Phytotherapics in COVID19: Why palmitoylethanolamide?
| Luisa Seguella
| Sara Cassarano
| Laura Aurino
| Jie Lu
| Chiara Corpetti
| Alessandro Del Re
| Giovanni Sarnelli
| Giuseppe Esposito
Department of Clinical Medicine and Surgery,
University of Naples "Federico II", Naples, Italy
Department of Physiology and Pharmacology,
Sapienza University of Rome, Rome, Italy
Sequentia Biotech SL, Barcelona, Spain
Department of Human Anatomy, College of
Basic Medical Sciences, China Medical
University, Shenyang City, China
Giuseppe Esposito, Department of Physiology
and Pharmacology, Sapienza University of
Rome, Rome, Italy.
At present, googling the search terms “COVID-19”and “Functional foods”yields
nearly 500,000,000 hits, witnessing the growing interest of the scientific community
and the general public in the role of nutrition and nutraceuticals during the COVID-
19 pandemic. Many compounds have been proposed as phytotherapics in the pre-
vention and/or treatment of COVID-19. The extensive interest of the general public
and the enormous social media coverage on this topic urges the scientific community
to address the question of whether which nutraceuticals can actually be employed in
preventing and treating this newly described coronavirus-related disease. Recently,
the Canadian biotech pharma company “FSD Pharma”received the green light from
the Food and Drug Administration to design a proof-of-concept study evaluating the
effects of ultramicronized palmitoylethanolamide (PEA) in COVID-19 patients. The
story of PEA as a nutraceutical to prevent and treat infectious diseases dates back to
the 1970s where the molecule was branded under the name Impulsin and was used
for its immunomodulatory properties in influenza virus infection. The present paper
aims at analyzing the potential of PEA as a nutraceutical and the previous evidence
suggesting its anti-inflammatory and immunomodulatory properties in infectious and
respiratory diseases and how these could translate to COVID-19 care.
COVID19, palmitoylethanolamide, phytotherapy, SARS-CoV2
1|NUTRACEUTICALS DURING THE
COVID-19 PANDEMIC: STATE OF THE ART
The COVID-19 pandemic has hit a somber milestone with an ever-
rising death toll of 1,087,118 people worldwide, as of October
13 (https://www.worldometers.info/coronavirus/). Although the
pathogenic mechanisms underlying SARS-CoV2 infection are still
obscure, the induction of an uncontrolled release of cytokines and
other pro-inflammatory mediators appears to be pivotal in severely ill
COVID-19 patients (García, 2020; Mahmudpour, Roozbeh, Keshavarz,
Farrokhi, & Nabipour, 2020; Soy et al., 2020; Tay, Poh, Rénia,
MacAry, & Ng, 2020).
On this ground, many immunosuppressive drugs have been pro-
posed to counteract this process, with encouraging results (Amin
Jafari & Ghasemi, 2020; Jamilloux et al., 2020; Magro, 2020; Tufan,
glu Güler, & Matucci-Cerinic, 2020; Ye, Wang, & Mao, 2020).
Nonetheless, dampening the inflammatory response during infectious
diseases may impair the desired host response and predispose to sec-
ondary infections. In keeping with this, a recent single-center retro-
spective case-review analyzing the clinical outcomes and secondary
infections' rates in COVID-19 patients receiving the anti-interleukin
6 inhibitor, Tocilizumab, found a significantly higher mortality rate and
occurrence of secondary infections, particularly of bacterial pneumo-
nia superinfections, in patients treated with this immunosuppressive
drug (Kimmig et al., 2020; Pettit et al., 2020). Most of these ongoing
trials, hence, reserve these drugs for severely ill patients, given their
unwanted side effects, particularly in mild forms of infection (Nguyen
et al., 2020).
Received: 17 October 2020 Accepted: 24 November 2020
Phytotherapy Research. 2020;1–9. wileyonlinelibrary.com/journal/ptr © 2020 John Wiley & Sons, Ltd. 1
Diet and nutrition are receiving growing interest from the public,
given the compiling evidence of their pivotal role in modulating the
immune function (Butler & Barrientos, 2020; Zabetakis, Lordan, Nor-
ton, & Tsoupras, 2020). Both under- and over-feeding can indeed neg-
atively impact the immune response and ensuring the adequate
amount of micronutrients or functional foods may bear the potential
to increase the host defense against viral infections (Cena &
Chieppa, 2020; Stefan, Birkenfeld, Schulze, & Ludwig, 2020).
In this context, many phytotherapics and food supplements have
been proposed by the scientific community and the general public,
yielding conflicting information on this topic (Muscogiuri, Barrea,
Savastano, & Colao, 2020; Ribeiro, Sousa, & Carvalho, 2020). The
ideal nutraceutical should have proven immunomodulatory activities
and multitargeted mechanisms of action to avoid “escapism”given
the redundancy of the immune response, while at the same time, it
should be immediately translatable to clinical settings with pharmaco-
kinetic and pharmacodynamic studies proving its efficacy and safety
in clinical settings.
Endocannabinoid-related compounds are endogenous bioactive
lipid amides with pleiotropic homeostatic properties, including
immune response regulation, control of food intake, neuroprotection,
and inhibition of pain and inflammation (De Filippis et al., 2011; Gigli
et al., 2017; Matias & Di Marzo, 2007; Pesce et al., 2018; Pesce,
Esposito, & Sarnelli, 2018; Suardíaz, Estivill-Torrús, Goicoechea,
et al., 2007; Williams & Kirkham, 1999).
These well-known multifaceted properties, the readily clinical
translatability and the lack of unwanted side effects have already
attracted attention from the scientific community toward the
repurposing of these compounds during the COVID-19 pandemic
(Costiniuk & Jenabian, 2020; Esposito et al., 2020; Onaivi &
Sharma, 2020; Tahamtan, Tavakoli-Yaraki, & Salimi, 2020).
Oleoylethanolamide (OEA), cannabidiol, palmitoylethanolamide
(PEA), and other unsaturated fatty acids have all been put forward as
promising drug candidate as a treatment potential strategy in the
novel SARS-CoV-2 pandemic (Das, 2020; Ghaffari et al., 2020;
Onaivi & Sharma, 2020). All these compounds share similar character-
istics, being endogenous naturally occurring lipids taking part in the
host immune response to a variety of noxae, including viral infections
(Cabral, Ferreira, & Jamerson, 2015; Ganley, Graessle, &
Among these appealing compounds, checking all the boxes of the
ideal drug candidate is PEA, a naturally occurring lipid mediator pre-
sent in peanuts or fenugreek seeds and soybean lecithin (Ganley
et al., 1958) that has an entourage effect on the endocannabinoid sys-
tem (Lambert & Di Marzo, 1999), while lacking cannabinoids' psycho-
tropic side effects (Wallace et al., 2007). Recently, PEA has been
proposed as a potential drug for COVID-19 on the ground that this
and other compounds, such as sodium chromo-glycate, can prevent
mast cell (MC)-induced pulmonary inflammation and fibrosis during
SARS-CoV2 infection (Gigante et al., 2020). Not surprisingly, since
these were the first described effects of PEA (Aloe, Leon, & Levi-
Montalcini, 1993; Facci et al., 1995), the authors mainly focused on its
role as a mast-cell stabilizer during the so-called “cytokine storm”
occurring in COVID-19 pneumonia (Conti et al., 2020). It is now
accepted, however, that PEA has a multitargeted action and its poten-
tial anti-viral mechanisms may be related to several other signaling
pathways, such as toll-like receptors (TLRs), peroxisome proliferators-
activated receptor-α(PPARα), nitric oxide and cyclooxygenase-2
(COX2), and S100B and GFAP signaling pathways (Esposito
et al., 2014; Sarnelli et al., 2016; Sarnelli et al., 2016).
In this manuscript, we aim to introduce this bioactive lipid media-
tor as a novel potential pharmacological alternative for the manage-
ment of COVID-19 by analyzing systematically its multifaceted
properties and the previous evidence for its clinical applicability and
effectiveness in preventing and treating acute viral respiratory
We will finally outline how its multitargeted potential directly
translates to SARS-CoV2 infection and progression, identifying
PEA molecular targets, as well as its formulation, for COVID-19
2|PEA IMMUNOMODULATORY ACTIVITY
PEA has been under the spotlight of the scientific community for over
50 years given its analgesic, anti-allergic, and anti-inflammatory activi-
ties. As outlined above, Nobel-awarded Dr. Levi-Montalcini first
described that the anti-inflammatory properties of PEA were related
to the inhibition and degranulation of MCs, also known as the “Auta-
coid Local Injury Antagonism”ALIA-mechanism (Aloe et al., 1993). It
is now recognized that the PEA anti-inflammatory and analgesic prop-
erties are also related to the direct activation of a number of recep-
tors, including the PPAR-α(Sarnelli, Gigli, et al., 2016), the vanilloid
receptor (TRPV1) (Godlewski, Offertáler, Wagner, & Kunos, 2009; Ho,
Barrett, & Randall, 2008; Petrosino et al., 2016), or the G-protein
coupled receptor GPR55 and GPR119 (Godlewski et al., 2009; Ryberg
et al., 2007).
In addition, PEA belongs to the so-called endocannabinoid-related
compounds, since it has a close structural resemblance with classical
endocannabinoids, but displays no activity on cannabinoid receptors
(Lambert & Di Marzo, 1999). Given the close resemblance to endo-
cannabinoids, PEA shares with them similar biosynthetic and catabolic
pathways. PEA is indeed substrate of the fatty acid amide hydrolase
(FAAH), the enzyme responsible for anandamide degradation. By
either competing with endocannabinoids for FAAH or inducing its
down-regulation (Ho et al., 2008), PEA could reduce endo-
cannabinoids catabolism, thus ultimately increasing their concentra-
tions (entourage effect).
Its complex pharmacodynamic profile accounts for the multiface-
ted activities exerted on a wide number of inflammatory cells and
mediators. Most of the anti-inflammatory properties of PEA arise from
its ability to antagonize nuclear factor-κB (NF-κB) signaling pathway
via the selective activation of the PPARαreceptors (Esposito
et al., 2014; Sarnelli, D'Alessandro, et al., 2016).
PPAR-αreceptors are predominantly expressed in tissues
involved in fatty acids metabolism, such as liver, heart, kidney, and
2PESCE ET AL.
muscle, but more recently, it was also demonstrated to be expressed
on several types of immune cells, including undifferentiated mono-
cytes and differentiated human macrophages, T and B lymphocytes
(Magadum & Engel, 2018). PPARαactivation can effectively antago-
nize the NF-κB signaling pathway with a dual mechanism, either by
physically interacting with NF-κB p65 or by upregulating the expres-
sion of inhibitors of NF-κB(IκBs) in many cell types (Korbecki,
nski, & Dutka, 2019). By inhibiting NF-κB expression, PEA down-
stream regulates several genes involved in the inflammatory response.
These include pro-inflammatory cytokines (tumor necrosis factor
TNF-α, Il-1β), cell-adhesion molecules, and other signal mediators,
such as inducible nitric oxide synthase (iNOS), COX2, S100B, and
GFAP (Cipriano et al., 2015; Couch, Tasker, Theophilidou, Lund, &
PEA potent anti-inflammatory activity has been studied in a great
variety of animal and human models for a number of disorders, fea-
tured by overactive and dysfunctional hyper-inflammation, such as
osteoarthritis, traumatic brain injury, multiple sclerosis, amyotrophic
lateral sclerosis, Alzheimer's disease, inflammatory bowel disease,
asthma and allergic contact dermatitis (Beggiato, Tomasini, &
Ferraro, 2019; Britti et al., 2017; Esposito et al., 2013; Genovese
et al., 2008; Grill et al., 2019; Russo et al., 2018; Scuderi et al., 2011).
These anti-inflammatory effects have been firstly observed in
models of neuro-inflammation. For instance, in experimental spinal
cord injury in mice, PEA administration was proven to attenuate spinal
cord inflammation and tissue injury, neutrophils infiltration and the
expression of pro-inflammatory cytokines and iNOS, as well NF-κB
upregulation (Esposito et al., 2011).
Treatment with PEA also resulted in amelioration of intestinal
inflammation in animal and human models of inflammatory bowel dis-
ease (Borrelli et al., 2015). PEA treatment, indeed, dose-dependently
decreased the expression and release of pro-inflammatory cytokines
as well as neutrophil and macrophage infiltration in both dextran
sodium sulfate-induced ulcerative colitis (UC) in mice as well as in
cultured human biopsies deriving from UC patients (Lama
et al., 2020). Importantly, PEA is also able to downregulate, via a
PPARα-dependent mechanism, the expression of Toll-like recep-
tor 4 (TLR4) in both enteric glial cells and vascular smooth cells
(Sarnelli, D'Alessandro, et al., 2016). PEA also reduces the produc-
tion of reactive oxygen species in several models of inflammation
by reducing lipoperoxidation and reduction of nitric oxide by
downregulation of iNOS (Sarnelli et al., 2018). Finally, a recent
paper from Heide et al. proposed a novel anti-inflammatory mech-
anism of action for PEA in a mouse model of bacterial meningitis.
The authors fo und that prophylactic intrap eri toneal PEA adminis-
tration significantly reduced the systemic concentration of two
pro-inflammatory bioactive lipids, namely arachidonic acid (AA) and
20-hydroxyeicosatetraenoic acid (20-HETE). The authors concluded
that PEA effects on eicosanoid acids are particularly relevant in the
setting of meningitis, since 20-HETE is a potent vasoconstrictor of
brain microvessels that contributes to the development of vasospasm
and other cerebrovascular alterations occurring in bacterial meningitis
(Heide et al., 2018).
3|PEA IN PREVENTING AND TREATING
The role of PEA as a prophylactic and/or therapeutic agent in infec-
tious disease has been proven in six pioneeristic clinical studies from
the 1970s, long before the actual discovery of its receptor targets and
mechanisms of action (Keppel Hesselink, de Boer, & Witkamp, 2013).
Early results from animal studies supported the idea that PEA was a
non-specific enhancer of the host defenses against bacterial and viral
infection while exerting at the same time potent anti-inflammatory
activities (Bachur, Masek, Melmon, & Udenfriend, 1965). This led to
the commercialization of PEA, under the brand name of Impulsin, to
prevent upper respiratory tract infections (URTIs) and in treating
influenza-like symptoms. Overall, six placebo-controlled double-blind
randomized studies were published. An overview of the number of
participants, target population, primary aims, and duration and dosage
of PEA treatment used in the studies is provided in Table 1.
Taken together, these studies all point toward the efficacy of PEA
as a prophylactic and therapeutic agent against influenza, up to
1800 mg/daily, even in pediatric populations, with no relevant side
effects. The results suggested that repeated daily administration of
Impulsin (30 mg/kg) prevented the incidence of respiratory tract
infections both in pediatric and adult populations. Additionally, pro-
phylactic treatment with Impulsin markedly diminished the number of
episodes of fever, headache, and sore throat, while it showed no sig-
nificant effect on the mean duration of disability and fever. For a com-
plete review of these studies, readers are invited to refer to the
excellent review articles by Prof. Keppel Hesselink on the topic
(Keppel Hesselink et al., 2013).
Following these in vivo trials, only one retrospective observa-
tional study tested the effects of a nutritional product, branded under
the name of “Sinerga”that contained PEA, as well as other
nutraceuticals, such as bovine colostrum, phenylethylamine, and the
probiotic k1uyveromyces FM B0399 in preventing URTIs in children
(Nigro, Nicastro, & Trodella, 2014). In this observational small-sized
study (167 participants, mean age 4.5 years), the authors compared
the 4-month prophylactic administration of Sinerga to bacterial
extracts in children suffering from recurrent URTIs and evaluated the
frequency of episodes of a respiratory infection that had led to the
need of prescribing antibiotics. They found a reduction of the fre-
quency of URTIs and need for antibiotics in the group supplemented
with Sinerga, with all the subjects experiencing less than two episodes
of infection in the Sinerga group compared to 51% of the bacterial
Unfortunately, although the interest in PEA has continuously
risen during the last two decades, following the discovery of its mech-
anisms of action and subsequent commercialization as a nutraceutical
in several countries, no further studies tested its efficacy in respira-
tory infections in humans.
On the contrary, accumulating evidence have been produced
in vitro and in animal models of other communicable diseases, particu-
larly infections of the central nervous system (CNS), including bacte-
rial meningitis and sepsis driven by Escherichia coli K1 infection, given
PESCE ET AL.3
PEA well-known anti-inflammatory and neuroprotective effects. In
this paper, preventive treatment with PEA increased the phagocytosis
of E. coli K1 without inducing the release of cytokines by macro-
phages in vitro and delayed symptoms' onset and prolonged survival
of intracerebrally- or intraperitoneally-challenged mice in vivo (Heide
et al., 2018).
4|PEA POTENTIAL IN SARS-CoV2
Host immune response is a double-edged sword during SARS-CoV2
infection, as well as many others featured by hyperinflammatory
states. On one hand, in the early stages of infection, it is desirable to
have a competent immune system that can neutralize the pathogen,
while limiting the collateral damage to the host tissue, to accelerate
viral clearance. On the other hand, a deranged immune response with
over-production and systemic release of proinflammatory cytokines,
the so-called “cytokine storm”is thought to be responsible for the
systemic inflammatory response leading to acute respiratory distress
in severely-ill COVID-19 patients (Hu, Huang, & Yin, 2020).
In this scenario, PEA offers a unique pharmacodynamic profile. Its
properties as a non-specific immune enhancer against viral infections
have been tested in randomized clinical trials (RCTs) in humans
decades ago for the prophylaxis of respiratory tract infections (Nigro
et al., 2014). Furthermore, in vitro and in vivo studies in animal models
demonstrate that PEA can increase macrophage activation and phago-
cytosis without leading to an increase in proinflammatory cytokines
(Esposito et al., 2014).
SARS-CoV2 leads to an increased release of interleukin-6 (IL-6)
and IL-1b by binding the TLRs. The activation of the TLRs by SARS-
CoV2 leads to a cascade of events downstream culminating in the
activation of NF-κB, which is involved in the overexpression of inflam-
matory cytokines adhesion molecules and chemokines (McGonagle,
Sharif, O'Regan, & Bridgewood, 2020). The main receptor target of
PEA, PPARα, induces the expression of IkB, thus inhibiting NF-κB
pathway and modulates the expression of TLRs at the cell surface.
Being at the crossroads between these two pivotal signaling systems,
PEA can modulate the aberrant crosstalk between PPARαand TLRs
and may have a synergistic effect in COVID-19 infection (Esposito
et al., 2014).
One of the pharmaco-properties of PEA, the inhibition of MC
degranulation, known as the ALIA-mechanism has already attracted
attention from the scientific community and its relevance in SARS-
CoV2 infection has been extensively described elsewhere (Aloe
et al., 1993; Gigante et al., 2020).
Furthermore, PEA and other bioactive lipids act as anti-oxidant
molecules, reducing oxidative/nitrosative stress, thus preventing
endothelial damage, which is thought to contribute to the pathogene-
sis of the systemic inflammatory response in severe COVID-19
(Schönrich, Raftery, & Samstag, 2020).
There is compelling evidence that SARS-CoV2 is able to affect
not only the respiratory and cardiovascular function but also the gas-
trointestinal (GI) tract (Ho, Ho, Ho, & Ho, 2020; Wong, Lui, &
Sung, 2020) and the CNS system (Alomari, Abou-Mrad, &
Bydon, 2020; Asadi-Pooya & Simani, 2020). PEA is mostly used as a
phytotherapic for its neuroprotective and anti-inflammatory proper-
ties, particularly in neurodegenerative and inflammatory-related bowel
disorders, where it has been shown to decrease intestinal inflamma-
tion and restore the intestinal barrier function (Couch et al., 2019;
Karwad et al., 2017). It has been hypothesized that the COVID-
19-inflammatory state could disrupt the integrity of the intestinal bar-
rier leading to a hyper-permeable “leaky”gut, allowing bacterial trans-
location to the systemic circulation, potentially contributing to the
TABLE 1 Results from randomized trials evaluating PEA treatment in preventing acute respiratory infections
Skoda car factory
N. (PEA vs
(223 vs 221)
(436 vs 463)
(436 vs 465)
(411 vs 199)
(235 vs 118)
For 12 days
3×600 mg/day for
For 6 weeks
for 12 days,
For 6 weeks
for 12 days,
For 6 weeks
for 12 days,
For 6 weeks
4×600 mg/day for
Results 8% (18/223) vs 14.9%
14.7% (33/223) vs 18%
31% (135/436) vs
22.7% (99/436) vs
19.7% (80/411) vs
10.6% (25/235) vs
45.5% 32% 34% 52% 63% 15.7%
In terms of fever, headache, sore throat.
In terms of nasal stuffines, discharge, cough.
RTIs: respiratory tract infections.
4PESCE ET AL.
septic state of COVID-19 patients (Aktas & Aslim, 2020; Hoel
et al., 2020).
Another meaningful and interesting anti-inflammatory mechanism
of PEA that could directly translate to COVID patients, is the evidence
that its administration in mice is able to modify the levels of other bio-
active lipids in the systemic circulation. As mentioned, PEA signifi-
cantly downregulates AA and its metabolite 20-HETE, which is known
to be a potent vasoconstrictor of blood vessels, that could contribute
to vasospasm and endothelial dysfunction encountered in severe
COVID-19 (Heide et al., 2018). An overview of PEA activities and
how these could be relevant to SARS-CoV2 pathogenesis is provided
in Figure 1.
Anecdotal evidence suggest the use of nutraceuticals in fighting the
COVID-19 pandemic (Infusino et al., 2020). Long before COVID-19 was
under the lens of the scientific community, PEA had already been pro-
posed as a nutraceutical to fight viral respiratory infections. PEA has
been indeed tested in nearly 2000 individuals in RCTs as a prophylactic
treatment against viral respiratory infections, showing promising results
in the 1970s. PEA complex and redundant mechanism of action have
been unveiled many decades following these trials, showing its real
potential as an immunomodulatory compound rather than a simple
“non-specific immune enhancer”(Keppel Hesselink et al., 2013).
PEA formulations are readily available as a food for special medi-
cal purposes in Italy and Spain since 2008, under the brand name
Normast (Epitech Srl). With over 50 years of experience in using PEA
in clinical trials, even in pediatric populations, no significant adverse
side effects were reported (Gabrielsson, Mattsson, & Fowler, 2016),
making it an ideal nutraceutical for repurposing during the COVID-19
The interest toward this molecule as a readily useable medical
food supplement is continuously rising and is receiving increasing
attention from the scientific community, as witnessed by the recent
approval for a phase-2 clinical trial to treat patients with suspected or
confirmed COVID-19, granted by the Food and Drug Administration
(FDA). In this paper, we summarized the potential of PEA in COVID-
19 infection and believe that altogether several evidence point toward
its efficacy in respiratory infections and more importantly its very
benign side effect profile. One of the potential setbacks of PEA treat-
ment is the high doses required to achieve its therapeutic effect, fol-
lowing oral administration, given its unfavorable pharmacokinetic
profile and rapid metabolization in humans. This could limit its bio-
availability in clinical practice, and alternative strategies to efficiently
increase PEA bioavailability have been developed, such as
ultramicronized PEA (Impellizzeri et al., 2014).
In his almost prophetic-sounding statement, Professor Keppel
Hesselink states “the ease of application of PEA offers the possibility
to have a quick therapeutic answer ready in case of a flu epidemic,
especially in cases of a mismatch between circulating strains and the
FIGURE 1 Multitargeted activity of PEA and its potential in SARS-CoV2 infection. PEA exhibits immunomodulatory properties, though
inhibition of TLRs and NF-κB signaling pathways. On the other hand, PEA has been tested for respiratory viral infections as a “non-specific”
immune enhancer (1), it can reduce lipoperoxidation and the systemic concentration of AA and 20-HETE (2), and reduce intestinal permeability (3)
[Colour figure can be viewed at wileyonlinelibrary.com]
PESCE ET AL.5
recommendations from WHO.”We consider PEA a promising nutra-
ceutical in COVID-19 infection, based on the preclinical and clinical
studies and its relative safety profile in humans. Evidence from ongo-
ing clinical trials is eagerly awaited to confirm its beneficial activities
and turn PEA into an effective nutraceutical against COVID-19.
CONFLICT OF INTEREST
Marcella Pesce https://orcid.org/0000-0001-5996-4259
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How to cite this article: Pesce M, Seguella L, Cassarano S,
et al. Phytotherapics in COVID19: Why
palmitoylethanolamide? Phytotherapy Research. 2020;1–9.
PESCE ET AL.9