The Potential Benefits of Palmitoylethanolamide
in Palliation: A Qualitative Systematic Review
Mellar P. Davis
, Bertrand Behm
, Zankhana Mehta
and Carlos Fernandez
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.
palmitoylethanolamide, pain, neuropathy, depression, autism, Parkinson disease, stroke
N-palmitoylethanolamide (PEA) is an endogenous cannabimi-
metic saturated fatty acid available as a nutraceutical which
targets multiple potential noncannabinoid receptors and
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.
In addition, PEA may be clinically helpful in a wide range of
neurological disorders such as depression, Parkinson disease
(PD), autism, and strokes.
The purpose of this review is to
make clinicians aware of the benefits to PEA when treating var-
ious symptoms and disease.
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.
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
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.
Even earlier and
Geisinger Health System, Danville, PA, USA
Mellar P. Davis, Geisinger Health System, 100 N Academy Ave, Danville,
PA 17822, USA.
American Journal of Hospice
& Palliative Medicine
ªThe Author(s) 2019
Article reuse guidelines:
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.
toylethanolamide was eventually isolated in 1957 and was
found to be a fatty acid component in guinea pig and rat
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.
It was later
found that PEA reduced the viral serology of the influenza
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.
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-
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.
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.
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.
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]).
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.
little known about how PEA penetrates tissues or whether dis-
eases or inflammation influence distribution, clearance, or PEA
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.
rodents, PEA is the most abundant NAE in tissues, with levels
ranging from 78 to 50 000 pmol/g in tissue.
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.
The distribution of PEA within the brain is highly variable
despite being a saturated acyl ethanolamine.
tion does not follow the primary PEA target, the PPAR-a
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.
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).
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.
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.
Palmitoylethanolamide is an agonist for the PPAR-arecep-
tor, which is a critically important receptor in downmodulating
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
Palmitoylethanolamide also increases the
expression of PPAR-amessenger RNA.
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.
Activation of PPAR-aincreases
the production of intracellular neurosteroids, which alters cal-
cium channels and big conductance potassium channels lead-
ing to hyperpolarized neurons.
This accounts for the
antiseizure activity of PEA in animal models.
lone, one of the principal neurosteroids, reduces pain, prevents
seizures, and reinforces gamino butyric acid (GABA) signal-
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.
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.
increases CB2 receptor expression through PPAR-aactiva-
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.
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.
Palmitoylethanolamide interacts with vanilloid receptors in
a unique manner. Palmitoylethanolamide is a positive allosteric
modulator of the transient receptor potential vanilloid-1
This is the same receptor that is activated by
capsaicin and AEA. Paradoxically, PEA accelerates TRPV1
The interactions with the TRPV1
receptor contribute to analgesia and anti-inflammatory activity
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.
Palmitoylethanolamide activates the orphan receptor
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
Activation of GPR55 increases dopaminergic neuro-
transmission in the hippocampus.
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
Paradoxically, PEA blocks the increased dopa-
mine neurotransmission associated with nicotine, reducing its
rewarding effect also.
This action may also be through
Palmitoylethanolamide blocks cocaine behaviors
in animals as measured by conditioned place preference.
GPR55 is highly expressed in the gastrointestinal tract and
modulates inflammatory responses.
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.
Mast cells within the CNS sustain neuroinflammation and
disrupt the blood–brain barrier.
Mast cells migrate into the
CNS through penetrating blood vessels and release biogenic
amines, thus contributing to demyelination and neuropathic
pain associated with neuroinflammation.
Mast cells play
aroleinbrainischemia,spinal cord compression, and
amyotrophic lateral sclerosis.
Mast cells interact with
glia through Toll-like receptors, complement receptors,
and CD40 receptors to amplify neuroinflammation.
Palmitoylethanolamide and the antioxidant luteolin reduce
mast cell–mediated toxicity caused by brain ischemia in ani-
Palmitoylethanolamide has proven efficacious in mast
cell–mediated experimental models of acute and neurogenic
It has neuroprotective effects in spinal cord
trauma, delayed postglutamate excitotoxic neuron death, and
amyloid b-peptide-induced learning and memory impairment
It reduces brain edema from ischemia and hemor-
rhage by blocking mast cell activation in animals.
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-
N-methyl-D-aspartate receptors in pre- and
postlimbic areas cause neuroplasticity that leads to chronic
Palmitoylethanolamide is increased in the
median prefrontal cortex in neuropathically injured animals
and reduces NMDA neurotransmission.
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.
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.
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.
CB1 receptors in animals reduce synaptic serotonin caused
by selective serotonin reuptake inhibitors.
This appears to
be an entourage effect by delaying AEA metabolism through
Blocking CB1 receptors produces depression in
animals. Clinical depression leads to the removal of the CB1
antagonist rimonabant from the market.
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.
Palmitoylethanolamide is an uncompetitive inhibitor of
mice have reduced fibrillar A-bproteins and are protected from
Potential Uses and Clinical Studies of PEA
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.
Davis et al 3
prevents oxaliplatin hypersensitivity, allodynia, reduced
cyclooxygenase 2 expression, spontaneous neuron depolariza-
tion, and evoked spinal cord activity in rats.
It reduces pacli-
taxel pain behaviors and potentiates gabapentin antinociception
Minocycline upregulates PEA production in the
ipsilateral spinal as a mechanism of analgesia to selective
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
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.
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.
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.
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.
Neuropathic pain—Humans. Palmitoylethanolamide accumu-
lates in painful tissues in humans. This was seen in trapezius
muscle of women with chronic neck pain.
nolamide blood levels also increase in pain processing
disorders such as fibromyalgia and in individuals with wide-
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.
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-
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.
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
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.
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.
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.
Visceral—Human studies. Intestinal PEA levels are on average
1.8-fold greater in individuals with ulcerative colitis compared
with healthy controls.
Intestinal PEA levels are increased
2-fold during active celiac disease and return to normal with
Liver and hepatic vein PEA levels are signifi-
cantly elevated in cirrhosis, more than AEA.
nolamide is increased in patients with pain from pancreatitis
and pancreatic cancer.
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
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.
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.
of PEA with transpolydatin significantly reduced pain, dysme-
norrhea, and dyspareunia associated with endometriosis in
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.
Participants PEA Dose/Time Frame Comparator Outcomes Results Adverse Effects
Schifilliti et al
postintervention, N ¼30,
mPEA, 600 mg/d, 60 days – Michigan Neuropathic Screening
Instrument, Total Symptom Score,
Neuropathic Pain Symptom
Reduced pain severity (P< .0001),
reduction in related symptoms (P<
Desio et al
Observational, N ¼30,
unresponsive to pregabalin
umPEA, 1200 mg/d with pregabalin, 45
– VAS (0-10) With the addition of umPEA VAS 7 to 1.3
Biasiotta et al
Observational, N ¼30,
PEA, 600 mg/d, added on to analgesics – Neurophysiologic parameters, pain
Improved laser-evoked potentials in the
hands and feet, reduced pain severity
Truini et al
Observational, N ¼20,
PEA, 600 mg/d – Neurophysiologic studies, pain,
Douleur Neuropathique 4 (DN4)
scale, motor and sensory fiber
Improved laser-evoked potentials,
improved A-a,A-b,A-dfiber function
Cocito et al
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
Observational N ¼25,
reduced mean nerve
PEA, 1200 mg/d, 16 weeks – Nerve conduction studies, VAS Increased conduction amplitude and
Hesselink et al
Case series, N ¼7,
neuropathic pain, chronic
to standard analgesics
mPEA, 1200 mg/d, various time periods
starting from day 14, add-on to
– Pain severity 30% to 50% reduction in pain intensity
over 2 to 3 weeks
Hesselink et al
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
upset in 1 to
Andresen et al
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
Impact of neuropathic pain
QoL using Pain Survey, Insomnia by the
Insomnia Severity Index, Major
Depression Inventory, number
needed to treat, general anxiety
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
Guida et al
RCT, N ¼636, chronic sciatic
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/
Table 1. (continued)
Participants PEA Dose/Time Frame Comparator Outcomes Results Adverse Effects
Desio et al
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
RCT, N ¼111, lumbosacral
spine pain with a
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
Palomba et al
RCT, N ¼81, open
comparison, chronic low-
back pain on gabapentin,
tricyclic antidepressants, or
PEA, 1200 mg for 21 days, then 600 mg for
Standard analgesics VAS pain Less pain than standard (P< .05) No AE
Observational, N ¼85,
PEA, 600 mg/d “Usual care” Pain reduction by VAS Usual care pain reduction by 2.69, with
PEA 3.85 (P< .05)
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
Passavanti et al
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
mg/d, 6 months
VAS pain, DN4, Oswestry Disability
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
Observational, N ¼35, failed
umPEA, 1200 mg for 1 month, then 600
mg the second month while on
tapentadol 150 mg/d and pregabalin 300
Tapentadol 150 mg
300 mg 3 month
prior to starting
VAS pain severity Tapentadol/pregabalin, VAS 5.7 to 4.3,
added PEA 4.3 to 1.7 (P< .0001)
Morera et al
Observational, N ¼112,
PEA – SF-12 QoL Improved mental health better in men
Observational, N ¼155,
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
– 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
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.
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.
Certain nonsteroidol anti-
inflammatory drugs, such as nimesulide, increase tissue PEA
levels by blocking catabolism of PEA.
mide reduces formalin-induced pain at intraperitoneal doses
that produce no increase in circulating PEA levels in mice.
Palmitoylethanolamide reduces hyperalgesic responses to com-
plete Freund adjuvant.
Spinal allopregnanolone levels are
increased by PEA both in formalin- and carrageenan-exposed
mice, which is associated with reduction in pain.
lethanolamide reduces tibial fracturepaininrodentsand
increases fracture healing.
arthritis in rodents caused by injections of bovine collagen
It reduces mechanical and thermal hyperalgesia and
macrophage infiltrate into the temporomandibular joint caused
by injections of complete Freund adjuvant in rats.
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.
Palmitoylethanolamide levels in
synovial tissues at the time of total knee replacement correlate
with disability, but not with pain severity.
In 2 meta-
analyses, PEA has significant analgesia either as a single agent
or as an add-on analgesic in multiple pains.
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.
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
Strokes and Ischemic–Reperfusion Injury—Animal
Palmitoylethanolamide reduces infarct size, neuron loss, and
improves motor behaviors in Wistar rats after ischemic–reper-
fusion cerebral injury.
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
RCT, open label,
umPEA, 1200 mg/d,
Sleep quality by PSQI, NRS
Sleep quality improved
(P< .000), increased total
sleep time, reduced latency,
reduced pain (P< .0001)
RCT, N ¼56,
PEA, 600 mg/d for
Placebo Sensory nerve conduction
velocity, distal motor
action potential, US
cross section of median
Sensory conduction was
improved with PEA,
increased cross section of
median nerve with PEA, pilot
and underpowered for
RCT, N ¼68,
PEA, 600 mg/d for
Placebo ENG, Levine questionnaire,
Symptom Severity Scale,
Durkin test, Phalen test,
No improvement in clinical or
improvement in the Boston
Questionnaire FSS subscale
RCT, N ¼26,
PEA, 600 mg/d,
1200 mg/d for
Standard care Median nerve latency, Tinel
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)
RCT, N ¼40,
CTS and a VAS
of 7 to 8
PEA, 1200 mg/d Placebo VAS
PEA improved pain (P< .0001),
improved sensory action
conduction velocity, and
median nerve latency
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
Paladini et al
Meta-analysis, N ¼12 studies, 3 RCTs,
N¼1485 patients, multiple
mPEA or umPEA, 300-1200 mg/
d for 60 days, add-on to
In RCT placebo or
VAS pain severity Pain severity reduced at 2 weeks with
placebo decreased by 0.2 with PEA 1.04
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
Meta-analysis, N ¼10 RCT, N ¼1289
patients, multiple pain phenotypes
PEA, 300 to 1200 mg/d, 14 to
Active and inactive
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
Del Giorno et al
prospective, N ¼80, fibromyalgia
on duloxetine plus pregabalin at
low doses (39 mg, 47 mg/d) for 6
umPEA, 1200 mg/d for 30 days,
then 600 mg/d for 60 days
for 6 months
VAS pain severity. Number of tender
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
Ottaviani et al
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
RCT, N ¼24, temporomandibular
PEA, 900 mg/d for 7 days, then
600 mg/d for 7 days
Ibuprofen 600 mg
3 times daily for
VAS pain severity, maximum mouth
VAS pain severity reduction PEA
>ibuprofen (P¼.0001), maximum
mouth opening PEA >ibuprofen
Cremon et al
RCT, N ¼54, irritable bowel
syndrome (IBS) by Rome III criteria
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
endocannabinoids, TRPV1, CB
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
Gatti et al
Observational, N ¼610, chronic pain
(pain >6 months, except herpes
zoster), various phenotypes,
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
Observational, N ¼8, herpes zoster
of the face
Topical PEA – VAS pain severity 5 of 8 had a mean reduction of 88% of
Bacci et al
RCT, N ¼30, third molar extraction,
split mouth randomization (patient
umPEA, 800 mg/d for 15 days Placebo VAS pain severity
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
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.
Table 4. Palmitoylethanolamide and Pelvic Pain Syndromes.
Study Design/Numbers PEA/Time Frame Comparator Outcome Results
Tartaglia et al
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
Observational, N ¼4,
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
Lo Monte et al
Observational, N ¼24, severe
pelvic pain from
for 90 days
– Pain, dysmenorrhea,
Decreased pain, dysmenorrhea,
dyspareunia, improved QoL P< .05),
decreased NSAID use
Giugliano et al
Observational, N ¼47, pain
from endometriosis on 6
months of hormone therapy
400/40 mg/d for 90 days
– VAS pain severity,
VAS pain 5.6-2.2, dysmenorrhea, VAS
6.8-4.1, dyspareunia, VAS 6.9-3.2
Caruso et al
Observational, N ¼56, pain
mPEA/lipoic acid, 600/600 mg/d,
– VAS pain severity, Female
Sexual Distress Scale,
Pain improved (P< .001), QoL,
improved (P<.001), sexual function
improved (P< .001)
Giammusso et al
RCT, N ¼44, chronic pelvic
pain or prostatitis
mPEA/lipoic, 300/300 mg/d,
NIH-CPSI and IIEF
PEA improved the NIH-CPSI score, not
Corbellis et al
RCT, N ¼61, pain from
800/80 mg/d, 90 days
Placebo for 90 days,
400 mg/d for
VAS pain severity,
PEA >placebo (P< 01), celecoxib >PEA
Indraccolo et al
Meta-analyses, N ¼4 trials,
800/80 mg/d, 90 days
– VAS pain severity,
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.
astrogliosis, and preserves cognitive function.
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.
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.
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
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.
may be by way of reduction in adhesive molecules, thus reduc-
ing vascular occlusion.
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.
blood levels of PEA at the time of a stroke correlate with the
degree of neurological deficits.
In an observational study,
PEA improved cognitive function, spasticity, and disabilities
from a stroke.
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).
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
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).
Serum amyloid protein increases in
axon myelin in Alzheimer disease and multiple sclerosis (MS).
Palmitoylethanolamide plus luteolin reduces serum amyloid
Dysfunctional endocannabinoid systems could
play a role in Alzheimer disease.
Multiple Sclerosis—Animal Studies
Palmitoylethanolamide reduces motor disabilities in mice
models of MS.
Exogenously administered endocannabinoids
and PEA ameliorate spasticity in chronic relapsing experimen-
tal autoimmune encephalomyelitis.
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.
blocks endocannabinoid metabolism centrally and reduces
autoimmune encephalomyelitis in mice.
Fatty acid amide
hydrolase inhibitors do the same and reduce spasticity in mouse
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.
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.
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.
A small study reported only as an
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.
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.
of PEA plus luteolin blocks both the neuroinflammation and
the autophagic pathway involved in PD in mice.
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.
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
Hashemi et al
RCT, N ¼58, major
Hamilton Rating Scale for
Depression- 17 (HAMD)
umPEA, 1200 mg/d
for 6 weeks plus
citalopram 40 mg/d
Citalopram 40 mg/d
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
Khalaj et al
RCT, N ¼70, autism, ages
4-12, Aberrant Behavior
PEA, 1200 mg/d plus
PEA >placebo irritability (P¼.002) and
hyperactivity (P< .001), inappropriate
Antonucci et al
Two case report, autism ages
13 and 15
umPEA, 600 mg/d – Childhood Autism Rating Scale Improved socialization, language, improved
cognition, reduced aggression
Brotini et al
Observational, N ¼30,
Parkinson disease on
umPEA, 600 mg/d for
– Revised Movement Disorder Society/
Unified Parkinson Disease Rating
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)
Orefice et al
RCT, N ¼29, multiple
sclerosis relapsing remitting
subtype on interferon-1b
for 6 months
umPEA, 600 mg/d for
Placebo Expanded Disability Status Scale,
Multiple Sclerosis Quality of Life
Scale-54, Paced Auditory Serial
Addition Test, VAS pain severity,
endocannabinoid blood 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
Caltagirone et al
Observational, N ¼267,
individuals with first stroke,
stabilized and in
– Canadian Neurological Scale, MMSE,
Ashworth Scale for spasticity, NRS
pain severity, Barthel Index for
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
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.
hippocampal BDNF signaling pathways and improved mito-
chondrial dysfunction, both known to be consistently associ-
ated with autism.
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.
There are 2 case reports and a small randomized trial of PEA in
the management of autism.
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).
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
The actions appear to be
similar to the fatty acid valproic acid.
amygdala kindling. Palmitoylethanolamide was also effec-
tive against pentylenetetrazol-induced convulsions at a dose
of 40 mg/kg.
In another mouse model, PEA blocked kai-
nic acid chronic seizures and was neuroprotective to
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.
Certain antidepressants increase PEA
levels in the brain. Antidepressant withdrawal reduces
PEA in critical brain areas (frontal cortex, hippocampus,
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
Circulating PEA levels are significantly lower in women who
are depressed compared with healthy controls.
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
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.
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.
Another FAAH inhibitor, URB597, increases brain endocanna-
binoids and reduces acute and chronic stress in rats.
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.
Post-traumatic stress disorder is asso-
ciated with a significant incidence of suicide, and endocanna-
binoids and neurosteroid biosynthesis are reduced in suicidal
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.
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.
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
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
Palmitoylethanolamide improves oxycodone,
codeine, and tapentadol analgesia (Table 1).
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.
The same can be said for ultramicronized
PEA versus PEA that is not micronized.
The claim of
increased bioavailability has not been correlated with clinical
studies in humans.
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
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.
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.
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.
The authors received no financial support for the research, authorship,
and/or publication of this article.
Mellar P. Davis https://orcid.org/0000-0002-7903-3993
Carlos Fernandez https://orcid.org/0000-0002-5561-6211
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