (𝑃 < 0.0002). The relevant values in the 1974 trial (610 tablets following the same regime as the PEA group.
volunteers) were 19.7% and 40.7% (𝑃 < 0.002) and in the 1975 Blood samples were taken before the study and 8 weeks
trial (353 volunteers) 10.6% and 28.8% (𝑃 < 0.004) [14]. later in 65% of all children. After 8 weeks, children treated
In all studies, Kahlich et al. studied serology in order to with PEA had 15.7% fewer acute respiratory tract infections
document the influenza strains. The codes of these strains are than the control group. In children from 11 to 13 years
described below; however, the nomenclature is outdated. A of age, the difference was even more pronounced: 25.5%.
fourfold increase in the antibody titer was taken as evidence Due to the short duration of the intake of PEA and the
for infection. absence of epidemic influenza during the trial period, the
In the 1973 study, serum was obtained from 358 persons. differences between both groups were not very large, and thus
6.9% of the subjects experienced influenza A 2 E in the no significance was reached.
PEA group and 18.7% of the subjects in the placebo group
Taken together, in the period between 1972 and 1977
(𝑃 < 0.005). The manifestation rate (MR), expressing the
in total 3627 patients and volunteers completed 6 different
proportion of sick persons out of all sensitive subjects with
placebo-controlled double-blind trials of which 1937 received
serologically proved infection, was 15.4% in the PEA group
PEA up to 1800 mg/day. Relevant side effects were not
and 44.9% in the placebo group (𝑃 < 0.0002).
reported and especially the trials conducted during the flu
In the study of 1974, sera of 108 subjects were analyzed.
season demonstrated a treatment, as well as a prophylactic
In the PEA group 3.8% of the subjects suffered from the
effect. The last study in children was not significant due to
influenza B Hong-Kong and 21.4% of the subjects in the
the fact that during the study period no influenza epidemic
placebo group (𝑃 < 0.01). The MR was 14.3% in the PEA
occurred.
group and 57.1% in the placebo group (𝑃 < 0.001).
In the study of 1975, with serum gathered from 212
subjects, only 4.3% of the subjects in the PEA group had 6. PEA: Anti-Inflammatory Actions and
influenza A Port Chalmers and 7% of the subjects in the Its Mechanism of Action via PPAR-Alpha
placebo group (nonsignificant difference). The incidence rate Agonism and Other Targets
of influenza A 2 England was 15.4% in the PEA group and
44.9% in the placebo group (𝑃 < 0.0002). Since a decade, NAEs, both as saturated fatty amides (such
All these clinical trials pointed in the same direction as PEA) and as poly-unsaturated forms, are found to play an
that PEA has clear treatment effects in respiratory infections, important physiological role in the modulation of immune
can be used as influenza-prophylaxis, and is safe in its use. reactions in a number of autoimmune disorders via a number
Side effects were not reported, and Kahlich et al. explicitly of different receptors. For instance, Celiac disease is an
stated that “No side effects were registered after several autoimmune disorder of the small intestine caused by a
years of clinical testing of Impulsin in military and civilian reaction to gliadin, a gluten protein found in wheat. Most
International Journal of Inflammation 5

likely endocannabinoids play here an important modulating membranes and function as stable precursors and source of
role [16]. Anandamide and PEA concentrations in Celiac their respective NAEs. Palmitic acid is incorporated from
disease were significantly elevated (100% and 90%, resp.) the sn-1 position of a donor phospholipid like phosphatidyl-
during the active phase, as was the number of CB1 receptors. choline and transferred to an ethanolamine phospholipid, for
The levels returned to normal after remission with a gluten- example, phosphatidylethanolamine, which is catalysed by a
free diet [17]. This clearly can be interpreted as the activation Ca2+ -dependent N-acyltransferase [26–28]. Next, free PEA
of a self-repairing mechanism. can be generated by a NAPE-hydrolyzing phospholipase D
In an elegant study on the anti-inflammatory and pro- (NAPE-PLD). However, recent studies also demonstrate the
apoptotic activities of anandamide, it was shown that it can presence of NAPE-PLD-independent multistep pathways to
inhibit tumor necrosis factor-𝛼-induced NF-𝜅B activation form NAEs from NAPE [28].
[18]. The NF-𝜅B inhibitory activity of anandamide was An alternative pathway involves formation of NAEs from
independent of CB1 and CB2. Structure-activity relationships N-acylated plasmalogen-type ethanolamine phospholipid
demonstrated that analogs with saturated fatty acyl groups (N-acyl-plasmenylethanolamine) through both NAPE-PLD-
were more active than unsaturated analogs. Saturated dependent and independent pathways [28]. In general, tissue
acylethanolamides such as PEA therefore offer a new oppor- patterns of NAEs are considered to reflect the local availability
tunity to modify chronic inflammation in autoimmune dis- of their precursor fatty acids in the phospholipid membranes,
orders. which are amongst others diet-related [29]. However, in case
For a long period of time after the first description of of PEA, tissue levels hardly seem to be influenced by variation
PEA, its mechanism of action remained unsolved, and this in intake of dietary fatty acids, except in the small intestine
led to a weaning interest in the compound after the set of where dietary fat results in decreased levels of PEA and other
publications on the efficacy and safety of PEA in respiratory NAEs [27, 30]. Several studies indicate that free PEA levels
infections and flu (in the period of 1970–1980). New interest increase during inflammation [27, 30, 31]. Concentrations of
in the mechanism of action of PEA emerged only after the PEA in tissues and plasma have been published in various
work of the Nobel laureate Professor Rita Levi-Montalcini, papers, as recently reviewed by [27, 30, 31]. In humans, PEA
who published a seminal paper in 1993, opening the door plasma concentrations are subject to considerable variation
to a new understanding of PEA’s anti-inflammatory and during the day [32].
analgesic actions [19, 20]. Starting with her work, it became
clear that PEA regulates many pathophysiological processes, 7.2. Breakdown. Like with other NEAs, endogenous PEA
and PEA has since been found to be effective in a number is produced on demand and acts locally. Tissue levels are
of animal models for inflammation, neuroinflammation, tightly regulated through a balance between synthesis and
neurotoxicity, and chronic pain. Levi-Montalcini highlighted breakdown. The primary degrading enzyme is fatty acid
the importance of activation of inflammatory cascades via amide hydrolase (FAAH, now also known as FAAH-1),
the activation of nonneuronal cells, such as the mast cells localised on the endoplasmatic reticulum [33]. A second
[21]. PEA reduces mast cell migration and degranulation FAAH enzyme, now called FAAH-2, was found in humans,
and reduces the pathological overactivation of these cells located on cytoplasmic lipid droplets [33, 34]. Recently,
[21]. Mast cells shift from activated immune- to resting a third NAE hydrolysing enzyme, N-acyl ethanolamine-
phenotypes under influence of PEA. PEA further reduces the hydrolyzing acid amidase (NAAA) has been identified [28].
activity of the proinflammatory enzymes, cyclooxygenase, In the cytosol, fatty-acid binding proteins and heat-shock
and endothelial, and inducible nitric oxide synthases. PEA proteins may serve as carriers for PEA to their degrading
has an additional number of other pharmacological and enzymes [27].
physiological properties, such as its affinity for the novel
orphan cannabinoid receptors GPR55 and GPR119 and for 8. PEA Anti-Influenza Activity: Decrease of
the vanilloid receptor TRPV1, as well as for the nuclear Proinflammatory Cytokines
peroxisome proliferator-activated receptor-𝛼 (PPAR-𝛼) [22–
25]. These are probably the most relevant mechanisms of After an infection with the influenza virus, the immune
action of PEA related to immunopathology. system reacts by an increased production of many cytokine-
patterns. One pattern is related to a proinflammatory
7. Metabolism of PEA response and a second one to an antiviral response. Infections
with virulent influenza viruses together with an aberrant and
7.1. Synthesis. In the body, PEA is synthesized from palmitic excessive cytokine production are linked to increased mor-
acid (C16:0), which is the most common fatty acid in animals bidity and mortality [35]. Increased production of specific
and a product of normal fatty acid synthesis. Palmitic acid is inflammatory cytokines, such as the tumor necrosis factor
also present in many foodstuffs including palm tree oil, meats, (TNF)-𝛼, interleukin- (IL-) 1, IL-6, and IL-10, is characteristic
cheeses, butter, and dairy products. Synthesis of PEA takes during an influenza infection [36]. More virulent viruses
place in membranes of various cell types and involves differ- are also associated with rapid and sustained induction of
ent steps and partly parallel pathways. The most studied path- inflammatory cytokines and such an early dysregulation of
way goes via N-palmitoyl-phosphatidyl-ethanolamine, which the host response is seen as contributing to the severity and
belongs to the class of N-acylphosphatidylethanolamines outcome of the infection [37, 38]. The increased production
(NAPEs). NAPEs in general are present in phospholipid of proinflammatory cytokines, hypercytokinemia, is thus
6 International Journal of Inflammation

a clear player in the disease progression and death of patients and degenerative retina disorders, multiple sclerosis, amy-
infected by influenza viruses [39, 40]. Recently, it was demon- otrophic lateral sclerosis, and Alzheimer’s disease.
strated that highly elevated levels of serum IL-6 and IL-10 Given the results of 6 clinical trials in flu and the common
in A (H1N1) patients may also lead to disease progression cold, seen in the context of the serious criticism on the
[41]. efficacy and safety of oseltamivir and zanamivir, PEA should
Overactive and nonfunctional hyper induction of proin- be reconsidered by clinicians as a new treatment modality
flammatory cytokines might therefore play a key role in the for the flu and respiratory infections due to its documented
symptomatology and may lead to increased morbidity and efficacy and more importantly its very benign side effect
mortality. PEA is widely known for its anti-inflammatory profile. Furthermore, oseltamivir and zanamivir are known to
activity and to date more than 60 PubMed indexed papers induce resistance; PEA has a very low likelihood of inducing
discuss this property of PEA. Its inhibitory action on TNF- resistance due to its mechanism of action. Finally, the ease
alpha secretion is sufficiently documented [42]. But PEA has of application of PEA offers the possibility to have a quick
a much wider modulating effect on interleukins. For instance, therapeutic answer ready in case of a flu epidemic, especially
recently PEA was shown to significantly attenuate the in cases of a mismatch between circulating strains and the
degree of intestinal injury and inflammation and to inhibit recommendations from WHO.
proinflammatory cytokine production (TNF-𝛼, IL-1𝛽), adhe-
sion molecules (ICAM-1, P-selectin) expression, and NF-𝜅B
expression [43]. PEA also significantly decreases inflamma-
Conflict of Interests
tion caused by ischemia-reperfusion injury, a pathological The authors declare that they have no conflict of interests.
state characterized by a strong enhanced interleukin-cascade
[44]. As PEA downmodulates a number of proinflammatory
cytokines, this could very well be the reason for the decreased References
influenza and common cold symptomatology in individuals [1] A. F. Coburn and L. V. Moore, “The prophylactic use of sul-
treated with PEA. fanilamide in streptococcal respiratory infections, with especial
reference to rheumatic fever,” Journal of Clinical Investigation,
9. Conclusions and Therapeutic Perspective vol. 18, pp. 147–155, 1939.
[2] A. Coburn, “The concept of egg yolk as a dietary inhibitor to
Over 350 papers have been referenced in PubMed in the rheumatic susceptibility,” The Lancet, vol. 275, no. 7129, pp. 867–
last 50 years describing the physiological properties of PEA 870, 1960.
and its pharmacological and therapeutical profile. PEA has [3] A. F. Coburn, C. E. Graham, and J. Haninger, “The effect
a broad spectrum of biological targets and target molecules, of egg yolk in diets on anaphylactic arthritis (passive Arthus
among which are PPAR-alpha, TRPV1, and orphan receptors phenomenon) in the guinea pig,” The Journal of Experimental
such as GPR-55. Medicine, vol. 100, pp. 425–435, 1954.
This review on the role of PEA as an anti-inflammatory [4] D. A. Long and A. J. P. Martin, “Factor in arachis oil depressing
agent and as a therapeutic agent for influenza and the sensitivity to tuberculin in B.C.G.-infected guineapigs,” The
common cold discusses 6 clinical trials in a total of nearly Lancet, vol. 267, no. 6921, pp. 464–466, 1956.
4000 patients and volunteers where PEA’s effectiveness and [5] O. H. Ganley and H. J. Robinson, “Antianaphylactic and
safety for the treatment in these indications was shown. antiserotonin activity of a compound obtained from egg yolk,
Furthermore, since the focus on respiratory inflammation peanut oil, and soybean lecithin,” Journal of Allergy, vol. 30, no.
and flu between 1971 and 1980, PEA has also been extensively 5, pp. 415–419, 1959.
tested in a great variety of animal models for a number of [6] F. A. Kuehl Jr., T. A. Jacob, O. H. Ganley, R. E. Ormond, and
other indications, such as central and peripheral neuropathic M. A. P. Meisinger, “The identification of N-(2-hydroxyethyl)-
palmitamide as a naturally occurring anti-inflammatory agent,”
pain, pain in osteoarthritis, traumatic brain injury, multiple
Journal of the American Chemical Society, vol. 79, no. 20, pp.
sclerosis, amyotrophic lateral sclerosis, Alzheimer’s disease, 5577–5578, 1957.
irritable bowel disease, interstitial cystitis, and other visceral
[7] G. H. Stollerman, “Alvin F. Coburn, 1899–1975,” Journal of
pain states. Consistently, the effective dose range has been Infectious Diseases, vol. 133, no. 5, p. 595, 1976.
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