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Abstract and Figures

Palmitoylethanolamide (PEA) is a nutraceutical endocannabinoid that was retrospectively discovered in egg yolks. Feeding poor children with known streptococcal infections prevented rheumatic fever. Subsequently, it was found to alter the course of influenza. Unfortunately, there is little known about its pharmacokinetics. Palmitoylethanolamide targets nonclassical cannabinoid receptors rather than CB1 and CB2 receptors. Palmitoylethanolamide will only indirectly activate classical cannabinoid receptors by an entourage effect. There are a significant number of prospective and randomized trials demonstrating the pain-relieving effects of PEA. There is lesser evidence of benefit in patients with nonpain symptoms related to depression, Parkinson disease, strokes, and autism. There are no reported drug–drug interactions and very few reported adverse effects from PEA. Further research is needed to define the palliative benefits to PEA.
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Medical Manuscript
The Potential Benefits of Palmitoylethanolamide
in Palliation: A Qualitative Systematic Review
Mellar P. Davis
1
, Bertrand Behm
1
, Zankhana Mehta
1
,
and Carlos Fernandez
1
Abstract
Palmitoylethanolamide (PEA) is a nutraceutical endocannabinoid that was retrospectively discovered in egg yolks. Feeding poor
children with known streptococcal infections prevented rheumatic fever. Subsequently, it was found to alter the course of
influenza. Unfortunately, there is little known about its pharmacokinetics. Palmitoylethanolamide targets nonclassical
cannabinoid receptors rather than CB1 and CB2 receptors. Palmitoylethanolamide will only indirectly activate classical
cannabinoid receptors by an entourage effect. There are a significant number of prospective and randomized trials
demonstrating the pain-relieving effects of PEA. There is lesser evidence of benefit in patients with nonpain symptoms related
to depression, Parkinson disease, strokes, and autism. There are no reported drug–drug interactions and very few reported
adverse effects from PEA. Further research is needed to define the palliative benefits to PEA.
Keywords
palmitoylethanolamide, pain, neuropathy, depression, autism, Parkinson disease, stroke
Introduction
N-palmitoylethanolamide (PEA) is an endogenous cannabimi-
metic saturated fatty acid available as a nutraceutical which
targets multiple potential noncannabinoid receptors and
ion channels.
1-4
Related endogenous cannabinoids are
N-arachidonoyl ethanolamine (AEA), also known as
anandamide, 2-arachidonoyl glycerol (2-AG), and oleoyl etha-
nolamine (OEA). Palmitoylethanolamide does not bind to clas-
sical cannabinoid receptors (CB1, CB2) to any significant
degree and only indirectly activates classical receptors through
an entourage effect. The main targets of PEA have been clinically
associated with analgesia, antidepressant, and antineuroinflam-
matory activity and are peroxisome proliferator-activated recep-
tor a(PPAR), the vanilloid receptor TPRV1, the orphan receptor
GPR-55, and indirectly through alterations in monoamine neuro-
transmission and classical cannabinoid receptors. There are both
animal and clinical studies that have demonstrated analgesia with
PEA as a single agent and in conjunction with other analgesic.
2-12
In addition, PEA may be clinically helpful in a wide range of
neurological disorders such as depression, Parkinson disease
(PD), autism, and strokes.
13-16
The purpose of this review is to
make clinicians aware of the benefits to PEA when treating var-
ious symptoms and disease.
Method
We did a PubMedsearch using the term “palmitoylethanolamide”
which generated 707 references. We then did individual
searches using the terms, “palmitoylethanolamide and pain,”
which generated 209 references, “palmitoylethanolamide
and appetite,” 18 references, “palmitoylethanolamide and
Alzheimer’s disease,” 14 references, “palmitoylethanolamide
and heart,” 25 references, “palmitoylethanolamide and COPD
0 references,” “palmitoylethanolamide and stroke, 12
references,” and “palmitoylethanolamide and age,” 20 refer-
ences. Hand searches were made of multiple reviews and
clinical studies for completeness. A meta-analysis has been
reported recently on the use of PEA for pain and no addi-
tional studies were available.
11
Forty-seven clinical studies
were then summarized in 5 tables. The first 4 tables are a
summary of studies using PEA for pain and the last table
summarizes the studies of PEA for nonpain symptoms in
various diseases.
History of PEA
Palmitoylethanolamide was discovered more than 60 years ago
as a biologically active nutrient in soybean lecithin, egg yolks,
and peanut meal. It was the active component that blocked
passive joint anaphylaxis in guinea pigs.
17
Even earlier and
1
Geisinger Health System, Danville, PA, USA
Corresponding Author:
Mellar P. Davis, Geisinger Health System, 100 N Academy Ave, Danville,
PA 17822, USA.
Email: mdavis2@geisinger.edu
American Journal of Hospice
& Palliative Medicine
1-21
ªThe Author(s) 2019
Article reuse guidelines:
sagepub.com/journals-permissions
DOI: 10.1177/1049909119850807
journals.sagepub.com/home/ajh
clinically relevant, Coburn described the clinical benefits to
feeding poor children dried egg yolks to prevent rheumatic
fever despite streptococcal exposure. This observation leads
to the discovery of PEA a decade and a half later.
18,19
Palmi-
toylethanolamide was eventually isolated in 1957 and was
found to be a fatty acid component in guinea pig and rat
brain.
20,21
In the 1960s, SPOFA United Pharmaceuticals
brought PEA to market as 300 mg Impulsin. The nutraceutical
was promoted as a treatment for influenza and the common
cold. Multiple studies at the time demonstrated that PEA
reduced viral symptoms and clinical influenza.
22,23
It was later
found that PEA reduced the viral serology of the influenza
virus.
24
This benefit has largely been ignored in the recent
literature, which now is largely concentrated on PEA benefits
as an analgesic and modulator of neurological disorders.
Pharmacokinetics
N-acyl ethanolamines (NAEs) are derived from plasma mem-
branes by a 2-step process. N-acyl ethanolamines differ from
anandamide and 2-AG in that they do not bind to classical
cannabinoid receptors. The most common NAEs are OEA and
PEA, with PEA being the most abundant. The first involves the
transfer of palmitic acid to a phospholipid donor by a calcium-
dependent N-acyl transferase (NAPE). The second step
involves removing the phosphatidyl group by NAPE phospha-
tase.
25,26
Palmitoylethanolamide is produced on demand. Local
tissue levels are highly regulated through a balance between
synthesis and catabolism. Palmitoylethanolamide is metabo-
lized intracellularly by fatty acid amide hydrolase (FAAH).
Within the cell, PEA binds to fatty acid binding protein and
heat shock protein.
27
Palmitoylethanolamide can also be meta-
bolized by N-acyl acid amidase to palmitic acid and ethanola-
mine. It competes for FAAH with AEA and by this entourage
effect increases levels of AEA, thus indirectly activating clas-
sical cannabinoid receptors.
28-30
Little is known about the pharmacokinetics of PEA in
humans. The bioavailability and apparent volume of distribu-
tion have not been studied. Diet changes in palmitoyl do not
influence circulating levels and diet changes in omega fatty
acids do not change NAE blood levels.
31,32
Fasting blood levels
of PEA range from 3 to 24 ng/mL and, at least in animals, do
not accurately reflect levels in the peripheral compartment
(central nervous system [CNS]).
33
In animals, NAE brain lev-
els diminish with age. The commercial form of PEA (either
micronized or ultramicronized) has increased bioavailability in
animals compared to nonmicronized forms, but there are no
clinical data to suggest this is true for humans.
34,35
There is
little known about how PEA penetrates tissues or whether dis-
eases or inflammation influence distribution, clearance, or PEA
circulating half-life.
31
However, if animal models reflect what
occurs clinically, PEA levels are increased either systemically
or regionally in the face of neuropathic injury and inflamma-
tion. This may be due to downregulation of FAAH.
36
In
rodents, PEA is the most abundant NAE in tissues, with levels
ranging from 78 to 50 000 pmol/g in tissue.
37-39
Paradoxically,
PEA concentrations in leukocytes are reduced in chronic
inflammation, which may reflect reduced production or
increased release and PEA depletion over time with chronicity
of the disease process.
40,41
The distribution of PEA within the brain is highly variable
despite being a saturated acyl ethanolamine.
42
The distribu-
tion does not follow the primary PEA target, the PPAR-a
receptor.
37
In animals, there is a diurnal variation in CNS
PEA. Palmitoylethanolamide generally increases in light and
increases selectively in the pons, hypothalamus, and hippo-
campus when lights are off, presumably increasing sleep
behaviors and reducing feeding behaviors.
37
In vitro, PEA has
been shown to be produced not only by neurons but also by
astrocytes and in greater quantities than AEA (production
ratio of 26:1).
43
Pharmacodynamics
Palmitoylethanolamide levels in the peripheral compartment
(CNS) may be an important clinical site of action. There is
an inverse relationship between PEA levels in the CNS and
pain in animal models.
44,45
N-acyl ethanolamines interact with
multiple receptors and ion channels with a multitude of biolo-
gical effects. As mentioned, PEA does not directly interact with
CB1 or CB2 receptors. In animal models, PEA reduces appetite
(though not demonstrated clinically), reduces the rewarding
effects of nicotine and cocaine, improves neuropathic and
inflammatory pain, improves cardiac failure, reduces Alzhei-
mer type dementia, acts as an antidepressant, and reduces brain
damage from strokes and brain trauma.
2-4,46-50
Palmitoylethanolamide is an agonist for the PPAR-arecep-
tor, which is a critically important receptor in downmodulating
neuroinflammation.
9,51
The PPAR-areceptor also mediates
mood, pain, and neuroinflammation, as demonstrated in ani-
mals. Palmitoylethanolamide bound to PPAR-areceptors
forms heterodimers with retinoic acid receptors. The dimer acts
as a transcription factor promoter of peroxisome proliferator
response elements.
52
Palmitoylethanolamide also increases the
expression of PPAR-amessenger RNA.
53
Interactions with
response elements results in downregulation of nuclear factor
kB(NF-kB) and subsequent downstream signaling cascades
which are the “gateway” to neuroinflammation. The NF-kB
inhibitor, inhibitory I-k(Ik-B), is upregulated. The NF-kBis
responsible for upregulating inflammatory cytokines, such as
tumor necrosis factor a(TNF-a) and interleukin 1 and 6 as well
as cyclooxygenase 2.
30,50,54-60
Activation of PPAR-aincreases
the production of intracellular neurosteroids, which alters cal-
cium channels and big conductance potassium channels lead-
ing to hyperpolarized neurons.
9,61
This accounts for the
antiseizure activity of PEA in animal models.
62
Allopregnano-
lone, one of the principal neurosteroids, reduces pain, prevents
seizures, and reinforces gamino butyric acid (GABA) signal-
ing.
61,63,64
Palmitoylethanolamide and downstream allopregna-
nolone reduce stress in animals and post-traumatic stress
disorder (PTSD)-like behaviors in animal models. Stress and
PTSD reduce pain thresholds.
65
The antiallodynia effects of
2American Journal of Hospice & Palliative Medicine
PEA are dependent on the presence of PPAR-areceptors. This
has been demonstrated in animal models of paclitaxel-induced
and diabetic neuropathic pain.
66,67
Palmitoylethanolamide
increases CB2 receptor expression through PPAR-aactiva-
tion.
68
This upregulation of CB2 on microglia facilitates AEA
and 2-AG downmodulation of neuroinflammation as an entou-
rage effect of PEA.
There are several other benefits to PPAR-areceptor activa-
tion. Activation of PPAR-areceptors and subsequent neuro-
steroid production has an antioxidant effect, which increases
resistance to reactive oxygen species.
69
The PPAR-aagonists
cause a release of oxytocin from the supraoptic and paraven-
tricular hypothalamic nuclei which project to the amygdala,
raphe nuclei, and dorsal horn. This pathway is associated with
antinociception in animal models.
70,71
Palmitoylethanolamide interacts with vanilloid receptors in
a unique manner. Palmitoylethanolamide is a positive allosteric
modulator of the transient receptor potential vanilloid-1
(TRPV1).
1,10
This is the same receptor that is activated by
capsaicin and AEA. Paradoxically, PEA accelerates TRPV1
receptor desensitization.
72
The interactions with the TRPV1
receptor contribute to analgesia and anti-inflammatory activity
and vasorelaxation.
1,10,73,74
Perivascular sensory nerves
express TRPV1. Palmitoylethanolamide is present in signifi-
cant concentrations in perivascular sensory neuron areas. The
binding of TRPV1 by AEA and PEA causes vasorelaxation.
75
Palmitoylethanolamide activates the orphan receptor
GPR55.
76,77
Although PEA increases GABA neurotransmis-
sion, through GPR55, PEA also reduces GABAergic tone by
increasing postsynaptic 2-AG production that binds to presy-
naptic CB1 receptors, which in turn reduces GABAergic
tone.
78
Activation of GPR55 increases dopaminergic neuro-
transmission in the hippocampus.
79
One would assume that this
increase in dopamine in the mesolimbic system would increase
the rewarding or “drug-liking” effects of addicting drugs, but in
fact this leads to a reduction in the morphine rewarding effects
in animals.
80-82
Paradoxically, PEA blocks the increased dopa-
mine neurotransmission associated with nicotine, reducing its
rewarding effect also.
47
This action may also be through
PPAR-a.
83
Palmitoylethanolamide blocks cocaine behaviors
in animals as measured by conditioned place preference.
84
GPR55 is highly expressed in the gastrointestinal tract and
modulates inflammatory responses.
85
Palmitoylethanolamide
has the potential to influence intestinal motility, secretion,
inflammation, and cellular proliferation, not only through
GPR55 but also by way of PPAR-aand the entourage effect
on CB1 and CB2.
86,87
Mast cells within the CNS sustain neuroinflammation and
disrupt the blood–brain barrier.
46
Mast cells migrate into the
CNS through penetrating blood vessels and release biogenic
amines, thus contributing to demyelination and neuropathic
pain associated with neuroinflammation.
88,89
Mast cells play
aroleinbrainischemia,spinal cord compression, and
amyotrophic lateral sclerosis.
90,91
Mast cells interact with
glia through Toll-like receptors, complement receptors,
and CD40 receptors to amplify neuroinflammation.
92,93
Palmitoylethanolamide and the antioxidant luteolin reduce
mast cell–mediated toxicity caused by brain ischemia in ani-
mals.
94
Palmitoylethanolamide has proven efficacious in mast
cell–mediated experimental models of acute and neurogenic
inflammation.
95
It has neuroprotective effects in spinal cord
trauma, delayed postglutamate excitotoxic neuron death, and
amyloid b-peptide-induced learning and memory impairment
in mice.
46
It reduces brain edema from ischemia and hemor-
rhage by blocking mast cell activation in animals.
96,97
Palmitoylethanolamide modulates glutamate neurotrans-
mission. The glutamate receptor, N-methyl-D-aspartate
(NMDA), is upregulated in the median prefrontal lobe in ani-
mals subject to neuropathic injury. This upregulation in the
prefrontal lobe may be responsible not only for pain but also
for anxiety and depression commonly observed with neuro-
pathic pain.
98-100
N-methyl-D-aspartate receptors in pre- and
postlimbic areas cause neuroplasticity that leads to chronic
neuropathic pain.
101
Palmitoylethanolamide is increased in the
median prefrontal cortex in neuropathically injured animals
and reduces NMDA neurotransmission.
102
Glutamate causes
synaptic modification in the medial prefrontal lobe with injury
characterized by changes in density proteins and amino acid
levels. Increased PEA levels in the region cause a resolution of
pain and depressive-like syndrome in selective nerve injured
mice. Palmitoylethanolamide restores glutamatergic synapse
proteins and changes in amino acid release.
102
Palmitoyletha-
nolamide also increases NR23 subunits of the metabiotic glu-
tamate receptor 3, which modulates glutamate
neurotransmission and may be an additional mechanism for anti-
nociception in animals.
102
Palmitoylethanolamide increases serotonergic neurotrans-
mission through the serotonin receptor 5HT1 and downregu-
lates 5HT2A/C receptors. CB1 agonists are reported to reduce
the reuptake of dopamine and serotonin.
103,104
Deletions of
CB1 receptors in animals reduce synaptic serotonin caused
by selective serotonin reuptake inhibitors.
105
This appears to
be an entourage effect by delaying AEA metabolism through
FAAH.
106-109
Blocking CB1 receptors produces depression in
animals. Clinical depression leads to the removal of the CB1
antagonist rimonabant from the market.
110-112
Conventional
antidepressants such as fluoxetine increase CB1 receptor den-
sity in prefrontal lobes of treated animals, which could be
targeted by CB1 agonists or by entourage effects of PEA.
113
Palmitoylethanolamide is an uncompetitive inhibitor of
CNS butylcholinesterase.
114
Butylcholinesterase knockout
mice have reduced fibrillar A-bproteins and are protected from
Alzheimer disease.
115,116
Potential Uses and Clinical Studies of PEA
Pain
Neuropathic pain—Animals. Palmitoylethanolamide in animal
models reduces pain behaviors from neuropathic injury resulting
from chemotherapy. These studies also demonstrate objective
improvements in nerve function.
117,118
Palmitoylethanolamide
Davis et al 3
prevents oxaliplatin hypersensitivity, allodynia, reduced
cyclooxygenase 2 expression, spontaneous neuron depolariza-
tion, and evoked spinal cord activity in rats.
118
It reduces pacli-
taxel pain behaviors and potentiates gabapentin antinociception
in mice.
66
Minocycline upregulates PEA production in the
ipsilateral spinal as a mechanism of analgesia to selective
nerve injury.
119
Mice with chronic constrictive injury to sciatic
nerves have reduced hyperalgesia with PEA. The mechanism
appears to be activation of PPAR-aand the entourage effect on
CB1 receptors.
74
Rats made diabetic through exposure to strep-
tozocin develop neuropathy and hypersensitivity. The combi-
nation of PEA plus acetaminophen reduces evoked pain better
than either agent alone.
120
Tramadol plus PEA synergistically
reduces pain from formalin injections in mice. Analgesia in this
model was derived through opioid, PPAR-a, TRPV1 receptors,
and ion channel interactions.
121
Cognitive impairment accom-
panies mice subject to spared nerve injury. Palmitoylethanola-
mide not only reverses mechanical and thermal allodynia from
injury but improves memory deficits. The benefits are depen-
dent on PPAR-areceptors.
122
Objectively, PEA reduces mye-
lin loss from sciatic nerve injury, maintains neuron cell
diameters, and reduces nerve edema and macrophage infiltrate
that is associated with reduced hypersensitivity. Mice null for
PPAR-afail to respond to PEA.
6
Neuropathic pain—Humans. Palmitoylethanolamide accumu-
lates in painful tissues in humans. This was seen in trapezius
muscle of women with chronic neck pain.
123
Palmitoyletha-
nolamide blood levels also increase in pain processing
disorders such as fibromyalgia and in individuals with wide-
spread pain.
124,125
There have been multiple prospective observational and
randomized PEA trials that have been largely used as an
add-on analgesic nutraceutical (Table 1). We found 19 studies
and 5 randomized controlled trials (RCTs). Trial quality was
mixed with little information regarding allocation, randomiza-
tion procedures, blinding, and attrition. However, PEA reduced
painful diabetic neuropathy, neuropathy from chemotherapy,
pain from idiopathic axonal neuropathy, nonspecific neuropa-
thy, and pain from sciatic and lumbosacral spine disease. Pal-
mitoylethanolamide, however, failed to improve pain from
spinal cord injury in 1 RCT.
133
Palmitoylethanolamide
improves pregabalin, oxycodone, and codeine analgesia. Mul-
tiple studies of PEA in carpal tunnel syndrome demonstrate
improvement in symptoms and objective improvement in nerve
function (Table 2).
Visceral pain—Animal studies. There are sparse data regarding
PEA benefits to visceral pain relative to neuropathic pain.
There are negative studies. For instance, AEA, but not PEA,
reduced viscerovisceral responses to turpentine cystitis in ani-
mals.
149
However, PEA has had some beneficial effects on
gastrointestinal signs and symptoms. Palmitoylethanolamide
reduced enteric glia responses and diarrhea related to HIV-1
Tat proteins in rats.
150
In vitro using both Coco-2 colon cell
lines and human colon explants, the combination of
cannabidiol (CBD) and PEA reduced reactive inflammatory
cytokine production, CBD through CB2 receptors and PEA
through PPAR-areceptors.
151
Dinitrobenzenesulfonic acid is
often used to induce colitis in mice. Palmitoylethanolamide
reduced inflammation and reduced colonic permeability in this
colitis model. Palmitoylethanolamide stimulates mucosal cell
proliferation and increases colonic expression of TRPV1 and
CB1 receptors. It benefits in colitis require the presence of
GPR55, PPAR-a, and CB2 receptors.
86
It also reduced intest-
inal permeability caused by interferon-gand TNF-a.The
PPAR-areceptors are the important receptors mediating these
benefits. N-acyl acid amidase inhibition increases PEA levels
in the colon, which reduces colon inflammation and systemic
inflammation in 2 mice models of colitis.
152
Enteric glia acti-
vation amplifies intestinal inflammation via the enteroglial-
specific S100B protein. In mouse models of dextran sodium
sulfate–induced colitis and colonic biopsies derived from
patients with ulcerative colitis, PEA improved macroscopic
colitis and decreased the expression and release of all pro-
inflammatory markers. This was mediated by the selective tar-
geting of the S100B/Toll-like receptor-4.
57
Visceral—Human studies. Intestinal PEA levels are on average
1.8-fold greater in individuals with ulcerative colitis compared
with healthy controls.
153
Intestinal PEA levels are increased
2-fold during active celiac disease and return to normal with
remission.
154
Liver and hepatic vein PEA levels are signifi-
cantly elevated in cirrhosis, more than AEA.
155
Palmitoyletha-
nolamide is increased in patients with pain from pancreatitis
and pancreatic cancer.
156
In a small series of patients with
colonic inertia, FAAH enteric neuron expression was found
to be reduced, CB1 receptor expression on enteric ganglions
was also reduced, and intestinal PEA, AEA, and 2-AG levels
were increased.
157
These findings reflect either an entourage
effect of PEA or a direct effect of AEA and 2-AG on CB1
receptors and motility. Overall, PEA appears to be upregulated
in multiple visceral inflammatory and painful diseases.
There are no studies of PEA in the treatment of colitis that
we could find. There is one study centered on irritable bowel
syndrome reviewed in Table 3 with symptom improvement.
161
Most studies involving visceral pain include women with
chronic pain syndromes, the majority of which are due to endo-
metriosis (Table 4). Most clinical studies combined PEA with
transpolydatin, which is a stilbenoid glucoside of resveratrol.
This agent becomes trans-resveratrol and transversatrol-3-O-
glucuronide in the small bowel, which leads to much higher
(1000-fold) blood and tissue levels of resveratrol. Resveratrol
increases PEA levels in the CNS and increases PPAR-aas well
as CB1 and CB2 receptors expression.
173,174
The combination
of PEA with transpolydatin significantly reduced pain, dysme-
norrhea, and dyspareunia associated with endometriosis in
multiple studies.
Other pain syndromes—Animal studies. Intracerebroventricular
PEA reduces peripherally (paw) injected carrageenan inflam-
matory pain in mice through activation of PPAR-areceptors.
4American Journal of Hospice & Palliative Medicine
Table 1. Palmitoylethanolamide Neuropathic Pain Trials.
Study
Design/Number of
Participants PEA Dose/Time Frame Comparator Outcomes Results Adverse Effects
Schifilliti et al
126
Observational, pre-/
postintervention, N ¼30,
diabetic neuropathy
mPEA, 600 mg/d, 60 days Michigan Neuropathic Screening
Instrument, Total Symptom Score,
Neuropathic Pain Symptom
Inventory
Reduced pain severity (P< .0001),
reduction in related symptoms (P<
.0001)
No SAE
Desio et al
127
Observational, N ¼30,
neuropathic pain
unresponsive to pregabalin
umPEA, 1200 mg/d with pregabalin, 45
days
VAS (0-10) With the addition of umPEA VAS 7 to 1.3
Biasiotta et al
128
Observational, N ¼30,
neuropathic pain
PEA, 600 mg/d, added on to analgesics Neurophysiologic parameters, pain
severity
Improved laser-evoked potentials in the
hands and feet, reduced pain severity
Truini et al
129
Observational, N ¼20,
chemotherapy-related
neuropathy (thalidomide
and bortezomib)
PEA, 600 mg/d Neurophysiologic studies, pain,
Douleur Neuropathique 4 (DN4)
scale, motor and sensory fiber
function
Improved laser-evoked potentials,
improved A-a,A-b,A-dfiber function
(P< .05)
Cocito et al
130
Observational, N ¼30,
chronic neuropathic pain,
DN4 scale score >4 and
VAS (0-10) >6
umPEA, 1200 mg/d, 40 days VAS, Neuropathic Pain Symptom
Inventory, Health Questionnaire
5 dimensions (EQ-5D)
VAS 8.2 to 6.4 at day 10 (P< .002), 8.2 to
5.8 on day 40 (P< .001)
NPSI improves from 5.2 to 3.8 on day
40 (P¼.025), EQ-5D improves from
0.36 to þ0.5 (P< .001)
Semprini et al
131
Observational N ¼25,
diabetic neuropathy,
reduced mean nerve
conduction time
PEA, 1200 mg/d, 16 weeks Nerve conduction studies, VAS Increased conduction amplitude and
reduced pain
Hesselink et al
132
Case series, N ¼7,
neuropathic pain, chronic
idiopathic axonal
polyneuropathy refractory
to standard analgesics
mPEA, 1200 mg/d, various time periods
starting from day 14, add-on to
analgesics
Pain severity 30% to 50% reduction in pain intensity
over 2 to 3 weeks
Hesselink et al
8
Case series, N ¼7, various
neuropathies on analgesics
mPEA, 1200 mg sublingual for 10 days,
then 1200 mg by mouth
NRS for pain intensity 40% to 80% reduction in pain intensity
over 2 weeks
Mild diarrhea
and stomach
upset in 1 to
2 patients
Andresen et al
133
RCT, N ¼73, neuropathic
pain from spinal cord
injury, add-on to analgesics
umPEA, 1200 mg sublingual/d, 12 weeks Placebo NRS (0-10)
Average intensity weeks 2 to 12
Daily spasticity modified Tardieu
Muscle stiffness
Rescue analgesics
Pain descriptors
Impact of neuropathic pain
QoL using Pain Survey, Insomnia by the
Insomnia Severity Index, Major
Depression Inventory, number
needed to treat, general anxiety
disorder
No difference in the primary outcome
(NRS), reduced rescue medications
with PEA, increased subjective but not
objective spasticity with PEA, no
difference in other outcomes
No difference in
SAE
Guida et al
134
RCT, N ¼636, chronic sciatic
pain
PEA, 300 mg/d, 600 mg/d Placebo VAS pain severity VAS 6.5 to 4.5 on placebo, VAS 6.5 to 3.5
on 300 mg/d, VAS 7.1 to 2.1 on 600 mg/
d(P< .05)
No AE
(continued)
5
Table 1. (continued)
Study
Design/Number of
Participants PEA Dose/Time Frame Comparator Outcomes Results Adverse Effects
Desio et al
135
Observational, N ¼30,
chronic low-back pain not
responding to analgesics
PEA, 100 mg/d plus oxycodone 5 to 25 mg/
d, 30 days
VAS pain VAS 7 to 2.5 No AE
Canteri et al
136
RCT, N ¼111, lumbosacral
spine pain with a
neuropathic component
PEA, 300 mg/d, 600 mg/d, +NSAID Placebo VAS pain VAS 9 to 6 on placebo, VAS 9 to 3.5 on
300 mg/d, VAS 9 to 1.5 on 600 mg/d (P
< .05)
No AE
Palomba et al
137
RCT, N ¼81, open
comparison, chronic low-
back pain on gabapentin,
tricyclic antidepressants, or
duloxetine
PEA, 1200 mg for 21 days, then 600 mg for
51 days
Standard analgesics VAS pain Less pain than standard (P< .05) No AE
Dominguez
et al
138
Observational, N ¼85,
lumbosciatic pain
PEA, 600 mg/d “Usual care” Pain reduction by VAS Usual care pain reduction by 2.69, with
PEA 3.85 (P< .05)
No AE
Dominquez
et al
139
RCT, N ¼118, neuropathic
pain from lumbosciatica
PEA, 600 mg/d plus standard therapy Standard therapy VAS pain, Oswestry Disability Index, S-
12 Health Survey
VAS and the 2 physical components of the
SF-12 improved relative to standard
care
Passavanti et al
140
Observational, N ¼55,
chronic low-back pain with
a neuropathic component
by DN4 > 4
umPEA, 1200 mg/d, 6 months plus
tapentadol 100 500 mg/d
Retrospective on
tapentadol
alone,100-500
mg/d, 6 months
VAS pain, DN4, Oswestry Disability
Index (ODI)
VAS on tapentadol 7.7 to 5.9, PEA 7.4 to
4.5 (P< .0001)
DN4 6.1 to 5.0 on tapentadol, PEA 6.1 to
3.2 (P< .0001), ODI on tapentadol 54.6
to 44.6, PEA 56.9 to 37.7 (P< .0012)
Diarrhea in 15%
of PEA group
Paladini et al
141
Observational, N ¼35, failed
back surgery
umPEA, 1200 mg for 1 month, then 600
mg the second month while on
tapentadol 150 mg/d and pregabalin 300
mg/d
Tapentadol 150 mg
and pregabalin
300 mg 3 month
prior to starting
PEA
VAS pain severity Tapentadol/pregabalin, VAS 5.7 to 4.3,
added PEA 4.3 to 1.7 (P< .0001)
Morera et al
142
Observational, N ¼112,
lumbosciatic pain
PEA SF-12 QoL Improved mental health better in men
than woman
Chirchiglia
et al
143
Observational, N ¼155,
nonsurgical lumbar
radiculopathy
Acetaminophen/codeine 500/30 for 7
days, then switched to umPEA 1200
mg/d for 30 days; if no response, then
addition PEA 600 mg for 30 days
followed by 30 days of acetaminophen
plus codeine
VAS pain severity First cycle those with mild pain (3-4)
responded to 1, those with moderate
pain (5-6) responded to 2 (75%),
second cycle, all moderate pain
responded, but 26% of severity pain did
not respond
Abbreviations: AE, Adverse effects; mPEA, micronized palmitoylethanolamide; NRS, Numerical rating scale; NSAID, nonsteroidol anti-inflammatory drug; QoL, quality of life; RCT, randomized controlled trials; SAE,
Serious, adverse effects; umPEA, ultramicronized palmitoylethanolamide; VAS, Visual Analog Scale.
6
Palmitoylethanolamide reduces cyclooxygenase 2 and induci-
ble nitric oxide synthase and increases PPAR-aexpression in
sciatic nerves and L4-6 dorsal root ganglion. Palmitoylethano-
lamide prevents Ik-B degradation and translocation of
NF-kB nuclear translocation.
54
Certain nonsteroidol anti-
inflammatory drugs, such as nimesulide, increase tissue PEA
levels by blocking catabolism of PEA.
45
Palmitoylethanola-
mide reduces formalin-induced pain at intraperitoneal doses
that produce no increase in circulating PEA levels in mice.
9
Palmitoylethanolamide reduces hyperalgesic responses to com-
plete Freund adjuvant.
9
Spinal allopregnanolone levels are
increased by PEA both in formalin- and carrageenan-exposed
mice, which is associated with reduction in pain.
63
Palmitoy-
lethanolamide reduces tibial fracturepaininrodentsand
increases fracture healing.
175
Palmitoylethanolamide prevents
arthritis in rodents caused by injections of bovine collagen
II.
176
It reduces mechanical and thermal hyperalgesia and
macrophage infiltrate into the temporomandibular joint caused
by injections of complete Freund adjuvant in rats.
177
Other pain syndromes—Human studies. Palmitoylethanolamide
is an effective analgesic or adjuvant analgesic in a multitude of
pain syndromes. Circulating PEA levels are increased in the
burning mouth syndrome.
178
Palmitoylethanolamide levels in
synovial tissues at the time of total knee replacement correlate
with disability, but not with pain severity.
179
In 2 meta-
analyses, PEA has significant analgesia either as a single agent
or as an add-on analgesic in multiple pains.
11,12
In one meta-
analyses, the weighted mean differences between PEA and
inactive comparator (placebo or equivalent) were remarkably
high, indicating a very large effect size.
11
However, the anal-
yses involved a small number of studies with significant poten-
tial biases. Palmitoylethanolamide responses in trials with
active controls were also significantly different with a large
effect size difference. Palmitoylethanolamide was effective in
reducing pain from fibromyalgia, burning mouth syndrome,
temporomandibular joint disease, and molar extractions.
Neurodegenerative and Neuropsychiatric
Disorders
Strokes and Ischemic–Reperfusion Injury—Animal
Studies
Palmitoylethanolamide reduces infarct size, neuron loss, and
improves motor behaviors in Wistar rats after ischemic–reper-
fusion cerebral injury.
16
Palmitoylethanolamide prevents neu-
roinflammatory responses to brain anoxic injury, reduces
Table 2. Palmitoylethanolamide in Entrapment Neuropathies.
Study Design/Numbers PEA/Time Frame Comparator Outcomes Results
Adverse
Effects
Evangelista
et al
144
RCT, open label,
N¼42,
patients with
CTS
umPEA, 1200 mg/d,
pre- and
postsurgery
Standard care
without PEA
Sleep quality by PSQI, NRS
pain intensity
Sleep quality improved
(P< .000), increased total
sleep time, reduced latency,
reduced pain (P< .0001)
Coraci
et al
145
RCT, N ¼56,
mild to
moderate CTS
PEA, 600 mg/d for
30 days
Placebo Sensory nerve conduction
velocity, distal motor
latency, compound
action potential, US
cross section of median
nerve
Sensory conduction was
improved with PEA,
increased cross section of
median nerve with PEA, pilot
and underpowered for
significance
Faig-Marti
et al
146
RCT, N ¼68,
mild to
moderate CTS
PEA, 600 mg/d for
60 days
Placebo ENG, Levine questionnaire,
Symptom Severity Scale,
Durkin test, Phalen test,
Boston Questionnaire
No improvement in clinical or
ENG parameters,
improvement in the Boston
Questionnaire FSS subscale
with PEA
Conigliaro
et al
147
RCT, N ¼26,
moderate CTS
PEA, 600 mg/d,
1200 mg/d for
30 days
Standard care Median nerve latency, Tinel
sign, pain
PEA improved median nerve
latency (P< .0004), improved
pain and Tinel sign. Placebo
VAS pain 5.4 to 5.4, PEA
600 mg/d; VAS 6.6 to 4.8,
PEA 1200 mg/d; VAS 6.0 to
3.9 (P< .0005)
Assini
et al
148
RCT, N ¼40,
diabetics with
CTS and a VAS
of 7 to 8
PEA, 1200 mg/d Placebo VAS
ENG
PEA improved pain (P< .0001),
improved sensory action
potentials, sensory
conduction velocity, and
median nerve latency
No AE
Abbreviations: AE, Adverse effects; CTS, carpal tunnel syndrome; ENG, electroneurogram; mPEA, micronized palmitoylethanolamide; NRS, Numericalratingscale;
PSQI, Pittsburgh Sleep Quality Index; RCT, randomized controlled trials; umPEA, ultramicronized palmitoylethanolamide; US, ultrasound; VAS, Visual Analog Scale.
Davis et al 7
Table 3. Palmitoylethanolamide in Miscellaneous Pain Phenotypes.
Study Design/Number PEA/Time Frame Comparator Outcomes Results
Adverse
Effects
Paladini et al
144
Meta-analysis, N ¼12 studies, 3 RCTs,
N¼1485 patients, multiple
phenotypes, 2010-2014
mPEA or umPEA, 300-1200 mg/
d for 60 days, add-on to
analgesics
In RCT placebo or
active
comparator
VAS pain severity Pain severity reduced at 2 weeks with
placebo decreased by 0.2 with PEA 1.04
(P< .001)
VAS pain severity at 60 days placebo
6.6 to 6.6, VAS pain with PEA 6.6 to 2.9,
VAS 3/10 placebo 41%, PEA 82%
Artukoglu et al
145
Meta-analysis, N ¼10 RCT, N ¼1289
patients, multiple pain phenotypes
PEA, 300 to 1200 mg/d, 14 to
180 days
Active and inactive
controls
VAS pain severity PEA >placebo with WMD 2.03 (P< .001),
no difference if blinded or open-label
study, active controls PEA >control
WMD 1.31 (P< .005), no association of
benefits to duration of therapy
Attrition PEA
1.1%,
comparator
4.3%
Del Giorno et al
158
Observational, retrospective/
prospective, N ¼80, fibromyalgia
on duloxetine plus pregabalin at
low doses (39 mg, 47 mg/d) for 6
months
umPEA, 1200 mg/d for 30 days,
then 600 mg/d for 60 days
Duloxetine plus
pregabalin alone
for 6 months
VAS pain severity. Number of tender
points (TP)
On duloxetine plus pregabalin, TP 14/18
to 8/18, VAS 6.9 to 4.0 at 3 months, TP
at 6 months 4/18, and VAS 3.0,
prospective study, addition of PEA at 3
months reduced TP 1/18 and VAS 1.9
(P< .0001)
No AE
Ottaviani et al
159
RCT, N ¼35, burning mouth
syndrome, NRS >5
umPEA, 1200 mg/d for 60 days Placebo NRS pain severity Reduced sensation (P< .0132) No AE
Marini et al
160
RCT, N ¼24, temporomandibular
joint osteoarthritis
PEA, 900 mg/d for 7 days, then
600 mg/d for 7 days
Ibuprofen 600 mg
3 times daily for
2 weeks
VAS pain severity, maximum mouth
opening
VAS pain severity reduction PEA
>ibuprofen (P¼.0001), maximum
mouth opening PEA >ibuprofen
(P¼.022)
Cremon et al
161
RCT, N ¼54, irritable bowel
syndrome (IBS) by Rome III criteria
umPEA/transpolydatin, 400/40
mg/d for 12 weeks
Placebo Symptom scale for flatulence, abdominal
pain/discomfort, dyspepsia changes and
frequency of stool, Bristol Stool Scale,
GI immunohistochemistry, mast cell
quantification, mucosal
endocannabinoids, TRPV1, CB
receptors
Mast cells increased in IBS not changed
with treatment, no change in
histochemistry with treatment, OEA
reduced and CB2 receptors increased
in IBS, PEA reduced pain (P¼.049),
PEA responders 62% versus placebo
40% (P¼.115)
No AE
Gatti et al
162
Observational, N ¼610, chronic pain
(pain >6 months, except herpes
zoster), various phenotypes,
NRS >4
umPEA, 1200 mg/d for 3 weeks,
then 600 mg/d for 4 weeks
added to analgesics, in 95,
PEA was the only analgesic
NRS pain severity NRS 6.4 to 2.4 (P¼.001), unrelated to
pain phenotype, age, or gender, PEA
alone 6.5 to 2.4 (P< .0001), NRS
improvement better if PEA is started
early in herpes zoster (P¼.0183)
Phan et al
163
Observational, N ¼8, herpes zoster
of the face
Topical PEA VAS pain severity 5 of 8 had a mean reduction of 88% of
their pain
Therapy well
tolerated
Bacci et al
164
RCT, N ¼30, third molar extraction,
split mouth randomization (patient
own control)
umPEA, 800 mg/d for 15 days Placebo VAS pain severity
Facial swelling
Trismus
NSAID consumption
Complications
Tolerability
VAS improved with PEA >placebo 3.8
versus 5.5 as day 7, 1.0 versus 1.5 day
15 (P< .0221), Trismus the same
between PEA and placebo, edema same
between groups
One patient
had
palpitation
and 1
drowsiness
on PEA
Abbreviations: CB, cannabinoid, GI, gastrointestinal; mPEA, micronized palmitoylethanolamide; NRS, Numerical rating scale; NSAID, nonsteroidol anti-inflammatory drug; OEA, oleoyl ethanolamine; RCT, randomized
controlled trials; TRPV1, transient receptor potential vanilloid-1; umPEA, ultramicronized palmitoylethanolamide; VAS, Visual Analog Scale; WMD, weighted mean difference.
8
Table 4. Palmitoylethanolamide and Pelvic Pain Syndromes.
Study Design/Numbers PEA/Time Frame Comparator Outcome Results
Adverse
Effects
Tartaglia et al
166
RCT, N ¼220, primary
dysmenorrhea in adolescents
and young women
mPEA/transpolydatin, 400/40 for
10 days beginning the 24th day
of the menstrual cycle
Placebo VAS pelvic pain Improved pain PEA 98.2% versus 56.4%,
mean improvement with PEA 4 points
versus 1 point (P< .001)
Indraccolo et al
165
Observational, N ¼4,
endometriosis
mPEA/transpolydatin,
400/40 mg/d for 90 days
VAS pain severity Pain reduced from 77 to 31 mm
(P< .0069), improved dyspareunia,
and reduced analgesic use
One patient
had nausea
Lo Monte et al
167
Observational, N ¼24, severe
pelvic pain from
endometriosis
mPEA/transpolydatin, 800/80/d
for 90 days
Pain, dysmenorrhea,
dyspareunia, dyschezia,
QoL
Decreased pain, dysmenorrhea,
dyspareunia, improved QoL P< .05),
decreased NSAID use
Giugliano et al
168
Observational, N ¼47, pain
from endometriosis on 6
months of hormone therapy
mPEA/transpolydatin,
400/40 mg/d for 90 days
VAS pain severity,
dysmenorrhea,
dyspareunia, dyschezia
VAS pain 5.6-2.2, dysmenorrhea, VAS
6.8-4.1, dyspareunia, VAS 6.9-3.2
(P< .05)
Caruso et al
169
Observational, N ¼56, pain
from endometriosis
mPEA/lipoic acid, 600/600 mg/d,
90 days
VAS pain severity, Female
Sexual Distress Scale,
SF-36
Pain improved (P< .001), QoL,
improved (P<.001), sexual function
improved (P< .001)
Giammusso et al
170
RCT, N ¼44, chronic pelvic
pain or prostatitis
mPEA/lipoic, 300/300 mg/d,
12 weeks
Serenoa Repens
320 mg/d
NIH-CPSI and IIEF
questionnaire
PEA improved the NIH-CPSI score, not
IIEF5 score
No AE
Corbellis et al
171
RCT, N ¼61, pain from
endometriosis
mPEA/transpolydatin,
800/80 mg/d, 90 days
Placebo for 90 days,
celecoxib
400 mg/d for
7 days
VAS pain severity,
dysmenorrhea,
dyspareunia
PEA >placebo (P< 01), celecoxib >PEA
(P< .001)
Indraccolo et al
172
Meta-analyses, N ¼4 trials,
N¼81 patients
mPEA/transpolydatin,
800/80 mg/d, 90 days
VAS pain severity,
dysmenorrhea,
dyspareunia
VAS pain reduced by 4.1, VAS for
dysmenorrhea by 3.68, dyspareunia
by 3.18 (P< .001)
Abbreviations: IIEF, International Index of Erectile Function; mPEA, micronized palmitoylethanolamide; NIH-CPSI, National Institutes of Health Chronic Prostatitis Symptom Index; NSAID, nonsteroidol anti-inflammatory
drug; RCT, randomized controlled trials; umPEA, ultramicronized palmitoylethanolamide; QoL, Quality of Life; VAS, Visual Analog Scale.
9
astrogliosis, and preserves cognitive function.
180
It exerts neu-
roprotective effects on cultured cortical neurons in newborn
rats subjected to hypoxic episodes. These protective effects
were not mediated by PPAR areceptors or TRPV1.
181
In many
of these studies, luteolin was added to PEA. Luteolin is an
antioxidant flavonoid that downmodulates neuroinflammation.
Luteolin is neuroprotective, improves memory, and reduces
anxiety in animal models. Palmitoylethanolamide administered
before an experimental ischemic episode and with traumatic
brain injury reduces infarct size and neurologic deficits.
182
The
combination of PEA and luteolin works in several animal
studies where each agent alone did not work. There is, how-
ever, no clinical evidence that the combination is better than
PEA alone.
2,94,176,183-185
The mechanism of action remains
unknown. It is known that it does not depend on the usual PEA
targets, such as TRPV1 and or PPAR-a.
186
One mechanism
may be by way of reduction in adhesive molecules, thus reduc-
ing vascular occlusion.
187
Strokes—Human Studies
Patients undergoing CNS microdialysis after a stroke had
increased NAE in the area of stroke, including PEA that is
also increased in surrounding brain tissue.
16,188
Circulating
blood levels of PEA at the time of a stroke correlate with the
degree of neurological deficits.
189
In an observational study,
PEA improved cognitive function, spasticity, and disabilities
from a stroke.
16
Dementia and Alzheimer Disease—Animal Studies
There is a large amount of animal studies using PEA in
Alzheimer disease models, but no clinical studies that we could
find. In the 3xTg-AD animal model, PEA improved context
learning and memory and reduced depression behaviors as well
as anhedonia (sucrose preference test).
190
Palmitoylethanola-
mide reduces the expression of amyloid protein (AB1-42) and
prevents tprotein phosphorylation. The NF-kB expression is
reduced, as well as inflammatory cytokines. Astrogliosis is
curtailed.
190-192
The combination of PEA plus luteolin reduces
inducible nitric oxide synthase expression, astrocyte activation,
and neuron loss in organotypic hippocampal slices exposed to
AB1-42. In addition, PEA upregulates brain-derived neuro-
trophic factor (BDNF).
193
Serum amyloid protein increases in
axon myelin in Alzheimer disease and multiple sclerosis (MS).
Palmitoylethanolamide plus luteolin reduces serum amyloid
expression.
194
Dysfunctional endocannabinoid systems could
play a role in Alzheimer disease.
195,196
Multiple Sclerosis—Animal Studies
Palmitoylethanolamide reduces motor disabilities in mice
models of MS.
197
Exogenously administered endocannabinoids
and PEA ameliorate spasticity in chronic relapsing experimen-
tal autoimmune encephalomyelitis.
198
Cannabidiol and PEA
diminished inflammation, demyelination, axonal damage, and
inflammatory cytokine expression, while concurrent adminis-
tration of CBD and PEA was not as effective in induced
experimental autoimmune encephalomyelitis.
199
Flurbiprofen
blocks endocannabinoid metabolism centrally and reduces
autoimmune encephalomyelitis in mice.
200
Fatty acid amide
hydrolase inhibitors do the same and reduce spasticity in mouse
autoimmune encephalomyelitis.
201
Multiple Sclerosis—Human Studies
Circulating PEA levels are reported in 2 MS studies. In one
study, circulating levels were increased in secondary pro-
gressive MS, while a second found levels increased in both
secondary progressive and relapsing remitting MS.
202
Sig-
nificantly reduced levels of all the tested endocannabinoids
were found in the cerebrospinal fluid (CSF) of patients with
MS compared to control patients, with lower levels detected
in the secondary progressive subtype. Higher levels of AEA
and PEA, although below those of controls, were found in
the CSF of relapsing remitting patients during relapse.
203
Circulating endocannabinoids can arise from vascular
endothelium, platelets, and monocytes or may reflect an
impaired blood–brain barrier with leakage of PEA from
CNS such that circulating levels may not reflect disease
state of the CNS.
204,205
A small study reported only as an
abstractdemonstratedimprovedpainin14of20patients
treated with 300 mg of PEA twice daily (Table 5).
Parkinson Disease—Animal Studies
Palmitoylethanolamide improves dopamine neurotransmis-
sion and restores tyrosine hydroxylase activity within the
substantia niger in a mouse model of PD.
208,209
In a model
of PD in which injury was induced by the dopaminergic
toxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP),
intraperitoneal injections of PEA prevented Parkinsonian
behaviors, maintained the expression of tyrosine hydroxy-
lase reduced by MPTP, and blunted the upregulation of
a-synuclein that is associated with PD.
210
The combination
of PEA plus luteolin blocks both the neuroinflammation and
the autophagic pathway involved in PD in mice.
211
Parkinson Disease—Clinical Studies
The addition of ultramicronized PEA to patients with PD
receiving levodopa therapy significantly and progressively
reduced the revised Movement Disorder Society/Unified Par-
kinson Disease Rating Scale questionnaire score over 1 year
(Table 5). For each item, the mean scores between baseline and
end of treatment were significantly reduced for most nonmotor
and motor symptoms.
15
Autism—Animal Studies
BTBR Tþtf/J mice develop autistic behavior; PEA reversed
autistic behaviors in mice. This effect was contingent on acti-
vation of PPAR-areceptors. Palmitoylethanolamide restored
10 American Journal of Hospice & Palliative Medicine
Table 5. Palmitoylethanolamide in Neuropsychological and Neurodegenerative Disorders.
Study Design/Numbers PEA/Time Frame Comparator Outcome Results
Adverse
Effects
Ghazizadeh-
Hashemi et al
13
RCT, N ¼58, major
depressive disorder,
Hamilton Rating Scale for
Depression- 17 (HAMD)
>19
umPEA, 1200 mg/d
for 6 weeks plus
citalopram 40 mg/d
Citalopram 40 mg/d
plus Placebo
HAMD at 2, 4, 6 weeks
Response (50% reduction in HAMD),
remission HAMD <8
HAMD at 2 weeks PEA >placebo, reduced
8.3 versus 5.8 (P¼.004), 6 weeks PEA
>placebo in reduced depression
symptoms (P¼.021), response rate
>PEA (P¼.01)
No AE
Khalaj et al
14
RCT, N ¼70, autism, ages
4-12, Aberrant Behavior
Checklist–Community
(ABC-C) >12
PEA, 1200 mg/d plus
risperidone for
10 weeks
Risperidone plus
placebo
ABC-C
Adverse effects
PEA >placebo irritability (P¼.002) and
hyperactivity (P< .001), inappropriate
speech (P¼.05)
No AE
Antonucci et al
206
Two case report, autism ages
13 and 15
umPEA, 600 mg/d Childhood Autism Rating Scale Improved socialization, language, improved
cognition, reduced aggression
No AE
Brotini et al
15
Observational, N ¼30,
Parkinson disease on
levodopa
umPEA, 600 mg/d for
1 year
Revised Movement Disorder Society/
Unified Parkinson Disease Rating
Scale
Significant improvement in motor and
nonmotor symptoms. Motor total score
decreased from 43 to 23 including speech
(P¼.012) and walking and balance
(P¼.0004), nonmotor symptoms
improved, particularly mood, sleep, and
fatigue (P< .005)
No AE
Orefice et al
207
RCT, N ¼29, multiple
sclerosis relapsing remitting
subtype on interferon-1b
for 6 months
umPEA, 600 mg/d for
12 months
Placebo Expanded Disability Status Scale,
Multiple Sclerosis Quality of Life
Scale-54, Paced Auditory Serial
Addition Test, VAS pain severity,
endocannabinoid blood levels,
cytokine levels
PEA improved pain with interferon,
improved cognitive function with PEA
and QoL, no change in serial addition, no
change in disease course, reduced
interferon-g,TNF-a, and IL-17 with PEA,
slight increase in expression of FAAH in
placebo, inverse relationship between
interferon-gand PEA
No AE
Caltagirone et al
16
Observational, N ¼267,
individuals with first stroke,
stabilized and in
rehabilitation
umPEA/luteolin,
1400/140 mg/d
sublingual for
60 days
Canadian Neurological Scale, MMSE,
Ashworth Scale for spasticity, NRS
pain severity, Barthel Index for
disability
Improved Canadian Neurological Scale
(P¼.0049), improved MMSE (P< .0001),
improved spasticity (P< .0075),
improved pain (P¼.0014), improved
disabilities and activities of daily living
(P< .001)
No AE
Abbreviations: IL-17, interleukin 17; MMSE, Mini-Mental Status Examination; mPEA, micronized palmitoylethanolamide; RCT, randomized controlled trials; TNF-a, tumor necrosis factor a; umPEA, ultramicronized
palmitoylethanolamide; VAS, Visual Analog Scale.
11
hippocampal BDNF signaling pathways and improved mito-
chondrial dysfunction, both known to be consistently associ-
ated with autism.
212
Additional evidence supporting PPAR-a
as the important receptor target in autism comes from a study
using valproic acid. Valproic acid produces autistic behavior in
rats, which is directly associated with the reduction in expres-
sion of PPAR-areceptors.
213
Autism—Clinical Studies
There are 2 case reports and a small randomized trial of PEA in
the management of autism.
14,183,206
A randomized trial of 70
children with moderate to severe autism by the Aberrant Beha-
vior Checklist–Community Edition randomized children to ris-
peridone with or without PEA. Palmitoylethanolamide
significantly improved the therapeutic effects of risperidone
on irritability and hyperactivity (Table 5).
14
Seizures—Animal Studies
There is a modest amount of evidence that PEA has on
antiseizure activity, though there are no clinical studies.
Palmitoylethanolamide reduces tonic convulsions from max-
imum electroshock and chemical-induced seizures in mice.
Efficacy was similar to phenytoin at similar doses (8.9 vs
9.2 mg/kg). The therapeutic index of PEA was much wider
since unlike phenytoin, PEA impairment did not occur at
dosesashighas250mg/kg.
214
The actions appear to be
similar to the fatty acid valproic acid.
214
Palmitoylethano-
lamideincreasedthelatencytoclonusinratsexposedto
amygdala kindling. Palmitoylethanolamide was also effec-
tive against pentylenetetrazol-induced convulsions at a dose
of 40 mg/kg.
215
In another mouse model, PEA blocked kai-
nic acid chronic seizures and was neuroprotective to
ongoing seizures.
216
Neuropsychiatric Disorders
Depression—Animal Studies
There are multiple animal studies that have demonstrated
antidepressant activity. Palmitoylethanolamide reduces
depression (immobility) from forced swimming in mice
at a dose of 20 mg/kg, which is equivalent to fluoxetine
at the same dose.
217
Certain antidepressants increase PEA
levels in the brain. Antidepressant withdrawal reduces
PEA in critical brain areas (frontal cortex, hippocampus,
dorsal striatum).
218
Long-term corticosteroid exposure to
129Sv/Ev mice induces anxiety and depression. Palmitoy-
lethanolamide plus luteolin (1 mg/kg, intraperitoneal)
improves depression-like behavior, as assessed by open-
field, novelty suppressed feeding, forced swim test, and
elevated maze testing. Not only does anxiety and depres-
sion improve, but hippocampal neurogenesis and neuro-
plasticity improve, both of which are usually diminished
with depression.
185
Depression—Clinical Studies
Circulating PEA levels are significantly lower in women who
are depressed compared with healthy controls.
219,220
A rando-
mized double-blind trial added 1200 mg/d of PEA or placebo to
citalopram in 58 patients (Table 5). The Hamilton Depression
Rating Scale was used to measure outcomes at 2, 4, and
6 weeks.
13
Palmitoylethanolamide shows significantly greater
improvement in depressive symptoms compared to placebo
group throughout the trial period. The response rate defined
as a 50%reduction in the Hamilton Depression Rating Scale
was 100%for PEA and 74%for placebo at 6 weeks.
Post-Traumatic Stress Disorder—Animal Studies
Post-traumatic stress disorder is characterized by alterations in
mood, impaired socialization, and cognition. In animal models
of PTSD, CNS PEA and neurosteroids levels are reduced.
65
The FAAH inhibitor SSR411298 exerts anxiolytic-like effects
following exposure to a traumatic event, in a mouse defense
test battery and social defeat procedure. SSR411298 increases
CNS endocannabinoid levels, including PEA in rodents.
221
Another FAAH inhibitor, URB597, increases brain endocanna-
binoids and reduces acute and chronic stress in rats.
222
Post-Traumatic Stress Disorder—Clinical Studies
In a study that investigated PTSD-associated differences in
human hair endocannabinoids, patients with PTSD had reduced
hair concentrations of PEA. Regression analyses demonstrated
a strong negative relationship between all investigated NAEs
and severity of PTSD.
223
Post-traumatic stress disorder is asso-
ciated with a significant incidence of suicide, and endocanna-
binoids and neurosteroid biosynthesis are reduced in suicidal
individuals.
65
Paradoxically in individuals with PTSD com-
pared with individuals who sustain trauma but do not develop
PTSD, PEA levels were higher in the PTSD group. Clinician
Administered PTSD Scale scores correlated positively with
circulating PEA levels.
224
There are no observational or rando-
mized trials of PEA in the treatment of PTSD.
Morphine Analgesic Tolerance—Animal Studies
Morphine analgesic tolerance is associated with neuroinflam-
mation and astrogliosis.
225
In rats, PEA significantly attenuates
morphine analgesic tolerance and doubles the number of days
of morphine antinociceptive. Palmitoylethanolamide prevents
morphine-related microglia and astrocyte proliferation in the
dorsal horn.
226
Morphine Analgesia—Clinical Studies
In a randomized study of 42 total knee arthroplasty, patients
were given either intrathecal morphine (200 mg) or placebo at
the time of the spinal anesthesia. Patients receiving intrathecal
morphine had reductions in AEA, PEA, and OEA compared to
12 American Journal of Hospice & Palliative Medicine
placebo.
227
Palmitoylethanolamide improves oxycodone,
codeine, and tapentadol analgesia (Table 1).
Discussion
Palmitoylethanolamide is a multifaceted endocannabinoid
nutraceutical with intriguing activity, but evidence as to clin-
ical benefits is fragmentary for pain and nonpain symptoms in a
number of diseases. Initial interests in PEA were related to
influenza A and the management of rheumatic fever, which
have largely been ignored over the past 3 decades. Palmitoy-
lethanolamide is best known in the literature as a co-analgesic
for neuropathic pain since most studies added PEA to preexist-
ing analgesics, and rarely was it used as a single analgesic. Two
recent meta-analyses of trials involving patients with multiple
pain syndromes have demonstrated significant analgesic bene-
fits to PEA with very few adverse effects. Palmitoylethanola-
mide has been used for entrapment neuropathies in a fair
number of studies as well as pain from endometriosis. Combi-
nations with luteolin and transpolydatin have been used in a
multitude of studies, but there are no randomized comparisons
to PEA alone.
176
The same can be said for ultramicronized
PEA versus PEA that is not micronized.
228,229
The claim of
increased bioavailability has not been correlated with clinical
studies in humans.
230
Palmitoylethanolamide has promising potential but
with sparse clinical evidence in the management of several
neurodegenerative disorders, such as Alzheimer disease
(although there are no clinical trials), PD, autism, MS, and
strokes.
14,15,196,198,202,211,231,232
What is fairly remarkable is
PEA safety in both animal studies and clinically. There are
no reported drug–drug interactions. Diarrhea and stomach
upset occur rarely.
117
There are large gaps in our understanding of the pharmaco-
kinetics and clinical pharmacodynamics of PEA. In animal
studies, critical targets involve PPAR-areceptors, TRPV1
receptors, GPR55, and the entourage effects involving other
endogenous cannabinoids. Which receptor or interaction is
responsible for which clinical benefit is not known? Most clin-
icians are unaware of PEA. There is a need for clinical trials,
but this is a nutraceutical and not a medication according to the
US Food and Drug Administration so that funding from phar-
maceutical companies is unlikely to occur. Pilot studies have
been done using N-of-1 study designs, which may be a step
forward in advancing clinical trials.
233
Conclusion
Palmitoylethanolamide is a nutraceutical with a complex phar-
macodynamic profile and relatively unknown pharmacoki-
netics. The palliative benefits for multiple patients are
intriguing but require more research.
Declaration of Conflicting Interests
The authors declared no potential conflicts of interest with respect to
the research, authorship, and/or publication of this article.
Funding
The authors received no financial support for the research, authorship,
and/or publication of this article.
ORCID iD
Mellar P. Davis https://orcid.org/0000-0002-7903-3993
Carlos Fernandez https://orcid.org/0000-0002-5561-6211
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Davis et al 21
... Neither time frame nor language limits were set. Already published systematic reviews and meta-analyses on PEA [18,19,26,27] were also screened for collecting more references on PEA clinical series. More articles were collected by screening the Epitech Group SpA database on spontaneous studies on m-PEA. ...
... The articles cited for the organizing database [16,18,[24][25][26][27]29] report the corresponding authors' names and contacts. Authors can be contacted for information on data. ...
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Background: Palmitoylethanolamide is reported to solve pain and neuroinflammation in different models of chronic and neurodegenerative diseases. Some concerns have been illustrated for cautiously interpreting the available literature on the topic. Specifically, there is a lack of evidence about palmitoylethanolamide and female chronic pelvic pain. Concerns will be best solved by randomized trials. The present study was aimed at finding the best responders to micronized palmitoylethanolamide in female patient with chronic pelvic pain, using the existing literature at individual patient level, to help further randomized trial planning. Methods: After a systematic research, eligible studies (the ones enrolled female patients treated for chronic pelvic pain or for dyspareunia, dysuria, dyschezia, and dysmenorrhea with or without chronic pelvic pain) were assessed at individual patient data level. Conditional probabilities were calculated to assess variables conditioning the rates of good responders (pain score points more or equal to 3 reduction), poor responders (2 pain score reduction), and nonresponders at a three-month follow-up. Results: Only cases treated with palmitoylethanolamide comicronized with polydatin for a short period can be assessed. Good responders are more than 50%. In chronic pelvic pain, there is a 19.0% conditional probability to find good responders among patients with pain score at enrolment of 6 to 8 and of 6.8% to find poor responders among patients with a pain score at enrolment of 6 to 8. Painful disease does not matter on responders' rates. Conclusion: Best responders to comicronized palmitoylethanolamide/polydatin are patients with pain score higher than 6 at enrolment, irrespective of other variables.
... Indeed, increased LF of HRV indicates a low parasympathetic activity of HRV, which is interrelated with the reduction in the threat perception mediated by the brain networks responsible for the evaluation of stressful events [12]. On the other hand, PEA is believed to be implicated in endogenous protecting processes that are mobilized by the stimulation of inflammatory or nociceptive procedures [35]. ...
... The obtained associations between the peripheral OEA ligands of eCB and time domain of the HRV at baseline (the heart rate and HRV), as well as the peripheral PEA ligands eCB and the frequency domain of the HRV at baseline (LF and HF), suggests that peripheral eCB ligands believed to be involved in anti-inflammatory and anorexigenic effects evoked by prolonged stress exercise might be related to emotional stress-related changes in the SNS and PNS. These results support evidence based on preclinical studies, indicating that elements of the peripheral eCB system reflect central dysfunctions of eCB [35,37]. ...
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Background: Recent research indicates that both endocannabinoids (eCB) and heart rate variability (HRV) are associated with stress-induced experiences. However, these underlying mechanisms are not elucidated. The present study aims to investigate whether exposure to acute and chronic stress conditions can give rise to measurable changes, both to the peripheral eCB ligands and HRV. Methods: Thirteen candidates under intense preparation for their enlistment in the Hellenic Navy SEALs (HNS) participated in the study. All subjects underwent mental state examination, while HRV variables in time and frequency domain recordings were acquired. Furthermore, at baseline and 30 days after prolonged and intensive physical exercise, hair was collected to measure eCB ligands, such as anandamide (AEA), 2-arachidonoylglycerol (2-AG), and the N-acyl ethanolamine (NAE) molecules: palmitoylethanolamide (PEA) and oleoylethanolamide (OEA). Results: Comparing basal hair concentrations of eCB ligands before and after intense physical exercise, we found that AEA, PEA, and OEA were notably increased, whereas no differences were observed regarding the ligand 2-AG. Furthermore, there were observed associations between the concentrations of peripheral eCB ligands, both at baseline and after the prolonged physical exercise and the time and frequency domains of HRV. Conclusions: These findings suggest that endocannabinoid-HRV interrelations might share a short-term, and long-term adaptability of the changes in self-regulation associated with stress. Further studies will be required to determine the validity of peripheral eCB signaling and HRV as a biomarker for different aspects of the stress response.
... PEA was rst isolated from egg yolk, soybeans, and peanuts where its anti-anaphylactic activity was also reported [18,19]. Later on, anti-in ammatory, neuroprotective, analgesic and anti-nociceptive effects of PEA were shown in experimental animal studies [16,20,21,27,38,39], and con rmed in human clinical trials [40,41]. It has been reported in rodent models that PEA also inhibits lung, liver and retinal brosis [42][43][44]. ...
... The activation of PPAR-α can aid in the regeneration of mice peripheral nerves at the level of axon repair [57], mediated via satellite glial cells [57,58]. PPARα activation downregulates nuclear factor kB (NF-kB) followed by the decrease of proin ammatory proteins, such as inducible NO synthase (iNOS), cyclo-oxygenase-2 (COX2), tumour necrosis factor-α (TNFα) or interleukin 1 and 6 or prostaglandin E2 (PGE2) [41,59], which all can contribute to the anti-in ammatory properties of AM/ACM grafts. PEA also stimulates macrophages to remove invading bacteria and apoptotic neutrophils [60,61]. ...
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Human amniotic and amniochorionic membranes (AM, ACM) are the most often used grafts accelerating wound healing due to their …
... In addition, this survey found that nearly all respondents were unfamiliar with PEA, which is an endogenous cannabinoid classified as a nutraceutical, or a food that has potential health or medicinal benefits. 29 PEA has activity at both CB 1 and CB 2 receptors, ...
... although it is not itself a component of cannabis 29 and possesses anti-inflammatory effects. [30][31][32] Therefore, the endocannabinoid system could be positively manipulated via PEA without negotiating the legal restrictions surrounding cannabis. ...
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Introduction: Cannabinoids are an increasingly popular therapy among orthopaedic patients for musculoskeletal conditions. A paucity of evidence to support their use in orthopaedics exists, likely because of the incongruence of federal and state legalization and the stigma surrounding cannabis. The purpose of this study is to elucidate sentiments and knowledge base of the orthopaedic trauma community with regard to cannabinoid-containing compounds. Methods: A 21-question online survey was distributed to the members of the Orthopaedic Trauma Association with a response window of 3 months. Results: We evaluated 251 responses. Most (88%) of the respondents did not believe that they were knowledgeable about the mechanism of action of cannabis/cannabidiol (CBD) but did feel that cannabis or CBD products play a role in managing postoperative pain (73%). Most respondents did not believe that they would be stigmatized if they suggested CBD (83%) or cannabis (67%) to patients. Despite this, fewer respondents have suggested CBD (38%) or cannabis (29%) to their patients. Conclusions: Sentiment toward cannabinoids among orthopaedic traumatologists is remarkably favorable; however, in-depth understanding is admittedly poor and routine use is uncommon. More clinical research for cannabinoids is needed to help orthopaedic traumatologists provide guidance for patients seeking advice for this recently popular therapeutic.
... Despite of its long history, pharmacokinetics of PEA are still insufficiently known, and experiences in man are limited [38]. It has become very popular in recent years. ...
... Like CBD, it targets also TRPV1. Similar to AEA, PEA levels are elevated in chronic inflammation (38), and also similar to AEA, PEA is degraded by FAAH. Thus, CBD modulates not only a physiological balance of AEA but also of PEA and is able to increase the level of both. ...
... It is responsible for targeting non classical cannabinoid receptors and shows no excitatory modulation of CB1 and CB2. Classical receptors of cannabinoid system are only activated by entourage effect [46]. In a mouse-model of PD, PEA restored tyrosine hydroxylase activity in the SNPc, thereby improving dopamine neurotransmission [198,199] In MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine) induced PD model intraperitoneal PEA injections, maintained expression of tyrosine hydroxylase activity, prevented parkinsonian like behaviors, and had a blunted effect on upregulation of a-synuclein [200]. ...
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Medical benefi ts of cannabis and related compounds is widely known. Discovery of psychotropic plant cannabinoid Δ9-tetrahydrocannabinol have urged researchers to study more about the cannabinoid system and related therapeutics in the fi eld of neurology and medicine. Where activation of cannabinoid receptor type 1 (CB1R) yielded in unwanted and serious side eff ects, discovery of cannabinoid receptor type 2 (CB2R) and its ligands gave a new hope. Till now there is limited success in this fi eld because of complex expanded endocannabinoid system comprising of receptors, ligands and enzymes. In this review we will update about the role of endocannabinoidome relevant to neurological disorders.
... Although exploring the exact pathways involved in TcdAinduced inflammation was beyond the purpose of the present study, one could speculate that pNAPE-LP beneficial effects could also be mediated by PEA ability to counteract EGCs activation, as demonstrated in different models of colitis (Borrelli et al., 2015;Ippolito et al., 2015). Additionally, PEA is known for its "entourage effect" on the endocannabinoid system (ECS), being able to potentiate the effect of prototypical endocannabinoids, but not carrying their potential side effects (Davis et al., 2019). Interestingly, the non-psychotropic cannabinoid cannabidiol (CBD) was able to prevent the cytotoxic damage caused by TcdA in vitro cultured Caco-2 cells (Gigli et al., 2017). ...
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Genetically engineered probiotics, able to in situ deliver therapeutically active compounds while restoring gut eubiosis, could represent an attractive therapeutic alternative in Clostridium difficile infection (CDI). Palmitoylethanolamide is an endogenous lipid able to exert immunomodulatory activities and restore epithelial barrier integrity in human models of colitis, by binding the peroxisome proliferator-activated receptor-α (PPARα). The aim of this study was to explore the efficacy of a newly designed PEA-producing probiotic (pNAPE-LP) in a mice model of C. difficile toxin A (TcdA)-induced colitis. The human N-acyl-phosphatidylethanolamine-specific phospholipase D (NAPE-PLD), a key enzyme involved in the synthesis of PEA, was cloned and expressed in a Lactobacillus paracasei that was intragastrically administered to mice 7 days prior the induction of the colitis. Bacteria carrying the empty vector served as negative controls (pLP).In the presence of palmitate, pNAPE-LP was able to significantly increase PEA production by 27,900%, in a time-and concentration-dependent fashion. Mice treated with pNAPE-LP showed a significant improvement of colitis in terms of histological damage score, macrophage count, and myeloperoxidase levels (−53, −82, and −70.4%, respectively). This was paralleled by a significant decrease both in the expression of toll-like receptor-4 (−71%), phospho-p38 mitogen-activated protein kinase (−72%), hypoxia-inducible factor-1-alpha (−53%), p50 (−74%), and p65 (−60%) and in the plasmatic levels of interleukin-6 (−86%), nitric oxide (−59%), and vascular endothelial growth factor (−71%). Finally, tight junction protein expression was significantly improved by pNAPE-LP treatment as witnessed by the rescue of zonula occludens-1 (+304%), Ras homolog family member A-GTP (+649%), and occludin expression (+160%). These protective effects were mediated by the specific release of PEA by the engineered probiotic as they were abolished in PPARα knockout mice and in wild-type mice treated with pLP. Herein, we demonstrated that pNAPE-LP has therapeutic potential in CDI by inhibiting inflammation and restoring tight junction protein expression in mice, paving the way to next generation probiotics as a promising strategy in CDI prevention.
... Palmitoylethanolamide (PEA) Suggested dose 300 mg po bid to prevent infection, 600 mg po tid x two weeks to treat infection Mechanism(s) of action against non-COVID-19 viruses 115 Favorably modulate cellular defense and repair mechanisms Favorably modulate viral-induced pathological cellular processes Outcomes data supporting their mitigating effects on illness from other viral strains No data available Strength of evidence PEA = conditional (treatment) PEA = strong (prevention) Risk of harm [116][117][118][119] Mimimal ...
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As the novel infection with SARS-CoV-2 emerges, objective assessment of the scientific plausibility of nutraceutical and botanical interventions for prevention and treatment is important. We evaluate twelve such interventions with mechanisms of action that modulate the immune system, impair viral replication, and/or have been demonstrated to reduce severity of illness. These are examples of interventions that, mechanistically, can help protect patients in the presence of the prevalent and infectious SARS-CoV-2 virus. While there are limited studies to validate these agents to specifically prevent COVID-19, they have been chosen based upon their level of evidence for effectiveness and safety profiles, in the context of other viral infections. These agents are to be used in a patient-specific manner in concert with lifestyle interventions known to strengthen immune response (see related article in this issue of IMCJ).
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Neurodegenerative disorders are a widespread cause of morbidity and mortality worldwide, characterized by neuroinflammation, oxidative stress and neuronal depletion. The broad-spectrum neuroprotective activity of the Mediterranean diet is widely documented, but it is not yet known whether its nutritional and caloric balance can induce a modulation of the endocannabinoid system. In recent decades, many studies have shown how endocannabinoid tone enhancement may be a promising new therapeutic strategy to counteract the main hallmarks of neurodegeneration. From a phylogenetic point of view, the human co-evolution between the endocannabinoid system and dietary habits could play a key role in the pro-homeostatic activity of the Mediterranean lifestyle: this adaptive balance among our ancestors has been compromised by the modern Western diet, resulting in a “clinical endocannabinoid deficiency syndrome”. This review aims to evaluate the evidence accumulated in the literature on the neuroprotective, immunomodulatory and antioxidant properties of the Mediterranean diet related to the modulation of the endocannabinoid system, suggesting new prospects for research and clinical interventions against neurodegenerative diseases in light of a nutraceutical paradigm.
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Objectives This preliminary randomized double-blind controlled trial was performed to test the efficacy of ultramicronized palmitoylethanolamide treatment in the burning mouth syndrome. Materials and methods Patients with referred burning mouth intensity greater than 4, according to the Numeric Rating Scale, were included in the study according to established inclusion and exclusion criteria. Patients were randomized into two groups and received either placebo or ultramicronized palmitoylethanolamide 600 mg twice daily for 60 days. Patients were assessed at baseline, 30 and 60 days after treatment start, and 4 months after treatment discontinuation. In order to evaluate the change in the burning mouth sensation over time, the generalized linear mixed model was employed. Results A total of 35 patients were considered eligible, among which 6 withdrew prior to the end of treatment. A statistically significant reduction of burning mouth sensation (p < 0.0132) was registered at the end of the active treatment in the ultramicronized palmitoylethanolamide group compared to the placebo one. Any side effect related to the active treatment was neither observed nor reported both by patients and by physicians. Conclusions The significant decrease of burning sensation in the ultramicronized palmitoylethanolamide group compared to the placebo group suggests to consider this naturally occurring molecule as a viable therapy in the management of burning mouth syndrome. Clinical relevance The use of an effective compound to manage the burning mouth syndrome, devoid of adverse effects for the patient and that does not interfere with other pharmacological therapies, could find wide employability from clinicians.
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The plant Cannabis sativa contains cannabinoids represented by Δ⁹-tetrahydrocannabinol, which exert psychoactivity and immunomodulation through cannabinoid CB1 and CB2 receptors, respectively, in animal tissues. Arachidonoylethanolamide (also referred to as anandamide) and 2-arachidonoylglycerol (2-AG) are well known as two major endogenous agonists of these receptors (termed “endocannabinoids”) and show various cannabimimetic bioactivities. However, only 2-AG is a full agonist for CB1 and CB2 and mediates retrograde signals at the synapse, strongly suggesting that 2-AG is physiologically more important than anandamide. The metabolic pathways of these two endocannabinoids are completely different. 2-AG is mostly produced from inositol phospholipids via diacylglycerol by phospholipase C and diacylglycerol lipase and then degraded by monoacylglycerol lipase. On the other hand, anandamide is concomitantly produced with larger amounts of other N-acylethanolamines via N-acyl-phosphatidylethanolamines (NAPEs). Although this pathway consists of calcium-dependent N-acyltransferase and NAPE-hydrolyzing phospholipase D, recent studies revealed the involvement of several new enzymes. Quantitatively major N-acylethanolamines include palmitoylethanolamide and oleoylethanolamide, which do not bind to cannabinoid receptors but exert anti-inflammatory, analgesic, and anorexic effects through receptors such as peroxisome proliferator-activated receptor α. The biosynthesis of these non-endocannabinoid N-acylethanolamines rather than anandamide may be the primary significance of this pathway. Here, we provide an overview of the biological activities and metabolisms of endocannabinoids (2-AG and anandamide) and non-endocannabinoid N-acylethanolamines.
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Rationale The endocannabinoid neurotransmitter, anandamide, has been implicated in the central modulation of stress responses. Previous animal experiments have shown that inhibitors of the anandamide-degrading enzyme, fatty acid amide hydrolase (FAAH), enhance the ability to cope with acute and chronic stress. Objectives Here, we investigated the effects of the globally active FAAH inhibitor URB597 in a rat model of predator stress-induced long-term anxiety. Results Rats exposed to 2,5-dihydro-2,4,5-trimethylthiazoline (TMT), a chemical constituent of fox feces, developed a persistent anxiety-like state, which was assessed 7 days after exposure using the elevated plus maze (EPM) test. Systemic administration of URB597 [0.03–0.1-0.3 mg/kg, intraperitoneal (ip)] 2 h before testing suppressed TMT-induced behaviors with a median effective dose (IC50) of 0.075 mg/kg. This effect was strongly correlated with inhibition of brain FAAH activity (r² = 1.0) and was accompanied by increased brain levels of three FAAH substrates: the endocannabinoid anandamide and the endogenous peroxisome proliferator-activated receptor-α (PPAR-α) agonists, oleoylethanolamide (OEA), and palmitoylethanolamide (PEA). The anxiolytic-like effects of URB597 were blocked by co-administration of the CB1 receptor antagonist rimonabant (1 mg/kg, ip), but not of the PPAR-α antagonist GW6471 (1 mg/kg, ip). Finally, when administered 18 h after TMT exposure (i.e., 6 days before the EPM test), URB597 (0.3 mg/kg, ip) prevented the consolidation of anxiety-like behavior in a CB1-dependent manner. Conclusions The results support the hypothesis that anandamide-mediated signaling at CB1 receptors serves an important regulatory function in the stress response, and confirm that FAAH inhibition may offer a potential therapeutic strategy for post-traumatic stress disorder.
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Introduction: Perinatal hypoxic–ischemic (HI) encephalopathy is defined as a neurological syndrome where the newborn suffers from acute ischemia and hypoxia during the perinatal period. New therapies are needed. The acylethanolamides, oleoylethanolamide (OEA) and palmitoylethanolamide (PEA), possess neuroprotective properties, and they could be effective against perinatal HI. These lipid mediators act through peroxisome proliferator-activated receptors subtype α (PPARα), or transient receptor potential vanilloid (TRPV), such as TRPV subtype 1 and 4. Materials and Methods: The objectives of this study were to discern: (1) the neuroprotective role of OEA and PEA in parietotemporal cortical neurons of newborn rats and mice subjected to hypoxia, and (2) the role of the receptors, PPARα, TRPV1, and TRPV4, in neuroprotective effects. Cell culture of cortical neurons and the lactate dehydrogenase assay was carried out. The role of receptors was discerned by using selective antagonist and agonist ligands, as well as knockout (KO) PPARα mice. Results: The findings indicate that OEA and PEA exert neuroprotective effects on cultured cortical neurons subjected to a hypoxic episode. These protective effects are not mediated by the receptors, PPARα, TRPV1, or TRPV4, because neither PPARα KO mice nor receptor ligands significantly modify OEA and PEA-induced effects. Blocking TRPV4 with RN1734 is neuroprotective per se, and cotreatment with OEA and PEA is able to enhance neuroprotective effects of the acylethanolamides. Since stimulating TRPV4 was devoid of effects on OEA and PEA-induced protective effects, effects of RN1734 cotreatment seem to be a consequence of additive actions. Conclusion: The lipid mediators, OEA and PEA, exert neuroprotective effects on cultured cortical neurons subjected to hypoxia. Coadministration of OEA or PEA, and the TRPV4 antagonist RN1734 is able to enhance neuroprotective effects. These in vitro results could be of utility for developing new therapeutic tools against perinatal HI.
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Autism spectrum disorders (ASD) are a group of heterogeneous neurodevelopmental conditions characterized by impaired social interaction, and repetitive stereotyped behaviours. Interestingly, functional and inflammatory gastrointestinal diseases are often reported as a comorbidity in ASDs, indicating gut-brain axis as a novel emerging approach. Recently, a central role for peroxisome-proliferator activated receptor (PPAR)-α has been addressed in neurological functions, associated with the behaviour. Among endogenous lipids, palmitoylethanolamide (PEA), a PPAR-α agonist, has been extensively studied for its anti-inflammatory effects both at central and peripheral level. Based on this background, the aim of this study was to investigate the pharmacological effects of PEA on autistic-like behaviour of BTBR T+tf/J mice and to shed light on the contributing mechanisms. Our results showed that PEA reverted the altered behavioural phenotype of BTBR mice, and this effect was contingent to PPAR-α activation. Moreover, PEA was able to restore hippocampal BDNF signalling pathway, and improve mitochondrial dysfunction, both pathological aspects, known to be consistently associated with ASDs. Furthermore, PEA reduced the overall inflammatory state of BTBR mice, reducing the expression of pro-inflammatory cytokines at hippocampal, serum, and colonic level. The analysis of gut permeability and the expression of colonic tight junctions showed a reduction of leaky gut in PEA-treated BTBR mice. This finding together with PEA effect on gut microbiota composition suggests an involvement of microbiota-gut-brain axis. In conclusion, our results demonstrated a therapeutic potential of PEA in limiting ASD symptoms, through its pleiotropic mechanism of action, supporting neuroprotection, anti-inflammatory effects, and the modulation of gut-brain axis.
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Objective and design Temporomandibular disorder (TMD) is a common painful condition in the temporomandibular joint (TMJ). Joint inflammation is believed to be a chief cause of pain in patients with TMD, through the release of pro-inflammatory cytokines that induce peripheral sensitization of nerve terminals followed by microglial stimulation. Materials and subject TMJ was induced in rats with the injection of complete Freund’s adjuvant (CFA) emulsion into the left TMJ capsule. Treatment The present study would assess the effects of micronized palmitoylethanolamide (m-PEA) on glial activation and trigeminal hypersensitivity. Methods Ten mg/kg m-PEA or corresponding vehicle was administered 1 h after CFA and mechanical allodynia and edema were evaluated at 24 and 72 h after CFA injection. Results CFA-injected animals showed TMJ edema and ipsilateral mechanical allodynia accompanied by a robust growth in GFAP protein-positive satellite glial cells and activation of resident macrophages in the TG. Moreover, m-PEA administration significantly reduced the degree of TMJ damage and pain, macrophage activation in TG and up-regulation of Iba1. Conclusions The results confirm that m-PEA could represent a novel approach for monitoring pain during trigeminal nerve sensitization.
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Background Myocardial ischemia/reperfusion (I/R) injury is the principal cause of death, happens after prolonged obstruction of the coronary arteries. The first intervention to limit myocardial damage is directed to restoration of perfusion, to avoid inflammatory response and a significant oxidative stress triggered by infarction. Palmitoylethanolamide (PEA), is a well-known fatty acid amide-signaling molecule that possess an important anti-inflammatory and analgesic effects. PEA does not hold the ability to inhibit free radicals formation. Baicalein, a bioactive component isolated from a Chinese herbal medicine, has multiple pharmacological activities, such as a strong anti-oxidative effects. Purpose A combination of PEA and Baicalein could have beneficial effects on oxidative stress produced by inflammatory response. Study design In the present study we explored the effects of composite containing PEA and Baicalein in a model of myocardial I/R injury. Methods Myocardial ischemia/reperfusion injury was induced by occlusion of the left anterior descending coronary artery for 30 min followed by 2 h of reperfusion. PEA-Baicalein (9:1), was administered (10 mg/kg) 5 min before the end of ischemia and 1 h after reperfusion. Results In this study, we clearly demonstrated that PEA-Baicalein treatment decreases myocardial tissue injury, neutrophils infiltration, markers for mast cell activation expression as chymase and tryptase and pro-inflammatory cytokines production (TNF-α, IL-1β). Moreover, PEA-Baicalein treatment reduces stress oxidative and modulates Nf-kB and apoptosis pathways. Conclusion These results support the idea that the association between PEA and Baicalein should be a potent candidate for the treatment of myocardial I/R injury.